Eve C. Johnstone

Adverse effects of anticholinergic medication on positive schizophrenic symptoms

In a series of 36 patients with acute schizophrenia flupenthixol dosage was blindly adjusted to give a fixed level of sedation. Patients were than randomly allocated to procyclidine or placebo. The patients receiving procyclidine experienced more positive schizophrenic symptoms and less severe extrapyramidal features by comparison with placebo patients. Blood levels of prolactin and flupenthixol estimated by radioimmunoassay were not significantly changed by the addition of procyclidine. Flupenthixol dosage and levels and prolactin levels were significantly related. There was no significant association between clinical and laboratory measures, with the exception that a curvilinear (inverted U) relationship was demonstrated between flupenthixol levels and antipsychotic and extrapyramidal effects. This relationship may be due to the fact that, in a study of this design, patients resistant to the effects of neuroleptic medication are likely to be given the highest doses. The findings support earlier claims that anticholinergic medication has adverse effects on schizophrenic symptoms.

POSSIBLE VIRUS IN SCHIZOPHRENIA AND SOME NEUROLOGICAL DISORDERS

Cerebrospinal fluid from 13 of 38 patients with schizophrenia had a cytopathic effect in cultures of MRC5 cells. The cytopathic agent passed a 100 nm but not a 50 nm filter and was unaffected by heat at 56 degrees C for 30 min, treatment with chloroform, or the presence in cultures of bromodeoxyuridine. The agent could not be propagated serially in a satisfactory manner but its properties were those of a virus. A similar cytopathic effect was induced by cerebrospinal fluid from 8 of 11 patients with serious or chronic nervous system disease but only 1 of 25 patients with surgical or general medical conditions.

Dopaminergic mechanisms in schizophrenia: The antipsychotic effect and the disease process

Abstract A controlled trial of the isomers of flupenthixol in acute schizophrenia demonstrated that only the α-isomer possesses antipsychotic activity. The result is consistent with the hypothesis that dopamine receptor blockade is the only requirement for therapeutic activity. However, the onset of the therapeutic effect was slow, and delayed by at least two weeks by comparison with the establishment of receptor blockade as indicated by increased prolactin secretion. In post-mortem brain tissue dopamine turnover was found not to be increased in patients with schizophrenia. However, receptor density, assessed by the spiroperidol-binding technique, was significantly increased, and this increase was present in five patients who apparently had not received neuroleptic medication for at least one year before death.

Neuroendocrine changes in acute schizophrenia as a function of clinical state and neuroleptic medication.

Changes in levels of prolactin, growth hormone, luteinizing hormone, and follicle stimulating hormone in serum, and testosterone in plasma, have been studied in 38 patients with acute schizophrenic illnesses in a 4-week double-blind comparison of the 2 isomers of flupenthixol and placebo. Only prolactin showed changes which could be related either to changes in clinical state or to the effects of medication. Prolactin levels increased during treatment with the therapeutically active alpha-isomer of flupenthixol but were unchanged with the inactive beta-isomer and placebo. Although there was a significant relationship between prolactin level and antipsychotic effect in patients on alpha-flupenthixol, in the individual case prolactin level was not a strong predictor of therapeutic response; and in patients on inactive medication changes in prolactin level could not be related to sympton change. There was a time lag of at least 2 weeks between the increase in prolactin secretion in patients on alpha-flupenthixol and the therapeutic effect attributable to medication. This delay suggests that if the antipsychotic effect is dependent upon dopamine receptor blockade it is not a direct consequence of this action. Perhaps dopamine receptor blockade permits other, and slower, changes to take place and it is these changes, rather than dopamine receptor blockade itself, which are reflected in clinical improvement.

The coincidence of schizophrenia and Parkinsonism: some neurochemical implications

The hypothesis has recently been advanced that increased activity of central dopaminergic mechanisms underlies the symptomatology of the schizophrenias. The evidence that dopaminergic transmission in the corpus striatum is impaired in Parkinsons disease suggests that observations on the relationship between Parkinsons disease and schizophrenia may illuminate the patholophysiology of the latter disease. Four cases are reported in which an illness with schizophrenic features developed in the setting of longstanding Parkinsons disease; attention is drawn to earlier reports of schizophrenic illnesses occurring as postencephalitic sequelae in the presence of a parkinsonian syndrome. These observations appear to conflict with the view that increased dopamine release in the striatum is necessary for the expression of schizophrenic psychopathology, but do not exclude the possibility that increased transmission may occur at other dopaminergic sites in the brain, for example the nucleus accumbens, tuberculum olfactorium or cerebral cortex. Similarly the dopamine receptor blockade hypothesis of the therapeutic effects of neuroleptic drugs cannot be maintained with respect to an action in the striatum in view of the differences between the actions of thioridazine and chlorpromazine in this structure, but may be tenable for actions at extra-straital sites.

Controlled Trials of Electroconvulsive Therapy

Electroconvulsive therapy, like every physical treatment in psychiatry with the exception of penicillin for GPI, was introduced on an entirely empirical basis. It became widely adopted before systematic evidence on its efficacy had been collected, and a clinical lore on its indications was built upon a minimal background of objectivity. Slowly a body of evaluation through clinical trials has accumulated, focusing first upon the procedure as a whole and more recently upon the element-the convulsion-that is widely believed to be necessary for the therapeutic effect.

Neurotransmitter Enzymes and Receptors in Post-mortem Brain in Schizophrenia: Evidence that an Increase in D2 Dopamine Receptors is Associated with the Type I Syndrome

The functional psychoses, including schizophrenia, were distinguished from the organic psychoses by Kraepelin and Bleuler, who considered that intellectual impairment was not a significant feature of the former group of illnesses. However, some recent work suggests that defects of temporal orientation, often considered a hallmark of the organic psychoses, do occur in schizophrenia (Crow and Mitchell, 1975; Crow and Stevens, 1978) and that in some chronic schizophrenic states intellectual impairments are associated with structural changes in the brain (Johnstone, Crow, Frith, Husband and Kreel, 1976). Such conditions may be an exception rather than the rule and it is commonly assumed that the defect in most schizophrenic illnesses has a chemical rather than an anatomical basis. It is plausible that the primary change is a disturbance of neurohumoural transmission, and in the past 25 years a number of hypotheses have been proposed (Table 1).

The northwick park «functional» psychosis study. Phase 2 : maintenance treatment

This study blindly compared the value as a prophylaxis against relapse over a period of up to 6 years, of pimozide, lithium, pimozide+lithium and placebo of 30 patients with functional psychotic illness who had achieved satisfactory recovery on the same medications during an acute episode of illness. Pimozide was significantly more effective than placebo pimozide in preventing relapse (p=0.01). No significant effect for lithium was found. There was a significant deterioration in positive symptoms (p < 0.05) as relapse approached, but otherwise features of impending relapse were not detected. It is concluded that prophylactic neuroleptic medication is of value even in patients who have recovered from an acute episode of psychosis without active neuroleptics. Such an acute response does not identify a group of patients who can be predicted to do well without continued medication.

Depression in Functional Psychosis

Despite a recent reappraisal of the concept of Unitary Psychosis (1), the Kraepelinian dichotomy of functional psychotic illnesses remains the theoretical and clinical orientation of most psychiatrists. The validity of this in defining separate disease entities is, of course, crucially based on outcome. Thus in establishing a diagnosis, Kraepelin urged consideration of... n“the entire picture... especially... the changes which it undergoes in the course of the disease” (2). nSuch longitudinal methodology has, however, largely been abandoned in favour of the cross-sectional evaluation of symptomatology. Schneider, for example, stated that: n“Psychiatric diagnosis must be based on the presenting situation, not on the course taken by the illness” (3).