The mechanism of action for all antipsychotics, including cariprazine, is not fully known¹. However, based on its receptor profile and numerous studies including in vivo preclinical studies and human PET studies, enough evidence exists to elucidate the key factors contributing to the mechanism of action of cariprazine.

Cariprazine has high affinity for dopamine D₃ and D₂ receptors as well as serotonin 5‑HT_2B and 5‑HT_1A receptors, moderate affinity to 5‑HT_2A, histamine H₁, and sigma σ1 receptors, low affinity for serotonin 5‑HT_2C and adrenergic α 1 receptors, and no appreciable affinity for cholinergic muscarinic receptors^1,2. It is believed that cariprazine’s therapeutic effects are mediated through some combination of partial agonist activity at dopamine D₃, D₂, and serotonin 5‑HT_1A receptors and antagonist activity at 5‑HT_2B receptors¹.

Reference: Adapted from Kiss. J Pharmacol Exp Ther 2010.333:328–340; Partial agonism is represented with dots, circles show pKi values.²

Antipsychotics are generally thought to be effective against positive symptoms of schizophrenia, though they are less effective for treating cognitive deficits and negative symptoms associated with schizophrenia. Results from animal models suggest that the dopamine D₃ receptor plays an important role in regulating cognition, mood, and social functions³. Most currently available antipsychotics have a lower affinity for D₃ receptors relative to the very high affinity of dopamine itself for the D₃ receptor that is why they do not occupy dopamine D3 receptors in the living brain³. Cariprazine, on the other hand, is unique among antipsychotics in that it has a higher potency for the D₃ receptor than dopamine itself, meaning that the net effect of cariprazine administration is D₃ receptor blockade^4-8. D₃ receptor blockade in patients with schizophrenia is hypothesized to result in procognitive, antidepressant, and reduced negative symptom effects³. Cariprazine has demonstrated efficacy in behavioral preclinical models of negative/mood symptoms and cognitive impairment^9–14. The efficacy in these animal models has been shown to be at least partially dependent on its activity at the dopamine D₃ receptor, since its effects on anhedonia and cognitive impairment were apparent in wild-type mice but not in D₃ receptor‑knockout mice^10,14.

At pharmacologically effective doses, cariprazine shows relatively similar occupancy at both D₃ and D₂ receptors, as demonstrated by in vivo nonclinical and human PET studies¹⁵. Dose-dependent occupancy of dopamine D₃ and D₂ receptors was observed in patients with schizophrenia dosed with cariprazine in the therapeutic dose range¹. In brain regions with higher D₃ receptor expression, cariprazine displayed greater preferential occupancy for D₃ versus D₂ receptors¹⁵. Drug affinities for D₃ receptors for many agents are about the same than their affinities for D₂ receptors, but they are mostly lower than dopamine’s affinity for the D₃ receptor³. Therefore, effects attributed to D₃ receptor blockade are not associated with any drug other than cariprazine, since in the living brain, in the presence of natural dopamine, D₃ receptors are not blocked by any antipsychotic other than cariprazine^3,4. Concerning safety, blockade of the nigrostriatal or tuberoinfundibular pathways, which is associated with extrapyramidal symptoms (EPS) and elevated prolactin levels, could potentially be avoided with partial agonist¹⁶; so theoretically, cariprazine should cause fewer side effects of this nature. However, as observed in clinical studies, this has proven to be true for prolactin levels, which do not increase in response to treatment with cariprazine¹⁷, although increased incidence of EPS/akathisia is noted¹⁷, for which there is no apparent explanation¹⁶.

References: Adapted from Stahl SM. CNS Spectrums (2017), 22, 375–384.³ ; Howes J Psychopharmacol. 2015 February; 29(2): 97–115.¹⁸

In vitro, cariprazine exhibits partial agonist activity at D3 receptors¹. Since most D₃ receptors are localized in brain areas where hyperdopaminergia is present in schizophrenia (ie, in the mesolimbic dopaminergic system)^15,18, cariprazine acts as a functional antagonist on these receptors. D₃ receptor antagonism is associated with pro-cognitive, antidepressant, and anti-negative symptom effects³. Confusingly, these same effects are also linked to cortical functions, where hypodopaminergia is present in schizophrenia¹⁸. Herein lies the question of how does cariprazine normalize these hypodopaminergic states by D₃ receptor blockade?

Hypothesis 1: References: Adapted from Howes J Psychopharmacol. 2015 February; 29(2): 97–115.¹⁸; Stahl SM. CNS Spectrums (2017), 22, 375–384.³
Hypothesis 2: References: Adapted from Bouthenet et al. Brain research 1991.564, 203-219²⁸; Gurevich, Neuropsychopharmacology 1999. 20, 60-80.²⁹; Loiseau, Eur Neuropsychopharmacol 2009.19, 23-33.³⁰; Watson, D.J. Neuropsychopharmacology 2012.37, 770-786.³¹; Clarkson, J Neurosci 2017.37, 5846-5860.³²; Yang, S. Cell Rep 2016.16, 1518-1526.³³; Neill, J.C. Eur Neuropsychopharmacol 2016. 26, 3-14.¹¹; Zimnisky, R. Psychopharmacology (Berl) 2013.226, 91-100.¹⁴

Negative symptoms and cognitive impairment have been associated with a hypodopaminergic state in the prefrontal cortex (PFC)¹⁸. The cause of this may be decreased dopamine release in the PFC due to activation of presynaptic dopamine D₃ autoreceptors in the ventral tegmental area (VTA) that project to the PFC³. Under these conditions, it is believed that D₃ receptor antagonists/partial agonists may block the inhibition of these neurons, which in turn results in an increase in dopamine levels in the PFC, normalizing the hypodopaminergic condition³. This increase in dopamine may reverse the hypodopaminergic state and result in improvements in negative symptoms and cognition via activation of D₁ receptors in the PFC, which are not active in low dopamine conditions due to the low affinity of dopamine for these receptors³.
Although the exact mechanism of action of cariprazine and in fact all other antipsychotics is still unknown, results from preclinical experiments with cariprazine do not appear to support this hypothesis^19-26. However, it is possible that a different effect would be seen in humans, as the mechanisms and functional consequences of somatodendritic dopamine transmission in the VTA has been reported to vary among species. These differences would be expected in vivo to affect the downstream activity of the mesocorticolimbic dopamine system and subsequent terminal release²⁷.

Despite the relatively low expression of D₃ receptor in the PFC^28-29, evidence suggests that D₃ receptors in the PFC can modulate PFC function and influence cognition^5,6.
In rodents, local infusions of D₃ receptor antagonists in the PFC resulted in efficacy in animal models of negative symptoms and cognition; efficacy was not seen in the nucleus accumbens (NAc) or striatum^30,31, suggesting that antagonizing D₃ receptors locally in the PFC has procognitive effects. This ability of D₃ receptors to modulate mood and cognition despite low expression may be related to the specialized location of D₃ receptors in the PFC. D₃ receptors have been shown to play a distinct role in regulating excitability in layer 5 pyramidal cells in the PFC³² . A different study found that D₃ receptor agonists suppress axon initial segment Ca_v3 channel excitability through an arrestin-dependent mechanism³³. Collectively, these results suggest that cariprazine antagonism at postsynaptic D₃ receptors in the PFC could contribute to efficacy in negative symptoms and cognition by modulating glutamate neuron action potentials and glutamate neurotransmission. This is further supported by the positive findings that cariprazine was able to reverse PCP induced cognitive impairment in animal behavioral models^11,14

Cariprazine has 2 pharmacologically active metabolites with activities that are similar to cariprazine, desmethyl‑cariprazine (DCAR) and didesmethyl‑cariprazine (DDCAR)¹. Total cariprazine (molar sum of cariprazine with DCAR and DDCAR) exposure is near 50% of steady state exposure after approximately 1 week of daily dosing, while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately 2 to 3-fold higher than exposure to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure¹.
Cariprazine, DCAR, and DDCAR are primarily eliminated through hepatic metabolism (CYP3A4 and CYP2D6). The effective half-life is about 2 days for cariprazine and DCAR, 8 days for DDCAR, and ~1 week for total cariprazine. The plasma concentration of total cariprazine gradually declines after dose discontinuation, with decreases of 50% in approximately 1 week and >90% in 3 weeks¹.

Reference: Adapted from Nakamura, T. et al. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des. Devel. Ther. 10, 327–338 (2016)³⁴.