mdl-100907 and Depressive-Disorder--Major

Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission.. To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity.. An in silico molecular modeling study, based on homology, was conducted to determine the three-dimensional structure of the 5-hydroxytryptamine 2A receptor (5- HT2AR), then molecular docking studies were performed and the predisposition for cytotoxicity risk among identified molecules was examined. A model for 5-HT2AR homology, with satisfactory results, was obtained indicating the good stereochemical quality of the model. The phenylpropanoid 4-allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.

Topics: Antidepressive Agents; Depressive Disorder, Major; Eugenol; Humans; Molecular Docking Simulation; Propanols; Serotonin 5-HT2 Receptor Antagonists

Agomelatine is a novel antidepressant that acts as a melatonin MT1 and MT2 receptor agonist and serotonin 5-HT2C receptor antagonist, putatively reversing circadian rhythm disruption in major depressive disorder (MDD) and promoting dendritic neurogenesis in animal models of depression. It may be a preferable alternative to antidepressants currently in use due to its improved tolerability profile.. The PubMed database was searched for published randomized controlled trials (RCTs) evaluating the efficacy of agomelatine as well as its tolerability and safety in the treatment of MDD. The key search term used was agomelatine combined with major depressive disorder/depressive disorder/depression and antidepressant. Article selection was based upon sample size and overall methodological quality.. Agomelatine is a multi-modal agent with novel mechanisms of action, having sound evidence supporting its overall statistical efficacy and adequate tolerability profile for MDD treatment. However, the clinical significance of agomelatine has been contested, calling for additional studies in evaluation of its effect size. Of further concern are reported transient elevations in transaminases and severe but rare liver reactions.

Topics: Acetamides; Animals; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Neurogenesis; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

Agomelatine is a relatively new antidepressant with a mechanism of action that is different from other antidepressants: it is a melatonergic agonist and a 5-HT2C antagonist. It is an effective treatment for depression, with relatively mild side effects. It may be a valuable pharmacological alternative in the clinical approach on depression.. The literature about agomelatine has been comprehensively reviewed. Agomelatine's efficacy, safety and tolerability are reviewed based on the studies undertaken in patients with major depressive disorder (MDD) and bipolar disorder (BPD).. Agomelatine has shown an antidepressant effect in preclinical models, and the results of a large-scale clinical trial program, conducted in MDD, indicate both an antidepressant activity and a favorable tolerability profile. Agomelatine has no discontinuation syndrome, sexual discomfort is rare, and it is generally weigh neutral. The drug appears to be relatively safe in case of overdose. However, some cases of elevated hepatic transaminases are reported during treatment. As agomelatine has a mechanism of action that differs from other agents, it may represent a valuable additional treatment option in those patients who do not respond fully or who do not tolerate the side effects of other antidepressants.

Topics: Acetamides; Animals; Antidepressive Agents; Bipolar Disorder; Depressive Disorder, Major; Humans; Melatonin; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Most studies in this journal describe recent patents. The present study only has one such reference. Instead, we hope that its contents will trigger investigation of antidepressant drugs along the suggested lines and lead to ensuing patent applications - first and foremost by more focus on astrocytes. Clinical research has already pointed towards the importance of these cells, which account for one quarter of brain cortical volume and at least as much of its oxidative metabolism. Astrocytes express a multitude of receptors, including 5-HT(2B) receptors. In cultured astrocytes acute treatment with any of the five SSRIs, fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram, stimulates equipotently and with sufficient affinity to be therapeutically relevant, the 5-HT(2B) receptor. Following EGF receptor transactivation and a resultant autocrine HB-EGF stimulation, these drugs activate two interdependent signal pathways i) the Ras-Raf-Mek-ERK phosphorylation pathway and ii) the PI3K-AKT-GSK-3β pathway, eventually altering gene expression. Chronic treatment with fluoxetine upregulates gene expression of cPLA₂, ADAR2, GluK2 and 5-HT(2B) receptors, and RNA editing of the later two in cultured astrocytes and in astrocytes obtained by fluorescence-activated cell sorting of cells from fluoxetinetreated mice. Chronic treatment also down-regulates the Gq-protein-coupled receptor-induced increase of intracellular Ca²⁺ by inhibiting TRPC function, compromising astrocytic Ca²⁺ re-filling. This affects glycogenolysis and several steps in the signal pathways. Since astrocytes in the mature brain and in our cultures do not express SERT, both acute and chronic effects in cultured astrocytes must be directly mediated by 5-HT(2B) receptor activation.

Topics: Animals; Astrocytes; Depressive Disorder, Major; Drugs, Investigational; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Nerve Tissue Proteins; Neurons; Patents as Topic; Receptor, Serotonin, 5-HT2B; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.

Topics: Acetamides; Animals; Antidepressive Agents; Biological Clocks; Chronobiology Disorders; Depressive Disorder, Major; Humans; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

To demonstrate the clinical effectiveness of an antidepressant drug requires evidence beyond short- and long-term efficacy, including a favourable adverse-effect profile and sustained treatment adherence. Under these conditions, patients should experience enhanced social and functional outcomes. The novel antidepressant agomelatine, a melatonergic MT(1)/MT(2) receptor agonist with serotonin 5-HT(2C) receptor antagonist activity, displays antidepressant efficacy with a favourable adverse-effect profile that is associated with good patient adherence. Specifically, agomelatine has demonstrated significant short-term (6-8 weeks) and sustained (6 months) antidepressant efficacy relative to placebo, as well as evidence of relapse prevention (up to 10 months). In head-to-head comparative studies with venlafaxine and sertraline, there was evidence of early (at 1-2 weeks) and sustained (at 6 months) advantages for agomelatine. In addition to evidence of early efficacy, agomelatine also restored disturbed sleep-wake patterns early in treatment. There was no evidence of antidepressant-induced sexual dysfunction, weight gain or discontinuation-emergent symptoms. Agomelatine has demonstrated a range of properties that suggest it could offer advantages over current treatments for major depressive disorder, although further comparative trials are still required, as is evidence from real-world clinical practice.

Topics: Acetamides; Antidepressive Agents; Anxiety Disorders; Depressive Disorder, Major; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

Agomelatine (Valdoxan) is licensed by the European Medicines Agency for the treatment of major depressive episodes in adults. The objective of this review was to consider how the drug should be used in clinical practice in particular starting, stopping and switching to and from the drug.. The existing clinical evidence was reviewed.. Data suggest that when switching to agomelatine from other antidepressants consideration should be given to tapering the previous antidepressant in order to minimize the risk of the original drug causing discontinuation/withdrawal symptoms. The risk of pharmacological interactions between most antidepressants and agomelatine is low and so tapering the previous antidepressant can usually be done after agomelatine has been started. An exception is fluvoxamine which should not be concurrently prescribed with agomelatine. As agomelatine appears to cause no significant discontinuation symptoms, it can probably be stopped abruptly when treatment is completed or when switching to another antidepressant.. While this guidance may change as clinical evidence and experience grows, currently agomelatine appears to have a good tolerability profile and is relatively easy to use, though prescribers should note the requirement to conduct liver function tests (LFTs) in accordance with the Summary of Product Characteristics (SPC).

Topics: Acetamides; Animals; Antidepressive Agents; Contraindications; Depressive Disorder, Major; Drug Interactions; Drug Monitoring; Fluvoxamine; Humans; Liver; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Substance Withdrawal Syndrome

Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

Topics: Acetamides; Animals; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Drug Design; Drug Discovery; Humans; Melatonin; Serotonin 5-HT2 Receptor Antagonists

In DSM-IV the occurrence of disturbed sleep is one of the principal diagnostic criteria for major depressive disorder (MDD). Further, there is evidence of reciprocity between the two conditions such that, even in the absence of current depressive symptoms, disturbed sleep often predicts their development. The present review discusses the effects of antidepressants on sleep and evaluates the use of the recently developed melatonin agonist-selective serotonin antagonists on sleep and depression. Although many antidepressants such as the tricyclics, monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, several serotonin receptor antagonists and selective serotonin reuptake inhibitors (SSRIs) have all been found successful in treating depression, their use is often associated with a disruptive effect on sleep. SSRIs, currently the most widely prescribed of the antidepressants, are well known for their instigation or exacerbation of insomnia. The recently introduced novel melatonin agonist and selective serotonin antagonist antidepressant, agomelatine, which has melatonin MT(1) and MT(2) receptor agonist and 5-HT(2c) antagonist properties, has been useful in treating patients with MDD. Its rapid onset of action and effectiveness in improving the mood of depressed patients has been attributed to its ability to improve sleep quality. These properties underline the use of melatonin analogues as a promising alternative for the treatment of depression.

Topics: Acetamides; Affect; Antidepressive Agents; Brain; Depressive Disorder, Major; Humans; Indenes; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep; Sleep Initiation and Maintenance Disorders

There are many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants. As there is large prevalence of circadian dysfunction in various affective disorders, including depression, one of the approaches is the development of antidepressant drugs with melatonergic agonist properties. Agomelatine, with its melatonergic agonistic (at both MT(1) an MT(2) receptors) and 5-HT(2C) antagonistic properties, represents a new concept for the treatment of depression. The antidepressant action of agomelatine has been initially demonstrated in animal models of depression, such as the forced swim - the learned helplessness - and the chronic mild stress paradigms. Subsequent studies demonstrated that the antidepressant activity of agomelatine does not solely depend on its agonistic action at melatonergic receptors, but also on its antagonistic activity at 5-HT(2C) receptors. Agomelatine also exhibits anxiolytic properties that bear a striking resemblance to those of selective 5-HT(2C) receptor antagonists. In patients with major depressive disorder, agomelatine had efficacy at least comparable to that seen with available antidepressants. Interestingly, agomelatine demonstrated antidepressant efficacy not only in patients with a moderate depressive episode but also in a more severe depressed subpopulation of patients. The treatment effect increased with the severity of the disease. Agomelatine also rapidly regulates the sleep-wake cycle without causing sedation and improves daytime condition. Agomelatine has an excellent safety profile, is weight neutral, does not affect sexual functioning and does not cause discontinuation syndrome. Collectively, its efficacy, together with its excellent tolerability, makes agomelatine an especially promising antidepressant for the near future.

Topics: Acetamides; Animals; Anti-Anxiety Agents; Antidepressive Agents; Circadian Rhythm; Depressive Disorder; Depressive Disorder, Major; Dopamine; Humans; Hypnotics and Sedatives; Norepinephrine; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin; Serotonin 5-HT2 Receptor Antagonists

Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.

Topics: Acetamides; Animals; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

Antidepressant pharmacotherapy forms the basis of management of major depressive disorder (MDD). In principle, the management of MDD should first elicit rapid relief of symptoms and then restore normal functioning and prevent relapse. It is recommended that treatment should continue for at least one year to minimize the risk of recurrence. Currently, most antidepressants fail to fulfill these goals, and rates of remission and long-term compliance are usually unsatisfactory. These shortcomings may be linked to tolerability and residual symptoms. Agomelatine is a novel antidepressant with an innovative mode of action characterized by agonism at the melatonergic MT(1)/MT(2) receptors and antagonism at the 5-HT(2C) receptors. As early as one week into treatment, depressive symptoms evaluated by the Clinical Global Impression Scale - Improvement (CGI-I) showed a significant improvement with agomelatine compared with venlafaxine (p < 0.0001). This rapid antidepressant efficacy was also seen at 2 weeks on the Hamilton Rating Scale for Depression (HAM-D), on which the mean total scores for agomelatine were lower than those for placebo (p < 0.05). At 6-8 weeks, evaluation on HAM-D, CGI-I and the CGI - Severity of illness (CGI-S) showed significant improvements with agomelatine versus placebo (p < 0.05). Patients treated with agomelatine also experienced greater relief of symptoms on CGI-I at 6 weeks compared with venlafaxine (p < 0.05). The antidepressant efficacy of agomelatine is maintained over the long term; almost 80% of patients remain free from relapse after 10 months of treatment. Agomelatine also significantly improves disturbed sleep and anxiety within depression, and this broad efficacy minimizes the risk of residual symptoms. The recent registration of agomelatine by the European Medicines Agency now offers the potential of fulfilling many currently unmet clinical needs throughout the time course of management of MDD.

Topics: Acetamides; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder, Major; Humans; Psychiatric Status Rating Scales; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

Agomelatine (beta-methyl-6-chloromelatonin), which is structurally homologous to melatonin, is a potent agonist of melatonin MT1 and MT2 receptors as well as an antagonist of serotonin 5-HT(2C) receptors. Agomelatine appears to improve sleep without causing daytime sedation. It has not been found to be associated with sexual side effects and discontinuation symptoms. Three placebo-controlled trials, one of them a dose finding study and two of them pivotal trials, suggest that agomelatine is an antidepressant at doses of 25 - 50 mg/day. Agomelatine appears to be well tolerated, without sexual or cardiac adverse effects, weight gain or discontinuation syndromes. Animal studies suggest a possible neuroprotective action of agomelatine, although there are more data in favor of an anxiolytic effect. Substantially more research is needed to establish its role in the treatment of mood and circadian rhythm disorders.

Topics: Acetamides; Animals; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder, Major; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Sleep

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo-controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25mg/day, with the possibility of increasing doses to 50mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine's efficacy over a longer treatment period.

Topics: Acetamides; Animals; Circadian Rhythm; Depressive Disorder, Major; Dopamine; Frontal Lobe; Humans; Hypnotics and Sedatives; Melatonin; Norepinephrine; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

Most of the available antidepressants, with different pharmacological profiles, such as inhibitors of serotonin reuptake (SSRIs) or norepinephrine reuptake (NRIs) or both (SNRIs), have limitations leading some patients to drop out of treatment. Another direction of research has therefore been undertaken, based initially on the fact that affective disorders are most often characterized by abnormal patterns of circadian rhythms. This consideration has led to the synthesis of agomelatine, a novel antidepressant combining melatonergic MT(1) and MT(2) agonism and serotonergic 5-HT(2C) antagonism. The antidepressant effects of agomelatine have been investigated in different animal models, including chronic mild stress, forced swimming, learned helplessness and psychosocial stress. All studies reported an antidepressant-like effect of agomelatine. A resynchronizing activity of agomelatine was seen in animal models for delayed sleep phase syndrome and in several original models of circadian disturbance, such as rodents infected by trypanosome or old hamsters. This activity of agomelatine on circadian rhythms was further confirmed in humans. Furthermore, several randomized, double-blind, placebo-controlled and comparator-controlled studies of agomelatine in the treatment of major depressive disorder indicate that agomelatine is effective and well tolerated.

Topics: Acetamides; Animals; Antidepressive Agents; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Humans; Models, Animal; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome

Desynchronisation of normal circadian rhythms, including the sleep-wake rhythm, is common in major depressive disorder (MDD). The association between sleep disturbances and depression has long been recognised. Disturbed sleep is a diagnostic criterion for MDD, and insomnia commonly precedes the onset of symptomatic mood disorders. Disruptions of the sleep-wake cycle (sleep architecture and timing) are residual symptoms that may prevent the attainment of high-quality remission and delay recovery from MDD. Therefore, early recognition and treatment of sleep disturbances may be important for the treatment and prevention of recurrent depression. Evidence suggests that melatonergic (MT(1) and MT(2)) and the 5-HT(2C) serotonergic receptor subtypes are important modulators of circadian rhythmicity. Agomelatine is the first melatonergic antidepressant; an agonist of melatonin MT(1) and MT(2) receptors, with additional antagonist properties at the 5-HT(2C) receptors. Agomelatine combines antidepressant efficacy including quality and efficiency of sleep, with a more favourable side-effect profile than current antidepressant treatments, including neutral effects on sexual function, bodyweight and the absence of discontinuation symptoms. These positive features provide a novel approach to the treatment of depression and the attainment of high-quality remission in MDD.

Topics: Acetamides; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep; Sleep Disorders, Circadian Rhythm; Time Factors; Treatment Outcome

Major depressive disorder (MDD) is a prevalent condition with substantial heterogeneity in terms of clinical symptom profiles, overlapping syndromes and degree of severity. The challenge for any new antidepressant is to demonstrate efficacy across the spectrum of patient subpopulations with a diagnosis of MDD. The anxious depressed patient historically has a lower rate of response to traditional antidepressants and high pretreatment anxiety symptoms have also been shown to increase the risk of recurrence. In addition, severity based on standard antidepressant rating scale scores influences treatment outcomes. Some antidepressants display greater placebo separation at higher levels of severity while others fail to separate from placebo in more severe populations. Gender differences in antidepressant response have also been reported in several studies. In particular, women appear to experience a greater side-effect burden with current antidepressants. This is also important in treating late-life depression, where elderly patients are more prone to experiencing side effects and drug interactions. Despite the improved tolerability with SSRIs and other novel antidepressants, restoration of healthy sleep patterns has frequently been lacking. Finally, antidepressant efficacy must include demonstrated relapse prevention during placebo-controlled drug discontinuation trials. As a novel antidepressant with melatonin receptor agonist and 5HT(2C) antagonist properties, agomelatine has demonstrated efficacy in randomized placebo-controlled trials. Additional analyses support the benefits of agomelatine in anxious depression, increasing efficacy with greater baseline severity, including severe late-life depression. Agomelatine has also demonstrated favourable tolerability and efficacy in separate analyses of women and men and displays successful relapse prevention at doses 25 and 50 mg. Both subjective and polysomnographic measures of sleep support increased sleep efficiency and decreased awakenings during agomelatine treatment. Combining these efficacy data with favourable effects on sexual function, CNS and GI systems, there are grounds to endorse the view that agomelatine is a well-tolerated and efficacious antidepressant for a diverse range of depressed populations.

Topics: Acetamides; Age Factors; Antidepressive Agents; Anxiety; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Female; Humans; Male; Patient Selection; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Sleep; Time Factors; Treatment Outcome

Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment-resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD.. Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross-referencing the term 'depression' with each of the six AAPs.. After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia.. The existing research provides some support for the beneficial effects of AAPs when combined with SSRI's in TRD. These medications pose significant risks that must be considered in their use.

Topics: Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Depressive Disorder, Major; Dibenzothiazepines; Dopamine D2 Receptor Antagonists; Drug Resistance; Drug Therapy, Combination; Fluoxetine; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Serotonin 5-HT2 Receptor Antagonists; Thiazoles; Trazodone; Triazoles

To compare response rates among patients with major depressive disorder (MDD) treated with either a serotonin-2 (5HT2-) receptor antagonist or a selective serotonin reuptake inhibitor (SSRI).. Medline and PubMed were searched for double-blind, randomized clinical trials comparing either trazodone or nefazodone with an SSRI for the treatment of MDD. Data from 9 reports involving a total 988 patients were identified and combined using a random-effects model.. Patients randomized to treatment with a 5HT2 antagonist were as likely to experience clinical response as patients randomized to treatment with an SSRI (RR=1.002, 95% CI: 0.85-1.17, P=0.978). Pooled response rates for trazodone/nefazodone and the SSRIs were 61.1% and 61.7%, respectively. There was also no difference in overall discontinuation rates (P=0.334), discontinuation due to adverse events (P=0.676), or discontinuation due to inefficacy (P=0.289) between the two groups.. These results suggest that the 5HT2-receptor antagonists trazodone and nefazodone and the SSRIs do not differ with respect to their overall efficacy and tolerability in the treatment of MDD. Although the sample size was relatively large and conveyed sufficient statistical power to test for differences in the overall sample, depression is a heterogeneous condition and differences may exist between treatments in particular subgroups of patients.

Topics: Depressive Disorder, Major; Humans; Piperazines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Trazodone; Triazoles

Full remission of symptoms is the goal for the acute treatment of depression, because incomplete remission is associated with poor outcomes including higher risk of relapse and chronicity. The current definitions for remission (e.g. a score of

Topics: Acetamides; Antidepressive Agents; Depressive Disorder, Major; Humans; Hypnotics and Sedatives; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

The limitations of current antidepressant medications merit the exploration of alternative agents with novel antidepressant mechanisms of action. The established clinical finding that desynchronization of internal rhythms plays an important role in the pathophysiology of depressive disorders has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential. Recent experiments using the novel melatonin receptor agonist and serotonin 2 (5-HT2c) receptor antagonist agomelatine (S20098; N[2-(7-methoxy-1-naphthyl)ethyl]- acetamide) revealed a notable chronobiotic activity and clear antidepressant-like effects in a variety of preclinical models. Binding studies performed in vitro proved that agomelatine is a high-affinity agonist at both the melatonin MT1 and MT2 receptor types. In addition, these studies revealed that agomelatine, in contrast to melatonin, blocks 5-HT2c receptors with significant affinity. Antagonism of 5-HT2c receptors is reported for various established antidepressant compounds. The antidepressant properties of agomelatine are thus based on its melatonergic actions and 5-HT2c receptor antagonism.

Topics: Acetamides; Animals; Antidepressive Agents; Biological Clocks; Brain; Depressive Disorder, Major; Disease Models, Animal; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Tupaiidae

Agomelatine is a new antidepressant that is a potent agonist of melatonin receptors and an antagonist of the serotonin 5-HT(2C) receptor subtype. It is in late-phase trials for the treatment of major depressive disorder (MDD). Symptoms of depression significantly improved with agomelatine compared with placebo in large placebo-controlled trials, and agomelatine appears to be as efficacious in treating MDD as other antidepressants but with fewer adverse effects. Agomelatine appears to improve sleep quality and ease of falling asleep, as measured subjectively in depressed patients. Polysomnographic studies have shown that agomelatine decreases sleep latency, decreases wake after sleep onset (WASO), and improves sleep stability as measured by changes in the cyclic alternating pattern. Agomelatine is generally well tolerated in patients with MDD; in clinical trials, adverse events were generally mild to moderate in nature, with an overall frequency close to that of placebo. Discontinuation of agomelatine because of adverse effects occurred at a similar rate to placebo.

Topics: Acetamides; Animals; Antidepressive Agents; Depressive Disorder, Major; Humans; Hypnotics and Sedatives; Receptors, Melatonin; Serotonin 5-HT2 Receptor Antagonists

The intimate relationship between depressive disorders and biological rhythm disturbances has long been known. One major component in diurnal rhythm regulation in mammals, like humans, is the melatonin axis and its close connections with serotonergic and noradrenergic structures. In major depression various functional anomalies have been shown in all of these systems. Agomelatine is a novel antidepressant with direct agonist activity at the melatonin MT1 and MT2 receptors, and a selective antagonist action at the serotonin 5HT2C receptor. It has no measurable affinity to any other known receptor. In animal models agomelatine has antidepressant-like and anxiolytic-like properties, it promotes sleep, and is able to resynchronize various experimentally uncoupled or phase-shifted biological rhythms. In randomized and controlled clinical trials agomelatine appears to be an effective antidepressant, comparable to standard SSRI/SNRI drugs, with excellent safety and tolerability profile. It usually produces mild and transient side effects, similar to those seen in patients receiving placebo. Sleep architecture and subjective measures of sleep quality may also respond favorably. Agomelatine causes significantly less sexual dysfunction than a reference SNRI. No discontinuation symptoms have been observed upon abrupt withdrawal. The overall dropout rates in the clinical trials have been remarkably low, suggesting good acceptability and compliance. Even though most current antidepressants are effective, they also have weaknesses; therefore we still need innovative drugs with novel biochemical actions, faster efficacy and/or better tolerability.

Topics: Acetamides; Animals; Anti-Anxiety Agents; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Hypnotics and Sedatives; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Sleep

This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.. For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS₁₇) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS₁₇ insomnia factor score and KSS score, correlation between the HDRS₁₇ insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6.. At baseline, HDRS₁₇ insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo.. Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function.. ClinicalTrials.gov identifier: NCT03018340.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Piperidines; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders; Treatment Outcome; Urea; Young Adult

To identify which specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression.. This is a secondary analysis of data from a late-life treatment resistant depression trial examining the safety and efficacy of aripiprazole augmentation. Participants aged 60 and above were randomized to aripiprazole augmentation (N = 91) versus placebo (N = 90). The main outcome was depression remission. Clinical predictors included individual Montgomery-Asberg Depression Rating Scale (MADRS) item scores categorized as symptomatic (scores >2) or nonsymptomatic (scores ≤2).. Three MADRS items predicted depression remission with aripiprazole augmentation: symptomatic scores on sleep disturbance and nonsymptomatic scores on apparent sadness and inability to feel. The 2-way and 3-way interaction terms of these MADRS items were not significant predictors of remission; therefore, the models' ability to predict remission was not improved by combining the significant MADRS items.. The identification of specific depressive symptoms, which can be clinically assessed, can be used to inform treatment decisions. Older adults with treatment resistant depression that present with sleep disturbances, lack of apparent sadness, or lack of inability to feel should be considered for aripiprazole augmentation.

Topics: Aged; Antidepressive Agents; Aripiprazole; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

A randomised placebo-controlled "dose relation study" was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10 mg/day, n=133), fixed dosage (25 mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25-50 mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D₁₇ total scores in favour of each agomelatine dose regimen (2.46 ± 0.76 points, p=0.001 at 10 mg; 4.71+0.75 points, p<0.0001 at 25 mg and 4.92 ± 0.76 points, p<0.0001 at 25-50 mg) with statistically significant differences between 25 mg and 25-50 mg dose regimens compared to the 10 mg dose. The response rate according to HAM-D₁₇ was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10 mg p=0.005; 25.9% and 27.4% respectively at 25 mg and 25-50 mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25 mg and 25-50 mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10 mg and the therapeutic dose regimen of agomelatine 25-50 mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10 mg) daily dose. The data support a definitive statement regarding the utility of 25 mg as the threshold dose for initiating agomelatine in depressed patients.

Topics: Acetamides; Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Middle Aged; Patient Dropouts; Psychiatric Status Rating Scales; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Young Adult

Post-hoc analysis of two randomized controlled trials with agomelatine was undertaken to compare data on pretreated versus untreated patients with major depressive disorder.. Selected trials were Olié and Kasper (2007), a placebo-controlled trial, and Kasper et al. (2010), a randomized, double-blind comparison with sertraline.. A total of 40% and 57.7% of patients had been pretreated with antidepressants in the placebo-controlled trial and sertraline-controlled trial, respectively. In the previously-treated patients in the placebo-controlled study, the mean decrease in the total score on the HAM-D₁₇ over 6 weeks was significantly greater with agomelatine than placebo (delta=4.43, P=0.005) and 67.5% of patients were responders. In the previously-treated patients of the sertraline-controlled study, the improvement on the HAM-D₁₇ total score remained numerically higher with agomelatine (delta=1.63, P=0.124), with 55.2% responders. In both studies, agomelatine was well tolerated.. Data from the subset of previously treated depressed patients, who can be considered more difficult to treat, indicate that agomelatine, due to its different mode of action, demonstrated antidepressant efficacy, and favorable side effect profile-with proven benefits in first-line treatment-is also an effective candidate for patients with major depressive disorder previously treated with other antidepressants.

Topics: Acetamides; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Monitoring; Drug Resistance; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Psychiatric Status Rating Scales; Receptors, Melatonin; Secondary Prevention; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Sertraline

Flibanserin, a novel 5-HT(1A) agonist and 5-HT(2A) antagonist, has the potential to treat sexual dysfunction.. Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction, based on post hoc analyses of data.. The Arizona Sexual Experiences (ASEX) scale and the Hamilton depression rating scale (HAMD) Genital Symptoms item.. Sexual function outcomes are presented from four double-blind, randomized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder. Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint. Two studies placebo, flibanserin (50mg bid), or fluoxetine (20mg qd) for 6 weeks and two involved placebo, flibanserin (50-100mg bid), or paroxetine (20-40mg qd) for 8 weeks.. Individual study completion rates were 77-80%. At baseline, 38% of men and 67% of women reported sexual dysfunction. Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent. Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies. In one study, 70% of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function, compared with 30% of placebo-treated women. Mean change from baseline on the HAMD "Genital Symptoms" item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4, 6, and 8 (P<0.05). Sexual function adverse events across flibanserin groups were generally comparable to placebo.. Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.

Topics: Adult; Benzimidazoles; Depressive Disorder, Major; Female; Humans; Libido; Male; Orgasm; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunction, Physiological

The objective of this international, 8-week, randomized, double-blind study was to show the superiority of the antidepressant efficacy of agomelatine, the first MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, versus fluoxetine in outpatients fulfilling Diagnostic and Statistical Manual of Mental Disorders-volume IV-TR criteria for major depressive disorder of severe intensity, defined by a baseline Hamilton Depression Rating Scale (HAM-D17) total score of at least 25 and CGI severity of illness score of at least 4. Patients received agomelatine 25-50 mg/day (n=252) or fluoxetine 20-40 mg/day (n=263) for 8 weeks. The main efficacy outcome measure was HAM-D17 total score (change from baseline to last post-baseline assessment). Secondary outcome measures were Clinical Global Impressions-improvement (CGI), severity (CGI-S), anxiety (HAM-A), and sleep (HAM-D sleep items) scores. The mean decrease in HAM-D17 total score over 8 weeks was significantly greater with agomelatine than fluoxetine with a between-group difference of 1.49 (95% confidence interval, 0.20-2.77; P=0.024). The percentage of responders at last post-baseline assessment was higher with agomelatine on both HAM-D17 (decrease in total score from baseline ≥50%; 71.7% agomelatine vs. 63.8% fluoxetine; P=0.060) and CGI-improvement (score 1 or 2; 77.7 vs. 68.8%; P=0.023). There was a significant between-group difference of 0.37 (95% confidence interval, 0.06-0.68) in HAM-D sleep subscore in favor of agomelatine (P=0.018). Similar improvements were observed on HAM-A with agomelatine and fluoxetine. Both treatments were safe and well tolerated. In conclusion, in this study, agomelatine showed superior antidepressant efficacy over fluoxetine in treating patients with a severe episode of major depressive disorder after 8 weeks of treatment with a good tolerability profile.

Topics: Acetamides; Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Female; Fluoxetine; Humans; Internationality; Male; Middle Aged; Patient Dropouts; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Young Adult

This study evaluates the efficacy of agomelatine, the first antidepressant that is an agonist at MT(1)/MT(2) receptors and an antagonist at 5-HT(2C) receptor, in the prevention of relapse of depression following successful response.. Patients with DSM-IV-TR major depressive disorder who responded to an 8- or 10-week course of agomelatine 25- or 50-mg daily treatment were randomly assigned to receive continuation treatment with agomelatine (n=165) or placebo (n=174) during a 24-week, randomized, double-blind treatment period. The main outcome measure was time to relapse during the double-blind treatment period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. The study was conducted from February 2005 to February 2007.. During the 6-month evaluation period, the incidence of relapse was significantly lower in patients who continued treatment than in those switched to placebo (P=.0001). The cumulative relapse rate at 6 months for agomelatine-treated patients was 21.7%; that for placebo-treated patients was 46.6%. Agomelatine was also superior to placebo in preventing relapse in the subset of patients with baseline 17-item Hamilton Depression Rating Scale total score > or = 25. Measures of tolerability and safety of both doses of agomelatine were similar to placebo. No pattern of early relapse or adverse events suggestive of withdrawal symptoms was obtained after abrupt cessation of agomelatine.. The findings are important in 2 respects. First, agomelatine is an effective and safe antidepressant continuation therapy, which confirms efficacy seen in short-term studies. Second, few early relapses were observed in the patient group switched to placebo: the survival curve for placebo separated gradually from that of patients taking agomelatine. We suggest this reflects solely the underlying properties of the illness, which is only possible due to the lack of discontinuation syndrome after agomelatine withdrawal. It underlines the novel clinical profile of agomelatine, which quite likely reflects its innovative pharmacology.. isrctn.org Identifier: ISRCTN53193024.

Topics: Acetamides; Adolescent; Adult; Aged; Depressive Disorder, Major; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypnotics and Sedatives; Kaplan-Meier Estimate; Male; Melatonin; Middle Aged; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Secondary Prevention; Serotonin 5-HT2 Receptor Antagonists; Substance Withdrawal Syndrome; Treatment Outcome

Current antidepressants used in major depressive disorder (MDD) are still not efficacious enough for many patients due to high levels of treatment resistance and bothersome side-effects. Using a novel blinding method (interactive voice response system), this flexible-dosing study examined the effects of therapeutic doses of agomelatine, a new approach to depressive therapy offering potent melatonergic MT1/MT2 receptor agonism with 5-HT2C receptor antagonist properties, in patients with moderate-to-severe MDD. This 6-wk, double-blind, parallel-group study randomized 238 patients to 25 mg/d agomelatine (with dose adjustment at 2 wk to 50 mg/d in patients with insufficient improvement) or placebo. Depression severity was assessed using the Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression (CGI) scale. Agomelatine was significantly more efficacious than placebo, with an agomelatine-placebo difference of 3.44 (p<0.001) using the HAMD final total score. Compared with placebo, agomelatine also had a significant positive impact on CGI - Improvement (treatment difference=0.45) and CGI - Severity (treatment difference=0.50) (both p=0.006), response rate (54.3% vs. 35.5% with placebo, p<0.05) and time to first response (p=0.008). Similar results were seen in patients with the most severe MDD. Depressed mood and sleep items of the HAMD were also significantly improved with agomelatine, which was well tolerated with a safety profile similar to placebo at both doses. This study confirms that agomelatine is effective in treating major depression, including the most severely depressed patients, with a good safety and tolerability profile, therefore providing physicians with an effective pharmacological approach to antidepressant therapy.

Topics: Acetamides; Adolescent; Adult; Aged; Analysis of Variance; Antidepressive Agents; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Prospective Studies; Receptors, Melatonin; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Time Factors; Treatment Outcome

Animal studies have found that many antidepressants induce decreases in both the density and the functional activity of the serotonin 2A (5-HT2A) receptor subtype. However, the extrapolation of findings to humans has been inconclusive. A physiological platelet response mediated by this receptor, the serotonin-amplified platelet aggregation, was measured to study whether long-term antidepressant treatment induces changes in 5-HT2A receptor functioning in endogenous depressed patients.. The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle scale). This index was used as an indirect measurement of the functional status of platelet 5-HT2A receptors. Aggregation studies were repeated once remission of the symptoms was achieved during treatment with imipramine (150-300 mg/day). A group of 15 concurrent normal subjects was used as a control.. A statistically significant decrease (p = 0.038) in the percentage of serotonin-amplified platelet aggregation to ADP was observed when remission was achieved (after 145 +/- 27 days).. The results showed a decrease in a platelet functional response mediated by 5-HT2A receptors following effective imipramine treatment, suggesting that desensitization or down-regulation of the 5-HT2A receptor function could be linked to the therapeutic effect of some antidepressants. The data also support the use of platelet aggregometry as a surrogate measurement of antidepressant action, particularly in intra-subject designs.

Topics: Adult; Antidepressive Agents, Tricyclic; Blood Platelets; Depressive Disorder, Major; Drug Administration Schedule; Female; Humans; Imipramine; Male; Platelet Aggregation; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists

Dysregulation of the serotonin (5-HT) system is a pathophysiological component in major depressive disorder (MDD), a condition closely associated with abnormal emotional responsivity to positive and negative feedback. However, the precise mechanism through which 5-HT tone biases feedback responsivity remains unclear. 5-HT2C receptors (5-HT2CRs) are closely linked with aspects of depressive symptomatology, including abnormalities in reinforcement processes and response to stress. Thus, we aimed to determine the impact of 5-HT2CR function on response to feedback in biased reinforcement learning.. We used two touchscreen assays designed to assess the impact of positive and negative feedback on probabilistic reinforcement in mice, including a novel valence-probe visual discrimination (VPVD) and a probabilistic reversal learning procedure (PRL). Systemic administration of a 5-HT2CR agonist and antagonist resulted in selective changes in the balance of feedback sensitivity bias on these tasks.. Specifically, on VPVD, SB 242084, the 5-HT2CR antagonist, impaired acquisition of a discrimination dependent on appropriate integration of positive and negative feedback. On PRL, SB 242084 at 1 mg/kg resulted in changes in behaviour consistent with reduced sensitivity to positive feedback. In contrast, WAY 163909, the 5-HT2CR agonist, resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback.. These results suggest that 5-HT2CRs tightly regulate feedback sensitivity bias in mice with consequent effects on learning and cognitive flexibility and specify a framework for the influence of 5-HT2CRs on sensitivity to reinforcement.

Topics: Aminopyridines; Animals; Azepines; Depressive Disorder, Major; Discrimination Learning; Indoles; Male; Mice; Probability Learning; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Reversal Learning; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Task Performance and Analysis; Visual Perception

Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here.

Topics: Adrenergic alpha-1 Receptor Antagonists; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Thiophenes

Topics: Acetamides; Animals; Antidepressive Agents; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome