Olanzapine-fluoxetine

Olanzapine-fluoxetine combination (OFC) was approved for the treatment of bipolar I depression in 2003. The approval was based on replicated evidence of efficacy in adults (18 or older who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for bipolar I disorder).Reference Tohen, Vieta and Calabrese²

The primary objective of the 8-week study was to compare the efficacy and safety of olanzapine monotherapy and placebo in the treatment of bipolar I depression. This was a single-protocol study divided into 2 identical 8-week studies. The OFC treatment arm was included concurrently for exploratory purposes. The pivotal registration trials were published as a combined paper wherein a total of 1072 patients were recruited from inpatient and outpatient services of 84 study sites in 13 countries.Reference Tohen, Vieta and Calabrese²

Eligible subjects were required to have a score of at least 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS) at randomization. Subjects were also required to have had a history of at least 1 prior manic or mixed episode of sufficient severity to require treatment with a mood stabilizer or antipsychotic agent. Randomization was disproportionate for olanzapine (n = 370), placebo (n = 377), and OFC (n = 86) assignment (ie, 4:4:1, respectively). Olanzapine dosing was 5–20 mg while OFC was 6 and 25 mg, 6 and 50 mg, or 12 and 50 mg for olanzapine and fluoxetine, respectively. Patients were permitted adjunctive use of benzodiazepine (up to 2 mg of lorazepam equivalents per day) throughout screening and acute phases of the study. Anticholinergic therapy was permitted throughout the study for the treatment of extrapyramidal symptoms (ie, benztropine mesylate or biperiden ≤ 6 mg per day or trihexyphenidyl ≤12 mg per day).Reference Tohen, Vieta and Calabrese²

The patients taking OFC had the highest rate of study completion (ie, 64%) with higher rates of discontinuation with olanzapine (ie, 48.4%) and placebo (ie, 38.5%). Starting at week 1 and continuing throughout the study, both the olanzapine and OFC groups demonstrated significantly greater mean improvement in MADRS total scores than those receiving placebo. Starting at week 4 and continuing to week 8, the OFC group also demonstrated significantly greater mean total MADRS score when compared to olanzapine alone. The therapeutic effect size for OFC and olanzapine was 0.68 and 0.32, respectively. The response rate for the olanzapine group was 39.0% while for OFC it was 56.1%, both of which were significantly greater than placebo. The remission rate for olanzapine was 32.8% while for OFC it was 48.8%, again significantly higher than reported for placebo. The olanzapine-treated subjects demonstrated greater mean improvements on the Clinical Global Impressions Bipolar Version—Severity of Depression Scale (CGI-BP-S) than placebo, while OFC showed greater mean improvement than placebo and olanzapine.Reference Tohen, Vieta and Calabrese²

Treatment-emergent mania was defined as a Young Mania Rating Score (YMRS) of ≤15 at baseline and ≥15 at any time thereafter. There were no significant differences between groups in the rate of treatment-emergent mania (ie, 6.7%, 5.7%, and 6.4% for placebo, olanzapine, and OFC, respectively). The most commonly reported adverse events for OFC were somnolence, diarrhea, weight gain, dry mouth, and headache. The most commonly reported adverse events for olanzapine were somnolence, weight gain, increased appetite, headache, and dry mouth. Mean weight gain was higher in individuals receiving olanzapine (ie, olanzapine 2.59 ± 3.24 and OFC 2.79 ± 3.23 vs. placebo –0.47 ± 2.62). Both olanzapine and OFC groups exhibited significant change from baseline in total cholesterol.Reference Tohen, Vieta and Calabrese²

Olanzapine monotherapy is not FDA-approved for the acute treatment of bipolar I depression. However, olanzapine is approved for the acute treatment of bipolar depression in several other countries (eg, Japan).Reference Tohen, Vieta and Calabrese² The efficacy of olanzapine as a monotherapy in bipolar depression is supported by the foregoing single-protocol studies.Reference Tohen, McDonnell and Case³ Further evidence supporting olanzapine's efficacy in bipolar depression is from a separate study that primarily evaluated olanzapine (5–20 mg) compared to placebo in adults with bipolar I depression as part of a parallel-group study. Eligibility criteria were similar to the foregoing study that also included OFC. The olanzapine monotherapy study was, however, a 6-week randomized, double-blind, placebo-controlled trial. A total of 514 patients were randomly assigned to either olanzapine (n = 343) or placebo (n = 171).Reference Tohen, McDonnell and Case³

The baseline to endpoint decrease in least squares mean MADRS total score was significantly greater in the olanzapine group than in the placebo group after 6 weeks of double-blind treatment (–13.82 vs –11.67; P = 0.018), with an effect size of 0.22. Significantly higher rates of response and remission were noted in the olanzapine vs. placebo-treated subjects (ie, 52.5% vs 43.3%; 38.5% vs 29.2%, respectively). The olanzapine-treated subjects had significantly greater reduction in least-squares mean MADRS total scores in each visit other than week 1. The olanzapine-treated subjects also exhibited a greater baseline-to-endpoint improvement in CGI-BP depression, CGI-BP mania, and CGI-BP subscale scores. The adverse event profile (eg, clinically significant weight gain and significant change from baseline in fasting cholesterol, fasting triglycerides, and fasting glucose) was also noted.Reference Tohen, McDonnell and Case³ A separate pooled analysis further supports the efficacy of olanzapine in bipolar depression.Reference Tohen, Katagiri, Fujikoshi and Kanba⁴

Quetiapine

Quetiapine was approved as monotherapy for the treatment of bipolar depressive episodes by the FDA in October 2006. The efficacy of quetiapine in acute bipolar depression is supported by results from 5 studies with quetiapine immediate release (IR) and 1 study with quetiapine extended release (XR). The design of all 6 clinical trials was similar insofar as the principal aim was to compare the efficacy of quetiapine monotherapy to placebo in adults with bipolar I/II depression (the registration trial that compared quetiapine XR to placebo was limited to depression in bipolar I disorder).

The subjects were outpatients 18–65 years of age; all subjects were required to have a Hamilton Depression Rating Scale (HAM-D) score of ≥20, HAM-D item 1 score ≥2, and YMRS ≤12 at the screening and randomization visits. The primary efficacy parameter was the MADRS in all studies. The dosing of quetiapine used was 300 mg or 600 mg per day (the quetiapine XR study aimed for quetiapine XR dosing of 400–800 mg from day 3 to day 22).Reference Cutler, Datto and Nordenhem⁵ Concomitant psychiatric medications that were permitted were zolpidem tartrate (5–10 mg per day) and lorazepam (1–3 mg per day for severe anxiety) for the first 3 weeks but withheld for 8 hours before psychiatric assessments were conducted.Reference Cutler, Datto and Nordenhem^5–Reference Calabrese, Keck and Macfadden¹⁰

The primary outcomes for each of the studies are presented in Table 1. The results of the first 2 trials [ie, BipOLar DEpRession I and II studies (BOLDER I and BOLDER II)] were summarized in a post hoc analysis of combined data.Reference Weisler, Calabrese and Thase^7–Reference Young, McElroy and Bauer⁹ In the combined analysis individuals with bipolar I depression receiving quetiapine 300 mg and 600 mg per day exhibited statistically significant improvement in symptoms of depression compared with those of placebo throughout the 8-week treatment period, beginning at week 1. The effect size for quetiapine was 0.78 for 300 mg and 0.80 for 600 mg. There was a similar reduction seen in 2 individuals in BOLDER I and II studies in patients with bipolar I disorder.Reference Thase, Macfadden and Weisler⁶ The rates of response (defined as a ≥50% decrease in MADRS total score from baseline) were higher in the quetiapine 600 mg group than placebo while remission rates (defined as a reduction in MADRS score to ≤12) were higher for both doses of quetiapine vs placebo. The efficacy of quetiapine was noted to be significantly higher in bipolar I depression vs bipolar II depression. The most commonly reported adverse events with quetiapine 600 mg were dry mouth, sedation, somnolence, dizziness, and fatigue. Significant advantage in efficacy was also noticed on CGI-BP-S and Clinical Global Impression of Change in Bipolar Depression Scale (CGI-BP-C) scores.Reference Weisler, Calabrese and Thase⁷

Table 1

Studies Evaluating Treatment Options for Bipolar Depression

MADRS: Montgomery–Åsberg Depression Rating scale; YMRS: Young Mania Rating Scale; CGI-BP: Clinical Global Impression-Bipolar version; HAM-A: Hamilton Anxiety Scale; QIDS-SR₁₆: Quick Inventory of Depressive Symptomatology; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction-Short Form; SDS: Sheehan Disability Scale; BMI: Body Mass Index; HRSD-17, HAMD-17: Hamilton Rating Scale for Depression; MMRM: Mixed-effects Model Repeated Measures; HARS: Hamilton Anxiety Rating Scale; PSQI: Pittsburg Sleep Quality Index; MOS-Cog: Medical Outcomes Study Cognitive Scale; BDI: Beck Depression Inventory; Quetiapine XR: Quetiapine Extended Release; VAS: Visual Analog Scales; BPRS: Brief Psychiatric Rating Scale; CADSS: Clinician Administered Dissociative Scale; IDS: Inventory of Depressive Symptoms.

The efficacy of quetiapine was further supported by 2 similarly designed studies [Efficacy of Monotherapy Seroquel in BipOLar DepressioN I and II (EMBLODEN I and II)]. Efficacy of Monotherapy Seroquel in BipOLar DepressioN I included lithium as an active control while EMBOLDEN II included paroxetine as an active control. The overall effect sizes in tolerability profiles for quetiapine in both studies were similar to what was reported in the original BOLDER registration trials.Reference McElroy, Weisler and Chang^8, Reference Young, McElroy and Bauer⁹

Lurasidone

Lurasidone was approved for the treatment of adults with bipolar I depression as a monotherapy or an adjunct to lithium or divalproex. The monotherapy study design was a double-blind, placebo-controlled, 6-week study, wherein eligible subjects were assigned to lurasidone 20–60 mg per day, lurasidone 80–120 mg per day, or placebo. All subjects started on 20 mg for the first 2 days then increased to 80 mg by day 7 and flexibly dosed thereafter. The double-blind phase was followed by 24 weeks open-label extension with lurasidone 20–120 mg per day. The monotherapy study enrolled subjects 18–75 with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR)-defined major depressive episode in individuals diagnosed with bipolar I disorder with or without rapid cycling, and without psychotic features. The MADRS total score at baseline was ≥20 at screening and YMRS score ≤12. The primary efficacy parameter was a change from baseline in total MADRS score at week 6. All eligible subjects had to have had lithium or valproate for at least 28 days prior to entry.¹¹

A total of 331 subjects were assigned to lurasidone (n = 164 at 20–60 mg per day; n = 167 at 80–120 mg per day; n = 168 assigned to placebo). The percent of subjects that discontinued were similar across groups (ie, 26% of total participants in the 2 lurasidone groups and 25% for placebo). The modal dose of lurasidone in the 20–60 mg group was 20 mg per day, while the modal dose in the 80–120 mg group was 80 mg per day.¹¹

The change from baseline in the total MADRS score Mixed-Effects Model Repeated-Measures (MMRM) was significantly greater (ie, –15.4 for both lurasidone groups and –10.7 for placebo) in the lurasidone-treated groups. Both lurasidone-treated groups exhibited significant reductions in MADRS scores at all visits except week 1. Significant change from baseline was also noted for both lurasidone groups on the CGI-BP-S at endpoint (ie, all visits for the 80–120 mg group and all visits except week 1 for the 20–60 mg group). The response rates were higher in both lurasidone-treated groups vs placebo with a number needed to treat (NNT) = 5. Moreover, remission rates were also significantly higher for both lurasidone groups with NNT = 6 and 7 for the lower and higher doses of lurasidone, respectively. Evidence of efficacy was also evident as measured by the Hamilton Anxiety Rating Scale (HAM-A) and Quick Inventory of Depressive Symptomology-Self Report (QIDS-SR) with significant reductions in both lurasidone groups vs placebo. Significant improvements were also noted in measures of function [ie, Sheehan Disability Scale (SDS)] and quality of life [ie, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF)].¹¹

There were no significant changes between the 2 lurasidone groups and placebo in weight, body mass index (BMI), fasting cholesterol, triglycerides, and glucose. The most commonly reported adverse events were nausea, headache, akathisia, insomnia, somnolence, and sedation.¹¹

The adjunctive trial had a similar study design and was a randomized, double-blind, placebo-controlled trial that compared adjunctive lurasidone 20–120 mg per day to adjunctive placebo. Lurasidone was started at 20 mg per day and increased to 60 mg per day. All subjects were required to take lithium (0.6–1.2 mEq/L) or valproate (50–125 μg.mL) for ≥28 days. The double-blind phase was also followed by an open-label extension, flexibly dosed (ie, lurasidone 20–120 mg/day) for 24 weeks. Eligibility criteria as well as primary and secondary endpoints were similar to the monotherapy trial.¹¹

A similar number of individuals was assigned to adjunctive lurasidone (n = 179) and placebo (n = 161) with a similar percentage receiving lithium or valproate (50%/50% and 45%/54% in the lurasidone and placebo group, respectively). The overall rate of discontinuation was similar in the lurasidone and placebo groups (ie, 22% and 18%, respectively). The mean plasma concentration of lithium at endpoint was 0.7 mEq/L in both groups, and for valproate it was similar at 71.1 and 72.4 μg/mL in the placebo and lurasidone groups, respectively.¹¹

The least square mean change from baseline from MMRM was significantly greater in the adjunctive lurasidone group (–17.1) vs the adjunctive placebo group (–13.5). The first observation week wherein the adjunctive lurasidone group separates from placebo was at week 3. Evidence of efficacy as measured by CGI-BP-S was also evident at endpoint for the adjunctive lurasidone group and at each observation point except week 1. The response and remission rates were significantly higher in the lurasidone treated group with an NNT = 7 for both outcomes, respectively. Further evidence of efficacy was apparent on the QIDS-SR, HAM-A, SDS, and Q-LES-Q-SF. There was no evidence of treatment-emergent mania; with only 1 subject in each group meeting a priori criteria (ie, YMRS ≥16 on any 2 consecutive visits, or at final assessment). There were no significant between-group differences on change from baseline on total weight, BMI, fasting cholesterol, triglycerides, or glucose. There was a significant median change from baseline in prolactin in the lurasidone treated group (ie, 3.8 ng/mL) versus the placebo group (0.0 ng/mL) (2.8 ng/mL vs –0.1 ng/mL; 5.1 ng/mL vs. 0.2 ng/mL in the lurasidone vs. placebo groups in males and females, respectively). The most common adverse events were nausea, headache, somnolence, tremor, akathisia, and insomnia with differences between the lurasidone and placebo treated groups, which were <7% apart for all adverse events.¹¹

Lamotrigine

The anticonvulsant lamotrigine was approved for maintenance treatment of bipolar I disorder. Despite replicated evidence supporting the efficacy of lamotrigine in improving secondary outcome measures, lamotrigine failed to show consistent improvement on the primary outcome measure (eg, change in MADRS baseline-to-endpoint score) in acute bipolar depression trials. A significant positive result in the primary efficacy measure was reported, however, in a meta-analysis of 5 studies.Reference van der Loos, Mulder and Hartong¹²

The primary objective of the 8-week, randomized, double-blind study was to assess the therapeutic effects of lamotrigine adjunctive to the existing lithium treatment in individuals with bipolar depression. The study included 124 eligible subjects, who were diagnosed with bipolar I or II disorder as outlined by DSM-IV-TR criteria. At the time of screening, the participants were required to have a score of at least 18 on the MADRS and 4 on the CGI-BP-S depression scale. Subjects were treated with lithium (0.6–1.2 mmol/L, plasma level) for at least 2 weeks prior to the study. Eligible subjects were then assigned to lamotrigine (200 mg/d, n = 64) or placebo (n = 60). Benzodiazepines (2 mg lorazepam equivalents per day) were permitted throughout the investigation.Reference van der Loos, Mulder and Hartong¹²

Mean change in baseline MADRS total score was greater in the lamotrigine group (–15.38) when compared to placebo (–11.03). Response rate was defined as greater than 50% reduction in MADRS total score or change in CGI-BP-S depression by less than or equal to 2 compared to baseline. Response rate was significantly higher in the lamotrigine group compared to the placebo group (51.6% and 31.7%, respectively, for MADRS score and 64.1% and 49.2, respectively, for CGI-BP-S score). Few subjects showed a switch to mania or hypomania (7.8% in the lamotrigine and 3.3% in placebo). Adverse events were mild to moderate with no significant difference in their frequency between the 2 groups. Headache, fatigue, and nausea were commonly reported side effects.Reference van der Loos, Mulder and Hartong¹²

In another study, van der Loos etal Reference van der Loos, Mulder and Hartong¹³ observed the long-term effects of the aforementioned study over the span of 68 weeks. Eligibility criteria for subjects were identical to the one described above. After 8 weeks of treatment with lamotrigine, the nonresponders identified by the CGI-BP depression or mania score lower than 4 were treated with open-label paroxetine (20 mg/day) for another 8 weeks in addition to the ongoing lamotrigine or placebo treatment. Responders were followed until week 68 or until a relapse of manic or depressive episode.Reference van der Loos, Mulder and Hartong¹³

Significant improvement in MADRS total score was observed in the lithium–lamotrigine group compared to the lithium–placebo group (–15.37 and –11.16, respectively) after the first 8 weeks; however, adjunctive paroxetine to nonresponders (n = 37) did not yield a significant difference in MADRS total score between the lithium–lamotrigine–paroxetine and the lithium–placebo–paroxetine groups (–17.91 and –15.40, respectively). The median time to recurrence was longer in the lamotrigine group (10 months) compared to the placebo group (3.5 months). The probability of no recurrence, as well as the percentage of responders, were higher in the lamotrigine group compared to the placebo group throughout the study period.Reference van der Loos, Mulder and Hartong¹³

Ketamine

Glutamate receptor dysfunction is implicated in the pathophysiological course of bipolar depression. Recent studies have demonstrated that ketamine, an N-methyl-D-aspartate (NMDA) agonist, exerts immediate antidepressant effects.Reference Diazgranados, Ibrahim and Brutsche¹⁴ The primary goal of a randomized, placebo-controlled, double-blind, cross-over study was to evaluate the effect of ketamine vs placebo in individuals with treatment-resistant bipolar depression.Reference Diazgranados, Ibrahim and Brutsche¹⁴ Eligible subjects were required to be diagnosed with DSM-IV-TR-defined bipolar I or II depression with a minimum MADRS score of 20. Participants were required to have used at least 1 antidepressant and resistant to either lithium (0.6–1.2 mEq/L) or valproic acid (50–125 μg/mL) treatment lasting at least 4 weeks. Eligible subjects were then randomly assigned to, and treated with, intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 different test days that were 2 weeks apart. The single intravenous infusion of ketamine was combined with either lithium or valproate treatment.Reference Diazgranados, Ibrahim and Brutsche¹⁴

For all subjects, the MADRS scores were measured at baseline (60 min before infusion); 40, 80, 110, and 230 minutes; and days 1, 2, 3, 7, 10, and 14 after the infusion. Significantly fewer depressive symptoms were observed with ketamine compared to placebo (P < 0.01) 40 min following infusion from day 1 to day 3. The largest effect size (0.80) was reported on day 2, post-infusion. No significant difference between ketamine and placebo was observed from baseline and day 7 thereafter. A decrease in depressive symptoms with ketamine was also seen in the results obtained by the Beck Depression Inventory (BDI) and the Visual Analog Scales (VAS). Significantly fewer anxiety and manic symptoms were observed intermittently with ketamine treatment starting at 40 minutes and 80 minutes post-infusion, respectively.Reference Diazgranados, Ibrahim and Brutsche¹⁴

The robust antidepressant effects of ketamine were replicated in another study of similar design, where 15 patients diagnosed with bipolar I or II depression received ketamine hydrochloride or saline intravenous infusion. With the exception of the appetite and sleep items, 8 out of 10 individual MADRS items showed improvement with ketamine treatment compared to placebo. The median response time to ketamine was 40 min, whereas the mean relapse time was 4.5 days. Subjects (N = 15) met remission criteria (defined as a MADRS score <10) from 40 minutes until day 3 post-infusion. Moreover, ketamine treatment reduced suicidal ideation when compared to placebo and was reflected in MADRS, HDRS, and BDI scores.Reference Zarate, Brutsche and Ibrahim¹⁵

The most common side effects reported were dissociative symptoms (40 min post-infusion), sensation of oddity, dry mouth, tachycardia, and increased blood pressure. No serious adverse events were reported. No significant difference in adverse events between ketamine and placebo were observed following the 80-min assessment.Reference Diazgranados, Ibrahim and Brutsche¹⁴

Modafinil Armodafinil

Modafinil is not an FDA-approved treatment for bipolar depression; however, it is approved for the treatment of excessive sleepiness, which is often a characteristic of bipolar depression. The antidepressant effect of modafinil in bipolar depression has been studied. In 1 randomized, double-blind, placebo-controlled study, 85 eligible subjects diagnosed with bipolar I or II depression as outlined by DSM-IV-TR criteria, unresponsive to mood stabilizers, were treated with modafinil (n = 41) or placebo (n = 44) for 6 weeks. All subjects received 100 mg/day at week 1, which was increased to 200 mg/day at week 2 and every week thereafter.Reference Frye, Grunze and Suppes¹⁶

The primary efficacy measure was a change in the Inventory of Depressive Symptoms (IDS) score from baseline to endpoint. Significant reductions in total IDS score, 4-item IDS subset score, and CGI-BP depression severity were observed in the modafinil vs placebo group. A significantly greater percentage of subjects in the modafinil group (43.9%) achieved at least a 50% reduction in their IDS score compared to placebo (22.7%). Significantly greater response (greater than 50% reduction in IDS score at endpoint) and remission (final IDS score <12) rates (44% vs 39% and 23% vs 18%, respectively) were observed with modafinil compared to placebo. The frequency of treatment-emergent hypomania or mania did not differ significantly between the modafinil and placebo groups.Reference Frye, Grunze and Suppes¹⁶

A separate 8-week, randomized, double-blind, placebo-controlled study evaluated the efficacy of armodafinil as a treatment for bipolar I depression. Two hundred fifty-seven subjects participated in the study. Subjects unresponsive to previous treatment with lithium (≥0.6 mEq/L plasma), olanzapine (≥5 mg/day), or valproic acid (≥50 μg/mL plasma) were randomized to adjunctive armodafinil (n = 128, 150 mg/day) or placebo (n = 129).Reference Calabrese, Ketter and Youakim¹⁷

Mean change from baseline to endpoint values on the 30-item IDS (IDS-C₃₀) was used as the primary efficacy measure. Individuals receiving armodafinil displayed a greater mean change from baseline to endpoint on the IDS-C₃₀ when compared to placebo (–15.8 and –12.8, respectively). Depressive symptomatology improved with armodafinil treatment compared to placebo as measured by the total IDS-C₃₀ scores without reaching statistical significance. No statistically significant improvement in remission (24% vs 18%) or response rates (37% vs 38%) was observed with armodafinil or placebo during the final 4 weeks. Armodafinil treatment did not yield any significant improvement on any secondary measures (ie, HARS, MADRS, CGI-BP, Q-LES-Q-SF, and QIDS-SR₁₆),Reference Calabrese, Ketter and Youakim¹⁷ leaving it uncertain whether armodafinil can be considered a reliable treatment in bipolar depression.

Adverse events were categorized as mild to moderate. The most common adverse events reported with armodafinil treatment were headache, hypomania, infection, nausea, pepsia, insomnia, and rapid heart rate.Reference Frye, Grunze and Suppes¹⁶ There was no significant difference in the percentage of the subjects who discontinued treatment due to adverse events in the armodafinil (13%) and placebo groups (9%).Reference Calabrese, Ketter and Youakim¹⁷