Secondary Logo

Journal Logo

Original Articles

Evaluation of cariprazine in the treatment of bipolar I and II depression

a randomized, double-blind, placebo-controlled, phase 2 trial

Yatham, Lakshmi N.a; Vieta, Eduardb; Earley, Williec

Author Information
International Clinical Psychopharmacology: May 2020 - Volume 35 - Issue 3 - p 147-156
doi: 10.1097/YIC.0000000000000307

Abstract

Introduction

Acute and chronic major depressive episodes, subsyndromal depressive symptoms, and dysphoria with mixed features comprise the majority of time spent unwell for patients with bipolar I or bipolar II disorder (Kupka et al., 2007). Episodes of depression are associated with increased rates of complications, including disability, morbidity, and suicide (Chen and Dilsaver, 1996; Bottlender et al., 2000). Despite being a highly debilitating condition associated with significant psychiatric and medical comorbidities (Baldessarini et al., 2010), depressive episodes associated with bipolar disorder are less understood than manic or hypomanic episodes and relatively few pharmacologic agents with proven treatment efficacy exist for their treatment (Post, 2012, 2016; Yatham et al., 2018). Traditional antidepressants continue to be commonly used for the treatment of depressive episodes despite limited empirical evidence indicating their efficacy, and availability of evidence suggesting their use may induce a switch to hypomanic, manic, or mixed features episode when used long term or intensify disease severity by increasing mood cycle frequency (Pacchiarotti et al., 2013; McGirr et al., 2016).

Dopamine receptor modulators are efficacious as a class treatment of bipolar mania, but currently, only olanzapine-fluoxetine combination (SYMBYAX, 2009), quetiapine (Seroquel, 2013), cariprazine (Vraylar, 2019), and lurasidone (LATUDA, 2017) have obtained regulatory approval as first-line treatment options for acute bipolar depression. Unlike the other agents that show low or negligible affinity for D3 receptors (Graff-Guerrero et al., 2009; Mizrahi et al., 2011), cariprazine exhibits preferential binding to D3 receptors (Kiss et al., 2010) and also has high affinity for serotonin 5-HT1A receptors in preclinical models (Blier et al., 1997). Presumably, through these interactions, cariprazine enhances cognition (Marder et al., 2016), mood, and measures of reward, and reduces anhedonia in patients with schizophrenia (Gross and Drescher, 2012; Nakajima et al., 2013; Papp et al., 2014). Cariprazine is FDA-approved for the treatment of adults with schizophrenia as well as acute manic, acute mixed, or depressive episodes associated with bipolar I disorder and is under investigation for the treatment of major depressive disorder (MDD).

A clinical trial program systematically assessed the efficacy of cariprazine in the treatment of depressive episodes associated with bipolar disorder. To date, three phase 2b/3 trials (Durgam et al., 2016; Earley et al., 2019a,b) reported on the efficacy of cariprazine in treatment of bipolar I depression. This is the first study to evaluate the efficacy, safety, and tolerability of flexible-dose ranges of cariprazine in the treatment of depressive episodes in patients with either bipolar I or II disorder.

Methods

This phase 2 study (protocol MD-52) was conducted from June 2009 to June 2010 in 26 centers in the USA (NCT00852202). The Institutional Review Board at each study center approved the study protocol and amendments. All patients were recruited and screened in compliance with the International Conference on Harmonization Good Clinical Practice Guideline and the Declaration of Helsinki and provided written consent after receiving a complete study description and prior to any study participation.

Study design

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adult patients with bipolar I or II depression, which assessed two flexible dosages of cariprazine (‘low-dose’: 0.25–0.75 mg/day and ‘high-dose’: 1.5–3.0 mg/day) compared with placebo. The double-blind treatment period was 8 weeks, which was preceded by ≥1-week drug washout period and followed by a 2-week safety follow-up (no study medication). Eligible patients were randomized 1:1:1 to placebo, low-dose, or high-dose cariprazine using an interactive voice/web response system that assigned randomization and treatment allocation codes matching codes on the blinded medication packages. Patients, investigators, and study site personnel were blinded to allocation and treatment assignment; blinding was maintained throughout and until completion of the study.

All investigational products provided by the Sponsor were identical in appearance and packaging, with codes corresponding to treatment allocation; patients were instructed to take the investigational product once daily consistently in either the morning or evening. Patients in the low-dose cariprazine group received the 0.25 mg/day dose during weeks 1–4. Patients in the high-dose cariprazine group were titrated from 0.5 to 1.5 mg/day during the first week, and then continued 1.5 mg/day. After week 4, the dose was increased to the higher dose (0.75 mg/day for low-dose group or 3.0 mg/day for high-dose group) if the response determined to be inadequate [<40% improvement from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score] (Montgomery and Åsberg, 1979). After week 4, a dose decrease was allowed up to week 6, but no dose adjustments were allowed during the first four or final two weeks of the double-blind treatment period.

Patients

Adult outpatients (18–65 years of age) with a principal diagnosis of bipolar I or II disorder using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (APA, 2000) criteria without psychotic features and with a current major depressive episode of ≥4 weeks and ≤12 months, <8 episodes of a mood disturbance (depression, mania, hypomania, or mixed state) in the previous 12 months, and having at least one verified manic, hypomanic, or mixed episode were included in the study. Enrollment criteria also included scores of ≥20 on the 17-item Hamilton Depression Rating Scale (HAMD17) (Hamilton, 1960), ≥2 on Item 1 of the 24-item HAMD (HAMD24) rating scale, and ≤12 on the Young Mania Rating Scale (YMRS) (Young et al., 1978). A physical examination, clinical laboratory, and electrocardiogram (ECG) with no significant clinical results (as judged by investigators) were also required. Additional inclusion/exclusion criteria and permitted psychotropic medications are listed in Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ICP/A74.

Efficacy

Efficacy was assessed by the change from baseline to week 8 in MADRS total score (primary) and Clinical Global Impressions – Improvement (CGI-I) score (secondary). Additional efficacy parameters included changes from baseline to week 8 scores on the Clinical Global Impressions – Severity (CGI-S) (Guy, 1976), HAMD-24 and HAMD-17 scales, and rates of MADRS response (≥50% reduction from baseline in total score), MADRS remission (score ≤ 10), CGI-I response (score ≤ 2), and HAMD17 remission (total score ≤ 7) at week 8.

Safety

Safety assessments included adverse event reporting (at every visit), clinical laboratory evaluations (at screening and end of study), and ECGs (at screening, weeks 1, 4 and 8). Safety assessments conducted at baseline and at each double-blind study visit included vital signs, mania (using YMRS) (Young et al., 1978), and extrapyramidal symptoms (EPS) [Barnes Akathisia Rating Scale (BARS) (Barnes, 1989), the Abnormal Involuntary Movement Scale, and the Simpson–Angus Scale (SAS) (Simpson and Angus, 1970)]. Suicide risk was monitored at every visit using the Columbia-Suicide Severity Rating Scale (Posner et al., 2011).

Data analyses

Efficacy analyses were performed on the intent-to-treat population (patients who took at least one dose of investigational product and had at least one postbaseline MADRS assessment). MADRS total score changes from baseline to week 8 were analyzed by mixed-effects model for repeated measures (MMRMs) with treatment group, study center, visit, and treatment group-by-visit as covariates. Primary MADRS score comparison was between placebo and the average of the low- and high-dose cariprazine groups. If positive, a pairwise comparison between placebo and each cariprazine group was to be tested; this is a process for controlling for multiple comparisons. Two sensitivity analyses, using last-observation carried forward (LOCF) and observed cases approach, were performed on the primary efficacy parameter. An analysis-of-covariance model with treatment group and study center as factors and baseline MADRS total score as a covariate were used for both sensitivity analyses.

Analyses of the secondary outcome and additional continuous variables were each conducted using an MMRM method that was similar to the primary comparison, using the respective baseline scores as covariates. Analyses of categorical variables (response and remission rates) were done using a logistic regression model with treatment group and the corresponding baseline score as explanatory variables. All statistical analyses were performed using version 9.1.3 of Statistical Analysis Software (SAS Institute; Cary, North Carolina, USA).

Safety analyses were based on the safety population (randomized patients who took at least one dose of investigational product). For each safety parameter, the last assessment before the first dose of double-blind study medication was used as baseline; continuous variables were summarized by number of patients, mean, and SD, and categorical variables were summarized by number and percentage of patients.

Sample size

The sample size was determined by calculating that 75 patients per arm would provide 85% power to detect a treatment difference of 3.8 points in the primary efficacy parameter between the placebo group and the average of the two cariprazine treatment groups at the two-sided, 5% significance level, assuming a common SD of 8 for the primary efficacy parameter, a correlation coefficient of 0.5 for within-patient assessments, and a 30% patient drop-out rate.

Results

Patient disposition and demographics

Of 448 patients screened, 233 were randomized (Fig. 1). Of 227 patients in the safety population, 172 (75.8%) completed the study (placebo = 77.9%; low-dose cariprazine = 84.0%; high-dose cariprazine = 65.3%). ‘Lost to follow-up’ was among the most common reasons for discontinuation in each treatment group, along with adverse events and protocol violations in the high-dose cariprazine group. Baseline demographics, clinical history, and baseline assessment scores were similar across treatment groups (Table 1). The majority of patients (72.7%) were diagnosed with bipolar I disorder. Mean baseline MADRS and YMRS scores of ~30.5 and ~6.1, respectively, suggested the patient population was moderately depressed on average, with low levels of mania (Snaith et al., 1986; Berk et al., 2008).

Table 1
Table 1:
Patient characteristics at baseline in the safety population
Fig. 1
Fig. 1:
CONSORT flow diagram for study patients.

Efficacy

Primary efficacy parameter

MADRS scores were not significantly improved from baseline to week 8 compared with placebo for the average of the combined low- and high-dose cariprazine groups [least-squares mean difference (LSMD) = −0.3, 95% confidence interval (CI) = −3.8, 3.2; P = 0.8522]. Similarly, the improvement in MADRS total scores from baseline to week 8 was not appreciably different relative to placebo in low-dose cariprazine (LSMD = −0.7, 95% CI = −4.6, 3.3; P = 0.7408) or high-dose cariprazine groups (LSMD = 0.0, 95% CI = −4.1, 4.1, P = 0.9961) (Fig. 2).

Fig. 2
Fig. 2:
Mean change from baseline in MADRS total score (MMRM, ITT population). ITT, intent to treat; MADRS, Montgomery–Åsberg Depression Rating Scale; MMRM, mixed-effects model for repeated measures.

Secondary and additional efficacy parameters

No significant difference between groups was observed in mean CGI-I scores at week 8, with a mean score of 2.1 points for all treatment groups. Additional efficacy parameters were also similar across treatment groups, with no significant differences between groups (Table 2).

Table 2
Table 2:
Secondary and additional efficacy outcomes at week 8 in the (ITT) population

Exploratory analysis of efficacy

To evaluate the influence of placebo response on the results, a band-pass filter analysis was conducted, which excluded patient data from study centers with >50% MADRS response rates in the placebo group. The band-pass filter analysis used MMRM with an unstructured covariance matrix using treatment group, pooled center, visit, and treatment group-by-visit interaction as factors, and baseline plus baseline-by-visit interaction as covariates. The data at week 6 were chosen for analysis as it has been suggested that treatment effect vs. placebo may be greater at 4–6 weeks than at week 8. In the band-pass analysis, significant differences vs. placebo were observed for both the low-dose cariprazine (LSMD = −5.0, 95% CI = −9.61, −0.48; P < 0.05) and high-dose cariprazine groups (LSMD = −5.2, 95% CI = −9.81, −0.52, P < 0.05) (Supplementary Fig. 1, Supplemental digital content 2, http://links.lww.com/ICP/A75).

Safety

Extent of exposure

Median duration of treatment was similar across treatment groups (55–56 days) with a mean (SD) mg/day dose of 0.35 (0.12) and 1.52 (0.42) in the low-dose and high-dose cariprazine groups, respectively. Dose increases were administered in 38% of placebo, 45% of low-dose cariprazine, and 31% of high-dose cariprazine groups.

Adverse events

Overall treatment-emergent adverse events (TEAEs) were reported in similar percentages across all treatment groups (Table 3); however, adverse events leading to treatment discontinuation occurred more frequently in the high-dose group (9.3%) than in the placebo (2.6%) or low-dose cariprazine group (4.0%). Two patients each prematurely discontinued from the study due to suicidal ideation (high-dose cariprazine group), mania (low-dose cariprazine group), bipolar I disorder (high-dose cariprazine group), and depression (placebo and high-dose cariprazine groups). No premature discontinuations were due to EPS-associated TEAEs.

Table 3
Table 3:
Summary of adverse events in the safety population

Common TEAEs among both cariprazine groups occurring in ≥5% of patients and at least twice the rate of placebo included insomnia, akathisia, dry mouth, nausea, weight increased, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Akathisia was reported in 17% of high-dose cariprazine, 3% of low-dose cariprazine, and 4% of placebo groups. TEAEs considered related to treatment occurred in 53, 55, and 69% of patients in the placebo, the low-, and high-dose cariprazine groups, respectively. Most adverse events were judged to be mild to moderate in intensity. Serious adverse events related to treatment occurred in six patients during the double-blind treatment period and were bipolar disorder and suicidal ideation (placebo), suicide attempt and spontaneous abortion (low-dose cariprazine), and bipolar I disorder and suicidal ideation (high-dose cariprazine). One death, a suicide in the placebo group, occurred 20 days after being lost to follow-up but was considered unrelated to treatment. Suicidal ideation (of the lowest severity classification) was reported by ~20% of patients in each cariprazine group and 12% of patients in the placebo group, and suicidal behavior was reported in one patient in the low-dose cariprazine group.

Treatment-emergent mania

Mean decrease in YMRS scores was similar across treatment groups with a score change of −2.1, −1.3, and −1.9 for placebo, low-dose cariprazine, and high-dose cariprazine, respectively. Treatment-emergent mania (postbaseline YMRS total score ≥ 16) was reported in 10, 8, and 15% of patients in the placebo, low-dose cariprazine, and high-dose cariprazine groups, respectively.

Clinical parameters

Changes in clinical laboratory values, vital signs, and ECGs were unremarkable, with a low incidence of potentially clinically significant values across treatment groups (Table 4). Changes in clinical laboratory values and vital sign parameters were similar across treatment groups (Supplementary Table 2, Supplemental digital content 1, http://links.lww.com/ICP/A74); however, changes in alanine aminotransferase and prolactin values were slightly higher in both cariprazine groups compared with placebo group. Mean (SD) kg weight changes were +0.30 (2.16), +0.62 (2.76), and +1.42 (2.93) in the placebo, low-dose cariprazine and high-dose cariprazine groups, respectively. Weight increases ≥7% of body weight occurred in 5% of the low-dose cariprazine and 7% of high-dose cariprazine groups.

Table 4
Table 4:
Potentially clinically significant postbaseline laboratory values in the safety population during the double-blind treatment period

Discussion

This exploratory phase 2 trial in patients with bipolar I or bipolar II depression failed to detect statistically significant differences between cariprazine and placebo on any prospectively defined efficacy outcomes. The results of this study are discordant with results from other trials evaluating dopamine receptor modulators, including quetiapine (Calabrese et al., 2005; Thase et al., 2006), lurasidone (Loebel et al., 2014), and olanzapine (Tohen et al., 2012), which all demonstrated efficacy for the treatment of bipolar depression. Learnings from the present trial, as discussed below, were used to design three subsequent phase 2b/3 randomized controlled trials of cariprazine for the treatment of bipolar I depression, which successfully demonstrated improvement in depressive symptoms with both 1.5 and 3.0 mg/day cariprazine vs. placebo (Durgam et al., 2016; Earley et al., 2019a,b).

In the present trial, a high rate of placebo response was a major confounding factor. Although all four trials had comparable mean baseline MADRS scores (30.0–31.3), the average change from baseline in MADRS total score for placebo patients in the present trial was approximately −16 at week 6 (Fig. 2), while it was much smaller for placebo groups in subsequent positive studies (−11.1 to −12.9) (Durgam et al., 2016; Earley et al., 2019a,b).

The exploratory post-hoc band-pass analysis supports greater efficacy at week 6 and indicates that a high placebo response at some clinical sites may have impaired the ability to detect treatment differences in the total population.

Flexible dosing may also have reduced the ability to see differences at later time points.

Given the option to increase to a higher dose (including the placebo group, because all patients and investigators were blinded), patients on placebo who did not respond initially may have been given a higher ‘dose’ later. This could increase the chances of a placebo effect, whereby they report a perceived improvement in symptoms despite only receiving placebo. Even with fixed-dosing, patients who receive placebo may tend to report progressive symptom improvement over time. Evidence of this was seen in a subsequent fixed-dose trial where symptom improvement began to plateau around 4–6 weeks in the active treatment groups but continued to decline in the placebo group (Durgam et al., 2016).

In retrospect, the study probably did not have sufficient power to detect efficacy given the smaller sample size; the anticipated difference of 3.8 points was overly optimistic, and a more realistic estimate would have been lower. In the subsequent studies of cariprazine in bipolar depression, the average difference was ~2.7 points for the 1.5 and 3 mg groups combined (Saraf et al., 2019). Moreover, the current study included an ineffective low-dose (0.25–0.75 mg) group, which further reduced the expected treatment effect and power. Additionally, approximately one-quarter of the patients in the study population had a bipolar II disorder diagnosis, which may have increased variability and impaired the ability to detect a treatment effect. Nevertheless, this study provided useful information that was used to improve the design and success of subsequent studies of cariprazine. While the primary efficacy analysis did not observe an effect for low-dose cariprazine (0.25–0.75 mg), it did show that high-dose cariprazine (1.5–3.0 mg) had a signal. Subsequent studies used 1.5 or 3.0 mg fixed-doses were restricted to bipolar I disorder, and were powered with twice as many patients randomized to double-blind treatment.

A high proportion of failures in clinical trials of treatments for depressive symptoms in patients with acute bipolar depression and MDD have presumably resulted from higher than expected rates of placebo response and is recognized as a major impediment to the clinical development of new medications (Khan et al., 2003; Yatham et al., 2016). Various analyses have shown that antidepressant monotherapy trials with placebo response rates higher than 30% have a low probability of demonstrating statistically significant efficacy for active compounds over placebo (Khan et al., 2003; Iovieno and Papakostas, 2012). A post-hoc band-pass filter analysis of the data from this study suggested that both low- and high-dose cariprazine were effective in treating depression if all the data from centers that had >50% placebo response were excluded, confirming that higher placebo response was a major contributor to the failure of this study to detect a significant treatment effect. Strategies for addressing high placebo response rates and improving the ability to detect meaningful differences between active compounds and placebo in clinical trials include reducing the number of trial sites, keeping the number of capsules the same even with the dose increase, reducing the duration of the double-blind phase, and developing novel study designs and analyses (Khan et al., 2004).

Learnings in the present study, which were applied to subsequent phase 2b/3 trials in the program, included employing a more gradual titration methodology, to potentially lower rates of akathisia and discontinuations due to adverse events, assessment of higher doses of cariprazine, and inclusion of only patients with bipolar type I disorder. In this study, aggressive dose escalation may have had a negative impact on efficacy and tolerability outcomes, particularly in the high-dose cariprazine patients who experienced high levels of discontinuation due to adverse events. Rates of discontinuations in the high-dose cariprazine group were higher than comparable dose groups in other cariprazine bipolar depression trials (Durgam et al., 2016; Earley et al., 2019a,b). Also, increasing attrition over time may partly explain why the initial numerical separation between high-dose cariprazine and placebo was not maintained. This trend was also observed in two failed aripiprazole bipolar depression studies (Thase et al., 2008), which also had an aggressive titration methodology, high rates of attrition (~41–47%), and initial separation from placebo (from baseline to week 6) that was not maintained at trial endpoint (week 8) (Thase et al., 2008; Post, 2016).

Additionally, the phase 3 trials in the cariprazine program reported rates of akathisia of less than 10% (Earley et al., 2019a,b), compared to 17% in this study. High akathisia rates may have negatively affected efficacy outcomes, as its symptoms may be experienced by the patient and interpreted by the clinician as a worsening of the underlying depression. The titration methodology was modified in the phase 3 trials to only allow dose escalations to the highest dose (3.0 mg/day) after two weeks of treatment at 1.5 mg/day. Furthermore, the present study may have selected a cariprazine dose too low to effectively treat depressive symptoms, partially explaining the lack of significant improvement in the low-dose (0.25–0.75 mg/day) group. The mean daily dose of cariprazine for the group was only 0.35 mg/day, and significant improvement in depressive symptoms has not been previously reported with daily dose less than 1.5 mg/day (Durgam et al., 2016). This learning was applied to the phase 3 program by assessing a minimum cariprazine dose of 1.5 mg/day (Earley et al., 2019a,b).

Cariprazine was generally well tolerated in this study, and TEAEs occurred with similar frequency across treatment groups. As would be expected for a dopamine receptor modulator, the incidence of akathisia (both as a reported adverse event and as measured by the BARS) was highest among patients treated with high-dose cariprazine (1.5–3.0 mg/day) and the rates may be partially explained by the titration methodology used, as previously discussed. Other than akathisia, the incidence of EPS events was low and comparable to placebo in both cariprazine dose groups. The incidence of somnolence and sedation, which were significantly higher for dopamine receptor modulators vs. placebo analyzed in a meta-analysis (De Fruyt et al., 2012), were low among all treatment groups in this study. Mean weight gain was highest in the high-dose cariprazine patients, but no treatment groups exceeded 1.5 kg. Weight gain exceeding 7% of body weight was more frequently reported among patients in the high-dose cariprazine group than other groups, with an overall incidence of approximately 7%. Metabolic parameter shifts into abnormal ranges were minimal and not considered to be clinically relevant. The reasonable benefit–risk ratio of cariprazine in regards to weight gain and metabolic findings is important because patients with bipolar disorder and those treated with dopamine receptor modulators often experience an increased risk of cardiovascular disease, metabolic disorders, diabetes, and clinical obesity (Correll et al., 2008), and because incidences of these complications can lead to decreased medication adherence (Kemp, 2014).

Limitations

Limitations of this study included the lack of an active comparator to establish assay sensitivity and exclusion of patients with significant medical and psychiatric conditions, including suicidality, which is prevalent in this population (APA, 2002; Valtonen et al., 2006), limiting the generalizability of these findings. Although more aligned with clinical practice, the fixed-flexible dose design prevented assessment of specific cariprazine doses.

Conclusion

Although cariprazine did not significantly separate from placebo in this bipolar depression trial, factors that may have affected the outcome of the trial were identified. These factors helped to inform the design and conduct of subsequent phase 2b/3 clinical trials, which found significant improvements in depressive symptoms in patients with bipolar I disorder and a current depressive episode. Efforts to understand the causes of placebo response and minimize its occurrence in bipolar depression treatment trials will improve research efforts and support the development of the new treatments that are needed for bipolar depression. Both cariprazine doses did not affect metabolic parameters and weight changes to a clinically significant degree and had favorable tolerability profiles.

Acknowledgements

Kaifeng Lu, PhD and Yan Zhong, PhD conducted the statistical analyses. Writing assistance and editorial support for preparation of this manuscript was provided by Erika von Grote, PhD and Cherisse Loucks, PhD, of Allergan (Madison, New Jersey).

Supported by funding from Allergan plc (Madison, New Jersey) and Gedeon Richter Plc (Budapest, Hungary).

Allergan and Gedeon Richter Plc. were involved in the study design, collection (via contracted clinical investigator sites), analysis and interpretation of data, and decision to present these results.

Presented in the Autumn Conference of the International Society for CNS Clinical Trials and Methodology; 3–4 October 2011; Amelia Island, Florida, USA; and The 169th Annual Meeting of the American Psychiatric Association; 14–18 May 2016; Atlanta, Georgia, USA.

Data reported in this manuscript are available within the article (and/or) its supplementary materials. Allergan will share de-identified patient-level data and/or study-level data, including protocols and clinical study reports, for Phase 2-4 trials completed after 2008 that are registered on ClinicalTrials.gov or EudraCT. The indication studied in the trial must have regulatory approval in the United States and/or the European Union and the primary manuscript from the trial must be published prior to data sharing. To request access to the data, the researcher must sign a data use agreement. All shared data are to be used for noncommercial purposes only. More information can be found on http://www.allerganclinicaltrials.com/.

Conflicts of interest

W.E. is an employee of Allergan and owns stock in Allergan, AstraZeneca, and Eli Lilly. L.N.Y. has been an advisory board member or speaker for or received grant/research support from Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb, DSP, Forest, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sunovion, and Valeant and research support from the Stanley Foundation, the National Alliance for Research on Schizophrenia and Depression, Canadian Institutes of Health Research, and the Canadian Psychiatric Research Foundation. E.V. has received grants and served as consultant, advisor, or speaker for: AB-Biotics, Abbott, Alexza, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Casen-Recordati, Cephalon, Dainippon Sumitomo, Pharma, Elan, Eli Lilly, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson and Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Schering-Plough, Shire, the Spanish Ministry of Science and Innovation, the Seventh European Framework Programme, the Stanley Medical Research Institute, Sunovion, Takeda, Teva, United BioSource Corporation, and Wyeth.

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 20004th ed, Washington, DC: American Psychiatric Association
American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002; 159:1–50
Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden CL. Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010; 18:143–157
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989; 154:672–676
Berk M, Ng F, Wang WV, Calabrese JR, Mitchell PB, Malhi GS, Tohen M. The empirical redefinition of the psychometric criteria for remission in bipolar disorder. J Affect Disord. 2008; 106:153–158
Blier P, Bergeron R, De Montigny C. Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response. Neuropsychopharmacology. 1997; 16:333–338
Bottlender R, Jager M, Strauss A, Moller H. Suicidality in bipolar compared to unipolar depressed inpatients. Eur Arch Psychiatry Clin Neurosci. 2000; 250:257–261
Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005; 162:1351–1360
Chen Y, Dilsaver S. Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorder relative to subjects with other axis I disorders. Biol Psychiatry. 1996; 39:896–899
Correll C, Frederickson A, Kane J, Manu P. Equally increased risk for metabolic syndrome in patients with bipolar disorder and schizophrenia treated with second-generation antipsychotics. Bipolar Disord. 2008; 10:788–797
De Fruyt J, Deschepper E, Audenaert K, Constant E, Floris M, Pitchot W, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol. 2012; 26:603–617
Durgam S, Earley W, Lipschitz A, Guo H, Laszlovszky I, Nemeth G, et al. An 8-Week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry. 2016; 173:71–281
Earley W, Burgess M, Rekeda L, Dickinson R, Szatmari B, Nemeth G, et al. Cariprazine treatment of bipolar depression: a randomized, double blind, placebo-controlled phase 3 study. Am J Psychiatry. 2019a; 176:439–448
Earley W, Burgess MV, Khan B, Rekeda L, Suppes T, Tohen M, et al. Efficacy and safety of cariprazine in bipolar I depression: a double blind, placebo-controlled phase 3 study. Bipolar Disord. 2019b
Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, et al. The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study with [11C]-(+)-PHNO. Arch Gen Psychiatry. 2009; 66:606–615
Gross G, Drescher K. The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb Exp Pharmacol. 2012; 213:167–210
Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education, and Welfare Publication (ADM). 1976, Rockville, MD: National Institute of Mental Health218–222
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23:56–62
Iovieno N, Papakostas G. Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2012; 73:1300–1306
Kemp DE. Managing the side effects associated with commonly used treatments for bipolar depression. J Affect Disord. 2014; 169Suppl 1S34–S44
Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis. 2003; 191:211–218
Khan A, Kolts RL, Thase ME, Krishnan KR, Brown W. Research design features and patient characteristics associated with the outcome of antidepressant clinical trials. Am J Psychiatry. 2004; 161:2045–2049
Kiss B, Horvath A, Nemethy Z, Schmidt E, Laszlovszky I, Bugovics G, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333:328–340
Kupka RW, Altshuler LL, Nolen WA, Suppes T, Luckenbaugh DA, Leverich GS, et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007; 9:531–535
LATUDA. LATUDA (lurasidone HCL) tablets [package insert]. 2017, Marlborough, MA: Sunovion Pharmaceuticals Inc
Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, Sachs G. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014; 171:160–168
Marder S, Laszlovszky I, Szalai E, Szatmári B, Harsányi J, Barabássy A, et al. Efficacy of cariprazine on predominant negative symptoms of patients with schizophrenia: post hoc analysis of PANSS data, marder factors, and cognition. Eur Neuropsychopharmacol. 2016; 26:S550
McGirr A, Vöhringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials. Lancet Psychiatry. 2016; 3:1138–1146
Mizrahi R, Agid O, Borlido C, Suridjan I, Rusjan P, Houle S, et al. Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. Schizophr Res. 2011; 131:63–68
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979; 134:382–389
Nakajima S, Gerretsen P, Takeuchi H, Caravaggio F, Chow T, Le Foll B, et al. The potential role of dopamine D(3) receptor neurotransmission in cognition. Eur Neuropsychopharmacol. 2013; 23:799–813
Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013; 170:1249–1262
Papp M, Gruca P, Lasoń-Tyburkiewicz M, Adham N, Kiss B, Gyertyán I. Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav Pharmacol. 2014; 25:567–574
Posner K, Brown GK, Stanley B, Brent DA, Yershova K, Oquendo M, et al. The Columbia–Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168:1266–1277
Post RM. The sorry state of treatment research in bipolar disorder: an ongoing but preventable catastrophe. J Nerv Ment Dis. 2012; 200:924–927
Post RM. Treatment of bipolar depression: evolving recommendations. Psychiatr Clin North Am. 2016; 39:11–33
Saraf G, Pinto JV, Yatham LN. Efficacy and safety of cariprazine in the treatment of bipolar disorder. Expert Opin Pharmacother. 2019; 20:2063–2072
Seroquel XR. Quetiapine Fumarate Extended-Release [package insert]. 2013, Wilmington, DE: AstraZeneca Pharmaceuticals LP
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand suppl. 1970; 212:11–19
Snaith RP, Harrop FM, Newby DA, Teale C. Grade scores of the montgomery-asberg depression and the clinical anxiety scales. Br J Psychiatry. 1986; 148:599–601
SYMBYAX. SYMBYAX (olanzapine and fluoxetine) Capsules [package insert]. 2009, Indianapolis, IN: Eli Lilly and Company
Thase ME, Jonas A, Khan A, Bowden CL, Wu X, Mcquade RD, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008; 28:13–20
Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006; 26:600–609
Tohen M, Mcdonnell DP, Case M, Kanba S, Ha K, Fang YR, et al. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. Br J Psychiatry. 2012; 201:376–382
Valtonen HM, Suominen K, Mantere O, et al. Prospective study of risk factors for attempted suicide among patients with bipolar disorder. Bipolar Disord. 2006; 8:576–585
Vraylar. Vraylar [package insert]. 2019, Irvine, CA: Allergan
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018; 20:97–170
Yatham LN, Vieta E, Goodwin GM, Bourin M, De Bodinat C, Laredo J, et al. Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Br J Psychiatry. 2016; 208:78–86
Young R, Biggs J, Ziegler V, Meyer DA. A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978; 133:429–435
Keywords:

bipolar depression; bipolar I disorder; bipolar II disorder; cariprazine; dopamine receptor modulator; randomized-controlled trial

Supplemental Digital Content

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.