Increased levels of cytosolic phospholipase A2 in dyslexics.

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.

Niacin skin flush in schizophrenia: a preliminary report.

The aim of this pilot study was to evaluate a potential skin test for schizophrenia based on the effect of aqueous methyl nicotinate (AMN) on the production of prostaglandin D2 (PGD2) from skin macrophages and the resultant cutaneous capillary vasodilatation. Four concentrations of AMN were applied topically to the forearm skin in patients and controls, and any resulting vasodilatation was rated as redness after 5 min. The test was carried out on 38 patients with schizophrenia diagnosed according to DSM-III-R criteria, and 22 normal control subjects. At all concentrations of AMN, the schizophrenics were highly significantly different from the controls. One concentration gave the greatest degree of differentiation: at this concentration at 5 min, 83% of schizophrenics but only 23% of controls had a zero or minimal response to AMN. The skin flushing seen after oral administration of nicotinic acid is due to the same reaction, and this has been normal in those with affective illness and neurosis; cyclo-oxygenase inhibitors, e.g., aspirin, give a false-positive result (failure of vasodilatation). This result is consistent with the concept of reduced membrane arachidonic acid levels in schizophrenia. This test may contribute to the reliable diagnosis of schizophrenia.

Membrane fatty acids, niacin flushing and clinical parameters.

Clinical definitions of schizophrenia are unreliable and difficult to use. The niacin flush test, which involves prostaglandin-induced vasodilatation, offers a method of exploring essential fatty acid metabolism in schizophrenic patients and may serve to define a subgroup of patients. In a multicentre study of schizophrenic patients with negative symptoms, we have examined the clinical accompaniments of the niacin response. Patients failing to flush with niacin showed significantly reduced levels of arachidonic and docosahexaenoic acids. Conversion from non-flushing to flushing during the 6 month supplementation period was predicted by an increase in arachidonic acid levels in red blood cell membranes irrespective of nature of supplementation. In this study, patients were selected for their negative symptoms and, therefore, it was not surprising that further measures of negative or positive symptoms did not predict flushing. However, an increased score for affective symptoms was significantly associated with a positive flush response. The stability of the niacin test needs to be examined in relation to the periodicity of symptoms in schizophrenia and manic depressive illness. New information on the anandamide system suggests that it may be associated with periodic phenomena and should be investigated in relation to the niacin test.

Possible relevance of phospholipid abnormalities and genetic interactions in psychiatric disorders: the relationship between dyslexia and schizophrenia.

The fatty acids of cell membrane phospholipids are essential for normal membrane structures, for the functioning of membrane-bound and membrane-associated proteins and for normal cell-signalling responses. In dyslexia, there is evidence for reduced incorporation of docosahexaenoic acid and arachidonic acid into cell membranes, while in schizophrenia, there is evidence for an increased rate of docosahexaenoic acid and arachidonic acid loss from membranes because of enhanced phospholipase A2 activity. The presence of both defects will cause a much greater degree of abnormality than either one alone. It is hypothesized that unequivocal clinical schizophrenia may occur when both genes are present in the same individual. The dyslexia gene along will produce dyslexia while the schizophrenia gene alone may produce bipolar or schizoaffective disorders. These proposals could explain: 1. The reduced asymmetry of the brain, especially of the planum temporale in both schizophrenia and dyslexia; 2. The schizotypal personality characteristics of dyslexics; 3. The increased risks of dyslexia in families with a schizophrenic proband; 4. The increased risks of bipolar and schizoaffective disorders in families with a schizophrenic proband; 5. The earlier onset and possibly increased severity of both disorders in males since females have a lower requirement for arachidonic acid and docosahexaenoic acid; 6. The absence of selective pressure against schizophrenia since reproduction would be impaired only when the schizophrenic gene coexisted with a dyslexic gene. The schizophrenic gene alone might even lead to improved reproductive performance.

The membrane hypothesis of schizophrenia.

The phospholipid structure of neuronal membranes is essential for normal functioning of the nervous system. Evidence is accumulating that phospholipid metabolism in both brain and red blood cells may be disturbed in schizophrenia. In particular, in patients with negative symptoms, levels of arachidonic acid and docosahexanoic acid in red blood cell membrane phospholipids are severely abnormal. The membrane hypothesis of schizophrenia may represent a new and fruitful paradigm for future research.

A red cell membrane abnormality in a subgroup of schizophrenic patients: evidence for two diseases.

There are several reports of abnormalities in fatty acids in brain and blood phospholipids in schizophrenic patients. In order to see if the broad categories of negative and positive schizophrenia were linked to specific changes in fatty acids, an initial study was made of patients showing severe symptoms of these two types. Thirteen patients had persistent chronic negative symptoms of apathy and withdrawal while 12 patients had persistent positive symptoms of either thought disorder or hallucinations and delusions. The positive and negative groups were matched for length of history and drug exposure. Negative symptoms were associated with high levels of saturated fatty acids and low levels of long-chain unsaturates in red blood cell (RBC) membranes, while the positive symptom patients showed the opposite picture. In order to see if this bimodal distribution would be found in patients diagnosed as schizophrenic but without classification of symptoms, we examined frequency distribution curves for fatty acids in plasma and in RBC membranes in 68 individuals classified as schizophrenics and 259 normal individuals. A bimodal distribution was found for 20- and 22-carbon unsaturated fatty acids in RBC membranes from the schizophrenics; the same fatty acids in normal RBC membranes showed an unimodal distribution.

Essential fatty acids in plasma phospholipids in schizophrenics.

Blood samples were taken from schizophrenics and control patients in three different centers. The phospholipids were extracted from plasma and their fatty acid composition analyzed. Similar and consistent differences between schizophrenics and controls were observed at all three centers. The n-6 essential fatty acid levels were significantly reduced, whereas n-3 essential fatty acids were elevated.

Repeated automated assessment of abstinent male alcoholics: essential fatty acid supplementation and age effects.

A double-blind trial carried out with alcohol-dependent males randomly allocated to n-6 essential fatty acid (EFA) supplementation or placebo capsules over a 6-month period incorporated a battery of automated neuropsychological tests. Results from problem-solving and perceptual motor speed tests are used. The effect that EFA supplementation had on recovery over 6 months of abstinence is shown, as well as the tests in which younger (aged 20-39) alcohol-dependent males differ from the older (aged 40-59) subjects.

Lithium prophylaxis of recurrent affective disorders.

The mode of action of lithium is reviewed in the light of advances in the understanding of calcium channelling and calmodulin-activated Ca ATPase. The relevance to changes in receptor sensitivity is discussed.

Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind, controlled trial.

A detailed analysis of the results of a multi-centre clinical trial shows that, while the relapse rate following recovery from an operationally defined depressive illness was smaller among patients subsequently treated with either amitryptiline or lithium than with a placebo, there was no clinically significant difference between the prophylactic efficacy of the 2 antidepressants. An account is given of the relative adverse effects of the treatments, and the implications of the findings are discussed.

Plasma lithium levels and therapeutic outcome in the prophylaxis of affective disorders: a retrospective study.

Patients receiving prophylactic lithium therapy for primary affective disorder during a four year period were studied for recurrence of affective illness. Patients who had affective episodes during this period did not differ from those who remained well in age, sex or diagnosis. Those with a favourable outcome had spent significantly less time at serum lithium levels above 0.9 mmol/litre than those who had a recurrence of affective episodes.

The efficacy of cognitive therapy in depression: a treatment trial using cognitive therapy and pharmacotherapy, each alone and in combination.

We report an extensive study which compares cognitive therapy, antidepressant drugs and a combination of these two, in depressed patients seen either in general practice or an out-patient department. One-hundred and forty patients were screened for primary major depression and 64 patients completed the trial. All were rated on seven measures of mood, including independent observer-rated and self-rated depression and scales of anxiety and irritability. Patients were randomly assigned to cognitive therapy, antidepressants or a combination of the two. The antidepressant drug group did less well in both hospital and general practice and combination treatment was superior to drug treatment in both hospital and general practice. In general practice, cognitive therapy was superior to drug treatment. The presence of endogenous features did not affect response to treatment. The results are discussed in terms of Beck's cognitive theory of depression and factors of presumed causal importance of depression in general practice.

Choline uptake in patients with Alzheimer pre-senile dementia.

Serum and CSF choline levels were measured in 12 patients with pre-senile Alzheimer's disease before and 1 hour after administration of 1.5 g choline chloride or 25 g lecithin granules. Serum choline levels were increased threefold and CSF choline levels by 72%. CSF choline levels in the untreated Alzheimer patients did not differ significantly from age-matched controls. In 35 neurological controls, CSF choline levels increased with age (R = 0.64, p less than 0.001). Choline influx into erythrocytes from 10 male and 10 female Alzheimer patients did not differ significantly from 40 male and 43 female controls. Choline influx into erythrocytes was not related to age or sex, although the range of values was greater (p less than 0.05) in females than in males. Our results indicate that there is no impairment of choline transport into CSF or erythrocytes in patients with pre-senile Alzheimer's disease.

Physostigmine and arecoline: effects of intravenous infusions in Alzheimer presenile dementia.

Physostigmine (0.25 mg-1 mg), arecoline (2 and 4 mg) and saline were administered intravenously over 30 minutes in a randomized double blind design to 11 patients with a clinical diagnosis of Alzheimer presenile dementia. Significant improvement was seen on a picture recognition test with physostigmine 0.375 mg and arecholine 4 mg. A trend towards improvement was also seen with physostigmine 0.25 mg and 0.75 mg, and arecholine 2 mg. For the majority of the patients improvement was only slight but in two patients it was clear cut and consistent.

Mortality on lithium.

A register of patients receiving lithium in the Edinburgh and Lothian area of Scotland has been kept by the Medical Research Council Brain Metabolism Unit since 1967. Using this register, information was obtained on 784 patients receiving lithium for a period of up to 115 months (97.4% of the population available for study). 33 patients died during the period of study due predominantly to cardiovascular causes or to suicide. There was nothing to suggest that long-term exposure caused more deaths than short-term exposure and the pattern of mortality resembled that found in other studies of manic-depressive illness, i.e. the majority of deaths occurred in the early stages of follow-up.

Lithium neurotoxicity. I. The concentration of lithium in dopaminergic systems of rat brain determined by flameless atomic absorption spectrophotometry.

Severe neurotoxicity has been reported in patients receiving combinations of lithium and butyrophenones and halogenated phenothiazines and the suggestion has been made that lithium is preferentially concentrated in dopamine systems in brain. Conventional flame atomic absorption spectrophotometry does not allow analysis of sufficiently small samples of brain tissue to allow accurate association with specific transmitter systems, although previous reports have suggested that lithium is concentrated in the striatum. A method has been developed using flameless atomic absorption spectrophotometry to allow accurate measurement of lithium concentrations in 10--100 ng fresh weight of brain tissue. Using this technique in experiments where rats were fed lithium over a period of three weeks, we could not confirm a direct association of lithium with an area predominetly served by dopamine transmitters.