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 Huntington's 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 chi2 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 chi2 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.

Low blood selenium concentrations in schizophrenic patients on clozapine.

AIMS: To compare plasma and red-cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders. METHODS: Plasma and red-cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations. RESULTS: Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups. CONCLUSIONS: Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.

A randomised, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids.

Huntington's Disease (HD) is a serious dominantly inherited neurodegenerative disorder for which there are no current treatments. Open label and animal studies have suggested that highly unsaturated fatty acids (HUFAs) may be beneficial. Seventeen patients with HD were entered into a randomised, placebo-controlled, double blind trial of HUFA therapy. Patients were assessed on the Rockland-Simpson Dyskinesia Rating Scale (RSDRS) and the Unified Huntington's Disease Rating Scale (UHDRS). On the RSDRS and the UHDRs motor scale patients on HUFA treatment improved while those on placebo deteriorated, with a significant difference between the two groups on the RSDRS. A similar trend was noted on the UHDRS functional performance scales. Little change was seen on the neuropsychology scales. There were no treatment-related adverse events. This is the first time that a significant improvement has been noted in a randomised trial in HD. The results are consistent with open label observations; a second placebo-controlled study in end-stage patients, and a study in a transgenic mouse model of HD.

Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington's disease.

Transgenic R6/1 mice incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of the Huntingtin gene responsible for Huntington's disease. They develop late-onset neurological deficits in a manner similar to the motor abnormalities of the disorder. As essential fatty acids are phospholipid components of cell membranes which may influence cell death and movement disorder phenotype, R6/1 and normal mice were randomised to receive a mixture of essential fatty acids or placebo on alternate days throughout life. Over mid-adulthood, topographical assessment of behaviour revealed R6/1 transgenics to evidence progressive shortening of stride length, with progressive reductions in locomotion, elements of rearing, sniffing, sifting and chewing, and an increase in grooming. These deficits were either not evident or materially diminished in R6/1 transgenics receiving essential fatty acids. R6/1 transgenics also showed reductions in body weight and in brain dopamine D(1)-like and D(2)-like quantitative receptor autoradiography which were unaltered by essential fatty acids.These findings indicate that early and sustained treatment with essential fatty acids are able to protect against motor deficits in R6/1 transgenic mice expressing exon 1 and a portion of intron 2 of the Huntingtin gene, and suggest that essential fatty acids may have therapeutic potential in Huntington's disease.

Cue dependent right hemineglect in schizophrenia: a kinematic analysis.

OBJECTIVES: Schizophrenia may result from disturbed attentional processes and/or defective internal cueing. Attention for subsequent action within a cued movement task was therefore studied, testing specific hypotheses of hemispheric dysfunction and of impaired interhemispheric communication. METHOD: Fifteen patients with schizophrenia and 15 matched controls were either cued or uncued when moving a pen to a target on their right or left side with their right or left hand. Pen tip position was sampled at 200 Hz on a WACOM SD420 graphics tablet for subsequent kinematic analysis. RESULTS: Patients with schizophrenia were slower initiating rightwards movements without a cue. Patients also exhibited reduced abductive/adductive differences in the shape of their movement trajectories, implying differences in interhemispheric communication. CONCLUSIONS: It is speculated that schizophrenia is a form of cue dependent right hemineglect.

Response programming in patients with schizophrenia: a kinematic analysis.

Schizophrenia may involve disturbed subcortical mechanisms or anomalous functional asymmetries. We therefore examined any anomalies of functional asymmetry in a kinematic analysis of a cued sequential movement task previously found to be sensitive to basal ganglia dysfunction. Twenty patients with schizophrenia and 20 matched controls used preferred or non-preferred hand to connect a series of targets on a WACOM SD420 graphics tablet, in response to the pattern of illumination of light emitting diodes (LEDs). Movements were to be initiated with or without an external cue as to target location. Patients with schizophrenia exhibited relatively normal functional asymmetries, but had programming deficits, taking longer to initiate (i.e. self generate) movements in the absence of an external cue. The movements of patients with schizophrenia were more variable and less efficient, resembling those seen in Huntington's disease. Results supported a hypothesis of disturbance at some level in fronto-subcortical circuitry in schizophrenia.

Mental illness, physical abuse and burden of care on relatives: a study of acute psychiatric admission patients.

As mental health care policies increasingly emphasize treatment and care in community settings, there has been concern over the burden that families of mentally ill people might suffer as a result. We conducted a study of the prevalence of abuse faced by relatives of patients admitted during a 6-month period to the acute psychiatric unit of a busy general hospital, who had previously been living with a relative. Patients and their relatives were assessed using semi-structured interview schedules. The experience of burden and the specific experiences of abuse since the onset of their relative's illness were recorded. In total, 32 (32%) of the 101 relatives had been struck on at least one or two occasions. Verbal abuse, threats and temper outbursts were reported by over 50% of the relatives. Principal correlates of abuse were diagnosis, concurrent drug misuse and a poor pre-morbid relationship between carer and patient.

Schizophrenia, tardive dyskinesia and essential fatty acids.

Several reports have indicated that people suffering from schizophrenia show an associated abnormality in levels of certain essential fatty acids (EFAs) in blood cells. Similar abnormalities have also been noted in association with the presence of tardive dyskinesia (TD). In order to study this further, 72 patients with the diagnosis of schizophrenia or schizoaffective disorder were examined to assess the relationship between psychiatric status, movement disorder (TD) and relative levels of the n-3 and n-6 essential fatty acids in red blood cell membranes and plasma. Patients were followed up over the next 4.5 years to determine whether or not changes in clinical state showed any systematic relationship to changes in essential fatty acid levels. We hypothesised that patients with schizophrenia would show persistently lowered levels of n-6 and n-3 series essential fatty acids, compared with normal controls. We further hypothesised that this abnormality would be greater in the presence versus absence of TD and the dominance of negative rather than positive symptoms. The only consistent findings were that lower levels of linoleic acid and higher levels of dihomogamma-linolenic acid characterised the patient population compared with control subjects but there was considerable variability in patients' EFA profile.

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.

Use of gamma-linolenic acid in the treatment of schizophrenia and tardive dyskinesia.

There is good background evidence to suggest that essential fatty acids and their eicosanoid derivatives may play a role in schizophrenia and in with tardive dyskinesia. Trials involving treatment with essential fatty acids, or eicosanoids or drugs which stimulate eicosanoid synthesis have shown modestly promising results. Particularly favourable outcomes in both schizophrenia and tardive dyskinesia were associated with combined treatment using essential fatty acids and nutritional supplements.

A double-blind trial of essential fatty acid supplementation in patients with tardive dyskinesia.

This study reports the results of a trial of essential fatty acid (EFA) supplementation in psychiatric patients (predominantly schizophrenics) with movement disorders. Evidence of EFA deficiency in these patients was observed. The antidyskinetic effect of EFA supplementation was marginally significant but not clinically important. However, active treatment produced highly significant improvements in total psychopathology scores and schizophrenia subscale scores, and a significant improvement in memory.

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.

HIV virus, prostaglandins and essential fatty acids; a suggested mechanism for T helper cell penetration.

Prostaglandins and or its precursors are present in certain body fluids. It has been suggested that critical concentrations of PGE are essential for the HIV to penetrate a lymphocyte. Certain clinical implications of this hypothesis have been discussed.

Mood, memory, and motor performance and the severity of tardive dyskinesia.

This study tested the hypothesis that the features of tardive dyskinesia were associated with motor slowing, memory impairment, and depressive apathy all of which are considered to characterize the so-called subcortical dementias. In a sample of 48 psychiatric patients all fulfilling research criteria for tardive dyskinesia and without other signs of organic illness age-independent correlations were observed between severity of orofacial dyskinesia and measures of memory, motor performance and mood providing some empirical support for the hypothesis.

A controlled trial of prostaglandin E1 precursor in chronic neuroleptic resistant schizophrenic patients.

The postulated deficiency of prostaglandin E1 series (PGE1) in schizophrenia has been investigated in a controlled therapeutic trial. Twenty-one inpatients with a schizophrenic illness resistant to neuroleptic drug treatments were randomly assigned to one of three treatment conditions in a blind controlled trial of dihomo-gammalinolenic acid (DHLA), a PGE1 precursor. Patients received depot neuroleptic medication and DHLA capsules, placebo depot medication and DHLA capsules, or placebo depot medication and placebo capsules. No marked treatment effects were noticed on ratings of the patients' behaviour or symptomatology, though some clinical effects were noted in dyskinetic patients. Abnormalities in red blood cell lipids were observed in the patients entering the trial, suggesting that further investigation of an EFA/prostaglandin deficiency hypothesis in schizophrenia is worth pursuing.

A clinical assessment of zuclopenthixol dihydrochloride (Clopixol tablets) in the treatment of psychotic illness.

An open, multi-centre study was carried out in 69 patients with an acute psychotic episode to assess the efficacy and side-effects of treatment with oral zuclopenthixol dihydrochloride. Patients were treated until the acute episode was considered terminated by the clinician and, although dosage could be adjusted to allow optimum clinical response, the majority received 25 mg zuclopenthixol dihydrochloride 3-times daily throughout the trial period. Assessments were made before and during treatment using the BPRS and CGI rating scales and a check-list of side-effects. The results showed that 55 (80%) patients had a successful response to treatment. Almost half (33) of the patients responded fully to the drug within 3 weeks and by the end of 5-weeks' treatment this had increased to over 70% (49). A further 6 patients responded after 6 to 9 weeks of treatment. The drug was generally well tolerated and the majority of patients had either no side-effects or side-effects which did not overtly affect performance.

The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and schizophrenia.

Three long-stay, hospitalised schizophrenics who had failed to respond adequately to conventional drug therapy were treated with gamma-linolenic acid and linoleic acid in the form of evening primrose oil. They became substantially worse and electroencephalographic features of temporal lobe epilepsy became apparent. In all three the clinical state dramatically improved when carbamazepine, the conventional therapy for temporal lobe epilepsy was introduced. It can be extremely difficult to distinguish on clinical grounds between schizophrenia and temporal lobe epilepsy, and electroencephalographic studies do not always reveal an abnormality in the temporal lobe syndrome, unless additional procedure such as sphenoidal electroencephalography is undertaken. A trial of therapy with gamma-linolenic acid may prove of considerable value in distinguishing between these two states, so allowing specific therapy to be introduced.