Melatonergic Agonist Research Articles

Circadian aspects in nonpharmacologic and pharmacologic treatment of insomnia.

Insomnia disorder is a frequent sleep disorder leading to significant health and economic consequences. It has been proposed that individuals with insomnia may experience compromised deactivation systems of arousal, leading to a chronic state of hyperactivation of arousal known as hyperarousal, along with instability in the flip-flop system. Such disruptions may have a primarily impact on the sleep homeostatic drive process. Insomnia may indeed be associated with a disruption in the body's internal clock, known as chronodisruption. Despite the differentiation established in diagnostic nosology between insomnia disorder and circadian rhythm disorders, there is a significant body of evidence suggesting a complex interplay and frequent co-occurrence between these two conditions. In particular, circadian factors can predispose individuals to insomnia disorders, as well as precipitate and perpetuate their symptoms. Accordingly numerous pieces of evidence suggest that both pharmacologic and nonpharmacologic options for treating insomnia can have a resynchronization effect on circadian rhythms. The first-line treatment for chronic insomnia, according to current guidelines, is cognitive behavioral therapy for insomnia while pharmacologic interventions comprise of benzodiazepine receptor agonists also known as Z-drugs and short- to medium-acting benzodiazepines, melatonergic agonists such as ramelteon and melatonin 2mg prolonged release, and dual orexin receptor antagonists such as daridorexant, suvorexant, and lemborexant. At the same time, certain therapies recommended for circadian rhythm disorders can be utilized as adjunctive treatments for insomnia. Therefore, this chapter will discuss the circadian aspects of insomnia disorder and of its therapeutic approach. Furthermore, the effects of chronobiologic interventions, recommended for the treatment of circadian rhythm sleep-wake disorders, will be examined in individuals afflicted with chronic insomnia.

LİPOPOLİSAKKARİT İLE İNDÜKLENMİŞ HİPOKAMPAL TOKSİSİTEDE RAMELTEON'UN ETKİSİ

Objective
 Despite the advances in medicine, sepsis still remains
 a major health problem worldwide and brain tissue is
 one of the structures damaged in the early period of
 sepsis. Neuroinflammation (NI) is considered as the
 main mechanism in septic brain injury. Ramelteon
 (RML) is a non-selective (MT1 / MT2) melatonin
 receptor agonist and was approved by the FDA in 2005
 with the indication of insomnia. RML shows relatively
 higher affinity for both receptor subtypes among other
 melatonergic agonist drugs.
 Material and Method
 Twenty-eight male Wistar Albino rats were used
 to investigate the protective effect of RML on
 lipopolysaccharide (LPS) induced NI. Control, LPS (5
 mg/kg, intraperitoneally), RML (8 mg/kg, orally) and
 LPS + RML (45 minutes before LPS) groups were
 created. Six hours following the last drug administration,
 rats were sacrificed. Blood for hemogram analysis and
 cortical and hippocampal tissues for histopathological
 evaluation were collected.
 Results
 LPS increased white blood cell and neutrophil/
 lymphocyte ratio (NLR) while it decreased lymphocyte
 and platelet counts. RML decreased NLR and
 increased platelet counts significantly. In histochemical
 evaluation, marked inflammatory cell infiltration and
 apoptosis were observed in both hippocampal and
 cortical areas of LPS group. RML decreased the
 inflammatory response and apoptotic bodies in these
 areas.
 Conclusion
 RML may be protective on LPS-induced NI observed in
 hippocampus via anti-inflammatory and anti-apoptotic
 mechanisms.

The Effect of Agomelatine in Behavioral and Psychological Symptoms of Dementia.

Moderate and severe behavioral and psychological symptoms of dementia (BPSD) often need medical treatment to improve symptoms. Agomelatine is a selective melatonergic (MT1/MT2) agonist that has normalizing effects on disturbed circadian rhythms and disrupted sleep-wake cycles. Its activity of 5HT-2C receptor antagonism is associated with lessening depression and anxiety and increasing slow-wave sleep. Based on past clinical records and current findings it suggests that agomelatine can improve BPSD for patients. This retrospective cohort study was designed to compare the BPSD before and after using agomelatine. Records of dementia cases who had ever received agomelatine treatment for BPSD in a general hospital setting during the past 2.5 years were identified and reviewed. Scores from before and after 3 months of treatment with agomelatine were collected for Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI) to compare and analyze the difference of psychological and behavioral symptoms pre- and post-agomelatine used. Records of 144 cases of dementia with BPSD who had ever used agomelatine from January 2015 to June 2017 were collected. All of the 112 cases had BPRS and CGI scores, of which 75 cases had additional NPI scores. Among these 112 cases, the BPRS and CGI scores were significantly improved in all types of dementia. NPI scores indicated that the use of agomelatine alleviated obvious symptoms and decreased overall distress, especially in the depression/poor mood, anxiety, and sleep/night behavior. It is consistent with an effective result of agomelatine in improving BPSD.

The melatonergic agonist agomelatine ameliorates high fat diet-induced obesity in mice through the modulation of the gut microbiome

Background and purposeMelatonin has shown beneficial effects on obesity, both in humans and experimental models, via regulating the altered circadian rhythm and thus ameliorating the gut dysbiosis associated with this metabolic condition. However, its clinical use is limited, mostly due to its short half-life. Agomelatine is an agonist of the melatonin receptors that could be used to manage obesity and offer a better profile than melatonin. Experimental approachMale C57BL/6 mice were fed a high fat diet and orally treated for five weeks with agomelatine, or melatonin or metformin, used as control drugs. Metabolic profile, inflammatory status, vascular dysfunction and intestinal microbiota composition were assessed. Key resultsAgomelatine lessened body weight gain, enhanced glucose and lipid metabolisms, and improved insulin resistance. It also reduced the obesity-associated inflammatory status and endothelial dysfunction, probably linked to its effect on gut dysbiosis, consisting of the restoration of bacterial populations with key functions, such as short chain fatty acid production. Conclusions and implicationsAgomelatine can be considered as a novel therapeutic tool for the management of human obesity and its associated comorbidities.

Melatonin and melatonergic drugs in sleep disorders.

Melatonin is an endogenous chronobiological regulator secreted mainly from the pineal gland, which has been used as a dietary supplement in the treatment of sleep problems, including insomnia, parasomnia, and circadian rhythm sleep disorders. However, the short half-life and rapid metabolism of melatonin limit its suitability as a drug. There are many melatonergic drugs used in the treatment of sleep disorders and several drugs are under investigation for approval. Ramelteon was the first melatonergic agonist approved as hypnotic agent by U.S. Food and Drug Administration for the treatment of insomnia. It exhibits higher selective affinity for melatonin 1a (MT1) receptor than melatonin 1b (MT2) receptor. This selectivity suggests that it targets sleep onset with no significant adverse effect or dependency. Agomelatin, naphtahalenic compound, act as a potent MT1/MT2 melatonergic receptor agonist and serotonergic receptor antagonist was approved for treatment of depression in 2009. This dual action drug is the first melatonergic agent used in depression. Another melatonergic agonist, tasimelteon has high affinity for the MT1/MT2 receptors in humans. It was approved for the treatment of non-24 hours sleep-wake rhythm disorder. The newly developed melatonin and melatonergic drugs have the potential to be used extensively in various clinical situations and substitute the old benzodiazepine and its derivatives in the treatment of insomnia. However, the efficacy and safety of newly developed melatonergic drugs should be elucidated through long-term clinical trials.

Agomelatine prevents gentamicin nephrotoxicity by attenuating oxidative stress and TLR-4 signaling, and upregulating PPARγ and SIRT1

Kidney injury is a relatively common complication of the use of aminoglycosides. Inflammation and oxidative stress play a key role in gentamicin (GM) nephrotoxicity. We investigated the protective effect of the melatonergic agonist agomelatine (AGM) on GM nephrotoxicity, emphasizing the involvement of TLR-4 signaling, SIRT1 and PPARγ. Rats received 25 mg/kg AGM for 15 days and 100 mg/kg GM for eight days starting at day 7. Elevated serum creatinine, urea and Kim-1 along with multiple histological alterations in the kidney were observed in GM-intoxicated rats. Malondialdehyde (MDA), TNF-α, IL-1β, nitric oxide (NO) and myeloperoxidase (MPO) were increased, and GSH, SOD and catalase were decreased in the kidney of GM-intoxicated rats. Treatment with AGM significantly ameliorated the kidney function biomarkers, prevented tissue injury, decreased inflammatory cytokines, MDA, NO and MPO, and boosted antioxidants. In addition, AGM suppressed the expression of TLR-4, NF-κB p65, p38 MAPK, ERK-1, VCAM-1 and iNOS, whereas upregulated SIRT1 and PPARγ in the kidney of GM-intoxicated rats. In conclusion, AGM prevented GM nephrotoxicity in rats by attenuating oxidative injury and inflammation. AGM suppressed TLR-4 signaling, enhanced antioxidants and upregulated SIRT1 and PPARγ in the kidney of GM-induced rats.

О возможной роли некоторых психотропных препаратов в терапии COVID-19 (краткий обзор)

Бушующая ныне в мире пандемия COVID-19 и связанный как с ней самой, так и с карантинными ограничениями и другими мерами борьбы с ней выраженный дистресс привели к резкой актуализации проблемы психических расстройств в человеческой популяции, прежде всего за счет повышения частоты встречаемости депрессивных, тревожных и связанных со стрессом расстройств. Это значительно увеличило количество тех людей в мире, которые нуждаются в приеме тех или иных психотропных препаратов. С другой же стороны, отсутствие в настоящее время эффективных специфических средств для лечения инфекции COVID-19 поставило перед исследователями и практическими врачами задачу найти среди уже зарегистрированных лекарств потенциальные кандидаты на перепрофилирование по новому показанию — для лечения этой инфекции. Среди подвергнутых скринингу на потенциальную эффективность в отношении нового вируса SARS-CoV-2 тысяч зарегистрированных в мире лекарств, разумеется, были и психотропные препараты. Некоторые из них действительно оказались перспективными кандидатами на такое перепрофилирование. В данном кратком обзоре мы показываем, что потенциальными кандидатами на перепрофилирование для лечения COVID-19 являются несколько классов психотропных лекарств: лиганды сигма-1 рецепторов (прежде всего — флувоксамин, но, возможно, и другие, в том числе инновационный российский анксиолитик фабомотизол (афобазол)), мелатонинергические агонисты (экзогенный мелатонин и, возможно, также агомелатин (вальдоксан) и фабомотизол (афобазол)), а также пептидные биорегуляторы с ноотропными, антидепрессивными, противотревожными и иммуномодулирующими свойствами, такие, как, например, ноопепт, селанк.

The role of melatonin and its analogues in epilepsy.

Extensive research has gone into proposing a promising link between melatonin administration and attenuation of epileptic activity, the majority of which suggest its propensity as an antiseizure with antioxidant and neuroprotective properties. In the past few years, a number of studies highlighting the association of the melatonergic ligands with epilepsy have also emerged. In this context, our review is based on discussing the recent studies and various mechanisms of action that the said category of drugs exhibit in the context of being therapeutically viable antiseizure drugs. Our search revealed several articles on the four major drugs i.e. melatonin, agomelatine, ramelteon and piromelatine along with other melatonergic agonists like tasimelteon and TIK-301. Our review is suggestive of antiseizure effects of both melatonin and its analogues; however, extensive research work is still required to study their implications in the treatment of persons with epilepsy. Further evaluation of melatonergic signaling pathways and mechanisms may prove to be helpful in the near future and might prove to be a significant advance in the field of epileptology.

New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others.

After the development of "classical" tricyclic antidepressants and monoamine oxidase inhibitors, numerous other classes of antidepressant drugs have been introduced onto the market. The selective serotonin reuptake inhibitor class is the best-known one, but many others exist, usually identified by their mechanism of activity. In this second part of the review, focused on new-generation antidepressants not included among selective serotonin reuptake inhibitors, the following classes are considered: noradrenergic and selective serotonergic antidepressants; norepinephrine reuptake inhibitors; serotonin, norepinephrine and dopamine reuptake inhibitors; melatonergic agonists and selective serotonergic antagonists; norepinephrine and dopamine reuptake inhibitors; and so forth. These different mechanisms underlie tolerability and safety profiles that can be very different among the classes, with each one providing significant advantages and disadvantages in comparison with others. The main characteristics of the following antidepressants are described: mianserin, mirtazapine, setiptiline, reboxetine, viloxazine, teniloxazine, atomoxetine, nefazodone, agomelatine, bupropion, esketamine, and tianeptine. The paper is focused on their metabolism and interactions, but also includes brief notes on analytical methods useful for their therapeutic drug monitoring.

Agomelatine protects against permanent cerebral ischaemia via the Nrf2-HO-1 pathway

Stroke is a major cause of death and permanent disability worldwide. It has been reported that 85% of stroke patients undergo an ischaemic stroke. The standard treatment is currently recanalization. However, only 5% of patients have access to this treatment. Therefore, new strategies for permanent ischaemic stroke treatment need to be investigated. Agomelatine is a melatonergic agonist that acts on MT1/2 receptors and is an antagonist of 5-HT2c receptors, and melatonergic has pleiotropic effects, such as antioxidation or anti-inflammation effects. In this study, we focused on the effect of agomelatine on permanent cerebral ischaemia in a rat model. Male Wistar rats were randomly divided into the following four groups (n = 6/group): sham operating group, permanent ischaemic model group, permanent ischaemic model plus agomelatine (40 mg/kg, i.p) group and permanent ischaemic model plus melatonin (10 mg/kg, i.p) group. Twenty-four h after ischaemic onset, we investigated the neurological deficits and infarct volume using neurological deficit scores, 2,3,5-triphenyltetrazolium chloride (TTC) and transmission electron microscopy (Kochanski et al.). Moreover, we analysed Nrf2-HO-1 protein expression by Western blot. The results showed that agomelatine and melatonin decreased neuronal injury and promoted the Nrf2-HO-1 signalling pathway. These findings suggest that agomelatine and melatonin exert beneficial effects on permanent cerebral ischaemia.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. PRISMA-based systematic review of the literature. The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

Melatonergic agonist regulates circadian clock genes and peripheral inflammatory and neuroplasticity markers in patients with depression and anxiety

ObjectiveCircadian dysfunction is a core manifestation and a risk factor for psychiatric disorders. Ramelteon (RMT), a melatonin receptor agonist, has been shown to induce sleep phase shifts and has been used to normalize sleep onset time. RMT has been used in sleep disorders, depression and anxiety. In this study, we aimed to investigate the effects of RMT in regulating gene expression profiles of the circadian clock and peripheral markers of inflammation and neuroplasticity. MethodsSixteen patients with a diagnosis of primary insomnia comorbid with depression and anxiety and ten healthy controls were recruited in an 8-week open-label trial. The patients with primary insomnia received RMT 8 mg/day. The morning expression profiles of 15 core clock genes from peripheral blood mononuclear cells (PBMCs), urine and plasma levels of melatonin and its metabolite levels, and plasma inflammatory markers and neurotrophin levels were evaluated at baseline, 4th and 8th week of RMT treatment. ResultsRMT treatment was associated with significant clinical improvement in depression scores at 8th week (Hamilton depression rating scale scores (Mean ± SEM) from 21.5 ± 2.44 to 14.31 ± 2.25, p ≤ 0.05). The overall poor sleep quality (Pittsburgh sleep quality index) of the patient group significantly improved (p ≤ 0.05) following RMT treatment. The mRNA level analysis showed a significant association between RMT treatment and alterations of the nine core circadian genes (CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 and TIMELESS) in the patient group when compared with the control group (p ≤ 0.05). Compared with the controls, the patient group had a decrease in neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and beta-nerve growth factor; p ≤ 0.05) but an increase in pro-inflammatory cytokine levels (interleukin-6, interleukin-1b, tumour necrosis factor-alpha and interferon gamma; p ≤ 0.05); RMT treatment normalized the levels of neurotrophins and cytokine levels. ConclusionRMT treatment is able to restore phase-shifted melatonin markers, normalized the altered expression of the circadian genes, the levels of inflammatory cytokines and neurotrophins in patients with insomnia comorbid anxiety and depression.

RETROSPECTIVELY ASSESSING THE EFFICACY OF AGOMELATINE IN BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA

Introduction Behavioral and psychologic symptoms of dementia (BPSD) are sources of increasing stress to patients and caregivers and escalate the cost of overall care for dementia cases. Moderate and severe BPSD often need medical treatment to improve symptoms. However, the use of antipsychotic medications or antidepressants often leads to side effects and increases disability. Agomelatine is a selective melatonergic (MT1/MT2) agonist that has normalizing effect on disturbed circadian rhythms and disrupted sleep–wake cycles. Its activity of 5HT-2C receptor antagonism is associated with antidepressant and antianxiety and increases slow-wave sleep. Agomelatine is also considered to be antioxidant and anti-inflammatory activity. It restores stress-affected hippocampal neuronal activity and promotes adult hippocampal neurogenesis and neuroplasticity. Previous clinical findings prompt that agomelatine can improve the BPSD of dementia patients. This retrospective cohort study was used to evaluate the BPSD of dementia cases before and after agomelatine use. Methods Dementia cases who ever received agomelatine treatment for depressive symptoms in a general hospital for past 2.5 years were fully reviewed. Their chart records, including the scores of Neuropsychiatric Inventory (NPI), were recorded. The changes of NPI score were used to evaluate the difference of psychological and behavioral symptoms before and after agomelatine use. The linear mixed-effect model is used to model the changes by controlling the confounding effects of age and sex, hypnotics, antipsychotic drugs, and the adjuvant drug –Mesyrel using. The side effects of agomelatine use were also invest. This study was approved by the institutional review board of National Cheng Kung University Hospital. Results There are 75 cases (male 26, female 49) with Alzheimer's Dementia (AD) 25, Dementia with Lewy Bodies (DLB) 21, Vascular Dementia (VaD) 15, Mixed type dementia 9, and other type dementia 5 cases having both NPI records, pre-and post-agomelatine use 3 months or more. The mean age is 80.7 years old. The dose of agomelatine is from 12.5mg to 50mg per day. The severity and distress of NPI records all show improvement after agomelatine use (p=0.001), especially in the items of delusion, hallucination, agitation/aggression, depression/dysphoria, anxiety, disinhibition, irritability/lability, motor disturbance, sleep/nighttime behavior disturbance (p Eight cases discontinued from agomelatine use due to side effects: 6 with headache, oversleep, dizziness; 1 ever had violence in the midnight, and 1 increased falling down risk in the night. The causes of switching from other antidepressants (such as sertraline, citalopram, escitalopram, paroxetine, venlafaxine, duloxetine, mirtazepine, bupropion, imipramine, doxeine or trazodone) to agomelatine were depression related symptoms not improved or the side effects of using these antidepressants. These side effects include psychomotor slowing, drowsiness or insomnia, dizziness, fatigue, weak, increasing extrapyramidal symptoms, loss of appetite, constipation, bruising or increasing skin itching. Conclusions Agomelatine is effective on improving behavioral and psychological symptoms of dementia, no matter in depression, sleep disturbance, delusion, hallucination, or aggression. The start low and go slow rule should be considered since side effects of headache, dizziness, sedation or triggering the fall. This research was funded by Agomelatine is effective on improving BPSD.

Recent Findings in Melatonin Research and Their Relevance to the CNS.

Several recent developments in melatonin research deserve attention and divulgation. The role of melatonin in the brain has been extended to its synthesis in the cerebellum as a response to inflammation, findings that exceed the earlier demonstration of aralkylamine Nacetyltransferase expression. The release of melatonin via the pineal recess into the third ventricle appears to be more important than previously believed and has been discussed as a strong direct signal to the suprachiasmatic nucleus. The mitochondrial role of melatonin has been substantially extended by the demonstration of the melatonin receptor MT1 in this organelle and evidence for melatonin synthesis in mammalian mitochondria, in addition to the previously shown uptake into these organelles. Contrary to rats and mice, melatonin can act in a prodiabetic way, especially under conditions of MT2 overexpression, an effect that leads to reduced insulin secretion. These findings are discussed in the context of brain insulin resistance as an early change in low-grade neuroinflammation, however, with emphasis to the distinction between reduced insulin and insulin resistance. Various new data underline the stimulation of sirtuins 1 and 3 by melatonin in the context of aging and of inflammation. Data support a nexus between sirtuins, circadian oscillators and melatonin, and hints for the transduction of melatonin effects by sirtuin 1. Further transduction mechanisms concern the upregulation of microRNAs as well as their transmission via exosomes. The recent findings on melatonin have also to be seen in their consequences to the use of synthetic melatonergic agonists.

Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery.

Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the α2δ subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined along with novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia.

Novel Therapeutics in Bipolar Disorder

Existing pharmacological treatments for bipolar disorder have demonstrated insufficient efficacy, delayed onset of action, and significant side effects. Emerging evidence suggest that rapid antidepressant activity can be achieved in humans, and findings from the use of glutamatergic and anticholinergic drugs, for instance, reveal promising results. In the present article, we review evidence supporting the use of novel therapies in bipolar disorder, with focus on drugs acting in the glutamatergic system. In addition, anticholinergic drugs, melatonergic agonists, glucocorticoid modulators, and mechanistically diverse anti-inflammatory agents will be briefly discussed. While preliminary findings on novel therapies for bipolar disorder are encouraging, current evidence is still insufficient to support extensive use of these drugs routinely. Long-term safety, tolerability, and efficacy remain unclear; several clinical trials are underway and may add clarity to these questions. Early detection and prompt intervention have the potential to decelerate illness progression and lessen the burden associated with bipolar disorder; thus, novel therapies with rapid and sustained clinical benefits are urgent.

Effect of agomelatine on psychomotor function tests in healthy human volunteers

Background: Agomelatine is a melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and 5-HT2C antagonism. The present study was taken up to evaluate the effect of Agomelatine 25mg on psychomotor function in healthy human volunteers.Methods: The effect of Agomelatine was studied in 12 healthy volunteers of either gender. The study was a randomised, cross over, placebo controlled study, done after obtaining permission from NIMS Institutional Ethics Committee and informed consent taken from all the subjects, after briefly explaining the study procedure and training them adequately. Psychomotor function was assessed using Choice reaction time (CRT), Critical Flicker fusion test (CFFT), Digit letter substitution test (DLST), Six letter cancellation test (SLCT), Card sorting test (CST) and Visual analog scale (VAS). Psychomotor function tests were performed, 90 minutes after administering Agomelatine 25 mg or placebo. Washout period of seven days was allowed between the cross over. Statistical analysis was done by comparing groups using unpaired t test.Results: There was significant decrease in the mean percentage of time (p<0.01) in CRT in Agomelatine group (20.09±9.47%) when compared to placebo (10.48±3.68%). Improved mean percentage of performance was seen in CFFT with Agomelatine (6.2±2.1%) compared to placebo (9.11±2.99%). No significant difference was noted in the performance of DLST, SLCT and CST. Drug was subjectively rated as sedative on VAS.Conclusions: There is no significant effect of Agomelatine on psychomotor performance. CNS processing of information also improved. Agomelatine can thus be safely administered to depressed patients.

Contrasting Findings on Melatonin Concerning Inflammation and Glucose Tolerance - Consequences to the Development of Melatonergic Drugs

The pleiotropy of melatonin is a reason for using this hormone or synthetic melatonergic agonists for testing their suitability in various diseases and disorders. However, it is important to remain aware that many preclinical findings cannot be translated to humans, because of the different relationship between melatonin and sleep or activity in diurnally compared to nocturnally active mammals...

The effect of chronotherapy on delirium in critical care-a systematic review.

Delirium is highly prevalent within critical care and is linked to adverse clinical outcomes, increased mortality and impaired quality of life. Development of delirium is thought to be caused by multiple risk factors, including disruption of the circadian rhythm. Chronotherapeutic interventions, such as light therapy, music and use of eye shades, have been suggested as an option to improve circadian rhythm within intensive care units. This review aims to answer the question: Can chronotherapy reduce the prevalence of delirium in adult patients in critical care? This study is a systematic review of quantitative studies. Six major electronic databases were searched, and a hand search was undertaken using selected key search terms. Research quality was assessed using the critical appraisal skills programme tools. The studies were critically appraised by both authors independently, and data were extracted. Four themes addressing the research question were identified and critically evaluated. Six primary research articles that investigated different methods of chronotherapy were identified, and the results suggest that multi-component non-pharmacological interventions are the most effective for reducing the prevalence of delirium in critical care. The melatonergic agonist Ramelteon demonstrated statistically significant reductions in delirium; however, the reliability of the results in answering the review question was limited by the research design. The use of bright light therapy (BLT) and dynamic light application had mixed results, with issues with the research design and outcomes measured limiting the validity of the findings. Multi-component non-pharmacological interventions, such as noise and light control, can reduce delirium in critical care, whereas other interventions, such as BLT, have mixed outcomes. Melatonin, as a drug, may be a useful alternative to sedative-hypnotics. Chronotherapy can reduce the incidence of delirium within critical care, although further research is warranted. Staff education is essential in the implementation of chronotherapy.

Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors

AimsThe hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation. Main methodsBrain slices containing the SCN were prepared from male Wistar rats and maintained in a recording chamber. Changes in firing rates of SCN neurons were recorded after perfusion of drugs. Key findingsSCN firing rates were dose-dependently suppressed by 19.2–80.9% following perfusion of 0.04–0.32mM agomelatine (p<0.001, IC50=0.14mM). Perfusion with melatonin (0.4–3.2mM) resulted in 16.6–62.5% dose-dependent reductions in firing rates (at least p<0.01, IC50=1.59mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32mM) and a 5-HT2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16mM agomelatine by 35% and 50.2%, respectively. A 5-HT2C receptor antagonist (S32006; 0.03–0.12mM) significantly decreased SCN firing rates (19.6–91.8%; at least p<0.05, IC50=0.05mM). Co-perfusion of S32006 (0.06mM) with a 5-HT2C agonist (Ro60-0175; 0.003mM) reduced suppressions evoked by S32006 alone by ~72.1%. SignificanceThese results are consistent with the hypothesis that agomelatine acts directly on the SCN via both agonist effects at melatonergic receptors and antagonist effects at 5-HT2C receptors, which parallel its mechanisms of action as an antidepressant.