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Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry
Volume 17 Issue 1 Article 7
January 2002
A New Onset Paranoid Psychosis Associated With Fluoxetine and A New Onset Paranoid Psychosis Associated With Fluoxetine and
Bupropion: A Case Report Bupropion: A Case Report
Vassili V. Arkadiev M.D. MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH
Stephen L. Ruedrich M.D. Case Western Reserve University, Cleveland, OH
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Recommended Citation Recommended Citation Arkadiev, Vassili V. M.D. and Ruedrich, Stephen L. M.D. (2002) "A New Onset Paranoid Psychosis Associated With Fluoxetine and Bupropion: A Case Report," Jefferson Journal of Psychiatry: Vol. 17 : Iss. 1 , Article 7. DOI: https://doi.org/10.29046/JJP.017.1.008 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol17/iss1/7
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Letters to the Editor
A NEW ONSET PARANOID PSYCHOSIS ASSOCIATED WITH FLUOXETINE AND
BUPROPION: A CASE REPORT
To th e editor : Bupropion, a uni cyclic aminoke to ne, has a chem ica l st ru ctur e that isuniqu e a mong a ntide press a nts (I ). Bupropion a lso has a relatively favor able side effec t profi le(2); but occasiona l seve re side effec ts, including del irium a nd psychoses, have been report ed(2- 11). We pr esent a patient who appear ed to hav e a bupropion-induced psycho tic disord er ,with a lmost exclusively delu sion al sym ptoma tology.
Ms. A was a 45 yea r old sing le Afri can -Am eri can mother of two when she was seen in theoutpatient psychi atric clinic for depression. Her medi cal hist ory was significant for obesity,diabetes type 2, and ost eoarthritis, for whi ch sh e took glyburide 5 mg/d ay and ibuprofen 1600mg/day. In her la te 30's, Ms . A had her uterus rem oved seco ndary to uterine fibroids ; shesubsequent ly had very mi ld postmenopausal sym ptoms, whi ch last ed for less than a year. Hermed ica l condi tion was stable, with blood glucose ran gin g betw een 150 - 200 mg/d l. Herhemoglobin Al c was between 6.4 and 9.3%. Blood coun t, elec tro lytes , TSH, 1'4, urinalysis, andliver function tests were normal. Her HDL wer e 34 mg/d l (normal ran ge 35 a nd high er) andcholes te rollH DL rat io was 5.38 (normal ran ge 0.00-4.44) .
Ms. A had no pr evious history of psychiatric inpatient tr eatment , suicide atte mpt, man ia,psychosis or confus ion, and no history of drug or alcoho l use. Her family history was significantfor schizophrenia in her old er sist er, who had died of myocardial infar cti on, a nd a hist ory ofdepression in th e younger sist er, who was taking an unknown psychi atric medi cation .
Ms. A had graduated from high school, and for more than 20 yea rs wor ked as a nursingassista n t. She had been married a nd divor ced twice , has two child ren, and lives with heryoungest daught er. Ms . A's first depressiv e episode occurred at th e age of 43; apparent ly notprovoked by any external or physical stressor. Her condition had gr ad ua lly det eri or at ed to th epoint that sh e had been unable to work , and had to q uit her job. Most of th e tim e she rema inedin bed , and became socia lly wit hd rawn, whi ch was com ple te ly different from her premorbi dper sonalit y. Aft er approxima tely ten months of depressive sym ptoms, Ms. A was referred byher internist to th e outpatient psych iatric clinic. According to th e pati ent 's medi cal record, shehad demonstra ted depress ed mood, depressive cognit ion, veget ative symptom s of dep ression,motor retarda tion, an d impai red con centration. Sh e was tr eat ed in iti all y with fluoxctine 20 mgper day, with gradual titration to 60 mg/day over th e next 8 weeks. Ms. A respond ed to th ehigh er dos e with sign ificant improvem ent in her mood, a llevia tion of mot or re ta rda tion ,improvem ent in her cognition, a nd significant improvem ent in her vege ta t ive sym ptoms as
Vassi li Va lerievich Arkadiev, MD , PGY- III Resident in Psychi atry, MetroH ea lth Medi calCenter, Case West ern Reserve University, C leveland, OHSt ephen Lawren ce Ru edr ich, MD, Associat e Professor of Psych ia try, Cas e West ern ReserveUnivers ity, Cl eveland , OHCorrespondenc e to : Dr. V. Arkadiev, MetroHeal th Medi cal Cen te r, Cl eveland, OH, 44 109,T el.: 216 7784428, Fax : 2 16 77884 12, email: [email protected]
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64 JEFFERSON JOURNAL O F PSYCHIATRY
well. O ver the next seve ra l months, whil e she cont inue d to tak e 60 mg of fiuoxetine daily, Ms.A did well. Sh e became more socia l, was helping her family as she had don e before thedepression, and even returned to work .
Aft er five months of treatmen t with 60 mg of fluoxetine dai ly, Ms. A had sto pped themedi cation , and dropped out of treat ment. She remained asymptomatic for a no ther fourmonths, when she red evelop ed depressive sym pto ms, a nd was seen ag a in a t our outpat ientclinic. On exa m Ms. A had depress ed mood , psychomotor retardation , low ene r!:,')" level , seve reanhedonia , initial a nd middle in somnia, hop elessn ess, helplessn ess, self - depreciati on , a ndruminative th ou ght s. Her cognit ive exam was normal , a nd she had no psychotic sym pto ms .Flu oxetine was rest art ed and titrat ed to 80 mg/day over th e next 2 mo nt hs . She remained on80 mg/d ay for 5 weeks, without significa nt improvem ent , a t whi ch tim e bupro pion SR wasadded to her fluoxetine regim en , at 50 mg/d ay, Aft er 3 days bupropion was incr eased to 100mg/day. On th e 3rd day of treatment with bupropion 100 mg a day, Ms. A devel oped ideas tha tpeopl e were talking a bout her, st ra ng ers on th e st ree ts were wat ching her, a nd she feltreluctant to leave her hou se. On th e 7'h day of bupropion tr ea tment Ms. A was re-evalu a tedas an outpatient. H er exa m at th at tim e revealed no significan t impairment in orie nta tion,conce n tra t ion, or m emory. Sh e had delusion al ideas of referen ce (as above) and no insight in toher psychotic symptoms. She rep orted her mood to be better, a nd her affec t was lessdepressed, with no hop elessn ess, or helplessn ess. Her e ne rgy was a lso bett er, as was herappe tite . No manic sym ptoms were obs erved . The bupropion was di scontinued , a nd Ms. A wasgiven risperidone 1.5 mg bid . She took only on e do se, th en s topped th e a ntipsychot icm edi cation secondary to severe seda t ion. O ver the next 7 days, her psychotic symptomsresolved comple tely, but she began to experience a n exace rba tion of her dep ress ive sym ptoms.Three week s later her fluoxetine was stopped, and Ms. A was switched to ve nla fax ine. O nfollow up aft er 3 months , Ms . A had mild depressive sympto ms, no psychoti c symptoms, an dno cog n itive impairment.
The mech anism of acti on of buprop ion is not well unders tood ( I); however, it is beli evedth at th e an tide pressa nt effec t, an d possibly some sid e effec ts, a re du e to nor ep inephrineturnover, and to less er ex te nt, dopamin e reuptak e blockad e ( 1,2) . T here have been severa lcase reports of appa re nt bupropion-associat ed psychosis (2- 11), however , most of th e patie nt swho developed psych osis whil e taking bu pr op ion had a history of psychosis pri or to buprop iontreatment. Som e of th ese rep orts describe not only pathology of th ou ght pro cesses, andperceptual di sturbances, but also definit e cog nitive impairment with clo ude d consciousness .We were abl e to identify only 3 report s of psychotic sym pto ms in th e abse nce of cog nit iveim pa irme nt in non-predi sposed ind ividuals followin g buprop ion treatment (2 cases of hallucina t ions, and one cas e of delusion s and hallu cin ation s) (9- 11). T o ou r knowled ge, no reportsdescribed pure delusional psychosis without perceptual di sturban ces. Addi t iona lly, all of thereports of bupropion-induced psychosis a nd bupropion-induced delirium involved daily doses inth e range of 300 mg a nd a bove (2- 10) . In our patient , th e maximum dose d id not exceed 100mg/d ay of bupropion SR.
Bupropion undergoes extensive hep at ic metaboli sm , mainly through th e CYP 450 IIB6a nd IIIA 3/4 syst ems (15); th e latter of whi ch is known to be suppressed by fiuoxetine ( 14,15).Bupropion docs not appear to be metabolized by IID 6 isoen zym es; however, th ere a rc somedat a th at bupropion and it s metabolites may in hibi t IID 6 ( 14), whi ch is a secon dary met ab olicpathway for fluoxetine. Bupropion met ab olites may be eleva ted in people wit h hepa tic di seasea nd in th e elde rly, whi ch ma y be contributory to side effec ts ( 10, 15). In our pa t ient , th e
LErrERS TO THE EDI TOR 65
significa nt improvem ent in he r moo d bega n afte r several days of treatment wit h bupropion, atapproxima te ly th e same ti me th at she s tarte d experienc ing de lus ions. Both her moodim provement , as well as psychotic sym ptoms, migh t be a tt r ibuted to an inc reased level ofbupropion met abolites.
Alte rna tively, th e ph en om ena of dru g-associated delusions might be expla ined by ser oton ergic mecha nisms . Flu oxetine inc reases ve n tra l stria ta l serotoni n ( 17), stimulating 5-HT3receptor-me d ia te d dopam in e release in th e ventral stria ta l region, wh ich may lead to psych osis( 18). Unde rle ider a nd Pechnick ( 19), in reviewi ng th e mecha nisms of act ion of hall ucinogens,co ncl ude d th at th ese age nts work throu gh effects a t 5-HT2 receptor s. However , Pie rce andPeroutka (20) sugges te d th at ac tion a t 5-I-IT IC, a nd not 5-1-1'1'2 receptor s, may account for th ehallucin ogenic pr op erties. Am on g several report s d escribing Iluoxetine a nd psych oses, (18,2 124) we were able to identify only one case of possibl e f1u oxetine-induced persecutory delusionsin a patient who did not have pr evious hist or y of psych osis (20); as we ll as 3 re ports of visualhallucinosis (22-24) . One of those patient s was a lso taking L-dopa, a nd ano t he r develop edvisua l hallucinosis aft er dextromethorphan had been adde d to her regimen. Althou gh it ispos sibl e to attribut e Ms. A's psychotic sym ptoms to eleva te d level s of f1u oxetine, ca used bybupropion-associat cd 2D 6 inhibit ion , we beli eve that it is unlikely, s ince th e CYPIID6 systemis onl y a minor pathway for f1uoxetine ( 13).
One other possible expla na tion for th e development of psych oti c sym ptoms in Ms. Awou ld be a so-ca lle d "sc hizoa ffcc tive evolut ion" in th e course of her a ffec tive illness . AlthoughMs. A had a fa m ily hist or y of schizophrenia a nd de press ion, we th ink th is is ext rem ely un likely,du e to th e sho rt sym ptomat ic per iod of th e delusion s (a bo ut 8 days), t hei r di sappea ra ncewi t ho ut specific an tipsycho tic treatme nt , th e obvious temporal rela tionsh ip wit h t he initiationof bupropion tr ea t me nt , a nd th e lack of negative sympto ms be tween her de pressive episodes .
Of add it ional in terest was Ms. A's initial res po nse to Iluoxet ine, but lack of response toth e sa me medi cation wh en it was rest a rt ed , eve n at incr eased dose . The development oftol erance to th e therapeutic effec ts of SSRI 's, whi ch Goodnick a nd Go lds tei n (25) hav e te rmed" ne uro phys iologica l tole ran ce" , is a well-known ph en om en a , an d has be en reported elsewh er e(25 -3 1). Fava e t a l (26) in th eir s tudy of re-initiation of ant ide pressan t t reat men t in patient swh o pr eviously responded to fluoxctine, but lat er we re switc he d to placeb o and relapse d, foundthat 38% of th e patients did not respond to th e re -init ia t ion of fl uoxe tin e. Mi ch elson e t a l (29 )rep or ted th at Iluox e tin e occasiona lly lost efficacy afte r 9 months of co ntinued t reatment ,foll owin g res po nse to 12-14 week s of initial treatment. Fava e t a I., (30) rep ort ed t ha t rela pseor recurren ce of depressive sym pto ms occurr ing in pa tie nts receivin g conti nua tion or mainten an ce th erapy with Huoxet in e 20 rug/d ay, ca n be tr ea ted effectivel y by increasing the dos eto 40 rug/day. Conversely, Cain (31) postulating that overmedi cation with Iluoxet ine mighta ppear as a response failure, report ed 4 patients who continue d to det eri or at e wh en their doseof f1uoxetine was raised, but that symptoms improved dram aticall y during sys te ma tic tri al s oflowe r doses. Ca in noted th at higher doses of Iluoxetine may co rre la te with high plasm aco nce n tra tion of norfluox ct in e, th e ac t ive metabolite of fluoxetine, wh ich was sometimesas socia te d with a poor clinical response. (3 1).
The m ech anism of this loss of efficacy of SSRI's, a nd flu ox et inc in particul a r, rema insunclear. One hypothesis sugges ts th at long-t er m trea t ment with Iluoxet iue may ca use arelative dop amine deficien cy, whi ch may resp ond to tr eatment wit h pos tsy na ptic do pamineagonists (33). Our case may lend support to this th eory, surround ing th e fac t th a t Ms. Adevelop ed delusion al ideas, but a lso had rep ort ed some imp roveme nt in her mood.
66 J EFFERSON JOURNAL OF PSYCHI ATRY
One final possible explana t ion for Ms. A' s treatment resist an ce may be th e cont ribut ionof her medi cal cond itions, diab et es in particul a r. Her diab et es was not well controlled, basedon th e hem oglobin Al c level, as well as incr eased cholesterollH DL and low HDL. Howeve r, th crest of her laboratory exa ms wer e normal , so it see ms unlikely th at her ini tia l lack of responseto fluoxetine ma y be a tt r ibute d to her medi cal cond it ion. Also, th e re a re som e reports th atfluoxetine has prov en effec t ive as an ant ide pressan t in th e tr eat ment of depression assoc ia tedwith se rous physical illn esses, including diab et es (34).
\Ve pr esent th e case of a 45 yea r old wom an with depression unresponsive to fluoxet ine,whos e depression responded to th e adj unc tive addition of bupropion , but who developed fra nkpsychosi s soon aft er initiation of bupropion in low-moderate dose. We sugges t a cautiousapproach in th e concurrent use of bupropion and substances that int erfere with its metabolism.
Vassili Ark adiev, MDStephe n Rued rich , MDCleveland, OH
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