cariprazine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia and bipolar disorder. It is also prescribed as an add-on treatment for bipolar depression and major depressive disorder. Cariprazine acts primarily as a D₃ and D₂ receptor partial agonist, with a preference for the D₃ receptor. It is a partial agonist at the serotonin 5-HT_1A receptor and acts as an antagonist at 5-HT_2B and 5-HT_2A receptors. It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.

Cariprazine was approved for medical use in the United States in September 2015. It was approved as a generic medication in 2022, but is covered by patents until 2029. Cariprazine was approved by the TGA for use in Australia in 2020. As of 2025, the cost of Cariprazine is generally around $50.00USD, $30.60AUD on the PBS and £80.36 in the UK when on the NHS.

Medical uses

Cariprazine is used to treat patients with schizophrenia, schizoaffective disorder and manic, depressive, or mixed episodes associated with bipolar I disorder. In the United States it is approved for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression).

Cariprazine consistently improved clinical severity across a spectrum of patients with bipolar disorder or schizophrenia - effectively reducing psychosis, anxiety, manic and depressive symptoms. In Australia, the United Kingdom, and the European Union it is approved only for treating schizophrenia.

Side effects

Side effects may first appear several weeks after starting cariprazine. Cariprazine does not appear to impact prolactin levels, and unlike many other antipsychotics, does not increase the QT interval on the electrocardiogram (ECG). In short term clinical trials, extrapyramidal effects, sedation, akathisia, nausea, headache, dizziness, vomiting, insomnia, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo" but a second called the incidence of movement-related disorders "rather high".

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time. "Cariprazine blocks the effects of THC.

Because cariprazine and its active metabolites have long half-lives, many healthcare professionals monitor for adverse effects up to several weeks after starting cariprazine. A longer monitoring period is also indicated for dosage changes, whether they represent an increase or a decrease, because elimination may take several weeks.

Pharmacology

Pharmacodynamics

Unlike many antipsychotics that are D₂ and 5-HT_2A receptor antagonists, cariprazine is a D₂ and D₃ partial agonist. It also has a higher affinity for D₃ receptors. 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. Cariprazine's high selectivity towards D₃ receptors could prove to reduce side effects associated with the other antipsychotic drugs, because 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. Cariprazine also acts on 5-HT_1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D₃ receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.

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. In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 ''μ''g/kg), the D₂/D₃ receptors were 94% occupied, while at the lowest dose (1 ''μ''g/kg), receptors were 5% occupied. Dopamine D₂ and D₃ receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D₂/D₃ receptors, while striatal D₂/D₃ occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% 9 In an open-label, fixed-dose, 2-week trial in eight males with schizophrenia, PET scans of dorsal striatal regions (caudate nucleus and putamen) and ventral striatum (nucleus accumbens) showed maximum occupancy (‡ 90%) at a 3-mg target dose of cariprazine following 14 d of treatment 0,41 After 14 d of cariprazine 1.5 mg/d, receptor occupancy was 69% in the caudate nucleus, 69% in the nucleus accumbens, and 75% in the putamen".

Cariprazine, as well as other third generation antipsychotics, possesses a lower chance of exacerbating extrapyramidal symptoms. However the ability to induce akathasia remains relatively high. This may be mediated through a lack of anticholinergic effects (as agents of this class are sometimes used to treat akathisia), as well as a lack of a balanced dopaminergic(D₂)/serotonergic(5-HT_2A) ratio . Moreover, partial agonists, through their limited response triggering, ironically often have the tendency to occupy near all targeted receptors at relatively low dosages of the drug. An extreme example is aripiprazole with an average occupancy of 70% (D₂) at a 2 mg dose, well below its usual antipsychotic dosage (the often cited threshold of occupancy for an antipsychotic effect is 70%). This could be another reason for akathasia from partial agonists.

Partial agonists are drugs that bind to and activate specific receptors, but they produce a weaker response than full agonists, even when all receptors are occupied. In neuronal signaling pharmacology, their activity is often described using two models: one considers how much of the drug binds to postsynaptic receptors, which can block stronger agonists from activating the receptor, while the other looks at how the drug can activate receptors by itself, but only to a limited extent compared to a full agonist. Partial agonists can act as both weak activators and blockers, depending on the presence of natural neurotransmitters like dopamine. When natural dopamine levels are high, partial agonists compete for the same receptors, reducing excessive signaling. When dopamine levels are low, partial agonists provide some activation, but not as much as dopamine or a full agonist would. The effectiveness of a partial agonist is often measured by the EC50 value, which is the concentration needed to produce half of its maximum possible effect. Drugs like aripiprazole, cariprazine, and brexpiprazole are examples of partial agonists used as antipsychotics. They help stabilize mood and reduce psychotic symptoms by balancing dopamine activity in the brain..

Pharmacokinetics

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic. In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).

Cariprazine is metabolized primarily by the cytochrome P450 3A4 isoenzyme (CYP3A4), with some minor metabolism by CYP2D6. Cariprazine does not induce the production of CYP3A4 or CYP1A2 in the liver, and weakly, competitively inhibits CYP2D6 and CYP3A4.

Research

Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015.

Cariprazine is also potentially useful as an add-on therapy in major depressive disorder. It is being developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the US, Canada, Japan, Taiwan and certain Latin American countries (including Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela). In February 2022, AbbVie requested approval by the US Food and Drug Administration (FDA) for adjunctive treatment for major depressive disorder. Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.

References

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