Abstract
To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1–4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.
Keywords: adjunctive treatment, cariprazine, major depressive disorder, safety
Introduction
Although antidepressant therapy (ADT) is a common first-line strategy for treating major depressive disorder (MDD), many people have inadequate response to standard therapy (Rush et al., 2006; Pigott et al., 2010; Papakostas, 2016) and only a minority of patients achieve remission of symptoms (Rush et al., 2006; Carvalho et al., 2007). Inadequate treatment response is a critical unmet need since MDD is a leading cause of worldwide disability and mortality (Walker et al., 2015; Friedrich, 2017), and a source of considerable economic burden (Greenberg et al., 2015). Augmenting ongoing ADT with another agent (e.g. atypical antipsychotic, lithium salts) is a recommended strategy for improving treatment response (APA, 2010; Kennedy et al., 2016) and meta-analyses support the efficacy of several second-generation antipsychotics (SGAs) for adjunctive treatment of MDD (Papakostas et al., 2007; Nelson and Papakostas, 2009; Zhou et al., 2015; Mishra et al., 2022; Nunez et al., 2022; Yan et al., 2022). In the USA, aripiprazole, quetiapine XR, brexpiprazole and cariprazine are approved for this indication. Since SGAs are associated with some relatively common adverse effects (e.g. akathisia, weight gain, metabolic dysfunction) (Spielmans et al., 2016) and a small risk of tardive dyskinesia with extended therapy, clinicians must balance tolerability and safety concerns against potential efficacy when selecting treatment for patients with MDD.
Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist that is Food and Drug Administration-approved to treat adults with schizophrenia, acute manic/mixed and depressive episodes of bipolar I disorder, and as adjunctive treatment in MDD. The clinical development program for adjunctive cariprazine in MDD included 3 early flexible-dose studies (Durgam et al., 2016; Earley et al., 2018; Fava et al., 2018) and 2 identically designed phase 3 fixed-dose studies investigating cariprazine 1.5 or 3 mg/d (Riesenberg et al., 2023; Sachs et al., 2023) (Table 1). Statistically significant differences versus placebo on the primary outcome, change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) total score, were seen in favor of cariprazine 2–4.5 mg/d plus ADT in one flexible-dose study (Durgam et al., 2016) and for cariprazine 1.5 mg/d plus ADT in one fixed-dose study (Sachs et al., 2023). Across all studies, adjunctive cariprazine was generally well tolerated, with reported adverse experiences consistent with the monotherapy safety profile observed in studies of schizophrenia, mania, and bipolar I depression (Earley et al., 2017b, 2017a, 2020).
Table 1.
Summary of clinical studies: cariprazine as adjunctive treatment for MDD
| Study identifier/NCT (phase) US/non-US enrollment period |
Study design/treatment duration | Treatment (n)a | Cariprazine dosing and titration scheduleb |
|---|---|---|---|
| 3111-301-001/NCT03738215 (phase 3) US and non-US 11/09/2018–9/27/2021 (Sachs et al., 2023) |
6-week DB; inadequate response to 1–3 ADTs |
Cariprazine 1.5 mg + ADT (n = 252) Cariprazine 3 mg + ADT (n = 252) Placebo + ADT (n = 253) |
Fixed • All patients received 1.5 mg on days 1–14 • 3 mg group: patients uptitrated to 3 mg on day 15 |
| 3111-302-001/NCT03739203 (phase 3) US and non-US 11/10/2018–9/6/2021(Riesenberg et al., 2023) |
6-week DB, inadequate response to 1–3 ADTs |
Cariprazine 1.5 mg + ADT (n = 250) Cariprazine 3 mg + ADT (n = 251) Placebo + ADT (n = 250) |
Fixed • All patients received 1.5 mg on days 1–14 • 3 mg group: patients uptitrated to 3 mg on day 15 |
| RGH-MD-71c/NCT00854100 (phase 2) US 6/23/2009–12/6/2010 (Fava et al., 2018) |
8-week OL ADT + SB placebo/nonresponders randomized to 8-week DB; inadequate response to 1–2 ADTs |
Cariprazine 0.1–0.3 mg + ADT (n = 76) Cariprazine 1–2 mg + ADT (n = 73) Placebo + ADT (n = 81) |
Flexible • 0.1–0.3 mg group received 0.1 mg/d from randomization; for nonresponse, dose increase to 0.3 mg/d was possible after week 4 • 1.0–2.0 mg group received 0.5 mg/d in week 1; uptitrated to 1.0 mg/d in week 2; for nonresponse, dose increase to 2.0 mg/d was possible after week 4 |
| RGH-MD-72c/NCT01715805 (phase 3) US 11/15/2012–6/24/2016 (Earley et al., 2018) |
8-week OL ADT + SB placebo/nonresponders randomized to 8-week DB; inadequate response to 1–2 ADTs |
Cariprazine 1.5–4.5 mg/d + ADT (n = 269) Placebo + ADT (n = 258) |
Flexible • Uptitrated from 0.5 mg/d (day 1) to 3.0 mg/d (day 6) by 0.5 mg/d increments • Dose increases to 4.5 mg/d maximum allowed for inadequate responders at weeks 2, 3, and 4 • Dose reduction after increase allowed for tolerability issues |
| RGH-MD-75/ NCT01469377 (phase 2b) US and non-US 12/15/2011–12/12/2013 (Durgam et al., 2016) |
8-week DB; ongoing inadequate ADT response |
Cariprazine 1–2 mg/d + ADT (n = 273) Cariprazine 2–4.5 mg/d + ADT (n = 273) Placebo + ADT (n = 266) |
Flexible • Dose levels were titrated to the initial dose (1 or 2 mg/d) over the first week • Stepwise 0.5 mg dose increases to 1.5 or 2 mg/d were available in the 1–2 mg/d group; increases to 3 and 4.5 mg/d were available in the 2–4.5 mg/d group • Increases were allowed at weeks 1, 2, 4, and 6 |
ADT, antidepressant treatment; DB, double-blind; OL, open-label; SB, single-blind.
Safety population (all patients in the randomized population who received ≥1 dose of study drug).
Patients continued background ADT during the screening/washout and double-blind treatment periods.
Study included a 1- or 1–2-week no-drug screening period before a prospective open-label ADT treatment phase.
To characterize the safety of adjunctive cariprazine in patients with MDD, we conducted analyses of data from these short-term treatment trials; because different study designs and dosing schedules were employed, separate analyses were conducted using different pooling strategies. In the main analysis, data from the fixed-dose trials were pooled to evaluate the safety and tolerability of cariprazine 1.5 mg/d and 3 mg/d (recommended adjunctive doses in MDD). In a supportive analysis, data from all 5 fixed- and flexible-dose trials (1.5–4.5 mg/d) were pooled to evaluate outcomes in the overall cariprazine population and in modal-daily dose subgroups (the most frequently taken dose during the study). Collectively, these analyses allowed us to evaluate the safety of adjunctive cariprazine in MDD, with findings anticipated to expand the known safety profile across approved indications.
Methods
Study protocols were approved by institutional review board (US sites) or ethics committee (non-US sites); studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Participants provided written informed consent. All randomized treatment was administered adjunctively with ongoing ADT at the same dose patients were taking at baseline; no patients received monotherapy cariprazine or placebo.
Study design
Data from 5 randomized, double-blind, placebo-controlled, parallel-group trials of cariprazine plus ongoing ADT were pooled for analysis (Table 1); because the studies had different designs and durations, 2 distinct pooling strategies were used. In an analysis based on the fixed-dose studies only, data were pooled from the 2 identically designed phase 3 studies of cariprazine 1.5 and 3 mg/d to explore safety in the approved dose range for cariprazine in MDD; treatment was initiated at a therapeutic 1.5 mg/d starting dose, with up-titration on day 15 for patients randomized to 3 mg/d. In a separate analysis, data from all 5 short-term fixed- and flexible-dose studies were pooled in order to capture the totality of safety information in the clinical development program for MDD and to increase sample size. Despite some differences in the fixed- and flexible-dose study designs, pooling the 5 studies was viable because the populations and inclusion/exclusion criteria were generally similar across trials, with all patients having inadequate response to 1–2, or 1–3 ADTs of adequate dose and duration in the current depressive episode. In the 5-study analysis, outcomes were reported in the overall cariprazine group and in modal-dose groups (<1.5 mg/d, 1.5 mg/d, 2 mg/d, 3 mg/d, 1.5–4.5 mg/d, and 4.5 mg/d). In the analysis based on modal dose, categorization by modal-dose group may have differed from randomized group assignments because some patients in the flexible-dose studies were titrated to their target dose over a period of weeks; some outcomes could also be disproportionately distributed to lower modal-dose groups as a result of early study discontinuation.
Detailed methods of the fixed- (Riesenberg et al., 2023; Sachs et al., 2023) and flexible-dose (Durgam et al., 2016; Earley et al., 2018; Fava et al., 2018) studies have been published. Briefly, male and female participants (18–65 years, inclusive) had a Diagnostic and Statistical Manual of Mental Disorders MDD diagnosis (APA., 2000, 2013) and a current depressive episode at least 8 weeks’ duration (maximum duration varied by study). All patients had inadequate response to ADT in the current depressive episode. Clinical inclusion criteria specified that patients have a minimum Hamilton Depression Rating Scale (HAMD-17) total score (i.e. ≥18, 20, or 22) (Hamilton, 1960) and a HAMD item 1 score ≥2, or a MADRS total score ≥22. Exclusion criteria were typical of MDD trials (e.g. prior manic/hypomanic episode, alcohol/substance-related disorders, suicidality, nonresponse to >3 adequate ADT trials in the current depressive episode).
Safety assessments
Safety parameters included treatment-emergent adverse events (TEAEs), changes in clinical laboratory parameters and vital signs, and electrocardiogram (ECG) findings. Extrapyramidal symptoms (EPS) were evaluated through adverse event (AE) reporting and rating scale measures including the Simpson-Angus Scale (SAS) (Simpson and Angus, 1970) and Barnes Akathisia Rating Scale (BARS) (Barnes, 1989). Suicidality was evaluated by AEs and Columbia–Suicide Severity Rating Scale (C-SSRS) scores (Posner et al., 2011). Treatment-emergent mania was assessed in the fixed-dose studies.
Data analysis
Fixed- and modal-dose analyses were based on the pooled safety populations (all patients who received ≥1 dose of placebo or cariprazine plus ongoing ADT). Mean changes from baseline to the last available double-blind assessment were summarized using descriptive statistics. TEAEs were reported as preferred terms and defined as AEs that occurred during the 6-week (fixed-dose studies) or 8-week (flexible-dose studies) double-blind periods and within 30 days after the last dose of study drug. Treatment-emergent parkinsonism (SAS score ≤3 at baseline and >3 postbaseline), akathisia (BARS score ≤2 at baseline and >2 postbaseline), and mania (Young Mania Rating Scale [YMRS] (Young et al., 1978) total score ≥16 at any postbaseline visit [fixed-dose studies only]) were assessed.
Results
Analysis based on fixed-dose studies
Patient demographics, baseline characteristics, and disposition
There were 1508 patients in the pooled safety population of fixed-dose studies (cariprazine plus ADT: overall = 1005; 1.5 mg/d = 502; 3 mg/d = 503; placebo plus ADT = 503). Demographic characteristics are presented in Table 2. Most patients had moderately severe recurrent MDD; across groups, the mean number of lifetime MDD episodes was similar (~6) and the mean current episode duration was longer than 6 months. Around 90% of patients in each group completed double-blind treatment; fewer 3 mg/d patients than 1.5 mg/d patients completed the study, with a potential dose-dependent response observed for discontinuation due to AEs (Table 2). Mean treatment duration was similar across groups (1.5 mg/d = 40.8 days, 3 mg/d = 39.9 days, placebo = 40.7 days).
Table 2.
Pooled fixed-dose studies: baseline characteristics and disposition (safety population)
| Demographic Characteristics | Placebo + ADT n = 503 |
Cariprazine + ADT | ||
|---|---|---|---|---|
| 1.5 mg/d n = 502 |
3.0 mg/d n = 503 |
Overall Cariprazine + ADT n = 1005 |
||
| Age, mean (SD), years | 46.3 (12.0) | 44.1 (13.3) | 45.3 (12.9) | 44.7 (13.1) |
| Age group, n (%) | ||||
| <55 years | 344 (68.4) | 363 (72.3) | 348(69.2) | 711(70.7) |
| ≥55 years | 159 (31.6) | 139 (27.7) | 155 (30.8) | 294 (29.3) |
| Men, n (%) | 128 (25.4) | 126 (25.1) | 126 (25.0) | 252 (25.1) |
| Race or ethnicity, n (%)a | ||||
| Asian | 9 (1.8) | 4 (0.8) | 12 (2.4) | 16 (1.6) |
| Black or African-American | 72 (14.3) | 69 (13.7) | 52 (10.3) | 121 (12.0) |
| Hispanic | 55 (10.9) | 62 (12.4) | 53 (10.5) | 115 (11.4) |
| Other | 2 (0.4) | 8 (1.6) | 3 (0.6) | 11 (1.1) |
| White | 420 (83.5) | 421 (83.9) | 436 (86.7) | 857 (85.3) |
| Weight, mean (SD), kg | 84.8 (22.0) | 85.1(22.2) | 82.4 (20.6) | 83.8 (21.5) |
| BMI, mean (SD), kg/m2 | 30.0 (7.4) | 30.2 (7.5) | 29.4 (6.9) | 29.8 (7.2) |
| Psychiatric history | ||||
| MDD, n (%) | ||||
| Single episode, moderate | 33 (6.6) | 28 (5.6) | 33 (6.6) | 61 (6.1) |
| Single episode, severe | 11 (2.2) | 12 (2.4) | 19 (3.8) | 31 (3.1) |
| Recurrent episode, moderate | 345 (68.6) | 325 (64.7) | 313 (62.2) | 638 (63.5) |
| Recurrent episode, severe | 114 (22.7) | 137 (27.3) | 138 (27.4) | 275 (27.4) |
| Number of lifetime episodes, mean (SD) | 5.8 (14.4) | 5.7 (6.9) | 5.7 (6.2) | 5.7 (6.6) |
| Lifetime duration of MDD, mean (SD), years | 13.7 (11.5) | 13.2 (11.4) | 13.7 (11.9) | 13.4 (11.6) |
| Duration of current episode of MDD, mean (SD), monthsb | 7.6 (4.7) | 6.5 (4.0) | 7.5 (4.6) | 7.0 (4.3) |
| Number of ADTs in current episode | ||||
| 1 | 421 (83.7) | 415 (82.7) | 422 (83.9) | 837 (83.3) |
| 2 | 78 (15.5) | 81 (16.1) | 72 (14.3) | 153 (15.2) |
| 3 | 4 (0.8) | 6 (1.2) | 9 (1.8) | 15 (1.5) |
| Patient Disposition | ||||
| Completed double-blind treatment, n (%) | 464 (92.2) | 464 (92.4) | 445 (88.5) | 909 (90.4) |
| Reasons for discontinuation, n (%) | ||||
| Adverse event | 12 (2.4) | 12 (2.4) | 31 (6.2) | 43 (4.3) |
| Withdrawal by subject | 17 (3.4) | 15 (3.0) | 15 (3.0) | 30 (3.0) |
| Lost to follow-up | 4 (0.8) | 4 (0.8) | 7 (1.4) | 11 (1.1) |
| Noncompliance with study drug | 1 (0.2) | 4 (0.8) | 2 (0.4) | 6 (0.6) |
| Lack of efficacy | 3 (0.6) | 2 (0.4) | 1 (0.2) | 3 (0.3) |
| Protocol deviation | 1 (0.2) | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Other | 1 (0.2) | 0 (0.0) | 1 (0.2) | 1 (0.1) |
ADT, antidepressant treatment; BMI, body mass index; MDD, major depressive disorder.
Race and ethnicity were self-reported.
Duration of current episode (months) = the number of months between the date of informed consent and the date of onset of current episode of MDD.
Adverse events
A higher percentage of cariprazine- than placebo-treated patients had TEAEs and treatment-related TEAEs (Table 3); among patients with TEAEs, >90% had mild/moderate events. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine-treated patients (any group) and twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Akathisia was the only event leading to discontinuation of >1% of patients in any group. Less than 1% of participants across groups reported serious AEs (SAEs) (placebo = 3 [intestinal obstruction, multiple sclerosis, depression]; overall cariprazine = 5 (injury [2], atrial fibrillation, kidney infection, social stay hospitalization [1 each]); none were considered related to the study drug. One death was reported during safety follow-up in the placebo group (not related to study drug, unknown cause). Of note, preferred individual terms for akathisia, insomnia, and somnolence were reported in this analysis, while grouped terms for these events were reported in the USA prescribing information (USPI) for Vraylar (Allergan, 2022). As such, reported percentages for these events and EPS (different grouped terms) vary slightly in this analysis and the USPI (see footnote in Table 3), and the USPI should be consulted as the basis for treating patients.
Table 3.
Pooled fixed-dose studies: double-blind and EPS-related adverse events (safety population)
| Treatment-Emergent Adverse Events | Placebo + ADT n (%) n = 503 |
Cariprazine + ADT | Overall Cariprazine + ADT n (%) n = 1005 |
|
|---|---|---|---|---|
| 1.5 mg/d n (%) n = 502 |
3.0 mg/d n (%) n = 503 |
|||
| TEAE Summary | ||||
| All TEAEs | 198 (39.4) | 253 (50.4) | 267 (53.1) | 520 (51.7) |
| Treatment-related TEAEs | 111 (22.1) | 176 (35.1) | 186 (37.0) | 362 (36.0) |
| Serious AEs | 3 (0.6) | 3 (0.6) | 2 (0.4) | 5 (0.5) |
| TEAEs leading to discontinuation | 12 (2.4) | 12 (2.4) | 31 (6.2) | 43 (4.3) |
| Most frequent TEAE by individual preferred term (≥5% in any treatment group)* | ||||
| Headache | 42 (8.3) | 46 (9.2) | 38 (7.6) | 84 (8.4) |
| Akathisiaa | 10 (2.0) | 32 (6.4) | 49 (9.7) | 81 (8.1) |
| Insomnia | 19 (3.8) | 34 (6.8) | 41 (8.2) | 75 (7.5) |
| Nausea | 15 (3.0) | 34 (6.8) | 32 (6.4) | 66 (6.6) |
| Somnolence | 18 (3.6) | 25 (5.0) | 28 (5.6) | 53 (5.3) |
| EPS-related TEAEs | ||||
| Patients with any EPS-related TEAEs | 30 (6.0) | 63 (12.5) | 84 (16.7) | 147 (14.6) |
| Patients with any EPS-related TEAEs excluding akathisia/restlessnessb,* | 16 (3.2) | 23 (4.6) | 22 (4.4) | 45 (4.5) |
| Patients with any akathisia/restlessness TEAE | 19 (3.8) | 48 (9.6) | 65 (12.9) | 113 (11.2) |
| Akathisiaa | 10 (2.0) | 32 (6.4) | 49 (9.7) | 81 (8.1) |
| Restlessness | 9 (1.8) | 18 (3.6) | 19 (3.8) | 37 (3.7) |
| Dystonia clusterc | 2 (0.4) | 2 (0.4) | 1 (0.2) | 3 (0.3) |
| Parkinsonism clusterd | 13 (2.6) | 18 (3.6) | 20 (4.0) | 38 (3.8) |
| Musculoskeletal stiffness | 2 (0.4) | 3 (0.6) | 0 (0.0) | 3 (0.3) |
| Tardive dyskinesia | 0 (0.0) | 0 (0.0) | 1 (0.2) | 1 (0.1) |
| Rating scale-defined treatment-emergent EPS | ||||
| Treatment-emergent akathisiae | 23/497 (4.6) | 52/500 (10.4) | 65/503 (12.9) | 117/1003 (11.7) |
| Treatment-emergent parkinsonismf | 8/497 (1.6) | 6/500 (1.2) | 11/503 (2.2) | 17/1003 (1.7) |
| Discontinuations due to EPS-related TEAEs | ||||
| Any EPS-related TEAE leading to discontinuation | 4 (0.8) | 4 (0.8) | 13 (2.6) | 17 (1.7) |
| Patients with any akathisia/restlessness TEAE | 2 (0.4) | 3 (0.6) | 13 (2.6) | 16 (1.6) |
| Patients with any EPS-related TEAEs excluding akathisia/restlessness | 2 (0.4) | 1 (0.2) | 0 (0.0) | 1 (0.1) |
| Akathisia | 2 (0.4) | 3 (0.6) | 11 (2.2) | 14 (1.4) |
| Restlessness | 0 (0.0) | 0 (0.0) | 2 (0.4) | 2 (0.2) |
| Parkinsonism clusterd | 2 (0.4) | 1 (0.2) | 0 (0.0) | 1 (0.1) |
ADT, antidepressant treatment; AE, adverse event; BARS, Barnes Akathisia Rating Scale; EPS, extrapyramidal symptoms; SAS, Simpson-Angus Scale; TEAE, treatment-emergent AE; USPI, USA prescribing information.
A most frequent preferred term and an EPS-related TEAE.
Grouped term: tremor, extrapyramidal disorder, musculoskeletal stiffness, salivary hypersecretion, drooling, dyskinesia, muscle rigidity, myoclonus, oromandibular dystonia, parkinsonism, tardive dyskinesia, trismus, muscle tightness.
Grouped term: myoclonus, trismus, oromandibular dystonia.
Grouped term: tremor, extrapyramidal disorder, salivary hypersecretion, drooling, dyskinesia, muscle rigidity, parkinsonism, muscle tightness.
BARS score ≤2 at baseline and >2 at any post-baseline visit.
SAS score ≤3 at baseline and >3 at any post-baseline visit.
Individual preferred AE terms were used for akathisia, somnolence, and insomnia in this safety analysis, while a grouped term for each of these events was reported in the USPI; different grouped terms were also reported for EPS. As a result, the reported percentages for these events are slightly different in this analysis than in the USPI. In the USPI, the grouped terms and percentages of patients reported for placebo + ADT, cariprazine 1.5 mg/d +ADT, and cariprazine 3 mg/d + ADT, respectively, were (1) akathisia: akathisia, psychomotor hyperactivity, feeling jittery, nervousness, tension (2%, 7%, 10%); (2) somnolence: hypersomnia, sedation, lethargy, somnolence (4%, 5%, 7%); (3) EPS (additional terms included in the USPI but not in this safety analysis): muscle spasms, restless legs syndrome, muscle twitching, hypotonia, muscle contractions involuntary, resting tremor, stiff leg syndrome, stiff tongue (4%, 5%, 6%); and (4) insomnia: initial insomnia, insomnia, middle insomnia, poor sleep quality, sleep disorder, terminal insomnia (5%, 9%, 10%).
Rescue medications for insomnia (i.e. eszopiclone, zaleplon, zolpidem, zolpidem tartrate, zopiclone, suvorexant) were used by 4.0%, 7.2%, and 7.6% of placebo-, cariprazine 1.5 mg/d-, and cariprazine 3 mg/d-treated patients, respectively. Rescue medications for agitation, restlessness, and hostility were used by 0.4%, 1.2%, and 2.0% of patients in the placebo- and cariprazine 1.5 mg/d- and 3 mg/d-treatment groups, respectively.
Extrapyramidal events
A higher number of cariprazine- than placebo-treated patients had EPS-related TEAEs (Table 3); among patients with TEAEs, most events were mild/moderate (placebo = 100%; overall cariprazine = 96.6%) and none met criteria for an SAE. Potential dose-dependent responses were observed for any EPS-related TEAEs, any akathisia/restlessness TEAEs, akathisia, restlessness, and discontinuations due to EPS-related TEAEs (Table 3). A greater percentage of cariprazine- than placebo-treated patients had BARS-defined akathisia; the incidence of SAS-rated parkinsonism was low and similar for placebo and overall cariprazine (Table 3). Rescue medications to manage akathisia and EPS (i.e. propranolol, anticholinergic agents) were used by 0.4%, 2.6%, and 3.4% of patients in the placebo- and cariprazine 1.5 mg/d- and 3 mg/d-treatment groups, respectively.
Treatment-emergent mania
One placebo- and no cariprazine-treated patients experienced treatment-emergent mania (YMRS total score ≥16); mean change from baseline in YMRS total score was similar between groups (placebo = −1.0; cariprazine: 1.5 mg/d = −1.2; 3 mg/d = −1.0).
Metabolic parameters
From baseline to the end of treatment, slight decreases in total cholesterol and low-density lipoprotein (LDL) were observed for cariprazine and placebo, while changes in high-density lipoprotein (HDL) were small and variable; a greater increase in triglycerides was seen for cariprazine versus placebo (Table 4). Less than 10% of patients in any group shifted from normal/borderline baseline levels to high levels for total cholesterol and LDL at any time during double-blind treatment; higher percentages of patients across groups shifted from normal/borderline to high levels of fasting triglycerides (placebo = 10.2%; overall cariprazine = 10.1%) (Table 4). Mean increase in fasting glucose and increase >10 mg/dl were greater for overall cariprazine than placebo. Shifts from normal/impaired levels to high levels of fasting serum glucose occurred at a slightly higher rate for cariprazine than placebo but were less than 5% in all groups. Mean weight gain was less than 1 kg for cariprazine (0.70 kg) and placebo (0.16 kg); body weight increase of ≥7% was observed in <3% in all dose groups.
Table 4.
Pooled fixed-dose studies: metabolic and key clinical laboratory parameters (safety population)
| Metabolic parameters | Placebo + ADT n = 503 |
Cariprazine + ADT | Overall cariprazine + ADT n = 1005 |
|
|---|---|---|---|---|
| 1.5 mg/d n = 502 |
3.0 mg/d n = 503 |
|||
| Lipids, mean change (SD) | ||||
| Total cholesterol, mg/dl | −4.0 (29.6) | −2.1 (27.1) | −4.9 (27.5) | −3.5 (27.3) |
| Combined LDL cholesterol, direct and calculated, fasting, mg/dl | −4.3 (24.5) | −4.6 (24.1) | −7.0 (25.3) | −5.8 (24.7) |
| HDL cholesterol, mg/dl | −0.3 (9.5) | 0.5 (9.6) | 0.0 (8.7) | 0.3 (9.2) |
| Triglycerides, fasting, mg/dl | 3.3 (64.7) | 7.5 (66.1) | 12.1 (59.5) | 9.7 (62.9) |
| Shifts in lipid levels, n/N1 (%) | ||||
| Total cholesterol (normal/borderline [<240 mg/dl] to high [≥240]) | 25/349 (7.2) | 26/394 (6.6) | 24/373 (6.4) | 50/767 (6.5) |
| Fasting LDL cholesterol (normal/borderline [<160 mg/dl] to high [≥160]) | 24/324 (7.4) | 19/358 (5.3) | 12/324 (3.7) | 31/682 (4.5) |
| HDL cholesterol (normal [≥40 mg/dl] to low [<40 mg/dl]) | 24/401 (6.0) | 20/421 (4.8) | 21/428 (4.9) | 41/849 (4.8) |
| Fasting triglycerides (normal/borderline [<200 mg/dl] to high [≥200]) | 35/343 (10.2) | 40/356 (11.2) | 31/348 (8.9) | 71/704 (10.1) |
| Glucose | ||||
| Fasting, mg/dl, mean change (SD) | 0.4 (15.9) | 3.1 (18.9) | 4.2 (15.8) | 3.6 (17.4) |
| Shift from normal/impaired (<126 mg/dl) to high (≥126 mg/dl), n/N1 (%) | 11/387 (2.8) | 15/398 (3.8) | 18/396 (4.5) | 33/794 (4.2) |
| Increase ≥10 mg/dl, n/N1 (%) | 80/402 (19.9) | 91/413 (22.0) | 112/405 (27.7) | 203/818 (24.8) |
| Body weight, mean change (SD) | ||||
| Body weight, kg | 0.16 (1.8) | 0.68 (2.2) | 0.72 (2.4) | 0.70 (2.3) |
| BMI, kg/m2 | 0.05 (0.6) | 0.25 (0.8) | 0.26 (0.9) | 0.25 (0.8) |
| Waist circumference, cm | −0.12 (9.5) | 0.72 (8.4) | 0.60 (7.9) | 0.66 (8.2) |
| Clinically significant changes in body weight, n/N1 (%) | ||||
| ≥7% increase from baseline | 4/ 497 (0.8) | 11/ 499 (2.2) | 8/ 503 (1.6) | 19/1002 (1.9) |
| ≥7% decrease from baseline | 4/ 497 (0.8) | 3/ 499 (0.6) | 3/ 503 (0.6) | 6/1002 (0.6) |
| Other key clinical laboratory parameters, mean change (SD) | ||||
| ALT, U/L | 0.1 (9.3) | 3.4 (29.7) | 1.0 (10.1) | 2.2 (22.2) |
| AST, U/L | 0.0 (6.2) | 2.0 (16.1) | 0.4 (7.5) | 1.2 (12.6) |
| Total bilirubin, mg/dl | −0.01 (0.2) | −0.02 (0.3) | −0.03 (0.2) | −0.03 (0.2) |
| Prolactin, ng/mL | 1.05 (12.7) | 3.94 (7.9) | 2.76 (13.9) | 3.35 (11.4) |
| Creatine phosphokinase, U/L | −2.1 (94.9) | 22.4 (278.2) | 18.6 (241.6) | 20.5 (260.4) |
| Systolic blood pressure, mmHg | −0.1 (9.6) | −0.7 (9.8) | −0.1 (9.9) | −0.4 (9.8) |
| Diastolic blood pressure, mmHg | 0.2 (7.4) | 0.1 (7.2) | 0.1 (7.5) | 0.1 (7.3) |
Mean changes are from baseline to end of double-blind treatment period.
n/N1 = number of patients who met the criterion/number of patients meeting the baseline criteria with ≥1 nonmissing postbaseline value.
ADT, antidepressant treatment; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Other key clinical laboratory parameters
Mean changes from baseline in aspartate aminotransferase [AST] and alanine aminotransferase [ALT] were greater for cariprazine- than for placebo-treated patients (Table 4); 1 patient met Hy’s Law criteria (ALT or AST ≥ 3 × upper limit of normal [ULN] with concurrent total bilirubin ≥2 × ULN and alkaline phosphatase <2 × ULN). A higher mean increase in creatine phosphokinase (CPK) was seen for cariprazine versus placebo, although large standard deviations suggested high variability across groups. Seven cariprazine- and zero placebo-treated patients had at least 1 treatment-emergent CPK value >1000 U/L. One cariprazine 1.5 mg/d patient had a CPK value >5000 U/L and a urine myoglobin value <1.0 ng/mL, with isolated concurrent elevation of AST and no other liver function parameter alterations; no AE was reported.
Cardiovascular safety
Mean (SD) changes from baseline to end of treatment in blood pressure parameters were small and similar for overall cariprazine- and placebo-treatment groups, respectively (systolic: -0.4 [9.8] and -0.1 [9.6]; diastolic: 0.1 [7.3] and 0.2 [7.4]) (Supplemental Table 1, Supplemental digital content 1, http://links.lww.com/ICP/A125). The incidence of orthostatic hypotension (reduction in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg while changing from a supine to a standing position) was similar for overall cariprazine (9.5%) and placebo (9.7%). Shifts from normotensive to hypertensive status occurred in few patients in either the overall cariprazine- (3%) or placebo-treatment (3.1%) group. No patient had a postbaseline clinically significant ECG parameter value of clinical relevance; 1 cariprazine 1.5 mg/d patient had a postbaseline QTcB interval increase >60 ms and no patients had a postbaseline QTcF interval increase >60 ms.
Suicidality
The percentage of patients with C-SSRS–rated suicidal ideation during double-blind treatment was similar among groups (placebo = 7.4%; cariprazine: 1.5 mg/d = 7.8%, 3 mg/d = 7.2%); most C-SSRS suicidal ideation ratings were in the least severe category and no suicidal behavior was reported. One cariprazine 3 mg/d patient experienced a suicidality AE (intentional self-injury) that was not considered serious and did not lead to study discontinuation.
Analysis based on modal-daily dose
In a supportive analysis based on modal dose, the safety population included 3077 patients from the 2 fixed-dose studies and 3 flexible-dose studies (overall cariprazine = 1969, placebo = 1108). Findings were consistent with the analysis based on the fixed-dose studies and the known safety profile for cariprazine; cariprazine-treated patients had high rates of study completion and TEAEs were the most common reason for study discontinuation (Table 5). A higher percentage of cariprazine- than placebo-treated patients experienced TEAEs (Table 5); maximum severity was mild or moderate for over 90% of patients. Only akathisia and restlessness occurred in ≥5% of overall cariprazine patients and at least twice the rate of placebo, and fewer than 1% of patients in any group had an SAE. Metabolic and clinical laboratory profiles were similar to what was observed in the fixed-dose analysis; overall cariprazine-treated patients had low rates of shift from normal/impaired to high glucose levels (4.1%) and weight gain ≥7% (2.3%) (Supplemental Table 2, Supplemental digital content 2, http://links.lww.com/ICP/A126). No patient had a clinically significant postbaseline ECG. The rate of C-SSRS suicidal ideation was the same for overall cariprazine- and placebo-treated patients (8.4%); no suicidal behavior was reported. Suicidal ideation TEAEs were reported for 2 overall cariprazine and 1 placebo patient; 1 event in the cariprazine 4.5 modal-dose group was considered serious and led to study discontinuation.
Table 5.
Analysis based on modal-daily doses: patient disposition and double-blind adverse events (safety population)
| Patient Disposition | Placebo + ADT n (%) n = 1108 |
Cariprazine modal-daily dose + ADT | Overall cariprazine + ADT n (%) n = 1969 |
|||||
|---|---|---|---|---|---|---|---|---|
| <1.5 mg/d + ADT n (%) n = 213 |
1.5 mg/d + ADT n (%) n = 619 |
2 mg/d + ADT n (%) n = 265 |
3 mg/d + ADT n (%) n = 699 |
4.5 mg/d + ADT n (%) n = 173 |
1.5–4.5 mg/d + ADT n (%) n = 1756 |
|||
| Completed study | 992 (89.5) | 170 (79.8) | 559 (90.3) | 224 (84.5) | 581 (83.1) | 157 (90.8) | 1521 (86.6) | 1691 (85.9) |
| Reason for premature discontinuation | ||||||||
| Adverse event | 25 (2.3) | 15 (7.0) | 23 (3.7) | 23 (8.7) | 57 (8.2) | 5 (2.9) | 108 (6.2) | 123 (6.2) |
| Withdrawal by Subject | 42 (3.8) | 9 (4.2) | 20 (3.2) | 10 (3.8) | 27 (3.9) | 4 (2.3) | 61 (3.5) | 70 (3.6) |
| Protocol Deviation | 23 (2.1) | 11 (5.2) | 6 (1.0) | 6 (2.3) | 11 (1.6) | 6 (3.5) | 29 (1.7) | 40 (2.0) |
| Lost to Follow-Up | 15 (1.4) | 5 (2.3) | 4 (0.6) | 1 (0.4) | 19 (2.7) | 1 (0.6) | 25 (1.4) | 30 (1.5) |
| Other | 5 (0.5) | 1 (0.5) | 4 (0.6) | 0 (0.0) | 3 (0.4) | 0 (0.0) | 7 (0.4) | 8 (0.4) |
| Lack of Efficacy | 6 (0.5) | 2 (0.9) | 3 (0.5) | 1 (0.4) | 1 (0.1) | 0 (0.0) | 5 (0.3) | 7 (0.4) |
| Adverse events | ||||||||
| All treatment-emergent AEs | 533 (48.1) | 137 (64.3) | 346 (55.9) | 196 (74.0) | 405 (57.9) | 107 (61.8) | 1054 (60.0) | 1191 (60.5) |
| Treatment-related TEAE | 313 (28.2) | 98 (46.0) | 265 (42.8) | 159 (60.0) | 300 (42.9) | 80 (46.2) | 804 (45.8) | 902 (45.8) |
| Serious AEa | 8 (0.7) | 1 (0.5) | 3 (0.5) | 0 (0.0) | 4 (0.6) | 1 (0.6) | 8 (0.5) | 9 (0.5) |
| Treatment-emergent AE leading to discontinuation | 25 (2.3) | 14 (6.6) | 22 (3.6) | 23 (8.7) | 57 (8.2) | 5 (2.9) | 107 (6.1) | 121 (6.1) |
| Most frequent TEAEs (≥5% in any treatment group) | ||||||||
| Akathisiab | 27 (2.4) | 10 (4.7) | 61 (9.9) | 41 (15.5) | 85 (12.2) | 15 (8.7) | 202 (11.5) | 212 (10.8) |
| Insomnia | 53 (4.8) | 15 (7.0) | 54 (8.7) | 24 (9.1) | 61 (8.7) | 10 (5.8) | 149 (8.5) | 164 (8.3) |
| Headache | 87 (7.9) | 11 (5.2) | 57 (9.2) | 28 (10.6) | 52 (7.4) | 10 (5.8) | 147 (8.4) | 158 (8.0) |
| Nausea | 42 (3.8) | 15 (7.0) | 44 (7.1) | 24 (9.1) | 47 (6.7) | 13 (7.5) | 128 (7.3) | 143 (7.3) |
| Somnolence | 34 (3.1) | 13 (6.1) | 37 (6.0) | 24 (9.1) | 38 (5.4) | 7 (4.0) | 106 (6.0) | 119 (6.0) |
| Restlessness | 22 (2.0) | 16 (7.5) | 36 (5.8) | 15 (5.7) | 37 (5.3) | 5 (2.9) | 93 (5.3) | 109 (5.5) |
| Fatigue | 28 (2.5) | 8 (3.8) | 25 (4.0) | 17 (6.4) | 25 (3.6) | 13 (7.5) | 80 (4.6) | 88 (4.5) |
| Tremor | 17 (1.5) | 12 (5.6) | 17 (2.7) | 11 (4.2) | 22 (3.1) | 6 (3.5) | 56 (3.2) | 68 (3.5) |
| Dizziness | 25 (2.3) | 11 (5.2) | 16 (2.6) | 11 (4.2) | 15 (2.1) | 5 (2.9) | 47 (2.7) | 58 (2.9) |
| EPS-related TEAEs (≥5% in any treatment group) | ||||||||
| Patients with any EPS TEAE | 74 (6.7) | 33 (15.5) | 110 (17.8) | 66 (24.9) | 143 (20.5) | 27 (15.6) | 346 (19.7) | 379 (19.2) |
| Patients with any EPS TEAE excluding akathisia/restlessness | 33 (3.0) | 16 (7.5) | 31 (5.0) | 17 (6.4) | 41 (5.9) | 13 (7.5) | 102 (5.8) | 118 (6.0) |
| Participants with any EPS TEAE including akathisia/restlessness | 49 (4.4) | 25 (11.7) | 91 (14.7) | 54 (20.4) | 116 (16.6) | 19 (11.0) | 280 (15.9) | 305 (15.5) |
| Akathisia | 27 (2.4) | 10 (4.7) | 61 (9.9) | 41 (15.5) | 85 (12.2) | 15 (8.7) | 202 (11.5) | 212 (10.8) |
| Restlessness | 22 (2.0) | 16 (7.5) | 36 (5.8) | 15 (5.7) | 37 (5.3) | 5 (2.9) | 93 (5.3) | 109 (5.5) |
| Parkinsonism clusterc | 30 (2.7) | 16 (7.5) | 24 (3.9) | 14 (5.3) | 39 (5.6) | 13 (7.5) | 90 (5.1) | 106 (5.4) |
| Rating scale-defined treatment-emergent EPS | ||||||||
| Treatment-emergent parkinsonismd | 15/1100 (1.4) | 6/211 (2.8) | 10/617 (1.6) | 5/265 (1.9) | 17/697 (2.4) | 7/173 (4.0) | 39/1752 (2.2) | 45/1963 (2.3) |
| Treatment-emergent akathisiae | 41/1100 (3.7) |
20/211 (9.5) |
86/617 (13.9) |
39/265 (14.7) |
103/697 (14.8) | 18/173 (10.4) |
246/1752 (14.0) |
266/1963 (13.6) |
| Discontinuations due to EPS-related TEAEs | ||||||||
| Patients with any EPS TEAE leading to study discontinuation | 5 (0.5) | 5 (2.3) | 7 (1.1) | 8 (3.0) | 27 (3.9) | 1 (0.6) | 43 (2.4) | 48 (2.4) |
| Participants with any EPS TEAE excluding akathisia/restlessness | 3 (0.3) | 2 (0.9) | 1 (0.2) | 1 (0.4) | 3 (0.4) | 0 (0.0) | 5 (0.3) | 7 (0.4) |
| Participants with any akathisia/restlessness TEAE | 2 (0.2) | 4 (1.9) | 6 (1.0) | 8 (3.0) | 24 (3.4) | 1 (0.6) | 39 (2.2) | 43 (2.2) |
| Akathisia | 2 (0.2) | 2 (0.9) | 5 (0.8) | 7 (2.6) | 20 (2.9) | 1 (0.6) | 33 (1.9) | 35 (1.8) |
| Restlessness | 0 (0.0) | 2 (0.9) | 1 (0.2) | 2 (0.8) | 4 (0.6) | 0 (0.0) | 7 (0.4) | 9 (0.5) |
| Parkinsonism clusterc | 3 (0.3) | 2 (0.9) | 1 (0.2) | 1 (0.4) | 3 (0.4) | 0 (0.0) | 5 (0.3) | 7 (0.4) |
ADT, antidepressant treatment; AE, adverse event; BARS, Barnes Akathisia Rating Scale; EPS, extrapyramidal symptoms; SAS, Simpson-Angus Scale; TEAE, treatment-emergent AE.
No deaths occurred during double-blind treatment; 1 death occurred during safety follow-up in a fixed-dose study (cause unknown, not related to treatment).
A most frequent preferred term and an EPS-related TEAE.
Group term: tremor, extrapyramidal disorder, salivary hypersecretion, muscle rigidity, drooling, dyskinesia, parkinsonism, cogwheel rigidity, muscle tightness, and reduced facial expression.
SAS score ≤3 at baseline and >3 at any post-baseline visit.
BARS score ≤2 at baseline and >2 at any post-baseline visit.
Discussion
To more fully characterize the safety of cariprazine plus ongoing ADT in patients with MDD and inadequate response to monotherapy ADT, we conducted post hoc analyses of short-term clinical trial data. In an analysis based on 2 fixed-dose studies using the recommended adjunctive doses of cariprazine in MDD (1.5 and 3 mg/d), outcomes were consistent with the known safety profile in schizophrenia, bipolar mania, and bipolar depression; no new safety signals were identified. The rate of study completion was 90.4% for overall cariprazine-treated patients and only 4.3% of participants discontinued treatment because of TEAEs. Most TEAEs were mild or moderate, with akathisia, nausea, and insomnia the only events occurring in ≥5% of cariprazine-treated patients and at least twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. The high study completion rate, along with low rates of rescue medication use, suggest that TEAEs were generally tolerable and well managed, and in most cases, did not cause treatment discontinuation. Importantly, no increased risk for hypomania/mania was observed in cariprazine-treated patients.
Overall fixed-dose cariprazine had a favorable metabolic profile as seen in no increased risk of impaired glucose, similar changes in cholesterol parameters versus placebo, and low rates of shift from normal/borderline baseline to high levels of total cholesterol and LDL (<10%). Further, mean weight increase was low (<1 kg), as was the percentage of overall cariprazine patients with weight increases ≥7% (~2%), which is in harmony with the pharmacologic characterization of cariprazine (i.e. lower affinity for 5-HT2C and histamine H1 receptors) (Allergan, 2022). Collectively, these findings are consistent with the neutral weight and metabolic profile for cariprazine across its indications of schizophrenia (Earley et al., 2017a; Barabassy et al., 2021), acute manic/mixed episodes (Earley et al., 2017b), and bipolar I depression (Earley et al., 2020).
In a supportive analysis based on modal-daily doses including all 5 short-term adjunctive cariprazine trials, results were similar to the analysis based on the fixed-dose studies and consistent with the known cariprazine safety profile. The rate of study completion for overall cariprazine was high (85.9%); TEAEs were the most common reason for premature discontinuation (6.2%). Akathisia and restlessness were the only AEs reported in ≥5% of overall cariprazine patients and at least twice the placebo rate. Again, there was no increased risk of impaired glucose or weight gain for adjunctive cariprazine therapy, supporting the relatively neutral metabolic and weight profile seen in other indications. Of note, the analysis based on modal doses included a positive phase 2, flexible-dose study, in which statistically significant reduction in MADRS total score was observed for cariprazine 2–4.5 mg/d plus ADT (mean daily dose = 2.6 mg/d) versus placebo plus ADT (Durgam et al., 2016); these data were used to support the recommended 3 mg/d adjunctive dose for MDD. In this positive study, akathisia, nausea, and insomnia were the only TEAEs that occurred in ≥10% of cariprazine-treated patients and mean changes in metabolic parameters, vital signs, and ECG values were generally similar for cariprazine and placebo; no suicide-related AEs were reported. Interestingly, rates of cariprazine TEAEs were higher in this flexible-dose study (1–2 mg/d = 69.2%; 2–4.5 mg/d = 78.4%) and in the analysis based on modal doses (60.5%) than in the analyses based on fixed doses (51.7%), which may be related to faster titration schedules utilized in the flexible-dose studies (Table 1). This hypothesis is consistent with findings of better tolerability in cariprazine studies with slower titration and lower doses, such as in the bipolar I depression versus the bipolar mania studies (Earley et al., 2020). Importantly, slower titration, as used in the fixed-dose adjunctive MDD studies, is in line with recommended dosing in clinical practice for patients with MDD.
The safety of longer courses of treatment with novel antidepressant therapy is also an important consideration given the tendency for chronicity and relapse/recurrence in MDD, and guideline recommendations for maintenance treatment to improve longer-term outcomes (APA, 2010; Kennedy et al., 2016). In one longer-term (26-week) open-label cariprazine safety study including 345 patients with MDD and inadequate response to monotherapy ADT, the rate of TEAEs was 79.4% for overall cariprazine 1.5–4.5 mg/d and 13.9% prematurely discontinued treatment due to AEs (Vieta et al., 2019). Akathisia (15.9%) and headache (11.6%) were the only events reported by ≥10% of patients; most TEAEs were mild or moderate (97.1%). Only 2.0% of patients reported an SAE, with no event occurring in more than 1 patient; 2 deaths that were judged to be unrelated to treatment were also reported. Less than 10% of patients had EPS-related TEAEs excluding akathisia/restlessness; similar to other cariprazine studies, a higher percentage of patients had EPS-related TEAEs including akathisia/restlessness (28.4%). It has not, however, been determined if treatment-induced akathisia during adjunctive therapy heightens the risk of developing tardive dyskinesia during more extended courses of therapy; likewise, it is not known if the ultimate risk is increased by concomitant therapy with antidepressants. As such, the decision to extend a course of therapy for a patient with clear-cut response and good tolerability should be made on a case-by-case basis, considering both known benefits and largely uncertain longer-term risks. Long-term cariprazine was not associated with increased risk of impaired glucose, weight gain, orthostatic hypotension, or suicide, with results suggesting that adjunctive cariprazine was a safe and generally well-tolerated longer-term treatment option for MDD.
Limitations of these analyses include no active comparators in the constituent studies and exclusion of potential participants with more complex and comorbid conditions. Short study duration precludes fuller evaluation of some outcomes that may require long-term treatment to become more problematic (e.g. weight gain). Included patients met strict inclusion and exclusion criteria that may limit generalizability to a wider MDD population; however, criteria were consistent across the individual studies, ensuring that the pooled safety population was homogenous and appropriate for analysis. Generalizability may also be affected by participants providing informed consent to accept a randomized treatment that might be an inert placebo. Because cariprazine patients were receiving 2 active treatments (i.e. cariprazine plus ADT), it is not possible to determine how each treatment contributed to treatment-emergent events or if there were combined effects; however, the safety profile of adjunctive cariprazine was consistent with the known safety profile in monotherapy indications. There are inherent complexities associated with modal-dose analysis (e.g. modal dose could be lower than randomized dose, early study discontinuations can bias results against lower-dose groups), but fixed- and modal-dose findings were generally consistent, with only a few treatment-emergent outcomes disproportionately distributed to the lowest modal-dose group (i.e. restlessness, tremor, dizziness, parkinsonism cluster).
Adjunctive cariprazine plus ADT was safe and generally well tolerated in patients with MDD and inadequate response to monotherapy ADT; no new safety signals were identified. Although some dose-related effects were observed for cariprazine 1.5 mg/d and 3 mg/d plus ADT in the fixed-dose analysis, high rates of completion, mild or moderate TEAEs, and a neutral metabolic profile suggest that the recommended adjunctive doses were generally appropriate and acceptable for the treatment of patients with MDD. These analyses provide evidence for the safety and tolerability of cariprazine plus ADT in patients with MDD and inadequate ADT response, supporting the known safety profile of cariprazine and substantiating its viability as an adjunctive treatment in MDD.
Acknowledgements
AbbVie and the authors thank the patients, study sites, and investigators who participated in the clinical trials that were included in these analyses. Additionally, AbbVie and the authors thank Willie R. Earley and Arlene Hankinson (employees at the time of the study) for their contributions to this work. Medical writing support was provided by Carol Brown, MS, of Prescott Medical Communications Group, Chicago, IL, and funded by AbbVie.
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Data availability: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g. protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data-sharing/.
Conflicts of interest
M.E. Thase has served as an advisor or a consultant for Axsome Therapeutics, Inc.; Clexio Biosciences; Gerson Lehman; GH Therapeutics; H. Lundbeck, A/S; Janssen Pharmaceuticals, Inc.; Johnson & Johnson; Luye Pharma Group, Ltd.; Merck & Company, Inc.; Otsuka Pharmaceutical Company, Ltd.; Pfizer, Inc.; Sage Pharmaceuticals; Seelos Pharmaceuticals; Sunovion Pharmaceuticals, Inc.; and Takeda Pharmaceutical Company, Ltd.; has received grants from Acadia Inc.; Alkermes; Axsome Therapeutics Inc.; Intracellular, Inc.; Janssen Pharmaceuticals, Inc.; Myriad; National Institute of Mental Health; Otsuka Pharmaceutical Company, Ltd.; Patient-Centered Outcomes Research Institute (PCORI); and Takeda Pharmaceutical Company, Ltd.; and has received royalties from the American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; and W.W. Norton & Company, Inc. P.P. Yeung was an employee of AbbVie at the time of the study and may hold stock. L. Rekeda, M. Liu, and S. Varughese are employees of AbbVie and may hold stock.
Supplementary Material
Footnotes
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.intclinpsychopharm.com.
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