Is melatonin beneficial in schizophrenia? prog neuro psycho biol. June.2013


Insomnia can become a significant clinical problem among individuals with schizophrenia. Patients with insomnia report lower mean scores on all quality of life domains independent of comorbid de- pression, side-effects related to antipsychotic medication, or distress. Treatment of underlying disorder ( ie with antipsychotics)  usually improves sleep.

Jaime M. Monti and colleagues review the current understanding of this area in this article.

Cycles of sleep and wakefulness is maintained by two component processes, the circadian ( intrinsic circadian timing and synchronization of body functions to the light–dark cycle of day and night) and the homeostatic or evoked component  (that regulates the “need for sleep” which builds up during wakefulness and dissipates during sleep).

Circadian timing apparatus comprises oscillators  at cellular level and a central pacemaker generator located in the hypothalamic suprachiasmatic nuclei (SCN).Rhythms are driven by the self-regulatory interaction of a set of clock genes and their protein products.Expression of proteins from one positive and one negative loop oscillates, forming a circadian rhythm.

Studies show abnormalities in the circadian organization of sleep–wake cycles in  schizophrenia.Melatonin profiles help to detect circadian misalignments with the sleep–wake cycle or the desynchronization to the light–dark cycle.

Schizophrenic patients show reduced sleep efficiency, longer sleep latencies and increased number of nighttime awakenings. Measuremnets of melatonin show differences among the timing of the circadian melatonin profile, the timing of the major sleep and wake episodes and the external day–night cycle.

Several studies have shown melatonin produces inhibition of dopamine release ,reduced dopamine content ,increased turnover  and alteration of dopamine receptor activation.Melatonin has protective effects on dopaminergic systems.(direct free-radical scavenger and indirect anti-oxidant). It is possible that Melatonin may have additional benefits in schizophrenia.

Melatonin is a hypnotic and a chronobiotic and is recommnded for the treatment of insomnia, parasomnia and circadian rhythm sleep disorders  in patients over 55 years. Melatonin is effective in sleep entrainment but its efficacy in maintaining sleep has not been consistently demonstrated. Prolonged release preparations of melatonin or melatonin agonists with a longer duration of action may address this issue (ramelteon, agomelatine, tasimelteon and TK-301 ).

Studies suggest that melatonin improves sleep efficiency in patients with schizophrenia whose sleep quality is poor. (Shamir et al. (2000).Suresh Kumar et al. (2007) .Borba et al., 2011  showed that adding Ramelteon  to stable antipsychotic regimen decreased total cholesterol and ratio of cholesterol to high-density lipoprotein, as well as showing a trend toward reduction in fat in the abdominal and trunk areas.

First and second generation antipsychotics, except risperidone, are consistently associated with an increase in total sleep time and sleep efficiency in both patients and normal controls .Patients treated with clozapine had remarkably highly ordered rest-activity cycles, whereas patients on classical antipsychotics such as haloperidol or flupentixol had minor to major circadian rhythm abnormalities.

Conclusions: Sleep-onset and maintenance insomnia is a characteristic feature of schizophrenic patients .The majority of studies show that slow wave sleep and REM Latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged.  Deficits in melatonin may cause overactivity of the striatal dopamine system leading both to insomnia and to increased positive symptoms. Preliminary studies with melatonin suggest that it may be a useful treatment for sleep disturbances in schizophrenia and further investigation of its utility in treating schizophrenic symptoms is warranted.

Summary of the article:

Sleep and circadian rhythm dysregulation in schizophrenia.

Monti JM, BaHammam AS, Pandi-Perumal SR, Bromundt V, Spence DW, Cardinali DP, Brown GM.

Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jun 3;43:209-16

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