Children at risk for schizophrenia. Clinical and attentional characteristics.

Adolescent high-risk subjects, offspring of schizophrenic mothers, who were placed in foster homes at an early age, are compared with foster children whose biological parents have no record of psychiatric hospitalization and with non-foster children. The high-risk group showed increased social isolation, difficulties in the student role, elevated total symptom scores on the Psychiatric Status Schedule, and elevated schizophrenic scale scores on the Minnesota Multiphasic Personality Inventory. Half of the high-risk subjects showed significant impairment on a battery of eight attention-demanding tasks.

Effect of neuroleptics on altered cerebral glucose metabolism in schizophrenia.

This study examines whether the duration of treatment with antipsychotic drugs influences the regional distribution of cerebral [18F]2-fluoro-2-deoxy-D-glucose utilization as measured by positron emission tomography. Two groups of schizophrenic patients are compared with normal volunteers (n = 10). One group (n = 5) consisted of patients treated for one year, and the second (n = 12) of patients medicated for four to 14 years (mean +/- SD duration, 7.4 +/- 3.4 years). The first group was also examined before patients received their first dose ever of antipsychotic medication. One year of medication was not sufficient to alter the schizophrenic profile of cerebral cortical glucose activity but did elevate activity of the corpus striatum. Medication for 7.4 years also did not alter the schizophrenic pattern of frontal hyperactivity and posterior hypoactivity, although deviations from control values appeared less marked than after one year. On the other hand, in patients medicated for 7.4 years, there was perhaps an even greater increase in the activity of the corpus striatum and of the thalamus. Thus, duration of exposure to antipsychotic medication may affect the pattern of cerebral glucose activity; possibly, even longer exposure may contribute to the hypofrontality noted by others, although this can be confounded with the duration of illness as a factor. In considering the biological significance of the observed profile of cortical glucose activity, we introduce the concept of cerebral metabolic tone. We suggest that a disturbance of this tonus may account for some symptoms of schizophrenia and could be consistent with the hypothesis of abnormal developmental changes in the brains of schizophrenics.

The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: a preliminary study.

The effects of exogenous, supraphysiologic doses of melatonin on the total sleep time and daytime alertness of patients with chronic insomnia was examined in a double blind, single crossover study. Melatonin (75 mg per os) or identical placebo was administered at 10 PM daily to 13 insomniac patients for 14 consecutive days. A significant increase in the subjective assessment of total sleep time and daytime alertness was demonstrated with melatonin but not with placebo. However, 7 of the 13 patients reported that the active treatment had no significant effect on subjective feelings of well-being.

Growth hormone responses to graded doses of apomorphine HCl in schizophrenia.

Growth hormone (GH) responses to graded doses of apomorphine HCl (APO) were established in 14 normal males, ages 18-50, and 10 drug-free schizophrenic (SCZ) subjects; 99% confidence intervals were calculated for normal subjects' GH responses to graded doses of APO. Patients' GH peak levels were found to be outside the interval only when they had positive symptoms of psychosis. When they are actively psychotic, the schizophrenics' GH response to small doses of APO is more sensitive than that of normals.

Toward a brain map of auditory hallucinations.

OBJECTIVE: This study asks whether auditory hallucinations are reflected in a distinctive metabolic map of the brain. METHOD: Regional brain metabolism was measured by positron emission tomography with [18F]-fluorodeoxyglucose in 12 DSM-III schizophrenic patients who experienced auditory hallucinations during glucose uptake and 10 who did not. All patients were free of neuroleptics and 19 had never been treated with neuroleptics. Nine patients were reexamined after 1 year to assess effects of neuroleptic treatment. RESULTS: Compared with the patients who did not experience hallucinations, the patients who did experience hallucinations had significantly lower relative metabolism in auditory and Wernicke's regions and a trend toward higher metabolism in the right hemisphere homologue of Broca's region. Hallucination scores correlated positively and significantly with relative metabolism in the striatum and anterior cingulate regions. Neuroleptic treatment resulted in a significant increase in striatal metabolism and a reduced frontal-parietal ratio, which was significantly correlated with a decrease in hallucination scores. CONCLUSIONS: Auditory hallucinations involve language regions of the cortex in a pattern similar to that seen in normal subjects listening to their own voices but different in that left prefrontal regions are not activated. The striatum plays a critical role in auditory hallucinations.

Substance abuse and schizophrenia: effect on symptoms but not on neurocognitive function.

The authors compare symptoms and neuropsychological test performance in DSM-III schizophrenic patients who reported prior substance abuse (N = 38) with those in patients who reported no such abuse (N = 25) to determine the impact of substance abuse on the psychopathology of schizophrenia. Positive and negative symptom scores were derived from the Schedule for Affective Disorders and Schizophrenia. Sixty neuropsychological measures drawn from commonly used tests of intelligence, memory, learning, fluency, and problem solving were calculated. Separate analyses were performed on patients in a psychotic episode who were free of neuroleptics (N = 27) and on those taking maintenance neuroleptics (N = 36). Among unmedicated patients, those who reported prior substance abuse had significantly higher thought disorder scores. Among neuroleptic-medicated patients, hallucination and delusion scores were significantly higher in the patients who reported prior substance abuse. The substance abuse followed withdrawal from social relations and preceded the onset of positive symptoms. None of the neuropsychological tests discriminated between abusers and nonabusers.

Influence of renal clearance on peripheral homovanillic acid measurements in healthy subjects and schizophrenic patients.

In order to investigate the effect of renal clearance on plasma homovanillic acid (HVA) concentrations, we examined plasma concentration and urinary excretion of HVA and creatinine per 4 h over 24 h in eight male schizophrenic patients and eight healthy male subjects. Renal clearances of HVA and of creatinine were determined per 4 h period. No significant differences were found between groups in the total 24 h excretion of either HVA or creatinine. Although differences between groups in plasma HVA concentrations and urinary HVA excretion per 4 h did not reach statistical significance, the renal clearance of HVA was significantly lower in the patient group than in the control group. There was no difference between groups in creatinine clearance. Diurnal changes were seen in the renal clearance of HVA and creatinine in both groups. Renal HVA clearance decreased from 23.00-07.00 h, with a coincident decrease in urinary HVA excretion and an increase in plasma HVA concentration. We provide evidence that renal clearance is an important determinant of plasma HVA concentration, and should be considered when interpreting plasma HVA data.

Neuroleptic drug effects on cognitive function in schizophrenia.

Neuropsychological test performance was compared in 37 neuroleptic treated DSM-III schizophrenic patients, 27 untreated schizophrenic patients, and 27 normal controls. Neuroleptic treated patients performed significantly less well than untreated patients at recalling a complex figure, at planning on a mazes test, and had poorer fine motor coordination. Controls and untreated patients performed equally well on these tests. The results were not altered in 16 neuroleptic treated patients who had been prescribed low doses of benztropine, nor 38 patients who reported prior substance abuse. Similar cognitive impairments are observed in Parkinson's disease and are associated with dopaminergic antagonist drugs in schizophrenics. Therefore, they do not comprise part of the Schizophrenic Deficit State. Two tests were better performed by controls than patients. Reaction time was slower and more variable in both treated and untreated patient groups than controls. The recall of paraphrased passages was significantly poorer in both patient groups than controls, a finding that is robust in subgroups matched for IQ. Neuroleptic treatment was associated with significantly better performance on this test.

Three clinical syndromes of schizophrenia in untreated subjects: relation to brain glucose activity measured by positron emission tomography (PET).

A number of studies of chronically ill, medicated patients have found that the clinical symptoms of schizophrenia segregate into three syndromes which can be labelled poverty, disorganization, and reality distortion. It has been previously found that each of these syndromes is associated with a specific pattern of perfusion (rCBF) in paralimbic and association cortex and in related subcortical nuclei. We replicated the symptom factors in 20 untreated subjects. Utilizing positron emission tomography with 18-F-fluorodeoxyglucose as a tracer for glucose metabolism, we reconstructed a map of the entire cortical activity from 16 to 20 tomographic slices. Each of the three syndromes was associated with a different pattern of regional glucose metabolism. Findings in common with previous studies were an association of poverty with left cortical metabolic activity in prefrontal and superior parietal areas, reality distortion with left temporal activity, and disorganization with left inferior parietal lobule. This is the first report of an association between regional metabolic activity and clinical syndromes in untreated patients, strengthening previous models of distributed neural networks in this disorder.

Variations in ovarian steroid levels during the luteal phase of the menstrual cycle.

1. Six subjects were investigated during the luteal phase of the menstrual cycle to determine whether the ovarian steroids, estrogen and progesterone were released in an episodic manner. 2. Analysis of plasma obtained every 20 min. during a normal working day provided no evidence for pulsatile release of either steroid although values were lower in the afternoon than in the morning (p less than 0.001). A good correlation (r=0.908) was obtained for the release of both hormones. 3. Cortisol secretion was inversely related to that of the ovarian steroids.

Longitudinal instability of hormone responses in schizophrenia.

We have shown that SCZ patients show higher GH responses to APO than do normals but only on certain occasions when studied longitudinally. GH responses tend to be exaggerated at the time of relapse, and during remission may be blunted or exaggerated. Only patients who at some time demonstrate incoherent thinking and formed delusions, have exaggerated GH responses. Resting serum PRL varies in some patients much more than in normal controls and tends to decline to very low levels at the time of relapse. Several possible sources of variance remain to be controlled. However, it is tempting to infer that the instability of GH responses and resting PRL levels may signify instability in the regulation of these hormones by DA.

Sensitization and tolerance to apomorphine in men: yawning, growth hormone, nausea, and hyperthermia.

This study investigated whether the indices of dopaminergic function, yawning and growth hormone release induced by apomorphine, as well as the drug-induced nausea and hyperthermia, show sensitization or tolerance to repeated injections. Five normal volunteers received 12 injections of apomorphine hydrochloride (0.75 mg/70 kg) every 2 weeks. Yawning, as measured by the latency of onset and the time of peak activity, showed sensitization. The growth hormone response showed no change. Feelings of nausea and hyperthermia showed tolerance to repeated injections. These findings suggest that yawning may be a suitable index of dopaminergic function in studies of schizophrenia.

Dose-response profiles of plasma growth hormone and vasopressin after clonidine challenge in man.

The objective of the study was to determine dose-response relationships of growth hormone, vasopressin, blood pressure, heart rate, and behavioral responses to clonidine. Ten healthy male volunteers were tested with each of three doses of clonidine (0.7, 1.4, and 2.1 micrograms/kg) with at least 1 week between tests. All doses gave a significant growth hormone response with a peak at 50 min. The high dose gave a significantly higher response than either the medium dose or the low dose, which did not differ from each other. Within individual subjects, there was a consistency of response to the different doses; thus, three of the volunteers had responses of 5 ng/ml or higher to the low dose. Those three subjects had higher growth hormone peaks after the highest dose than did six other subjects. Vasopressin showed a drop following clonidine after the two higher doses. Systolic blood pressure dropped following clonidine, showing a significantly greater drop for the medium and high doses than for the low dose. Diastolic blood pressure also showed a drop, but responsiveness did not differ between doses. There was significant dryness of mouth produced by clonidine, but no difference between doses. There was a significant sedative effect following clonidine which was greater for the high dose than for the medium or low dose. The finding that some subjects had a growth hormone peak of 5 ng/ml or greater after the low dose supports the hypothesis that use of a low dose strategy may be useful in confirming supersensitivity in conditions where increased responsiveness is suspected. The lack of difference between blood pressure responses to the medium and high doses of clonidine--doses that have different effects on growth hormone--supports the hypothesis that differences in responsiveness of presynaptic and postsynaptic alpha 2-adrenergic receptors exist.

Seasonal variations in prolactin levels in schizophrenia.

As part of an ongoing longitudinal study of drug-free schizophrenic patients, we serially sampled resting early morning prolactin levels in 10 subjects. In a preliminary analysis, these levels were compared to those found in matched normal control subjects over a 4-year period. Both control and schizophrenic subjects showed a marked annual variation in prolactin levels. Six schizophrenic patients sampled in each quarter of the year showed a significant annual rhythm, with prolactin highest in the spring (March-May). In seven schizophrenic patients and nine controls sampled at two seasons in the year, prolactin was significantly higher in spring-summer (March-August) than in fall-winter (September-February), with no difference between patients and control subjects.

Apomorphine effects on brain metabolism in neuroleptic-naive schizophrenic patients.

Since neuroleptic treatment produces a significant increase in striatal metabolism relative to cortical metabolism, we wished to determine whether the dopamine agonist apomorphine (APO) might have the opposite effect, and whether it would discriminate schizophrenic patients from healthy controls. Eleven neuroleptic-naive schizophrenic patients (diagnosed according to DSM-III) and eight normal subjects were compared with respect to cerebral accumulation of 18F-fluorodeoxyglucose measured by positron emission tomography following APO, 0.75 mg/70 kg (weight adjusted), or saline. Relative striatal glucose metabolism decreased significantly after APO in schizophrenic patients but not in control subjects. Post hoc analysis of data in 12 other regions revealed that relative superior temporal metabolism decreased very slightly, but significantly, in schizophrenic patients but not in control subjects after APO, and that the posterior frontal region increased in control subjects but not in the patient group.

Longitudinal growth hormone studies in schizophrenia.

The growth hormone (GH) response to apomorphine hydrochloride (APO) was examined monthly in 12 schizophrenic patients on drug holiday for up to 22 months and compared with age- and sex-matched controls. There was more variability in the response of patients than controls on the first trial and on several subsequent challenges. Patients' and controls' GH responses to an APO challenge did not distinguish them from each other on the first trial. However, longitudinal data revealed that in a subgroup of five schizophrenic patients and five controls, studied for 12 consecutive trials, the GH response averaged over the 12 trials was significantly lower in the patients than in the controls. Moreover, when schizophrenics' responses on each successive trial were compared, responses decreased over time, but were significantly different from controls only in the later trials. Three of the patients were followed for more than 12 trials, and their GH responsivity increased in the later trials. GH response to APO was significantly correlated with positive symptom scores in three patients but not in four others. There was a trend toward an association between the occurrence of relapse and GH increment induced by APO. A significant association between change in body weight and change in GH response to APO was discovered, suggesting that a changing body weight may contribute to the variability in subjects' response to APO.

Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia.

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

Implications of positron emission tomography research for the investigation of the actions of antipsychotic drugs.

Positron emission tomography studies of regional brain metabolic activity, cerebral blood flow and D2 dopamine receptor binding in schizophrenics and controls are reviewed. Methodological influences on the validity of the data generated by these technologies include problems with measurement as well as clinical and anatomical heterogeneity. Work in these fields to date, however, has produced strong support for the role of D2 dopamine receptor blockade in antipsychotic efficacy. Neuroleptic-induced changes in regional brain metabolism over time have also been observed; however, the relationship between such actions and symptomatic change needs to be further clarified. Future studies on time-course of neuroleptic-associated changes in regional brain metabolism, blood flow and dopamine receptor binding in schizophrenics have the potential to provide greater insight into the relationship of these actions to symptomatic changes and drug-induced side-effects.