*2.3.2 Orexin and schizophrenia*

*Weight Management*

Humans and animals

Humans and animals

**Table 2.**

step in the onset of depression [28].

*Neuroendocrine effects of orexin.*

Animals Administration of orexin antagonists

tration of orexin-A antagonist [36].

leading to functional disorders of neuroplasticity, which is regarded as a cardinal

**Species Interventions Results References**

Humans Orexin administration No effect on ACTH

Humans High orexin levels Insulin resistance and

Animals Orexin administration ↑ ACTH, cortisol Czerwinska et al. [18] Animals Orexin administration ↑ cortisol, aldosterone Malendowicz et al. [19]

and cortisol

obesity

Orexin administration Inhibits prolactin Lyons et al. [21], Samson

Orexin administration ↑ insulin secretion Mediavilla and Risco [25]

Improves glucose tolerance

Patel et al. [20]

Gupta et al. [23], Cigdem

et al. [22]

et al. [24]

Tsuneki et al. [26]

Diurnal variation in orexin serum levels revealed that high orexin levels are occurring at the middle of night. It has been reported that orexin level is significantly decreased in patients with depression in comparison with healthy subjects [29]. But paradoxical high orexin serum levels are seen in some depressed patients, which is normalized by selective serotonin reuptake inhibitors. Since, orexin-A CSF

Long-term antidepressant agents improve orexin serum levels regardless of the type of antidepressant medications [31]. Nevertheless, there are different findings concerning orexin levels in depression. Feng et al. reported that depression is linked to reduction of serotonergic neuronal activity which is responsible for modulation of orexinergic activity [32]. Thus reduction of serotonergic neuronal activity leads to activation of orexin neuroactivity leading to depression. However, orexin levels are significantly reduced in depression compared with healthy control [33].

The initial animal model study observed reduction in the orexinergic neurons by 18% with diminution in size of these neurons in comparison with normal rats. As well, prepro-orexin mRNA expression and orexin-A were reduced compared with

Previous preclinical study revealed a strong connection between low orexin and risk of depression which are inconsistent with previous studies that illustrated hypoactivity of orexinergic neurons in patients with depression since short-term antidepressant therapy improves sleep pattern through increasing and decreasing

Ito et al. showed that administration of orexin-A leads to significant reduction of despair behavior in depression with important hippocampal neurogenesis via upregulation of neuropeptide Y (NPY). These changes are inhibited by co-adminis-

Therefore, orexin levels are different according to the pathophysiology of depression. Low orexin in depressed patients is associated with hypersomnia, whereas high orexin in depressed patients is associated with insomnia and interrupted sleep [17]. Ji et al. illustrated that orexinergic neurons have direct connection to the ventral pallidum (VP) which is concerned with stress response and rewarding system. Orexin stimulates the VP and prevents depressive behavior. Therefore, high orexin in the VP is associated with elevated serum corticosterone serum levels

the expression of mRNA of orexin-A and orexin-B, respectively [35].

levels are negatively correlated with depressive symptoms [30].

**50**

control [34].

The association between orexin and schizophrenia had not been previously explored precisely [38]. Clinical and preclinical findings proposed that orexin and orexin agonist are of great value and useful in treating cognitive deficit in schizophrenia [39]. There are widespread connection and interaction between orexin and dopaminergic neurons in midbrain, thalamocortical region, and amygdala suggesting the potential role of orexinergic neurons in schizophrenia [40].

Modafinil is an atypical dopamine reuptake inhibitor used in the treatment of narcolepsy and antipsychotic drug-induced sleep disorder (**Figure 3**) [41]. Modafinil has been revealed as a complement of drugs in therapy of schizophrenia, and it reduce negative symptoms with no effect on the positive symptoms. Modafinil improves locomotor and psychomotor performances through activation of orexinergic neurons [42].

Therefore, activations of orexinergic neurons by modafinil may be an imperative step for future antipsychotic medications. These findings document that dopaminergic agonists mainly at D1 and D2 receptors modify orexinergic neurotransmissions [43]. Also, dopamine antagonists that cause weight gain lead to activation of orexin pathway, but dopamine antagonists which do not cause weight gain do not activate orexin pathway [44]. Nevertheless, amphetamine which indirectly activates dopamine leads to activation of orexinergic neurotransmission despite induction of weight loss. Moreover, clozapine activates only orexinergic neurons in the prefrontal cortex [45]. Similarly, orexin antagonists abolish olanzapine and haloperidol effect on midbrain dopaminergic neurons, suggesting that orexin is an important neurotransmitter mediates the action of antipsychotic drugs [46]. As well, Chen et al. illustrated that orexin-A is stimulated and upregulated by non-obesegenic antipsychotic drugs [47]. Also, the high orexin level in patients with schizophrenia treated with antipsychotic drugs is regarded as a protective factor against the development and risk of drug-induced metabolic syndrome [48]. Furthermore, orexin agonist like modafinil ameliorates cognitive function, attention, and antipsychoticinduced sedation.
