Increased noradrenaline levels in CSF and plasma of schizophrenic patients.

Noradrenaline (NA), dopamine (DA), and adrenaline (A) concentrations were determined by means of a specific and sensitive radioenzymatic method in plasma, CSF, and urine of schizophrenic patients and in a group of age- and sex-matched controls without history of mental disorder. NA levels were found to be significantly increased both in plasma and CSF of schizophrenics, particularly in paranoids. The increase in plasma NA concentration can probably be ascribed to the higher unspecific arousal level of these patients, whereas the increase of CSF NA levels probably reflects a rise of central noradrenergic activity. The physiopathological significance of this overactivity, however, is questionable.

QEEG alpha 1 changes after a single dose of high-potency neuroleptics as a predictor of short-term response to treatment in schizophrenic patients.

Baseline quantitative electroencephalographic (QEEG) characteristics and their changes after a single test dose of either haloperidol or clopenthixol were investigated in a group of 29 schizophrenics as possible predictors of short-term response to those drugs. On baseline QEEG assessment, responders (R) to subsequent treatment showed fewer slow and more fast activities than nonresponders (NR). A large overlap between R and NR with respect to these measures was observed, however, revealing their practical inadequacy to predict short-term response in individual patients. On the contrary, changes in alpha 1, observed 6 hr after the administration of a single test dose of either haloperidol or clopenthixol, discriminated to a very large extent between R and NR, correctly identifying 17 out of 18 R and 8 out of 10 NR. The QEEG test dose procedure might be used in the selection of the most appropriate antipsychotic drug for individual schizophrenic patients.

Drugs and the frog retina. Effect of dopaminergic agents on the pigment screening of light- and dark-adapted frogs.

This is a study, using the light and electron microscope, of the action of a dopamine agonist (apomorphine) and of a dopamine antagonist (haloperidol) on the retinal pigment screening (PS) of light- and dark-adapted frogs. Pigment screening is a phenomenon which consists of the migration of melanin granules into processes of the pigment epithelium that extend between photoreceptors, in response to changes in the conditions of illumination. In the light the pigment migrates vitreally , in the dark it aggregates sclerally . A single intravenous injection of apomorphine (0.15 mg/kg) and of haloperidol (1 mg/kg) did not induce substantial modifications in the pattern of pigment screening which was similar to that of controls both in light- and dark-adapted frogs. This suggests that dopamine is probably not directly involved in the phenomenon of pigment screening in the retina of the frog.

Lysergic acid diethylamide: morphological study of its effect on synapses.

A morphometric analysis of the effect of LSD on synapses was performed in the habenulae and the interpeduncular nucleus of the frog. The OsO4-fixed nervous tissue was treated with ethanol phosphotungstic acid (EPTA). Intersection of lattice lines with synapses were counted as a proportion of the total length of lines. LSD-treated frogs had a higher total area of synaptic contact than control frogs. Exocytosis profiles were observed only in LSD-treated frogs Other qualitative changes in the ultrastructural characteristic of synapses were appreciable after LSD administration.

Long-term outcome of lithium prophylaxis in patients initially classified as complete responders.

The long-term outcome of lithium prophylaxis was explored in 43 bipolar and 36 unipolar patients who had been classified as complete responders after the first 2 years of treatment. These patients were followed up prospectively for a further period of 5 years (treatment period II), during which their psychopathological state was assessed monthly or bimonthly. Forty-nine patients completed treatment period II, 2 died during this period, 7 did not attend the unit any more and could not be traced, and 21 definitively interrupted lithium treatment before the end of the period. In 18 cases the decision to stop lithium was taken by the patient. Twenty-five patients relapsed during the treatment period II. Four relapsers had three or more episodes concentrated during the last 2 years of treatment. These results suggest that the predictive value of an initial favourable response to lithium should not be overrated, and that the impact of the drug on the long-term course of major affective disorders in ordinary clinical conditions might be less dramatic than currently believed.

Low platelet MAO activity in chronic schizophrenics: a long-term effect of neuroleptic treatment?

Platelet MAO activity was determined, using 14C-tryptamine and 14C-beta-phenylethylamine as substrates, in two groups of schizophrenic patients and a normal control population. The first patient group consisted of 75 schizophrenics who had been medication-free for 2 weeks and had not been exposed to neuroleptic drugs for at least 2 months before the off-drug period. The second patient group comprised 55 schizophrenics who were on treatment with haloperidol for at least 2 months. The enzyme activity was found to be significantly decreased in both drug-free (using only tryptamine as substrate, P less than 0.05) and haloperidol-treated (P less than 0.001) chronic schizophrenics as compared with normal controls, and to be significantly lower (P less than 0.05) in haloperidol-treated than in off-drug chronic schizophrenics. An in vitro study confirmed the lowering effect of haloperidol on MAO activity. It is suggested that low platelet MAO values observed in chronic schizophrenics might be in part an effect of neuroleptic treatment.

CEEG mapping in drug-free schizophrenics. Differences from healthy subjects and changes induced by haloperidol treatment.

A topographic CEEG investigation was carried out in 20 drug-free, DSM-IIIR diagnosed schizophrenics and in a group of matched healthy controls. The effects of acute and chronic haloperidol treatment were then assessed in the patient group. On the baseline recording, schizophrenics showed a widespread increase in delta, theta 1 and beta 3 amplitude. Acute haloperidol administration produced a decrease in delta and an increase in slow beta amplitude. After 28 days of treatment, delta and fast beta were reduced while theta 2 and alpha 1 were increased. CEEG abnormalities in schizophrenic subjects appear, therefore, to be reduced by chronic neuroleptic treatment.

Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics.

The 24-h profiles of plasma melatonin and cortisol were evaluated in 7 drug-free male paranoid schizophrenics and in 7 healthy subjects matched to the patients for age, sex, body weight, height and season of testing. Blood samples were obtained at 20.00, 22.00, 24.00, 01.00, 02.00, 06.00, 08.00 and 12.00 h. Light was turned off from 21.00 to 07.00 h. Compared with that of the normal controls, the circadian rhythm of plasma melatonin was absent in paranoid schizophrenics (F7.84 = 7.30, p less than 0.0001; two-way ANOVA with repeated measures) whereas the 24-h profile of plasma cortisol was preserved, although at a slightly higher level (F1.12 = 26.810, p less than 0.0002). The melatonin/cortisol ratio was significantly higher in healthy subjects than in the schizophrenic patients. A functional relationship between disturbances in the melatonin rhythm especially and schizophrenia may be proposed, although the significance of this relationship remains to be elucidated.

Prediction of outcome by historical, clinical and biological variables in schizoaffective disorder, depressed type.

The usefulness of several historical, clinical and biological variables as possible predictors of outcome was tested in a sample of patients with a cross-sectional diagnosis of schizoaffective disorder, depressed type. Four historical items were found to be successful: a family history of chronic schizophrenia, the occurrence of schizophrenic symptoms at some stage of the illness in the absence of depression and an onset of the index episode as exacerbation of previous symptoms (all associated with a relatively poor outcome), and a personal history of previous manic episodes (associated with a relatively good outcome). The various aspects of the clinical picture during the index episode, as well as the response on dexamethasone suppression test, were not found to have any predictive value. These findings confirm that, in patients with a cross-sectional diagnosis of schizodepressive disorder, the previous course of the illness is of crucial importance for prognosis, and support the usefulness of a multiaxial classification of schizoaffective states, taking into account not only cross-sectional symptomatology but also course.

Platelet monoamine oxidase activity in schizophrenia: relationship to family history of the illness and neuroleptic treatment.

Platelet monoamine oxidase (MAO) activity was determined in a large population of drug-free and haloperidol-treated schizophrenic patients and healthy controls and, in a second study, in a sample of schizophrenics after a wash-out period and at different times during treatment with haloperidol. Enzyme activity was significantly decreased in both acute and chronic haloperidol-treated schizophrenics, but not in drug-free schizophrenics, compared with normal controls. No significant difference was observed between drug-free schizophrenics with a family history of the illness and those without such history, and between healthy relatives of schizophrenic patients and normal controls without a family history of schizophrenia. MAO activity was significantly reduced after 14 and 21 days of haloperidol treatment, and such reduction did not correlate with response to treatment. These data strongly support the idea that neuroleptic intake may, at least in part, explain low MAO values repeatedly reported in schizophrenics.

Clinical and neuropsychological correlates of cerebral ventricular enlargement in schizophrenia.

A comprehensive assessment of computed tomography (CT) with respect to clinical, historical and neuropsychological variables has been carried out in a sample of DSM III schizophrenics fairly heterogeneous with respect to duration and severity of illness and in a normal control group matched for sex, age and educational level. The mean value of ventricular brain ratio (VBR) was significantly higher in schizophrenics than controls. Seven patients (21.2%) who had VBRs exceeding 2 SD of the control mean showed a significantly longer duration of illness than the other schizophrenics with significantly higher scores on the subscales alogia, effective flattening and attentional impairment of SANS, on the scales self-care and behaviour in crises and emergencies of DAS, on the scales rhythm, tactile, visual, reading, arithmetic, memory and left hemisphere of LNNB, and on the subtests arithmetic, digit span, digit symbol and block design of WAIS. These results confirm earlier reports of an enlargement of lateral cerebral ventricles in a subset of schizophrenics, and its association with a higher degree of cognitive and neuropsychological impairment, social maladjustment and defectual symptomatology. Moreover, they suggest that the neuropathological process likely to underlie the increase of cerebral ventricular size progresses during the course of the illness rather than predating its onset.

Research on schizophrenia in Southern European countries.

The research on schizophrenia during the last 50 years in the Latin language countries of Southern Europe is briefly surveyed. Particular emphasis is given to the contributions of French authors to the diagnostic concept of schizophrenia, as well as to the phenomenological studies concerning the "essence" of schizoidia/schizophrenia, and some initial schizophrenic "Erlebnisse." The development of biological, psychological, and sociological theories concerning the etiology of schizophrenia is outlined, and contributions such as the "aminotoxic theory" of V. M. Buscaino and the theoretical principles of "alternative psychiatry" are examined in detail. Lastly, the role of French, Italian, Spanish, and Portuguese psychiatrists in the introduction and improvement of somatic treatments is described.

Lithium decreases retinal melatonin levels in the frog.

The effect of the acute i.p. administration of lithium chloride (1 mg/kg) and of haloperidol (1 mg/kg) on retinal melatonin levels was studied in light-adapted and dark-adapted frogs of the species Rana esculenta. Two hours following drug administration, animals were killed by decapitation and a single retina from each frog was collected and homogenized in 1 ml of chilled 0.1 N HCl. After centrifugation, the pH of the supernatant was adjusted to 7.0. Melatonin was extracted by diethylether and assayed by double antibody radioimmunoassay (RIA). Lithium induced a significant decrease of retinal melatonin levels both in light-adapted (P less than 0.006) and in dark-adapted (P less than 0.01) animals, whereas no change was observed after haloperidol treatment. These results suggest that the scleral aggregation of pigment granules induced by lithium in the frog retina is not mediated by a stimulation of melatonin synthesis.

Factors associated with increased noradrenaline levels in schizophrenic patients.

1. CSF NA levels were determined in a sample of DSM III-diagnosed schizophrenics and in a non-psychiatric control group. Schizophrenics with NA levels above and below the median were compared with respect to several clinical, historical, neuropsychological and biological variables. 2. Mean CSF NA levels were significantly higher in schizophrenics than in controls. 3. Schizophrenics with high CSF NA levels, as compared to those with low levels, had significantly higher scores on the CPRS subscale for positive symptoms. Moreover, in the former subgroup, C-EEG alpha relative activity was significantly lower and C-EEG beta relative activity was significantly higher in frontal and central leads. Two of the three patients who had been never treated with neuroleptics, and three of the six patients who had been neuroleptic-free for more than four weeks had high CSF NA levels. 4. These data support the relationship between increased CSF NA levels and the condition of overarousal of the schizophrenic patients, and suggest that prior neuroleptic treatment is not a major determinant of high CSF NA concentration in schizophrenics.

Factors associated with decreased platelet MAO activity in chronic schizophrenics.

Platelet MAO activity was determined in a sample of chronic schizophrenics, including drug-free and neuroleptic-treated patients, and in a normal control group. Patients with MAO values below and above the median were compared with respect to several clinical, historical, neuroradiological and neuropsychological variables. The enzyme activity was significantly decreased in the whole patient group and in the subgroup of neuroleptic-treated patients, but not in the subgroup of drug-free patients. The only significant difference between low MAO and high MAO patients concerned drug status (higher percentage of patients on neuroleptics in the former subgroup). On stepwise discriminant function analysis, drug status (on neuroleptics vs. off neuroleptics) correctly classified 63.4% of patients.

C-EEG brain mapping in DSM-III schizophrenics after acute and chronic haloperidol treatment.

A multi-lead C-EEG investigation was carried out, in order to evaluate changes induced by acute and chronic treatment with haloperidol in DSM-III-R schizophrenics. After the acute treatment the main C-EEG changes were (1) a significant decrease of delta relative power (RP) over all the explored leads and of theta 1 over the occipital leads; (2) an increase in alpha 2 and beta 2 RP, as well as a decrease of beta 3 RP confined to the anterior temporal leads (T3, T4). During chronic treatment, C-EEG changes observed were (1) a significant decrease of delta RP and an increase of theta 1 RP; (2) an increase of alpha 1 and alpha 2 RP; (3) a significant decrease of beta 1, beta 2 and beta 3.

Pineal response to isoproterenol in rats chronically treated with electroconvulsive shock.

Chronic electroconvulsive shock (ECS) has been shown to induce a downregulation of beta 1-adrenergic receptors in the rat cerebral cortex. Because the secretion of melatonin in the pineal gland is regulated primarily by beta 1-adrenoceptors, in the present study we investigated the effect of chronic administration of ECS on pineal beta-adrenergic responsiveness to isoproterenol. To this purpose, young adult male rats received once daily for 8 days ECS (80 mA, 0.5 s) or sham ECS. On the day after the last ECS or sham treatment, they were injected with isoproterenol hydrochloride (1 mg/kg SC) or volume-matched saline at 1600 h. Two hours later they were killed by decapitation. Results showed that the isoproterenol-induced increase in the pineal melatonin content was blunted in rats treated with ECS as compared to sham-treated animals (shock x drug interaction = p < 0.01). These data indicate that chronic ECS treatment affects beta 1 receptor-mediated melatonin production in the pineal gland. Further studies need to elucidate whether the blunted melatonin response to isoproterenol in ECS-treated rats is due to a downregulation of pinealocyte beta-adrenergic receptors.

Physical exercise at night blunts the nocturnal increase of plasma melatonin levels in healthy humans.

The effects of physical exercise on nighttime melatonin secretion have never been investigated in humans. For this purpose, plasma melatonin levels were measured at different times during the day and the night in seven healthy men (aged 26-33 yrs), both in resting condition and before and after a physical exercise performed between 10.40 and 11.00 p.m.. The exercise consisted in bicycling on a bicycle ergometer at 50% of the personal maximal work capacity (MWC) for 10 min, followed by other 10 min of bicycling at 80% of the MWC. The results clearly showed that physical stress at night significantly blunts the nocturnal increase in plasma melatonin levels (group X time interaction: p less than 0.00001; two-way ANOVA with repeated measures). These findings, taken together with the data of the literature, suggest that the response of the pineal gland to provocative stimuli may depend on its level of activity when the stimulus is applied.

A multicenter Italian study of amineptine (Survector 100).

This study reports the antidepressant efficacy and the safety of amineptine (Survector 100) in a national multicenter open clinical trial (32 hospital centers). Three hundred twenty-four patients with depressive disorders, selected according to DSM-III Diagnostic Criteria and INSERM classification, were treated with amineptine (200 mg/day) for 40 days (mean). Amineptine proved to be significantly effective with a rapid onset of action (beginning on the 7th day) on depressive symptoms, as shown by the decrease in the Hamilton Depression Rating Scale total score. The assessment of the results in the different diagnostic subgroups confirmed the wide-spectrum antidepressant activity of amineptine. Particularly in reactive and neurotic depression (nonpsychotic depression according to INSERM) and dysthymic disorders according to DSM-III, amineptine induced an improvement in 90% of patients. Nevertheless, amineptine was also effective in psychotic depression (INSERM) and in major depressive episodes (DSM-III), in which improvement occurred in 76% of patients. The low frequency of side effects and the remarkable acceptability (clinical, biological, and cardiovascular) of amineptine were also confirmed.

Melatonin and cortisol secretion in patients with primary obsessive-compulsive disorder.

Plasma levels of melatonin and cortisol were measured over a 24-hour period in seven patients with primary obsessive-compulsive disorder (OCD) and seven matched healthy control subjects. In OCD patients, the 24-hour secretion of melatonin was reduced as compared with that in healthy control subjects, whereas its circadian rhythm was preserved. In addition, in OCD patients, the overall secretion of cortisol was higher than that in control subjects, but there was no change in the circadian pattern of cortisol secretion. No correlation was found between clinical parameters and hormone levels.