D.F. Horrobin

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.

Ethyl-EPA in Huntington disease A double-blind, randomized, placebo-controlled trial

Background: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). Methods: A total of 135 patients with HD were randomized to enter a multicenter, double-blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntingtons Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a χ2 test on response, defined as absence of increase in the TMS-4, were performed. Results: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the χ2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. Conclusions: Ethyl-eicosapentaenoate (ethyl-EPA) (purity >95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.

MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment.

A 6-month randomized, placebo-controlled pilot study of the ethyl-ester of eicosapentaenoic acid (ethyl-EPA) was carried out in seven in-patients with advanced (stage III) Huntingtons disease (three on ethyl-EPA, four on placebo; no significant difference in age or sex between the groups). After 6 months all the patients treated with ethyl-EPA improved on the orofacial component of the Unified Huntingtons Disease Rating Scale while all the patients on placebo deteriorated on this scale (p <0.03). Following subvoxel registration of follow-up 3D MRI brain scans with baseline scans, subtraction images showed that while the placebo was associated with progressive cerebral atrophy, the ethyl-EPA was associated with a reverse process. We conclude that treatment with ethyl-EPA is associated with beneficial motor and MRI changes.

Lipid metabolism, human evolution and schizophrenia.

There are only small genetic differences between humans and the great apes. Yet these differences must be very important. Major known differences include the accumulation of subcutaneous fat, the expansion of breasts and buttocks, the growth of the brain and the connectivity of neurons. All these involve lipid metabolism yet, because fat leaves no fossils, lipids are rarely mentioned in discussions of human evolution. This paper attempts to identify some candidate areas of lipid metabolism which may be important in human evolution. It draws attention to abnormalities in phospholipid metabolism in schizophrenia and suggests that these may have proved important in enhancing brain connectivity in the later stages of evolution of modern humans.

MRI changes in multiple sclerosis following treatment with lofepramine and L-phenylalanine

As part of a large, randomized placebo-controlled trial of inpatients with multiple sclerosis (MS), a subsample of 15 underwent cerebral MRI at baseline and 6-months (eight on lofepramine and l-phenylalanine; seven on placebo). Unlike the placebo group, the active group showed a significant reduction in lesion number visible on T1-weighted scans (p < 0.05). The lateral ventricular volume increased, on average, by 1020 mm3 in the untreated group and 600 mm3 in the treated group. In the treated patients the ventricular size change correlated with both change in Gulick MS-related symptoms scale scores (rs = 0.71, p = 0.07) and Gulick MS-related activities of daily living scale scores (rs = −0.83, p = 0.02). It is concluded that treatment with lofepramine and l-phenylalanine is associated with significant MRI changes.