Biologic correlates and laboratory studies

Neuro-hormonal correlates For a number of years probes into the pathophysiologic mechanisms of the affective disorders have used various neurohormones whose secretion is regulated by one or more of the CNS neurotransmitters. One consistent finding from these studies has been that a significant subpopulation of patients with major depression hypersecrete Cortisol and have abnormal Cortisol circadian secretion patterns. In addition, even though it is now somewhat controversial, the dexamethasone suppression test (DST) has been useful in both diagnosis and monitoring of treatment. The standard DST used in psychiatry involves the administration of 1 mg of dexamethasone at 2300 hours with subsequent Cortisol determinations at 1600 and 2300 hours the following day. The nonsuppression of Cortisol is an abnormal or positive response (>5 u.g/dL Cortisol concentration in the 1600 or 2300 sample). Initial studies reported that up to 50 percent of patients with serious major depression were nonsuppressors on the DST. Further investigations indicate that DST nonsuppression is most likely a state marker, which is positive during the depressive episode but returns to normal after successful resolution of the episode. False positives on the DST can occur in patients with alcoholism, malnutrition, obesity, pregnancy, major physical illnesses, and in patients over 65 years and this has eroded the usefulness of the test. In addition, more recently a number of studies have appeared in the literature reporting a much smaller percentage of DST nonsuppressors associated with major depressive episodes and an increased percentage in many other psychiatric illnesses. The range of DST nonsuppression among depressed patients has now been reported as low as 10 to 15 percent to as high as 50 percent. While the status of this diagnostic marker is still controversial, it is useful in monitoring treatment efficacy in DST-positive depressives, since the DST response reverts to normal when the episode remits.

Other neuroendocrine markers have also been explored, but none psychiatry as widely as the DST. In major depression, between 25 and 30 percent of patients respond to thyrotropin releasing hormone (TRH) with blunted thyroid stimulating hormone (TSH) responses. TSH blunting is not specific to depressive episodes and the use of this test for diagnostic purposes has been abandoned. Small subgroups of depressed patients have manifested blunted growth hormone responses to the following challenge agents: clonidine, amphetamine, l-dopa, 5-hydroxytryptophan, and hypoglycemia (insulin tolerance test). Even though 15 to 25 percent of depressed patients have blunted growth hormone responses, it has not proved to be diagnostically useful. More recently, blunted prolactin responses to both TRH and opiate alkaloid challenges have also been reported in subpopulations of depressed patients; while these findings may be of interest in terms of pathophysiologic mechanisms, they are not useful diagnostically.

Sleep studies

The disruption of sleep patterns is present in virtually every patient with major affective disorder, and polysomnographic studies of sleep in these patients have proved to be of interest. In 25 to 45 percent of cases of major depression there is a significantly shortened time period between the onset of sleep and the appearance of the first rapid eye movement (REM) (i.e., decreased REM latency). In addition, the density of the REM epoch, measured by the number of eye movements, is increased, there is a tendency for the REM epoch to be increased in duration, and there is a shift of REM activity to an earlier part of the night. These findings from all-night EEG sleep recordings have remained among the most consistent biologic markers for major depression, although they lack specificity, since short REM latency has also been reported in anorexia nervosa, obsessive-compulsive disorders, schizoaffective schizophrenia, and narcolepsy.

Neurotransmitter metabolites

The neurotransmitter hypotheses of affective disorders have stimulated a number of studies correlating biogenic amine metabolites with manic and depressive episodes. The data are inconsistent and have not been useful either diagnostically or therapeutically. The one possible exception is MHPG, a metabolite of norepinephrine. Some workers have reported low МНЮ excretion as predicting a positive therapeutic response to the antidepressants imipramine, desipramine, etc., and high MHPG excretion as predicting a response to amitriptyline, nortriptyline, etc. While these data are of interest and with further study may result in the identification of biochemical subtypes in major depression, these findings have not been consistently replicated in other laboratories.