Cariprazine for the Treatment of Bipolar Disorder

Findlay, Lillian Jan; El-Mallakh, Peggy; El‐Mallakh, Rif S.

doi:10.1111/ppc.12150

Cited by 12 publications

(8 citation statements)

References 46 publications

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“…Cariprazine is approved for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar I disorder (Agai-Csongor et al, 2012; Veselinovic et al, 2013; Findlay et al, 2017) It is a dopamine D2/D3 receptor partial agonist(McCormick et al, 2010; Kiss et al, 2012; Ellenbroek and Cesura, 2015) and in a mouse model of depression, it produced antidepressant-like activity (Duric et al, 2017). We tested if cariprazine, used in a dose previously reported in mice and equivalent to a typical human dose, has any effect on sterol levels in the brain and serum.…”

Section: Resultsmentioning

confidence: 99%

Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis

Genaro-Mattos

Tallman

Allen³

et al. 2018

Toxicology and Applied Pharmacology

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While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established.

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Section: Resultsmentioning

confidence: 99%

Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis

Genaro-Mattos

Tallman

Allen³

et al. 2018

Toxicology and Applied Pharmacology

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“…The neuropharmacological profile of cariprazine is generally considered to be similar to aripiprazole, another atypical antipsychotic that is commonly used for the treatment of schizophrenia and bipolar disorder, except that cariprazine has a greater affinity and selectivity for D 3 vs. D 2 receptors ( Tadori et al, 2011 ; Ellenbroek and Cesura, 2015 ; Findlay et al, 2016 ; Stahl, 2016 ). Aripiprazole also has been shown to be effective as an adjunct treatment for major depressive disorder ( Bourin et al, 2009 ; Lenze et al, 2015 ; Zhou et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cariprazine, a novel, orally active antipsychotic agent that is a potent dopamine D 2 /D 3 receptor partial agonist with preferential binding to D 3 receptors, was recently approved by the U.S. Food and Drug Administration for the treatment of both schizophrenia and acute manic or mixed episodes associated with bipolar I disorder ( Ágai-Csongor et al, 2012 ; Veselinovic et al, 2013 ; Findlay et al, 2016 ). Among atypical antipsychotics, cariprazine displays the highest D 3 receptor binding affinity and D 3 vs. D 2 receptor selectivity (by approximately 6- to 8-fold) ( Kiss et al, 2010 ; McCormick et al, 2010 ; Ellenbroek and Cesura, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

Đurić

Banasr

Franklin

et al. 2017

International Journal of Neuropsychopharmacology

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BackgroundCariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine’s antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors.MethodsWild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors.ResultsResults showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity.ConclusionsIn combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

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“…Cariprazine, which has been authorized for use in the treatment of mania accompanying BD, is a partial D 2 /D 3 receptor agonist [332][333][334][335][336][337][338]. It appears to be a safe and effective medication for acute mania and mixed episodes in BD [339][340][341][342]. Some research data have indicated that both low and high doses of cariprazine are effective and well tolerated as a drug treatment for mania, depression, and psychosis [343][344][345].…”

Section: Cariprazinementioning

confidence: 99%

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder

Madireddy

2022

IJMS

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Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive–behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.

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Cariprazine for the Treatment of Bipolar Disorder

Abstract: Cariprazine will be a promising addition in the treatment of patients with acute mania and schizophrenia.

Cited by 12 publications

References 46 publications

Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis

Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder

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