To the Editor: In their article, published in the April 2009 issue of the Journal, Trisha Suppes, M.D., Ph.D., et al. (1) concluded that quetiapine plus lithium or divalproex caused a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex in bipolar patients. We feel that the design, methodology, data analysis, interpretation, and writing of the study need to be examined critically before the clinician can extrapolate these findings to the usual clinical situation.
First, with the exception of rapid cyclers, there was no information about the number and frequency of prior episodes and residual symptoms of the patients entering the randomization phase. This information would have been helpful as well as controlling statistically for the effect of prior and residual symptoms, since it is well known that frequency of past episodes and residual symptoms are strong predictors of future episodes (2, 3). Second, it was not clear why the patients were started on a quetiapine-mood stabilizer combination immediately in the pre-randomization phase. The authors may wish to provide a rationale or evidence supporting this decision. Third, two-thirds of the pre-randomization patients discontinued during the pre-randomization phase for a number of reasons, including lack of therapeutic response, developing an adverse event, and lost to follow-up. Could it be possible that the remaining patients, who did eventually proceed to the randomization phase, represented a group favorably predisposed to the quetiapine combination? Fourth, the authors may wish to discuss the limitation that there was no structured interview used to ascertain the index episode; rather, at times it was left to the medical judgment of the clinical investigator. Fifth, it would have strengthened the study if an increase of lithium/divalproex dose could have been included in the definition of a “mood event,” since this is what would be done first in clinical situations of recurrence. Sixth, although the authors only mentioned the hazard ratios, the median ratio of time to recurrence in the quetiapine group versus the placebo group could give additional meaning regarding the actual magnitude of the difference (4). Last, the findings regarding the metabolic side effects of the quetiapine combination should have been mentioned in the conclusion section of the abstract.
Suppes T, Vieta E, Liu S, Brecher M, Paulsson B: Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry 2009; 166:476–4882.
Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, Ketter TA, Miklowitz DJ, Otto MW, Gyulai L, Reilly-Harrington NA, Nierenberg AA, Sachs GS, Thase ME: Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2006; 163:217–2243.
Kessing LV, Anderson PK, Mortensen PB, Bolwig TG: Recurrences in affective disorder, I: case register study. Br J Psychiatry 1998; 172:23–284.
Spruance SL, Reid JE, Grace M, Samore M: Hazard ratio in clinical trials. Antimicrob Agents Chemother 2004; 48:2787–2792
The authors report no competing interests.
This letter (doi: 10.1176/appi.ajp.2009.09050662) was accepted for publication in July 2009.