Schizophrenia and bipolar disorder are severe psychiatric conditions in which a person's perception, thoughts, moods, and behavior are changed from normal.1,2 Schizophrenia affects 21 million people worldwide and is a leading cause of disability.3 A diagnosis of schizophrenia is confirmed by a psychiatrist after full assessment using criteria from The International Statistical Classification of Diseases and Related Health Problems, 10th edition,4 or the Diagnostic and Statistical Manual of Mental Disorders, fifth edition.5 Schizophrenia symptoms can be divided into two groups: positive (such as hallucinations and delusions) and negative (which affect the patients' ability to function, such as a lack of motivation).6 These symptoms need to be present for a least 1 month before the diagnosis is made. The etiology of schizophrenia is not fully understood; however, genetic and environmental factors, including stress, traumatic life experiences, and cannabis use could be involved.7 About 80% of patients with schizophrenia have a relapse within 5 years of recovery;8 this risk is decreased by using maintenance antipsychotic medications.9 Antipsychotics provide relief from these debilitating symptoms and have been used successfully in the treatment of bipolar disorders.10
First-generation antipsychotics such as haloperidol and chlorpromazine are dopamine (D2) receptor antagonists and can block histamine, muscarinic, and alpha-1 receptors.11 Second-generation antipsychotics (SGA) are serotonin-dopamine antagonists.12 Antagonism of the serotonin 2A receptor (5-HT2A) can increase dopaminergic neurotransmission in the nigrostriatal pathway with less risk of extrapyramidal symptoms (EPS).13 SGA's main side effects are weight gain, glucose intolerance, and hyperprolactinemia.14,15
In this review we describe cariprazine, a new atypical antipsychotic drug for the management of schizophrenia and bipolar disorder.16 Cariprazine acts as a D2 and D3 receptor partial agonist with a higher affinity for the D3 receptor,17 which differs from current antipsychotics.10 Cariprazine metabolism occurs via the cytochrome P450 (CYP)3A4 and CYP2D6 pathways. There are two clinically relevant metabolites, desmethyl-cariprazine and didesmethyl-cariprazine, that have similar pharmacological activity to cariprazine, but didesmethyl-cariprazine has a much longer half-life (1–3 weeks) compared to cariprazine (2–4 days).18,19 Common side effects of cariprazine include restlessness, akathisia, and insomnia.17,18
Pharmacology of Cariprazine
Schizophrenia is associated with multifactorial dysfunctions in glutamatergic, dopaminergic, and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the central nervous system. Serotonin (5-HT) also plays a crucial role in regulating psycho-emotional, cognitive, and motor functions.20,21 Cariprazine could influence acute changes in glutamate, dopamine, noradrenaline, and serotonin levels in a dose-dependent manner.21 Cariprazine binds dopamine D2 and D3 receptors in a dose-dependent/saturable manner,22 acting as a partial agonist of the D2 receptor similar to aripiprazole,23 with a 10-fold higher affinity for the D3 receptor compared to the D2 receptor (pKi of 10 and 9, respectively). Cariprazine has high affinity to 5-HT2B receptor as an antagonist, moderate affinity to the 5-HT1A receptor as a partial agonist, and low affinity to the 5-HT2A receptor as an antagonist.24 Moreover, cariprazine displays moderate/low affinity for the histamine (H1) and 5-HT2C receptors.25,26 Activation of D2 modulates G-protein/cyclic AMP-dependent signaling and Akt-GSK-3 signaling with effects on behaviors (such as the activity of lithium for management of mania). In a study from 2015, cariprazine was more potent than aripiprazole as an antagonist in inhibiting isoproterenol-induced cyclic AMP and in D2R/beta-arrestin 2-dependent interactions.27 Cariprazine upregulated the D2, D3, and 5-HT1A receptor levels and decreased N-methyl-D-aspartate receptor levels in several brain regions.28 Dopamine receptors differ in signal transduction, binding profile, localization, and physiological effects, with the D3 receptor involved in schizophrenia, Parkinson's disease, addiction, anxiety, and depression.29
Pharmacokinetics of Cariprazine
Cariprazine has good blood-brain barrier penetration with slow washout.30 Oral bioavailability is 52% with a brain to plasma area-under-the-curve ratio of 7.6:1.31 Cariprazine is mainly metabolized hepatically by CYP3A4.32 The CYP2D6-mediated pathway plays a minor role in cariprazine metabolism, with CYP2D6 inhibitors unlikely to have clinically relevant effects.33 It has two equipotent metabolites: desmethyl and didesmethyl cariprazine.34 Cariprazine and its active didesmethyl derivative are cleared slowly (elimination half-lives range from 2–5 days for cariprazine to 2–3 weeks for didesmethyl-cariprazine),35 and steady state is reached within 1 to 2 weeks.18 Cariprazine is a P-glycoprotein (P-gp) inhibitor in vitro, so the use of P-gp substrates with a narrow therapeutic index such as dabigatran and digoxin requires careful monitoring.33
Cariprazine in the Management of Bipolar Disorder
Bipolar disorder is a chronic disorder characterized by episodic recurrences of mania and depression with periods of remission.36 In animal studies, cariprazine showed similar efficacy to lithium.27 Several human studies showed the efficacy of cariprazine using the Young Mania Rating Scale (YMRS) total score, YMRS single items, and Clinical Global Impressions-Severity of Illness (CGI-S) score. In a clinical trial with 497 patients, cariprazine showed superiority on all 11 YMRS scale single items.37 Rates of remission and global improvement were greater for cariprazine, with no decline or switch to depression.38 Another trial confirmed cariprazine's superiority in reducing YMRS and CGI-S scores, with a significant percentage of patients achieving remission.39
Cariprazine in the Management of Schizophrenia
Compounds with combined 5-HT1A/D2 activities could be effective in managing a broader range of schizophrenia symptoms,40 as 5-HT1A activation leads to improved negative/cognitive symptoms with reduction of EPS induced by D2 antagonism.21,41 Cariprazine significantly attenuated disrupted social recognition, attention, and memory in a study by Zimnisky et al.,42 and caused reversal of novel object recognition impairment in a study by Watson et al.43
Cariprazine is efficacious in controlling schizophrenia symptoms, as patients have a significantly longer time to relapse.44 Cariprazine was shown to reverse cognition and social behavior deficits in rats,45 and in humans it showed better efficacy compared to risperidone46 and was superior to many antipsychotics, including aripiprazole.47
Randomized controlled trials have shown significant efficacy of cariprazine on the Positive and Negative Syndrome Scale (PANSS; on total, positive, and negative scales), with fewer patients discontinuing treatment.48,49 CGI-S score changes at week 6 were significant.50 Patients with predominantly negative symptoms achieved better health states and less anhedonia compared with risperidone, with estimated quality-adjusted life year gain of 0.029 per patient.51,52
Cariprazine in the Management of Other Psychiatric Conditions
Cariprazine could be used as an adjunctive therapy in depression management. In a study by Leggio et al.53 dopamine regulation was associated with the efficacy of some antidepressants, such as desipramine, as dopaminergic dysfunction in the mesolimbic system contributed to anhedonia and psychomotor retardation, whereas D3 receptor expression is down-regulated in depression. Cariprazine attenuated anhedonic-like behavior in mice while reducing drinking latency (anxiolytic-like activity).54 Cariprazine was efficacious in reducing the Montgomery-Åsberg Depression Rating Scale total score.55,56
Cariprazine showed significant efficacy in reducing hostile and aggressive behavior as determined using the PANSS hostility item (P7), especially in patients with greater baseline hostility.57 Cariprazine could prevent relapse in people with cocaine addiction and reduce the cocaine-rewarding effect.58
Cariprazine had low (<10%) rates of sedation and treatment discontinuation (<5%) but high rates of akathisia (33%)59 with fewer EPS compared to risperidone60 (cariprazine 3 mg: 8.9%; risperidone 4 mg: 12.9%) in patients with acute exacerbation of schizophrenia.49 Insomnia, vomiting, and headache were reported in 10% or more of patients, whereas prolactin levels decreased with no significant changes in liver enzymes; mean body weight change was 1.58 kg.61 More cariprazine patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or EPS (cariprazine: 16%; placebo: 1%).37 Cariprazine was associated with akathisia, EPS, and diastolic blood pressure symptoms in a dose-response relationship, with significant fasting glucose level changes (7 mg/dL compared to just 1.7 mg/dL for placebo), whereas no clinical changes in electrocardiogram parameters or high QTc (>500 ms) were observed.19 A multicenter clinical trial showed no unexpected safety issues/deaths.62 Restlessness, nausea, dyspepsia, tremor, and back pain were common (incidence ≥5%).63 Somnolence is uncommon as cariprazine is considered an activating medication (number needed to harm = 65; low somnolence risk).64,65 Cariprazine is similar to haloperidol and aripiprazole in that it affects 7-dehydrocholesterol conversion to cholesterol.66
This review investigated the efficacy and safety of cariprazine for psychiatric conditions management. Cariprazine is taken once daily (1.5–6 mg) and without regard to food. The cariprazine dose should be adjusted in patients who receive CYP450 inhibitors, and it is contraindicated for patients with severe hepatic or renal disease.67 Cariprazine is a D3 and D2 receptor partial agonist with higher selectivity for the D3 receptor, which is expressed mainly in brain areas associated with motivation and reward-related behavior.68
In patients with schizophrenia, cariprazine resulted in significant improvement in PANSS total score and improved negative symptoms compared to other antipsychotics such as risperidone. Patients taking cariprazine showed significant improvements in CGI-S score and many shifted from the extremely/severely ill category to the mildly ill/better category.69 This second-generation antipsychotic with D3 receptor partial agonist properties could also improve cognitive function. In people with bipolar disorder, cariprazine resulted in significant improvements in YMRS and was efficacious as monotherapy, resulting in improved remission rates (odds ratio, 2.08).70 It is recommended alone or in combination as a first-line treatment for acute mania.71 There was significantly higher risk of EPS72 but a lower risk of discontinuing.69 Clinical trial results need to be interpreted with caution as treatment length was short (3–6 weeks) in most of the studies, several different doses were used, and there was no clear evidence for long-term effects.
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