Potential of cannabinoids as treatments for autism spectrum disorders.

Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics. Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD. Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.

Chronological milestones to guide drug change. When should clinicians switch antidepressants?

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received placebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

Can the effects of antidepressants be observed in the first two weeks of treatment?

Recently the claim that there is a lag in the time of onset of antidepressant effects has been questioned. This issue rests on contrasting the time course of ultimate responders versus nonresponders on imipramine and amitriptyline. It is concluded that in 1 week on antidepressants "clinicians were capable of detecting changes in general states between the groups and the specific effects of depressed mood and anxiety and the physical expression of distress" (Katz et al. 1987). To examine this issue, we first used the design in which ultimate responders and ultimate nonresponders to antidepressants were compared at 1 and 2 weeks. Clearly there were statistically significant differences between ultimate responders and nonresponders on drug. However, the same was true on placebo. When the ultimate responders on placebo were contrasted to the ultimate responders on drug at 1 and 2 weeks using the Clinical global Impression (CGI) scale and the Hamilton Depression Rating Scale (HDRS), there was no difference between drug and placebo. This was also true for a subgroup of patients who met the criteria for melancholia. We conclude that, if the effects of nonspecific improvement are partialed out, there is no evidence of a medication effect at 1 and 2 weeks.

Does mirtazapine have a more rapid onset than SSRIs?

BACKGROUND: A single study utilizing a cross-sectional analysis of scores on the Hamilton Rating Scale for Depression (HAM-D) suggested that mirtazapine has a more rapid onset than selective serotonin reuptake inhibitors (SSRIs). Analysis based on the HAM-D may favor drugs with sleep-producing effects. The purpose of the present study was to determine if a review of all studies comparing an SSRI with mirtazapine, utilizing persistent improvement as the dependent variable, would suggest that mirtazapine had a more rapid onset than SSRIs. METHOD: All double-blind studies comparing mirtazapine with SSRIs were analyzed. Included in the analysis to determine speed of onset were 298 patients taking mirtazapine and 285 taking an SSRI. Pattern analysis, which has been described and used by other researchers, was employed to study speed of onset. RESULTS: At the end of each of the 3 studies, the total number of responders for each of the drugs did not differ. However, the proportion of responders with onset of persistent improvement in week 1 was greater for mirtazapine (13%, 38/298) than for the SSRIs (6%, 18/285; chi2 = 6.95, df = 1, p = .008). CONCLUSION: These data support the possibility that mirtazapine may have a more rapid onset than SSRIs. This observation should be considered preliminary because of the retrospective nature of the analysis and the absence of a placebo group.

Placebo run-in period in studies of depressive disorders. Clinical, heuristic and research implications.

BACKGROUND: In spite of the virtually ubiquitous nature of the initial 10-day placebo run-in period (IPR) in drug trials, there is little empirical data establishing its relevance. METHOD: Data from 593 subjects were examined retrospectively to determine whether or not the prognosis of subjects minimally improved during the IPR was different to those who were unimproved. The IPR period was single-blind and was followed by a six-week double-blind phase in all studies. RESULTS: Twenty-six per cent of the subjects were minimally improved and 74% were unimproved. Approximately 10% of the subjects who were much improved were not followed systematically. Across a range of diagnosis, severity and chronicity subjects minimally improved (versus unimproved) after IPR had a more favourable prognosis whether assigned to drug or placebo. CONCLUSIONS: Change during IPR appears to be a meaningful predictor. Stratification should be considered in future antidepressant studies.