Embracing Uncertainty in Bipolar Disorder Treatment: The Balancing Act in Post‐Mania Adjunctive Antipsychotic Therapy

The long-term treatment of bipolar disorder often forces clinicians, particularly trainees, to embrace uncertainty and utilize limited knowledge in clinical decisions. As trainees ourselves, we have frequently encountered ambiguity surrounding the maintenance treatment of bipolar disorder following acute manic episodes. In the hospital setting, conventional medication regimens are frequently employed, often a combination of traditional mood-stabilizing medications such as lithium or divalproex, alongside adjunctive antipsychotic therapies like olanzapine or risperidone. We have witnessed firsthand the tangible outcomes these interventions promise, including rapid symptom relief and the generally favorable tolerability profile, which pave the way for outpatient care. However, amidst these improvements, one daunting question continues to confront us: when and how should adjunctive antipsychotic treatment be discontinued after patients discharge from the hospital? As we have shifted our training focus from hospitals to ambulatory care, we now grapple with this crucial question that once occupied our thoughts during hospital rotations. Inspired by the existing literature on acute mania treatment, we embarked on a comprehensive literature search to find answers to this clinical query. The results of our search were unsurprising—we did not discover clarity, and instead found information that can inform complicated medical decisions. Through this process, we also learned to tolerate uncertainty and how to model that tolerance for patients while offering hope despite clinical ambiguity. We initially thought we would find a definitive answer regarding the maintenance treatment of bipolar disorder, and thus embarked upon a scoping review to explore the recommended duration of adjunctive antipsychotic treatment following remission of an acute manic episode. Our comprehensive scoping review combed through an array of English-language clinical studies, treatment guidelines, and observational research pertaining to the discontinuation of adjunctive antipsychotics in outpatient bipolar disorder during the maintenance period. We searched the literature from 1945 to January 2023, entering the search terms “bipolar disorder,” “mania,” “psychosis,” “antipsychotic,” “maintenance,” “duration,” and “continuation” into EMBASE, PUBMED, the COCHRANE LIBRARY, and APA PsychINFO. Studies on children and adolescents were excluded due to the variance of treatment guidelines for acute mania, often requiring different management plans for bipolar disorder between the two populations. The search returned 9155 papers, which were narrowed down to 15 full-text papers and 8 treatment guidelines. K.S. screened papers by title and abstract, assisted by (A.C.) to review full-text articles, focusing only on studies related to discontinuing antipsychotics in outpatient bipolar disorder management post-acute manic episodes. Unlike the treatment of acute mania, which offers more consistent and clear guidance around pharmacologic interventions, we found fewer reports investigating the role of adjunctive antipsychotics for long-term maintenance treatment of bipolar disorder. Moreover, we found ourselves challenged by how to best phrase our clinical research question—were we looking at when to discontinue an acute phase treatment or when to “de-intensify” a maintenance treatment? We wondered if our own uncertainty in how to frame the question was related to the relatively few studies directly addressing this question. The scarcity of evidence addressing this issue became apparent as we navigated through a sea of diverse opinions and conflicting views. Among the few reports that addressed our question, Yatham et al. [1] demonstrated that while continuing adjunctive risperidone or olanzapine following resolution of an acute manic episode for 24 weeks was beneficial, outcomes were the same in those who discontinued at 24 and 48 weeks, raising the question of whether adjunctive antipsychotic treatment beyond 6 months conferred any additional benefit in reducing relapse risk. In a separate research study conducted by Brioschi et al. [2] in the year 2020, their findings indicated that discontinuing adjunctive antipsychotic therapy (specifically, haloperidol and risperidone) within a relatively short time frame of 4–8 weeks did not lead to a deterioration in bipolar disorder symptoms during the early phases of remission, which spanned the first 6 months following the resolution of an acute episode. This conclusion was based on an assessment using the Young Mania Rating Scale score. Of note, these two studies included patients receiving treatment with haloperidol, risperidone, and olanzapine; thus, the information may not generalize to patients treated with other antipsychotic medications. In addition to reviewing clinical trials, we also reviewed existing treatment guidelines published after 2012. The guidelines highlighted some variation among proposed maintenance treatments. For instance, the International College of Neuropsychopharmacology guidelines recommended that acute treatment be continued for a minimum of 2 months following remission of an acute manic episode (which may include antipsychotic mono- or adjunctive therapy) but noted the absence of data concerning the duration of maintenance treatment [3]. The British Association for Psychopharmacology guidelines suggested reducing and/or discontinuing the acute treatment after full remission of symptoms (which may take about 3–6 months) in favor of pursuing monotherapy with a mood stabilizer like lithium [4]. The Canadian Network for Mood and Anxiety Treatments guidelines highlighted that continuing adjunctive atypical antipsychotics for the first 6 months of treatment appears to offer a clear benefit in reducing recurrence of a mood episode, but the benefits beyond 6 months are uncertain; thus, providers are encouraged to evaluate the risks and benefits of continuing combination treatment with an atypical antipsychotic after 6 months of sustained response [5]. As physicians, we are responsible for promoting our patients' well-being, carefully weighing the risks and benefits of every medical decision. In bipolar disorder care, maintaining the balance between risks and benefits is paramount. Antipsychotic medications clearly have proven efficacy in the treatment of individuals with acute mania. However, the potential adverse effects of antipsychotic medications, such as sedation, metabolic disturbances, and movement disorders, accumulate over time, demanding our vigilant attention and careful consideration, especially if the degree of benefit changes over time. Simultaneously, prematurely discontinuing adjunctive antipsychotics can increase the risk of relapse, jeopardizing patients' overall clinical status and functioning. Our training has instilled in us a deep appreciation for evidence-based guidelines, but we have come to understand that navigating the intricate terrain of psychiatry often means embracing the unease that accompanies the uncertainties and complexity of clinical decision-making. What we initially perceived as uncertainty attributable to our level of training has, in fact, been unveiled as a broader and more profound uncertainty within the field. Our commitment to promoting the well-being of our patients persists, and we acknowledge the critical role of rigorous research in moving towards clarity amidst uncertainty. We advocate for ongoing investigations to explore the timing of adjunctive antipsychotic discontinuation following remission of an acute manic episode, long-term outcomes, and patient preferences. Such investigations will continue to inform practice guidelines, equipping clinicians with tools to make informed choices regarding adjunctive antipsychotic therapy following remission of an acute manic episode. We acknowledge Dr. Joseph Cerimele for guiding our idea development and manuscript drafting. We sincerely appreciate his invaluable contributions to our work. The authors declare no conflicts of interest. The authors have nothing to report.

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