Sleep deprivation and brain acetylcholine.

Rats deprived of D-state sleep (and, to some extent, of slow-wave sleep) for 96 hours show a significant fall in brain acetylcholine in the telencephalon; there were no significant changes in the diencephalon and brain stem. Restraint stress and activity wheel stress produced no significant change in acetylcholine levels in any of these regions; the telencephalic response to sleep deprivation, therefore, cannot be attributed to nonspecific stress. The effects of D-state deprivation and the psychoactive anticholinergic drugs on telencephalic acetylcholine levels are similar.

Psychoses precipitated by psychotomimetic drugs. A follow-up study.

Fifteen patients who developed prolonged psychotic reactions following psychotomimetic drug use (probably primarily LSD) were followed up 1.9 to 5.8 years later. Two patients had committed suicide. Approximately half of the patients had a relatively good outcome and half did poorly. Aspects of the initial clinical picture that correlated with outcome measures are discussed. The possibility is considered that vulnerability to a prolonged psychotic reaction following psychotomimetic drug use may be related to a genetic vulnerability to illnesses in the manic-depressive/schizo-affective spectrum. In some instances this vulnerability may implicate central serotonergic neuronal systems.

Delusional unipolar depression: description and drug response.

This retrospective study describes the response of 13 delusional unipolar depressives to combination antipsychotic-tricyclic antidepressant drug therapy. The Research Diagnostic Criteria were used by two independent raters to verify the presence of a delusional, primary, unipolar, major depressive disorder. Thirteen patients met the criteria and received combined antipsychotic-antidepressant pharmacotherapy. Twelve of the 13 responded. This contrasts sharply with the low response rate described for delusional depressives when treated with tricyclic antidepressants alone. Descriptive characteristics of the delusional depressives were compared with those of a group of nondelusional unipolar depressives. Delusional depressives had histories of a greater number of prior depressive episodes and more of the delusional depressives demonstrated a psychomotor disturbance.

Desipramine plasma concentration and antidepressant response.

The relationship of desipramine hydrochloride plasma concentration and antidepressant response was determined in 30 depressed inpatients treated for three weeks with desipramine. All patients had a nondelusional unipolar depression, met DSM-III criteria for major depressive episode with melancholia, and had a Hamilton score of 18 or greater after one week of hospitalization without medication. Eighty-nine percent of the patients with plasma concentrations above 115 ng/mL responded, in contrast to 14% of those with concentrations below this level, a significant difference (Fisher's exact test, P less than .001). Ten initial nonresponders were converted to responders when dosage increase raised desipramine plasma concentration to 125 ng/mL or above. In clinical practice a plasma concentration of 125 ng/mL would be a useful guideline as a threshold above which desipramine is likely to be effective.

A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression.

Prompted by a recent study suggesting that the combination of desipramine hydrochloride and fluoxetine down-regulates beta-adrenergic receptors more rapidly than either drug alone, we administered both desipramine and fluoxetine to 14 inpatients with major depression in an open, 4-week trial. Desipramine plasma levels drawn 24 hours after an initial standardized dose were used to rapidly adjust desipramine dosage and compensate for the interactive effects of fluoxetine on desipramine levels in the blood. Responses were retrospectively compared with those of 52 inpatients who were descriptively similar and previously treated in the same setting with desipramine alone. Response was significantly more rapid in the group that received both drugs. One week after treatment began, the mean change in Hamilton Depression Rating Scale scores was 42% in the group that received both drugs and 20% in the group that received desipramine alone (Mann-Whitney U test, P = .007). Two weeks after administration of the drugs, the mean change in scores of the group that received both drugs was 60%, while a 30% change was noted in the patients treated with desipramine alone (P = .001). Ten (71%) of the 14 patients in the group that received both drugs completely remitted (change in Hamilton Depression Rating Scale score of greater than 75%, and final score of less than 7) within 4 weeks, while few patients treated with desipramine alone met these criteria within 4 weeks. This preliminary study suggests that treatment with both desipramine and fluoxetine is a rapid and effective strategy for treatment of major depression, and supports recent hypotheses of noradrenergic-serotonergic synergism.

Dopamine and serotonin metabolism in neuropsychiatrically disturbed children. CSF homovanillic acid and 5-hydroxyindoleacetic acid.

Lumbar cerebrospinal fluid homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and probenecid were measured in four subgroups of neuropsychiatrically disturbed children and a contrast group of pediatric patients. With the exception of a serotonin metabolite difference between autistic and nonautistic psychotic children, there were no significant differences in metabolite concentrations among autistic, nonautistic psychotic, aphasic, and cognitively and attentionally impaired groups, or between the developmentally disabled and contrast groups of children. Younger children had higher concentrations of HVA than older children. Girls had significantly lower HVA/probenecid ratios than boys, which did not appear to be related to underlying neuropsychiatric disorder. Significant probenecid-metabolite correlations indicate the importance of measuring probenecid in the cerebrospinal fluid in clinical studies.

Major adverse reactions during desipramine treatment: relationship to plasma drug concentrations, concomitant antipsychotic treatment, and patient characteristics.

Major adverse reactions interrupting drug therapy during treatment of 84 patients with desipramine hydrochloride were studied to determine their relationship to desipramine plasma concentrations and other clinical variables. The frequency of adverse reactions was higher in patients over 60 years old (39%), and in patients also receiving antipsychotic medications (32%), but low in patients under 60 years old (7%). Desipramine plasma concentrations in patients having side effects did not differ significantly from those in patients without side effects. Steady state desipramine plasma concentrations did not increase with age. Symptomatic orthostatic hypotension, the most common side effect encountered, occurred early in treatment at low desipramine plasma concentrations. Other side effects, usually described as anticholinergic, occurred exclusively in the 34 patients receiving both desipramine and antipsychotic drugs. The concentration of 2-hydroxy-desipramine, the total concentration of 2-hydroxy-desipramine and desipramine, and the ratio of 2-hydroxy-desipramine to desipramine were not higher in 11 patients having side effects than in a comparison group without side effects.

Chronic, multiple tics of Gilles de la Tourette's disease. CSF acid monoamine metabolites after probenecid administration.

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

BACKGROUND: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor. METHODS: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. RESULTS: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4-hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. CONCLUSIONS: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

CSF monoamine metabolites in child and adult psychiatric patients. A developmental perspective.

Concentrations of acid metabolites of dopamine and serotonin were measured in lumbar CSF of a diagnostically heterogeneous group of 154 psychiatric patients following oral probenecid loading. The patients ranged in age from 2 to 67 years old. No patients had received psychoactive medications for at least two weeks prior to the lumbar puncture. Children had higher mean CSF homovenillic acid (HVA) levels, higher mean CSF HVA-probenecid ratios, higher CSF HVA-log probenecid ratios, and lower mean CSF probenecid levels than adults. Age was negatively correlated with CSF HVA level and with CSF HVA-probenecid ratio. These correlations were more pronounced in male patients than in female patients.

CSF acid monoamine metabolites in psychotic syndromes: what might they signify?

Research thus far indicates that CSF 5HIAA and HVA may be correlated with state components of psychotic syndromes. HVA may be positively correlated with a component of arousal or activity. The negative correlation between 5HIAA and state variables of activity or agitation in one study suggests an inhibitory deficit in some acute psychoses or a circulating psychotomimetic substance acting on 5HT receptors. Low CSF HVA values in some psychotic patients could be a manifestation of DA receptor supersensitivity which may antedate and promote the occurrence of acute psychosis. The low CSF HVA is also consistent with a Type B monoamine oxidase deficiency in chronic patients. Such a deficiency could theoretically play a role in either (or both) state or trait behavioral components of psychotic illnesses. Decreased CSF HVA could also be related to trait behaviors in psychoses as a possible reflection of MBD. An increasingly important aspect of biological research in psychotic states in the recognition that biological studies should relate to the component behaviors which make up particular psychotic disorders.

CSF amine metabolites, clinical symptoms, and body movement in psychiatric patients.

The relationships between CSF monoamine metabolites (HVA and 5HIAA), nurses' ratings of clinical symptoms, and telemetered measures of motor movement of ten schizophrenic and ten depressed patients were investigated. There was a significant negative correlation between CSF 5HIAA and both agitation ratings and motor movement in the schizophrenics. CSF HVA correlated positively to anxiety and anger in the depressives. The schizophrenics had a significantly higher CSF HVA than the depressives which appeared unrelated to motor movement. The effects of serotonin turnover and arousal in schizophrenia and the association between CSF metabolite gradients, stress, motor movement, and biogenic amine levels in depression are discussed.

Recent life stressors and biological markers in newly admitted psychotic patients.

The association of recent life stressor severity to putative biological markers of stress was examined in 34 newly admitted patients with acute psychosis. Of the biological variables examined, only pretreatment admission serum cortisol was correlated with stressor severity. Pretreatment serum prolactin, plasma homovanillic acid (HVA), and methoxyhydroxyphen-ethylglycol were not associated with severity of recent life stressors. We controlled for clinical and psychosocial variables that might affect the relationship of stressor severity to biological markers, and found that duration of psychotic symptoms was negatively correlated with stressor severity; however, when both cortisol and duration were entered in a stepwise multiple regression analysis, only pretreatment admission cortisol remained significantly and positively correlated with stressor severity. These findings suggest that serum cortisol may be a useful biological marker when investigating the relationship of life stress to episode onset. In addition, pretreatment HVA was correlated with early neuroleptic response but not with stressor severity, suggesting that HVA has value as a predictor of response independent of recent life stressors.

14C-homovanillic acid in the cerebrospinal fluid of parkinsonian patients after intravenous 14C-L-dopa.

Six patients with Parkinson's disease and five controls were premedicated with probenecid and the peripheral decarboxylase inhibitor alpha-methyldopathydrazine (Carbidopa) before intravenous administration of 50 muc of 14C-L-dopa in tracer quantity. Seven-and-one-half hours later lumbar CSF was obtained. 14C-homovanillic acid (HVA), a major metabolite of brain dopamine, was isolated by thin-layer chromatography and measured. The statistically significant positive correlation between endogenous HVA and 14C-HVA in the entire patient group and the slightly lower values of endogenous HVA and 14C-HVA in the CSF of the parkinsonians support the assumption that the concentration of HVA in the CSF after probenecid treatment reflects brain dopamine turnover. Measurement of labeled HVA here seems to have little advantage over measurement of endogenous HVA alone.

Plasma free homovanillic acid (HVA) as a predictor of clinical response in acute psychosis.

The relationship of plasma free homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) to early clinical response was prospectively studied in a new series of acutely psychotic inpatients given a fixed dose of perphenazine elixir for 10 days. Elevated pretreatment plasma HVA but not MHPG was significantly associated with good response. Change in HVA was correlated with a favorable response and a significant decline in MHPG was found in responders. Results suggest that HVA can provide a useful clinical predictor of response, and that both dopamine metabolism and noradrenergic functioning, as measured by plasma HVA and MHPG, are reduced in effective neuroleptic treatment.

The effect of neuroleptic discontinuation on psychopathology, involuntary movements, and biochemical measures in patients with persistent tardive dyskinesia.

As some of the pharmacological activities of neuroleptic medication may involve pathophysiological mechanisms underlying schizophrenia and tardive dyskinesia (TD), it is useful to study patients undergoing medication discontinuation. In this study, 19 stable, neuroleptic-maintained patients with persistent TD underwent taper and discontinuation of their neuroleptic medication over a 3-week period, and multiple behavioral and biochemical (plasma HVA, MHPG, and prolactin) measures were obtained. The major finding was that early relapsing patients had lower baseline and a significantly greater increase in plasma HVA levels after discontinuation than nonrelapsing patients. In addition, patients exhibiting withdrawal-exacerbated TD had significantly lower plasma MHPG levels than patients not exhibiting this phenomenon. The clinical and pharmacological implications of these findings are discussed.

Lithium in combination with perphenazine: effect on plasma monoamine metabolites.

The addition of lithium to perphenazine altered the pattern of plasma homovanillic acid (HVA) during the course of treatment for acute psychosis. In the perphenazine-treated group plasma HVA declined significantly by days 7-9 of treatment, whereas in the perphenazine-plus-lithium group plasma HVA tended to increase. The pattern for plasma methoxyhydroxyphenethyl-glycol (MHPG) was not significantly different for the two groups. The addition of lithium to a neuroleptic may enhance the metabolism of dopamine.

Tardive dyskinesia and plasma homovanillic acid.

Using 61 patients with tardive dyskinesia (TD) and 25 normal controls, we explored the possibility that plasma HVA may reflect alterations in central dopamine activity or clinical aspects of TD. There were no significant differences between the two groups in plasma HVA level. Analyses of variance with age and sex as independent variables revealed that the major variance in plasma HVA was accounted for by age in both TD patients (p less than 0.001) and normals (p less than 0.049). Examining the TD patients alone, using multiple regression analysis, revealed that age, neuroleptic dose, and severity of TD accounted for 40% of the variance in plasma HVA in males, with age alone accounting for 28%. By comparison, females showed no association to neuroleptic dose or severity, and age only accounted for 8.9%. When severity of TD was the criterion variable, neuroleptic dose, plasma HVA, and age accounted for 20% of the variance in severity in female TD patients and showed no relationship in males. Possible implications of these differing findings in male and female TD patients are discussed.

Plasma homovanillic acid and the dopamine transporter during cocaine withdrawal.

BACKGROUND: Plasma homovanillic acid (HVA) has been used as a measure of central dopaminergic activity but the validity of this method continues to be investigated. We used single photon emission tomography (SPECT) assessment of the dopamine (DA) transporter for comparison with plasma HVA in subjects at varying stages of abstinence from cocaine. METHODS: Nineteen subjects were studied in two separate treatment sites. Plasma HVA and methoxyhydroxyphenethyleneglycol (MHPG) were measured by gas chromatography-mass spectroscopy (GC-MS). The DA transporter was quantified using the SPECT ligand [123I]B-CIT. RESULTS: At 2 weeks of abstinence and beyond there was an increasing positive correlation between plasma HVA and the SPECT measurement of the DA transporter (V3"). CONCLUSIONS: Plasma HVA may be more likely to reflect DA transporter density in the striatum when there is not a major drug-related change in the DA system.

Plasma catecholamine metabolites and treatment response at neuroleptic steady state.

Using either haloperidol or perphenazine in a fixed-dose protocol, plasma free homovanillic acid (HVA) and methoxyhydroxyphenethylglycol (MHPG) were decreased in 37 nonorganic psychotic inpatients at neuroleptic steady state (7-9 days) in comparison with pretreatment values. The data indicate that the magnitude of the decline in HVA and MHPG was associated with treatment response and not with neuroleptic plasma levels.