Background
Schizophrenia is a chronic and debilitating neuropsychiatric disorder with high rates of medical morbidity and mortality [
1]. To manage symptoms and prevent relapse, long-term pharmacotherapy is often required [
2]. Antipsychotic drugs, which are the foundation of treatment in schizophrenia, differ in many properties and cannot therefore be easily categorized by first- or second-generation distinctions [
3]. Even antipsychotics introduced since clozapine (ie, the atypical antipsychotics) do not share a similar class-related pharmacologic profile [
4]. Although only small differences in efficacy have been observed among antipsychotic agents in clinical trials, there is variability in individual patient response, as well as in the side effect and tolerability profiles [
3]. These factors warrant careful consideration when choosing an antipsychotic treatment.
While first-generation agents are associated with high risk of extrapyramidal symptoms (EPS) and sustained prolactin elevation, second-generation agents have shown a propensity for other important adverse effects including weight gain, metabolic and cardiac abnormalities, somnolence, and sedation [
5,
6]. Understanding the side effect profile of an antipsychotic is critical since efficacy can only be viewed within the context of tolerability and the ability of the patient to remain on treatment. In this vein, poor tolerability has been identified as a barrier to medication adherence for patients with schizophrenia [
7], and medication nonadherence is associated with considerable consequences including greater risk of relapse, longer time to remission, hospitalization, and attempted suicide [
8].
Cariprazine is a potent dopamine D
3 and D
2 receptor partial agonist with preferential binding to D
3 receptors; it is FDA-approved in the United States for the treatment of schizophrenia (1.5–6 mg/d) and manic or mixed episodes associated with bipolar I disorder (3–6 mg/d) in adults. Cariprazine has demonstrated preferential binding to D
3 receptors in vitro [
9], and it has shown high in vivo occupancy of both D
3 and D
2 receptors at antipsychotic-effective doses in rats [
10] and in clinically active dose ranges in patients with schizophrenia [
11]. Other atypical antipsychotics, such as aripiprazole, clozapine, olanzapine, and risperidone, show varying levels of in vitro affinity for D
3 receptors, but fail to show substantial in vivo D
3 receptor occupancy in patients at clinically relevant doses [
12‐
14]. Cariprazine also acts as an antagonist at serotonin 5-HT
2B receptors and as a partial agonist at 5-HT
1A receptors, with lower affinity for 5-HT
2A, 5-HT
2C, histamine H
1, and adrenergic α
1 receptors and negligible affinity at other receptors [
9]. This receptor binding profile may provide potential tolerability benefits since some negative side effects, such as sedation and weight gain, have been associated with affinity at the 5-HT
2C and H
1 receptors [
15‐
17], and some cardiovascular AEs may be associated with affinity at adrenergic α
1 receptors [
18]. Of note, cariprazine has a complex pharmacokinetic profile, with 2 major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, and a long effective half-life for the total active moieties [
19].
The short-term safety and efficacy of cariprazine in schizophrenia have been demonstrated in 3 randomized, 6-week, double-blind, placebo-controlled, phase II (RGH-MD-16) and phase III (RGH-MD-04 and RGH-MD-05) clinical trials [
20‐
22]; active comparators to assess assay sensitivity were used in RGH-MD-16 (risperidone) and RGH-MD-04 (aripiprazole). The long-term safety and tolerability of cariprazine has been evaluated in two 48-week, open-label, flexible-dose extension studies (RGH-MD-11 [NCT01104792] and RGH-MD-17 [NCT00839852]) [
23,
24]. Study RGH-MD-11 included rollover patients from the short-term lead-in studies (RGH-MD-04 and RGH-MD-05) as well as newly enrolled patients, while study RGH-MD-17 only included rollover patients from RGH-MD-16. To further characterize the long-term safety of cariprazine, data from these extension studies were pooled for post hoc analyses.
Methods
The protocols of the constituent studies included in these pooled post hoc analyses were approved by an institutional review board or ethics committee and the studies were conducted in compliance with guidelines for good clinical practice; all patients gave informed written consent to participate.
Since the long-term studies included in these analyses were flexibly dosed, this post hoc investigation evaluated safety and tolerability parameters in both the overall pooled population and in patient subgroups based on modal daily dose (the most frequently used dose during the study). Modal daily dose groups allowed us to assess long-term cariprazine exposure and the potential for dose-response relationships in various safety parameters within the FDA-recommended dose range. The modal daily dose groups that were evaluated in these investigations were cariprazine 1.5–3 mg/d, 4.5–6 mg/d, and 9 mg/d.
Study design
Results from 2 long-term, open-label, flexible-dose studies were pooled for these analyses. In RGH-MD-11, cariprazine was administered in a range of 3–9 mg/d and in RGH-MD-17, the dose range was 1.5–4.5 mg/d. Each study was 53 weeks in duration, consisting of a no-drug screening period of up to 7 days, a 48-week open-label flexible-dose cariprazine treatment period, and a 4-week safety follow-up period. Cariprazine was initiated at 1.5 mg/d on day 1 of both studies. In RGH-MD-11, 1.5-mg dose increases could be made on days 2, 3, and 5, and on day 8, a 3-mg increase could be made to the maximum 9 mg/d dose. In RGH-MD-17, 1.5-mg dose increases could be made on days 2 and 3 to reach the 4.5 mg/d maximum dose. Doses were increased only if response was inadequate and there were no tolerability issues; dosage could be decreased by 1.5-mg/d increments at any time due to tolerability issues.
In both studies, all patients were hospitalized during the first week of open-label treatment; thereafter, patients remained hospitalized for an additional 1 or 2 weeks at the discretion of the investigator or they were discharged and followed-up as outpatients. In the event of clinical deterioration, outpatients could be rehospitalized for safety reasons. For patients who completed a lead-in study, the medical, psychiatric, and medication histories obtained at the first lead-in study visit were used in the extension.
Inclusion criteria
All patients who participated in the long-term safety studies were 18 to 60 years of age, inclusive, and had a current
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [
25] diagnosis of schizophrenia for a minimum of 1 year. Participants had normal physical examination, clinical laboratory, vital sign, and electrocardiogram (ECG) results or abnormal results that were not considered clinically significant; female patients of childbearing age were not pregnant or breastfeeding. In RGH-MD-11, patients had either completed 6 weeks of double-blind treatment in a lead-in study (RGH-MD-04 [
20] or RGH-MD-05 [
22]) or were newly enrolled patients; all patients were required to have a score ≤ 25 on the Positive and Negative Syndrome Scale (PANSS) [
26] positive subscale score (PANSS items P1 to P7) and a score ≤ 3 on the Clinical Global Impressions-Severity of Illness (CGI-S) [
27]. In RGH-MD-17, eligible patients had completed 6 weeks of double-blind treatment in lead-in study RGH-MD-16 [
21] and responded to treatment (CGI-S score ≤ 3 and PANSS total score reduction ≥20% from lead-in study baseline). Patients had a designated caregiver to attend study visits with them or provide written documentation verifying medication compliance.
Exclusion criteria
Typical exclusion criteria for clinical trials in schizophrenia were applied. Briefly, patients were excluded if they had various psychiatric diagnoses other than schizophrenia (eg, other psychotic disorders, bipolar disorder, cognitive disorders, or alcohol or substance abuse or dependence [with the exception of nicotine or caffeine dependence] within 3 months of the study). Patients with treatment-resistant schizophrenia (no symptomatic response to at least 2 antipsychotic trials of adequate dose and duration), suicide risk (ie, attempt within past 2 years or investigator judged), and a first psychotic episode were also excluded. Additionally, patients were excluded for any concurrent medical condition that may have interfered with the conduct of the study, confounded the interpretation of the study results, or endangered the patient’s well being. Existing issues related to safety and tolerability including clinically significant, uncontrolled adverse events (AEs), EPS that were not adequately controlled by EPS medications, and various ophthalmology assessment criteria were exclusionary. Patients who required concomitant treatment with prohibited medications including psychotropic drugs were excluded; lorazepam (for agitation, irritability, hostility, and restlessness), eszopiclone, zolpidem, zolpidem extended release, chloral hydrate, or zaleplon (for insomnia), and diphenhydramine, benztropine or equivalent, or propranolol (for EPS or akathisia) were allowed.
Outcome assessments
The long-term safety and tolerability of cariprazine were the primary objectives of the extension studies. Safety parameters included AEs, vital signs, clinical laboratory tests, ECGs, physical examinations, and ophthalmologic examinations. Suicidality was assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) [
28] in RGH-MD-11 and the Suicidality Tracking Scale (STS) [
29] in RGH-MD-17. EPS and movement disorders were evaluated by AE reports and rating scale assessments: Barnes Akathisia Rating Scale (BARS), [
30] Abnormal Involuntary Movement Scale (AIMS), [
31] and Simpson-Angus Scale (SAS) [
32].
Pooled PANSS findings summarized changes in the symptoms of schizophrenia. Although no efficacy conclusions can be made based on changes in PANSS because of the lack of a comparator group in this open-label study, it is of note that increased (worse) PANSS scores could indicate a worsening of the clinical condition and could also be evaluated as a safety concern.
Data analysis
Safety analyses were performed on the safety population, which consisted of patients who received at least one dose of cariprazine during the open-label extension period; findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5–3, 4.5–6, and 9 mg/d). Analysis of modal daily dose groups were conducted to evaluate potential dose-response relationships in safety parameters. For patients continuing from a lead-in study, the lead-in study safety baseline was used as the baseline for all analyses of safety parameters; for new patients (RGH-MD-11), the baseline was the last value before the first dose of open-label cariprazine.
AEs were classified by the preferred term. For patients who completed a lead-in study, an AE that started during open-label treatment was considered a treatment-emergent adverse event (TEAE) if it was not present before the first dose of double-blind treatment in the lead-in study or if it increased in intensity after the first dose of open-label treatment. For new patients, an AE that started during open-label treatment was considered a TEAE if it was not present before the first dose of open-label treatment or if it increased in intensity after the first dose of open-label treatment.
In the studies that were pooled, efficacy assessments were collected but not categorized as primary, secondary, or additional. Change from baseline to end of treatment in PANSS total score was summarized using descriptive statistics; no inferential statistics were performed.
Discussion
Pooled analyses of data from these 2 open-label, 48-week extension studies supported previous findings from studies investigating safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia. These data may approximate safety findings in the recommended dose range for cariprazine in schizophrenia since almost 80% of patients were in modal daily dose groups in the 1.5–6 mg/d range (1.5–3 mg/d = 170 patients; 4.5–6 mg/d = 361 patients) as opposed to a higher dose (9 mg/d = 148 patients). Approximately 40% of cariprazine-treated patients overall completed the study, with higher completion rates observed in the approved daily dose range (1.5–6 mg/d) than in the 9 mg/d modal daily dose group. The overall completion rate for open-label cariprazine was comparable to rates seen in similarly designed safety studies for other atypical antipsychotics including lurasidone (12-month completion = 36.7% [
33]), iloperidone (25-week completion = 41.6% [
34], and ziprasidone (12-month completion = 36.9% [
35]).
At least 1 TEAE was reported by most patients in the long-term schizophrenia studies; approximately 70% were considered mild or moderate and approximately 60% were considered related to treatment. Discontinuations due to AEs occurred more frequently in the 1.5–3 mg/d and the 9 mg/d dose groups than in the 4.5–6 mg/d group, which is counterintuitive and may have been the result of a patient selection bias. The only AEs that led to discontinuation of ≥2% of patients in any group were akathisia, worsening of schizophrenia, and worsening of psychotic disorder.
Cariprazine has a complex pharmacokinetic profile, with 2 major active metabolites, desmethyl cariprazine and didesmethyl cariprazine. The effective half-life for the total active moieties, which takes into account cariprazine and the 2 major active metabolites, is approximately 1 week [
19]. The long half-life triggered initial concern that cariprazine could potentially be associated with dose-related adverse effects and accumulation of the parent drug and active metabolites beyond levels needed for effectiveness. Specifically, post hoc analyses of safety findings from the short-term controlled cariprazine studies in schizophrenia [
20‐
22] showed a dose-response relationship for some TEAEs and clinical laboratory values including akathisia, extrapyramidal disorder, CPK elevations, transaminase elevations, and increases in blood pressure [
36]. However, investigating the incidence of safety events in modal daily dose groups helped alleviate concerns about the pharmacokinetics of cariprazine since the risk of these events was determined to be lower at doses ≤6 mg/d than at doses ≥9 mg/d. As such, better tolerability observed at lower cariprazine doses helped establish the FDA-recommended dose range of 1.5–6 mg/d for treating schizophrenia. Results from the post hoc analyses of long-term cariprazine safety data presented here found no new safety concerns related to the pharmacokinetic profile and long half-life of cariprazine. Additionally, there was no evidence of delayed resolution of adverse effects after cariprazine discontinuation. AEs that resulted in discontinuation resolved in 80% of patients, with the median time to resolution of 12 days; the median time to resolution of akathisia/restlessness was 15 days.
The only TEAES reported in ≥10% of patients overall were akathisia, insomnia, headache and weight increased; anxiety and tremor were reported in ≥10% in 1 of the dose groups within the FDA-recommended dose range and worsening of schizophrenia was reported in 11% of patients in the 9 mg/d dose group. The incidence of treatment-related sedation and somnolence, which can interfere with quality of life in a substantial minority of patients with schizophrenia [
6], was generally low (3%–4%) and no dose response was observed for these TEAEs. SAEs were nearly twice as likely to occur at the highest dose (9 mg/d) than in the FDA-recommended dose range (1.5–6 mg/d), although the most commonly reported SAEs (worsening of schizophrenia and psychotic disorder) were reported in <5% of patients overall.
Weight gain, dyslipidemia, and glucose dysregulation, which contribute to cardiovascular risk in patients with schizophrenia, are common treatment-related side effects of atypical antipsychotics [
37]. Consequently, the effect of cariprazine on these parameters is an important long-term safety consideration. In these post hoc analyses, no dose-response relationship was observed for metabolic parameters and there were no mean increases from baseline in lipid parameters over time with long-term cariprazine treatment. Mean changes from baseline to the end of long-term treatment for fasting glucose (4.5 mg/dL) and the proportion of patients with treatment-emergent significant changes in lipid parameters were similar to changes observed in the 6-week controlled studies [
36]; however, the incidence of significant treatment-emergent changes in fasting glucose tended to increase over time with long-term treatment. The overall mean change from baseline in weight at the end of long-term open-label treatment was small (1.58 kg) and only slightly greater than the weight change observed in the 6-week controlled cariprazine studies in schizophrenia (~1 kg) [
20‐
22]. Although weight increases ≥7% were observed in 23%–29% of cariprazine-treated patients across the modal dose groups during long-term treatment, no weight gain event was an SAE or led to study discontinuation. Unlike data from the 6-week controlled trials in schizophrenia, which showed a dose-response relationship for weight gain in cariprazine-treated patients, no consistent pattern of weight-related changes was seen among the dose groups in the pooled 48-week dataset. Weight decreases ≥7% occurred in 11% of cariprazine-treated patients overall, with an apparent dose-response relationship observed (1.5–3 mg/d = 7.5%; 4.5–6 mg/d = 10.3%; 9 mg/d = 16.2%).
Cardiac AEs were minimal among all dose groups, with no individual TEAE occurring in ≥2% of cariprazine-treated patients. There was no mean increase in QTc interval overall; 3 patients had a postbaseline QTcB value >500 msec, one of whom also had a postbaseline QTcF value >500 msec. Shift from normotensive blood pressure to Stage I or Stage II hypertension occurred in a higher percentage of patients in the 9–12 mg/d group than in the lower dose groups.
Akathisia is one of the most commonly recognized treatment-emergent effects associated with antipsychotic treatment, although it is generally reported to be less prevalent with second-generation antipsychotics than with first-generation agents [
38‐
40]. It remains a clinically significant adverse effect however, as shown by results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, which found that the percentage of patients with schizophrenia who developed akathisia was not significantly different for the intermediate-potency first-generation antipsychotic perphenazine and 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) [
41]. Although the distress of antipsychotic-induced akathisia can be severe enough to adversely affect treatment adherence and long-term patient outcomes [
38], it is routinely managed along with other disease-induced or drug-induced symptoms in clinical practice [
39].
Akathisia was the most commonly observed TEAE in this pooled 48-week dataset; most occurrences were mild to moderate in severity, considered related to treatment, and rarely led to treatment discontinuation. The first occurrence of akathisia was generally reported within the first 6 weeks of treatment and it resulted in few discontinuations overall (0.9%) or in the modal daily dose groups (0 [9 mg/d group] to 2.9% [1.5–3 mg/d group]). In long-term cariprazine treatment, the majority of patients used medication to manage symptoms of akathisia/restlessness, regardless of the severity of the event. Along with the low rate of discontinuation due to akathisia, this suggests that akathisia was managed by most patients while continuing treatment with cariprazine.
Ocular safety was evaluated in the long-term cariprazine studies in patients with schizophrenia in response to ocular findings from preclinical studies in dogs and rats. In these long-term, open-label pooled analysis, blurred vision was the most commonly reported ocular AE. One patient in the 1.5–3 mg/d group had an AE of cataract that in the judgement of an independent ophthalmologist was not considered a pathological event based on its unilateral nature and rapid reversal, which are atypical of drug-induced cataracts. No ocular SAEs were reported. From these analyses, ophthalmologic AEs associated with cariprazine appear to be rare and not likely related to treatment.
These analyses were subject to the limitations inherent in post hoc analyses, as well as the limitations of open-label study design in which there was no placebo- or active-comparator group. Per the constituent study protocols, safety parameters were not analyzed using inferential statistics. The results of these analyses may have been confounded by a heterogeneous dataset that included patients who had completed a lead-in study as well as patients who were newly enrolled; additionally, patients who continued from a lead-in study may have received either placebo, cariprazine, or aripiprazole. Lack of a randomized study population and the use of modal dose groups may have resulted in patient selection bias. A tolerability bias in favor of patients in the high modal daily dose group may have existed since patients with tolerability issues at lower doses may have been more likely to discontinue the study and less likely to increase their dosage. Conversely, completion rates may have been effected by a bias against patients in the 9 mg/d dose group in reference to discontinuations due to insufficient therapeutic response, as well as discontinuations due to AEs of schizophrenia and psychotic disorder. These events, which occurred at the greatest frequency in the high dose group, may reflect the propensity to increase the dose in patients who do not respond at a lower dose level, indicating potential treatment resistance. Of note, worsening of the underlying condition, in this case schizophrenia and psychotic disorder, is categorized as an AE when in actuality it may be an additional indication of poor treatment response or lack of efficacy. Furthermore, worsening of schizophrenia may be a sign of treatment noncompliance or inconsistency, which is a common problem that may lead to worse outcomes in patients with schizophrenia [
8].
Acknowledgements
Writing assistance and editorial support for this manuscript were provided by Carol Brown, MS, of Prescott Medical Communications Group, Chicago, Illinois, a contractor of Allergan.
Competing interests
HN has been a consultant for Acadia, Alkermes, Allergan, Boehringer Ingelheim, Grünenthal USA, Inc., Janssen Pharmaceuticals, Inc., Lundbeck, Merck Sharp & Dohme Corp., Novartis Corporation, Otsuka Pharmaceutical Co., Ltd., Roche/Genentech, Sunovion Pharmaceuticals, Inc., and Vanda Pharmaceuticals; he has served on speakers’ bureaus for Acadia, Alkermes, Allergan, Janssen Pharmaceuticals, Inc., Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Inc. and Vanda; he has received grant/research support from Forest Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., and Roche/Genentech. AC has received research grants and consultant/speaker fees from Acadia, Alkermes, Allergan, AstraZeneca, Braeburn Pharmaceuticals, Forum Pharmaceuticals, Janssen (Johnson & Johnson), Eli Lilly, Lundbeck, Neurocrine, Novartis, Otsuka, Reckitt Benckiser, Sunovion, Takeda, Teva, and Vanda. SD, WE, YW, and KL acknowledge a potential conflict of interest as employees of Allergan. IL and GN acknowledge a potential conflict of interest as employees of Gedeon Richter Plc.