Abstract

A molecular clock in the suprachiasmatic nucleus of the anterior hypothalamus, which is entrained by the dark-light cycle and controls the sleep-wake cycle, regulates circadian rhythms. The risk of developing mental disorders, such as schizophrenia, has long been linked to sleep abnormalities. Additionally, a common aspect of mental disorders is sleep disturbance, which has a direct impact on the intensity of the symptoms and the quality of life of the patient. This relationship can be explained by gene alterations such as CLOCK in schizophrenia which are also important components of the physiological circadian rhythm. The function of dopamine and adenosine in circadian rhythm should also be noted, as these hypotheses are considered to be the most popular theories explaining schizophrenia pathogenesis. Therefore, determining the presence of a causal link between the two can be key to identifying new potential targets in schizophrenia therapy, which can open new avenues for clinical research as well as psychiatric care. We review circadian disruption in schizophrenia at the genetic, metabolic, and clinical levels. We summarize data about clock and clock-controlled genes’ alterations, neurotransmitter systems’ impairments, and association with chronotype in schizophrenia patients. Our findings demonstrate that in schizophrenia either homeostatic or circadian processes of sleep regulation are disturbed. Also, we found an insufficient number of studies aimed at studying the relationship between known biological phenomena of circadian disorders and clinical signs of schizophrenia.

Introduction

Circadian rhythms are about 24-h variations in physiology and behavior that have developed through the course of phylogeny to help organisms anticipate daily environmental changes like the light/dark cycle. The suprachiasmatic nucleus (SCN), located in the anterior region of the hypothalamus, contains a molecular clock that regulates circadian rhythms and is entrained by the dark-light cycle. Circadian locomotor output cycles kaput protein (CLOCK), brain and muscle ARNT -like 1 (BMAL1), period circadian regulators 1 and 2 (PER1 and PER2), and cryptochrome circadian regulators 1 and 2 (CRY1 and CRY2) are some of the core clock genes that make up the molecular clockwork. The transcription-translation feedback loop that controls these genes oscillates every 24 h (Caba et al., 2018; Takahashi, 2017).

Almost every cell in the body contains this fundamental clock machinery (Dibner et al., 2010). A network of cell-autonomous circadian oscillators controls rhythmic outputs owing to the coordination of peripheral clocks by the master circadian pacemaker in the SCN. The principal time cue or “zeitgeber” for the entrainment of the clock to environmental changes is a perception of light input directly from the retina by SCN through the retinohypothalamic tract. The sleep-wake cycle is one of these rhythms governed by the circadian system, but it is also regulated by physiological sleep pressure, which builds up during waking and decreases during sleep (Ashton and Jagannath, 2020; Kandeger et al., 2021). Peripheral clock genes are also entrained by various time cues such as feeding rhythms and daily activity. Altered signaling of time cues may change the rhythms of both peripheral and central clock genes and even result in their uncoupling (Fedchenko et al., 2022).

Conclusions and future perspectives

Circadian rhythms have evolved throughout phylogeny to allow organisms to predict daily environmental changes, such as the light/dark cycle. Additionally, important to consider is its role in sleep regulation. Sleep disturbances are a common feature of several psychiatric pathologies such as schizophrenia. These disorders and their association with sleep disturbances can emerge as a potential therapeutic target and warrant further investigation. We demonstrated that in schizophrenia either homeostatic or circadian processes of sleep regulation are disturbed. Patients with schizophrenia show a higher prevalence of circadian rhythm disturbances in comparison to the general population.

In conclusion, the potential link between being born at certain times of the year and increased risk of developing schizophrenia has been extensively studied. Studies have suggested that exposure to high levels of UVR at certain times, as well as disruptions of circadian rhythms due to factors such as season of birth, socioeconomic status, and sleep disturbances during pregnancy, may be a risk factor. However, recent research has indicated that the month of conception, rather than the month of birth, may be more critical in the development of schizophrenia. Moreover, changes in eating behavior and meal timing can lead to changes in the circadian release of endocrine hormones.