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Bipolar Depression Research Review

Sanjay Gupta, MD
Roger McIntyre, MD, FRCPC
Released: October 28, 2021

Effects of Cariprazine on Cognition in Patients With Bipolar Mania or the Mixed States: Post Hoc Analysis From 3 Randomized, Controlled Phase III Studies

McIntyre RS, et al. CNS Spectr. 2021;26:182.

Cariprazine, a dopamine D3-preferring D3/D2, and 5-HT1A receptor partial agonist, is approved for the treatment of schizophrenia and depressive, manic, or mixed episodes associated with bipolar I disorder. This post hoc analysis evaluated the effects of cariprazine on cognitive symptoms in patients with acute manic or mixed bipolar episodes.

Data from 3 randomized, double-blind, placebo-controlled phase II/III studies in patients with manic or mixed episodes associated with bipolar I disorder were pooled and analyzed. Patients were randomized to placebo or flexibly dosed cariprazine (3-12 mg/day, 3-6 mg/day, or 6-12 mg/day [one study only]) for 3 weeks of double-blind treatment; all dose groups were combined for the pooled analysis. Cognitive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) Cognitive subscale (sum of PANSS items P2, N5, N7, G10, G11); a score ≥15 at baseline indicated the presence of cognitive symptoms. Mean changes from baseline to Week 3 in PANSS cognitive subscale/item scores and YMRS total score were evaluated in the overall intent-to-treat population and in the subgroup of patients with baseline cognitive symptoms. A mixed-effects model for repeated measures was used to impute missing values.

Among the 1012 patients in the intent-to-treat population, 174 (103 receiving cariprazine, 71 receiving placebo) had a PANSS Cognitive subscale score ≥15 at baseline. At Week 3, the cariprazine group demonstrated a statistically significantly greater mean improvement than the placebo group on PANSS cognitive subscale scores in both the intent-to-treat population and the subgroup with baseline cognitive symptoms. In patients with baseline cognitive symptoms, improvement was statistically significantly greater for cariprazine- vs placebo-treated patients on YMRS total score and the individual PANSS cognitive subscale items of conceptual disorganization, difficulty in abstract thinking, stereotyped thinking, and poor attention.

In patients with manic or mixed episodes associated with bipolar I disorder, cariprazine vs placebo was effective in improving cognitive symptoms in the overall patient population as well as in patients with baseline cognitive symptoms. In addition, cariprazine vs placebo also demonstrated efficacy in improving manic symptoms in patients with baseline cognitive symptoms.

Clinical Commentary by Roger McIntyre MD, FRCPC
Cognitive deficits in adults with bipolar disorder are prevalent, pervasive, and often persistent between episodes. The effect of cognitive deficits in bipolar disorder is clinically significant, and in some individuals, cognitive deficits may be progressive. Currently, no treatment is approved by the FDA for cognitive deficits in adults with bipolar disorder, underscoring the unmet need.

Cariprazine, especially at lower dosing, is a D3-preferring D3/D2 (and 5-HT1A) receptor, partial agonist, with FDA approvals for the treatment of mania, mixed, and depressive episodes as part of bipolar I disorder.

This study post hoc analyzed data from 3 randomized, double-blinded, placebo-controlled phase II/III studies in patients with mania or mixed episodes associated with bipolar I disorder. Cognitive symptoms were assessed using the PANSS cognitive subscale with a score ≥15 at baseline defining the presence of cognitive symptoms. After 3 weeks of treatment, statistically significantly greater mean improvement in the cariprazine group compared with the placebo group was noted in the intent-to-treat group and the subgroup with baseline cognitive symptoms. The benefit in the cariprazine group was also noted on select cognitive items (ie, conceptual disorganization, abstract thinking difficulties, stereotype thinking, and poor concentration).

A limitation is the study’s post hoc methodology and the dosing of cariprazine evaluated 3-12 mg/day. It would be interesting to evaluate effect of cariprazine on cognition at lower doses (eg, 1.5 mg) wherein it is known to be more D3 selective.

Clinical Insights
These data provide evidence that cariprazine does not worsen cognition. This is important clinically as cognitive impairment due to psychotropic drugs in bipolar disorder is amply documented. Moreover, data suggest that cariprazine may benefit cognitive symptoms in persons experiencing a manic or mixed episode.

Theoretically, targeting D3 would be expected to improve cognitive (and hedonic) measures as D3 is situated within cognitive and reward circuits. Moreover, research conducted in animals and separate lines of evidence in adults with schizophrenia provides additional support for the procognitive effects of cariprazine. This research supports speculation that the benefit of cariprazine in cognition may contribute to its ability to improve psychosocial functioning in bipolar disorder as well as its broad-spectrum efficacy across mania, mixed, and depressive symptoms.

Future studies will need to assess whether cariprazine is capable of procognitive effects in adults with bipolar disorder, and a dedicated study evaluating cariprazine on cognitive outcomes in remitted bipolar patients would be illuminating.

Taken together, the procognitive effect of cariprazine with modulating effects on hedonic tone aligns with priority unmet needs in bipolar disorder.

These post hoc data suggest that in addition to improving manic, mixed, and depressive symptoms, cariprazine may improve cognitive symptoms in adults with mood disorders. More rigorous studies will be needed before definitive statements can be made around cognition, but certainly, the unmet need of cognition in bipolar disorder would justify such a study.

Clinical Commentary by Sanjay Gupta, MD
Dr. McIntyre has done an excellent job of reviewing study design and receptor mechanisms, and hence, my commentary will have clinical emphasis. There has been significant importance placed on symptom recovery in bipolar disorder treatment, but not much emphasis is placed on cognitive recovery. It is important to note that, ultimately, cognitive recovery will help patients lead lives as close to normal as can be. In mental health, we have begun to assess symptoms more objectively using rating scales like Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorder Questionnaire-7 for anxiety, and Mood Disorder Questionnaire), but we are not assessing cognition at all. This study is a welcome first step in the direction of focus on cognition and highlights the need for a prospective study in the future. We have entered the era of measurement-based treatments in psychiatry, and cognition should also be assessed. Screening tools in the form of emerging digital applications, questionnaires, and memory tasks designed to measure cognition can be used to determine whether cognitive functioning is impaired and how treatment affects cognition.

Clinical Insights

  • Many agents used to treat bipolar disorder, such as divalproex, lamotrigine, and lithium, may blunt cognition (cognitive dulling) particularly resulting in attentional problems. The patient with no prior history comes back, saying, “I need something for attention-deficit/hyperactivity disorder” and often gets prescribed stimulants.
  • The very fact that cariprazine does not interfere with cognition is a huge plus. The precognitive effects (possibly via D3 modulation) are just a bonus in treating lifelong illnesses. These effects are noted at dosages of 3-12 mg/day.
  • Cognitive deficits are well established in schizophrenia across multiple domains accompanying general intellectual impairment. Antipsychotic therapies worsen cognition. Therefore, having an agent that does not worsen cognition is a remarkable step ahead.
  • The procognitive effects of cariprazine at the 3-mg/day dose especially in outcomes assessing sustained attention are important clinically. These factors play an important role in functional reintegration into society after bipolar disorder is treated.

From a clinical perspective, the primary goal of treatment is remission. However, it is equally important to take cognition into consideration as it affects functional recovery and reintegration of patients into daily lives. A medication such as cariprazine, which not only does not worsen cognition but has been shown to have precognitive effects, should be considered when medication choices are made for the treatment of bipolar disorder. In addition, cariprazine also has an excellent metabolic profile. We need to monitor and treat the akathisia, which can occur with cariprazine.

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