## 4 Discussion
Circadian dysregulation has been linked to a variety of physical and mental diseases including sleep disorders and schizophrenia [30]. More specifically, schizophrenic patients exhibit irregular pattern of melatonin secretion which is indicative of a disruption in the circadian rhythmicity of melatonin [27]. In addition, recent studies have reported a loss of circadian expression of certain clock genes, including the CLOCK, in patients with schizophrenia [31; 32]. Our review's findings lend further support to the notion that circadian misalignment is implicated in sleep disturbances of schizophrenic patients and that melatonin plays a crucial role in regulating higher-order neurophysiological processes. However, it remains to be clarified whether this association represents a causal pathophysiological mechanism, or the co-existence of two distinct processes which exert their effect through a common, yet unspecified pathway, for example dopaminergic dysregulation [24; 33]. Likewise, the detection of a link between schizophrenia-related sleep disorders and genes implicated in neurotransmitter metabolism (_TH_ and _HNMT_) and signal transduction (_GNB3_ and _BTBD9_) emphasizes the central role of neurotransmission disturbances in the emergence of schizophrenia symptomatology. Tyrosine hydroxylase (TH) is a key-component of dopamine metabolism and has been implicated in schizophrenia, antipsychotic-induced extrapyramidal side-effects and RLS [34; 35; 36]. Histamine-N-methyltransferase(_HNMT_) is another enzyme which is implicated in neurotransmission by inactivating histamine in the central nervous system [37]. Research has shown that histamine is involved in sleep/wakefulness regulation and its levels demonstrate a circadian rhythmicity [38; 39]. Similarly, the G- protein \(\beta 3\) sub-unit (_GNB3_) enhances signal transduction and ion transport [40], and may thus be implicated in dopaminergic and serotoninergic transmission as evidenced by studies linking polymorphisms of _GNB3_ gene to depression, antipsychotic medications' efficacy and neuroleptics-associated weight gain [19; 41; 42]. Finally, as far as _BTBD9_ gene is concerned, it encodes a protein whose exact function has not yet been identified. However, it is broadly expressed in brain structures [43] and it belongs to a family of proteins which regulate ion channels' tetramerization and gating [44], potentially being involved in inter- and intra-neuronal signal transduction. It is worthy of note that after applying the Ingenuity Pathway Analysis, it was found that among the six genes which were relevant to out literature review, two of them, _GNB3_ and _TH_ participate in the same two signaling pathways; Protein Kinase A and Opioid signaling pathways. Protein kinase A (PKA) is an enzyme, activated by cAMP, which alters the activity of target-proteins through the phosphorylation of specific serine or threonine residues, and regulates a variety of physiological procedures in the nervous system including transcription, synaptic transmission and plasticity, etc. Phosphorylation is a very important procedure, as it can effectively control the activity of proteins and affect their structural, thermodynamic, kinetic and regulatory properties [45]. Opioids receptors are G-protein coupled receptors (GPCR) and are divided into four classes of receptors; mu (MOR), kappa (KOR) delta (DOR), and the nociceptin (NOP) [46]. All of them link to inhibitory G-proteins and their activation can be followed by the initiation of intracellular signaling pathways and, through a variety of cellular processes, can lead to a decreased in nerve impulse transmission and an inhibition of neurotransmitter release [47]. The vast majority of the studies included in this review focused on drug-induced sleep disorders, mainly RLS and somnolence. In this respect it is not clear whether their findings reflect a differential pattern of genetic vulnerability to antipsychotic medications' side-effects or a distinct schizophrenia endophenotype.