Cariprazine – Mechanism of Action | Psychopharmacology | Clinical Application

MECHANISMS OF ACTION

Cariprazine’s mechanism of action is hypothesised to be mediated through the partial agonism of dopamine D2 / D3 receptors, serotonin 5-HT1A receptors, and antagonism of serotonin 5-HT2A receptors.

Cariprazine also shows a low affinity for alpha-type 1A receptors, where it acts as an antagonist. Cariprazine is reported to have no appreciable affinity for muscarinic receptors.

Binding Affinities: 

Cariprazine has very high binding affinities to the following receptors:

• Dopamine D3
• Dopamine D2L
• Dopamine D2S
• Serotonin 5-HT1A
• Serotonin 5-HT2B

There are two isoforms of the D2 receptor with different functions: [Martel & Gatti McArthur, 2020]

D2S receptor:

• The D2S is dominant in the cell bodies and projection axons of the dopaminergic cells in the mesencephalon (midbrain)
• D2S auto-receptors (on dendrites and soma) are known to inhibit cell firing, activate DA reuptake and inhibit DA synthesis
• D2S can inhibit the trace amine receptor TAAR1 with a final potentiating effect on the DA release in the striatum

D2L receptor:

• Postsynaptic receptor strongly expressed by neurons in the striatum and nACC, brain structures targeted by DA terminals.
• D2L activation pathway represents the main stimulus for dendritic formation in striatopallidal MSN (Medium spiny neurons)
• D2L receptor is mainly involved in the regulation of DARPP-32 phosphorylation in postsynaptic striatal MSN. DARPP-32 acts as an integrator of dopamine and glutamate signals.
• MSN neurons are the recipients of both DA and glutamatergic (from PFC and thalamus) projections; they represent a core neuronal element for both DA and NMDA hypothesis in schizophrenia.

Read dopamine hypothesis in schizophrenia.

Read the NMDA hypothesis in the article on Anti-NMDA encephalitis. 

Role of D3 antagonism : 

Cariprazine has a higher affinity for D3 receptors than D2 receptors (3- to 10-fold greater D3 affinity than aripiprazole), which is unique compared to other atypical antipsychotics such as aripiprazole and brexpiprazole.

An in vivo study in rats showed that cariprazine increased 5HT, NA and DA efflux in the nucleus accumbens (nACC) and hippocampus; Glycine and glutamate efflux in the nACC only. The neurotransmitter increase in key areas (nACC and hippocampus) contributes to the therapeutic efficacy in schizophrenia and bipolar disorder. [Huang et al. 2019]

The high affinity for cariprazine is functionally higher than the affinity of the dopamine itself for the D3 receptor. Thus, in the presence of dopamine in the living human brain, cariprazine is the only antipsychotic that blocks D3 receptors. [Stahl, 2016]

Role of D3 receptors: 

D3 receptors are situated in the mesolimbic regions of the brain and control reward, emotion and motivation.

D3 receptors are postulated to play a role in the modulation of negative symptoms, mood and cognition. [Correll C & Schooler N et al., 2020]

• Antagonism and partial agonism of dopamine D3 receptors can mediate social interaction improvements, anti-anhedonic and pro-cognitive effects.
• D3 antagonism in the midbrain can increase dopamine neurotransmission to the prefrontal cortex and the nucleus accumbens, reversing hypodopaminergic functioning linked to negative symptoms and mood deficits.
• The increase in dopamine in the prefrontal cortex could activate D1 receptors, which, in turn, could further mediate improvements in cognition and negative symptoms.
• D3 receptors are also known to increase acetylcholine in the prefrontal cortex and regulate glutamatergic excitability.

Read a detailed review on negative symptoms in schizophrenia. 

PHARMACOLOGICAL PROFILE

Pharmacokinetics

Cariprazine is well absorbed and can be administered with or without food. It will reach peak concentrations within 3 to 6 hours, and it has a half-life of 2 to 4 days. Cariprazine has two main metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and both metabolites have receptor binding profiles similar to cariprazine. [Kiss et al. 2019]

• DCAR reaches steady-state concentrations within 1 to 2 weeks
• DDCAR reaches steady-state concentrations within 4 to 8 weeks; it has a half-life of 1-3 weeks.
• Active metabolite that has a half-life of 1–3 weeks, the longest of any atypical antipsychotic

Using the half-life of total cariprazine (the sum of cariprazine and its major active metabolites DCAR and DDCAR), a time marker of 3 weeks for a steady-state has been estimated. [Citrome L,2013]

Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after starting cariprazine and after each dosage change.

Drug interactions

Cariprazine is extensively metabolised in the liver by CYP3A4 and, to a smaller degree, by CYP2D6 via hydroxylation and demethylation. Therefore, it is advised that patients currently being administered known inhibitors of the CYP3A4 enzyme should take a 50% dose reduction.

The Australian PI does not recommend reducing the Reagila dose by 50% with concomitant administration of strong or moderate CYP3A4 inhibitors but is a contraindication.

The Australian PI states the following: [REAGILA PI]

REAGILA is contraindicated with concomitant administration of strong or moderate CYP3A4 inhibitors and strong or moderate CYP3A4 inducers.

• Potent inhibitors of CYP3A4 include the atypical antidepressant, nefazodone, and antifungal agents (e.g., itraconazole and ketoconazole) and antiretroviral medications (e.g., ritonavir, indinavir, and saquinavir).
• The clinical impact of CYP3A4 inducers on cariprazine pharmacokinetics such as carbamazepine, modafinil, phenytoin, rifamycin, and St John’s wort has not been studied.

Read more on Pharmacogenomics and view tables on important CYP Enzymes with their substrates, inducers and inhibitors. 

DOSING

Schizophrenia :

Adults:  1.5-6 mg once daily at the same time of the day with or without food.  [VRYLAR PI]

• The starting dose: 1.5 mg/d
• Day 2: Can be increased to 3 mg/d
• Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3 mg increments to a maximum dose of 6 mg/d.

Australian Reagila PI states the following: [REAGILA PI]

• Taken once daily at the same time of the day with or without food.
• The recommended starting dose is 1.5 mg once daily.
• Thereafter the dose can be increased in 1.5 mg increments according to efficacy and tolerability to a maximum dose of 6 mg/day if needed.
• The lowest effective dose should be maintained according to the clinical judgement of the treating physician.

Bipolar I disorder:

For patients with Bipolar I disorder (acute manic or mixed episodes), the target dose is 3 to 6 mg/day. In both indications, titration adjustments of 1.5 or 3 mg/day are permitted. [FDA VRYLAR]

Doses appear to differ for the different mood states across the spectrum.

Bipolar Depression:

• 1.5 mg/day most consistently effective in bipolar depression, especially in those without subsyndromal manic symptoms

Bipolar Depression with subsyndromal manic symptoms:

• 1.5 mg/day or 3.0 mg/day

Mania with or without concomitant depressive symptoms. 

• 3.0-6.0 mg/day

Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.

In Australia, Cariprazine is not approved for Bipolar Disorder. 

SAFETY PROFILE OF CARIPRAZINE

Cariprazine and its two major metabolites accumulate over time, and thus adverse effects may take several weeks to appear.

The most common treatment-related adverse events that have been reported in clinical trials were akathisia, EPS, insomnia, headache, dizziness, tremor, and gastrointestinal disturbances. [Citrome, 2018]

• Akathisia was generally reported with mild or moderate severity; however, regardless of severity, it often resulted in the discontinuation of cariprazine. The high affinity at the alpha 1B receptor is hypothetically linked to reduced extrapyramidal symptoms (EPS) and akathisia.
• Antipsychotic-induced akathisia can exacerbate psychiatric symptoms and cause violence, aggression, and suicide. [Lohr et al. 2015]
• Akathisia may be prevented by slow up-titration. The dose should be individualised according to response and tolerability.
• Treatment measures include slight down-titration of dose or anti-EPSE medication. [View Video on the management of Akathisia]

Metabolic Syndrome

In addition, second-generation antipsychotics are associated with metabolic side effects, and therefore there is a potential for metabolic syndrome to occur. Clinically significant weight gain (versus placebo) was reported in a large meta-analysis of cariprazine use in schizophrenia, bipolar disorder, and unipolar depression. [Lao et al. 2016]

A more recent network meta-analysis comparing 18 antipsychotics on metabolic function showed the following for cariprazine vs placebo. [Pillinger et al., 2020]

• No evidence of weight gain with cariprazine
• No evidence of change in total cholesterol
• Decrease in LDL cholesterol
• No strong evidence of change in HDL cholesterol
• No strong evidence of change in triglyceride concentrations
• No strong evidence of change in glucose concentrations

For the indication of schizophrenia, cariprazine when compared to the two other partial agonists, the rank order is as follows: [Citrome, 2018]

The propensity for weight gain

• Brexpiprazole > Aripiprazole > Cariprazine

The propensity for somnolence

• Aripiprazole > Brexpiprazole > Cariprazine

The propensity for Akathisia

• Cariprazine > Aripiprazole > Brexpiprazole

Finally, there is a boxed warning for increased mortality in elderly patients with dementia-related psychosis, and therefore cariprazine is not approved in this population. [Vrylar, package insert]

Cariprazine is also associated with tardive dyskinesia, which is linked to its dopamine blockade. Although the potential for tardive dyskinesia cannot be predicted, it is more likely to occur in the elderly.

CLINICAL EVIDENCE

Schizophrenia: 

In Europe, cariprazine’s product label states that it predominantly reduces negative symptoms in patients with schizophrenia. This support is based on a large 26-week clinical trial that was published in The Lancet.  [Németh et al. 2017]

• The RCT compared the effects of fixed-dose cariprazine; 3mg, 4.5mg or 6mg per day, and risperidone; 3mg, 4mg or 6mg per day, on predominant negative symptoms of patients with stable and limited positive symptoms and without relevant depression or EPSEs showed significant differences and clinically relevant improvement in both negative symptoms and functional impairments in favour of cariprazine over risperidone, suggesting a meaningful clinical benefit for cariprazine in negative symptoms. [Németh G et al., 2017]
• Superiority regarding negative symptom improvement with cariprazine was also accompanied by improvements on the Clinical Global Impression Improvement Scale and the Personal and Social Performance Scale, indicating that improving the negative symptoms with cariprazine led to clinically meaningful advantages.
• Antagonism of D3 receptors enhances dopaminergic and cholinergic neurotransmission in the prefrontal cortex [Stahl, 2017], which may help alleviate negative and cognitive symptoms.

Following are points from real-world experiences and recommendations from an International Panel in treating schizophrenia with Cariprazine: [Fagiolini et al., 2020]

• Cariprazine was most often prescribed for patients presenting with their first episode of psychosis—in general, and these tend to be younger patients.
• Sufficient clinical experience with cariprazine in elderly patients (over 65 years) was not reported.
• The two other major groups considered to be ‘first-line candidates’ for cariprazine are those with predominantly negative symptoms and those with metabolic syndrome, including ethnic groups/non-Caucasians with diverse metabolic profiles.
• The majority of patients can be successfully managed on 1.5–3.0 mg, but this depends on several issues, such as the severity of symptoms and setting of treatment (community/inpatients), with more severe symptoms often requiring higher doses, and other patient characteristics, for example, BMI (higher BMI usually requires longer periods to achieve steady-state and hence therapeutical levels and may require a faster titration schedule or higher initial dose, to attain an earlier achievement of the therapeutical blood concentrations).
• When severe symptoms are present, there is usually a need to quickly achieve a higher dose (4.5- 6 mg).
• Patients with insomnia or agitation who are treated with cariprazine often need adjunctive treatment with a benzodiazepine or another sedating agent (Mirtazapine, Trazodone or low dose antipsychotic). In those cases, cariprazine is usually needed at doses of 4.5–6 mg.
• Treatment-resistant patients require the highest dosage (6.0 mg).
• Many physicians reported improvements in symptoms with 3.0 mg, in particular, favourable long-term effects on negative symptoms with 3.0 mg without the need to increase the dosage.
• Caution to be exercised when down-titrating medications with pronounced antihistaminergic/antimuscarinic effects like olanzapine, quetiapine or clozapine. In stable patients, switching from risperidone is not usually associated with histaminergic/muscarinic rebound. However, a dopaminergic rebound is possible, and hence an overlap of at least 2–3 weeks is usually recommended.
• If the patient is stable and treated with olanzapine, quetiapine or clozapine, the switch will be usually performed over a longer time period (3–4 weeks) owing to the risk of both antihistaminergic/muscarinic and dopaminergic rebound.
• Refer to the switching strategies 

Main patient characteristics for use : 

• First Episode of Psychosis
• Negative Symptoms in Schizophrenia
• Schizophrenia and concomitant substance use disorder – cariprazine is a partial agonist at dopamine D2/D3 receptors. As such, it may have a role in reducing cravings in schizophrenia patients with substance use disorder.
• Cariprazine improves social functioning and may have a place as add-on therapy (at low dosages) in treatment-resistant patients, including those on clozapine or long-acting antipsychotics (LAI).
• Two case reports of cariprazine add-on to clozapine showed remarkable and relatively rapid efficacy in treating subjects with inadequate response to clozapine. There were no reported adverse effects. [De Berardis et al, 2019]
• A further case series (n =5 cases) showed the benefits of augmenting clozapine with cariprazine for negative symptoms. In 4 of these cases, other augmentation strategies including amisulpride augmentation had failed. The dose of cariprazine used in all cases was 1.5 mg /day. [Oloyede et al, 2022]
• Those with significant side effects (i.e., metabolic side effects, hyperprolactinemia, or sedation) from other antipsychotics during periods of stability.

Mood Disorders: [Stahl et al., 2020]

Bipolar Depression:

• Cariprazine is the first D3-preferring dopamine-serotonin partial agonist (along with antagonists quetiapine, olanzapine/fluoxetine combination, and lurasidone) FDA-approved for the treatment of bipolar depression.

Bipolar I disorder:

• Cariprazine is FDA-approved for the treatment of bipolar I disorder across the spectrum from mania to depression.

Unipolar Depression: 

• One positive trial and others ongoing as an augmenting agent in patients with unipolar depression.

SUMMARY

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist with a promising safety and tolerability profile.

The unique pharmacokinetic and pharmacodynamic properties of cariprazine have important theoretical implications in terms of the therapeutic options for treating cognition, mood, and negative symptoms in patients with schizophrenia.

Evidence suggests that cariprazine may also be useful across the mood disorder spectrum.

Click on the image to download the PDF on Cariprazine (Reagila^®) for the treatment of Negative Symptoms in Adults with Schizophrenia.

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