Should we combine antipsychotics in patients with bipolar disorder?

Over the past years, antipsychotics have gained prominence in bipolar disorder treatment studies due to their observed effectiveness and established safety. Most first-line drugs for bipolar disorder are antipsychotics, both for acute episodes and maintenance treatment.1 Combined therapy is already indicated in the main guidelines, showing superiority over monotherapy in many cases.1 The available evidence points to combination of antipsychotics and mood stabilizers as first or second-line treatment in bipolar disorder. In acute mania, the first-line combined treatments involve an antipsychotic (quetiapine, aripiprazole, risperidone, or asenapine) associated with lithium or divalproex.1 In cases of depression, the scenario also points to the effective use of mood stabilizers (lurasidone plus lithium or divalproex, or lamotrigine as adjunctive treatment).1 However, when there is low tolerability to mood stabilizers or therapeutic failure, other combinations should be considered. Despite belonging to the same class, antipsychotics are very heterogeneous in their mechanisms of action, which has led some clinicians to prescribe them in combination. For instance, it is known that a representative portion of bipolar disorder patients are treated with persistent antipsychotic polypharmacy in outpatient settings. However, there is still insufficient data to fully support the combination of antipsychotics, and the most important guidelines in the field do not support this approach.1 Therefore, the aim of the present debate is to evaluate clinical scenarios where this combination has been used and review the evidence available on the topic. We will also present some recommendations to the field. The first scenario where the treatment with multiple antipsychotics is observed is when the medications are intended to address different clinical symptoms. A good example is quetiapine, which, in low doses, presents a sedative effect, while in intermediate doses can be employed for mood episodes without associated psychotic symptoms. To achieve an antipsychotic effect, quetiapine usually needs to be administered at doses exceeding 400 mg/day. The FDA approved dose of quetiapine for acute mania is 400–800 mg per day as monotherapy, but such high doses might not be well tolerated by some patients. Given that quetiapine is a first-line treatment for both manic and depression episodes,1 it is reasonable to consider adding a second antipsychotic if the patient also experiences psychotic symptoms. In addition, according to a recent meta-analysis, quetiapine is an effective treatment for sleep problems even in low doses (for instance, 50 mg/day), and was shown to significantly improve sleep quality and increase total sleep time in comparison with placebo.2 Therefore, it is relatively common to use low-dose quetiapine to treat insomnia, even in the presence of a second antipsychotic medication. Another situation to contemplate augmentation with a second antipsychotic is in patients with refractory symptoms. In such instances, introducing a second medication could enhance the desired effects and improve treatment tolerability. A common scenario involves the use of two antipsychotics to manage cases of refractory mania. In this regard, some clinicians enhance the treatment with a second antipsychotic such as haloperidol or risperidone, high-affinity D2 receptor antagonists. However, this practice should not be routine, as there is limited empirical evidence supporting it, and studies evaluating antipsychotic augmentation primarily involve patients with schizophrenia.3 A Finnish national cohort study involving over 62,000 patients with schizophrenia indicated that antipsychotic polypharmacy was associated with approximately 10% lower relative risk of psychiatric rehospitalization compared to antipsychotic monotherapy. However, the only specific oral combination therapy demonstrating superior outcomes over its individual components was the augmentation of clozapine with aripiprazole.3 Nevertheless, clozapine is not part of the first or second-line therapeutic options for bipolar disorder, limiting the applicability of these findings to this context.1 Another important point to consider is the use of a second antipsychotic for the treatment of side effects caused by a first antipsychotic. This case can be illustrated with a placebo-controlled trial, which investigated the use of adjunctive aripiprazole to treat risperidone-induced hyperprolactinemia (a significant adverse effect associated with the use of several antipsychotic drugs) in patients with schizophrenia.4 According to the results of the study, patients using adjunctive aripiprazole at 5, 10, and 20 mg/day, presented significantly lower prolactin levels in comparison with placebo, with effects being significantly higher at 10 and 20 mg/day doses in comparison with 5 mg/day.4 Antipsychotics are frequently combined when their pharmacodynamics differ, and there is a rationale for combining them to target different pathways. Diverse receptor profiles may lead to favorable effects. For example, a meta-analysis reported that adding the partial dopamine D2 receptor agonist aripiprazole to clozapine therapy improved negative symptoms and mitigated several adverse effects, including weight gain and increased prolactin levels.5 Conversely, combining two dopamine D2 antagonists resulted in higher prolactin elevation but reduced insomnia.5 A combination of antipsychotics could be considered in cases of non-adherent patients who benefit from the use of depot medication. In such cases, the depot antipsychotic could serve as a maintenance medication in case the oral drug is discontinued by the patient. Potential harms associated with antipsychotic combination treatment should also be considered. Adverse effects, including heightened prevalence and severity of extrapyramidal symptoms, increased metabolic disturbances such as diabetes, sexual dysfunction, prolonged QTc intervals, and arrhythmias, have been linked to the combination of antipsychotics. Most antipsychotics are also associated with an increased risk of cardiovascular events in the long term. Nonetheless, it is important to consider that these effects may be influenced by the prescription of higher doses in such treatment regimens. It is also important to highlight that these combinations must always respect the appropriate clinical indications for the isolated use of antipsychotics. Each drug used in bipolar disorder has its own level of evidence regarding polarity of the disease, acute or maintenance phase, effectiveness in refractory or recurrent cases, in addition to specific evidence for comorbid symptoms, such as anxiety.1 Therefore, the prescription of antipsychotics must take these indications into account even when in combination therapy. In conclusion, we have a few recommendations to the field: (1) while there are numerous potential combinations of antipsychotic medications, there is limited information available regarding their comparative risk–benefit profiles concerning overall therapeutic outcomes or specific symptom clusters; (2) considering this, the combined use of antipsychotics should be restricted and limited to specific situations such as those mentioned above; (3) future studies should consider the use of these combinations in clinical trials with designs that address the clinical situations outlined above (as shown in Table 1); (4) nevertheless, it is important to consider that a relevant criticism of randomized clinical trials is the use of restrictive and very specific inclusion and exclusion criteria, without taking into account complex patients (with relevant clinical and psychiatric comorbidity) that are commonly encountered in real world scenarios. Asenapine, aripiprazole, paliperidone, risperidone, ziprazidone, haloperidol: only for mania Lurasidone: only for depression Cariprazine, olanzapine: for both mania and depression Asenapine, aripiprazole, paliperidone, risperidone, ziprazidone, haloperidol: only for mania Lurasidone: only for depression Cariprazine, olanzapine: for both mania and depression This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. This work received financial supports from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasil. ICP is a CNPq research fellow. Ives Cavalcante Passos receives authorship royalties from Springer Nature and ArtMed. ICP has served as consultant, advisor, or CME speaker for the following entities: Janssen, LundBeck, Libbs, Daiichi Sankyo, EMS and Pfizer. The remaining authors do not have competing interests to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.