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;64:543-552

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;160:1252-1262

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 161:1537-1547, 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 www.nice.org.uk 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;163:232-239.

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; 356:1711-1722March 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 Med 2007;356:1711-1722

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 or divalproex + 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 disorder 2009 her

Recommendations for pharmacological treatment of acute bipolar II depression First line: Quetiapine Second line:Lithium, lamotrigine, divalproexa, lithium or divalproex + antidepressants, lithium + divalproex, atypical antipsychotics + antidepressants Third line: Antidepressant monotherapy (particularly for those with infrequent hypomanias), switch to alternate antidepressant, ziprasidone CANMAT guidelines for bipolar disorder 2009

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 line Adjunctive 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;165:370-377

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;118:347-356

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; 163:232–239) Gabriele S. Leverich et.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. In clinical 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 in practice 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 Journal Sachs 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 might—at least in some instances—represent 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 al and 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 sertraline The 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 topic—the 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; 161:564-566. 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; 164:1242-1249.

Treatment-resistant bipolar depression Other pharmacotherapies have been studied in uncontrolled augmentation, including donepezil, bupropion, riluzole, gabapentin, levetiracetam, and aripiprazole. Two brain-stimulating therapies—magnetic 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;25:137-140. 2. Dell’Osso B, Mundo E, D’Urso N, et al. Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord. 2009;11:76-81. 3-. Sakkas P, Mihalopoulou P, Mourtzouhou P, et al. Induction of mania by rTMS: report of two cases. Eur Psychiatry. 2003;18:196-198.

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.

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