Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials

Bipolar disorder (BD) is chronic psychiatric disorder associated with significant impairment in psychosocial functioning and quality of life. Although current pharmacological treatments for BD have improved its clinical management, many patients do not achieve remission, particularly those suffering from bipolar depression. In addition, available treatments are associated with a myriad of potential adverse effects, which highlights the need for novel therapeutic agents that can be effective for both phases of the illness with a reduced side effect burden. Cariprazine is a novel antipsychotic that is a dopamine D2/D3 partial agonist with a preference for D3 receptors. In this review, we examine the pharmacological properties, clinical efficacy and tolerability profile of cariprazine in patients with BD, taking into account the latest clinical trials data. We also review post hoc analyses addressing clinically relevant subgroups and symptom domains in BD. Current evidence suggests efficacy for cariprazine 3–12 mg/day in the treatment of acute manic and mixed episodes; for bipolar depression, the efficacy of cariprazine appears to be dose-related, with doses of 1.5–3 mg/day beneficial as monotherapy. Cariprazine is overall well-tolerated by patients in both manic and depressive episodes. Its most common side effects relative to placebo include akathisia, extrapyramidal symptoms and nausea. There are no metabolic concerns reported with cariprazine use. In summary, the latest evidence suggests that cariprazine is an effective and safe treatment option for BD.

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145 Incidence and Characteristics of Akathisia and Restlessness During Cariprazine Treatment for Bipolar I Disorder

CNS Spectrums ◽

10.1017/s1092852920000619 ◽

2020 ◽

Vol 25 (2) ◽

pp. 292-292

Author(s):

Leslie Citrome ◽

Lakshmi N. Yatham ◽

Mehul Patel ◽

Willie R. Earley

Keyword(s):

Adverse Events ◽

Bipolar Depression ◽

Partial Agonist ◽

Fixed Dose ◽

Double Blind ◽

Study Objective ◽

Bipolar I Disorder ◽

Bipolar Mania ◽

Post Hoc ◽

Depressive Episodes

Abstract:Study Objective:Akathisia and restlessness are common adverse events associated with atypical antipsychotic use; in severe cases, symptoms may lead to treatment discontinuation. Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is approved for the treatment of schizophrenia (1.5–6 mg/d), and manic or mixed (3–6 mg/d) and depressive episodes (1.5–3 mg/d) associated with bipolar I disorder. Pooled post hoc analyses were conducted to characterize the incidence and severity of cariprazine-related akathisia and restlessness in patients who participated in bipolar disorder studies.Method:All studies were Phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in patients with bipolar I disorder who were currently experiencing a manic/mixed (NCT00488618, NCT01058096, NCT01058668) or depressive (NCT01396447, NCT02670538, NCT02670551) mood episode. Patients received flexibly dosed cariprazine 3-12 mg/d (day 1: 1.5 mg; day 2: 3 mg; subsequent up-titration in 3-mg increments if needed) or placebo in the bipolar mania studies and fixed-dose cariprazine 1.5 mg/d, 3 mg/d (slow titration to 1.5 mg [day 8] and 3 mg [day 15] or initiation at 1.5 mg with escalation to 3 mg on day 15), or placebo in the bipolar depression studies. The incidence, severity, and timing of treatment-emergent adverse events (TEAEs) of akathisia and restlessness were evaluated in this analysis.Results:In the bipolar mania studies (N=1065), TEAEs of akathisia occurred in 20.2% of cariprazine-treated patients and 4.8% of placebo-treated patients; 2.4% of cariprazine-treated patients discontinued due to akathisia. TEAEs of restlessness occurred in 6.7% and 2.3% of cariprazine- and placebo-treated patients, respectively, and caused discontinuation of 0.3% of cariprazine-treated patients. In the bipolar depression studies (N=1407), akathisia occurred in 2.1%, 5.5%, and 9.6% of patients in the placebo, cariprazine 1.5 mg/d, and cariprazine 3 mg/d groups, respectively; <2% of patients in each group discontinued due to akathisia. Restlessness occurred in 3.2% of placebo-treated patients and 2.1% and 6.6% of patients in the 1.5 and 3 mg/d groups, respectively; discontinuations due to restlessness occurred in 0.2% and 1.1% of patients in the 1.5 and 3 mg/d groups. Akathisia and restlessness in cariprazine-treated patients was generally mild or moderate in severity (>92% in both populations). Most akathisia events in the bipolar mania studies were reported for the first time within the first 2-3 weeks of treatment.Conclusions:In these post hoc analyses, the incidence of akathisia and restlessness were generally higher with cariprazine than with placebo. However, most incidences were mild or moderate in severity, and infrequently led to discontinuation. Akathisia appears to be dose related in both mania and depression, suggesting lower doses and slower titration may reduce occurrence.Funding Acknowledgements:Allergan plc.

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Treatment of mixed features in bipolar disorder

CNS Spectrums ◽

10.1017/s1092852916000547 ◽

2016 ◽

Vol 22 (2) ◽

pp. 141-146 ◽

Cited By ~ 9

Author(s):

Joshua D. Rosenblat ◽

Roger S. McIntyre

Keyword(s):

Bipolar Disorder ◽

Bipolar Depression ◽

Treatment Resistance ◽

Course Of Illness ◽

Stabilizing Agents ◽

Dsm 5 ◽

Mixed Features ◽

Post Hoc ◽

Major Depressive Episodes ◽

Depressive Episodes

Mood episodes with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)–defined mixed features are highly prevalent in bipolar disorder (BD), affecting ~40% of patients during the course of illness. Mixed states are associated with poorer clinical outcomes, greater treatment resistance, higher rates of comorbidity, more frequent mood episodes, and increased rates of suicide. The objectives of the current review are to identify, summarize, and synthesize studies assessing the efficacy of treatments specifically for BD I and II mood episodes (ie, including manic, hypomanic, and major depressive episodes) with DSM-5–defined mixed features. Two randomized controlled trials (RCTs) and 6 post-hoc analyses were identified, all of which assessed the efficacy of second-generation antipsychotics (SGAs) for the acute treatment of BD mood episodes with mixed features. Results from these studies provide preliminary support for SGAs as efficacious treatments for both mania with mixed features and bipolar depression with mixed features. However, there are inadequate data to definitively support or refute the clinical use of specific agents. Conventional mood stabilizing agents (eg, lithium and divalproex) have yet to have been adequately studied in DSM-5–defined mixed features. Further study is required to assess the efficacy, safety, and tolerability of treatments specifically for BD mood episodes with mixed features.

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156 The Broad Efficacy of Cariprazine Across Symptoms in Patients with Bipolar I Disorder: Post Hoc Analysis of Randomized, Placebo-Controlled Trials

CNS Spectrums ◽

10.1017/s1092852920000723 ◽

2020 ◽

Vol 25 (2) ◽

pp. 300-300

Author(s):

Lakshmi N. Yatham ◽

Eduard Vieta ◽

Roger S. McIntyre ◽

Rakesh Jain ◽

Willie R. Earley ◽

...

Keyword(s):

Bipolar Disorder ◽

Depressive Symptoms ◽

Rating Scale ◽

Bipolar Depression ◽

Partial Agonist ◽

Controlled Trials ◽

Bipolar I Disorder ◽

Manic Symptoms ◽

Bipolar Mania ◽

Post Hoc

Abstract:Study Objective:Patients with bipolar disorder experience a wide range of depressive and manic symptoms. Only 2 drugs are FDA-approved to treat episodes of both mania and depression in patients with bipolar disorder, highlighting the need for treatments with proven efficacy at opposite poles of the bipolar spectrum. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, is approved in the US for the treatment of both bipolar depression and manic and mixed episodes associated with bipolar I disorder. Cariprazine has previously demonstrated broad efficacy in patients with bipolar mania, with significantly greater improvement in favor of cariprazine vs placebo (PBO) across all individual symptom domains (P<.001) measured by the Young Mania Rating Scale (YMRS). Additionally, cariprazine has demonstrated efficacy vs PBO in 3 phase II/III clinical studies in patients with depressive episodes associated with bipolar I disorder (NCT01396447, NCT02670538, NCT02670551). To further assess the broad efficacy of cariprazine in patients with bipolar I disorder, we performed post hoc analyses to evaluate the range of depressive symptoms comprising the individual items of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients from the bipolar depression studies.Methods:Data from the 3 randomized, double-blind, PBO-controlled trials in patients with bipolar depression were pooled. Least squares (LS) mean change from baseline to week 6 in MADRS individual items was assessed in the pooled cariprazine 1.5 and 3 mg/d groups vs PBO using a mixed-effects model for repeated measures in the intent-to-treat (ITT) population.Results:There were 1383 patients in the ITT population (placebo=460; cariprazine 1.5-3 mg/d=923). At week 6, LS mean change from baseline was significantly greater for cariprazine 1.5-3 mg/d vs PBO on 9 of 10 individual MADRS items: Apparent Sadness (-2.0 vs -1.6, P<.0001); Reported Sadness (-2.0 vs -1.6, P<.0001); Reduced Sleep (-1.6 vs -1.4, P=.0357); Reduced Appetite (-1.2 vs -1.0, P=.0001); Concentration Difficulties (-1.5 vs -1.2, P=.0002); Lassitude (-1.7 vs -1.4, P=.0003); Inability To Feel (-1.7 vs -1.5, P=.0009); Pessimistic Thoughts (-1.4 vs -1.2, P=.0054) and Suicidal Thoughts (-0.3 vs -0.2, P=.0383); differences between cariprazine and PBO on the Inner Tension item were not significant.Conclusions:Significant improvement in most MADRS single items suggests broad efficacy in depressive symptoms for cariprazine 1.5-3 mg/d vs PBO in patients with bipolar depression. Coupled with broad efficacy in manic symptoms as demonstrated by significant improvement in all YMRS individual items in patients with bipolar mania or mixed episodes, cariprazine appears be effective across the range of symptoms that affect patients with bipolar disorder.Funding Acknowledgements:Supported by Allergan plc.

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Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms

International Journal of Bipolar Disorders ◽

10.1186/s40345-019-0155-y ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

Maximilian Pilhatsch ◽

Thomas J Stamm ◽

Petra Stahl ◽

Ute Lewitzka ◽

Anne Berghöfer ◽

...

Keyword(s):

Bipolar Disorder ◽

Rating Scale ◽

Bipolar Depression ◽

Phenotypic Expression ◽

Anxiety Symptoms ◽

Controlled Study ◽

Double Blind ◽

Comorbid Anxiety ◽

Depressed Patients ◽

Depressive Episodes

Abstract Background Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression. Methods Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI). Results Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877). Conclusions This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839

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Age at onset, course of illness and response to psychotherapy in bipolar disorder: results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

Psychological Medicine ◽

10.1017/s0033291714000804 ◽

2014 ◽

Vol 44 (16) ◽

pp. 3455-3467 ◽

Cited By ~ 17

Author(s):

A. Peters ◽

L. G. Sylvia ◽

P. V. da Silva Magalhães ◽

D. J. Miklowitz ◽

E. Frank ◽

...

Keyword(s):

Bipolar Disorder ◽

Collaborative Care ◽

Bipolar Depression ◽

Age At Onset ◽

Number Needed To Treat ◽

Systematic Treatment ◽

Illness Duration ◽

Bipolar Patients ◽

Depressive Episodes ◽

Intensive Psychotherapy

Background.The course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients' prior courses of illness are related to responses to psychotherapy.Method.Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy with collaborative care (a three-session psycho-educational intervention). We assessed whether the number of previous mood episodes, age of illness onset, and illness duration predicted or moderated the likelihood of recovery and time until recovery from a depressive episode in patients in the two treatments.Results.Independently of treatment condition, participants with one to nine prior depressive episodes were more likely to recover and had faster time to recovery than those with 20 or more prior depressive episodes. Participants with fewer than 20 prior manic episodes had faster time to recovery than those with 20 or more episodes. Longer illness duration predicted a longer time to recovery. Participants were more likely to recover in intensive psychotherapy than collaborative care if they had 10–20 prior episodes of depression [number needed to treat (NNT) = 2.0], but equally likely to respond to psychotherapy and collaborative care if they had one to nine (NNT = 32.0) or >20 (NNT = 9.0) depressive episodes.Conclusions.Number of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression.

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Repetitive transcranial magnetic stimulation in the treatment of bipolar disorder

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125320973790 ◽

2020 ◽

Vol 10 ◽

pp. 204512532097379

Author(s):

Danielle Hett ◽

Steven Marwaha

Keyword(s):

Bipolar Disorder ◽

Transcranial Magnetic Stimulation ◽

Side Effects ◽

Magnetic Stimulation ◽

Sleep Problems ◽

Bipolar Depression ◽

Repetitive Transcranial Magnetic Stimulation ◽

Controlled Trial ◽

Total N ◽

Depressive Episodes

Bipolar disorder (BD) is a debilitating mood disorder marked by manic, hypomanic and/or mixed or depressive episodes. It affects approximately 1–2% of the population and is linked to high rates of suicide, functional impairment and poorer quality of life. Presently, treatment options for BD are limited. There is a strong evidence base for pharmacological (e.g., lithium) and psychological (e.g., psychoeducation) treatments; however, both of these pose challenges for treatment outcomes (e.g., non-response, side-effects, limited access). Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, is a recommended treatment for unipolar depression, but it is unclear whether rTMS is an effective, safe and well tolerated treatment in people with BD. This article reviews the extant literature on the use of rTMS to treat BD across different mood states. We found 34 studies in total ( N = 611 patients), with most assessing bipolar depression ( n = 26), versus bipolar mania ( n = 5), mixed state bipolar ( n = 2) or those not in a current affective episode ( n = 1). Across all studies, there appears to be a detectable signal of efficacy for rTMS treatment, as most studies report that rTMS treatment reduced bipolar symptoms. Importantly, within the randomised controlled trial (RCT) study designs, most reported that rTMS was not superior to sham in the treatment of bipolar depression. However, these RCTs are based on small samples ( NBD ⩽ 52). Reported side effects of rTMS in BD include headache, dizziness and sleep problems. Ten studies ( N = 14 patients) reported cases of affective switching; however, no clear pattern of potential risk factors for affective switching emerged. Future adequately powered, sham-controlled trials are needed to establish the ideal rTMS treatment parameters to help better determine the efficacy of rTMS for the treatment of BD.

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TMS in bipolar disorder

10.1093/oxfordhb/9780198568926.013.0041 ◽

2012 ◽

Author(s):

Nimrod Grisaru ◽

Bella Chudakov ◽

Alex Kaptsan ◽

Alona Shaldubina ◽

Julia Applebaum ◽

...

Keyword(s):

Bipolar Disorder ◽

Magnetic Stimulation ◽

Bipolar Depression ◽

Unipolar Depression ◽

Future Directions ◽

Induced Mood ◽

Mood Effects ◽

Clinical Potential ◽

Depressive Episodes ◽

Lateral Specificity

This article reviews the existing animal and human literature on the clinical potential of transcranial magnetic stimulation (TMS) in mania and bipolar depression, and discusses potential future directions for this work. Studies of TMS in depression and normal volunteers suggested lateral specificity of TMS-induced mood effects. Clinical trials to compare left versus right prefrontal TMS in mania have been developed. Studies to understand the effect of TMS in bipolar depression have been undertaken. The results show efficacy similar to that for unipolar depression. But this does not provide support for the concept of TMS as an anti-bipolar, or mood-stabilizing, treatment. The utility of TMS as prophylaxis for subsequent manic or depressive episodes has not been reported in bipolar disorder. More work is needed to clarify the risk of mood switch, and the potential of TMS as prophylaxis against future manic or depressive episodes.

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Lurasidone: Ten Years Treating Adults with Bipolar Depression

Revista Portuguesa de Psiquiatria e Saúde Mental ◽

10.51338/rppsm.2021.v7.i2.199 ◽

2021 ◽

Vol 7 (2) ◽

pp. 64-74

Author(s):

Margarida Albuquerque ◽

João Facucho-Oliveira ◽

Daniel Esteves-Sousa ◽

Nuno Moura ◽

Daniel Neto ◽

...

Keyword(s):

Bipolar Disorder ◽

Bipolar Depression ◽

Type I ◽

Pharmaceutical Drugs ◽

The European Union ◽

First Line ◽

The Usa ◽

Bipolar Type ◽

Depressive Episodes ◽

The Eu

Lurasidone is an atypical antipsychotic approved in 2010 in Canada and in the USA for the treatment of adults with schizophrenia or bipolar type I disorder. In 2014 it was approved in the European Union for the treatment of patients with 13 years‑old or older, with schizophrenia. Lurasidone is a benzisothiazole derivative with a binding profile that makes it an antidepressant candidate with a low metabolic impact. In patients with bipolar disorder, depressive episodes tend to be present for the majority of the time and are difficult to treat, as shown in multiple surveys indicating that more than three quarters of patients with bipolar depression receive at least two pharmaceutical drugs and more than one third receive three or more. Some relevant international guidelines include different first‑line options in the treatment of bipolar depression, among which is lurasidone. Considering the difficulties in treating depressive episodes in bipolar disorder, the EU marketing authorization limiting the use of lurasidone in schizophrenia only and the expectable commercialization in Portugal by 2021, we aim to review the literature regarding the efficacy and advantages of lurasidone for depressive episodes of bipolar disorder and to discuss the usefulness of approving this medication as an alternative treatment approach.

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Novel therapeutic targets for bipolar disorder

10.1093/med/9780198748625.003.0030 ◽

2017 ◽

Author(s):

Ioline D. Henter ◽

Rodrigo Machado-Vieira

Keyword(s):

Bipolar Disorder ◽

Mood Disorders ◽

Bipolar Depression ◽

Nmda Antagonist ◽

Excitatory Neurotransmitter ◽

Residual Symptoms ◽

Antidepressant Effects ◽

The Central Nervous System ◽

Depressive Episodes

The long-term course of bipolar disorder (BD) comprises recurrent depressive episodes and persistent residual symptoms for which standard therapeutic options are scarce and often ineffective. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders and in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in major depressive disorder (MDD) and BD. This chapter reviews the clinical evidence supporting the use of novel glutamate receptor modulators for treating BD—particularly bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics.

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Comparison of depressive episodes in bipolar disorder and in major depressive disorder within bipolar disorder pedigrees

The British Journal of Psychiatry ◽

10.1192/bjp.bp.110.088823 ◽

2011 ◽

Vol 199 (4) ◽

pp. 303-309 ◽

Cited By ~ 52

Author(s):

Philip B. Mitchell ◽

Andrew Frankland ◽

Dusan Hadzi-Pavlovic ◽

Gloria Roberts ◽

Justine Corry ◽

...

Keyword(s):

Bipolar Disorder ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Clinical Features ◽

Bipolar Depression ◽

Bipolar Affective Disorder ◽

Probabilistic Approach ◽

Psychomotor Retardation ◽

Major Depressive ◽

Depressive Episodes

BackgroundAlthough genetic epidemiological studies have confirmed increased rates of major depressive disorder among the relatives of people with bipolar affective disorder, no report has compared the clinical characteristics of depression between these two groups.AimsTo compare clinical features of depressive episodes across participants with major depressive disorder and bipolar disorder from within bipolar disorder pedigrees, and assess the utility of a recently proposed probabilistic approach to distinguishing bipolar from unipolar depression. A secondary aim was to identify subgroups within the relatives with major depression potentially indicative of ‘genetic’ and ‘sporadic’ subgroups.MethodPatients with bipolar disorder types 1 and 2 (n = 246) and patients with major depressive disorder from bipolar pedigrees (n = 120) were assessed using the Diagnostic Interview for Genetic Studies. Logistic regression was used to identify distinguishing clinical features and assess the utility of the probabilistic approach. Hierarchical cluster analysis was used to identify subgroups within the major depressive disorder sample.ResultsBipolar depression was characterised by significantly higher rates of psychomotor retardation, difficulty thinking, early morning awakening, morning worsening and psychotic features. Depending on the threshold employed, the probabilistic approach yielded a positive predictive value ranging from 74% to 82%. Two clusters within the major depressive disorder sample were found, one of which demonstrated features characteristic of bipolar depression, suggesting a possible ‘genetic’ subgroup.ConclusionsA number of previously identified clinical differences between unipolar and bipolar depression were confirmed among participants from within bipolar disorder pedigrees. Preliminary validation of the probabilistic approach in differentiating between unipolar and bipolar depression is consistent with dimensional distinctions between the two disorders and offers clinical utility in identifying patients who may warrant further assessment for bipolarity. The major depressive disorder clusters potentially reflect genetic and sporadic subgroups which, if replicated independently, might enable an improved phenotypic definition of underlying bipolarity in genetic analyses.

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