Statistical approaches to trial durations in episodic affective illness.

In light of the high variability in illness characteristics and patterns among patients with bipolar illness, parallel group designs present severe methodologic difficulties. Crossover, off-on-off-on (B-A-B-A), and other individualized designs may be a useful substitute, but no consensus exists about how to estimate the individual trial durations required in these instances. Several methods for determining optimum trial lengths in crossover designs are presented, illustrated, and discussed. These include: chi-square (chi2) for the expected versus observed number of either episodes or days well; exceeding two standard deviations for average duration of episodes or euthymic intervals; or the Sequential Probability Ratio Test (SPRT), which detects when mean values differ from prior statistical expectations. Each method was applied to three demonstration cases using data from actual clinical trials of three patients with different patterns of recurrent affective illness. Each method detected changes in illness severity, although different tests appeared to be sensitive to differing cycle patterns in the patients illustrated. We suggest that these types of analyses and others can be used as indicator statistics to augment global impressions and clinical judgment, and to assist in determining individualized trial durations, both in formal clinical trials and in clinical treatment settings. Once individual responsivity is confirmed with an appropriate interplay of trial design and statistical analysis, the percentage response in a given population can then be compared to other agents or in other populations. Moreover, meta-analytic techniques based on addition of z scores from individuals' effect sizes can then be used to assess overall significance of a drug effect in a given population or subpopulation. The need for further development of appropriate and alternate study designs and analysis methods for bipolar illness is highlighted. Approaches to estimating required trial durations in individuals with different cycle frequencies in crossover and B-A-B-A designs constitute one element of that exploration.

Asthma treatment costs using inhaled corticosteroids.

Asthma is a chronic inflammatory disorder of the airways that affects 10 to 17.5 million people and leads to more than $5 billion in treatment costs in the Unites States annually. This retrospective study is an initial step in understanding the beneficial economic outcomes of inhaled corticosteroid therapy by determining whether differences exist in healthcare utilization expenditures for three inhaled corticosteroids available for use in the United States: (1) beclomethasone dipropionate (Vanceril/Schering and Beclovent/Allan & Hanburys); (2) flunisolide (Aerobid/Forest); and (3) and triamcinolone acetonide (Azmacort/Rhône-Poulenc Rorer). This study was based on an analysis of 4,441 patients with at least one pharmaceutical claim for one of the study drugs, using inpatient, outpatient, and prescription drug claims data obtained from The MEDSTAT Group's MarketScan database for calendar years 1990 through 1993. We tested a null hypothesis for no differences in total asthma treatment costs, when drugs were excluded, using multivariate linear regression modeling controlling for patient demographic and clinical characteristics that might affect the study outcome. We found that, after excluding study drug payments and controlling for other contributing factors, total asthma healthcare expenditures to triamcinolone acetonide (Azmacort) users were higher than those for beclomethasone dipropionate (Vanceril and Beclovent) and flunisolide (Aerobid) users. When study drug costs were included in the expenditure measure, both triamcinolone acetonide (Azmacort) and flunisolide (Aerobid) users had higher expenditures than did beclomethasone dipropionate (Vanceril and Beclovent) users. No significant differences in expenditures were detected between Vanceril and Beclovent patients, a finding consistent with the fact that these drugs are the same type of inhaled corticosteroid. Other factors contributing to differences in total asthma healthcare costs included patient age, patterns of switching among and continuing with study drugs, prestudy asthma utilization or drug proxy severity, and comorbidities of precipitating illnesses.

Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients.

BACKGROUND: Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability. METHODS: Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design. RESULTS: Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived. CONCLUSION: Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

Comparative antidepressant effects of intravenous and intrathecal thyrotropin-releasing hormone: confounding effects of tolerance and implications for therapeutics.

A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood-brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.