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Letter to the Editor

Reply to Likelihood to Be Helped or Harmed Can Assist in Clinical Decision-Making

Keming Gao, MD, PhD; David E. Kemp, MD, MS; and Joseph R. Calabrese, MD

Published: February 15, 2011

See the original letter

Dr Gao and Colleagues Reply

To the Editor: We thank Dr Citrome for his comments on our article1 and for proposing the use of likelihood to be helped or harmed (LHH) for clinical decision-making.

We agree that the atypical antipsychotic family of medications will continue to play a growing role in the treatment of major depressive disorder (MDD) given the high population prevalence of MDD and because only one-third of patients reach remission with initial antidepressant treatment and only two-thirds of patients achieve remission after sequential treatments, including switching and augmenting with different pharmacologic agents.2 The US Food and Drug Administration has approved 3 atypical antipsychotics—aripiprazole, olanzapine, and quetiapine—for the treatment of patients with MDD who failed an initial treatment with an antidepressant. These approvals have provided those who prescribe treatments and their patients with much needed options to relieve the suffering associated with depression. However, some side effects including "tolerable" side effects such as somnolence/sedation, akathisia, and weight gain cannot be ignored.

We also agree that LHH, a ratio of the number needed to treat to harm (NNTH) to the number needed to treat to benefit (NNTB), can be used to help clinicians quantify the benefit versus risk.3 We also propose that future treatment guidelines incorporate such metrics when devising algorithms and recommendations for the management of MDD. When combining the NNTH for discontinuation due to adverse events in our study1 and the NNTB for response and remission in Dr Citrome’s study,4 the LHH of these 3 antipsychotics in MDD was close to 1. However, if measured with regards to reported somnolence associated with olanzapine and quetiapine and akathisia associated with aripiprazole, the LHH of these 3 antipsychotics was only about one-third to one-half.

More importantly, the impact of these acute side effects on the long-term treatment outcome remains unclear. In our previous studies, we found that patients with different psychiatric disorders have differential vulnerabilities for developing extrapyramidal side effects, somnolence/sedation, and weight gain with the treatment of antipsychotics.5,6 Patients with MDD were more likely to discontinue study participation due to adverse events than those with schizophrenia or bipolar mania.5 Therefore, the use of atypical antipsychotics in MDD should be carefully justified.


1. Gao K, Kemp DE, Fein E, et al. Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics [published online ahead of print]. J Clin Psychiatry. Oct 19, 2010. doi:10.4088/JCP.09r05535gre PubMed

2. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. 2009;23(8):627-647. PubMed

3. Citrome L, Kantrowitz J. Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks. Expert Rev Neurother. 2008;8(7):1079-1091. PubMed doi:10.1586/14737175.8.7.1079

4. Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med. 2010;122(4):39-48. PubMed doi:10.3810/pgm.2010.07.2174

5. Wang Z, Kemp DE, Chan PK, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Int J Neuropsychopharmacol. 2010;1-12. doi:10.1017/S146114571000101X

6. Gao K, Kemp DE, Ganocy SJ, et al. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol. 2008;28(2):203-209. PubMed doi:10.1097/JCP.0b013e318166c4d5

Keming Gao, MD, PhD

David E. Kemp, MD, MS

Joseph R. Calabrese, MD

Author affiliations: Department of Psychiatry, Mood and Anxiety Clinic in the Mood Disorders Program, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Potential conflicts of interest: Dr Calabrese has received support and served as a consultant for a number of pharmaceutical companies, including grant support and honoraria from Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, and Janssen. Dr Gao has been a consultant for Schering-Plough; receives grant support from AstraZeneca, National Alliance for Research on Schizophrenia and Depression (NARSAD), and the Cleveland Foundation; and has been on the speakers or advisory boards for Pfizer. Dr Kemp has acted as a consultant to Bristol-Myers Squibb, has served on a speaker’s bureau for AstraZeneca and Pfizer, and has received grant support from National Institutes of Health grant 1KL2RR024990 and grant/research support from Takeda (study medication only), NARSAD, and the Cleveland Foundation. Funding/support: Support for this manuscript included NIMH P20 MH-66054 (to Dr Calabrese).

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