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.

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.

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.

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.

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.

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.

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.

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.