Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

Han, Ying; Yuan, Kai; Zheng, Yong-Bo; Lü, Lin

doi:10.1007/s12264-019-00447-9

Cited by 68 publications

(50 citation statements)

References 162 publications

(193 reference statements)

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“…These neurons release orexin neuropeptides, OXA and OXB, which bind to and activate two Gαq-protein-coupled receptors, OX 1 R and OX 2 R 16 , which, once activated, increase intracellular calcium concentrations 54,55 . Although orexins were originally discovered for their role in regulating sleep and wakefulness 14,22 , they have now been implicated in host of other behaviors, including avoidance behavior 56 , drug-seeking behavior 23,24 , and psychosis 25 . Of interest to the current project, is the ability of both OXA and OXB to dosedependently modulate PVT neuron activity and the ability of a DORA to reverse aberrant dopamine neuron activity when administered directly in the PVT 26,27 .…”

Section: Discussionmentioning

confidence: 99%

“…The orexin system was first discovered as a modulator of sleep and appetite, but recent studies suggest this neuropeptide system plays a pleiotropic role, regulating a variety of biological processes, such as pain, cardiovascular function, and neuroendocrine regulation [19][20][21][22] . Although the orexin system is widespread and diverse in function, recent studies have shown that targeting this system may be beneficial in treating substance use disorder as well as psychosis [22][23][24][25] . Importantly, both OXA and OXB have been shown to dose-dependently increase the firing rate of PVT neurons and increase dopamine neuron population activity, without affecting the firing rate of these neurons in vivo 26,27 .…”

Section: Introductionmentioning

confidence: 99%

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Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

et al. 2021

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Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

et al. 2021

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“…[ 26 , 27 ] Thus, block of the orexin-receptor pathway may be potentially effective for reducing the excitability of brain neurons. [ 28 ] Similar to insomnia, delirium is also a neuroexcitatory symptom. Also, the plasma levels (roughly reflecting the cerebrospinal fluid) of orexin-A, were found to be relatively higher in patients with delirium than those without, although no significant difference was observed.…”

Section: Discussionmentioning

confidence: 99%

Suvorexant for the prevention of delirium

Xu¹,

Cui²,

Shen

et al. 2020

Medicine

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Background: Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences. Methods: Eligible studies were identified by searching online databases of PubMed, EMBASE, and Cochrane Library. The pooled OR was calculated for binary outcomes (e.g., the incidence of delirium, mortality, or adverse events), while standardized mean difference (SMD) were expressed for continuous outcomes (e.g., time to delirium onset, length of stay in hospital and ICU, time on ventilation). Results: Seven studies which comprised 402 suvorexant treatment patients and 487 patients with control treatment were included in this meta-analysis. Overall, pooled analysis indicated the incidence of delirium could be significantly reduced (OR, 0.30; P < .001) and time to delirium onset was significantly lengthened (SMD, 0.44; P = .006) in patients undergoing suvorexant treatment compared with controls. Suvorexant had no beneficial effects on the secondary outcomes [length of stay in hospital (SMD, −0.65; P = .161) and ICU (SMD, 0.34; P = .297), time on ventilation (SMD, 1.09; P = .318), drug-related adverse events (OR, drug-related adverse events (OR, 1.66; P = .319) and mortality (OR, 2.21; P = .261)]. Subgroup analysis also confirmed the benefit of suvorexant on the development of delirium, which was significant in any subgroup. Conclusion: Suvorexant should be recommended for the prevention of delirium in clinic.

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“…Orexin is also thought to play a role in stress response with alterations in orexin found in depression and anxiety ( 214 ). Based on the research finding that orexin levels are increased in CSF of individuals with PD ( 215 ), orexin is thought to have anxiogenic effects, leading to research on orexin-1 and orexin-2 receptor, and dual-receptor antagonists for treatment of anxiety disorders ( 216 ). Suvorexant, an orexin-1 and orexin-2 receptor antagonist, is FDA-approved for primary insomnia, and is under study in PD, comparing the drug to placebo to monitor orexin levels and response to a carbon dioxide challenge (NCT02593682).…”

Section: Novel Treatments For Anxiety Disordersmentioning

confidence: 99%

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

et al. 2020

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Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

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Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

Cited by 68 publications

References 162 publications

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Suvorexant for the prevention of delirium

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

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