Paul J. Schwartz

Serotonin and Thermoregulation. Physiologic and Pharmacologic Aspects of Control Revealed by Intravenous m-CPP in Normal Human Subjects.

Meta-chlorophenylpiperazine (m-CPP), a probe of central serotonergic function, elevates core temperature in rodents, nonhuman primates, and humans via serotonin receptor-mediated mechanisms. To further characterize the thermoregulatory aspects of this response, we studied 16 healthy volunteers using multiple core and skin temperature recording sites. Compared to placebo, intravenous m-CPP (0.08 mg/kg) produced statistically significant biphasic changes in rectal temperature, characterized by initial hypothermia (−0.04°C at 12 minutes) followed by progressive hyperthermia (+0.17°C at 90 minutes). m-CPP also produced significant increases in plasma norepinephrine concentrations. Analysis of the skin temperature recordings suggests that the effector mechanism primarily responsible for m-CPP-induced core hyperthermia is increased metabolic thermogenesis. Individual differences in the magnitude of the hyperthermia were independent of m-CPP plasma concentrations but were found to be linearly correlated with the level of the previous nights core rectal temperature minimum and mean. It appears that m-CPP activates a mode of metabolic thermogenesis governed by a nocturnally sensitive proportional control mechanism. The operation of such a proportional controller is characterized by a set point and a gain, and has been implicated in the general economy of mammalian energy balance.

Light visor treament for seasonal affective disorder: A multicenter study

The effectiveness of light therapy in seasonal affective disorder (SAD) was evaluated in 105 subjects across five centers. Three intensities of light (60 lux, 600 lux, and 3500 lux) were used in a 2-week randomized, parallel design. There was no significant difference in antidepressant efficacy of the three intensities of light. All three intensities produced a similar frequency of antidepressant response to each other and to that reported in previous studies. There were site differences in the severity of depression during light treatment, but diagnosis and medication status did not affect antidepressant response. These findings suggest that light therapy has an antidepressant action by a nonspecific effect or that light is biologically active in the treatment of SAD across a wide range of intensities.

Bimodal patterns of human melatonin secretion consistent with a two-oscillator model of regulation

In many animals, changes in duration of nocturnal melatonin secretion chemically mediate effects of seasonal changes in nightlength on behavior and physiology. According to one model, the changes in duration of secretion result from adjustments in the timing of two circadian oscillators, one entrained to dusk, controlling onset, and another entrained to dawn, controlling offset. Consistent with this model, in six women, we found separate and reproducible evening and morning peaks of melatonin secretion that might represent the separate expressions of rhythms of two oscillators.

A Controlled Trial of Levodopa Plus Carbidopa in the Treatment of Winter Seasonal Affective Disorder: A Test of the Dopamine Hypothesis

The objectives of this study were to test the hypothesis that a dopaminergic deficiency plays a role in the pathogenesis of winter seasonal affective disorder (SAD) and to test the efficacy of levodopa plus carbidopa as a treatment for SAD. Two weeks of double-blind placebo washout were followed by random assignment to parallel treatments for 2 weeks with levodopa and carbidopa versus placebo. Observations were made during weekly outpatient visits. All subjects met criteria for SAD. Fifty patients entered the study. Twenty-four were significantly depressed after the washout period and were randomly assigned to medication or placebo. Twenty-three completed the study. Twelve patients received placebo capsules four times a day during the 2-week drug comparison period. On an identical schedule, 11 patients received capsules containing levodopa (up to 7 mg/kg per day by the end of the second week) and carbidopa (100 mg/day). Twenty-one item Hamilton Rating Scale for Depression scores were used to determine antidepressant efficacy. No differences were found in the rates of response. There is no evidence to support the use of levodopa for the treatment of SAD patients in general. A model of systemic dopaminergic deficiency does not readily explain the pathology of SAD.

Effects of season on electro-oculographic ratio in winter seasonal affective disorder

Low electro-oculographic (EOG) ratios have been reported in patients with seasonal affective disorder (SAD) during the winter. This study evaluated the effects of the changing seasons on EOG ratios in SAD patients. Sixteen outpatients with SAD and 16 age-, sex-, and medication-matched normal volunteers had EOG testing during the winter and again during the summer. There was a significant season x group interaction in EOG ratios, with normal subjects showing higher ratios in winter than in summer--a seasonal variation not observed in SAD patients. SAD patients may have a subsensitivity to environmental light that leads them to experience symptoms during the winter.

Salivary and plasma measures of dim light melatonin onset (DLMO) in patients with rapid cycling bipolar disorder

A number of researchers have suggested that the phase (timing) of circadian rhythms in depressed patients is abnormal. Longitudinal studies could help to elucidate the relationship between circadian phase and mood. Such studies would be facilitated by the development of a noninvasive method for measuring circadian phase. In normal volunteers, the concentration of salivary melatonin measurements has been shown to be significantly correlated with those obtained in plasma; however, it is unknown whether salivary melatonin measurements can reliably detect the unmasked time of onset of nocturnal melatonin secretion (a measure of circadian phase). In addition, the relationship between salivary and plasma melatonin measurements in medicated psychiatric patients is unknown. We measured plasma and salivary melatonin simultaneously in a sample of 12 medicated patients with rapid cycling bipolar disorder. The intraclass correlation coefficient between plasma and salivary measures of the dim light melatonin onset (DLMO) was 0.93. We therefore conclude that salivary melatonin can be used to determine the time of the DLMO in this population.

Seasonality and pituitary volume

Pituitary volume in humans has been reported to change size in response to experimental manipulations of photoperiod, and to be increased during an episode of non-seasonal major depression. We wanted to determine whether pituitary volume changes either across the seasons or during an episode of winter depression. Nineteen patients with winter-seasonal affective disorder and 19 sex-, age-, height-, and weight-matched controls underwent magnetic resonance imaging of the pituitary gland in both winter and summer. Images were obtained using 0.7-mm contiguous slices and the areas of all slices were summed to compute the final volume for each gland. We found no main effects or interactions involving either diagnosis or season in our primary analysis. In a post-hoc analysis, we found a trend towards a season x gender effect (P = 0.06), such that pituitary volume increased slightly (+4.0%) across seasons in women, whereas it decreased slightly (-4.3%) across seasons in men. The results suggest that neither winter depression nor the change of seasons is associated with a significant change in pituitary size.

Platelet [3H]paroxetine binding, 5-HT-stimulated Ca2+ response, and 5-HT content in winter seasonal affective disorder

The present study was designed to evaluate cellular serotonergic functions in winter seasonal affective disorder (SAD) using serotonin (5-HT)-stimulated Ca2+ response as an integrated measure of 5-HT2 receptor function in platelets, [3H]paroxetine binding to characterize the platelet 5-HT transporter and 5-HT content as an index of the platelet storage capacity for this neurotransmitter amine. Purified density-dependent subpopulations of platelets in untreated and light-treated SAD patients and matched controls were investigated in order to control for possible variations in platelet turnover. We found no differences between SAD patients and controls on any of the measures, nor between light therapy conditions in SAD patients, although we found a higher Bmax of [3H]paroxetine binding and 5-HT content in heavy platelets compared to light platelets. Although the validity of platelet serotonergic measures as a model for brain serotonergic systems still remains to be elucidated, we found no evidence of platelet serotonergic abnormalities in our sample of SAD patients.

Seasonal variation in core temperature regulation during sleep in patients with winter seasonal affective disorder

Nocturnal core temperature during sleep is elevated during depression compared with remission in nonseasonally depressed patients. Similarly, nocturnal core temperature is higher during winter depression compared with remission induced by light treatment in seasonal affective disorder (SAD) patients. We investigated whether nocturnal core temperature in SAD patients naturally becomes lower in summer (during remission) compared with winter (during depression). Twenty-four-hour core temperature profiles were obtained in winter and summer in 22 SAD patients and 22 controls. The nocturnal core temperature minima were lower in summer compared with winter in SAD patients (p < .005), but not controls (p > .4). The seasonal changes in nocturnal core temperatures in SAD patients may reflect a unique physiological responsiveness of SAD patients to the change of seasons, and may be intimately related to the seasonal disturbances of mood and energy that are characteristic of SAD.

Spontaneous eye blink rate in winter seasonal affective disorder

We investigated spontaneous eye-blink rates in 19 drug-free patients with winter seasonal affective disorder (SAD) and 18 normal control subjects. At baseline, there were no significant differences between the two groups (mean +/- SD blink rate: 15/minute +/- 8 vs. 15/minute +/- 7). Light therapy (10,000 lux: 1 hour each morning for 1 week) produced no significant change in mean (+/- SD) blink rates either in 10 SAD patients (13/minute +/- 8 vs. 10/minute +/- 7) or in 12 normal control subjects (15/minute +/- 6 vs. 14/minute +/- 6). A post hoc exploratory analysis of the effect of light therapy on premenopausal female subjects (5 patients and 9 control subjects) showed a significant decrease in mean (+/- SD) blink rate in the patients after treatment (17 +/- 6 vs. 12 +/- 8 compared with 15 +/- 7 vs. 16 +/- 5). These results do not support the idea that an elevated blink rate may be a general biological marker in SAD, but they suggest a possible link between light treatment and mechanisms that regulate blink rate in premenopausal SAD patients.