Effects of serotonin on memory impairments produced by ethanol.

Subjects treated with low or high doses of ethanol demonstrated impaired memory, particularly in tests involving the recall of poorly learned information. Zimelidine, an inhibitor of serotonin reuptake, reversed this ethanol-induced impairment. The serotonin neurotransmitter system may mediate learning and memory in humans and may determine some of the effects of alcohol on higher mental functions.

Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients.

Plasma-free homovanillic acid, a major metabolite of dopamine, was measured in chronically ill schizophrenic patients both before and during treatment with the antipsychotic phenothiazine, fluphenazine. Neuroleptic treatment was associated with a significant time-dependent decrease in plasma homovanillic acid from pretreatment values, which were significantly elevated when compared with those of age- and sex-matched healthy control subjects. Further, both the absolute concentrations as well as the neuroleptic-induced reductions in plasma homovanillic acid determined over 5 weeks of neuroleptic treatment were statistically significantly correlated with ratings of psychosis and improvement in psychosis, respectively. These findings suggest that the delayed effects of neuroleptic agents on presynaptic dopamine activity may more closely parallel their therapeutic actions than do their immediate effects in blocking postsynaptic dopamine receptors and that a decrease in dopamine "turnover" may be responsible for their antipsychotic effects.

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy.

Schizophrenic patients with high ventricle brain ratios and cortical brain atrophy, as shown by computerized tomography, had decreased spinal fluid concentrations of homovanillic acid and dopamine-beta-hydroxylase activity. These decreased cerebral spinal fluid concentrations in patients with brain atrophy support the proposal of disturbed noradrenaline and dopamine neurotransmission in a subgroup of schizophrenic patients.

Sensitivity of RBC membrane Ca2+-adenosine triphosphatase to calmodulin stimulation. Variations in patients with bipolar affective disorders.

The sensitivity of RBC membrane (RBCM) Ca2+-adenosine triphosphatase (Ca2+-ATPase) to calmodulin stimulation was repeatedly studied in healthy volunteers and in 12 patients with affective disorders. Whereas control response was relatively stable, the patients showed great variability. This phenomenon was not due to formation of resealed vesicles in the RBCM nor to the quantity of calmodulin remaining in the RBCM preparations present in the cells before hemolysis. Changes in calmodulin sensitivity did not correlate with changes of mood or of drug treatment. When Ca2+-ATPase was relatively unresponsive to calmodulin, considerable enzyme activity was maintained at low calcium concentrations without calmodulin. In samples showing a large response to calmodulin, virtually no enzyme activity was detected at low calcium concentrations without exogenous calmodulin. Thus, calcium dependence and calmodulin sensitivity of the Ca2+-ATPase appeared to correlate positively with each other. As a similar phenomenon has been linked to changes in the composition of membrane phospholipids responsible for the regulation of Ca2+-ATPase activity, variations in baseline activity and calmodulin-induced stimulation of this enzyme may represent a fundamental defect in systems regulating membrane phospholipid composition.

Enhanced thyrotropin response to thyrotropin releasing hormone in boys at risk for development of alcoholism. Preliminary findings.

Alcoholism is three times more prevalent in men than in women. We studied responses of thyrotropin to protirelin (thyrotropin releasing hormone) in nine sons and eight daughters of patients with familial alcoholism and in eight control boys and seven control girls. Basal and protirelin stimulated triiodothyronine, prolactin, and growth hormone concentrations were also measured. The controls were matched for age, sex, and past alcohol exposure with the index children. The sons of familial alcoholics had significantly higher basal thyrotropin levels, peak thyrotropin levels, and thyrotropin areas under the curve than did the control boys. The daughters of patients with familial alcoholism showed no differences from the control girls. Analyses of triiodothyronine, prolactin, and growth hormone concentrations revealed no differences between the index children and controls. We believe that this is the first report of a male-limited neuroendocrine difference between children of alcoholics and control children. Further studies are needed to elucidate the clinical significance of our preliminary findings.

Cerebrospinal fluid monoamine metabolites and suicidal behavior in depressed patients. A 5-year follow-up study.

We carried out a 5-year follow-up study of suicidal behavior among depressed patients who earlier had determinations of cerebrospinal fluid levels of monoamine metabolites. Patients who reattempted suicide during the follow-up had significantly lower cerebrospinal fluid levels of both the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid. The findings were most striking among melancholic patients. These follow-up results suggest that reduced central turnover of serotonin and dopamine may be associated with further suicidal behavior among depressed patients who have previously attempted suicide.

Family history of alcoholism in violent offenders and impulsive fire setters.

Fifty-six of 58 violent offenders and impulsive fire setters fulfilled the DSM-III criteria for alcohol abuse. Information necessary for evaluation of family history of alcoholism was obtained on 54 subjects. Forty-four of the 54 subjects had first- or second-degree blood relatives with alcoholism. Thirty-five had alcoholic fathers. Subjects with alcoholic fathers had a lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration and were more often impulsive than subjects without alcoholic fathers.

Extraversion in pathological gamblers. Correlates with indexes of noradrenergic function.

Pathological gamblers may have a disturbance of their central nervous system noradrenergic functioning. We administered the Eysenck Personality Questionnaire to pathological gamblers and examined relationships between their personality scores on this questionnaire and indexes of noradrenergic function. There were highly significant correlations between scores on the extraversion scale and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol, plasma levels of 3-methoxy-4-hydroxyphenylglycol, urinary outputs of vanillylmandelic acid, as well as with the sum of urinary outputs of norepinephrine and its major metabolites. These results suggest that the disturbance in the central noradrenergic system in pathological gamblers may be partly reflected in their personality.

Effects of antidepressant treatments on dopamine turnover in depressed patients.

Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional.

High correlation of norepinephrine and its major metabolite excretion rates.

Twenty-four-hour urinary excretion rates of norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and (vanillylmandelic) acid were repeatedly measured in 12 depressed patients. High (greater than. 83) positive correlations were found between the excretion rates of these four substances. Based on these findings, the conclusion was reached that in depressed patients the 24-hour urinary excretion rates of norepinephrine and any of its three major metabolites reflect total norepinephrine production in the body.

Effect of low-dose clorgyline on 24-hour urinary monoamine excretion in patients with rapidly cycling bipolar affective disorder.

Effects of clorgyline on urinary excretion of norepinephrine, dopamine, tyramine, and their major metabolites, 5-hydroxyindoleacetic acid and phenylethylamine, were studied in four women who suffered from primary, bipolar affective disorder. All patients had rapid mood cycles and were nonresponsive to lithium carbonate. During placebo administration, a strong correlation was found between the excretion rates of norepinephrine and dopamine and their respective metabolites. Clorgyline, 5 to 10 mg every or every other day, reduced overall-body norepinephrine turnover by 55% and increased tyramine but did not alter 5-hydroxyindoleacetic acid, phenylethylamine, or p-hydroxyphenylacetic acid excretion. These findings demonstrate the clinical actions of low-dose clorgyline and clorgyline's specificity as a monoamine oxidase A (MAO-A) inhibitor in vivo in humans, as well as the effects of specific MAO-A inhibition on monoamine metabolism.

A prospective follow-up study of alcoholic violent offenders and fire setters.

BACKGROUND: This study investigated biochemical and family variables and predictors of recidivism among forensic psychiatric patients who had committed violent offenses or set fires. METHODS: One hundred fourteen male alcoholic violent offenders and fire setters were followed up for an average of 4.5 years after release from prison. At the beginning of their incarceration, the first half of the offenders were administered clinical diagnostic interviews, whereas the latter half received the Structured Clinical Interview for DSM-III (SCID) that was blind rated. A structured family history questionnaire was administered to all available first-degree relatives of offenders. The offenders also received lumbar punctures for monoamine metabolites, an oral glucose tolerance test, and a measurement of fasting plasma cholesterol level. At the end of the follow-up, the Finnish criminal registry was searched for recidivist crimes. RESULTS: Among all offenders, low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) concentrations were associated with a family history positive for paternal alcoholism with violence. Low plasma cholesterol concentration was associated with a family history positive for paternal alcoholism without violence. The recidivists, who committed violent offenses or set fires during the follow-up period, had low CSF 5-HIAA and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations compared with those in nonrecidivists. Early family environments of the recidivists, compared with those of the nonrecidivists, were characterized by common paternal absence from and presence of brothers at home. CONCLUSION: Among male alcoholic violent offenders and fire setters, low CSF 5-HIAA and HVA concentrations are strongly associated with a family history positive for paternal violence and alcoholism, while low fasting plasma cholesterol concentration is associated with a family history positive for paternal alcoholism. Recidivist violent offenders and fire setters are predicted by low CSF 5-HIAA and MHPG concentrations and a developmental history positive for early paternal absence from and presence of brothers in the family of origin.

Depression among alcoholics. Relationship to clinical and cerebrospinal fluid variables.

Although depression is common among alcoholics, its determinants are poorly understood. Among 339 alcoholics, 111 (33%) had a history of major depression. Depressed, compared with never-depressed alcoholics, had a higher daily alcohol intake, more lifetime diagnoses of other anxiety and affective disorders and drug abuse, more had attempted suicide, and more reported alcoholism in both parents. Depressed alcoholics also had significantly lower cerebrospinal fluid levels of the dopamine metabolite homovanillic acid and of gamma-aminobutyric acid. Among subgroups of depressed alcoholics, secondary compared with primary depressives were more often divorced, of lower social status, with an earlier onset of alcoholism, and higher Michigan Alcohol Screening Test scores. Secondary depressives also had significantly lower cerebrospinal fluid concentrations of homovanillic acid than never depressed alcoholics. These results suggest that certain psychosocial variables, alcohol consumption, and neurochemical variables may be specifically associated with depression in alcoholics.

High correlations of norepinephrine, dopamine, and epinephrine and their major metabolite excretion rates.

We have previously reported high correlations between norepinephrine and its metabolite outputs in depressed patients. In this article, we expand this finding to healthy volunteers and alcoholic patients. Furthermore, we find similar high correlations between urinary outputs of dopamine, norepinephrine, and their major metabolites. The same is true, to a lesser degree, for epinephrine and metanephrine outputs. There are implications of these findings for psychobiological research on the monoamine systems.

High intercorrelations among urinary outputs of norepinephrine and its major metabolites. A replication in depressed patients and controls.

We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.

Psychobiological concomitants of history of suicide attempts among violent offenders and impulsive fire setters.

Psychobiological data on 58 violent offenders and impulsive fire setters were analyzed for associations with history of suicide attempts. Subjects with a history of suicide attempts serious enough to require an admission to a medical facility had significantly lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol concentrations than subjects who had not made such attempts. A linear discriminant function analysis based on psychobiological and behavioral variables correctly classified 79% of the subjects according to the suicide attempt history positive and negative outcomes.

Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.

Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.

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.

Electroconvulsive treatment and lithium carbonate. Their effects on norepinephrine metabolism in patients with primary, major depressions.

Effects of electroconvulsive treatment (ECT) and lithium carbonate on norepinephrine metabolism were investigated in eight patients with primary, major depressions. A series of 12 ECTs reduced urinary norepinephrine and normetanephrine output significantly, and showed a tendency to reduce urinary vanillylmandelic acid output as well as whole-body norepinephrine turnover. Treatment with lithium carbonate significantly reduced urinary norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid output as well as whole-body norepinephrine turnover. These findings point to a common effect of antidepressant treatments since they are similar to results produced by administration of three other types of antidepressant drugs: clorgiline, a specific monoamine oxidase A inhibitor; desipramine, a relatively specific norepinephrine reuptake Inhibitor; and zimelidine, a relatively specific serotonin reuptake Inhibitor. These drugs reduce total production of norepinephrine and/or its major metabolites in depressed patients. Thus, five antidepressant treatments with different mechanisms of action have a common overall effect on the system.

A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression.

Combined monoamine oxidase (MAO) inhibitor-tricyclic antidepressant therapy and electroconvulsive therapy (ECT) were compared in a population of refractory depressive patients. Seventeen patients were randomly assigned to either of the treatment groups, and an independent observer was used to rate overall progress. Between four and ten ECTs or a combination of phenelzine and amitriptyline were administered. Assays for MAO activity and plasma levels of amitriptyline and nortriptyline were performed. In both psychotic and neurotic depression, ECT was superior. When depression was accompanied by character disorder, the response was generally poor. Adequate levels of MAO inhibition were obtained, but tricyclic antidepressant levels were low. Electroconvulsive therapy is still considered to be the treatment of choice for severe depression, whereas the combination of low doses of phenelzine and amitriptyline are ineffective. This treatment modality needs further investigation.