Cariprazine
Cariprazine, sold under the brand names Vraylar in the United States and Reagila in the European Union, is an atypical antipsychotic which is used in the treatment of schizophrenia, bipolar mania, and bipolar depression. It acts primarily as a D receptor and D receptor partial agonist, with high selectivity for the D receptor. 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. It is also potentially useful as an add-on therapy in major depressive disorder. Rights are owned by Gedeon  Richter and Actavis. The drug received FDA approval on September 17, 2015. Medical uses. Cariprazine is used to treat schizophrenia and manic, depressive, or mixed episodes associated with bipolar I disorder. Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression, and has been considered an effective and well tolerated treatment for the condition. Side effects. Side effects may first appear on the first day after starting cariprazine. The most prevalent side effects for cariprazine include akathisia, and insomnia. 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, dizziness, vomiting, 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 side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time." Pharmacology. Pharmacodynamics. Unlike many antipsychotics that are D and 5-HT receptor antagonists, cariprazine is a D and D partial agonist. It also  has a higher affinity for D receptors. The D and D 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 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D 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 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 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  D/D receptors were 94% occupied, while at the lowest dose (1 "μ"g/kg), receptors were 5% occupied. 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. It has been investigated as a potential adjunct in treatment -resistant major depressive disorder, although trials to date have not found it to be beneficial.