A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer's Disease.

BACKGROUND: Piromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer's disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60-85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (https://clinicaltrials.gov/ct2/show/NCT02615002). OBJECTIVES: This study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS). DESIGN: Variant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking "responders" (i.e., >0.125 change from baseline in the cNTB) as cases and "non responders" as controls, using a Cochran-Armitage trend test. SETTING: 58 outpatient clinics in the US. PARTICIPANTS: 371 participants were randomized in the trial; 107 provided informed consent for genotyping. RESULTS: The GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1x10 -4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, "non-carriers" improved significantly with piromelatine compared to placebo on the ADAS-Cog14 ( 2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI. CONCLUSIONS: The 2q12 (2:107,510,000-107,540,000) 5-6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.

Exonal elements and factors involved in the depolarization-induced alternative splicing of neurexin 2.

The neurexin genes (NRXN1, NRXN2, and NRXN3) encode polymorphic presynaptic proteins that are implicated in synaptic plasticity and memory processing. In rat brain neurons grown in culture, depolarization induces reversible, calcium-dependent, repression of NRXN2α exon 11 (E11) splicing. Using Neuro2a cells as a model, we explored E11 cis elements and trans-acting factors involved in alternative splicing of NRXN2α E11 pre-mRNA under basal and depolarization conditions. E11 mutation studies revealed two motifs, CTGCCTG (enhancer) and GCACCCA (suppressor) regulating NRXN2α E11 alternative splicing. Subsequent E11 RNA affinity pull-down experiments demonstrated heterogeneous nuclear ribonucleoprotein (hnRNP) K and hnRNP L binding to this exon. Under depolarization, the amount of E11-bound hnRNP L (but not of hnRNP K) increased, in parallel to NRXN2α E11 splicing repression. Depletion of hnRNP K or hnRNP L in the Neuro2a cells by specific siRNAs enhanced NRXN2α E11 splicing and ablated the depolarization-induced repression of this exon. In addition, depolarization suppressed whereas hnRNP K depletion enhanced NRXN2α expression. These results indicate a role for hnRNP K in regulation of NRXN2α expression and of hnRNP L in the activity-dependent alternative splicing of neurexins which may potentially govern trans-synaptic signaling required for memory processing.

Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers.

BACKGROUND: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M. OBJECTIVES AND METHODS: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning. RESULTS: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found. CONCLUSIONS: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators.

Sleep and sleep disturbances: biological basis and clinical implications.

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.

Ca2+ -dependent splicing of neurexin IIalpha.

Neurexins are synaptic adhesion proteins encoded by 3 genes (NRXN1, NRXN2, and NRXN3) each transcribed from 2 promoters to yield longer (alpha) and shorter (beta) forms. The primary gene transcripts undergo extensive alternative splicing leading to products that may differ in synaptic coupling properties. Here we show that depolarization of neurons modulates splicing of NRXN2alpha, particularly at splice sites 1 and 3. Furthermore, we demonstrate that exclusion of exon 11 at splice site 3 is calcium-dependent. These data indicate neuronal activity-dependent splicing of NRXN2alpha. This dynamic process may be important for maintenance of mature neuronal circuits.

Role of protein kinase Calpha in melatonin signal transduction.

Melatonin induces nuclear exclusion of the androgen receptor (AR) via activation of protein kinase C (PKC). The specific members of the PKC superfamily involved in AR nuclear exclusion were investigated in prostate cancer PC3 cells stably transfected with the wild-type androgen receptor (PC3-AR). PKCalpha was essentially cytoplasmic whereas PKCbeta and PKCepsilon were essentially membranal, suggesting their constitutive activity in the PC3-AR cells. Melatonin treatment induced membrane association of PKCalpha in a time and dose dependent manner. The PKCalpha and PKCbeta1 specific inhibitor GO6976 and the PKCbeta isoform-specific inhibitor hispidin had no effects on AR localization under basal conditions. However, GO6976 but not hispidin negated the melatonin-mediated nuclear exclusion of the AR. These data indicate that PKCalpha activation is a critical step in AR nuclear exclusion by melatonin. They also imply that PKCalpha-activation is a potentially effective way to control of the AR activity in prostate cancer cells.

Melatonin and sleep in aging population.

The neurohormone melatonin is released from the pineal gland in close association with the light-dark cycle. There is a temporal relationship between the nocturnal rise in melatonin secretion and the 'opening of the sleep gate' at night. This association, as well as the sleep promoting effect of exogenous melatonin, implicates the pineal product in the physiological regulation of sleep. Aging is associated with a significant reduction in sleep continuity and quality. A decreased production of melatonin with age is documented in a majority of studies. Diminished nocturnal melatonin secretion with severe disturbances in sleep/wake rhythm has been consistently reported in Alzheimer's disease (AD). A recent survey on the effects of melatonin in sleep disturbances, including all age groups, failed to document significant and clinically meaningful effects of exogenous melatonin on sleep quality, efficiency and latency. However, in clinical trials involving elderly insomniacs and AD patients suffering from sleep disturbances exogenous melatonin has repeatedly been found to be effective in improving sleep. The results indicate that exogenous melatonin is more effective to promote sleep in the presence of a diminished production of endogenous melatonin. A MT1/MT2 receptor analog of melatonin (ramelteon) has recently been introduced as a new type of hypnotics with no evidence of abuse or dependence.

Subjective assessment of the effects of CNS-active drugs on sleep by the Leeds sleep evaluation questionnaire: a review.

The Leeds sleep evaluation questionnaire (LSEQ) comprises ten self-rating 100 mm line analogue questions concerned with sleep and early morning behaviour. A literature search identified 83 studies in peer-reviewed journals that reported the use of the LSEQ for psychopharmacological investigations of drug effects on self-reported aspects of sleep. High internal consistency and reliability of the questionnaire have been demonstrated. Findings from studies involving a variety of psychoactive agents indicated that the LSEQ was able to quantify subjective impressions of sleep and waking and the effects of drugs in healthy volunteers, depressed and insomnia patients. In accordance with their known activity profile nocturnal administration of sedative hypnotic agents and antihistamines induced dose-related improvements in self-reported ease of getting to sleep, and quality of sleep but a decrease in alertness and behavioural integrity the following morning. Psychostimulants, on the other hand, impaired subjective ratings of sleep and increased early morning alertness. Antidepressants and certain anxiolytic agents improved both self-reported sleep aspects and early morning alertness. Treatment effects measured by the LSEQ corresponded to those measured for the same drugs by other assessment methods. These data indicate that the LSEQ is a robust and reliable instrument for psychopharmacological evaluations. Self-evaluations of sleep, as obtained by the LSEQ, can therefore provide consistent and meaningful measures for estimating the effectiveness of sleep modulators and sedative-hypnotic drugs.

Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study.

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.

Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity.

BACKGROUND: The androgen receptor (AR) promotes growth and functionality of androgen sensitive benign and cancer tissues. The pineal hormone melatonin is an androgen protagonist in vivo and in vitro. The interference of melatonin in the AR cascade was explored. METHODS: The effects of melatonin on AR expression, level, agonist and androgen-response element (ARE) binding, reporter gene activity and intracellular localization were explored in prostate cancer LNCaP cell line. RESULTS: Melatonin increased immunoreactive AR cells in the absence and presence of dihydrotestosterone. Despite this increase and maintenance of AR agonist binding capacity, the androgen-induced reporter gene activity and suppression of AR-mRNA were attenuated. Immunocytochemical analysis and subcellular fractionation studies revealed nuclear exclusion of AR by melatonin. CONCLUSIONS: The melatonin-mediated nuclear exclusion of the AR may explain the attenuation of AR activity in the prostate cancer cells. This is the first demonstration of a hormone-induced mislocalization of the AR in prostate epithelial cells and may represent a novel route for regulating AR activity.

Circadian rhythm sleep disorders: pathophysiology and potential approaches to management.

An intrinsic body clock residing in the suprachiasmatic nucleus (SCN) within the brain regulates a complex series of rhythms in humans, including sleep/wakefulness. The individual period of the endogenous clock is usually >24 hours and is normally entrained to match the environmental rhythm. Misalignment of the circadian clock with the environmental cycle may result in sleep disorders. Among these are chronic insomnias associated with an endogenous clock which runs slower or faster than the norm [delayed (DSPS) or advanced (ASPS) sleep phase syndrome, or irregular sleep-wake cycle], periodic insomnias due to disturbances in light perception (non-24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder). Synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland is induced at night, directly regulated by the SCN. Melatonin can relay time-of-day information (signal of darkness) to various organs, including the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light. In addition, melatonin facilitates sleep in humans. In the absence of a light-dark cycle, the timing of the circadian clock, including the timing of melatonin production in the pineal gland, may to some extent be adjusted with properly timed physical exercise. Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Under conditions of entrainment to the 24-hour cycle, bright light in the early morning and avoidance of light in the evening should produce a phase advance (for treatment of DSPS), whereas bright light in the evening may be effective in delaying the clock (ASPS). Melatonin, given several hours before its endogenous peak at night, effectively advances sleep time in DSPS and adjusts the sleep-wake cycle to 24 hours in blind individuals. In some blind individuals, melatonin appears to fully entrain the clock. Melatonin and light, when properly timed, may also alleviate jet lag. Because of its sleep-promoting effect, melatonin may improve sleep in night-shift workers trying to sleep during the daytime. Melatonin replacement therapy may also provide a rational approach to the treatment of age-related insomnia in the elderly. However, there is currently no melatonin formulation approved for clinical use, neither are there consensus protocols for light or melatonin therapies. The use of bright light or melatonin for circadian rhythm sleep disorders is thus considered exploratory at this stage.

Temporal partitioning among diurnally and nocturnally active desert spiny mice: energy and water turnover costs.

Nocturnal Acomys cahirinus and diurnally active A. russatus coexist in hot rocky deserts. Diurnal and nocturnal activity exposes them to different climatic challenges. A doubly-labelled water field study revealed no significant differences in water turnover between the species at all seasons, reflecting the adaptations of A. russatus to water conservation. In summers the energy expenditure of A. russatus tended to be higher than that of A. cahirinus. Energy requirements of A. cahirinus in winter are double than that of A. russatus, and may reflect the cost of thermoregulating during cold nights.

Melatonin production in healthy infants: evidence for seasonal variations.

The objective of this study was to determine the normal range of nocturnal urinary excretion of the major melatonin metabolite, 6-sulfatoxymelatonin (6SMT) in a large sample of healthy full-term infants (8 and 16 wk old) and assess whether the endogenous production of melatonin changes with season. 6SMT was assessed in urine samples extracted from disposable diapers removed from full-term, 8- (n = 317) and 16-wk-old (n = 93) infants over the nocturnal period (19:00-08:00 h). In addition, 6SMT was assessed in 8-wk-old (n = 35) healthy infants over the entire 24-h period. 6SMT was determined by an ELISA assay. 6SMT excretion at 8 wk of age exhibited diurnal variations with (mean +/- SD) 61 +/- 18% of the daily production excreted during the nocturnal period regardless of season. The nocturnal 6SMT values in the entire cohort (at 8 as well as 16 wk of age) were found to significantly depart from normal distribution (Kolmogorov-Smirnov test). A normal distribution was obtained using a natural base logarithmic (ln) transformation of the data. The normal range (2.5-97.5 percentile of the ln 6SMT excretion per night) was thus defined as 4.66-8.64 (106-5646 ng/night) for 8-wk-old and 5.19-9.67 (180-15,820 ng/night) for 16-wk-old infants. A significant effect of the month of birth on 6SMT production at the age of 8 wk was found (ANOVA, p < 0.002) with maximal levels produced by infants born in June (summer solstice) and minimal excretion in infants born in December (winter solstice). Short-photoperiod-born infants excreted on average about threefold less 6SMT compared with long-photoperiod-born infants (t test, p = 0. 01). The seasonal variations were no longer present at 16 wk of age. No effect of breast-feeding at the time of sampling on seasonality of 6SMT was found. Normal ranges for the nocturnal urinary excretion of 6SMT in full-term infants at 8 and 16 wk of age are defined. This enables the evaluation of nocturnal 6SMT excretion as a prognostic and diagnostic factor for child development. The strong effect of season on the normal excretion of nocturnal 6SMT at 8 but not 16 wk of age suggests prenatal influence of the photoperiod on the ontogeny of melatonin.

Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin.

The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h) was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were blocked by GF- 109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization and androgen responses in target cells.

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.

First-night effect of melatonin treatment in patients with chronic schizophrenia.

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.

Low melatonin production in infants with a life-threatening event.

This study compares the urinary excretion of the main melatonin metabolite, 6-sulfatoxymelatonin (6SMT), in infants who have and have not experienced a life-threatening event (ALTE). 6SMT was assessed in the following groups of infants: 15 infants with ALTE for whom home monitoring had been recommended, 15 infants who had had an abrupt cyanotic apneic event but did not require mouth-to-mouth resuscitation, 15 siblings of those who had died from sudden infant death syndrome (SIDS), and 35 age-matched healthy comparison infants. All 80 infants were between 48 and 58 weeks of postconceptional age. On a double-blind basis, the total amount of 6SMT excreted over 24 hours and the diurnal rhythm in the rate of 6SMT excretion were assessed using urine samples taken from disposable diapers (nappies). The mean daily excretion of 6SMT was significantly lower in the ALTE (1,588 ng/24 hour) than in the comparison infants (3,961 ng/24 hour). No such difference was found between the infants with a cyanotic apneic event (3,268 ng/24 hour) and the SIDS siblings (2,962 ng/24 hour). The diurnal 6SMT rhythms in the ALTE infants were characterized by lower 24-hour mean and amplitude values, whereas the time of peak and nadir excretion rates (07:15 to 08:45 hours and 14:45 to 16:15 hours respectively) was similar in all four infant groups. Follow-up of the ALTE infants, performed 6 to 8 weeks later (59 to 66 weeks of postconceptional age), revealed that 6SMT excretion increased in all of them, suggesting a delayed ontogeny rather than permanent deficiency of melatonin production in ALTE.

Is melatonin treatment effective for tardive dyskinesia?

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.

Melatonin improves sleep quality of patients with chronic schizophrenia.

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.