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Diurnal Responses and Nocturnal Regulatory Mechanisms

Paul J. Schwartz, MD; Dennis L. Murphy, MD; Thomas A. Wehr, MD; Diego Garcia-Borreguero, MD; Dan A. Oren, MD; Douglas E. Moul, MD, MPH; Norio Ozaki, MD; Alisa J. Snelbaker, MA; Norman E. Rosenthal, MD

Arch Gen Psychiatry. 1997;54(4):375-385.

Abstract
Background
Multiple lines of evidence suggest that brain serotonergic systems may be disturbed in seasonal affective disorder (SAD). Previously, we found that the serotonergic agent meta-chlorophenylpiperazine (m-CPP) produced increases in activation and euphoria in depressed patients with SAD, but not in patients with SAD following light treatment or in the summer, nor in healthy control subjects in any condition. In the present study, we attempted to replicate and extend this finding using better methods.

Methods
Seventeen outpatients with SAD and 15 control subjects underwent successive 3-week periods of bright light treatment and light avoidance in a randomized order. During the third week of each condition, on 2 different occasions, subjects were admitted to the hospital for a night of sleep (core temperatures were recorded), followed by infusions of m-CPP (0.08 mg/kg) or placebo the next morning. Dependent measures included the 24-item National Institute of Mental Health Self-Rating Scale, plasma corticotropin, cortisol, prolactin, growth hormone, and norepinephrine concentrations, and core temperatures.

Results
Meta-chlorophenylpiperazine produced (1) significant increases in "activation-euphoria" ratings only in depressed patients with SAD in the untreated condition and (2) blunted corticotropin and norepinephrine responses in patients with SAD compared with controls across both light treatment conditions. In both groups, light treatment was associated with significant reductions in nocturnal core temperatures, which were correlated with similarly significant reductions in mean diurnal growth hormone concentrations. In patients with SAD, (1) the reductions in nocturnal core temperatures also were correlated with the reductions in baseline depression ratings and (2) the reductions in mean growth hormone concentrations were significantly smaller compared with controls.

Conclusions
The abnormal m-CPP—induced activationeuphoria responses represent a replicated state marker of winter depression in patients with SAD. The blunted m-CPP—induced responsiveness of the hypothalamicpituitary-adrenal axis and the sympathetic nervous system may represent traitlike abnormalities. The improvements in mood following light treatment in patients with SAD seem to be associated with the lowering of nocturnal core temperatures. The findings, although not easily explained based on a uniform abnormality of serotonin receptors, are nonetheless compatible with the notion that selected regions of the central nervous system are deficient in serotonin transmission during winter depression.

Author Affiliations
From the Clinical Psychobiology Branch (Drs Schwartz, Wehr, Garcia-Borreguero, Oren, Ozaki, and Rosenthal and Ms Snelbaker) and the Laboratory of Clinical Science (Dr Murphy), National Institute of Mental Health, Bethesda, Md; and the Epidemiology and Psychopathology Research Branch, National Institute of Mental Health, Rockville, Md (Dr Moul).

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