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The use of antidepressants in Bipolar depression: the controversy WALID SARHAN F.R.C.Psych. AMMAN-JORDAN
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Burning Issues in Psychiatry Congress The use of antidepressants
in Bipolar depression: the controversy
WALID SARHAN F.R.C.Psych. AMMAN-JORDAN Antidepressant Drugs In a
prescription-database study involving more than 7500 patients, 50%
of all initial treatment prescriptions for bipolar disorder were
for antidepressant monotherapy Merikangas KE,Akiskal HS,Angst J, et
al. Lifetime and 12-month prevalence of bipolar spectrum disorder
in the National Comorbidity Survey replication.Arch Gen
Psychiatry2007;64: FDA approval of antidepressants
With the exception of fluoxetine, which is approved in combination
with olanzapine for bipolar depression, all FDA-approved
antidepressants are indicated only for unipolar depression;
patients with a history of bipolar disorder were excluded from all
registration trials. Impact of antidepressant discontinuation after
acute bipolar depression remission on rates of depressive relapse
at 1-year follow-up Guidelines state that patients with bipolar
depression who are treated with an antidepressant should
discontinue therapy within 3 to 6 months after achieving remission.
However, discontinuation of antidepressants has been shown to cause
depressive relapse in these patients. Altshuler L, Suppes T, Black
D, et al. . Am J Psychiatry. 2003;160: Antidepressants for Bipolar
Depression: A Systematic Review of Randomized, Controlled
Trials
Antidepressants are effective in the short-term treatment of
bipolar depression. The trial data do not suggest that switching is
a common early complication of treatment with antidepressants. It
may be prudent to use a selective serotonin reuptake inhibitor or a
monoamine oxidase inhibitor rather than a tricyclic antidepressant
as first-line treatment. Given the limited evidence, there is a
compelling need for further studies with longer follow-up periods
and careful definition and follow-up of emerging mania and partial
remission. Am J Psychiatry 161: , September 2004 2004 American
Psychiatric Association Harm J. Gijsman et al The studies looking
at long-term response to antidepressants, in patients with bipolar
disorder, there are very few that suggest long-term benefit.
Bipolar disorder September 2008 Overview of the drug treatment of
bipolar disorder NICE Bipolar disorder guidelines 2006
Antidepressants Can be used to control depressive episodes (with
antimanic medications) e.g. SSRIs After successful treatment of an
acute depressive episode, do not continue long-term antidepressants
routinely Stop antidepressant at the onset of an acute episode of
mania (abruptly or slowly) National Prescribing Centre
Antidepressant treatment and risk monitoring
Antidepressants should be avoided for patients with depressive
symptoms who have: -rapid-cycling bipolar disorder -a recent
hypomanic episode -recent functionally impairing rapid mood
fluctuations NICE clinical guideline 2006 Stopping antidepressants
after an acute depressive episode
When a patient is in remission from depressive symptoms (or
symptoms have been significantly less severe for 8 weeks), stopping
the antidepressant medication should be considered to minimize the
risks of switching to mania and increased rapid cycling. The dose
of antidepressant should be gradually reduced over several weeks,
while maintaining the antimanic medication NICE clinical
guideline2006 Risk of switch in mood polarity to hypomania or mania
in patients with bipolar depression during acute and continuation
trials of venlafaxine, sertraline, and bupropion as adjuncts to
mood stabilizers. In a study with a 10-week acute phase and a
1-year continuation phase, 150 patients with bipolar I or bipolar
II disorder were treated with an antidepressant (bupropion,
sertraline, or venlafaxine) in addition to a mood stabilizer. In
the acute phase, 11.4% of the patients switched to hypomania and
7.9% switched to mania. In the continuation phase, 21.8% switched
to hypomania and 14.9% switched to mania. Only 23% of all patients
experienced a sustained response to the antidepressants. . Leverich
GS, Altshuler LL, Frye MA, et al. Am J Psychiatry. 2006;163:
Effectiveness of Adjunctive Antidepressant Treatment for Bipolar
Depression
The use of adjunctive, standard antidepressant medication, as
compared with the use of mood stabilizers, was not associated with
increased efficacy or with increased risk of treatment-emergent
affective switch. Longer-term outcome studies are needed to fully
assess the benefits and risks of antidepressant therapy for bipolar
disorder Gary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R.
Calabrese, M.D., Lauren B. Marangell, M.D., Stephen R. Wisniewski,
Ph.D., Laszlo Gyulai, M.D., Edward S. Friedman, M.D., Charles L.
Bowden, M.D., Mark D. Fossey, M.D., Michael J. Ostacher, M.D.,
M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D., Peter
Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D.,
Michael H. Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto,
Ph.D., Ellen B. Dennehy, Ph.D., and Michael E. Thase, M.D. N Engl J
Med 2007; 356: March 28, 2007 No value of antidepressants
in a longer (26-week) trial in which 366 patients with bipolar I or
bipolar II disorder who were receiving a mood stabilizer were
randomly assigned to adjunctive antidepressant therapy (paroxetine
or bupropion) or placebo,there were no significant differences
among groups in the rates of durable recovery, defined as 8
consecutive weeks of euthymia without a switch to mania or
hypomania. Sachs GS,Nierenberg AA,Calabrese JR, et al.
Effectiveness of adjunctive antidepressant treatment for bipolar
depression.N Engl J Med2007;356: Antidepressants for Bipolar
Disorder
There is some evidence, that antidepressants are effective in the
short-term treatment of bipolar depression, but a large recent
trial reported no benefit, and caution should be paid to the risk
of manic switching. Alternative agents, such as quetiapine or
lamotrigine, should be considered. When using an antidepressant, it
may be prudent to use an SSRI or bupropion rather than a TCA or
venlafaxine as first-line treatment Andrea Cipriani, , John R.
Geddes,June 1, 2008 Psychiatric Times. Vol. 25 No. 7
Recommendations for pharmacological treatment of acute bipolar I
depression
First line :Lithium, lamotrigine, quetiapine, lithium or divalproex
+SSRI, olanzapine + SSRI, lithium + divalproex, lithium or
divalproex +bupropion Second line :Quetiapine + SSRI, divalproex,
lithium ordivalproex + lamotrigine, adjunctive modafinil Third line
:Carbamazepine, olanzapine, lithium + carbamazepine, lithium +
pramipexole, lithium or divalproex + venlafaxine,lithium + MAOI,
ECT, lithium or divalproex or AAP + TCA, lithium or divalproex or
carbamazepine + SSRI + lamotrigine, adjunctive EPA, adjunctive
riluzole,adjunctive topiramate CANMAT guidelines for bipolar
disorder2009 her Recommendations for pharmacological treatment of
acute bipolar II depression
First line:Quetiapine Second line:Lithium, lamotrigine,
divalproexa, lithium ordivalproex + antidepressants, lithium +
divalproex, atypical antipsychotics + antidepressants Third
line:Antidepressant monotherapy (particularlyfor those with
infrequent hypomanias), switch to alternate antidepressant,
ziprasidone CANMAT guidelines for bipolar disorder2009
Recommendations for maintenance pharmacotherapy of bipolar
disorder
First line: Lithium, lamotrigine monotherapy (limited efficacy in
preventing mania), divalproex, olanzapine, quetiapine, lithium or
divalproex + quetiapine, risperidone LAI, adjunctive risperidone
LAI, aripiprazole (mainly for preventing mania), adjunctive
ziprasidone Second line :Carbamazepine, lithium + divalproex,
lithium + carbamazepine, lithium or divalproex + olanzapine,
lithium+ risperidone, lithium + lamotrigine, olanzapine +
fluoxetine Third lineAdjunctive phenytoin, adjunctive clozapine,
adjunctive ECT, adjunctive topiramate, adjunctive omega-3-fatty
acids, adjunctive oxcarbazepine, or adjunctive gabapentin Not
recommended Adjunctive flupenthixol, monotherapy with gabapentin,
topiramate or antidepressants r The prospective course of
rapid-cycling bipolar disorder: findings from the STEP-BD.
The Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD) included 1742 patients treated with a variety of approved
medications for bipolar I and bipolar II disorder, and 32% reported
having rapid-cycling at baseline. After 2 years of treatment, 5%
still had rapid-cycling bipolar disorder. Those who were treated
with an antidepressant were 3.8 times more likely to have
rapid-cycling bipolar disorder. Schneck CD, Miklowitz DJ, Miyahara
S, et al. Am J Psychiatry. 2008;165: Good and bad A meta-analysis
of seven trials involved 350 patients with bipolar I or bipolar II
disorder who were randomly assigned for at least 6 months to any
type of antidepressant with or without a mood stabilizer or to
placebo with or without a mood stabilizer. This study showed that
antidepressant therapy reduced the risk of recurrent depression
(relative risk, 0.73; 95% CI, 0.55 to 0.97) but increased the risk
of a switch to a hypomanic or manic episode (relative risk, 1.72;
95% CI, 1.23 to 2.41). Ghaemi SN,Wingo AP,Filkowski MA,Baldessarini
RJ. Long-term antidepressant treatment in bipolar disorder:
meta-analyses of benefits and risks.Acta Psychiatr Scand 2008;118:
Controversies in bipolar disorder: Trust evidence or
experience?
Gary E. Miller, MD Clinical professor of psychiatry, University of
Texas Health Science Center, Houston, TX Richard L. Noel, MD
Assistant clinical professor of psychiatry, University of Texas
Health Science Center, Houston, TX Vol. 8, No. 2 / February 2009
Current Psychiatry 2009 Quadrant HealthCom Inc. Manic switches A
few patients may benefit from antidepressant monotherapy , but the
predominant view in the literature is that antidepressants cause
rapid mood cycling or a switch to mania or hypomania. Manic
switches Bipolar patients who enter our practice on antidepressant
monotherapy exhibit, in approximate order of frequency, the
following 3 forms of mood instability: 3 forms of mood
instability
1-worsening of depressive symptoms, sometimes accompanied by
increased anxiety and agitation 2-rapid improvement of depressive
symptoms, followed by a depressive relapse 3-fluctuating but
incomplete antidepressant response Risk of Switch in Mood Polarity
to Hypomania or Mania in Patients With Bipolar Depression
Adjunctive treatment with antidepressants in bipolar depression was
associated with substantial risks of threshold switches to
full-duration hypomania or mania in both acute and long-term
continuation treatment. Of the three antidepressants included in
the study, venlafaxine was associated with the highest relative
risk of such switching and bupropion with the lowest risk Reprinted
with permission from American Journal of Psychiatry 2006;
163:232239) Gabriele S. Leverichet.al FOCUS THE JOURNAL OF LIFELONG
LEARNING IN PSYCHIATRY Winter 2007, Vol. V, No. 1 Do patients on
mood stabilizers require antidepressants?
Sachs et al found that although adding antidepressants to mood
stabilizers did not increase the rate of switches to mania,
antidepressants did not confer additional treatment efficacy.
Inclinical experience, however, the combination of a mood
stabilizer and an antidepressant benefits many patients. Practice
and studies Altshuler et al observed a significant depressive
relapse rate in patients on mood stabilizers whose antidepressants
had been discontinued. In the Sachs et al study, mood stabilizers
and antidepressants were initiated simultaneously, whereas
inpractice antidepressants are added to mood stabilizers only when
a mood stabilizer is ineffective in relieving depressive symptoms
or when breakthrough depression occurs Antidepressants do not have
sustained the effectiveness in patients with bipolar
depression
The study suggests that antidepressants do not have sustained the
effectiveness in patients with bipolar depression who are already
on an adequate level of a mood stabilizer. to understand this
study, it is important to understand how they measured response to
the medication. Instead of the usual approach, which typically
looks for a 50% reduction in depression scale scores as a criterion
for effectiveness, in this study they used "durable response":
patients had to have at least an 8-week period during the six-month
study in which they had neither depression nor significant manic
symptoms. April 2007 The New England JournalSachs and colleagues
New International Consensus Statement on Bipolar Depression
Marlene Busko Charles Vega, MD Medscape Medical News 09/08/2008
ECNP The statement, presented at the 21st European College of
Neuropsychopharmacology (ECNP) Congress, in Barcelona, Spain, is
based on discussions held in March 2007 including some 60 experts
in bipolar disorder. The group cautions: Switch to Mania
Switching from bipolar depression to mania or hypomania is a
particular risk that requires a different approach to treatment
from unipolar depression. Rapid cycles In the 1980s, some
researchers suggested that rapid cycling mightat least in some
instancesrepresent an iatrogenic phenomenon caused by long-term
antidepressant use. These issues remain controversial, but more
than 20 years of research suggest that antidepressants induce mania
or accelerate cycling in a smaller minority of bipolar disorder
patients than was once thought Switch A recent consensus statement
proposed a graduated series of definitions for treatment-emergent
affective switch: Definite switch involves fulfilling DSM-IV
syndromic criteria for a manic, hypomanic, or mixed episode for at
least 2 days, within 8 weeks of antidepressant introduction. Likely
switches call for at least 2 DSM-IV mania or hypomania symptoms
plus a Young Mania Rating Scale (YMRS) score >12, occurring for
at least 2 days, within 12 weeks of antidepressant introduction.
True antidepressant-induced polarity switches persist even after
the medication is discontinued No benefit of antidepressants
A meta-analysis of 15 randomized, double-blind trials comparing
short-term antidepressant treatment (up to 4 months) with either
placebo or an active comparison drug in 2373 patients with bipolar
I or II disorder likewise showed no major benefit of antidepressant
therapy Sidor MM, MacQueen GM. Antidepressants for acute treatment
of bipolar depression: a systematic review and meta-analysis. J
Clin Psychiatry 2010 October 5 Dispelling misconceptions leads to
rationale-based steps for treating bipolar depression
Joseph F. Goldberg, MD Current Psychiatry Vol. 9, No. 5 May 2010
MYTH -1 Antidepressant-induced mania is a highly prevalent,
widespread problem. Reality: Although some might argue that the
precise relative risk of antidepressant-induced mania or hypomania
is unknown. recent literature suggests that the emergence of mania
or hypomania can be reasonably attributed to antidepressant use in
no more than 10% to 25% of patients with bipolar disorder MYTH- 2
Antidepressant response rates are lower in bipolar
depression.
Reality: It is difficult to draw broad conclusions about
antidepressant response rates in unipolar vs bipolar depression
because: few direct comparisons have been reported , all relevant
studies are retrospective and small sample sizes Most
antidepressants have been systematically studied for treatment of
depression in bipolar disorder. Reality: Only paroxetine,bupropion,
and imipramine have been studied in randomized, large-scale,
adequately powered placebo-controlled trials MYTH -3 MYTH- 4 Risk
for inducing mania is higher with noradrenergic antidepressants.
Reality: This popular belief arose from a unifying hypothesis
offered by Sachs et aland Leverich et al to explain higher rates of
mania following treatment with desipramine than bupropion, SSRIs
compared with TCAs, or venlafaxine compared with bupropion or
sertralineThe risk for venlafaxine monotherapy to induce mania or
hypomania in patients with bipolar II depression has been reported
to be nonexistent MYTH -5 Coadministering an antimanic mood
stabilizer reliably prevents antidepressant-induced mania. Reality:
Most practice guidelines advise administering antimanic mood
stabilizers before initiating an antidepressant. The largest
dataset on this topicthe randomized controlled data from Systematic
Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found
that the risk for treatment-emergent manic switch with paroxetine
or bupropion was almost identical (about 10%) with or without an
FDA-approved antimanic agent MYTH -6 Antidepressants cause or
worsen rapid cycling. Reality:
Wehr et al reported that antidepressants may accelerate cycling
frequency (ie, inter-episode durations become shorter) in a small
subgroup (N=10) of patients nonrandomized study design.
Nevertheless, antidepressant use was not associated with reduced
depressive episodes over 1 year MYTH -6 cont. Antidepressants are
unlikely to improve a truly rapid-cycling illness course. In this
scenario, a more panoramic understanding of the need to treat
multiple relapses and polarity changes over time likely warrants
using multiple anti-cycling agents. Rapid cycling is treated over
the course of 1 year, rather than 1 episode Antidepressants should
never be used without a mood stabilizer for bipolar
depression.
Reality: This admonition is widely cited as a general
recommendation from modern practice guidelines; however, it mainly
pertains to depression treatment in patients with bipolar I
disorder, for whom most controlled trial data exist. The greatest
risk of using antidepressants to treat bipolar depression appears
to be lack of efficacy. A minority of patients may be at higher
risk for mood destabilization based on bipolar I subtype, mixed
episodes, recent mania, past antidepressant-induced mania, Comorbid
substance abuse, and other characteristics. MYTH -7 Bipolar
Disorder A Focus on Depression
Guidelines for the treatment of bipolar depression are currently
being revised by the American Psychiatric Association. The
guidelines of the International Society for Bipolar Disorders
recommend any of the following agents as first-line therapy for
bipolar depression: quetiapine, lamotrigine, or lithium
monotherapy; olanzapine with an SSRI (i.e., fluoxetine or another
SSRI); and lithium or divalproex with an SSRI or bupropion. These
guidelines antedate the trials showing the superiority of
quetiapine over lithium or paroxetine. Mark A. Frye, M.D. N Engl J
Med 2011; 364:51-59January 6, 2011 Treatment-resistant bipolar
depression
For treatment-resistant acute bipolar depression, the dopaminergic
agonist pramipexole and the wakefulness-promoting agent modafinil
which have been shown to have efficacy greater than placebo as
augmentation to standard treatments 1-Goldberg JF, Burdick KE,
Endick CJ. Preliminary randomized, double-blind, placebo-controlled
trial of pramipexole added to mood stabilizers for
treatment-resistant bipolar depression. Am J Psychiatry. 2004; 161:
2-Frye MA, Grunze H, Suppes T, et al. A placebo-controlled
evaluation of adjunctive modafinil in the treatment of bipolar
depression. Am J Psychiatry. 2007; 164: Treatment-resistant bipolar
depression
Other pharmacotherapies have been studied in uncontrolled
augmentation, including donepezil, bupropion, riluzole, gabapentin,
levetiracetam, and aripiprazole. Two brain-stimulating
therapiesmagnetic seizure therapy and repetitive transcranial
magnetic stimulation (TMS)have been studied as well. 1-Kayser S,
Bewernick B, Axmacher N, Schlaepfer TE. Magnetic seizure therapy of
treatment-resistant depression in a patient with bipolar disorder.
J ECT. 2009;25: DellOsso B, Mundo E, DUrso N, et al. Augmentative
repetitive navigated transcranial magnetic stimulation (rTMS) in
drug-resistant bipolar depression. Bipolar Disord. 2009;11: Sakkas
P, Mihalopoulou P, Mourtzouhou P, et al. Induction of mania by
rTMS: report of two cases. Eur Psychiatry. 2003;18: CONCLUSIONS
Antidepressants are not the first choice to treat bipolar
depression. Antidepressants may be beneficial in some patients in
short term but has poor long term effects. Close monitoring of
bipolar patients in depressive episodes is the clinical wisdom.
There is a clear difference between BPD1,BPD2,rapid cyclers,
switchers, and resistant patients. May need to be reclassified .
Bipolar depression is not one entity and needs different ways of
management accordingly. Thank you