Brain glucose metabolism during non-rapid eye movement sleep in major depression. A positron emission tomography study.

BACKGROUND: Depression is characterized by several sleep-related abnormalities shortly before and after sleep onset, such as prolonged sleep latency, loss of stage 3-4 sleep, reduced rapid eye movement (REM) latency, increased nocturnal core body temperature, and abnormal hormone secretion patterns. Sleep deprivation is associated with a temporary improvement in depression. We hypothesized that depressed patients may be "overaroused" and that absolute cerebral glucose metabolism would be elevated during the first nocturnal non-REM sleep period in depressed patients compared with normal controls. In addition, since hypofrontality (greater metabolic activity in occipital compared with frontal cortical activity) has been reported in waking positron emission tomographic studies of depressed patients compared with controls, we predicted significant hypofrontality in depressed patients during the first non-REM period. METHODS: Positron emission tomography with fludeoxy-glucose F 18 was used to compare 10 unmedicated men with unipolar depression with 12 normal men during the first non-REM sleep period at normal bedtime. RESULTS: Whole-brain absolute metabolic rate during non-REM sleep was significantly elevated (+47%) in patients compared with controls. Mean absolute cerebral glucose metabolic rate was also higher in every area of the brain in patients compared with normal controls. The greatest significant mean increases were in the posterior cingulate and amygdala (+44%), hippocampus (+37% to +43%), occipital and temporal cortex (+33% to +34%), and pons (+33%). Relative metabolic rates in specific neroanatomical areas, however, varied considerably both within the patient group and between patients and controls. Patients showed significant hypofrontality, particularly in the medio-orbital frontal cortex, compared with controls. Patients also showed significant reductions of relative metabolic rate in the anterior cingulate, caudate, and medial thalamus compared with controls. CONCLUSIONS: These findings provide further support for the hyperarousal hypothesis of some types of major depressive disorder. Abnormal patterns of cerebral metabolism during non-REM sleep in depressed patients confirmed earlier waking findings of decreased relative frontal and abnormal limbic metabolic activity and striatal metabolism in association with posterior cortical increases.

Achieving effective treatment of patients with chronic psychotic illness and comorbid substance dependence.

OBJECTIVE: The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over a 2-year period with the use of a sequential study group design. METHOD: The treatment outcome of 179 consecutively enrolled patients with chronic psychotic illness and comorbid substance dependence who entered a specialized day hospital dual-diagnosis treatment program from Sept. 1, 1994, to Aug. 31, 1996, was evaluated. The 24 months were divided into four successive 6-month periods for comparing the evolving effectiveness of the program for groups of patients entering the day hospital during these four periods. Treatment attendance, hospital utilization, and twice weekly urine toxicology analyses were used as outcome measures. RESULTS: The initial treatment engagement rate, defined as at least 2 days of attendance in the first month, increased significantly from group 1 to group 4, more than doubling. Thirty-day and 90-day treatment retention rates also substantially increased from group 1 to group 4. More patients had no hospitalization in the 6 months after entering the day hospital program than in the 6 months before entering the day hospital program. Urine toxicology monitoring indicated that the patients in group 4 were more likely than those in group 1 to remain abstinent at follow-up. CONCLUSIONS: The evolving clinical effectiveness of a developing program can be quantified by using a sequential group comparison design. The sequential outcome improvements may be related to the incremental contributions of assertive case management and skills training for relapse prevention.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

Functional brain imaging, sleep, and sleep deprivation: contributions to the "overarousal" hypothesis of depression.

In 1975 van den Burg and van den Hoofdakker hypothesized that depressed patients might be 'overaroused.' This suggestion is consistent not only with their seminal observations on the antidepressant effects of total sleep deprivation in depression, but with the short, fragmented, and shallow sleep of depressed patients, lowered arousal thresholds, hyperactivity of the hypothalamus-pituitary adrenal (HPA) axis, and elevated core body temperature commonly found in some patients during the sleep period.