Reduced plasma and CSF gamma-aminobutyric acid in affective illness: effect of lithium carbonate.

Plasma and CSF gamma-aminobutyric acid (GABA) levels were determined in patients with affective illness and normal volunteers. Plasma GABA was significantly lower in the medication-free euthymic bipolar group (n = 23, p = 0.03) compared to normal volunteers (n = 36). Lithium-treated euthymic bipolar patients (n = 26) tended to have higher plasma GABA levels (p = 0.09) than the medication-free euthymic bipolar group. Plasma GABA in nine patients, measured in the euthymic state on and off lithium, was higher during lithium treatment (p less than 0.02). In CSF, GABA was found to be significantly lower in a group of euthymic medication-free unipolar and bipolar patients (n = 9) compared to normal volunteers (n = 39, p less than 0.02). CSF GABA, on and off lithium in four bipolar patients, was significantly higher during lithium treatment (p less than 0.02). This effect of lithium, increasing CSF and plasma GABA, may be related to its mechanism of therapeutic action.

Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients.

In a search for trait markers in manic-depressive illness, we studied cerebrospinal fluid (CSF) and plasma monoamines and their metabolites in 25 lithium-treated euthymic bipolar patients (12 of whom provided unmedicated samples) and 30 normal volunteers. No group differences were found. Lithium treatment showed a trend to increase CSF hydroxy-indoleacetic acid (HIAA) (p = 0.05). Dopaminergic and serotonergic metabolites were highly correlated in the CSF of all three groups. We found no evidence of a trait marker for manic-depressive illness among CSF monoamines and their metabolites.

Intravenous physostigmine increases cerebrospinal fluid neuropeptide-Y.

The ability to measure directly central nervous system (CNS) neurotransmitter changes after an acute pharmacological challenge would be a useful clinical tool in psychiatric research. As one approach to this possibility, we attempted to measure cerebrospinal fluid (CSF) neuropeptide changes produced by an intravenous infusion of the indirect cholinergic agonist physostigmine. Six rhesus monkeys, with indwelling CSF catheters, had serial CSF samples removed before and after a 15 micrograms/kg physostigmine infusion. Five of six monkeys studied showed at least a 50% increase in CSF neuropeptide-Y (NPY) levels. Normal human subjects (n = 27) had CSF sampled before and 15, 30, and 45 min after an acute intravenous infusion of physostigmine (either 0, 5, or 15 micrograms/kg). An Analysis of Variance revealed a significant (p = 0.04) dose-time interaction, suggesting that physostigmine increased CSF NPY at the 15 micrograms/kg dose. CSF levels of seven other neuropeptides remained unchanged. These results suggest that the pharmacological challenge paradigm can be adapted to CSF neuropeptides, providing new measures of CNS stimulus-induced response beyond the peripheral plasma determinations usually employed.

CSF substance P immunoreactivity in affective disorders.

CSF substance P immunoreactivity was determined in a group of inpatient controls and acutely manic, euthymic, or depressed unmedicated unipolar and bipolar subjects; a second outpatient group of euthymic bipolar patients (on and off lithium) and normal volunteers was also studied. No group differences and no lithium effects were detected. CSF that was allowed to stand at room temperature for brief periods and then was refrozen contained elevated levels of the immunoreactive substance P, an observation that may account for a previous report of elevated CSF substance P immunoreactivity in psychiatric disorders.

Separate mechanisms for behavioral, cardiovascular, and hormonal responses to dextroamphetamine in man.

The neurochemical specificity of physiological, biochemical, and psychological responses to dextroamphetamine was tested by pretreating volunteers with haloperidol (0.014 mg/kg IM), propranolol (0.1 mg/kg IV), thymoxamine (0.1 mg/kg IV), or placebo prior to 0.3 mg/kg IV amphetamine. Healthy volunteers (N = 12) participated in the studies, but not all volunteers received each drug combination. Haloperidol prevented dextroamphetamine-induced behavioral excitation, but did not significantly affect plasma norepinephrine or pressor responses, whereas propranolol inhibited norepinephrine and pressor responses without influencing excitation or other behavioral responses. Thymoxamine did not affect any of the responses measured. None of the agents significantly affected plasma cortisol or growth hormone responses. The prolactin rise following dextroamphetamine was potentiated by haloperidol. The results are consistent with the hypothesis that behavioral excitation after dextroamphetamine occurs through a dopaminergic mechanism, and pressor responses through a noradrenergic mechanism.

Vasoactive intestinal peptide and bipolar affective illness. Evidence for an effect of lithium.

In an attempt to evaluate the role of VIP in affective disorder, measurements of lymphocyte VIP receptors, and plasma and CSF VIP levels were made in unmedicated and lithium-treated euthymic bipolars and controls. Lithium decreased plasma (P = 0.01) and CSF (P = 0.05) VIP levels and increased the affinity (decreased the KD) of the VIP lymphocyte receptor (P less than 0.01). This effect may be relevant to the psychotropic action of lithium in manic-depressive illness.

Growth hormone releasing factor in human cerebrospinal fluid.

Growth hormone releasing factor (GHRF) was determined by radioimmunoassay in cerebrospinal fluid (CSF) from 37 unmedicated healthy volunteers (mean +/- SD = 23.4 +/- 7.2 pg/ml). A second lumbar puncture in 11 of these subjects suggested that the CSF GHRF levels were stable over time. High performance liquid chromatography revealed that the CSF immunoreactivity co-eluted with the 1-44NH2 and 1-4ONH2 forms of GHRF. Measurements of GHRF in sequential CSF aliquots revealed no evidence of a rostro-caudal gradient, an observation that is compatible with the hypothesis that GHRF has a long half-life in CSF. A significant negative correlation with body weight was found in the 37 subjects. Levels of CSF GHRF were determined in 24 lithium-treated euthymic bipolar patients, 13 of whom provided a second CSF sample during the unmedicated state. No group differences or effects of lithium were noted.

Intravenous GABA administration is anxiogenic in man.

Seven persons (three normal volunteers and four euthymic bipolar patients) received one to four doses of gamma-aminobutyric acid (GABA) intravenously. All subjects reported dysphoria, and their mood disturbance scores on the Profile of Mood States were significantly increased in a dose-related fashion. Placebo infusions did not produce similar responses. Mood disturbance was accompanied by a dose-related increase in pulse and blood pressure.

Platelet vasopressin receptors in bipolar affective illness.

Determinations of the affinity constants (KD) and number of binding sites (Bmax) for platelet vasopressin receptors were done in euthymic bipolar patients and normal volunteers. No significant differences were found between these groups. In addition, lithium treatment did not alter these receptor parameters in the bipolar group.

Blunted ACTH and cortisol response to afternoon tryptophan infusion in euthymic bipolar patients.

The serotonin precursor tryptophan was used to test neuroendocrine responses in remitted bipolar patients and controls. Tryptophan was administered in the afternoon when spontaneous cortisol secretion is lower than in the morning. Following pilot studies at various doses, 50 mg/kg L-tryptophan was given i.v. over 20 min to 11 patients and 14 controls. Controls demonstrated cortisol release, whereas the response curve for patients was indistinguishable from placebo. Differences between groups were significant at 15, 30, and 45 min. Changes in adrenocorticotropic hormone were consistent with those in cortisol. Prolactin and growth hormone levels increased in both patients and controls following tryptophan. Higher doses caused gastrointestinal upset in some subjects.

Behavioral, physiological, and neuroendocrine responses to arecoline in normal twins and "well state" bipolar patients.

Cholinergic supersensitivity has been postulated to be an etiologic factor in affective disorder. After several pilot dose-response studies, we administered 8 mg of the cholinergic agonist arecoline subcutaneously to eight pairs of normal volunteer identical twins and eight bipolar patients currently euthymic and unmedicated. During the hour following arecoline administration, the Profile of Mood States (POMS) showed an increase in total mood disturbance in both patient and control groups. Mean systolic blood pressure, pulse, plasma cortisol, prolactin, and growth hormone also increased. Anger and elation scores on the POMS showed significant concordance in identical twins, as did change in prolactin, implying that these are the components of drug response possibly influenced by genetic factors. None of these responses differentiated well state patients from controls. Thus, mood, behavioral, and neurochemical responses to arecoline, which appears to have nonspecific neurochemical effects at the dose employed, are not markers of vulnerability to affective illness.

Pro-opiomelanocortin-related peptides in cerebrospinal fluid: a study of manic-depressive disorder.

Five peptide fragments of pro-opiomelanocortin (alpha-melanocyte-stimulating hormone, beta-lipoprotin, adrenocorticotropic hormone, beta-endorphin, and the N-terminal fragment of pro-opiomelanocortin) were measured by radioimmunoassay in cerebrospinal fluid (CSF) and plasma from 31 normal volunteers and 26 euthymic lithium-treated bipolar patients (14 of whom provided a second CSF sample in the unmedicated state). With the exception of alpha-melanocyte-stimulating hormone, in the normal volunteers' CSF, levels of these peptides were highly correlated with one another, suggesting that: (1) some common regulatory factor may control the levels of these four peptides in CSF; and (2) CSF alpha-melanocyte-stimulating hormone is independently regulated from the other pro-opiomelanocortin products. Some of these correlations were absent in the patient groups, suggesting subtle alterations in pro-opiomelanocortin processing in manic-depressive illness. No effect of lithium on the CSF levels of these peptides was observed. No group differences were found.

Genetic implications for major affective disorders.

This article reviews the current outcomes of twin, adoption, and family epidemiological studies. Psychiatric genetics research has made a major paradigm shift from epidemiology studies to molecular genetic research. The manner in which affective disorders are inherited continues to elude scientists. Nurses, in collaboration with patients, families and scientists, can facilitate the research process. Merging our professional caring with the biological research outcomes will assure our professional contribution in this expanding research and assist the affected persons from further stigmatization.