benzofurans and Depressive-Disorder

The development of new antidepressants has had mixed results over the past decade, with several notable failures. This paper reviews a number of major initiatives in the development of new antidepressant agents. Traditional strategies to build on agents that have monoaminergic effects at the synapse (e.g., vilazodone and ketamine) have been complemented with efforts that have emphasized devices and brain circuits (e.g., deep brain stimulation and transcranial magnetic stimulation) or chemical agents that modulate neuroendocrine systems (e.g., glucocorticoid antagonists, mixed melatonin agonists/serotonin type-2 receptor antagonists). Interestingly, chemical agents, such as onabotulinumtoxin A, may affect brain circuits as well. We present data from recent studies in drug and device development--reviewing progress made, stumbling blocks encountered, and issues that need to be addressed in future studies.

Topics: Antidepressive Agents; Benzofurans; Deep Brain Stimulation; Depressive Disorder; Drug Discovery; Humans; Indoles; Ketamine; Nerve Net; Neurosecretory Systems; Piperazines; Placebo Effect; Sulfides; Transcranial Magnetic Stimulation; Vilazodone Hydrochloride; Vortioxetine

New-generation antidepressants are a heterogeneous class of drugs used in the treatment of depression and related disorders. This review deals with the first new-generation antidepressant class to enter the pharmaceutical market, i.e., selective serotonin reuptake inhibitors (SSRIs), which are still the most prescribed and widely used ones. Their common characteristics are the comparable clinical efficacy, good tolerability and relative safety in comparison to "first generation antidepressants", i.e. classic tricyclic antidepressants and monoamine oxidase inhibitors. This class of drugs includes fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine and, since 2011, vilazodone. In this review, the main pharmacodynamic and pharmacokinetic properties of the six commercially available SSRIs are described, focusing on side and toxic effects, chemical-clinical correlations, interactions with other drugs, the role of therapeutic drug monitoring (TDM) and related bioanalytical methodologies.

Topics: Benzofurans; Citalopram; Depressive Disorder; Drug Monitoring; Fluoxetine; Fluvoxamine; Humans; Indoles; Paroxetine; Piperazines; Selective Serotonin Reuptake Inhibitors; Sertraline; Vilazodone Hydrochloride

Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, next-day hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1/MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.

Topics: Acetamides; Animals; Benzodiazepines; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Depressive Disorder; Humans; Hypnotics and Sedatives; Indenes; Indoles; Melatonin; Sleep Initiation and Maintenance Disorders

Vilazodone (Viibryd--Forest), a selective serotonin reuptake inhibitor (SSRI) and partial 5-HT(1A) receptor agonist, has been approved by the FDA for treatment of depression. It has been claimed to have no sexual side effects and not to cause weight gain.

Topics: Animals; Antidepressive Agents; Benzofurans; Clinical Trials as Topic; Depressive Disorder; Gastrointestinal Diseases; Humans; Indoles; Piperazines; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT₁ and MT₂ melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag.

Topics: Acetamides; Benzofurans; Central Nervous System Depressants; Cyclopropanes; Depressive Disorder; Humans; Indenes; Jet Lag Syndrome; Melatonin; Sleep Disorders, Circadian Rhythm

Although accumulating evidence suggests that activated microglia are associated with deficits in neurogenesis and contribute to the physiopathology of major depressive disorder, the role of microglia in treating depression remains poorly understood. Our previous study showed that salvianolic acid (SalB) has the regulation of neuroinflammatory responses and antidepressant-like effects. Here, we hypothesized that SalB's therapeutic effects occur because it modulates microglial phenotypes that are associated with neurogenesis. To test this hypothesis, we treated CMS-exposed C57BL/6 mice with SalB (20mg/kg, intraperitoneally, once daily) for 3weeks and investigated microglial phenotypic profiles and hippocampal neurogenesis. The results showed that the SalB treatment skewed M1 microglial polarization toward M2 activation in the hippocampus and cortex and remedied CMS-induced deficits in hippocampal neurogenesis. SalB (40µM) inhibited LPS-stimulated microglial M1 activation as well as induced M2 activation in vitro, and the cultured microglia with the SalB treatment showed enhanced neural precursor cell proliferation, differentiation, and survival. SalB treatment also ameliorated the depressive-like behaviors of the CMS-treated mice in sucrose preference, forced swimming, and tail suspension tests. These findings suggest a possible antidepressive mechanism for anti-inflammatory agents that is correlated with microglial polarization and hippocampal neurogenesis and which may provide a new microglia-targeted strategy for depression therapy.

Topics: Animals; Benzofurans; Cerebral Cortex; Depression; Depressive Disorder; Hippocampus; Inflammation; Inflammation Mediators; Male; Mice, Inbred C57BL; Microglia; Neurogenesis; Phenotype; Stress, Psychological

This article reviews the novel atypical antidepressant drug vilazodone (Viibryd(™)), which was approved by the U.S. Food and Drug Administration in January 2011 for the treatment of major depression. Vilazodone is a dual-acting antidepressant drug, with a primary mechanism of action of blocking the serotonin reuptake transporter together with acting as a 5-HT1A receptor partial agonist. The antidepressant efficacy of vilazodone was established in two 8-week placebo-controlled studies. One long-term (52-week) open-label study has been conducted. The most common side effects are diarrhea, nausea, and headache. The drug has not been studied in pediatric patients or well studied in patients older than 65. Vilazodone is efficacious, safe, and well tolerated, but does not appear to have major efficacy advantages compared with other antidepressant drugs. However, because of its unique pharmacology and relatively benign tolerability profile, it may be a more effective alternative for patients who do not respond to or cannot tolerate currently available antidepressant drugs.

Topics: Antidepressive Agents, Second-Generation; Benzofurans; Depressive Disorder; Drug Approval; Humans; Indoles; Patient Selection; Piperazines; Psychiatric Nursing; Safety; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome; United States; United States Food and Drug Administration; Vilazodone Hydrochloride

Ten endogenously depressed inpatients were treated once daily for at least 4 weeks with 40-50 mg citalopram (Lu 10-171) - a specific serotonin reuptake inhibitor. The Hamilton rating scale for depression and global assessment indicated pronounced or moderate response in seven patients and slight or no response in three. Side effects were few, mild and transient and neither anticholinergic nor cardiotoxic effects were observed. No difference was observed between responders and non-responders as regards psychopathology, plasma levels or uptake inhibition. It is concluded, that citalopram seems to possess antidepressant properties and that controlled trials are wanted to evaluate its therapeutic value as well as the underlying hypothesis of serotonin - deficient depressions.

Topics: Adult; Aged; Benzofurans; Citalopram; Depressive Disorder; Drug Evaluation; Female; Humans; Male; Middle Aged; Propylamines; Psychiatric Status Rating Scales; Serotonin; Serotonin Antagonists