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BACKGROUND: Antipsychotics remain the mainstay of drug intervention in the management of schizophrenia. However, long-term treatment with antipsychotics is associated with a variety of movement disorders, the most disabling of which is tardive dyskinesia (TD), which occurs in up to 50% of patients hospitalized with chronic schizophrenia. The pathophysiology of TD is still unclear and no definite treatment exists. Both dopamine receptor supersensitivity and oxidative stress-induced neurotoxicity in the nigrostriatal system are apparently implicated. The pineal hormone melatonin is a potent antioxidant and attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus. Thus, it may have a beneficial effect for both the treatment and prevention of TD. METHODS: Using a double-blind, placebo-controlled, crossover study, we evaluated the efficacy of 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia and TD. The primary outcome measure was the change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. RESULTS: The decrease (mean +/- SD) in AIMS score was 2.45 +/- 1.92 for the melatonin and 0.77 +/- 1.11 for the placebo treatment groups (P<.001). No adverse events or side effects were noted. CONCLUSION: This is the first clinical evidence for efficacy of melatonin in the treatment of TD.

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The first-night effect (FNE) is the tendency for individuals to sleep worse than normal during their first night of polysomnographic sleep evaluation. FNE reflects the adaptive increase of alertness and perhaps the stress resulting from an unfamiliar sleeping environment. This effect is usually absent in patients with chronic schizophrenia. Melatonin (N-acetyl-5-methoxy-tryptamine), the hormone secreted by the pineal gland at night, has been found to improve sleep in elderly patients with insomnia and recently in patients with chronic schizophrenia. The authors used FNE as a marker to explore the neurobehavioral responses of patients with chronic schizophrenia to melatonin treatment. In a randomized, double-blind, crossover trial, 14 patients with chronic schizophrenia were administered melatonin (2 mg in a controlled-release formulation) or placebo for 3 weeks with a 1-week washout between treatment periods. Polysomnography was performed during the last two consecutive nights of each treatment period. The following significant FNEs were observed with melatonin treatment: (1) rapid eye movement sleep latency was longer; (2) sleep efficiency was lower; and (3) the duration of wakefulness during sleep was lower on the first night than on the second night. These effects were not found when the patients received a placebo. The FNE was manifested regardless of whether melatonin was administered before or after the placebo treatment period. For the first time, these results show that melatonin treatment exaggerates FNE in patients with chronic schizophrenia, thereby suggesting an improved ability of these patients to mobilize alertness in unfamiliar surroundings.

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BACKGROUND: Tardive dyskinesia is a severe and disabling side effect of conventional antipsychotic treatment, with incidence rates reaching a high of 50% in chronically institutionalized populations. On the basis of recent studies showing some benefit of antioxidants, we evaluated the effect of melatonin, the most potent naturally occurring antioxidant, on tardive dyskinesia in patients with chronic schizophrenia. METHOD: Nineteen patients (8 men, 11 women), aged a mean +/- SD 74.0+/-9.5 years with chronic DSM-IV schizophrenia of 31.3+/-7.0 years' duration, were randomly assigned in a double-blind, placebo-controlled, crossover trial to receive slow-release melatonin, 2 mg/day, or placebo for 4 weeks. After a 2-week washout period, the patients were switched to the other treatment arm for an additional 4 weeks. The Abnormal Involuntary Movement Scale (AIMS) was administered at baseline, 4 weeks, 6 weeks, and 10 weeks. Regular administration of antipsychotic and other medications was kept unchanged throughout the study. RESULTS: Mean AIMS scores did not change significantly from baseline in either treatment arm. All patients completed the study, and there were no side effects or adverse events. CONCLUSION: Supraphysiologic doses of melatonin do not positively affect tardive dyskinesia. Considering that melatonin is a safe drug, further studies are needed of higher doses and in patients with shorter disease duration before its use in the treatment of tardive dyskinesia is ruled out.

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BACKGROUND: Accumulating evidence indicates decreased melatonin levels in patients with schizophrenia. Insomnia, mainly difficulty in falling asleep at night, is commonly reported in this population. Association of insomnia with low or abnormal melatonin rhythms has been repeatedly documented. Melatonin is an endogenous sleep promoter in humans. We hypothesized that insomnia in patients with schizophrenia may be partially due to diminished melatonin output. In this study, we measured melatonin output in patients with chronic schizophrenia and assessed the effects of melatonin replacement on their sleep quality. METHOD: In a randomized, double-blind, cross-over, clinically based trial, 19 patients with DSM-IV schizophrenia who were treated with the normal treatment regimen were given melatonin (2 mg, controlled release) or placebo for 2 treatment periods of 3 weeks each with 1 week washout between treatment periods (7 weeks total). For measuring endogenous melatonin production, urine was collected from each patient every 3 hours between 9:00 p.m. and 9:00 a.m. Actigraphy was performed for 3 consecutive nights at the end of each period. Activity- and rest-derived sleep parameters were compared for the whole population with treatment arm as the intervening variable. A separate analysis was performed for patients subgrouped into high versus low sleep efficiency. RESULTS: All patients had low melatonin output. Melatonin replacement significantly improved rest-derived sleep efficiency compared with placebo (83.5% vs. 78.2%, p = .038) in this population. Improvement of sleep efficiency was significantly greater (p < .0014) in low-efficiency (80% vs. 67%) than high-efficiency sleepers (88% vs. 90%). In addition, during melatonin therapy, tendencies toward shortened sleep latency (by 40 minutes, p < .056) and increased sleep duration (by 45 minutes, p < .078) were observed in low- but not high-efficiency sleepers. CONCLUSION: Melatonin improves sleep efficiency in patients with schizophrenia whose sleep quality is low.

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BACKGROUND: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone that mediates most of the growth effects of growth hormone. This study tested the hypothesis that recombinant human IGF-1 (rhIGF-1) will induce an anabolic response in malnourished patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: Six CAPD patients with protein-energy malnutrition underwent nitrogen balance studies in a clinical research center for 35 days each. Throughout the study, patients were maintained on their same CAPD regimen prior to hospitalization, and were fed a constant protein and energy intake that was similar to their diet prior to hospitalization. The first 15 hospital days were a baseline period; during the subsequent 20-day period, patients were given subcutaneous injections of rhIGF-1 (100 microg/kg/12 h), except for one patient who received 50 microg/kg/12 h for the first five days, followed by 100 microg/kg/12 h for the following 15 days. RESULTS: During the treatment with rhIGF-1, serum IGF-1 increased by about 100% (P = 0.03), and nitrogen balance became strongly positive (+2.0 g/day, P = 0.015 vs. baseline). This anabolic effect was observed within hours after commencing the rhIGF-1 treatment and was largely caused by a 20% decrease in peritoneal dialysate effluent nitrogen. There was a proportionate reduction in urine nitrogen and serum urea nitrogen. This decrease in nitrogen output was sustained during the entire 20 day of treatment with rhIGF-1. Serum phosphorus decreased significantly during the first several days of rhIGF-1 treatment, whereas serum calcium increased significantly during the rhIGF-1 treatment. Serum potassium and albumin did not change during the rhIGF-1 injections. There was no change in body weight and body composition, as assessed by anthropometry during the baseline or treatment phases of the study. Some patients exhibited minor possible adverse events that included a reduction in blood pressure and transient tachycardia. CONCLUSION: Injections of rhIGF-1 induce a strong and sustained anabolic effect, as indicated by a positive nitrogen balance in CAPD patients with protein-energy malnutrition. rhIGF-1 administration may be an effective method for treating malnutrition in maintenance dialysis patients.

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We demonstrate a significant association between longer CAG repeats in the hKCa3/KCNN3 calcium-activated potassium channel gene and schizophrenia in Israeli Ashkenazi Jews. We genotyped alleles from 84 Israeli Jewish patients with schizophrenia and from 102 matched controls. The overall allele frequency distribution is significantly different in patients vs controls (P = 0.00017, Wilcoxon Rank Sum test), with patients showing greater lengths of the CAG repeat. Northern blots reveal substantial levels of approximately 9 kb and approximately 13 kb hKCa3/KCNN3transcripts in brain, striated muscle, spleen and lymph nodes. Within the brain, hKCa3/KCNN3transcripts are most abundantly expressed in the substantia nigra, lesser amounts are detected in the basal ganglia, amygdala, hippocampus and subthalamic nuclei, while little is seen in the cerebral cortex, cerebellum and thalamus. In situ hybridization reveals abundant hKCa3/KCNN3 message localized within the substantia nigra and ventral tegmental area, and along the distributions of dopaminergic neurons from these regions into the nigrostriatal and mesolimbic pathways. FISH analysis shows that hKCa3/KCNN3 is located on chromosome 1q21.

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Tardive dyskinesia is an involuntary movement disorder developing following treatment with neuroleptics. As many as 50% of chronic psychotic patients develop this disabling condition. No treatment has been found effective for tardive dyskinesia. This study was undertaken to meta-analyze the effects of vitamin E (alpha-tocopherol) reported in the last decade. All studies published since 1987, focusing on vitamin E and tardive dyskinesia are reviewed. Double-blind studies are analyzed using measures of effect and variance as described by secondary analysis of magnitude of effects in pooled data. A total of 223 patients received vitamin E treatment (400-1600 IU/day) for tardive dyskinesia, in 12 studies. A significant subgroup (28.3%) showed a modest improvement. Vitamin E was well tolerated, and only rarely did side effects occur-of no clinical significance. Vitamin E is a safe, well-tolerated compound that may provide some beneficial effects in patients suffering from neuroleptic-induced tardive dyskinesia.

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Instrumental tremorgrams have been used to improve the diagnostic accuracy of various movement disorders, including tardive akathisia. The aim of the present work was to evaluate their place in the diagnosis of neuroleptic-induced tremor and to determine whether they can help to differentiate this disorder from other neuroleptic-induced movement disorders and from other types of tremor. Fourteen psychiatric patients treated with various neuroleptic medications were diagnosed as having neuroleptic-induced tremor on the basis of clinical criteria. They underwent accelerometric recordings following diagnosis. All patients demonstrated upper-limb tremor; four also had involvement of the lower limbs, jaw or tongue. Most demonstrated both resting and postural tremor, the latter being the more prominent. The tremor was mainly rhythmic, regular and sinusoidal. It did not significantly interfere with activities of daily living in the majority of patients, but four did exhibit some degree of impairment. Repeated accelerometric recordings showed constant and regular waveforms and frequencies (between 4 and 7 Hz) in each patient. We conclude that the presence of repeated constant waveforms and frequencies on accelerometric tracings may serve as confirmation of the diagnosis of neuroleptic-induced tremor. In light of the findings of this and other studies, we suggest that tremorgrams may be helpful in differentiating neuroleptic-induced tremor from other neuroleptic-induced movement disorders (e.g., tardive dyskinesia and tardive akathisia) and from psychogenic tremor. Although these techniques may also assist in the differentiation of neuroleptic-induced tremor from some tremor disorders (e.g., asterixis or ataxic tremor), their overall potential to distinguish it from other types of organic tremor is more limited.

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For the first time in Israel, hospitalized mentally ill patients were enabled to participate in the election of the prime minister and members of the Knesset (Israeli parliament) held on May 29, 1996. In a demonstration election held in Yehuda Abarbanel Hospital to teach and prepare the patients to vote, the outcome of the vote for the prime minister was identical to the results of the general public vote. The sample vote results for members of the Knesset were slightly different from those in the actual election. The character of the voting in this sample bolsters arguments for the rights of mentally ill individuals to participate in the basic democratic process of voting and should ease any misgivings felt by some of the public about their ability to vote as rationally as other members of the public.

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The formation of neuronal networks requires axonal growth towards target neurons. A simple set of grammar rules is introduced to describe axonal growth towards target cells situated both at short and long distances from the growing neuron. Growth for short distances is described by growth following the highest gradient of a chemical compound (which is spread by diffusion from the targets). This approach fails to describe long-distance growth, which is addressed by adopting a graph grammar theory for growing trees. With these rules a flexible tool to draw network of neurons by computer can be developed.

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