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Depressive Phase of Bipolar Disorder
Published in Dr. Ather Muneer, Mood Disorders, 2018
Cariprazine, a recently approved novel antipsychotic, is a partial agonist at the D2R/D3R, with higher affinity for the latter receptor. It has already been approved for schizophrenia and the treatment of manic and mixed episodes of BD type I, while studies are ongoing for negative-symptom schizophrenia, MDD, and BD maintenance. In a trial that was recently published, cariprazine’s efficacy was shown in acute BD type I depression. In this multicenter study, cases were randomized to either cariprazine monotherapy dosed at 0.75, 1.5 or 3 mg/d, or placebo. The primary and secondary efficacy parameters were change from baseline MADRS and CGI-BP scores, respectively, and data were analyzed using a mixed effects model for repeated measures on the adjusted intent-to-treat population. At week 6, cariprazine 1.5 mg/d was statistically better than placebo on the primary, as well as secondary, efficacy measures, whereas the other two doses were not significantly different from placebo. The most common adverse events with cariprazine (≥10%) were akathisia and insomnia, while weight gain was slightly higher with active treatment compared to placebo. In this rigorously conducted study, cariprazine monotherapy showed consistent efficacy against bipolar depression and maintained a good tolerability and safety profile.35
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Cariprazine (RGH-188) is an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes (Agai-Csongor et al. 2012; Altinbas et al. 2013; Calabrese et al. 2015; Choi et al. 2014; Citrome 2013a,b; Durgam et al. 2014; Gao et al. 2015; Grunder 2010; Gyertyan et al. 2011; Kiss et al. 2010; Sachs et al. 2015; Veselinovic et al. 2013). It is a D2 and D3 receptor partial agonist, with high selectivity toward the D3 receptor (Gyertyan et al. 2011; Kiss et al. 2010). The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low (Choi et al. 2014; Kiss et al. 2010; Veselinovic et al. 2013). Cariprazine’s high selectivity toward D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, since D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors (Choi et al. 2014; Tohen 2015; Veselinovic et al. 2013). Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors; when endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (Gyertyan et al. 2011; Seneca et al. 2011). The drug was approved by the FDA for bipolar I and schizophrenia in adults on September 17, 2015. Cariprazine is converted by hepatic CYP3A4 and 2D6 to two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine (Citrome 2013b). It is expected that cariprazine is subject to polymorphic metabolism and inhibition by a number of other drugs. Exposure to didesmethyl-cariprazine exceeds that of the parent drug. Common adverse events of cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation (Citrome 2013a; Tohen 2015; Veselinovic et al. 2013).
Addressing negative symptoms of schizophrenia pharmacologically with cariprazine: evidence from clinical trials, a real-world study, and clinical cases
Published in Expert Opinion on Pharmacotherapy, 2022
György Németh, Zsófia B. Dombi, István Laszlovszky, Ágota Barabássy
Cariprazine is a third-generation antipsychotic agent with a unique mechanism of action approved for the treatment of schizophrenia as well as bipolar I disorder (manic or mixed and depressive episodes) by the FDA. In contrast to other antipsychotic medications that are dopamine D2 receptor antagonists, cariprazine is a dopamine D3 receptor preferring D3/D2 receptors partial agonist in vitro as well in vivo, as shown by data acquired via positron emission tomography [2,3]. In fact, cariprazine’s potency for the D3 receptor is higher than what is exhibited by dopamine itself, which in turn leads to a full D3 receptor occupancy at clinically relevant doses [2]. Research has shown that alterations in dopamine D3 receptor activity are a major contributor to the pathogenesis of negative symptoms in schizophrenia [4]. Indeed, the overexpression of D3 receptors in the striatum in mice was found to disrupt incentive motivation [5], which is one of the five core domains of negative symptoms (avolition, anhedonia, asociality, alogia, blunted affect) [6].
Impact of chronic medications in the perioperative period: mechanisms of action and adverse drug effects (Part I)
Published in Postgraduate Medicine, 2021
Ofelia Loani Elvir-Lazo, Paul F White, Hillenn Cruz Eng, Firuz Yumul, Raissa Chua, Roya Yumul
A recent article by Kaye and his colleagues [91] provides a brief overview of newer psychiatric medications (e.g. Vortioxetine and vilazodone) for the treatment of major depressive disorders (MDD) in patients who have failed SSRI/SNRI therapy. These drugs appear to act similarly to SSRIs by blocking the reuptake of serotonin by presynaptic neurons. Steady-state plasma concentrations of vortioxetine are achieved after 2 weeks and vilazodone reaches a steady-state plasma concentration after only 3 days. Analogous to other antidepressants, there is a risk of perioperative bleeding and serotonin syndrome [91]. Cariprazine is used to treat schizophrenia and acute mania or mixed episodes associated with bipolar I disorders in adults. The cariprazine exhibits partial D2 receptor agonist activity along with 5-HT2A blockade. It is unique because it also acts as a D3 receptor partial agonist in addition to its D2 receptor agonist effect. By selectively blocking D3 receptors, it may affect both the cognitive and negative symptoms of schizophrenia [91]. Cariprazine is the recommended treatment for schizophrenic patients with predominantly negative symptoms. Increases the risk of cerebrovascular adverse reactions.
The efficacy of cariprazine on function in patients with bipolar depression: a post hoc analysis of a randomized controlled trial
Published in Current Medical Research and Opinion, 2021
Eduard Vieta, Joseph R. Calabrese, Jessica Whelan, Mauricio Tohen, Willie R. Earley
This multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study included adult patients with bipolar I disorder and a current major depressive episode (NCT01396447); detailed methods of this study have been published30. Briefly, the study consisted of a screening period of up to 14 days, 8-weeks of double-blind treatment, and a 1-week safety follow-up; per local clinical practice, patients could be hospitalized during screening and for up to 2 weeks of double-blind treatment. Patients were randomized (1:1:1:1) to placebo or cariprazine 0.75, 1.5, or 3 mg/d. All cariprazine patients initiated treatment at 0.5 mg/d, with dosage increased to 0.75 mg/d on day 3; in the 1.5 and 3 mg/d groups, dosage was increased to 1 mg and 1.5 mg on days 5 and 8, respectively, and in the 3 mg/d group, dosage was increased to 3 mg on day 15. Double-blind treatment was 8 weeks in duration, with the primary efficacy parameter (MADRS change from baseline) assessed at week 6 and FAST outcomes assessed at week 8 per the study protocol.