Time-dependent effects of phenothiazines on dopamine turnover in psychiatric patients.

Psychiatric patients studied early during treatment with chlorpromazine and thioridazine demonstrated elevated probenecid-induced accumulations of homovanillic acid, a major dopamine metabolite, in cerebrospinal fluid. In those studied after longer periods of treatment with phenothiazines, homovanillic acid values were not elevated. This suggests that there are time-dependent effects of phenothiazines on dopamine turn-over that may be relevant to the time course of antipsychotic efficacy.

Central norepinephrine metabolism in affective illness: MHPG in the cerebrospinal fluid.

Concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol in cerebrospinal fluid were measured by a gas chromatographic method in 34 patients with affective illness and in 44 controls. Concentrations of this metabolite in spinal fluid were significantly lower in depressed patients than in controls or manic patients. These low values may occur secondary to depressive phenomena such as reduced psychomotor activity, or they may reflect a primary change in norepinephrine metabolism in depressive illness.

Amine metabolites in human cerebrospinal fluid: effects of cord transection and spinal fluid block.

Patients with spinal cord transection had normal concentrations of 5-hydroxyindoleacetic acid and low concentrations of 3-methoxy-4-hydroxyphenyl glycol in lumbar cerebrospinal fluid. The presence or absence of spinal fluid block in these patients did not affect concentrations of either amine metabolite. However, the concentration of homovanillic acid was lower in patients with spinal fluid block than in those without block. The results suggest that the spinal cord contributes to concentrations of 3-methoxy-4-hydroxyphenyl glycol and possibly 5-hydroxyindoleacetic acid, but contributes little to that of homovanillic acid in the lumbar spinal fluid of man.

Brain endolases as specific markers of neuronal and glial cells.

There are three distinct enolase isoenzymes in brain; neuron-specific enolase (NSE), formerly referred to as neuron-specific protein, which is specifically localized in neurons, a nonneuronal enolase (NNE), and a third hybrid form. Light microscopy with immunocytochemical techniques has permitted localization of non-neuronal enolase. The NNE is located in glial cells with no staining of endothelial cells or neurons. Thus, NSE and NNE can be used as specific metabolic markers for neurons and glial cells, respectively.

Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior.

Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not bind to the brain benzodiazepine binding site in vitro, had no effect on the diazepam-induced increase in exploratory behavior. Behavioral effects produced by various combinations of inosine and diazepam indicate that the interaction between purine and benzodiazepine is antagonistic and support the hypothesis that the naturally occurring purines function in anxiety-related behaviors that respond to benzodiazepine treatment.

Phase advance of the circadian sleep-wake cycle as an antidepressant.

Sleep in depressed patients resembles sleep in normal subjects whose circadian rhythms of temperature and rapid-eye-movement sleep are phase-advanced (shifted earlier) relative to their sleep schedules. If this analogy is relevant to the pathophysiology of depressive illness, advancing the time of sleep and awakening should temporarily compensate for the abnormal timing of depressed patients' circadian rhythms. Four of seven manic-depressive patients studied longitudinally spontaneously advanced their times of awakening (activity onset) as they emerged from the depressive phase of their illness. In a phase-shift experiment, a depressed manic-depressive woman was twice brought out of depression for 2 weeks by advancing her sleep period so that she went to sleep and arose 6 hours earlier than usual. The antidepressant effect of the procedure was temporary and similar in duration to circadian desynchronization induced by jet lag in healthy subjects. This result supports the hypothesis that abnormalities of sleep patterns in some types of depression are due to abnormal internal phase relationships of circadian rhythms.

Light suppresses melatonin secretion in humans.

Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity, which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results of previous experiments in which ordinary room light was used, these findings establish that the human response to light is qualitatively similar to that of other mammals.

Effects of vasopressin on human memory functions.

Arginine vasopressin and a number of its synthetic analogs augment memory functions in experimental animals. One of these analogs, 1-desamino-8-D-arginine vasopressin (DDAVP), influences human learning and memory. Cognitively unimpaired, as well as cognitively impaired adults, treated with DDAVP for a period of several days, learn information more effectively, as measured by the completeness, organization, and consistency (reliability) of recall. DDAVP also appears to reverse partially the retrograde amnesia that follows electroconvulsive treatment.

Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Clinical response to imipramine or amitriptyline.

The urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in unipolar depressed patients before and during the fourth week of treatment with either imipramine hydrocloride or amitriptyline hydroxhloride. On the basis of strict rating criteria, 24 patients were selected as either unequivocal responders or nonresponders. In the imipramine group the mean pretreatment MHPG was significantly lower in the nine responders in the seven nonresponders; the converse was found with the amitriptyline patients. Of particular interest is that there was no overlap in individual values between the responders and nonresponders to either drug. Treatment with eigher imipramine or amitriptyline was associated with a significant decrease in MHPG excretion, which was independent of clinical response.

Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.

Rapid cycling in manic-depressives induced by tricyclic antidepressants.

Maintenance tricyclic antidepressants induced rapid cycling between mania and depression in five female bipolar (manic-depressive) patients. Lithium carbonate did not prevent the tricyclic-induced rapid cycling, although two patients subsequently responded well to lithium carbonate alone. In these patients, the action of tricyclics can be conceptualized as accelerating rather than counteracting the natural, cyclic course of the illness in all of its phases. In this respect, tricyclics are analogous to several other drugs that are capable of modulating the frequency of oscillatory biological processes.

A rapid and sensitive radioreceptor assay for benzodiazepine in plasma.

We describe a rapid and sensitive radioreceptor assay for measuring benzodiazepines in plasma. This method is based on the competition between tritiated diazepam and pharmacologically active benzodiazepines present in plasma, for binding sites on rat brain synaptosomal membranes. No interference is obtained with drug-free plasma or plasma samples containing high concentrations of other commonly used drugs. High correlations (r = 0.98; P less than .001) were obtained between the "diazepam equivalents" measured in plasma with the radioreceptor assay and the levels of diazepam and nordiazepam obtained by gas-liquid chromatography. The radioreceptor assay is rapid, sensitive, specific, and requires no sophisticated equipment or methods. It should therefore prove useful in monitoring blood benzodiazepine levels for both therapeutic and toxicologic purposes.

Effects of sleep deprivation on mood and central amine metabolism in depressed patients.

Nineteen patients, each hospitalized with a major depressive episode, were deprived of sleep for one night. Ten patients responded with clear improvement in depressive symptoms; the substantial clinical change was transient, usually lasting one day. Those who responded had significantly higher initial depression ratings (P less than .01) and tended to be older than nonresponders who experienced mild increases in irritability, fatigue, and discomfort following sleep deprivation. Amine metabolites, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were not substantially affected by sleep deprivation, although there was a significant interaction of clinical response and direction of 3-methoxy-4-hydroxyphenylglycol (MHPG) change. Sleep deprivation thus produces acute, but only transient improvement in a selected group of severely depressed patients; it appears to be an important tool in the study of the affective disorders.

Urinary 3-methoxy-4-hydroxyphenylglycol circadian rhythm. Early timing (phase-advance) in manic-depressives compared with normal subjects.

Twenty-four-hour (circadian) rhythms in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, motor activity, and oral temperature were studied in 14 normal subjects and ten manic-depressive patients. In both groups, a daily rhythm in MHPG excretion was present, with daytime peaks and nighttime lows. This pattern of urinary MHPG excretion may reflect a rhythm in central noradrenergic function. The physiological changes in levels of MHPG excretion associated with the circadian rhythm were at least as great as pathological changes associated with manic-depressive illness. Compared with controls, the timing or phase of circadian rhythms in each variable was one to three hours earlier in the patients, whether depressed or manic. Although the presence of circadian rhythms complicates the task of designing clinical research procedures, their early timing in manic-depressives suggests that disturbances in central biological clocks may be an integral part of the pathophysiology of affective illness and may be related to disturbances of sleep and neuroendocrine function associated with depression.

Cerebrospinal fluid monoamine metabolite levels in male arsonists.

Cerebrospinal fluid (CSF) monoamine metabolite levels were studied in 20 arsonists, 20 habitually violent offenders, and ten healthy inpatient volunteers. The arsonists and violent offenders had been in prison an average of six months before the study. Both the raw data and data adjusted by analysis of covariance for group differences in age, height, sex, and season of the lumbar puncture showed significantly lower concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in the arsonists than in the other groups. The finding remained the same when arsonists with violent suicide attempts were excluded from the analysis. Although CSF concentrations of MHPG or 5-HIAA did not correlate with the severity of repeated fire-setting behavior, low blood glucose nadir in the oral glucose tolerance test (a measure of the tendency toward hypoglycemia) did. These results support the hypothesis that poor impulse control in criminal offenders is associated with low levels of certain CSF monoamine metabolites and with a hypoglycemic tendency.

Cerebrospinal fluid amine metabolites in acute schizophrenia.

The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), respectively, were studied in cerebrospinal fluid of patients with acute schizophrenia. Base line levels of these metabolites were not significantly different from those in normal, neurological, and affectively ill controls. Accumulations of 5HIAA and HVA following probenecid administration, which provide a measure of serotonin and dopamine turnover, were also not significantly different in patients with acute schizophrenia and affective illness. After patients had recovered from their acute schizophrenic illness, HVA accumulations were significantly reduced. We discuss results in relation to amine hypotheses of schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia.

Urinary 3-methoxy-4-hydroxyphenylglycol and major affective disorders. A replication and new findings.

We studied group and subgroup differences in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with major affective disorder (66 depressed, 13 manic) and normal volunteers (27 subjects). Bipolar I depressed patients excreted less MHPG than unipolar depressed patients, manic patients, or normal volunteers. The mean (+/- SEM) MHPG excretion rate was 1.44 +/- 0.10 mg/day in 19 depressed bipolar I patients, 1.79 +/- 0.11 mg/day in 28 unipolar depressed patients, 2.11 +/- 0.19 mg/day in 13 manic patients, and 1.85 +/- 0.12 mg/day in 27 normal volunteers. Other sources of variance that affected urinary MHPG levels did not explain subgroup or state differences. There was only a trend for a low pretreatment MHPG level to be associated with positive response to imipramine hydrochloride or desipramine hydrochloride in the 19 patients treated with these drugs. The application of this biological test value for prediction of differential response to antidepressant drugs would therefore seem premature.

Relationship of psychobiological variables to recidivism in violent offenders and impulsive fire setters. A follow-up study.

Fifty-eight violent offenders and impulsive fire setters were followed up for an average of 3 years after release from prison. Recidivists who committed a new violent offense or arson had significantly lower cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid concentrations and blood glucose nadirs after oral glucose challenge than did nonrecidivists. A discriminant analysis, based on the blood glucose nadir and cerebrospinal fluid 5-hydroxyindoleacetic acid concentration, correctly classified 84.2% of the subjects.

RBC membrane adenosine triphosphatase activities in patients with major affective disorders.

Red blood cell Na+, K+-, Mg2+-, and Ca2+-adenosine triphosphatase (ATPase) activities were studied longitudinally in eight patients with affective disorders and 12 healthy volunteers. The patients had a higher mean Ca2+-ATPase activity than the volunteers, and the fluctuations in all three ATPase activities were greater in the patients than in the volunteers. Even though the mean Ca2+-ATPase activity was higher during manias and euthymic periods than during depressions, mood and ATPase activities did not correlate with each other in all patients. Lithium carbonate treatment did not alter the ATPase activities, and the quantity of vanadium present in the membranes could not account for the variations in the enzyme activities observed. We suggest that either the RBCs of manic-depressive patients are very sensitive to fluctuations of a lipophilic ATPase activity--regulating factor present in plasma or the patients have at times high levels of such a factor. In some patients, the level of this hypothesized regulator may fluctuate in synchrony with mood changes.

Thyroid abnormalities associated with rapid-cycling bipolar illness.

Bipolar patients taking lithium carbonate were classified as rapid-cycling or non-rapid-cycling based on whether they had ever experienced four or more affective episodes in a 12-month period. Overt hypothyroidism was found in 12 (50.7%) of the 24 rapid-cycling patients and in none of the 19 non-rapid-cycling patients. Elevated thyroid-stimulating hormone levels were present in 92% of the rapid-cycling group v 32% of the non-rapid-cycling group. Abnormalities of the hypothalamic-pituitary-thyroid axis, some of which may become apparent only during treatment with lithium carbonate, appear to interact with a predisposition to bipolar illness to produce rapid-cycling. These overt and covert abnormalities may help explain the reported efficacy of thyroid in treating "periodic catatonia" and rapid-cycling.