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Drug Sofei 1999 Me 20(3) 277middot 2b7ORIGINAL RESEARCH ARTICLE QJlol-5QI6990C1J3-0277S05 ~O -
Adverse Reactions of Selective
Serotonin Reuptake Inhibitors
Reports from a Spontaneous Reporting System -
Olav Spigset
Adverse Drug Reactions Monitoring Center Division of Clinical Pharmacology Norrland University Hospital Umea Sweden and Department of Clinical Pharmacology Regional and University Hospital Trondheim Norway -
i
Abstract Objective The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inshy
hibitors (SSRls) are extensively used in the treatment of depression panic disorshyder and obsess ive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders The aim of this study was to investigate the pattern of adverse reactions reported on SSRIs in Sweden and assess possible risk factors associated with the occurrence of adverse reactions to these agents
Methods A survey was made of 1202 reports describing 1861 adverse reacshy tions to SSRIs submitted to the Swedish Adverse Drug Reactions Advisory Comshy
miltee Results The most often reported adverse reactions were neurological sympshy
toms (2249d psychiatric symptoms (J 9Sk) and gastrointestinal symptoms (180) however dermatological symptoms (114) and general symptoms (98) were also frequent Compared with other drugs gastrointestinal sympshy toms were more often reported for fluvoxamine psychiatric symptoms were more
(
often reponed for sertraline and dermatological symptoms were more often reshy ~ (ported for f1uoxetine In total the diagnoses most frequently reported were nausea
(n = 139) rash (n =90) anxiety (n =84) paraesthesias (n =69) headache (n = 63) and diarrhoea (n = 63)
Parkinsonism confusion hallucinations euphoria hyponatraemia bradycarshydia and hypotension were more often reponed in the elderly whereas urticaria akathisia and haematological endocrinological sexual and some visual reacshy tions were more often reponed in individuals who were younger than average -
Dermatological reactions fatigue hyponatraemia and cough were more common in women hereas dyskinesiasakathisia and aggression more often were seen in men
(
The median SSRI dosages were above average in patients experiencing seizures Jhypomaniamania personality changes malaise bodyweight gain gynaecomastia
and hyperprolactinaemiaigalactorrhoea Severe symptoms such as seizures ~
hyponatraemia and the serotonin syndrome were rarely reported Conclusion Although the design of the study makes it difficult to draw conshy
clusions about causality a variety of adverse reactions were reported Therefore
bull
5 a -0 ru
lt ru J a 3 ru lt cr CD -0
o ro cgt ro a cr lt C (J)
() o -0
~ lt3 r
ru ~
278 ------~---------~~~--------- -~------------
the aareness that a particular symptom in a patient treated with an SSRI might be an adverse reaction should he high
The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of depression panic disorder and obsessive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders Aderse reactions asshysociated with the SSRIs are less prominent than and qualitatively different from those assoc iated with the tricycl ic antidepressantsllc l Nevertheshyless adverse reactions of SSRI s cover a broad specshytrum ranging from mild gastrointestinal symptoms to severe although rare events such as seizures IJI hypollatraemiaI~1 and the serotonin syndromeIgt1 In view of the increasing lise of these drugs the pattern of adverse reactions reported on SSRls in Sweden is presented and pos~ible risk factors idenshytified in this study
Materials and Methods
Since 1965 Sweden has had a system for sponshytaneous reporting of adcrse drug reactions to the Swedish Adverse Drug Rcactions Advisory Com-
Table I WHO criteria for causality assessment
mittee Since 1975 the reporting of serious or fatal reactions and new reactions has been compUlsory or the SSRls available in Sweden fluvoxamine was approved in June 1990 paroxetine in June 1991 citalopram in October 1992 sertraline in January 1995 and tluoxetine in September 1995
All reports received up to December 3 I 1997 were re viewed but only reactions that were classishyfied as having a possible probablelikely or certain causal relationship with the drug according to the WHO criteria (table I) and that were reported 3 times or more were included in lhis suney Moreshyover reports concerning overdoses and pharmacoshykinetic interactions which did not cause any adshyverse reactions were excluded
The classification of the reports was made by the monitoring centre staff From each report the following information was obtained bull age and gender of (he patient bull name and dosage of the suspected as well as
other drug or drugs bull outcome of dechallengerechallenge
Certain A clinical event including laboratory test abnormality occurring in a plausible time relationship to drug administration and which cannot be expfained by concurrent disease or other drugs or chemicals The response to withdrawal of the drug (dechallenge) should be clinically plausible The evenl must be definitive pharmacologically or phenomenofogically using a satisfactory rechallenge procedure il necessary
Probablellikely A clinical event incfuding laboratory test abnormality with reasonabfe lime sequence 10 administration 01 the drug unlikely to be aHributed to concurrent disease or other drugs or Chemicals and which follows a clinically reasonabfe response on withdrawal (dechallengel Rechallenge information is not required 10 fulfif Ihis definition
Possible
A Clinical event including laboratory tesl abnormality with a reasonable tesl sequence to adminislration of the drug bul which could also be explained by concurrent disease or other drugs or chemicals Information on drug withdrawal may be lacking or unclear
Unlikely
A clinical event including laboratory test abnormality with a temporal relationship 10 drug administration which makes a causal relationship improbable and in which other drugs chemicafs or underlying disease provide plausible expfanations
Conditionalunclassified A clinical event including laboratory test abnormality reported as an adverse reaction about which more data are essentiat for a proper assessment or the additional data are under examination
Unassessibfelunclassifiable
A report suggesting an adverse drug reaction which cannot be judged because information is insuHicient or contradictory and which cannot be supplemented or verified
Aderse r~actinl
20 eFluvox - ParoX u ro
OCitatOi iii DSertra 0- 15 6fluoxe ~ c ~ 0 ro L= 10 0 0 0
0 0
58 Q) co
(fJ
o F-shy1990 1991
Fig 1 Sales of selt reuptake inhibftors daily doses (000) 04 in 1991 15n 273 in 1996 anc citalopram fiuoxe 150mg tor liuvoxa
bull other potent bull time interv3
appearance Only repan
unkllown dech Ilot stopped 1
negative decha Total drug s
computerised s total amount 0
illacy and can terillS or in tt (ODDs) The 1 dose of a drug I adults for SSf ately severe d( sold per 1000 i although gross drug in the pOI are 20mg for ( tine 50mg for amineJ71
Results
Sales statist figure I The te
~ Adis Internolionalli I Adis InternOhOflol limiled All nghts reserveC Drug SOfely 1999 Mor 20 (3)
Ited with an SSRI mighl
~ pOrling of serious or ratal
Ins has been compulsory
in Sweden nuvoxalllilll
990 paroxctine in Junt
tober 1992 serlralinc ill
tille in September 1995
Ip to December I 1997
eactions that were classishy
probableI ikely or certain
the drug according to the
middotlIld that were reported
Ided in this survey Moreshy
lVerdoses and pharmacoshy
h did not causc any dshy
uded
he reports was made by ff From each report the
IS obtained
oatient
he suspected as well as
erechallcnge
inislralion and which cannol lechallenge) should be tory rechalenge procedure il
te drug unlikely to be onse on withdrawal
he drug but which could also king or unclear
ich makes a causal nations
ta are essential for a proper
conlradictory and which
Dug Sole ly 1Q9Q MO 20()
279 Adverse Reactions of SSRIs
20 bull Fluvoxamine bull Paroxetine
0 OCrtalopram o Serlraline a 15 6 Fluoxetine C ltfl
0 r 10 0 0 0
0 0
5e ltfl Q)
iii Cf)
O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fig 1 Sales 01 selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRls) in Sweden Total sales [in delined daily doses (000)1 000 inhabitants per day] for the SSRls were 04 in 199115 in 199243 in 199398 in 1994206 in 1995 273 in 1996 and 237 in 1997 The OOOs were 20mg for citalopram lIuoxetine and paroxetine 50mg for sertraline and 150mg for lIuvoxamine
bull other potential risk factors bull time interval between start of the trea tment and
appearance of the reaction Only reports with positive dechallenge with
unknown dechallenge or where drug therapy was not stopped were included whereas reports with
negative dechallenge were excluded Total drug sales statistics in Sweden have been
computerised since 1972 These statistics show the total amount of every drug sol d from each pharshymacy and can be expressed in volume monetary term s or in the number of defined daily doses (DDDs) The DDD is the assumed average daily dose of a drug prescribed for its main indication in adults for SSRIs that is the treatment of modershy
ately severe depression 16) The number of DDDs sold per 1000 inhabitants per day is thus a useful although gross measure of the consumption of a drug in the population The DDDs for the SSRls are 20mg for citalopram fluoxetine and paroxeshytine 50mg for sertraline and 150mg for fluvoxshyaminePI
Results
Sales statistics for the SSRls are presented in figure I The total sales from the time of introducshy
laquo Adls Inte rnational Limited All rights reserved
lion of the agent in question until the end of Deshycember 1997 in million DDDs was 1838 for citalopram 591 Cor paroxetine 223101 scrtraline
16 9 for tluoxetinc and 143 for flulOxamine A total of 1202 reports describing 1861 adverse
reactions re lated to SSRltreatmcnt were reviewed There wcre no ratal adcrse reaction The number of reports per ycar is illustrated in figure 2 In towl 67Yk of the reports concerncd women and 32 7~~ concerned men The median age or the patients as
49 yea rs For comparison 66CJr or thc DDDs sold during the years 1994 to 1997 were prescribed to women and 4cr to men and the median age of
these patients was 53 years The distribution of reports by organ system is
presented in table [I Compared with other SSR]s fluvoxamine was morc frequently repo rted to cause gastrointestinal adverse reactions (265 ~t- IS
a mean of 18 lt7c ) sCrlralinc was morc frequently reported to cause psychiatric symptoms (255 J IS a mean or 195lk) and Iluoxetinc was more often reported to cause dermatological symptoms
(17 A9c FS a mean of I 149C )
Neurologicol Reoctions
Neurological adverse reactions reported are presented in table Ill The predominating diagnoshy
200 bull Fluvoxamine bull Paroxetine o Cilalopram o Serlraline
150 6 Fluoxetine
~
a 100 a ci z
50
O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fi9 2 Annual numbers of adverse reaction reports for selective serolonin (5-hydroxytryptamine 5-HT) reuptake inhibitors in Sweden In general reporting is specifically encouraged in the year of approval and lhe following 2 years
Drug Sorelv I Q9Q MOl 20 (3)
J - (
J
- (
( 1 pound
-0 Q)
0 o ()
(1J Q) a (1J o ~ 5 c o (ij -~
m E Q)
-= l- shy
280 Spigset
Table II Organ groups implicaled in 1861 adverse reactions reported in patients receiving seleclive serotonin (S-hydroxytryptamine 5-HT) reuptake inhibitors For specilic diagnoses within each group see tables III-VIII
Reaction No 01 reports ()a
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Total no of reports ()
Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)
Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)
Gastrointestinal 104 (162) 12 (130) 91 (265) 105 (169) 23 (139) 336 (180)
Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)
General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)
Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)
Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)
a The percentage value indicates the percentage of the total number of reactions reported lor that individual drug
b The percentage value indicates the percentage of the total number of reactions reported for all drugs
ses were paraesthesias (n = 69) headache (n = 63)
dizziness (n = 60) Jnd tremor (n = 50) Headache
was the most typical initial reaction Other adverse
reaclions wjth an early onset were dizziness musshy
cle weakness muscle stiffness increased muscle
tone tremor and paraesthesias For the exshy
trapyramidal symptoms akathisia and dyskinesias
more than half of the reports concerned men Pashy
tients who developed parkinsonism were olda
than average whereas patients with dyskinesias
were generally young Patients experiencing seishy
zures were taking a median daily dose of 133
ODDs whereas patients experiencing other neuroshy
logical adverse reactions were taking a median daily dose of I DOD or less
Psychiatric Reactions
Psychiatric adverse reactions reported are preshysented in table I V The predominating diagnoses
were anxiety (n =84) confusion (n =32) halluci- nations (0 = 30) and sleep disturbances (n = 23) Aggression was predominantly reported in men Patients who developed hypomaniamania had most often been treated with an SSRI for a long period of time Confusion typically occurred in patients of advanced age Patients experiencing
Table III Neurological adverse reactions reported in patienls receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years Median time inteNala (range) involving women (range)
Paraesthesias 69 78 60 (23middot81) 6 days (O daysmiddot2y)
Headache 63 77 48 (25-88) 2 days (0 days-4wk)
Dizziness 60 77 48 (21middot88) 4 days (0 daysmiddot3mo)
Tremor 50 77 63 (23-88) 6 days (0 days-3mo)
Seizures 27 71 57 (18middot92) 2wk (1 day-2y)
Acute dystonia 14 67 42 (23-80) 6 days (2 days-9mo)
Dyskinesia 14 33 55 (44middot84) 2mo (1 day-6mo)
Muscle cramps 12 91 46 (23-77) 13 days (2 daysmiddot5mo)
Muscle weakness 10 80 42 (22middot74) 1 day (1 daymiddot3mo) Parkinsonism 8 57 74 (47middot87) 2wk (1 day-l mol
Muscle stiffness 8 50 54 (19-60) 6 days (1 day-2wk)
Akathisia 7 43 36 (26-57) 4wk (2wkmiddot4mo) Myoclonus 6 50 50 (24middot74) 4wk (1 day-6mo) Extrapyramidal symptoms 5 80 63 (38-87) 3wk (0 days-6wk) Increased muscle tone 4 25 51 (31-76) 5 days (3 days-7 days)
Migraine 4 100 51 (25middot62) 6wk (1 daymiddot2y)
Adverse Reactions of ~
Table IV Mental adverse
Reaction
Anxiety
Confusion
Hallucinations
Sleep disturbances
Hypomaniamania
Depersonalisation
Amnesia
Nightmares
Aggression
Insomnia
Psychosis
Concentration impaired
Agilation
Personality change
Euphoria
Pathological inebriation
a InteNal between the sla
hypomaniamania we
of 175 ODDs while t
were taking a median
tients experiencing ot
tions were taking a Ill
less
Gostrointestinof RE
Gastrointestinal ad
presented in table V T were nallsea (n = 139)
tients with constipati(
however no slich age
with dry mouth Nause
und dyspepsia mainly
of the treatment On glossitis parotitis and
were adverse reaclion~
reactions were mostly
elevated serum levels
increased levels ofy-gl
phosphatase and bilin
ported Patients expeJi
adverse reaction were a InteNaJ between the start of the treatment and the appearance of the adverse reaction of 1 DOD or less
1( Adis JnlernOfionoJ Limited lU fights reserved
--
nin (5-hydroxytryptamine 5-HT)
line Total no of reports ()b
82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)
7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug
- were taking a median ~ss _
actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)
inantly reported in men hypomaniamania haJ
with an SSRI for a long JI1 typically occurred in Patients experiencing
mine 5-HT) reuptake inhibitors Median time inteNala (range)
6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)
Drug Sofely t999Mor 20 (3
-281Adverse Reactions If SSRls
Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports
involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4
Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67
Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)
a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction
hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less
Gastrointestinal Reactions
Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less
e Adls Intemo lionoJ limited All ighfs reserved
Dermatological Reactions
Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less
General Reactions
General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long
Drug Solety 1999 Mar 20 (3)
(
-c Q-c C lt u
3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
5 a -0 ru
lt ru J a 3 ru lt cr CD -0
o ro cgt ro a cr lt C (J)
() o -0
~ lt3 r
ru ~
278 ------~---------~~~--------- -~------------
the aareness that a particular symptom in a patient treated with an SSRI might be an adverse reaction should he high
The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of depression panic disorder and obsessive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders Aderse reactions asshysociated with the SSRIs are less prominent than and qualitatively different from those assoc iated with the tricycl ic antidepressantsllc l Nevertheshyless adverse reactions of SSRI s cover a broad specshytrum ranging from mild gastrointestinal symptoms to severe although rare events such as seizures IJI hypollatraemiaI~1 and the serotonin syndromeIgt1 In view of the increasing lise of these drugs the pattern of adverse reactions reported on SSRls in Sweden is presented and pos~ible risk factors idenshytified in this study
Materials and Methods
Since 1965 Sweden has had a system for sponshytaneous reporting of adcrse drug reactions to the Swedish Adverse Drug Rcactions Advisory Com-
Table I WHO criteria for causality assessment
mittee Since 1975 the reporting of serious or fatal reactions and new reactions has been compUlsory or the SSRls available in Sweden fluvoxamine was approved in June 1990 paroxetine in June 1991 citalopram in October 1992 sertraline in January 1995 and tluoxetine in September 1995
All reports received up to December 3 I 1997 were re viewed but only reactions that were classishyfied as having a possible probablelikely or certain causal relationship with the drug according to the WHO criteria (table I) and that were reported 3 times or more were included in lhis suney Moreshyover reports concerning overdoses and pharmacoshykinetic interactions which did not cause any adshyverse reactions were excluded
The classification of the reports was made by the monitoring centre staff From each report the following information was obtained bull age and gender of (he patient bull name and dosage of the suspected as well as
other drug or drugs bull outcome of dechallengerechallenge
Certain A clinical event including laboratory test abnormality occurring in a plausible time relationship to drug administration and which cannot be expfained by concurrent disease or other drugs or chemicals The response to withdrawal of the drug (dechallenge) should be clinically plausible The evenl must be definitive pharmacologically or phenomenofogically using a satisfactory rechallenge procedure il necessary
Probablellikely A clinical event incfuding laboratory test abnormality with reasonabfe lime sequence 10 administration 01 the drug unlikely to be aHributed to concurrent disease or other drugs or Chemicals and which follows a clinically reasonabfe response on withdrawal (dechallengel Rechallenge information is not required 10 fulfif Ihis definition
Possible
A Clinical event including laboratory tesl abnormality with a reasonable tesl sequence to adminislration of the drug bul which could also be explained by concurrent disease or other drugs or chemicals Information on drug withdrawal may be lacking or unclear
Unlikely
A clinical event including laboratory test abnormality with a temporal relationship 10 drug administration which makes a causal relationship improbable and in which other drugs chemicafs or underlying disease provide plausible expfanations
Conditionalunclassified A clinical event including laboratory test abnormality reported as an adverse reaction about which more data are essentiat for a proper assessment or the additional data are under examination
Unassessibfelunclassifiable
A report suggesting an adverse drug reaction which cannot be judged because information is insuHicient or contradictory and which cannot be supplemented or verified
Aderse r~actinl
20 eFluvox - ParoX u ro
OCitatOi iii DSertra 0- 15 6fluoxe ~ c ~ 0 ro L= 10 0 0 0
0 0
58 Q) co
(fJ
o F-shy1990 1991
Fig 1 Sales of selt reuptake inhibftors daily doses (000) 04 in 1991 15n 273 in 1996 anc citalopram fiuoxe 150mg tor liuvoxa
bull other potent bull time interv3
appearance Only repan
unkllown dech Ilot stopped 1
negative decha Total drug s
computerised s total amount 0
illacy and can terillS or in tt (ODDs) The 1 dose of a drug I adults for SSf ately severe d( sold per 1000 i although gross drug in the pOI are 20mg for ( tine 50mg for amineJ71
Results
Sales statist figure I The te
~ Adis Internolionalli I Adis InternOhOflol limiled All nghts reserveC Drug SOfely 1999 Mor 20 (3)
Ited with an SSRI mighl
~ pOrling of serious or ratal
Ins has been compulsory
in Sweden nuvoxalllilll
990 paroxctine in Junt
tober 1992 serlralinc ill
tille in September 1995
Ip to December I 1997
eactions that were classishy
probableI ikely or certain
the drug according to the
middotlIld that were reported
Ided in this survey Moreshy
lVerdoses and pharmacoshy
h did not causc any dshy
uded
he reports was made by ff From each report the
IS obtained
oatient
he suspected as well as
erechallcnge
inislralion and which cannol lechallenge) should be tory rechalenge procedure il
te drug unlikely to be onse on withdrawal
he drug but which could also king or unclear
ich makes a causal nations
ta are essential for a proper
conlradictory and which
Dug Sole ly 1Q9Q MO 20()
279 Adverse Reactions of SSRIs
20 bull Fluvoxamine bull Paroxetine
0 OCrtalopram o Serlraline a 15 6 Fluoxetine C ltfl
0 r 10 0 0 0
0 0
5e ltfl Q)
iii Cf)
O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fig 1 Sales 01 selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRls) in Sweden Total sales [in delined daily doses (000)1 000 inhabitants per day] for the SSRls were 04 in 199115 in 199243 in 199398 in 1994206 in 1995 273 in 1996 and 237 in 1997 The OOOs were 20mg for citalopram lIuoxetine and paroxetine 50mg for sertraline and 150mg for lIuvoxamine
bull other potential risk factors bull time interval between start of the trea tment and
appearance of the reaction Only reports with positive dechallenge with
unknown dechallenge or where drug therapy was not stopped were included whereas reports with
negative dechallenge were excluded Total drug sales statistics in Sweden have been
computerised since 1972 These statistics show the total amount of every drug sol d from each pharshymacy and can be expressed in volume monetary term s or in the number of defined daily doses (DDDs) The DDD is the assumed average daily dose of a drug prescribed for its main indication in adults for SSRIs that is the treatment of modershy
ately severe depression 16) The number of DDDs sold per 1000 inhabitants per day is thus a useful although gross measure of the consumption of a drug in the population The DDDs for the SSRls are 20mg for citalopram fluoxetine and paroxeshytine 50mg for sertraline and 150mg for fluvoxshyaminePI
Results
Sales statistics for the SSRls are presented in figure I The total sales from the time of introducshy
laquo Adls Inte rnational Limited All rights reserved
lion of the agent in question until the end of Deshycember 1997 in million DDDs was 1838 for citalopram 591 Cor paroxetine 223101 scrtraline
16 9 for tluoxetinc and 143 for flulOxamine A total of 1202 reports describing 1861 adverse
reactions re lated to SSRltreatmcnt were reviewed There wcre no ratal adcrse reaction The number of reports per ycar is illustrated in figure 2 In towl 67Yk of the reports concerncd women and 32 7~~ concerned men The median age or the patients as
49 yea rs For comparison 66CJr or thc DDDs sold during the years 1994 to 1997 were prescribed to women and 4cr to men and the median age of
these patients was 53 years The distribution of reports by organ system is
presented in table [I Compared with other SSR]s fluvoxamine was morc frequently repo rted to cause gastrointestinal adverse reactions (265 ~t- IS
a mean of 18 lt7c ) sCrlralinc was morc frequently reported to cause psychiatric symptoms (255 J IS a mean or 195lk) and Iluoxetinc was more often reported to cause dermatological symptoms
(17 A9c FS a mean of I 149C )
Neurologicol Reoctions
Neurological adverse reactions reported are presented in table Ill The predominating diagnoshy
200 bull Fluvoxamine bull Paroxetine o Cilalopram o Serlraline
150 6 Fluoxetine
~
a 100 a ci z
50
O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fi9 2 Annual numbers of adverse reaction reports for selective serolonin (5-hydroxytryptamine 5-HT) reuptake inhibitors in Sweden In general reporting is specifically encouraged in the year of approval and lhe following 2 years
Drug Sorelv I Q9Q MOl 20 (3)
J - (
J
- (
( 1 pound
-0 Q)
0 o ()
(1J Q) a (1J o ~ 5 c o (ij -~
m E Q)
-= l- shy
280 Spigset
Table II Organ groups implicaled in 1861 adverse reactions reported in patients receiving seleclive serotonin (S-hydroxytryptamine 5-HT) reuptake inhibitors For specilic diagnoses within each group see tables III-VIII
Reaction No 01 reports ()a
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Total no of reports ()
Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)
Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)
Gastrointestinal 104 (162) 12 (130) 91 (265) 105 (169) 23 (139) 336 (180)
Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)
General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)
Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)
Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)
a The percentage value indicates the percentage of the total number of reactions reported lor that individual drug
b The percentage value indicates the percentage of the total number of reactions reported for all drugs
ses were paraesthesias (n = 69) headache (n = 63)
dizziness (n = 60) Jnd tremor (n = 50) Headache
was the most typical initial reaction Other adverse
reaclions wjth an early onset were dizziness musshy
cle weakness muscle stiffness increased muscle
tone tremor and paraesthesias For the exshy
trapyramidal symptoms akathisia and dyskinesias
more than half of the reports concerned men Pashy
tients who developed parkinsonism were olda
than average whereas patients with dyskinesias
were generally young Patients experiencing seishy
zures were taking a median daily dose of 133
ODDs whereas patients experiencing other neuroshy
logical adverse reactions were taking a median daily dose of I DOD or less
Psychiatric Reactions
Psychiatric adverse reactions reported are preshysented in table I V The predominating diagnoses
were anxiety (n =84) confusion (n =32) halluci- nations (0 = 30) and sleep disturbances (n = 23) Aggression was predominantly reported in men Patients who developed hypomaniamania had most often been treated with an SSRI for a long period of time Confusion typically occurred in patients of advanced age Patients experiencing
Table III Neurological adverse reactions reported in patienls receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years Median time inteNala (range) involving women (range)
Paraesthesias 69 78 60 (23middot81) 6 days (O daysmiddot2y)
Headache 63 77 48 (25-88) 2 days (0 days-4wk)
Dizziness 60 77 48 (21middot88) 4 days (0 daysmiddot3mo)
Tremor 50 77 63 (23-88) 6 days (0 days-3mo)
Seizures 27 71 57 (18middot92) 2wk (1 day-2y)
Acute dystonia 14 67 42 (23-80) 6 days (2 days-9mo)
Dyskinesia 14 33 55 (44middot84) 2mo (1 day-6mo)
Muscle cramps 12 91 46 (23-77) 13 days (2 daysmiddot5mo)
Muscle weakness 10 80 42 (22middot74) 1 day (1 daymiddot3mo) Parkinsonism 8 57 74 (47middot87) 2wk (1 day-l mol
Muscle stiffness 8 50 54 (19-60) 6 days (1 day-2wk)
Akathisia 7 43 36 (26-57) 4wk (2wkmiddot4mo) Myoclonus 6 50 50 (24middot74) 4wk (1 day-6mo) Extrapyramidal symptoms 5 80 63 (38-87) 3wk (0 days-6wk) Increased muscle tone 4 25 51 (31-76) 5 days (3 days-7 days)
Migraine 4 100 51 (25middot62) 6wk (1 daymiddot2y)
Adverse Reactions of ~
Table IV Mental adverse
Reaction
Anxiety
Confusion
Hallucinations
Sleep disturbances
Hypomaniamania
Depersonalisation
Amnesia
Nightmares
Aggression
Insomnia
Psychosis
Concentration impaired
Agilation
Personality change
Euphoria
Pathological inebriation
a InteNal between the sla
hypomaniamania we
of 175 ODDs while t
were taking a median
tients experiencing ot
tions were taking a Ill
less
Gostrointestinof RE
Gastrointestinal ad
presented in table V T were nallsea (n = 139)
tients with constipati(
however no slich age
with dry mouth Nause
und dyspepsia mainly
of the treatment On glossitis parotitis and
were adverse reaclion~
reactions were mostly
elevated serum levels
increased levels ofy-gl
phosphatase and bilin
ported Patients expeJi
adverse reaction were a InteNaJ between the start of the treatment and the appearance of the adverse reaction of 1 DOD or less
1( Adis JnlernOfionoJ Limited lU fights reserved
--
nin (5-hydroxytryptamine 5-HT)
line Total no of reports ()b
82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)
7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug
- were taking a median ~ss _
actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)
inantly reported in men hypomaniamania haJ
with an SSRI for a long JI1 typically occurred in Patients experiencing
mine 5-HT) reuptake inhibitors Median time inteNala (range)
6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)
Drug Sofely t999Mor 20 (3
-281Adverse Reactions If SSRls
Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports
involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4
Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67
Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)
a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction
hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less
Gastrointestinal Reactions
Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less
e Adls Intemo lionoJ limited All ighfs reserved
Dermatological Reactions
Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less
General Reactions
General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long
Drug Solety 1999 Mar 20 (3)
(
-c Q-c C lt u
3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
Ited with an SSRI mighl
~ pOrling of serious or ratal
Ins has been compulsory
in Sweden nuvoxalllilll
990 paroxctine in Junt
tober 1992 serlralinc ill
tille in September 1995
Ip to December I 1997
eactions that were classishy
probableI ikely or certain
the drug according to the
middotlIld that were reported
Ided in this survey Moreshy
lVerdoses and pharmacoshy
h did not causc any dshy
uded
he reports was made by ff From each report the
IS obtained
oatient
he suspected as well as
erechallcnge
inislralion and which cannol lechallenge) should be tory rechalenge procedure il
te drug unlikely to be onse on withdrawal
he drug but which could also king or unclear
ich makes a causal nations
ta are essential for a proper
conlradictory and which
Dug Sole ly 1Q9Q MO 20()
279 Adverse Reactions of SSRIs
20 bull Fluvoxamine bull Paroxetine
0 OCrtalopram o Serlraline a 15 6 Fluoxetine C ltfl
0 r 10 0 0 0
0 0
5e ltfl Q)
iii Cf)
O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fig 1 Sales 01 selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRls) in Sweden Total sales [in delined daily doses (000)1 000 inhabitants per day] for the SSRls were 04 in 199115 in 199243 in 199398 in 1994206 in 1995 273 in 1996 and 237 in 1997 The OOOs were 20mg for citalopram lIuoxetine and paroxetine 50mg for sertraline and 150mg for lIuvoxamine
bull other potential risk factors bull time interval between start of the trea tment and
appearance of the reaction Only reports with positive dechallenge with
unknown dechallenge or where drug therapy was not stopped were included whereas reports with
negative dechallenge were excluded Total drug sales statistics in Sweden have been
computerised since 1972 These statistics show the total amount of every drug sol d from each pharshymacy and can be expressed in volume monetary term s or in the number of defined daily doses (DDDs) The DDD is the assumed average daily dose of a drug prescribed for its main indication in adults for SSRIs that is the treatment of modershy
ately severe depression 16) The number of DDDs sold per 1000 inhabitants per day is thus a useful although gross measure of the consumption of a drug in the population The DDDs for the SSRls are 20mg for citalopram fluoxetine and paroxeshytine 50mg for sertraline and 150mg for fluvoxshyaminePI
Results
Sales statistics for the SSRls are presented in figure I The total sales from the time of introducshy
laquo Adls Inte rnational Limited All rights reserved
lion of the agent in question until the end of Deshycember 1997 in million DDDs was 1838 for citalopram 591 Cor paroxetine 223101 scrtraline
16 9 for tluoxetinc and 143 for flulOxamine A total of 1202 reports describing 1861 adverse
reactions re lated to SSRltreatmcnt were reviewed There wcre no ratal adcrse reaction The number of reports per ycar is illustrated in figure 2 In towl 67Yk of the reports concerncd women and 32 7~~ concerned men The median age or the patients as
49 yea rs For comparison 66CJr or thc DDDs sold during the years 1994 to 1997 were prescribed to women and 4cr to men and the median age of
these patients was 53 years The distribution of reports by organ system is
presented in table [I Compared with other SSR]s fluvoxamine was morc frequently repo rted to cause gastrointestinal adverse reactions (265 ~t- IS
a mean of 18 lt7c ) sCrlralinc was morc frequently reported to cause psychiatric symptoms (255 J IS a mean or 195lk) and Iluoxetinc was more often reported to cause dermatological symptoms
(17 A9c FS a mean of I 149C )
Neurologicol Reoctions
Neurological adverse reactions reported are presented in table Ill The predominating diagnoshy
200 bull Fluvoxamine bull Paroxetine o Cilalopram o Serlraline
150 6 Fluoxetine
~
a 100 a ci z
50
O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997
Year
Fi9 2 Annual numbers of adverse reaction reports for selective serolonin (5-hydroxytryptamine 5-HT) reuptake inhibitors in Sweden In general reporting is specifically encouraged in the year of approval and lhe following 2 years
Drug Sorelv I Q9Q MOl 20 (3)
J - (
J
- (
( 1 pound
-0 Q)
0 o ()
(1J Q) a (1J o ~ 5 c o (ij -~
m E Q)
-= l- shy
280 Spigset
Table II Organ groups implicaled in 1861 adverse reactions reported in patients receiving seleclive serotonin (S-hydroxytryptamine 5-HT) reuptake inhibitors For specilic diagnoses within each group see tables III-VIII
Reaction No 01 reports ()a
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Total no of reports ()
Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)
Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)
Gastrointestinal 104 (162) 12 (130) 91 (265) 105 (169) 23 (139) 336 (180)
Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)
General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)
Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)
Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)
a The percentage value indicates the percentage of the total number of reactions reported lor that individual drug
b The percentage value indicates the percentage of the total number of reactions reported for all drugs
ses were paraesthesias (n = 69) headache (n = 63)
dizziness (n = 60) Jnd tremor (n = 50) Headache
was the most typical initial reaction Other adverse
reaclions wjth an early onset were dizziness musshy
cle weakness muscle stiffness increased muscle
tone tremor and paraesthesias For the exshy
trapyramidal symptoms akathisia and dyskinesias
more than half of the reports concerned men Pashy
tients who developed parkinsonism were olda
than average whereas patients with dyskinesias
were generally young Patients experiencing seishy
zures were taking a median daily dose of 133
ODDs whereas patients experiencing other neuroshy
logical adverse reactions were taking a median daily dose of I DOD or less
Psychiatric Reactions
Psychiatric adverse reactions reported are preshysented in table I V The predominating diagnoses
were anxiety (n =84) confusion (n =32) halluci- nations (0 = 30) and sleep disturbances (n = 23) Aggression was predominantly reported in men Patients who developed hypomaniamania had most often been treated with an SSRI for a long period of time Confusion typically occurred in patients of advanced age Patients experiencing
Table III Neurological adverse reactions reported in patienls receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years Median time inteNala (range) involving women (range)
Paraesthesias 69 78 60 (23middot81) 6 days (O daysmiddot2y)
Headache 63 77 48 (25-88) 2 days (0 days-4wk)
Dizziness 60 77 48 (21middot88) 4 days (0 daysmiddot3mo)
Tremor 50 77 63 (23-88) 6 days (0 days-3mo)
Seizures 27 71 57 (18middot92) 2wk (1 day-2y)
Acute dystonia 14 67 42 (23-80) 6 days (2 days-9mo)
Dyskinesia 14 33 55 (44middot84) 2mo (1 day-6mo)
Muscle cramps 12 91 46 (23-77) 13 days (2 daysmiddot5mo)
Muscle weakness 10 80 42 (22middot74) 1 day (1 daymiddot3mo) Parkinsonism 8 57 74 (47middot87) 2wk (1 day-l mol
Muscle stiffness 8 50 54 (19-60) 6 days (1 day-2wk)
Akathisia 7 43 36 (26-57) 4wk (2wkmiddot4mo) Myoclonus 6 50 50 (24middot74) 4wk (1 day-6mo) Extrapyramidal symptoms 5 80 63 (38-87) 3wk (0 days-6wk) Increased muscle tone 4 25 51 (31-76) 5 days (3 days-7 days)
Migraine 4 100 51 (25middot62) 6wk (1 daymiddot2y)
Adverse Reactions of ~
Table IV Mental adverse
Reaction
Anxiety
Confusion
Hallucinations
Sleep disturbances
Hypomaniamania
Depersonalisation
Amnesia
Nightmares
Aggression
Insomnia
Psychosis
Concentration impaired
Agilation
Personality change
Euphoria
Pathological inebriation
a InteNal between the sla
hypomaniamania we
of 175 ODDs while t
were taking a median
tients experiencing ot
tions were taking a Ill
less
Gostrointestinof RE
Gastrointestinal ad
presented in table V T were nallsea (n = 139)
tients with constipati(
however no slich age
with dry mouth Nause
und dyspepsia mainly
of the treatment On glossitis parotitis and
were adverse reaclion~
reactions were mostly
elevated serum levels
increased levels ofy-gl
phosphatase and bilin
ported Patients expeJi
adverse reaction were a InteNaJ between the start of the treatment and the appearance of the adverse reaction of 1 DOD or less
1( Adis JnlernOfionoJ Limited lU fights reserved
--
nin (5-hydroxytryptamine 5-HT)
line Total no of reports ()b
82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)
7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug
- were taking a median ~ss _
actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)
inantly reported in men hypomaniamania haJ
with an SSRI for a long JI1 typically occurred in Patients experiencing
mine 5-HT) reuptake inhibitors Median time inteNala (range)
6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)
Drug Sofely t999Mor 20 (3
-281Adverse Reactions If SSRls
Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports
involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4
Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67
Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)
a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction
hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less
Gastrointestinal Reactions
Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less
e Adls Intemo lionoJ limited All ighfs reserved
Dermatological Reactions
Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less
General Reactions
General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long
Drug Solety 1999 Mar 20 (3)
(
-c Q-c C lt u
3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
280 Spigset
Table II Organ groups implicaled in 1861 adverse reactions reported in patients receiving seleclive serotonin (S-hydroxytryptamine 5-HT) reuptake inhibitors For specilic diagnoses within each group see tables III-VIII
Reaction No 01 reports ()a
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Total no of reports ()
Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)
Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)
Gastrointestinal 104 (162) 12 (130) 91 (265) 105 (169) 23 (139) 336 (180)
Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)
General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)
Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)
Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)
a The percentage value indicates the percentage of the total number of reactions reported lor that individual drug
b The percentage value indicates the percentage of the total number of reactions reported for all drugs
ses were paraesthesias (n = 69) headache (n = 63)
dizziness (n = 60) Jnd tremor (n = 50) Headache
was the most typical initial reaction Other adverse
reaclions wjth an early onset were dizziness musshy
cle weakness muscle stiffness increased muscle
tone tremor and paraesthesias For the exshy
trapyramidal symptoms akathisia and dyskinesias
more than half of the reports concerned men Pashy
tients who developed parkinsonism were olda
than average whereas patients with dyskinesias
were generally young Patients experiencing seishy
zures were taking a median daily dose of 133
ODDs whereas patients experiencing other neuroshy
logical adverse reactions were taking a median daily dose of I DOD or less
Psychiatric Reactions
Psychiatric adverse reactions reported are preshysented in table I V The predominating diagnoses
were anxiety (n =84) confusion (n =32) halluci- nations (0 = 30) and sleep disturbances (n = 23) Aggression was predominantly reported in men Patients who developed hypomaniamania had most often been treated with an SSRI for a long period of time Confusion typically occurred in patients of advanced age Patients experiencing
Table III Neurological adverse reactions reported in patienls receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years Median time inteNala (range) involving women (range)
Paraesthesias 69 78 60 (23middot81) 6 days (O daysmiddot2y)
Headache 63 77 48 (25-88) 2 days (0 days-4wk)
Dizziness 60 77 48 (21middot88) 4 days (0 daysmiddot3mo)
Tremor 50 77 63 (23-88) 6 days (0 days-3mo)
Seizures 27 71 57 (18middot92) 2wk (1 day-2y)
Acute dystonia 14 67 42 (23-80) 6 days (2 days-9mo)
Dyskinesia 14 33 55 (44middot84) 2mo (1 day-6mo)
Muscle cramps 12 91 46 (23-77) 13 days (2 daysmiddot5mo)
Muscle weakness 10 80 42 (22middot74) 1 day (1 daymiddot3mo) Parkinsonism 8 57 74 (47middot87) 2wk (1 day-l mol
Muscle stiffness 8 50 54 (19-60) 6 days (1 day-2wk)
Akathisia 7 43 36 (26-57) 4wk (2wkmiddot4mo) Myoclonus 6 50 50 (24middot74) 4wk (1 day-6mo) Extrapyramidal symptoms 5 80 63 (38-87) 3wk (0 days-6wk) Increased muscle tone 4 25 51 (31-76) 5 days (3 days-7 days)
Migraine 4 100 51 (25middot62) 6wk (1 daymiddot2y)
Adverse Reactions of ~
Table IV Mental adverse
Reaction
Anxiety
Confusion
Hallucinations
Sleep disturbances
Hypomaniamania
Depersonalisation
Amnesia
Nightmares
Aggression
Insomnia
Psychosis
Concentration impaired
Agilation
Personality change
Euphoria
Pathological inebriation
a InteNal between the sla
hypomaniamania we
of 175 ODDs while t
were taking a median
tients experiencing ot
tions were taking a Ill
less
Gostrointestinof RE
Gastrointestinal ad
presented in table V T were nallsea (n = 139)
tients with constipati(
however no slich age
with dry mouth Nause
und dyspepsia mainly
of the treatment On glossitis parotitis and
were adverse reaclion~
reactions were mostly
elevated serum levels
increased levels ofy-gl
phosphatase and bilin
ported Patients expeJi
adverse reaction were a InteNaJ between the start of the treatment and the appearance of the adverse reaction of 1 DOD or less
1( Adis JnlernOfionoJ Limited lU fights reserved
--
nin (5-hydroxytryptamine 5-HT)
line Total no of reports ()b
82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)
7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug
- were taking a median ~ss _
actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)
inantly reported in men hypomaniamania haJ
with an SSRI for a long JI1 typically occurred in Patients experiencing
mine 5-HT) reuptake inhibitors Median time inteNala (range)
6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)
Drug Sofely t999Mor 20 (3
-281Adverse Reactions If SSRls
Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports
involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4
Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67
Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)
a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction
hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less
Gastrointestinal Reactions
Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less
e Adls Intemo lionoJ limited All ighfs reserved
Dermatological Reactions
Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less
General Reactions
General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long
Drug Solety 1999 Mar 20 (3)
(
-c Q-c C lt u
3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
--
nin (5-hydroxytryptamine 5-HT)
line Total no of reports ()b
82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)
7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug
- were taking a median ~ss _
actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)
inantly reported in men hypomaniamania haJ
with an SSRI for a long JI1 typically occurred in Patients experiencing
mine 5-HT) reuptake inhibitors Median time inteNala (range)
6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)
Drug Sofely t999Mor 20 (3
-281Adverse Reactions If SSRls
Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports
involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4
Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67
Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)
a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction
hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less
Gastrointestinal Reactions
Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less
e Adls Intemo lionoJ limited All ighfs reserved
Dermatological Reactions
Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less
General Reactions
General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long
Drug Solety 1999 Mar 20 (3)
(
-c Q-c C lt u
3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
282 Spigscl
Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l
Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)
~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain
C1l
Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0
Parotitis~gt
14 64
14 75
11 40
8 63
7 71
4 50
49 (19-86)
49 (24-87)
54 (28-84)
48(17-90)
53 (30-78)
47 (28-74)
61 (30-75)
63 (55-88)
55 (46-81)
78 (75-84)
a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction
(range)
5 days (0 daysmiddot9mo)
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day-1mo)
7 days (2 days-1mo)
13 days (7 days-3mo)
12 days (8 days-2wk)
3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5
and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ
~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0
menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J
and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses
Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime
Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii
Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90
Urticaria 42
Pruritus 40
Angioedema 10
Photosensitivity 5
lt
involving women (range) (range)
73 52 (18-88) 5 days (1 day-3y)
74 38 (14-77) 2wk (2 days-5mo)
76 49 (27-83) 3wk (1 day-15mo)
90 37 (24-77) 13 days (1 day-2mo)
80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction
~ Adis ntefnotionol limrled AU rig - middote servec
dvers Reactions ()f SSRI
However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4
toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks
Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI
J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)
reflexia and agitation ( md hyper-retlexia and myoclonus
Discussion
Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in
Table VII General adverse react
Reaction
Fatigue
Hyperhidrosis
Oedema
BOdyweight gainb
Syncope
Pain
Fever
Malaise
Faintness
Somnolence
Anorexia
Chills a Interval between the start of It
b Two reports of bOdyweight gai
3
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
283 Sligsrl
nin (5-hydroxytryptamine 5-HT) reuptake
ge in years Median time interval shy(range)
5 days (0 days-9mo) shy
10 days (0 days-6mo)
5 days (0 days-4wk)
4wk (3 days-9mo)
7 days (1 day-5mo)
2 days (1 day-6 days)
4 days (1 day- lmo)
7 days (2 days-lmo)
13 days (7 daYS-3mo)
12 days (8 days-2wk)
disorders also had a late onse actorrhoea the highest serum
Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu
els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla
experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I
Hients experiencing the other
gttoms were more often reshyoung individuals and in those
[ for a long period of time
ytryplamine 5middotHT) reuptake inhib~ors
Median time interval (range)
5 days (1 daymiddot3y)
2wk (2 days-5mo)
3wk (1 day-15mo)
13 days (1 day-2mo)
2mo (3 days-2y)
Drug Solely 1 Q99 Mor 70 (3)
Adver~e Reactions of SSRls
However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks
Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)
tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus
Discussion
SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies
only I to 5ck of mild and 10 to 800k of serious
adverse drug reactions have becn founu to he re- j
ported I~lt)1 Moreover even though correcteu for (
sales figures spontaneous reponing cannot bc l
used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L
(
Iween drug because the extent of under-reporting 0 E
Inost pn1bahly varies hctween drugs The fre- -c
qucncy or reports may be influenced by factors ~
(l
such as puh lic knowledge of the uses and adverse 2t
effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E
As illustrated in figurc 2l11ost adverse reactions ~ c
for each S5 R I were reported during the first I years a c
following approval of the drug A high initia~ rc- middotc
porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~
these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro
c hlVe bee n studied cxclusively as a group whcn the 0
~ specific diagnoses have been considered z
The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of
o a connection increases A ith an increasing number 0 Q)
of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g
0 Q)
6 a o
Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)
Fatigue 42 76 48 (23middot89)
Hyperhidrosis 37 67 54 (23middot88)
Oedema 33 72 48 (29-82)
80dyweight gainb 12 73 39 (21middot60)
Syncope 10 67 38 (25middot71 )
Pain 8 57 48 (33middot63)
Fever 7 100 42 (34-48)
Malaise 5 40 49 (41 -43)
Faintness 4 75 66 (50middot79)
Somnolence 4 100 64 (50-81)
Anorexia 3 67 44 (28-75)
Chills 3 67 53 (43-65)
a Interval between the start 01 the trealment and the appearance of the adverse drug reaction
b Two reports 01 bodyweight gain due 10 oedema were excluded
ii Adis Infernolionollimlled All tights reserved
Median time interval (range) en ro ~
7 days (0 days-3mo)
9 days (0 days-4mo)
8 days (0 days-3mo)
3mo (12 daysmiddot4mo)
5 days (1 day-3mo)
1 day (1 day-5mo)
3wk (3 days-6wk)
2wk (2 days-2mo)
7 days (0 days-4mo)
11 days (5 days-7wk)
10 days (not reported)
7 days (not reported)
Q)
Ol ro 0
stn
c a ro ~ ro E Q) c f-
DIU Sofely 1909 Mor 20 (3)
1-shy
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
J )
~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
---i T CD
3 ()
~ ~ 0 gt
3 ihmiddot -0 ()
lt0 CD () U)
()
0 -0
CD Cl
(3 3 3 CD ()
Q CD l amiddot J
8shy3 [ CD
z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)
cr lt )
3 a I
c ~ shyu J shy3 u c -r 0 J 3 nshy)
D l
r f)
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~ shyT
234 Spigset
Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors
Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women
Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)
Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)
Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)
Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)
Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)
Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)
Endocrinological
Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea
Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)
Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)
Metabolic
HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)
Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)
Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)
Erection disturbance 8 0 43 (28middot54) Not reported
Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)
Respiratory
Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)
Musculoskelelal
Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)
Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol
Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)
Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)
Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)
Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased
Visual
Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)
Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)
Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)
Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)
Other
Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported
a Interval between the start ot the treatment and the appearance ot the adverse drug reaction
b Gender-specific diagnosis
SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion
Adverse Reactions of S~
the other hand spont an interesting tool il
quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI
actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0
unexpected reactions The high frequency
reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT
tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill
mgday has been reporte lions than citalopramf [2
The relatively high fr adverse reactions assoc
Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved
1_- ---- shy
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
SpissCI
ne 5-HT) reuptake inhibitors
le) Median time interval (rang)
7wk (3wk-5mo)
7wk (4wk-3mo)
7 days (1 day-6mo)
1 days (0 days-3 days)
2 days (1 day-3wk)
2 days (1 day-2mo)
4mo (2mo-11mo)
4wk (3wk-2mo)
9mo (3mo-9mo)
2wk (2 days -1 5y)
5wk (7 days-4mo)
2wk (0 days-4mo)
Not reported
10 days (7 days-3wk)
6wk (4wk-2mo)
6wk (3 days-7mo)
9 days (1 day-1 mol
9 days (1 day-3wk)
3 days (0 days-3wk)
4 days (O days-2wk)
3mo (5 days-4mo)
10 days (1 day-4mo)
1mo (8 days-l1 mol
1 day (1 day-1 day)
4 days (1 day-7 days)
10 days (1 day-6wk)
8mo (4wk-2y)
NOl reported
Drug Sofely 1m Mor 20 (3)
285Adverse Reactions of SSRIs
the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various
adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than
expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions
The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy
I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy
duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported
1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy
ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-
j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy
intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]
The relatively high frequency of dermatological adverse reactions associated with fluoxctine use
copy Ads Inlemo1ional Umlled All righls reserved
seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors
Most of the adverse reactions identified in this
survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association
In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is
Drug Sofely 1999 Mar 20 (3)
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
286 SJligser c _________________ ______________________________________________________
interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)
mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~
~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be
D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0
a ard dosages one may speculate that the dose-effect
treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)
ing cllJe for the antidepressant effect Alternashy()
Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10
might be a more important factor than the absolute 5 I
J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy
Most adverse reactions caused by SSRls can be J tions for which high median dosages were used
explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight
The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise
be explained by an impairment of blood platelet
)
L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved
As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy
mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy
stipation dry mouth and urinary retention are not dosage
uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give
explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of
properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy
that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more
ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy
cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high
I Adis Inlerno lio noJ umHed A I I ns rese rved
Adverse Reacti()n~ of S~
Acknowledgell
Martin Backstrom anI
Products Agency are 1l
database search
References I Song F Freemantie N ~
r~uplake inhibitors n abililY BMJ 1993 JOe
2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78
3 Spigset O Hedenmalm K lonus associated wim 31
potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt
~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic
5 Sporer KA The serOlooin 6 WHO collaborating cen
Guidelines for defined ( Iborating ccnlfe for dn
7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997
8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55
9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)
10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot
-1shy
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E
treatment with tricyclic al1shy
with increasing age and the
stipation and urinary relclI_
nt study indicates that Ihe
inergic effects with SSRls h increasing age
lelions are expeclcd 10 he
reo in principle avoidahle
fact that the majorit) or fed in this study were ohshy
ad been treated with slalld shy
eculate that the dosc-clfeci
adverse reactions is close
left side of the correspondshy
epressant effect Alternashy
s in drug concentralioll
nt factor than the ahsoltlle
-me adverse reactions Th~
tolerance might also modshy
ldividual patient 10 some
ment with high dosage
least for the adverse reacshy
dian dosages were used
laniaimania bodywcifh
sonalily change malaise
galactorrhoea
lr smaller extent are l11eahshy
cytochrome P450 (CYPJ 19 andor CYP2D6Icfli
~e based on the patients
ty might reduce the risk
ntratioLl-dependent ) adshy
idiosyncratiCimmunoshy
lth and urticaria can prillshy
by optimising the drug
nt with SSRls can give
se reactions mainly or nal and psychiatric 11lt1shy
mrely reported As more
eaction diagnoses were
awareness that a partieshy
t treated with an SSRI
)n should be high
Drug Safety J9X Mar 20 (3)
287Adverse Reactions 01 SSRls -Acknowledgements
Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search
References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill
r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy
ahilily BMJ I ~1)1 30( (~ 1 -7
2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~
3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84
4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225
5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~
Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76
7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997
8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55
9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6
10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S
Adis Inemotional Umifed AU rights reserved
II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H
12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy
pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1
d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1
ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy
ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5
14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26
IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~
16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6
17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315
IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11
I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~
20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23
--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno
Drug Safety 19X Mar 20 (3)
D Q)
0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E