2009 5th Annual Scientific Meeting – Development of Treatments for Bipolar Depression – Session Summary

Treatment of Bipolar Depression

A Plenary Symposium of the International Society for CNS Drug Trials Methodology (ISCTM),
Arlington, VA, 3 March 2009

Chairmen: Ross J. Baldessarini, M.D., Harvard Medical School, Boston; Eduard Vieta, M.D., Ph.D., University of Barcelona, Spain
Speakers: Drs. Baldessarini and Vieta, plus Joseph Calabrese, M.D., Chase-Western Reserve University, Cleveland; Mauricio Tohen, M.D., Dr.P.H., M.B.A., University of Texas Health Science Center at San Antonio
Primary Discussant: Charles Bowden, M.D., University of Texas Health Science Center at San Antonio

Summary

The premise of this symposium was that depression in bipolar disorder (BPD) patients is different from unipolar forms of major depressive disorder in many ways, notably including treatment responses [1]. Indeed, BP-depression remains a leading clinical and public-health challenge for psychiatry [2]. The disorder is often misdiagnosed as unipolar depression, particularly early and if only the patient is interviewed, without corroborating information from family or friends. Many BPD patients do not recognize increased mood, energy, libido, and activity as pathological, whereas most urgently seek relief from BP-depression. Average international latency to an appropriate diagnosis and the start of maintenance treatment with a mood-stabilizer is 5–10 years from illness-onset, and longer among women with type II bipolar disorder (BPD) than men with type I BPD [3]. Recurrent BP-depression commonly follows initial episodes of depression or mixed states of dysphoric agitation [4]. Even with acute episodes considered to represent pure depression, more than two-thirds of BP-depressive patients have at least subtle manic features [5]. Such mixed-states predict poor responses to standard treatments, risk of manic-switching, and perhaps rapid-cycling or recurring mood-shifts [5,6]. BP-depression and its subsyndromal or dysthymic forms remain the leading unresolved form of long-term morbidity among both types I and II BPD patients, both in mid-course of the illness and even from onset, including during treatment with commonly clinically employed mood-stabilizing or mood-elevating agents [7,8]. In BPD patients, depression and dysthymia account for approximately three-quarters of the typical 40%–45% of weeks/year in morbid states. Such unresolved depression is associated with long-term dysfunction and disability, substance abuse (particularly alcohol), and mortality due to a very high risk of suicide, accidents or other violence in youth, and moderately increased risk of dying from inter-current medical illnesses in later life [9–12]. 

Perhaps not surprisingly, antidepressants continue to be, by far, the leading drugs given to BPD patients in the US, both initially and long-term, in part owing to patient-demands and clinician optimism [13]. International practices vary greatly in use of antidepressants for BPD patients [14–16]. Ironically, there is no explicit regulatory approval for these practices, unless, implausibly, one construes all forms of major depression to be similar and responsive to similar treatments. Antidepressants perform unevenly in acute BP-depression, often fail initially or within several months, and their long-term prophylactic benefits appear to be both limited and very little-studied [17–18]. In addition, virtually all mood-elevating drugs carry dose-dependent risks of “switching” into excited, agitated, hypomanic, manic, mixed (much more broadly defined than by narrow DSM-IV criteria), or psychotic states [16,20]. This risk may be less than in the era before modern antidepressants, and appears to vary with specific drugs and doses, with highest risks associated with less-often used tricyclic-type antidepressants (TCAs), in adults diagnosed with BPD. Some modern antidepressants that potentiate both serotonin and norepinephrine, notably including venlafaxine, especially at high doses, also appear to have relatively high risks of inducing mood switching [21]. The value of co-treatment with a proved or putative mood-stabilizing agent and an antidepressant, as a means of potentiating benefits and diminishing risk of emotional destabilization also remains unclear [22]. 

Risk of switching or destabilizing mood may be lower with modern, selective serotonin reuptake-inhibitor antidepressants (SRIs) and bupropion. Whether mood-elevating agents can induce mania or excitement in otherwise non-bipolar, depressed patients as an adverse pharmacological effect also remains uncertain. Nevertheless, the presence of established BPD encourages extra caution with any mood-elevating agent, particularly in juveniles with apparent “depression ” [23]. Risk of switching into mania from depression may be greater in depressed juveniles than in adults, if only because BPD was not recognized early in depressed adolescents or children (Martin et al. 2004). This high risk seems paradoxical since antidepressants of all types have shown inferior efficacy in juvenile versus adult unipolar depression (Tsapakis et al. 2008). Curiously, risk of mood-switching with an SRI may exceed that with a TCA in juvenile depressed patients below age 14 years, suggesting important, but undefined, developmental changes [24]. Developmental changes may also be reflected in the generally poor antisuicidal effects of antidepressants in the young, with evidence that they may increase risk of self-damaging behaviors as well as suicidal thoughts in persons below age 25, but lower risk in older adults over age 60 [25,26]. 

Given the growing list of partially effective treatments for BP-depression, and its common resistance to full recovery, it is not surprising that most such patients end up with complex combinations of treatments. Such polytherapies are relatively expensive, and can exert complex risks of drug interactions and adverse effects. Indeed a worse history of BP-depression has been associated with complex treatment regimens among BPD patients, but the cause-effect relationships involved are not clear [27]. 

For depressive phases of BPDs, owing to poor short-term benefits of antidepressants, their limited long-term prophylactic value, nontrivial mood-destabilizing risk, and uncertain or variable antisuicidal efficacy, there is growing interest in considering alternative treatments [28]. Some experts recommend lithium or anticonvulsants including divalproex, carbamazepine (and its unapproved analog oxcarbazepine), or lamotrigine for both short- and long-term treatment of recurrent BP-depression, and perhaps other forms of recurrent major depression [29–37]. In addition, antimanic-antipsychotic agents, including aripiprazole, olanzapine, or quetiapine, are used increasingly to treat BP-depression, often in relatively low doses as adjuncts to other agents [38–47]. Older neuroleptics are suspected of inducing or worsening BP-depression, although evidence for this possibility remains limited and largely anecdotal [48,49]. 

Randomized, controlled trials (RCT) designed to test mood-stabilizers and antimanic-antipsychotics in the treatment of acute or recurrent BP-depression challenge trial-designs. BP-depression is a far more complex and rapidly-changing disorder than ordinary unipolar depression, and much more prone to recurrences, including when a presumably protective treatment is withdrawn rapidly, with or without obvious preceding clinical benefit [50,51]. In addition, high levels of substance-use or anxiety disorders, disability, and very high risk of suicide or accidents and later mortality from medical conditions among BPD patients add to their complexity, and should be considered in the design and conduct of trials. These characteristics call for innovative trial designs that not only score the degree and timing of improvement or recovery from an acute BP-depressive episode, but also consider risks of spontaneous or drug-associated switching into excited, mixed, manic, or psychotic states, as well as long-term protection against recurrences of all forms of BPD, including new episodes of depression, self-injurious behaviors, and consideration of complex patients who are commonly encountered clinically. 

Initiatives aimed at improving the validity of clinical trials for the treatment of BP-depression, in addition to this symposium, are emerging [52]. A recent ECNP report emphasizes challenges related to diagnostic, methodological, ethical, and regulatory issues of treatment trials for BP-depression. That report emphasizes the requirement of a longitudinal perspective and verification of prior episodes, including mania-related phases, and particularly of sometimes overlooked or misdiagnosed hypomanic or mixed states, as well as depression dysphoria. The statement also encourages trials that not only are randomized and double-blind, but also include both placebo and an active-comparator drug as controls (so-called “three-arm” trials). They also need adequate power and sensitivity to yield clear outcomes, with reasonable efforts to yield estimates of benefit/risk relationships. However, a major challenge is the choice of active comparator, since few drugs have adequate evidence of short-term efficacy or specific regulatory approval for treatment of BP-depression, even fewer for long-term prophylaxis, and almost none for type II BPD, which mainly involves recurrent depression as the primary clinical problem. Trials with placebo and active controls are well-suited for testing the efficacy of many new treatments, and specifically can limit exposure of larger numbers of BPD patients to experimental therapies in “non-inferiority” trials (new versus established treatment) that lack a placebo control. The ethics of including placebo-controls can be improved with adequate information in subject-consent procedures, as well as considering the severity and impact of BPD in particular candidate patient-subjects [53]. In addition, fixed-dose designs have been more successful in some trials than with flexible dosing (e.g. with olanzapine+fluoxetine and quetiapine, in contrast to aripiprazole). Finally, no pharmaceutical company has sought an indication for BP-depression (in either type I or II) for any drug classified as an “antidepressant,” despite widespread empirical use of these agents to treat or protect patients with BP-depression with little evidence of short- or long-term efficacy or safety [54,55]. Although, it is widely assumed that indications for “major depression” (MDD) support use of antidepressants in all types of depressive episodes, this assumption requires explicit and adequate testing for efficacy and safety in BPD-depression [56]. These and other complexities to be considered in the design of trials primarily directed at the depressive phase of BPD are summarized below (Table). 

Speakers at this ISCTM symposium considered various aspects of trials design that are not unique to BD-depression. Some standard international diagnostic schemes, such as DSM-IV, are not sensitive in distinguishing subgroups of BPD patients, other than the I/II dichotomy, very narrowly defined “rapid cycling,” and a narrow view of juvenile BPD that may be overly modeled on typical adult criteria [57]. In addition, standard rating scales may not be ideally suited for studies of BP-depressed patients, especially those with simultaneous minor mania-like features, and so-called “atypical” (for UP depression) symptoms, such as anergy, hypersomnia, or hyperphagia, which are common in BP-depression. However, among standard rating schemes for depression, the Montgomery-Åsberg scale (MADRS) may be less likely to show placebo responses than the older Hamilton scale (HDRS; [58]. The need for more sensitive measurement methods, especially those that detect subtle mixed states, hypomania, and changes in these and other symptoms are being developed [59]. 

Among other aspects of trial design, factors that limit responses in placebo-arms of trials can be important. These include selection of relatively severely ill but clinically homogeneous patient-subjects, initially hospitalized patients, enlisting the cooperation of subjects, close follow-up and assessments with sensitive rating scales, and limited use of adjunctive or “rescue” medicines, such as sedatives, and attention to apparently “nonspecific” but potentially influential effects, such as milieu influences, the impact of frequent supportive personal interactions, and the like. Generally, circumstances that favor larger contrasts from intake to end-point include relatively severe illness at baseline, relatively homogenous samples of patient-subjects without extensive anxiety or substance-use disorder co-morbidities, simplified regimens (even though use of more than one drug may seem necessary and is common in clinical practice), including fixed-doses of active trial agents, and inclusion of an active control drug as well as a placebo to assure adequate sensitivity of trial conditions to change and treatment effects. Longer trials are likely to limit placebo effects, but risk encountering relapses if continued beyond 2–3 months [43]. Nevertheless, relatively long trials are likely to be required to allow clinically relevant endpoints such as remission, rather than mere separation of drug from placebo on a symptom rating scale. Long-term trials currently often involve initial “enrichment” (short-term response in acute depression) as a precondition for continuing into a long-term phase, often, seemingly, to emphasize the virtues of a novel test agent, particularly versus placebo, but often at the expense of a standard comparator, especially if subjects initially have not been proved to tolerate and respond to it. Such trials may include treatment-discontinuation at some point when it is considered safe to do so, but with great uncertainty about the impact of drug-discontinuation itself, especially if abrupt or rapid, if patients are barely recovering, and without empirical information about optimal duration of dose-reduction protocols for most agents [50,60]. Such designs can lead to ethical questions if the ongoing treatment of initially severely ill, suicidal, or barely recovered patients is interrupted, and if the agents employed have uncertain effects and an unknown requirement for safe discontinuation rates and times [61]. 

Avoiding heterogeneous and complicated BPD patients may require more subjects to counteract variance, although narrow sampling is likely to constrain generalization to more typical, clinically encountered, BPD patients, who usually are often unstable and changeable over time, and commonly co-morbid with substance use or anxiety disorders. Very long-term trials, designed specifically to test for prophylaxis, and especially against recurrences of major BP-depression or continuation of BPD dysthymia or minor depressions, are conspicuous by their absence from the international experimental therapeutics literature. Most reported studies involve initial enrichment based on short-term responses of a specific type of acute BPD illness, followed by discontinuation of an apparently effective medicine, and relatively brief follow-up that rarely exceeds a few months [62]. Endpoints of such trials typically are time-to-a-recurrence of an illness similar to the index condition, or to clinically required therapeutic intervention. However, in BPD, illness other than major depression often intervenes, adding complexity to determining end-points based only on time-to-recurrence, rather than seeking reductions of episode-counts, sustained decreases in morbidity ratings, or improved functional status, over very long observation times. To some extent, polarities of subsequent illness episodes can be predicted from onset-polarity [4,8,63], the polarity of the most recent episode [64], or the predominant polarity of previous episodes [65]. Some limitations of currently standard trial-designs may be overcome by application of novel designs, or allowing for multiple randomizations to more than one treatment option per trial [66–68].

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