Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study

Earley, Willie; Burgess, Maria Victoria; Rekeda, Ludmyla; Dickinson, Regan; Szatmári, B.; Németh, György; McIntyre, Roger S.; Sachs, Gary S.; Yatham, Lakshmi N.

doi:10.1176/appi.ajp.2018.18070824

Cited by 94 publications

(100 citation statements)

References 54 publications

(72 reference statements)

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“…Dose arms tested in the trials have included cariprazine 0.25‐0.75 mg/d, 1.5 mg/d, 1.5‐3.0 mg/d and 3.0 mg/d. Three of the four studies evidenced efficacy of cariprazine 1.5 mg/d vs placebo based on change from baseline on the MADRS total score . Cariprazine 3.0 mg/d was statistically superior to placebo in two of the studies; however, after correction for multiplicity, the difference was no longer significant for one of the trials .…”

Section: Data Synthesismentioning

confidence: 90%

“…Query of the PubMed literature database identified 31 records, of which 2 were double‐blind placebo‐controlled studies of cariprazine in bipolar depression . Web of Science provided a total of 44 records and no additional relevant studies.…”

Section: Study Selectionmentioning

confidence: 99%

“…Web of Science provided a total of 44 records and no additional relevant studies. The manufacturer provided copies of posters describing two additional double‐blind placebo‐controlled trials …”

Section: Study Selectionmentioning

confidence: 99%

“…Two studies are Phase III trials of 6 weeks in duration (NCT02670551, NCT02670538). Two studies have been published in the peer‐reviewed literature, NCT01396447 and NCT02670551 . The other two studies have been presented as posters, NCT02670538 and NCT00852202 .…”

Section: Data Synthesismentioning

confidence: 99%

“…Two studies have been published in the peer‐reviewed literature, NCT01396447 and NCT02670551 . The other two studies have been presented as posters, NCT02670538 and NCT00852202 . Dose arms tested in the trials have included cariprazine 0.25‐0.75 mg/d, 1.5 mg/d, 1.5‐3.0 mg/d and 3.0 mg/d.…”

Section: Data Synthesismentioning

confidence: 99%

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Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Citrome

2019

Int J Clin Pract

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Objective Cariprazine is an oral antipsychotic approved in the US for the treatment of schizophrenia, acute bipolar mania, and most recently, bipolar depression. The aim of this systematic review is to describe the efficacy, tolerability and safety of cariprazine for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults. Data sources The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms “cariprazine” AND “bipolar” AND “depression,” and by also querying the Web of Science commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. Study selection Double‐blind placebo‐controlled studies in adults with bipolar depression. Data extraction Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were calculated from the available study reports and other sources of information. Data synthesis Cariprazine differs from other antipsychotics in that it has a 10‐fold higher affinity for dopamine D3 receptors than for D2 receptors. Cariprazine's principal active metabolite, didesmethyl‐cariprazine (DDCAR), has a half‐life of 1‐3 weeks and at steady state DDCAR is the predominant circulating moiety. Four double‐blind placebo‐controlled studies of cariprazine for bipolar depression were found of which three were considered positive and provided data on efficacy; all four studies were used to assess tolerability. Rates of treatment response, defined by a ≥50% reduction from baseline on the Montgomery‐Asburg Depression Ratting Scale (MADRS) total score at study endpoint, for the approved doses of 1.5 and 3.0 mg/d (pooled) vs placebo were 46.3% vs 35.9% (NNT 10, 95% CI 7‐21). Corresponding rates for remission (defined as MADRS total score ≤10 at endpoint) were 30.2% vs 20.9% (NNT 11, 95% CI 8‐22). Discontinuation rates because of an adverse event (AE) were 6.7% for cariprazine (all doses pooled) vs 4.8% for placebo (NNH 51, ns). Product labelling lists the most common AEs as nausea, akathisia, restlessness and extrapyramidal symptoms. Patients receiving cariprazine 3.0 vs 1.5 mg/d were more likely to experience AEs and discontinue the trials because of an AE. Conclusions Cariprazine is the fourth agent approved for bipolar depression in the US. The likelihood to experience a benefit (response or remission) is substantially greater than the likelihood to encounter a discontinuation because of an AE. Direct, head‐to‐head comparisons with the other approved choices for bipolar depression in the “real world” are needed.

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Section: Data Synthesismentioning

confidence: 90%

Section: Study Selectionmentioning

confidence: 99%

Section: Study Selectionmentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

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Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Citrome

2019

Int J Clin Pract

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Bipolar Disorder

2021

The Maudsley Prescribing Guidelines in Psychiatry

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This chapter provides expert guidance on mechanism of action of lithium, valproate, and carbamazepine as well as their formulations, indications, plasma levels, adverse effects, and prescribing for special patient groups. Calcium‐related genes have been implicated by genetic studies in bipolar disorder (BD). Clinical studies of the treatment of affective disorders variably use sodium valproate, semi‐sodium valproate, ‘valproate’ or valproic acid. Antipsychotics have been used in acute and maintenance treatment of BD since the 1960s, with evidence to suggest effectiveness at both poles of the illness, as well as mixed states. Oral paliperidone prevents manic relapse in BD and case reports describe good outcomes with the long‐acting injections form. Bipolar depression shares the same diagnostic criteria for a major depressive episode in major depressive disorder but episodes may differ in severity, time course, liability to recurrence and response to drug treatment.

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Transient effects of multi‐infusion ketamine augmentation on treatment‐resistant depressive symptoms in patients with treatment‐resistant bipolar depression – An open‐label three‐week pilot study

et al. 2020

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Introduction While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment‐resistant bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi‐infusion ketamine augmentation in patients with TRBPD. Methods The present three‐week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi‐infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD). Results Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment. Conclusions Multi‐infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.

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Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study

Cited by 94 publications

References 54 publications

Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Bipolar Disorder

Transient effects of multi‐infusion ketamine augmentation on treatment‐resistant depressive symptoms in patients with treatment‐resistant bipolar depression – An open‐label three‐week pilot study

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