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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 77-82

Cariprazine for late-life psychiatric illness: A review on therapeutic potential and challenges


1 Department of Psychiatry, Viswabharathi Medical College, Kurnool, Andhra Pradesh, India
2 Department of Psychiatry, Varma Hospitals, Bhimavaram, Andhra Pradesh, India

Date of Submission11-Nov-2021
Date of Decision12-Dec-2021
Date of Acceptance01-Jan-2022
Date of Web Publication31-Jan-2022

Correspondence Address:
Dr. Shiva Shanker Reddy Mukku
Department of Psychiatry, Viswabharathi Medical College, Kurnool - 518 463, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jgmh.jgmh_43_21

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  Abstract 


Clinicians often face many challenges in the pharmacological treatment of late-life psychiatric illness especially while choosing an antipsychotic drug. The choice of antipsychotic is mostly guided by the extension of evidence from the adult population and tolerability. In India, based on evidence commonly prescribed antipsychotic drugs for older adults are quetiapine (QTP) followed by olanzapine (OLZN) and risperidone. Cariprazine is a newer antipsychotic that was recently launched in India. It is a novel mechanism of action at D3 receptors is known to have antidepressant and procognitive action in addition to the antipsychotic effects which is desirable in geriatric population. It can be a potential option as an add-on drug in late-life depression in addition to the existing aripiprazole and OLZN. The treatment of late-life mania and very late-onset schizophrenia is limited by the paucity of studies, with randomized control studies done only on QTP and amisulpride, respectively. Cariprazine can be considered in late-life psychotic disorders with the evidence available from its efficacy studies in adult patients. Merits of cariprazine are favorable metabolic profile, cardiac safety, and procognitive action. Demerits include extrapyramidal symptoms and fluctuations in blood pressure. Slower titration and monitoring for akathisia are recommended. There is a need for controlled studies in older adults with cariprazine to get better informed about its efficacy and safety.

Keywords: Cariprazine, challenges, older adults, psychiatric illness, tolerability


How to cite this article:
Reddy Mukku SS, Nadella RK, Kornapalli SE. Cariprazine for late-life psychiatric illness: A review on therapeutic potential and challenges. J Geriatr Ment Health 2021;8:77-82

How to cite this URL:
Reddy Mukku SS, Nadella RK, Kornapalli SE. Cariprazine for late-life psychiatric illness: A review on therapeutic potential and challenges. J Geriatr Ment Health [serial online] 2021 [cited 2022 May 23];8:77-82. Available from: https://www.jgmh.org/text.asp?2021/8/2/77/336913




  Introduction Top


From the time since Arvid Carlsson proposed the dopamine hypothesis for Schizophrenia, many antipsychotic drugs were synthesized with dopamine 2 receptor (D2R) antagonistic action. The first-generation antipsychotics which have prominent D2R antagonism were effective in reducing positive symptoms, however, they are ineffective for negative symptoms and cause higher rates of adverse effects in the form of disabling extrapyramidal symptoms (EPS).[1] The antipsychotics introduced later (second-generation), which have different receptor profiles, tried to overcome some of these limitations. Most of the second-generation act through antagonism at D2R and Serotonin receptors (5HT2AR) conferring a lower risk of EPS.[2] Some of the newer antipsychotics act as dopamine stabilizers (Aripiprazole [ARP] and Brexpiprazole) through their partial agonist action[3] and, a few others (Blonanserin and Lurasidone [LRD]) have antidepressant properties through 5HT6 and 5HT7 receptors.[4],[5] In the eternal pursuit for an ideal antipsychotic, Cariprazine is the newest addition to the list of existing atypical antipsychotics. Cariprazine monotherapy received the Food and Drug Administration approval initially in 2015 for the treatment of schizophrenia, manic/mixed episodes in bipolar disorder, and later for bipolar depression in 2019.[6],[7],[8] It is a partial agonist at dopamine receptors-D2Rs, D3Rs, and serotonin receptor 5-HT1AR, as well as antagonist at 5-HT2AR. The partial agonistic action at D2R, D3R, and 5HT1A contributes to antipsychotic and antimanic action. In addition, its antipsychotic action is also mediated by downregulation of NMDA and AMPA receptors. Cariprazine's high affinity at D3R is known to cause upregulation of D3R in prefrontal cortex which increases dopaminergic neurotransmission in prefrontal cortex, attributing to procognitive, antidepressant effects, and reduction in negative symptoms. The procognitive action is also mediated by indirect increase in cholinergic neurotransmission. Repeated high dose use is known to upregulate D2R in basal ganglia which increases the risk of extrapyramidal side effects.[9],[10],[11]

Cariprazine is available in developed countries since 2015 and was recently launched in the Indian market. In India, the older adult population is steadily increasing creating many challenges in terms of treatment and care. The prevalence of severe mental illness in older adults in India as per the National Mental Health survey is 2.0% (lifetime) and 0.68% (current).[12] Considering the aging factor, poor help-seeking attitudes, neglect, and medical co-morbidity in addition to psychiatric illness, the choice of antipsychotic is a carefully weighed decision by a clinician. In this article, we have reviewed the literature related to the therapeutic use of Cariprazine in late-life depression, late-life mania, and very late-onset schizophrenia (VLOSP). We have also discussed challenges associated with its use in older adults.


  Pharmacodynamic Comparison of Cariprazine with Other Antipsychotics Top


Cariprazine is unique among antipsychotics in the way of having a higher affinity for the D3R than natural agonist dopamine itself. This is attributed to the active metabolites of Cariprazine, desmethyl-cariprazine (DCAR), and didesmethyl-cariprazine (DDCAR) that have a higher affinity for D3R. This results in D3R blockade with cariprazine administration. In addition, Cariprazine has a relatively high affinity for 5HT1A receptors, similar to other antipsychotics, but lower relative affinity for 5HT2A receptors Cariprazine also has an affinity for the alpha 1B receptor. The outcome as a result of this receptor action profile of Cariprazine is antipsychotic, antimanic, procognitive, and antidepressant effects. It also causes postural hypotension as a result of antagonism at the alpha 1B receptor.[11],[13] Of all the antipsychotic drugs, there is more resemblance of cariprazine with blonanserin. Blonanserin is an atypical antipsychotic with a higher affinity for D2R and D3R compared to other antipsychotics. However, the Blonanserin is relatively D2R preferring compared to cariprazine which is more D3R preferring.[14] There are also some shared properties with ARP and brexpiprazole in terms of D2R and D3R partial agonism. The subtle differences include brexpiprazole has the strongest affinity at D2R followed by ARP and cariprazine, whereas, cariprazine has the strongest affinity D3R followed by ARP and brexpiprazole.[15]


  Pharmacodynamic Profile and Implication for Older Adults Top


Aging is associated with changes in D2R and D3R located in the striatum. Studies reported there is a gradual decrease in specific neurons with D2R and D3R in older adults in the substantia nigra.[11] This leads to a higher risk of extrapyramidal side effects with cariprazine in older adults. Another downside as a result of the decline in D3R could be the procognitive and antidepressant effects of cariprazine could be lesser in older adults as compared to young adults. Postural hypotension could be another potential problem considering the risk of falls in older adults. Comparison of pharmacokinetic and pharmacodynamic properties of cariprazine with other atypical antipsychotics are as shown in [Table 1].[14],[16]
Table 1: Comparison of cariprazine with commonly used atypical antipsychotics in older adults

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  Pharmacokinetic and Implications for Older Adults Top


The absorption of cariprazine is minimally affected by food. Cariprazine undergoes demethylation to produce two major active metabolites, DCAR and DDCAR. The half-life of cariprazine, DCAR, and DDCAR in humans is 1–3 days, 1–2 days, and 2–3 weeks, respectively. DCAR and DDCAR are the major circulating metabolites in plasma. Cariprazine is metabolized through the CYP3A4 and to a lesser extent by CYP2D6. It is a weak inhibitor of CYP3A4 and CYP2D6.[11],[13],[17] Cariprazine clearance though not affected by mild-moderate hepatic/renal impairment, it is best avoided in severe hepatic and renal failure.

Though the long half-life of cariprazine is beneficial in patients who often miss medication doses, it also has negative consequences. The long half-life of metabolites of cariprazine metabolites means in case of any extrapyramidal adverse effects it takes weeks for this adverse effect to resolve completely. Older adults who are more prone to EPS compared to young adults, this could become a serious issue. In older adults, slower titration of cariprazine is advisable. It is also important to monitor for akathisia in the initial days of starting cariprazine in older adults. Another problem is when there is a requirement of switching from cariprazine to another antipsychotic; the process of up-titration of the second antipsychotic may take longer due to the long half-life of metabolites of cariprazine. This could cause undue delay in optimizing the treatment for older adult patients.


  Late-Life Depression and Bipolar Depression Top


Second-generation antipsychotics are often used as an augmentation for the treatment of depression in older adults. Randomized controlled studies (RCT) in older adults with depression have shown ARP and olanzapine (OLZN) as effective add-on treatments.[18],[19] Quetiapine (QTP) augmentation is another effective strategy for depression in older adults.[20],[21]

There is only evidence for ARP and OLZN at the RCT level. However, OLZ with its poor metabolic profile becomes a less acceptable option for older adults. Thus, ARP is currently a reasonable option as an add-on treatment in older adults with depression.

In terms of late-life bipolar depression, there is a paucity of studies on antipsychotics. Post hoc analyses of RCTs suggest the efficacy of QTP and LRD as monotherapy in older adults with bipolar depression.[22],[23]

Cariprazine with D3R profile action and partial agonism at 5HT1A Serotonin receptors has antidepressant action.[24] In addition to antidepressant action, its procognitive profile makes it an attractive option for treating older adults with unipolar and bipolar depression. Regarding this there is evidence on procognitive action of cariprazine from studies on schizophrenia involving younger adults.[25] These studies reported improvement in cognitive status as measured by Positive and Negative Syndrome Scale cognitive subscale and cognitive drug research system attention battery. Notably, there was significant improvement in attention domain.[26] However, cariprazine should not be seen as cognitive enhancer for neurodegenerative conditions.

Another favorable aspect of cariprazine is in having shared properties with ARP which is often used as add-on therapy for late-life depression. Although there are no studies as of now where cariprazine is used as monotherapy for late-life depression, it has a potential role as an augmenting agent in late-life depression.


  Late-Life Mania Top


Only a few studies have specifically investigated the efficacy of antipsychotics for mania in older adults. The current clinical practice in relation to prescribing for mania in older adults is guided by effectiveness and safety data from the adult population. Among the very few studies on late-onset mania, a post hoc analysis of data from two QTP trials for mania on patients more than 55-year-old revealed that QTP at doses of 400–800 mg/day was effective.[27] At this dose, the risk of postural hypotension, excess sedation, dizziness, and weight gain are high in older adults. In a case series of three older adults with treatment-resistant mania with psychotic symptoms, clozapine (CLZP) was found to be effective at a dose range: 25–112.5 mg/day.[28] Although CLZP was effective, it is rarely chosen as a first choice antipsychotic especially in older adults due to sedation, risk of aspiration, agranulocytosis, and requirement of frequent monitoring for blood counts.

The newer drug cariprazine, which received approval for manic/mixed episodes of bipolar disorder, is another option that can be considered in older adults. Cariprazine though has a higher risk of akathisia, it does have a favourable metabolic profile, and has less risk of excess sedation which makes it a potential choice in late life mania. The rapid titration of cariprazine is another favorable aspect which is useful in the treatment of acute stage of mania, though slower titration is advisable in older adults.


  Very Late Onset-Schizophrenia Like Psychosis Top


Studies reported that 4% of patients have onset of Schizophrenia after the age of 60 years. VLOSP is distinguished by higher prevalence of multimodal hallucinations, cognitive symptoms, sensory impairments, and less negative symptoms.[29] The antipsychotic treatment of this subgroup of older adults with de novo diagnoses of schizophrenia is guided mainly by the safety profile and tolerability. In the only study on antipsychotic efficacy, low-dose amisulpride was found effective for VLOSP compared to placebo in a 12 weeks randomized control trial.[30] In a survey from 15 Asian countries about prescription patterns of antipsychotics in older adults with Schizophrenia, the most commonly prescribed SGAs with schizophrenia were risperidone (RSPN) and OLNZ[31] Whereas, a similar study from the western world reported that QTP and CLZP were the most frequently prescribed SGAs for older adults with schizophrenia.[32]


  Antipsychotic For Persons With Dementia Top


All guidelines recommend against the routine use of antipsychotic medication for behavioral and psychological symptoms of dementia (BPSD). However, bit less than one-third of persons with dementia (PwD) receive antipsychotics as reported in a meta-analysis of 43 studies.[33] Among the antipsychotics, currently, low-dose RSPN is the only approved drug for the treatment of aggression in PwD.

In Indian settings, two retrospective studies from tertiary care hospitals reported that QTP is the most common antipsychotics for behavioral problems including psychosis.[34],[35] The frequent use of QTP could be due to less risk of EPS and sedation property which is therapeutic for sleep disturbances in PwD. When it comes to cariprazine, high risk of EPS, long half-life will make it a less preferable choice as an alternative to QTP and RSPN. In PwD due to synucleinopathies (Parkinson's disease dementia,  Lewy body dementia More Details), the use of cariprazine can lead to severe and at times life-threatening EPS. Similar to all antipsychotic drugs, cariprazine received a black box warning for older adults with dementia. In this context, it is important to avoid excess use of antipsychotic in PwD with BPSD as per the guidelines and preferably use nonpharmacological interventions.


  Adverse Effects Top


Short-term safety of cariprazine was examined in four placebo controlled trials (6 weeks' duration) in patients with schizophrenia. The pooled analysis of four RCT reported that at a dose between 1.5 and 3 mg treatment emergent adverse events were similar to placebo and significant increase in adverse effects were reported beyond a dose of 6 mg. The common adverse effects reported were EPS, akathisia, and elevated diastolic blood pressure (BP).[36] The EPS could decrease the acceptance rate in older adults. The implication of short-term elevation of diastolic BP in older adults is not clear, though isolated diastolic hypertension is reported to increase the risk of mortality (RR: 1.39) in prospective studies.[37]

Medium- and long-term safety of cariprazine is mostly from open label studies which reported akathisia, insomnia, modest weight again, and headache as adverse effects. The commonest reason for discontinuation of cariprazine was akathisia and exacerbation of schizophrenia.[38] Urinary retention and hyperprolactinemia have been reported in case studies.[39],[40] There is no significant derangement in metabolic parameters, prolactin levels and in the electrocardiogram in long-term studies. There were also no sexual adverse effects reported with cariprazine.[41]

Cariprazine is metabolized predominantly by CYP3A4 as mentioned earlier. Strong inhibitors of CYP3A4 such as antifungals (ketaconozole), macrolide antibiotics (clarithromycin), protease inhibitors (indinavir), and antidepressants (fluvoxamine, nefazodone) can increase the level of cariprazine and might enhance the risk of adverse effects. On the other hand, antiepileptic's (carbamazepine, phenobarbitone, and phenytoin), protease inhibitors (ritonavir), and antitubercular drugs (rifampin) can induce CYP3A4 and thus reduce the efficacy of cariprazine.[42] In older adult group where polypharmacy is common, the risk of drug-drug interaction should be given attention to while prescribing cariprazine. There are no reported specific drug interactions of cariprazine with commonly used medication in older adults. However, similar to atypical antipsychotics drugs, it can increase the risk of hypotension and arrhythmias when co-administered antihypertensives; myalgia's with statins; and reduces the effectiveness of anticoagulants.[43]


  Dosage And Safety Of Cariprazine In Older Adults Top


The safety of cariprazine was examined in a 48-week open-label randomized trial conducted in Japan on patients with chronic schizophrenia and older adult patients–aged between 65 and 74 years. The trial included 125 patients, out of which 27 were above the age of 65 years. Among them, 17 received cariprazine and 10 received RSPN. Cariprazine with flexible dosing of 1.5–9 mg/day (1.5 mg, 3 mg, 6 mg, or 9 mg) was compared with RSPN 2–12 mg/day (2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg) (ClinicalTrials.gov.NCT01625897, study A002-A7).

Nearly all patients have at least one treatment emergent adverse effect in the cariprazine group. In the cariprazine group 11 had adverse reactions compared to 9 in the RSPN group. The number of patients with at least one serious adverse event was 4 in the cariprazine group and one in the RSPN group. During the study, 7 patients discontinued cariprazine due to adverse effects compared to one patient in the RSPN group. The frequent adverse events with cariprazine were nasopharyngitis, insomnia, hypertension, increased weight and exacerbation of schizophrenia.[44] Notably, there was increase in mean plasma glucose level by 20.8 mg/dl by the end of study. QT prolongation was also noted in one older adult patient.


  Current Guidelines on Cariprazine Top


The American Psychiatric Association (APA) recommends use of cariprazine similar to other atypical antipsychotics in patients with schizophrenia.[45] The Canadian Network for Mood and Anxiety Treatments and International Society for Bipolar Disorders guidelines recommend cariprazine as first-line monotherapy for acute mania and second-line monotherapy for acute bipolar depression.[23] The National Institute for Health and Care Excellence (NICE) guidelines on psychosis which were last updated in 2015 have not recommended use of cariprazine for schizophrenia.[46] APA, NICE, or CANMET guidelines have not specifically commented about the use of cariprazine in older adult patients.


  Cost-Analysis and Challenges Top


In India, currently, only one company (Sun Pharmaceutical Industries Limited and its Subsidiaries) is marketing cariprazine. The price of 10 tablets of lowest dose (1.5 mg) and maximum available dose (6 mg) are INR. 99 and INR.310 respectively. Assuming a patient require medication for 1 year, the annual cost range from INR. 3613.5 (lowest dose) to INR. 11315 (highest dose). As per the recent National Sample Survey (2017–2018), nearly 70% of older adult in India are dependent on others for day to day needs. On this background and lack of adequate social security measures for older adults in India and most of health care payments are out of pocket expenditures, affording cariprazine can still put a financial stress on families.


  Cariprazine as an Alternative to Other Antipsychotic for Older Adults in India Top


Two retrospective studies on prescription pattern on older adults in India reported OLNZ followed by QTP and RSPN as commonly used antipsychotic drugs.[47],[48] From these studies, it is observed that there is a trend of choosing second generation antipsychotics in older adults, especially with low EPS risk. Now with the addition of cariprazine to the pool of the antipsychotics that are available to choose for older adults will certainly bring discussion among clinicians. Pointers that favor cariprazine use for older adults include lesser propensity to cause sedation, anticholinergic adverse effects, metabolic adverse effects, sexual adverse effects and broad spectrum utility for severe mental illness as shown in [Table 2]. Pointers against cariprazine use for older adults include risk of akathisia, parkinsonian symptoms, and lack of adequate studies that included older adults related to safety and efficacy.
Table 2: Beneficial implications of cariprazine in older adults

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  Conclusion Top


Choosing antipsychotic in older adults with psychiatric illness is associated with several challenges owing to medical comorbidity, cognitive impairment, higher risk of neuroleptic sensitivity and poor help seeking behaviors. The task is further compounded by the lack of clear guidelines and safety data for many antipsychotics in the older adult population. Cariprazine with its D3R preferring action has more similarities with blonanserin and ARP. Procognitive and antidepressant action in addition to antipsychotic effect of cariprazine make it a potential choice for older adults with VLOSP, mania and as an add-on for the treatment of depression. Cariprazine at dose above 6 mg significantly increases the risk of adverse effects. Slower titration, aiming for a lower dose and monitoring for akathisia is advisable when starting cariprazine for older adults. There is a need for more controlled studies related to the efficacy and safety of cariprazine in older adults to guide clinicians.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Pharmacodynamic ...
Pharmacodynamic ...
Pharmacokinetic ...
Late-Life Depres...
Late-Life Mania
Very Late Onset-...
Antipsychotic Fo...
Adverse Effects
Dosage And Safet...
Current Guidelin...
Cost-Analysis an...
Cariprazine as a...
Conclusion
References
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