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Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will look at a possible treatment option for pediatric patients with schizophrenia or bipolar I disorder. Now, I do not have to tell you that the need is enormous. This remains an understudied area and a challenge.
Although the current treatment options are helpful, they still need to be improved. Too many children, adolescents, and families suffer when treatment is only partially effective, ineffective, or if patients are treatment resistant. So, the need is huge, as the current treatment options still need to be improved. I am not bashing the treatment options. We use them, and they can be very effective in many patients, but there are risks and benefits, side effects, and some patients do not respond to or tolerate the medications. Thus, more work is needed.
The first-line medication treatment—the atypical antipsychotics—can also have significant side effects. We know youth are especially vulnerable to these side effects and much more exquisitely sensitive to experiencing them. Cariprazine is an interesting compound to study as it is a D3 preferring and D2 and 5-HT1A receptor partial agonist. Cariprazine is FDA approved to treat adults with schizophrenia and bipolar I disorder manic/mixed or depressive episodes.
So, this open-label study enrolled 50 pediatric patients with schizophrenia or bipolar disorder 13–17 years of age. Patients were assigned to either slow titration of cariprazine over 6 weeks from 1.5 mg–4 mg/day or fast titration to 4.5 mg/day. So, what did they find? The good news is that cariprazine was safe and well-tolerated in pediatric patients with schizophrenia and bipolar I disorder. The pharmacokinetic profile of cariprazine was consistent in pediatric and adult patients. Moreover, that is interesting because that is not always the case with psychotropic medicines in pediatric vs adult patients. Cariprazine was associated with no significant changes in prolactin levels. D2 receptor antagonism is associated with increased prolactin levels; however, cariprazine is a D3-preferring receptor partial agonist, which may be associated with its favorable effects regarding prolactin and metabolic levels, making it appealing potentially.
There was a greater incidence of weight gain in 10–12-year-olds treated with cariprazine than in the 13–17-year-olds. Some adverse events, such as increased transient diastolic blood pressure, were observed more commonly in the fast titration vs slow titration phase. This may be associated with a longstanding child and adolescent psychiatry principle: Start low and go slow to enhance tolerability. In my experience, I have seen far too many times where a good medication choice is ruined because of being too aggressive, starting too high, or increasing the dose too rapidly and not giving the child or adolescent time to become tolerant to the medicine.
One exciting finding that, if replicated, could be huge and underscores the need for future controlled studies was that not only symptoms improved in pediatric patients with schizophrenia or bipolar I disorder patients treated with cariprazine, but the improvement was maintained even during the follow-up period when cariprazine was discontinued. Now, some of the patients did restart their previous medicines. However, these findings are consistent with prior findings in adults with schizophrenia, where patients who discontinued cariprazine had delayed schizophrenia relapse compared with adults with schizophrenia who discontinued other medicines used to treat schizophrenia. Moreover, it has been suggested this may be due to the longer half-life of didesmethyl cariprazine—one of the active metabolites of cariprazine—which has been shown to occupy D2 and D3 receptors for 4 weeks after the last dose. The half-life of didesmethyl cariprazine in pediatric patients is also similar to that in adult patients. So, the sustained improvement with cariprazine observed in adults may also be seen in pediatric patients.
Now, this is an open-label study first look, so controlled studies are needed, but they are definitely merited. Moreover, if this is replicated, it would be a significant finding. The bottom line is that this is a very promising area, but it is not yet ready for prime time.
However, clinicians treating pediatric patients with schizophrenia and bipolar I disorder should keep this on their radar.
With controlled randomized clinical trials in pediatric patients warranted, exciting times are ahead.
Abstract
Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia
Todd Riccobene, Robert Riesenberg, Paul P Yeung, Willie R Earley, Arlene L Hankinson
Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. Methods: This phase I open-label study enrolled patients with schizophrenia (13-17 years of age) or bipolar I disorder (10-17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. Results: A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1-2 weeks for cariprazine and DCAR and within 4-5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. Conclusion: In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.
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Reference
Riccobene, T., Riesenberg, R., Yeung, P. P., Earley, W. R., & Hankinson, A. L. (2022). Pharmacokinetics, safety, and tolerability of Cariprazine in pediatric patients with bipolar I disorder or schizophrenia. Journal of Child and Adolescent Psychopharmacology, 32(8), 434-443.
