Commentary on comparison of alcoholism subtypes as moderators of the response to sertraline treatment.

THE PAPER BY Kranzler and colleagues (2012b) is the latest in a series of studies, demonstrating that alcoholism subtype moderates the response to selective serotonin reuptake inhibitor (SSRI) treatment such that one subgroup shows SSRI benefit over placebo, while the other subgroup shows SSRI inferiority in comparison with placebo. This paper is a secondary analysis of a randomized controlled trial of sertraline treatment for primary alcohol dependence. The original publication (Kranzler et al., 2011) used age of onset of alcohol dependence diagnosis as an a priori stratification variable and reported that early onset alcoholics (EOA) drank significantly more when given sertraline versus placebo, while late onset alcoholics (LOA) drank less with sertraline than with placebo—but that this was true only within the subgroup of patients who were homozygous for the triallelic “long” (La) insertion polymorphism of the serotonin transporter promoter. The current paper (Kranzler et al., 2012b) describes additional analysis of these data examining 2 different methods of determining age of onset and comparing these with the Type A/B classification scheme to determine which is the best approach for the prediction of sertraline response. A companion paper (Kranzler et al., 2012a) also published in ACER shows that both the beneficial and deleterious effects of sertraline persisted through the 3-month follow-up period after discontinuation of treatment. Modern scientific efforts to subgroup “types” of alcoholism began with the phenomenological description of 5 subtypes (Bowman and Jellinek, 1941) based upon disease severity and progression wherein the “delta” and “gamma” species described by Jellinek (1960) seemed to represent the 2 most common subtypes until the 1980s. Dichotomous subtyping into “Type I” versus “Type II” began when Cloninger and colleagues (Cloninger, 1987; Cloninger et al., 1981) proposed “milieu-limited” versus “male-limited” subtypes based upon familial inheritance patterns, suggesting a biological basis to typology. Buydens-Branchey and colleagues (1989a, b) significantly refined our thinking about the biological subtype when they reported that low plasma tryptophan/amino acid ratios may portray a serotonergic vulnerability to an “early age of onset” versus a “late age of onset” alcoholism subtype distinction. Then, Babor and colleagues (1992a,b) cogently argued that k-means statistical clustering techniques using multidimensional assessments of disease severity were a more empirically based approach to derive subtypes. The resultant “Type A” versus “Type B” typological schema has since been utilized in many studies and in fact was used first by Kranzler and colleagues (1996) to describe differential efficacy of fluoxetine in the treatment of alcoholism. The seminally important contribution of the current paper is the conclusion that age of onset did a better job than Type A/B statistical clustering to predict alcoholism subtypes that show differential sertraline outcomes. Further, the authors report that a single-item question about the age of onset of alcohol-related problems was at least as good as using the Structured Clinical Interview for Diagnosis (SCID) to make the age of onset determination. The importance of this finding is emphasized in terms of the ease of implementing assessment in clinical practice where post hoc statistical clustering techniques are not possible and thorough diagnostic assessments are certainly more difficult than a single-item assessment would be. Of course, age of onset from a singleitem question also was used by our group (Johnson et al., 2000b) to stratify randomization in a study, showing that the 5-HT3 antagonist, ondansetron, was superior to placebo to reduce drinking in EOAs but not LOAs, and as acknowledged in the current paper, we also found that age of onset was superior to multidimensional cluster methods in predicting ondansetron response (Roache et al., 2008). This, in fact, was the original premise of Johnson and colleagues (Johnson, 2000; Johnson et al., 2000a,b) in discussing early age onset of alcoholism as the cardinal sign of a biological vulnerability related to the low serotonergic function originally proposed by Buydens-Branchey. The specific age cutoff that best distinguishes early versus late onset for prediction of treatment outcome is not known. Although Buydens-Branchey and colleagues (1989a,b) defined early age of onset as <20 years, we previously showed (Johnson et al., 2000a) that age of onset is a continuous variable and that use of younFrom the Departments of Psychiatry and Pharmacology (JDR), University of Texas Health Science Center at San Antonio, San Antonio, Texas. Reprint requests: John D. Roache, PhD, Department of Psychiatry, UT Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; Tel. : +1-210-562-5401; Fax: +1-210-562-5403; E-mail: roache@uthscsa.edu Copyright© 2012 by the Research Society on Alcoholism.