# 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 D$_3$ and D$_2$ receptor partial agonist, with a preference for the D$_3$ 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.

## Medical uses

Cariprazine is used to treat patients with schizophrenia 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

Cariprazine :
| Site | K$_i$ (nM) | IA (%) | Action |
| 5-HT$_{1A}$ | 2.6 | ~40% | Partial agonist / functional antagonist |
| 5-HT$_{2AS}$ | 18.8 | | Inverse agonist |
| 5-HT$_{2B}$ | 0.58 | | Antagonist |
| 5-HT$_{2C}$ | 134 | | Inverse agonist |
| 5-HT$_7$ | 111 | | Antagonist |
| α$_{1A}$ | 155 | | Antagonist |
| D$_{2L}$ | 0.49 | ~30% | Partial agonist / functional antagonist |
| D$_{2S}$ | 0.69 | ~30% | Partial agonist / functional full agonist |
| D$_{3S}$ | 0.085 | ~70% | Partial agonist / functional full agonist |
| H$_1$ | 23.2 | | Antagonist |
| mAChTooltip Muscarinic acetylcholine receptor | >1,000 | | Antagonist |
| The smaller the K$^i$ value, the more strongly the drug binds to the site. IA=intrinsic activity. ||||
Unlike many antipsychotics that are D$_2$ and 5-HT$_{2A}$ receptor antagonists, cariprazine is a D$_2$ and D$_3$ partial agonist. It also has a higher affinity for D$_3$ receptors. The D$_2$ and D$_3$ 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 D$_3$ receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D$_3$ 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 D$_3$ 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 μg/kg), the D$_2$/D$_3$ receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied. Dopamine D$_2$ and D$_3$ receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D$_2$/D$_3$ receptors, while striatal D$_2$/D$_3$ occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% [39]. 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 [40,41]. 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(D$_2$)/serotonergic(5-HT$_{2A}$) ratio (compared to the second generation antipsychotics serving a more nuanced profile in this regard). 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% (D$_2$) 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.
This Partial agonist activity induces, considered through two depicted schematas in pharmacology (either in determining their intrinsic value of activity making up the proportions of how much of a dose of this molecule binds to postsynaptic (dopamine)receptors to inactivate further exacerbating signalling through agonists with locking the receptor making it unavailable for other molecules and binding to the presynaptic site at autoreceptors in the synaptic cleft which triggers the transmitting with agonistic behaviour, or, binding independently to the site in the synaptic cleft inducing a certain response in relative to its agonist maximum potential to activate its relative receptor, then, depicted as percentage of intrinsic activity for this specific partial agonist) but with both needed to express just a "half-maximal response" (caught statistically in EC-responsecurves in a response-inhibited curve for maximal activation in graphes stretched on their longitudes, which it's due to their effect enabling tendency in time) to be able to compete successfully, relative to their dependent natural agonists (in case of antipsychotics dopamine) at full partial agonist concentrations where it happens to turn out luckily that atypical antipsychotics working as partial agonists (or the so-called third generation; e.g. aripiprazole, cariprazine and brexpiprazole) demonstrating near full "occupation" or concentration of them in the brain where then this idea of competing and inhibiting dopamin tends to work out (because the alone-giveable possibility what a neuroleptic per definition has to be to called by this name, needs to have an antipsychotic (or positive symptoms erasing effect), e.g. being moodstabilizing), where without the pharmacologic term of a partial agonist would just work out to exacerbate and activate receptors by an unsatisfying concentration of it 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.