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INTRODUCTION
Back in the year 2000, Akiskal et al. reported that there is converging evidence for the prevalence of bipolarity in the general population to actually be to the tune of 5% rather than the long held 1% mark.1 In a recent World Health Organization (WHO) cross-sectional, household, face-to-face survey of more than 60000 community residing adults in 11 countries across Americas, Europe and Asia, the lifetime and 12-month prevalence of bipolar disorder (BD) was 4.8% and 3% respectively.2 As pointed out however, the largest increase in prevalence rates is accounted for by ‘softer’ clinical expressions of bipolarity rather than DSM-IV-TR bipolar I or II disorder.
Though mania/hypomania may be the defining feature of the illness, a good body of research supports the fact that depression predominates the overall picture in all BD patients,3 occupying about 67% of the total illness period in bipolar I disorder and about 93% in bipolar II disorder.4,5 In a naturalistic treatment setting, 258 outpatients with BD followed prospectively for one year showed three times as many days depressed as days manic despite intensive treatment.6 Furthermore, depressive episodes and symptoms are psychosocially more disabling and more difficult to treat than corresponding levels of manic or hypomanic symptoms,7,8 hence entail a greater socio-economic burden than either mania or even unipolar depression.10 This reiterates the fact that depression is the more enduring aspect of bipolarity and that substantial depressive morbidity in BD remains despite aggressive treatment strategies employed.10
Given this understanding and consensus that bipolar depression treatment poses a significant challenge to the treating psychiatrist, it is strange that treatment guidelines for bipolar depression are ambiguous and less well defined than other major psychiatric illnesses including mania, unipolar depression or schizophrenia. The majority of treatment recommendations are still based on limited data and leave considerable areas of uncertainty.11 Especially, the use of antidepressants (ADs) as monotherapy or in combination with mood stabilizers (MSs) is fraught with controversies and contentions, as there is dearth of research evidence to support their use; this despite the fact that they remain the most commonly prescribed class of psychotropic agents in BD,12,13 being prescribed to 50% of the patients and twice as often as MSs.13 This article is an effort to critically evaluate the literature regarding the risks and benefits of the use of ADs in bipolar depression. For the purpose of this writing, the use of the term ‘antidepressant’ does not include olanzapine-fluoxetine combination.
Current approved treatments for bipolar depression
Compounded by the fact that there are insufficient and indistinct guidelines for bipolar depression management, there is also a lack of licensed treatments for the same. The US-FDA (United States Food and Drug Administration) has approved only four agents, namely quetiapine (immediate or extended release), olanzapine-fluoxetine combination, and lurasidone (monotherapy or adjunctive to lithium or valproate) for the acute phase of bipolar depression, and lamotrigine for maintenance and preventive treatment.14 Most prescribing is therefore off-label.15 Inspite of there being few high-quality studies of use of lithium in acute or long term bipolar depression treatment, it remains a mainstay of clinical management and a first-line treatment recommended by many international guidelines.8,11,14 Lithium is effective in reducing suicidality, but 30% of lithium-treated patients experience breakthrough depression within 2 years.16 Lamotrigine has been advocated and approved for maintenance treatment of bipolar depression,17,18 but may not work for containing acute depression.19 Olanzapine-fluoxetine combination,20 as well as quetiapine21,22 are effective short-term in acute bipolar depression and quetiapine appears to be helpful long-term as well.22
Given the role of the above molecules in bipolar depression, what is the place of ADs? Clearly, the available research findings related to effects of AD treatment in BD do not necessarily reflect current experience and are far from adequate to guide rational therapeutics. The next two sections of this review try to ponder upon the efficacy and safety of ADs in the management of the depressed phase of BD.
Efficacy of antidepressants in bipolar depression
A systematic review of 18 randomized controlled trials (RCTs) assessing the use of ADs in acute bipolar depression (N = 4105) concluded that combination therapy with ADs failed to statistically outperform MS monotherapy.23 Another meta-analysis of 15 RCTs (N = 2373) found that ADs were not statistically superior to placebo or other current standard treatment for acute bipolar depression.24 In contrast though, Gijsman et al. in their review of 12 RCTs (N = 1088), found ADs to be effective at least in the short term treatment of bipolar depression.25 All the three reviews however, established the safety of AD use in acute bipolar depression, insofar as their potential to cause an affective switch is concerned.23-25
There are not many research reviews evaluating the effectiveness of long-term AD treatment in bipolar depression as monotherapy. Research concerning the long-term effects of ADs in BD patients is severely limited to few controlled trials, small patient samples and mainly older drugs. Nonetheless, in a meta-analytic review of seven RCTs (N = 350), long-term (>or=6 months) AD treatment adjunctive to MS was not shown to be superior to MS monotherapy, not yielding major protection from depression, but not substantially increasing the risk of mania either.26 In a retrospective study of patients with BD treated for an index episode of depression by adding AD to ongoing MS, discontinuation of AD significantly increased the risk of a depressive relapse while continuation was not significantly associated with an increased risk of mania.27 On the other hand, in a first of its kind RCT as a part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 70 patients with BD with acute major depression, initially responding to treatment with ADs plus MSs, and euthymic for 2 months, were openly randomly assigned to AD continuation versus discontinuation for 1-3 years.28 MS medications were continued in both groups. Results of this study showed no statistically significant symptomatic benefit with AD in the long-term treatment of BD, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued AD. Ghaemi et al. further argue that ADs do not reduce the risk of suicide, as against lithium; their efficacy is comparable to MSs in acute depression, while even less in preventing a depressive relapse,29 hence their use is highly questionable, and at best, avoided. Usefulness of maintaining AD treatment is suggested within the subpopulation of patients who require both an MS and an AD to achieve complete remission from depressive episodes.30
In effect, literature on the usefulness of ADs for acute and prophylactic management of bipolar depression is too scant and too unobvious to approve or refute such a therapy.31 ADs, in view of their uncertain efficacy, may now be considered as third-line choices following quetiapine, lithium, lamotrigine, and valproate, and at best, as an adjunct.32 Most treatment guidelines, consensus meetings and treatment algorithms on the acute treatment of bipolar depression updated or published since 2005 by scientific societies or international groups discourage AD monotherapy, although some support their use in combination with antimanic agents for a limited period of time.33 Existing literature and treatment guidelines, though more against use of ADs in bipolar depression, practicing psychiatrists seem to frequently use AD in routine clinical practice.12,13,34 Not strangely then, Paterniti and Bisserbe in their survey found that only 68% of the patients on pharmacotherapy for BD received treatment concordant with guidelines and the inappropriate use of ADs was at the origin of the non-concordance of treatment with respect to guidelines.34 But as correctly pointed out by Thase et al., there are holes in contemporary evidenced-based practice guidelines large enough to drive a truck through,35 hence apparently this profuse clinical use of ADs in bipolar depression despite non-recommendation by various guidelines.
Safety of antidepressants in bipolar depression: special focus on polarity switch
Use of ADs in bipolar depression has mainly been criticized on the ground that they may cause mood destabilization switching into mania or hypomania36-38 or increase the cycle frequency.39,40 Such risk however, is not very clearly associated with specific or defined illness or treatment related factors. What also remains unclear is the prevalence of such a switch. Alshutler et al. examined the longitudinal course of 51 patients with treatment-refractory BD to assess possible effects of heterocyclic ADs on occurrence of manic episodes and cycle acceleration.41 They found that 35% of the patients had a manic episode rated as likely to have been AD-induced, though no variable was a predictor of this vulnerability. Cycle acceleration was likely to be associated with AD treatment in 26% of the patients assessed. Leverich et al. in their study of 159 patients with bipolar I or bipolar II depression, reported that threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials (10 weeks) and in 21.8% and 14.9%, respectively, of the continuation trials (up to 1 year) of venlafaxine, sertraline, and bupropion as adjuncts to MSs.42 The wide variation and discrepancy in the switch rate reported in different studies may partly be attributed to the agreement or disagreement on what constitutes a switch, especially the nosological validity of subthreshold categories being debatable.14 Some authors have used the Young Mania Rating Scale (YMRS) to quantify affective change, but the score required to qualify as switching differs between studies, and indeed some research reports do not clearly delineate how such change was defined.14 Citing an example, Post et al. in their comparative study of polarity switch in bipolar depressed patients treated with venlafaxine, sertraline or bupropion found an overall switch rate of 9% by the more stringent criteria of YMRS score > 13, whereas more than double that (21%) switched using the Clinical Global Impression scale for Bipolar Disorder (CGI–BP) severity score (>or=3) of at least mild mania.43
Table 1: Potential risk factors for antidepressant induced manic/hypomanic switch
| Illness related factors
Bipolar I disorder (as compared to bipolar II)31,42,44,45 Presence of rapid cycling28,31,46 Presence of mixed states/baseline subthreshold manic symptoms31,47-49 Presence of hyperthymic temperament50 Family history of bipolar disorder31,51 Substance abuse or dependence52 |
| Treatment related factors
Use of tricyclic antidepressants31,53,54 Use of venlafaxine as against selective serotonin reuptake inhibitors/bupropion31,43 Lack of concomitant mood stabilizers54 Previous antidepressant induced manias51 Multiple antidepressant trials51,52 |
Though not evidently replicated by research, table 1 lists the plausible risk factors found in patients with treatment emergent polarity switch, while taking ADs. Presence of any of these putative risk factors in their patients may alert clinicians to reconsider their decision of prescribing ADs in such patients. Certain ADs are known to cause a switch more often than others (tricyclic ADs (TCAs) > venlafaxine > selective serotonin reuptake inhibitors (SSRIs) > bupropion) and their use may thus be avoided while managing bipolar depression. The noradrenergic effects of TCAs and venlafaxine, as also the anticholinergic effects of TCAs have been implicated in causing a higher rate of switch as compared to SSRIs.43
In a systematic review of six studies, the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism has been identified as a genetic risk factor for AD induced mania, with there being a higher frequency of s allele carriers (sl and ss genotypes) in those who switched while on AD treatment.55 However, another recent meta-analysis concluded that there is insufficient published data to confirm this association between 5HTTLPR and AD induced mania.56 To draw definitive conclusions, future pharmacogenomic studies need to be adequately powered and consider potential phenotypic confounders like rapid cycling and concurrent MS use.56
Therefore, even if scientific evidence is inconclusive, clinical wisdom hails that MSs should be implemented in addition to AD, as they may lower the switch rate, if not eliminate it altogether.57 Recent meta-analyses have not found ADs to increase the propensity of an affective switch while treating bipolar depression for both acute and long term management, especially when prescribed as an adjunct to ongoing MS.23-25,52 Another word of caution remains that ADs may significantly increase the risk of suicidal ideation in patients with BD.58 Consequently, clinicians should specifically monitor emergence or worsening of suicidality in all BD patients taking ADs to manage depressive symptoms.
Conclusion
Given the weak evidence base, the use of antidepressants in bipolar depression is like walking a tightrope, although they reportedly remain the most commonly prescribed class of drugs for the condition in real time clinical practice. It is needless to emphasize that clinicians need to exercise the utmost caution while they use antidepressants in bipolar depression, both for acute management as well as for prophylaxis. The apprehended risk of mood destabilization and/or cycle acceleration remains, at least in a subpopulation of patients; the risk being predicted by less defined risk factors. Most current treatment guidelines recommend discontinuation of antidepressants within 3 to 6 months after remission of acute depression, though such recommendations are essentially based upon expert opinion rather than hard facts. Consequently, the ball is in the treating psychiatrist’s court whether to use or not use antidepressants in bipolar depression based upon his/her own clinical judgment and past experience, and the decision may also be affected by individual patient profile. While mood stabilizers, especially lithium and lamotrigine remain the mainstay of treatment in bipolar depression, quetiapine and olanzapine-fluoxetine combination are viable and approved treatment alternatives. The definitive role, optimal use and exact place of antidepressant monotherapy or in combination with mood stabilizing agents or atypical antipsychotics in bipolar depression management deserve more intensive investigation. Future research should also focus upon direct comparisons of SSRIs and bupropion with the current approved treatments like lamotrigine and quetiapine for effectiveness, tolerability and switch risk in acute and maintenance treatment of bipolar depression. Based on current literature, it may be prudent to infer that use of antidepressants without mood stabilizer protection in bipolar depression should generally be avoided, as depressive relapse may diminish but manic/hypomanic relapse risk may substantially increase.
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