Platelet monoamine-oxidase activity in schizophrenia. Relation to genetic load of the illness and treatment with antipsychotic drugs

A significant decrease of mean platelet monoamine-oxidase (MAO) activity was observed in a sample of haloperidol-treated schizophrenic patients as compared with normal control subjects. The enzyme activity was not significantly reduced in drug-free schizophrenics. No significant difference was found between drug-free schizophrenics with and without a family history of the illness and between healthy relatives of schizophrenics and normal subjects without a family history of schizophrenia. MAO activity was significantly reduced after 14 and 21 days of treatment with haloperidol, in comparison with baseline values. It is suggested that neuroleptic intake may at least in part explain low MAO values repeatedly reported in schizophrenics.     

A probable neuroleptic effect on platelet monoamine oxidase in chronic schizophrenic patients

Platelet monoamine oxidase activity (MAO) was studied serially over time in 16 chronic schizophrenic patients when medication free and then when medicated. Thirteen of the 16 patients had significant decreases in platelet MAO activity following neuroleptic drug treatment. The change in MAO activity was found to be correlated with response to treatment and to dose of medication.     

Platelet monoamine oxidase in alcoholism

We studied platelet monamine oxidase (MAO) activity using 14C-tyramine as substrate in hospitalized alcoholic patients in the early phases of abstinence and in nonhospitalized normal control volunteers. Platelet MAO was determined in 75 patients (67 men, 8 women) with alcoholism and 123 normal control volunteers (52 men, 71 women). The platelet MAO activity in alcoholic patients was significantly lower than in normal control volunteers. We also observed that the mean platelet MAO activity in male alcoholics was significantly lower than in normal males. The analysis of platelet MAO in alcoholics revealed a mixture of two normal distributions. Alcoholic patients falling into the low MAO component were younger in age, with a lower age of onset of alcoholism, and had higher frequencies of family history of alcoholism. They thus resembled type II alcoholics described by other investigators. Platelet MAO may thus serve as a useful biological marker for subtyping alcoholism and identifying high-risk groups at an early stage. The findings of this study are consistent with previous reports of low platelet MAO activity in alcoholic patients.     

Platelet monoamine oxidase in chronic schizophrenic patients

The authors investigated platelet monoamine (MAO) activity in 40 chronic schizophrenic patients, 55 normal control subjects, and 16 hospitalized control subjects. The mean platelet MAO activity for the chronic schizophrenic patients was significantly lower than the mean in either control group. There were no significant differences between the mean platelet MAO activities in 21 chronic paranoid schizophrenic patients compared with 18 chronic undifferentiated schizophrenic patients.     

Effects of neuroleptics on platelet monoamine oxidase activity

Platelet MAO activity in schizophrenics was significantly decreased, by about 15%, after 3 weeks of treatment with haloperidol. Treatment with thioridazine or butaperazine also tended to decrease platelet MAO activity. The neuroleptic-induced decrease began to appear within a few days of treatment and did not show tolerance over 1-2 months of treatment with haloperidol. Platelet MAO activity of schizophrenic patients measured during drug-free base-line was not significantly different from that of normal controls, but MAO activity of schizophrenics was significantly lower than normals after 3 weeks of treatment with neuroleptics. The extent of decrease in platelet MAO activity correlated negatively with base-line prolactin and its increase after 24 hr. With PEA as substrate, the decrease in activity correlated positively with steady state plasma haloperidol.     

Reduction of blood platelet monoamine oxidase activity in schizophrenic patients on phenothiazines.

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets (serotonin used as substrate) was applied for the measurement of the enzyme activity in 76 schizophrenic patients. No significant reduction was found in the blood platelet MAO activity in a group of 33 untreated schizophrenic patients, as compared to that in the normal controls. Male patients revealed to have lower enzyme activity than females in the schizophrenic group, as we described previously in the normal subjects. Treatment with phenothiazines caused significant reduction of blood platelet MAO activity, while platelet serotonin content and platelet count appeared to be not affected by the drug treatment. The authors suggest that blood platelet MAO activity may be related to hormonal factors but not to psychiatric diagnosis of schizophrenia or constitution liable to schizophrenic illnesses.     

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.     

Relation of hypermagnesaemia to activity and neuroleptic drug therapy in schizophrenic states

In a study designed to explain conflicting reports of hypermagnesaemia in schizophrenia, significantly higher concentrations of plasma-magnesium were found in phenothiazine-treated schizophrenic women than in normal women of the same age. This did not apply to men. Magnesium levels were inversely related to motor activity in untreated chronic schizophrenic men in hospital as well as in patients of both sexes receiving butyrophenone or phenothiazine derivatives. The magnesium concentration fell significantly when institutionalized schizophrenic and non-schizophrenic men were placed on neuroleptic medication. It is concluded that age, sex, pharmacotherapy, and level of activity all influence the metabolism of magnesium in schizophrenic subjects.     

Biochemical markers in the study of clinical effects and extrapyramidal side effects of neuroleptics

Neuroleptic treatment was instituted in 20 female schizophrenic patients, who had not received neuroleptics for at least the preceding 3 months. Both the therapeutic response to neuroleptics and the development of parkinsonian side effects were monitored in these patients. In addition, plasma dopamine-beta-hydroxylase (DBH) and platelet monoamine oxidase (MAO) activities were measured. None of the neuroleptic responders developed parkinsonian symptoms. During the course of the 28-day treatment, there was a significant decrease in platelet MAO activity. There was a tendency for responders without parkinsonian symptoms to have lower plasma DBH activity than did nonresponders with parkinsonian symptoms.     

Platelet 5-HT(2A) receptors in schizophrenic patients with and without neuroleptic treatment

It has been suggested that abnormal function of the serotonergic system may be implicated in the pathophysiology of schizophrenia. In order to examine the role of this system in schizophrenia, we have determined 5-HT(2A) receptors on human platelets of 20 control subjects and 37 schizophrenic patients by using [3H]spiperone and ketanserin. The data showed that the maximum number (B(max)) of 5-HT(2A) receptors for schizophrenic patients without neuroleptic therapy was significantly higher than that for control subjects. The B(max) values for [3H]spiperone binding to platelets of schizophrenic patients on butyrophenone, phenothiazine, benzisoxazole and thioxanthene therapies were significantly lower than those obtained from the drug-free group, but were comparable to control values. The effect of various medication periods on platelet 5-HT(2A) receptors was also examined. We found that after 2-4 weeks, 1-4 months, 4-12 months and more than 1 year of neuroleptic treatments, the B(max) values were significantly decreased when compared with values in the drug-free group. The present results indicate that treatment with various types of neuroleptics decreases the hypersensitivity of platelet 5-HT(2A) receptors. Significant clinical improvements occurred in all types of neuroleptic-treated groups and for all different treatment durations in this study. The precise mechanisms of how neuroleptics achieve their therapeutic effects still need to be further delineated.     

Effects of six weeks' neuroleptic treatment on the pituitary-thyroid axis in schizophrenic patients

In order to investigate the effects of 6 weeks' neuroleptic treatment on the pituitary-thyroid axis in 25 male schizophrenic patients, and the diurnal variation in the thyrotropin (TSH) and prolactin (PRL) responses to thyrotropin-releasing hormone (TRH) in these patients, the TRH stimulation test was performed in each of them at 14.00 and 24.00 h of the same day, both before and after 6 weeks' treatment with neuroleptics (chlorpromazine or fluspirilene). Also, serum thyroxine (T4), in vitro radioactive triiodothyronine uptake (RT3 U) and free-thyroxine index (FTI) values were estimated from the pre-TRH blood sample. We found no evidence of diurnal variation in the TSH response to TRH in the schizophrenic patients, before or after 6 weeks' neuroleptic treatment. Only drug-free schizophrenic patients had significantly higher PRL responses to TRH at 14.00 h than those at 24.00 h. After 6 weeks' neuroleptic treatment, schizophrenic patients tended to have lower FTI values; also, they had significantly higher basal TSH and PRL values, as well as significantly augmented TSH and PRL responses to TRH, in comparison to their pretreatment values. These findings render possible the diagnosis of subclinical hypothyroidism in neuroleptic-treated schizophrenic patients.     

Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects

Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.     

Brain and skeletal muscle monoamine oxidase activity in schizophrenia

Monoamine oxidase (MAO) activity has been studied in postmortem brain specimens from chronic schizophrenics and comparison groups by various laboratories. There is no evidence for decreased MAO activity in the brains of the schizophrenic patients, but many possible sources of error in postmortem studies make the conclusions of these studies less than definitive. However, since almost complete inhibition of brain MAO activity appears necessary before it has any functional significance, reduced brain MAO activity is unlikely to have any significance for the pathogenesis of psychosis. Brain and platelet MAO activities in man have been found not to be significantly correlated with each other. There is some evidence neuroleptic drugs may inhibit human brain MAO activity in vitro, but indirect evidence from spinal fluid and postmortem studies is not consistent with this. Decreased MAO activity has been found in the skeletal muscle of various types of psychotic patients compared to normal controls. This suggests decreased MAO activity in peripheral tissues may be a nonspecific marker for vulnerability to the development of psychopathology.     

Neuroleptic drug effect on platelet monoamine oxidase and plasma amine oxidase in schizophrenia

Activity levels of platelet monoamine oxidase (MAO) and plasma amine oxidase (PAO) were determined in eight chronic schizophrenic patients who had been treated with neuroleptic drugs for 3 months. The mean reduction in platelet MAO activity was 18.6%. The extent of decrease was statistically significant. The reduction in enzyme activity was unrelated to serum iron levels. PAO activity was unaltered. The implications for schizophrenia research are discussed.     

Relationship of auditory hallucinations and paranoia to platelet MAO activity in schizophrenics: sex and race interactions

Platelet monoamine oxidase (MAO) activity was determined in 37 female and 64 male patients with Research Diagnostic Criteria diagnoses of paranoid or undifferentiated schizophrenia, or schizoaffective disorder, mainly schizophrenic, and for 71 female and 65 male normal controls (NCs). Female NCs had significantly higher adjusted mean platelet MAO activity than male NCs and female, paranoid, nonhallucinating schizophrenics. Male NCs had significantly higher adjusted mean platelet MAO activity than male, paranoid, hallucinating schizophrenics. Examination of main and interactive effects of diagnostic subtype, presence/absence of auditory hallucinations, gender, and race within the group of schizophrenic patients revealed no statistically significant main effect but, rather, significant interactive effects of auditory hallucinations with gender, with diagnostic group and gender, and with diagnostic group and race in the prediction of platelet MAO activity. The interaction of diagnostic subtype with race and gender in the prediction of platelet MAO activity was also statistically significant. In general, significantly decreased platelet MAO activity was associated with both paranoid subtype and presence of auditory hallucinations in male and in black schizophrenics; and with paranoid subtype alone in white male schizophrenics. These interactive relationships with platelet MAO activity in schizophrenics may account for discrepancies in previous reports of the activity of this enzyme in schizophrenics, and are consistent with reduced platelet MAO activity in subgroups of schizophrenics.     

Platelet MAO deamination of serotonin in depressed patients. Changes after imipramine treatment and clinical correlations

Monoamine oxidase (MAO) in blood platelets has been used as a model to study MAO in the central nervous system, where disorders in serotonergic systems are thought to occur in depression. Inconsistent changes in platelet MAO of depressed patients have been reported when several substrates other than serotonin (5-HT) have been used. To correlate changes in platelet MAO activity with the enzyme activity in central serotonergic systems, the platelet MAO activity of depressed patients (first unmedicated and then after 3 weeks and 2 months of imipramine treatment) and normal controls was measured using 5-HT as substrate. The results showed that there is a steady, measurable platelet MAO activity with that substrate. This activity was significantly higher in unmedicated depressed patients than in controls, and it decreased progressively with imipramine treatment, reaching a normal level when the patients were clinically recovered from depression after 2 months of therapy.     

Reduced platelet monoamine oxidase activity in a subgroup of schizophrenic patients.

Platelet monoamine oxidase (MAO) activity was significantly lower than control values in a subgroup of 16 schizophrenic patients (most of whom were paranoid) characterized by the presence of auditory hallucinations and delusions. Platelet MAO activity was not reduced in 16 other schizophrenic patients without auditory hallucinations. This finding suggests that reduced platelet MAO activity is not found in all schizophrenic patients but tends to occur in a clinically identifiable subgroup.     

Tardive dyskinesia in the mentally retarded: comparison of prevalence, risk factors and topography with a schizophrenic population.

Thirty mentally retarded patients treated with neuroleptics for aberrant behavior were compared with 30 neuroleptic-treated schizophrenics for the presence, topography and risk factors associated with tardive dyskinesia (TD). In the total sample (n = 60), female sex, schizophrenic diagnosis and increasing age were associated with TD. The length of neuroleptic treatment and current neuroleptic dose were not significantly associated with TD. The only topographical difference in TD presentation was that the mentally retarded group had significantly more tongue involvement.     

Prolactin bioassay in schizophrenia before and after neuroleptics.

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.     

MAO activity, csf amine metabolites, and drug-free improvement in schizophrenia

Platelet monoamine oxidase (MAO) activity and amine metabolites in cerebrospinal fluid were compared in 22 schizophrenic patients, 8 of whom improved during a 30-day drug-free period. CSF 5-hydroxyindoleacetic acid and homovanillic acid did not distinguish between drug-free improvers and nonimprovers. However, drug-free improvers had lower platelet MAO activities than did normal controls. The authors suggest that looking at clinical variables in patients with low MAO activity might provide a means of biologically subtyping schizophrenic patients.