David S. Janowsky

Acetylcholine and depression.

&NA; Physostigmine, a cholinesterase inhibitor which increases central acetylcholine levels, has been found in man to decrease manic symptoms, antagonize methylphenidate‐induced behavioral activation, and induce severe depression and psychomotor retardation in marijuana intoxicated normals. In the current study, physostigmine was found to increase depressed mood in patients with an affective component to their symptoms (manics, depressives, and schizoaffectives). Schizophrenics without an affective component did not become depressed. After physostigmine administration, all subject groups showed a significant increase in symptoms including lethargy, slowed thoughts, withdrawal, apathy, decreased energy, decreased thoughts, motor retardation, and feeling drained, indicating a state of psychomotor retardation; and all became less cheerful, friendly, and talkative. The above information is compatible with the hypothesis that acetylcholine may be involved in the etiology of affective disorders.

Cholinergic challenges in affective illness: behavioral and neuroendocrine correlates.

The cholinergic-adrenergic balance hypothesis of affective disorders suggests that, in the areas of the brain that regulate mood, depression may represent a relative predominance of central cholinergic tone over adrenergic tone and that mania may represent the converse. Currently, converging lines of investigation from a number of independent groups suggest that affective disorder patients may have a central cholinergic receptor hypersensitivity that induces a vulnerability to affective and neuroendocrine disturbances. This article reviews the evidence for cholinergic mechanisms in the regulation of affective state and describes current research strategies using centrally active cholinomimetic agents to explore disturbances in affective disorder subjects.

Correlations between mood, weight, and electrolytes during the menstrual cycle: a renin-angiotensin-aldosterone hypothesis of premenstrual tension.

&NA; Eleven female college age volunteers were studied over a total of 15 menstrual cycles under controlled conditions. Daily weights, urinary potassium/sodium ratios and self evaluations of negative affect were obtained. The different variables changed throughout the menstrual cycle, and were elevated in the luteal‐premenstrual and early menstrual phases and decreased at other times. The potassium/sodium ratio and weight changes suggest that activation of the renin‐angiotensin‐aldosterone system may underlie increases in psychopathology linked to the menstrual cycle, possibly through effects on central neurotransmitters.

Use of dexamethasone suppression test in clinical psychiatry.

The dexamethasone suppression test (DST) has been used in clinical medicine to evaluate overactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Consistent evidence has linked a specific dysfunction of the HPA axis to depressive illness. This article will review the physiology of the HPA axis and the method of the DST. After a critical review of the studies using the DST in psychiatric patients, the authors conclude that the overnight low dose DST can be a useful tool for the practitioner involved in the diagnosis and treatment of psychiatric illness.

Effects of Smoking Marihuana on Left Ventricular Performance and Plasma Norepinephrine: Studies in Normal Men

In 14 healthy men we assessed the effects of smoking marihuana cigarettes containing 6 mg of delta-9-tetrahydrocannabinol on ultrasound measures of left ventricular function. Four of this group and four additional subjects also had measurements of plasma norepinephrine. Both heart rate and left ventricular performance (mean rate of internal diameter shortening [mean Vcf]) were significantly increased for at least 1 h after drug exposure compared with these values after placebo cigarettes. The immediate tachycardia and increase in mean Vcf were not accompanied by raised plasma norepinephrine levels. However, by 30 min after marihuana exposure, sympathetic neurotransmitter levels were significantly greater than both control values and those after placebo cigarettes, and they remained elevated for at least 2 h. Excessive sympathoadrenal discharge, as evidenced by augmented left ventricular function and prolonged catecholamine release, could adversely affect patients with heart disease.

Effects of anesthesia on patients taking psychotropic drugs.

Psychotropic drugs, often given in combination with each other or with other nonpsychiatric drugs, generally exert profound effects on central and peripheral neurotransmitter and ionic mechanisms. Hence, prior intake of these drugs is an important consideration in the management of the patient about to undergo anesthesia and surgery. This article reviews the effects of anesthetics on patients taking antipsychotics, tricyclic antidepressants, monoamine oxidase inhibitors, and lithium carbonate.

Central cholinergic stimulation causes adrenal epinephrine release.

Cholinergic drugs administered into the cerebral ventricles of animals selectively stimulate the adrenal medulla. However, the effects of central cholinergic stimulation on the sympathoadrenal system have not been studied in man. We stimulated central cholinergic activity in man by administering the cholinesterase inhibitor physostigmine to subjects pretreated with peripheral cholinergic blocking agents. A dose of 0.022 mg/kg physostigmine dramatically increased plasma epinephrine levels and slightly increased norepinephrine levels, which is consistent with selective adrenomedullary stimulation. A smaller dose of physostigmine increased epinephrine but did not alter norepinephrine levels. Subjects had increased pulse rates and blood pressures, and felt anxious while they had high plasma epinephrine levels.

Effects of lithium on adrenergic function in man

Lithium is an effective agent in the treatment of mania. Since an abnormality of biogenic amines has been postulated to be a causative factor in mania and depression and since lithium has been found to alter biogenic amines in many animal systems, the effects of lithium on adrenergic function in man was investigated. The blood pressure response to infused norepinephrine (NE) and tyramine was investigated in 8 hypomanic patients who were studied during a control period and after 7 to 10 days of lithium treatment. Lithium decreased the pressor effect produced by NE by 22 ± 0.6 per cent. Lithium failed to alter the pressor effect to infused tyramine. Lithium failed to alter platelet serotonin content. Lithium decreased the pressor response to infused NE in man.

Doxepin: Effects on transport of biogenic amines in man

A new tricyclic antidepressant, doxepin, was evaluated for its ability to block the amine uptake mechanism of the peripheral adrenergic neuron and blood platelet in man. At low doses, there was no evidence of inhibition of the amine pump. However, at moderate doses (200–300 mg/day), necessary for effective antidepressant activity, doxepin was found to inhibit the pressor responses to tyramine and to reduce platelet 5-HT. These studies indicate that doxepin is a less potent inhibitor of the amine pump in the peripheral adrenergic neuron and blood platelet than is DMI or protriptyline. Doxepin, at the antidepressant dose level does alter biogenic amine uptake, an effect consistent with the biogenic amine hypothesis of depression. However, at 300 mg/day, a dose which blocks the pressor response to tyramine, antagonism of the antihypertensive effects of guanethidine and related drugs was demonstrated.

Monoamines and ovarian hormone-linked sexual and emotional changes: A review

Emotional upsets related to changes in ovarian hormones are highly prevalent and are responsible for psychiatric morbidity and mortality. Significant increases in acute psychiatric hospitalizations, suicidal activity, and other psychopathology occur during the premenstruum and during menstruation. This paper reviews evidence indicating that menstrual cycle psychopathology may be mediated by the effects of estrogen, progesterone, and possibly the renin—angiotensin—aldosterone system on the brain monoamines, norepinephrine, dopamine, and serotonin. During the menstrual cycle, psychopathology often begins with the onset of luteal estrogen—progesterone—angiotensin—aldosterone secretion and intensifies as these hormone levels later fall, prior to and during menstruation. Aldosterone is reported elevated in cases of premenstrual tension syndrome. There are numerous reports of affective upsets occurring with the use of estrogen—progestin oral contraceptives and following their withdrawal. Contraceptives stimulate the renin—angiotensin—aldosterone system and are reported useful in alleviating premenstrual—menstrual emotional upsets and postpartum depressive episodes. Affective lability, prevalent at parturition, occurs when estrogen, progesterone, and aldosterone levels are first high and later falling. Exogenous estrogen and progesterone profoundly affect mating activity in castrated rhesus monkeys, and cyclic fluctuations in sexual activity in humans may occur during the menstrual cycle. Much information links manic and depressive reactions with alterations in brain monoamines. Lithium, monoamine oxidase inhibitors, and tricylic antidepressants, specifically used to treat affective disorders, are reported useful in treating ovarian hormone—linked upsets. Similarities exist between changes in animal behavior caused by drugs altering affective states and the effects of ovarian hormones. Like certain antidepressants, estrogen induces hyperactivity in rats. Like reserpine, progesterone exhibits sedative and soporific effects. Sexual behavior in female rats is reported linked to changes in brain monoamines. Agents increasing brain monoamine levels and availability decrease mating responses, and monoamine depletors, such as reserpine may be substituted for progesterone in activating mating behavior. Serotonin and dopamine appear to be important in the regulation of ovulation. Brain norepinephrine varies with the phases of the rat estrus cycle. Castration increases brain norepinephrine and decreases brain dopamine. Exogenous estrogen decreases rat brain norepinephrine content. The monoamine-destroying enzymes, monoamine oxidase, and catechol O-methyl transferase are affected by ovarian steroids and show fluctuating levels during the reproductive cycle. The effects of reserpine, monoamine oxidase inhibitors, tricyclic antidepressants, and lithium on monoamines in neurophysiological preparations have been used as evidence supporting theories linking monoamine changes with human affective disorders. Estrogen, progesterone, and angiotensin also exhibit effects on in vitromonoamine systems. Like the tricyclic antidepressants, uptake of norepinephrine and dopamine by nerve endings is inhibited in the presence of estrogen, progesterone, and angiotensin. As with reserpine, the flow of these monoamines from nerve endings is increased by progesterone. Estrogen slows the flow of norepinephrine from nerve endings and decreases the electrically induced release of serotonin and norepinephrine from brain slices. The above information provides clues that ovarian hormone—linked psychopathology, like affective disorders in general, may be related to alterations in brain monoamines.