An Update on Assessment, Therapeutic Management, and Patents on Insomnia

Insomnia is an ordinary situation related to noticeable disability in function and quality of life, mental and actual sickness, and mishappenings. It represents more than 5.5 million appointments to family doctors every year. Nonetheless, the ratio of insomniacs who are treated keeps on being low, demonstrating the requirement for proceeding with advancement and dispersal of effective treatments. Accordingly, it becomes significant to provide a compelling treatment for clinical practice. It indicates a need for the determination of various critical viewpoints for the evaluation of insomnia along with various accessible alternatives for treatment. These alternatives incorporate both nonpharmacological therapy, specifically cognitive behavioural therapy for insomnia, and a number of pharmacological treatments like orexin antagonists, “z-drugs,” benzodiazepines, selective histamine H1 antagonists, nonselective antihistamines, melatonin receptor agonists, antipsychotics, antidepressants, and anticonvulsants. Besides in individuals whose insomnia is due to restless leg syndrome, depression/mood disorder, or/and circadian disturbance, there is insignificant proof favouring the effectiveness of different prescriptions for the treatment of insomnia though they are widely used. Other pharmacological agents producing sedation should be prescribed with care for insomnia therapy because of greater risk of next-day sleepiness along with known adverse effects and toxicities. This review is also aimed at providing an update on various patents on dosage forms containing drugs for insomnia therapy.

Treatment of antipsychotic-induced parkinsonism in schizophrenic patients

Antipsychotic-induced parkinsonism (AIP) is one of the prognostically unfavorable complications of psychopharmacotherapy in patients with schizophrenia. Many studies have investigated various drugs that are used to treat this neurological side effect. This review analyzes drugs that are used and may be perspective for the treatment of AIP. We searched for full-text publications in Russian and English in the following databases: E-Library, PubMed, Web of Science, Springer, using keywords and combined word searches over the past decade (2011—2020). The review covers drugs that are promising for the correction of AIP, including anticholinergic drugs; NMDA receptor antagonists; dopamine receptor agonists; selective inhibitors of monoamine oxidase B; catecholamine transferase inhibitors; melatonin preparations; melatonin receptor agonists; benzodiazepines; herbal preparations traditionally used for the prevention and correction of extrapyramidal syndrome of various etiologies. Currently, a small number of medications are used in clinical practice for the treatment of AIP. However, not all of them are registered in the Russian Federation. Along with the differences in the mechanisms of AIP pathogenesis in specific patients, the limited choice of AIP treatments makes it difficult to solve the problem of adverse neurological complications of psychopharmacotherapy in schizophrenia.

Elimination of the Causes of Poor Sleep Underlying Delirium is a Basic Strategy to Prevent Delirium

: Delirium is a very common but annoying clinical state that interferes with the treatment of background disease and delays recovery. Delirium is a troublesome condition that exhausts not only the patient but also his/her family and healthcare professionals. Since aging is a risk factor for delirium, how to control delirium is an extremely important issue in an aging society. Phenotype of delirium are so diverse that it is difficult to elucidate the mechanism of individual symptoms, but it is clinically well known that maintaining sleep quality is important in preventing and improving delirium. Drugs and factors that are known to disrupt the sleep-wake cycle also overlap with the risk factors for delirium, indicating the close connection between delirium and sleep. Although the sleep-wake cycle is tightly regulated by many neurotransmitters and hormones, and the role of each substance in this cycle is being elucidated in detail. It is well known that acetylcholine is one of the most important neurotransmitter involved in wakefulness, and anticholinergic drugs reduce rapid eye movement sleep. Anticholinergic drugs are also the major drug causing drug-induced delirium. Several clinical studies have reported that melatonin receptor agonists reduce delirium. Some clinical studies have examined the relationship between delirium and environmental factors that interfere with sleep, such as noise and brightness. The purpose of this review is to organize the cause of poor sleep underlying delirium and propose strategies to prevent delirium, based on rich neurological and pharmacological findings of sleep. We consider that elimination of causes of sleep deprivation underlying delirium is one of the most effective prevention strategies for delirium.

Delirium

The fundamental concept of delirium is altered consciousness and its fluctuation. Sleep–wake cycle disturbance is one of the common clinical features of delirium. Evidence suggests that disturbed sleep plays a key role in pathogenesis of delirium and restoration of sleep–wake cycle provides a clinical opportunity for prevention of delirium. It is essential to evaluate clinical factors such as medical illnesses, psychiatric disorders, substance use disorders, medication side effects, and environmental factors leading to sleep disturbance in delirium. In addition, multicomponent nonpharmacologic delirium prevention interventions are effective in reducing delirium incidence and preventing falls, with trend toward decreasing length of stay, but nonsignificant reductions in mortality. Approaches to regulating functions of melatonin or orexin on sleep–wake cycle lead to pharmacological interventions, and preventive effects of melatonin receptor agonists and an orexin receptor antagonist on delirium have been shown. This evidence suggests importance of treating sleep–wake cycle disturbance to prevent delirium. More research is warranted to develop comprehensive clinical strategies, targeting sleep disturbance to predict, prevent and treat delirium.

Insomnia in general practice: the role of doxylamine

The general practitioner encounters all three forms of insomnia: idiopathic, chronic and acute. Idiopathic and chronic patients should receive specialized care by neurologist, psychiatrist or sleep disorders specialists because they require deep differential diagnosis and complex treatment. Acute insomnia patients need quick help to prevent the negative health impact and chronisation of sleep disruption. In theRussian Federation, the GP has access to three kinds of sleep drugs: benzodiazepines, melatonin receptor agonists, antihistamines. However, modern benzodiazepines are unavailable inRussiaand older benzodiazepines can lead to dependence. Melatonin receptor agonists are not effective enough for acute insomnia. Among available antihistamines, doxylamine is the most convenient option in clinical practice. Doxylamine has a good profile of safety and efficacy, it is included in the local clinical guidelines for insomnia. Also, doxylamine is the only sleep drug available for pregnant women. This paper presents a portrait of doxylamine and comments on its clinical niches and contraindications. We also discuss the pharmacology of doxylamine, drug interactions, and prescription modes. There are also three clinical case studies, presenting the typical acute insomnia patients and logic for their evaluation, underlining key clinical features of this disorder.

Structure-based discovery of potent and selective melatonin receptor agonists

Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1. Moreover, two most potent agonists, including 21 and a close derivative of melatonin, 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.