Steven R. Hirsch

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years.

OBJECTIVE--To evaluate a novel approach to the prophylaxis of schizophrenic relapse characterised by administration of brief courses of neuroleptic for the earliest non-psychotic signs of relapse (prodromal symptoms). DESIGN--Two year follow up of subjects randomised, double blind, to receive either active (control group) or placebo (intermittent group) depot neuroleptic medication. Both groups received brief courses of oral neuroleptic when prodromal symptoms or relapse occurred. SETTING--Psychiatric outpatient department, Charing Cross Hospital, London. SUBJECTS--54 Stable patients in remission who met the American Psychiatric Associations DSM-III criteria for schizophrenia on the basis of case notes. MAIN OUTCOME MEASURES--Survival without relapse, survival without hospitalisation, point prevalence of extrapyramidal side effects and tardive dyskinesia, structured assessment of social functioning (social adjustment scale II), and frequency of prodromal symptoms. RESULTS--Of 19 relapses recorded over two years, 10 (53%) were preceded by non-psychotic prodromal signs. Survival rates for both relapse and hospitalisation were worse with intermittent treatment than continuous treatment over the two year follow up: 92% of controls and only 54% of patients given intermittent treatment survived the two year period without hospitalisation. Prolonged or frequent relapses as well as episodes of prodromal symptoms were more frequent with intermittent treatment. Lower scores for extrapyramidal side effects were recorded in the intermittent treatment group, but periodic assessments of social functioning failed to show any social advantages from this. CONCLUSION--The findings are at variance with a previous report of one year follow up in this cohort and attest to the superiority of continuous depot neuroleptic prophylaxis in preventing both psychotic and neurotic or dysphoric morbidity in schizophrenia.

Depression in schizophrenia: recognition and management in the USA

The recognition of depression as a distinct syndrome within schizophrenia is a relatively recent development. The International Survey of Depression in Schizophrenia was designed to evaluate current clinical practice and prescribing trends in the management of the depressive component of schizophrenia. A 48-item questionnaire, comprising fixed-response questions and questions stimulated by case scenarios, was distributed to 37513 psychiatrists in the USA. A total of 43484 psychiatrists in Canada, Australia and 21 European countries also received the questionnaire. A total of 1128 US psychiatrists responded. Analysis of the data revealed that US psychiatrists identify symptoms of depression in approximately one-third of patients with schizophrenia, and largely appreciate the magnitude of the resultant burden on patients and their families. Responses to questions regarding treatment approaches and case scenarios demonstrated that the level of adjunctive prescribing of antidepressants in the USA is often higher than in other regions. Levels of awareness of depression in patients with schizophrenia and recognition of the need for effective management appear to be high among US psychiatrists. However, more than a quarter of these specialists rarely or never prescribe adjunctive antidepressant medications. Disparities in treatment approaches varying from the existing scientific evidence base underscore the need for further investigation into ways of optimizing the management of this serious coexisting condition.

Impairment in frontal but not temporal components of mismatch negativity in schizophrenia

Impairment in mismatch negativity (MMN) potentials is a robust finding in schizophrenia. While previous studies suggested that MMN in man is generated by a single dipole source bilaterally in the primary auditory cortex, more recent data modified this assumption by showing differential modulation of MMN components over the frontal and temporal scalp. Here we used a roving standard experiment to record mismatch potentials to tone duration deviants with the aim to detect robust temporal and frontal mismatch components. Fourteen schizophrenic patients with normal intelligence and without overt cognitive deficits and age- and sex-matched controls were studied. In agreement with previous findings MMN recorded from the frontal scalp was markedly attenuated in patients. However, in contrast to previous reports, positive mismatch potentials of normal magnitude were recorded from temporal (mastoid) electrodes. This finding raises the possibility of a selective impairment in multiple mismatch generators in schizophrenia and may lend support for the notion of impaired cortico-cortical connectivity in schizophrenia.

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical outcome at one year.

A study was conducted to investigate a novel approach to the prophylaxis of schizophrenic relapse. The treatment strategy comprised brief intermittent courses of neuroleptic agents begun as soon as non-psychotic symptoms believed to be early signs of relapse appeared. Fifty four stable, remitted outpatients meeting the American Psychiatric Associations DSM-III criteria for schizophrenia were randomised double blind to receive brief intermittent treatment with either active or placebo depot neuroleptic injections. Only three patients given placebo injections and two controls were admitted to hospital during one year of follow up. Eight (30%) of the patients given placebo injections and only 2 (7%) of the controls, however, had a recurrence of schizophrenic symptoms. Patients given placebo injections experienced fewer extrapyramidal side effects and showed a trend towards a reduction in tardive dyskinesia. Dysphoric and neurotic symptoms were identified before eight out of 11 relapses, and these symptoms were more frequent in patients given placebo depot injections. These results suggest a viable but not necessarily better alternative to continuous oral or depot treatment for less ill, chronic, stabilised schizophrenics based on the early treatment of putative prodromal symptoms of relapse.

Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production

Cellular origins of methylarginines are not precisely known but the presence of free methyl and dimethylarginines in the brain were reported. We have investigated the circulating concentrations of asymmetrical dimethylarginine NG,NG-dimethylarginine (ADMA), NG,NG-dimethylarginine (SDMA), nitrate and nitrite levels in drug naive first episode schizophrenic patients and matched control subjects. Three of those patients were treated with neurolepties for 3 months. Plasma ADMA levels increased significantly but nitrate levels were significantly low compared to control subjects. Drug treatment apparently lowered ADMA levels and increased nitrate levels in plasma. Methylation of arginine to methylarginines may have an important role in regulating signal transduction through the nitric oxide system in the brain, and suggest novel therapeutic targets.

Effect of propranolol and phenothiazines on electrodermal orienting and habituation in schizophrenia.

Bilateral electrodermal orienting responses were measured to repeated auditory stimuli in schizophrenic patients and controls. In 3 studies phasic activity to moderate intensity sounds of patients on no drugs or phenothiazines was predominantly hyper- or hypo-responsive. Controls showed moderate or slow habituation. Propranolol was found to facilitate habituation in slow habituators and to reinstate responses in half of non-responders, especially when given as the sole drug. The effects seldom had a counterpart in changes in non-specific responses or levels of skin conductance. Modulatory influences on stimulus and response processing and on lateral asymmetries in responses may underlie propranolols efficacy in treating schizophrenia.

A volumetric biochemical niacin flush-based index that noninvasively detects fatty acid deficiency in schizophrenia

(1) It is possible to investigate aspects of phospholipid-related signal transduction in humans noninvasively using the niacin skin flush test. (2) Patients with schizophrenia have previously been reported to show a reduced flushing response. (3) The aim of this study was to devise a comprehensive index of cutaneous response to the niacin test, incorporating aqueous methyl nicotinate concentration and time, and to test this index in schizophrenia. (4) A discrete approximation to a continuous volumetric index, which we have named the volumetric niacin response (VNR), was devised. Its value was measured in 27 patients with DSM-IV schizophrenia and 26 age- and sex-matched normal controls. (5) The mean value of the VNR in the patients with schizophrenia (16.26) was significantly smaller than that of 26.77 in the normal controls (P<.0004). (6) With a threshold value for the VNR of 21, the test differentiated well between schizophrenia and normal controls (P=.002) with a sensitivity of 78% and a specificity of 65%. (7) The present results confirm that the flushing response is reduced in schizophrenia, and show that calculation of the VNR is an effective means of allowing the total response in different patients or patient groups to be readily compared.

Cholecystokinin messenger RNA deficit in frontal and temporal cerebral cortex in schizophrenia

No consistent markers of pathology have been established yet in schizophrenia, although abnormalities in frontal and temporal structures are indicated from positron emission tomography (PET) studies. We have used in situ hybridization to investigate functional changes focusing on the quantitation of cholecystokinin (CCK) mRNA, whose product has been shown to be depleted in schizophrenia. CCK mRNA and G(o) alpha-subunit mRNA were measured in eight schizophrenic and eight control subjects matched for age and postmortem delay. The study revealed a marked decrease in CCK mRNA of 83% in frontal cortex (BA10) and 63% in superior temporal cortex (BA22) in schizophrenia with no change in G(o) alpha-subunit mRNA in either region. This study was extended to a further series of eight patients to determine the reproducibility of this effect and to quantitate laminar changes in CCK mRNA. Quantitation of CCK mRNA in inner cortical layers (layer V/VI) was carried out in frontal and temporal cortex in comparison with G(o) alpha-subunit mRNA, which is also concentrated in this region; this study showed a similar selective decrease in CCK mRNA in frontal and temporal cortex of 47% and 51%, respectively. A confirmatory decrease in CCK mRNA was also obtained by slot blot analysis of CCK mRNA in tissue extracts of frontal cortex by reference to levels of beta-tubulin mRNA, CCK mRNA:beta-tubulin mRNA was significantly decreased (67%) in schizophrenic tissue compared to control tissue. There was no significant correlation of CCK mRNA loss with neuroleptic treatment or duration of illness.

The platelet polyphosphoinositide system in Schizophrenia: The effects of neuroleptic treatment

Signal transduction, mediated by the thrombin-stimulated polyphoshoinositide (PPI) turnover was studied in platelets from 44 schizophrenic patients and 33 healthy volunteers. The stimulated generation of inositol phosphates in the schizophrenic group was significantly greater than that in the control group. There was a lack of correlation between this augmented response and a variety of clinical parameters. The response in 9 drug-naive schizophrenic patients was not significantly different from that in controls. The response was significantly augmented in patients receiving neuroleptic treatment and in patients who had been off neuroleptics for at least 4 months. These results indicate that neuroleptic treatment may produce a long-term modification of signal transduction via the PPI system. Further studies are required to elucidate the exact nature of this modification and to explore the possibility that this effect of the neuroleptics may provide a novel approach to understanding the neurochemistry of schizophrenia and to monitoring the neuroleptic treatment.

Parental abnormalities of verbal communication in the transmission of schizophrenia.

A carefully controlled comparison of communication defects and deviances in parents of schizophrenics and neurotics was undertaken using the 41-category Rorschach manual of Singer and Wynne. Subjects were tested and scored blindly and scoring was shown to be reliable. Although a statistically significant difference was found between the two groups, the marked overlap of the distribution of scores found in this study is not compatible with theories advanced by other authors concerning communication abnormality in parents of schizophrenics. Evidence is presented which provides a more parsimonious explanation of the difference between groups and leads to a hypothesis which would explain the failure of this study to confirm the striking differences between groups reported by previous workers.