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Bipolar Depression Research Review

Sanjay Gupta, MD
Roger McIntyre, MD, FRCPC
Released: October 28, 2021

Atypical Antipsychotics for Acute Bipolar Depression: Efficacy and Tolerability Derived From a Network Meta-analysis

Kadakia A, et al. BMC Psychiatry. 2021;21:249.

Although clinical trial evidence has firmly established the efficacy of several AAPs for treating bipolar depression, no randomized controlled trials comparing AAPs have been conducted. This meta-analysis compared the relative efficacy and tolerability of AAP monotherapy in adults with bipolar depression.

Efficacy measures included change in Montgomery Åsberg Depression Rating Scale (MADRS), Clinical Global Improvement-Bipolar-Disorder Severity (CGI-BP-S), response, and remission. Multiple tolerability outcomes were examined. Results from random-effects models were reported as differences in change from baseline for continuous variables or odds ratios for dichotomous variables. The number needed to treat (NNT) and harm were calculated.

Eighteen randomized controlled trials met the inclusion criteria of the systematic literature review. On change in MADRS, quetiapine, olanzapine, and cariprazine were more efficacious than placebo. Lurasidone was associated with a significantly greater odds of response (≥50% improvement in MADRS) compared with cariprazine, aripiprazole, and ziprasidone but was similar to olanzapine and quetiapine. For the change in CGI-BP-S overall score, lurasidone was significantly better than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Lurasidone 0.34 kg and aripiprazole 0.20 kg, had a similar weight change compared with placebo, but olanzapine 2.88 kg, quetiapine 1.17 kg, and cariprazine 0.65 kg were associated with greater weight gain. The NNT for response was the lowest for lurasidone (NNT = 5) followed by quetiapine (NNT = 6), olanzapine (NNT = 10), and cariprazine (NNT = 12).

In this network meta-analysis in adults with bipolar depression, which evaluated change in depressive symptoms (assessed by MADRS) across short-term trials, the largest improvement vs placebo was observed for lurasidone, olanzapine, and quetiapine with cariprazine, showing a smaller treatment effect. Aripiprazole and ziprasidone were ineffective for the treatment of bipolar depression. Improvement in CGI-BP-S score for lurasidone was larger than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Based on short-term studies lurasidone and aripiprazole had similar weight gain compared with placebo.

Clinical Commentary by Sanjay Gupta, MD
A meta-analysis statistically evaluated the combined results of multiple scientific studies addressing the same scientific question. This method is often used to assess which interventions work. By combining multiple studies, the sample size can be significantly increased. A network meta-analysis is done to compare 3 or more treatments both within and across randomized clinical trials.

This is a key study as there are multiple agents for the healthcare professional to choose from when treating bipolar depression, but no head-to-head trials exist for bipolar depression comparing the FDA-approved AAPs.

The quetiapine trials also included patients with bipolar II, which could confound these results. There was inconsistent reporting of some variables such as extrapyramidal symptoms (EPS) that were not reported consistently for all trials. All metabolic laboratory tests were not known to be consistently in the fasting state. It should be noted that this network meta-analysis is based on monotherapy for the treatment of bipolar depression, whereas in clinical practice, patients may be receiving multiple medications. The study did not include lithium, lamotrigine, divalproex, or combination treatments.

Clinical Insights

  • Lurasidone response for bipolar depression was similar to olanzapine and quetiapine followed by cariprazine.
  • Lurasidone separates from olanzapine and quetiapine (similar efficacy for bipolar depression) due to it better metabolic profile. Emerging data suggest that obesity may be linked to relapse of bipolar depression.
  • Aripiprazole and ziprasidone were not effective for bipolar depression. Possibly a carry-over from augmentation uses in major depression is the false impression among healthcare professionals of aripiprazole being a treatment for bipolar depression.
  • The NNT (how many patients should be put on a drug so one has a response) is extremely relevant: lurasidone (NNT = 5), quetiapine (NNT = 6), olanzapine (NNT = 10), and cariprazine NNT = 12).

Lurasidone should be strongly considered for the treatment of bipolar depression not only because of its efficacy (NNT = 5) but also because of its relatively superior metabolic profile.

Clinical Commentary by Roger McIntyre MD, FRCPC
Depressive symptoms and episodes are the dominant presentations of bipolar disorder and differentially account for morbidity, decreased quality of life, and mortality (eg, suicide). There are relatively few treatments for bipolar depression. There are insufficient direct head-to-head studies providing results that inform clinical decisions at the point of care. Analysis of existing data is needed to indirectly compare existing treatments from the point of view of efficacy and tolerability. Network analysis is considered a sophisticated analytical approach to indirectly compare treatments that are especially relevant given the many competing for treatment options for bipolar depression.

Clinical Insights

  • Compared with placebo, lurasidone, quetiapine, cariprazine, and olanzapine were all significantly effective .
  • Olanzapine, however, is not approved by the FDA in bipolar depression as monotherapy but is approved for the olanzapine/fluoxetine combination.
  • The odds of response with lurasidone were similar to quetiapine and olanzapine, but as expected, lurasidone had a significantly lower risk of weight gain.
  • The results of this analysis are in accordance with the Florida Psychotherapeutic Guidelines for Bipolar Disorder that recommend treatments for bipolar depression that are efficacious with a low propensity for weight gain be considered as first-line treatment strategies.
  • A limitation of this report is that the basic assumption for network analysis is that if treatment A is superior to treatment B, and treatment B is superior to treatment C, then treatment A must be better than treatment C. There are limitations to this assumption due to the heterogeneity in psychiatric clinical research.
  • It would also be interesting to see sustained recovery rates and improvements in patient-reported outcomes between studies in the future.

The results of this network analysis further supplement findings of pivotal clinical trials indicating that lurasidone is highly effective in bipolar depression with a minimal propensity to treatment-limiting weight gain. Subsequent network analysis should primarily evaluate and compare existing treatments for bipolar depression on quality of life and function. It would also be extremely interesting (if they exist) comparing measures of suicidality across the FDA-approved treatments for bipolar disorder.

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