Site maintenance Wednesday, November 13th, 2024. Please note that access to some content and account information will be unavailable on this date.
Skip to main content
Full access
Letters to the Editor
Published Online: 1 September 2022

Treatments for Depression in Bipolar II Disorder: Reply to Durgam et al.

Publication: American Journal of Psychiatry
To the Editor: I thank Dr. Durgam and colleagues for their letter regarding my December 2021 editorial regarding “Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial.” I am glad to be able to address their points.
It is helpful to learn that the Mini-International Neuropsychiatric Interview (M.I.N.I.) was used in making the diagnosis of bipolar I and II disorder as this was not stated in the Methods. The Montgomery-Åsberg Depression Rate Scale (MADRS) is not specifically a diagnostic tool but a scale of depression severity, so its use does not address the question of whether bipolar II disorder is correctly diagnosed. The concern is not whether subjects are depressed in this trial, as that is well-documented, but whether their diagnosis of bipolar depression is accurate. Retrospective diagnosis of bipolar II disorder in depressed patients remains difficult, especially since no recent diagnosis of manic or hypomanic was required for entry in this study (although this is often the case in clinical practice.)
Functional unblinding remains a problem in many trials of treatments for psychiatric illnesses. While I appreciate the analyses of the impact of reported side effects on MADRS scores, a simpler method to determine whether subjects are unblinded could have been undertaken: asking the participants to guess their treatment assignment (one might consider this kind of measurement a mandatory part of clinical trials in psychiatry.) Side effect reporting differs from trial to trial, so it is problematic to assert that side effects are lower for lumateperone compared to other drugs. Only direct comparisons (in a single study) truly allow comparisons of adverse effects between drugs in bipolar depression.
It is important to understand p values. A low p-value does not “support the efficacy of lumateperone in patients with bipolar II disorder.” These p values only show that for this specific study, the probability that the null hypothesis was falsely rejected is small. The lack of posting or publication of prior failed trial data—despite the FDA acceptance for marketing of lumateperone for bipolar I and II disorder—makes it difficult for the reader to understand the meaning any individual comparison in the context of all the trial data. A low p value, of course, does not imply anything about the magnitude of the effect. Because the authors highlight a larger effect size for bipolar II disorder, my comment about confidence intervals certainly does have merit and is important to address. It is not clear that lumateperone treatment decreases MADRS scores more in bipolar II disorder compared to bipolar I disorder because the confidence interval is wider around the mean for the result in bipolar II disorder. A small sample size always leads to a less precise estimate of the effect than a much larger sample size. The results as presented are fair, but I maintain that raising concerns about study methodology is also fair.
I do not doubt that this study was conducted ethically and under the prevailing regulations from the FDA for their approval process. It remains difficult for clinicians in the field, however, to make complex and long-term treatment decisions in bipolar II disorder using data from a 6-week study that includes but 38 subjects in each arm for an illness that effects millions, and which, for many, is lifelong and requires decades of treatment.

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 690

History

Received: 27 January 2022
Accepted: 21 March 2022
Published online: 1 September 2022
Published in print: September 2022

Keywords

  1. Bipolar and Related Disorders
  2. Bipolar II Disorder
  3. Clinical Drug Studies
  4. Pharmacotherapy
  5. Antipsychotics
  6. Second Generation

Authors

Details

Notes

Send correspondence to Dr. Ostacher ([email protected]).

Competing Interests

Dr. Ostacher has received funding from Freespira, NIDA, Otsuka, and Palo Alto Health Sciences, and he has served on data monitoring committees for Janssen and Neurocrine and on advisory panels for Genomind, Janssen, Lundbeck, Otsuka, Sage, and Supernus.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share