Use of single case analyses in off‐on‐off‐on trials in affective illness: A demonstration of the efficacy of nimodipine

Abstract

This paper 1) demonstrates the ejgicacy of nimodipine in the treatment of a patient with rapid-cycling bipolar disorder using a n intensive single subject design, and 2) evaluates three statistical techniques that are usefil in the analysis of single case data. The patient is a 42-year-old bipolar II female reji-actory to multiple medication trials who underwent double-blind treatment with placebo (B), nimodipine (A), and verapamil (C) in a B-A-B-A-C-A design. The use of statistics in single subject studies has been the subject of controvery. One problem with single subject data is that data points are oj3en correlated with data points @om adjacent time periods (i.e., nonindependent), and therefore such data have been considered inappropriate f o r statistics that assume independence of error terms. One statistical technique we examined was a t-test in the context of repeated on-ofidrug trials suggested by Gentile, Roden, and Klein (1972), in which all data points @om treatment phases are aggregated and then compared to aggregated data ji-om baseline or placebo phases. We compared this t-test to a variant of meta-analysis in which each phase is statistically compared to its adjacent phases and the t-values ji-om those comparisons are summed and converted to a z-score. A s illustrated with this patient, the t-test method tended to be more conservative than the z-score method in instances where there is an overall time trend f o r improvement or deterioration. The Chassen technique also provides an alternative f o r analysis of data with time trends. The z method was more conservative than the single aggregated t-test i f t h e direction of predicted change on a given measure (i.e., improvement during a n active drug phase and deterioration during a placebo phase) did not occur as expected at each medication transition. These statistical techniques, in combination with the sequential off-on-off-on clinical trial design, provide strong evidence f o r the mood-stabilizing effect of nimodipine in this rapid-cycling BP II female. Depression 2: 259-271 (1 99411 995). 0 199y Wiley-Liss, Inc. *

Utility of the daily prospective National Institute of Mental Health Life-Chart Method (NIMH-LCM-p) ratings in clinical trials of bipolar disorder

“…Moreover, given the extreme variability of the illness, which can often make traditional study designs difficult ], the LCM-p may allow for the consideration and use of alternative, mirror-image, crossover, and off-on-off-on designs, in some phases of drug development [McDermut et al, 1995;Post et al, 1998;Post et al, 2000].…”

The place of anticonvulsant therapy in bipolar illness

“…In several instances these responses have been confirmed in double-blind B-A-B-A (off-on-off-on) designs McDermut et al 1995). In other instances the responses to nimodipine have been partial and the addition of a second mood stabilizer (carbamazepine) was required in order to show a full clinical remission of affec- Table 6 Partially controlled studies of clonazepam and lorazepam in acute mania.…”

“…Isradipine, another dihydropyridine L-type CCB, was successfully substituted for nimodipine in each of these instances, suggesting that the dihydropyridine class of L-type CCBs compared to the phenylalkylamine verapamil may have greater mood-stabilizing effects. The long-term efficacy of nimodipine in prophylaxis of bipolar illness and its potential as an alternative McDermut et al 1995) or adjunct (Manna 1991) to lithium remains promising, based on the small number of studies to date.…”

Beyond Lithium in the Treatment of Bipolar Illness

“…Using this design, response could be confirmed in patients with very different cycle frequencies, and appropriate statistical techniques could be applied in single-case analyses, as described by McDermut et al (1995).…”