Francesco Saverio Moschetta

The Emerging Role of Melatonin Agonists in the Treatment of Major Depression: Focus on Agomelatine

Major Depressive Disorder (MDD) is an extremely disabling, chronic and recurrent disease. Moreover, subthreshold depressive symptoms often persist during periods of apparent remission. Such symptoms include sleep disturbances, sexual dysfunction, weight gain, fatigue, disinterest, anxiety, and/or emotional blunting, which do not often respond to available antidepressant treatments. Agomelatine is a melatonergic agonist (at both MT1 and MT2 receptors) and serotonin 2C (5-HT2C) receptor antagonist. Agomelatine should be particularly useful in the treatment of MDD because of its unique pharmacological profile, accounting for its effective antidepressant action with a relative lack of serious adverse effects. Several clinical trials confirmed the antidepressant efficacy of agomelatine in patients with MDD, with significant efficacy even in severe manifestations of disease and on residual subtreshold symptoms. This compound showed a relative early onset of action as well as an excellent safety and tolerability profile linked to a low discontinuation rate in MDD patients. Moreover, some data suggest that agomelatine has not only antidepressant effects but also anxiolytic effects, with a potential benefit both on anxiety symptoms associated with MDD and in the treatment of generalised anxiety disorder. This review will summarise the role of the melatonergic system in MDD and will describe the characteristics of agomelatine, focusing on its efficacy and safety in the treatment of MDD.

THE EFFECT OF NEWER SEROTONIN-NORADRENALIN ANTIDEPRESSANTS ON CYTOKINE PRODUCTION: A REVIEW OF THE CURRENT LITERATURE

Cytokines may influence brain activities especially during stressful conditions, and elevated levels of IL-6 and C-reactive protein have been pointed out in subjects with Major Depression. If pro-inflammatory cytokines play a causative role in major depressive disorders, one would expect that antidepressants may down-regulate these cytokines or interfere with their actions, leading to improvement of depressive symptoms. Accumulating evidence has been published that antidepressants modulate cytokine production and this is particularly true for Tricyclics and Selective serotonin reuptake inhibitors (SSRIs), but the influence of newer antidepressants acting on both serotonin (5-HT) and norepinephrine (NE) such as venlafaxine, duloxetine and mirtazapine on cytokine levels has not been extensively studied. However, both pre-clinical and clinical studies examined in this review have demonstrated that newer serotonin-noradrenalin antidepressants can inhibit the production and/or release of pro-inflammatory cytokines and stimulate the production of anti-inflammatory cytokines, suggesting that reductions in inflammation might contribute to treatment response. Moreover, the results of the present review support the notion that the serotonin-noradrenalin antidepressants venlafaxine and mirtazapine may influence cytokine secretion in patients affected by MD, restoring the equilibrium between their physiological and pathological levels and leading to recovery. To date, no studies have evaluated the effect of duloxetine, the newest serotonin-noradrenalin antidepressant, on cytokine levels and therefore this should be evaluated in future studies.

Update on the Adverse Effects of Clozapine: Focus on Myocarditis

Clozapine, an atypical antipsychotic, is a dibenzodiazepine derivative and its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. In accordance to several studies, it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia. Moreover, clozapine appears to be particularly beneficial in patients with schizophrenia who are suicidal and in those with comorbid substance use disorder. However, despite its efficacy, the general use of clozapine in clinical practice is somewhat limited because of the risk of several serious adverse effects such as agranulocytosis and thromboembolism. Clozapine may be associated with fatal myocarditis and cardiomyopathy in physically healthy young adults. Consequently, the FDA and the drugs manufacturer have strengthened warnings to include that a potentially fatal myocarditis may occur when taking clozapine. In the present paper the literature on clozapine-related myocardis will be reviewed and practical advice will be given concerning the diagnosis and management of such potentially fatal adverse effect.

Alexithymia and Suicide Ideation in a Sample of Patients with Binge Eating Disorder

Objective. The goal of this cross-sectional study was to evaluate the relationships between alexithymia and suicide ideation in 80 adult outpatients with a DSM-IV diagnosis of binge eating disorder (BED). Methods. Alexithymia was measured with the 20-item Toronto Alexithymia Scale (TAS-20); suicide ideation was assessed with the Scale of Suicide Ideation (SSI); severity of BED was assessed with the Binge Eating Scale (BES); and depressive and anxiety symptoms were evaluated, respectively, with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (Ham-A). Results. Prevalence of current suicide ideation was 27.5% (n=22) in this sample and 10 subjects (12.5%) had attempted suicide at some time in their lives. Subjects with alexithymia had more significant suicide ideation, a higher prevalence of current suicide ideation, and more previous suicide attempts than those without alexithymia. In a linear regression model, higher MADRS scores and higher scores on the Difficulty in Identifying Feelings/Difficulty in Describing Feelings dimensions of the TAS-20 were associated with increased suicide ideation. Discussion. Suicidal behavior is no less common in BED than in other eating disorders. Individuals with BED may show increased suicide ideation, especially in the presence of alexithymia and depressive symptoms, even if these symptoms are subclinical. The authors also discuss limitations of this study and future research needs. (Journal of Psychiatric Practice 2012;18:5–11)

Impaired sustained attention in euthymic bipolar disorder patients and non-affected relatives: an fMRI study

Sepede G, De Berardis D, Campanella D, Perrucci MG, Ferretti A, Serroni N, Moschetta FS, Del Gratta C, Salerno RM, Ferro FM, Di Giannantonio M, Onofrj M, Romani GL, Gambi F. Impaired sustained attention in euthymic bipolar disorder patients and non‐affected relatives: an fMRI study. Bipolar Disord 2012: 14: 764–779.

The role of C-reactive protein in mood disorders.

Recently, a possible relationship between C-Reactive Protein (CRP), a marker of underlying low-grade inflammation, and mood disorders has been proposed by some researchers. The aim of this review is to elucidate the current facts and views about CRP in mood disorders such as Depressive and Bipolar Disorders. Several studies have examined the relationship between affective disorders and CRP, but the majority of the studies in literature have been limited by retrospective, case-controlled study design, and very few studies have examined the relationship between depression and CRP in large study samples. In conclusion, the role of CRP in mood disorders is, to date, intriguing but somewhat unclear. Further prospective studies are needed to introduce the CRP in clinical settings as a marker of affective states and suicidability.

Alexithymia, suicide risk and serum lipid levels among adult outpatients with panic disorder

To elucidate the relationships between alexithymia, suicide ideation and serum lipid levels in drug-naïve adult outpatients with a DSM-IV diagnosis of Panic Disorder (PD), 72 patients were evaluated. Measures were the Panic Attack and Anticipatory Anxiety Scale, the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI) and the Montgomery Åsberg Depression Rating Scale (MADRS). Alexithymic patients showed higher scores on all rating scales and altered serum lipid levels than non-alexithymics. In the hierarchical regression model, the presence of lower HDL-C and higher VLDL-C levels and Difficulty in Identifying Feelings dimension of TAS-20 were associated with higher suicide ideation. In conclusion, alexithymic individuals with PD may show a cholesterol dysregulation that may be linked to suicide ideation. The authors discuss study limitations and future research needs.

Neuropsychological functioning in young subjects with generalized anxiety disorder with and without pharmacotherapy.

The purpose of this study was to investigate the neuropsychological functioning and the effect of antidepressant drug intake on cognitive performance in a group of relatively young generalized anxiety disorder (GAD) patients. Forty patients with a DSM-IV diagnosis of GAD and 31 healthy subjects participated in the study (Control group, CON). None of the selected subjects had comorbid depression. GAD subjects were divided into two different subgroups: 18 were taking antidepressants [GAD-pharmacotherapy (GAD-p group)] and 22 were treatment-naïve (GAD group). Each group was administered with a comprehensive neuropsychological battery to assess attention, memory and executive functions. Performance on executive and non-verbal memory tasks of both GAD groups was largely worse than the CON group. However, these deficits seem to be more marked in patients taking antidepressants, especially in the domains of attention, non-verbal memory and executive functions. The present study indicates that GAD is associated with cognitive impairments among young adults. However, the observed association of neuropsychological deficits and the use of pharmacotherapy suggest a possible effect of antidepressant treatment on attention, executive functioning and non-verbal memory.

A case of obsessive-compulsive disorder successfully treated with agomelatine monotherapy.

To the Editors: Obsessive-compulsive disorder (OCD) is a chronic condition characterized by obsessions or compulsions that cause distress or interfere with functioning. Although there is extensive evidence pointing to the efficacy of clomipramine and selective serotonin reuptake inhibitors in the treatment of OCD, both antidepressant drugs are associated with numerous adverse effects (such as weight gain and sexual dysfunctions) that may significantly impact on patient quality of life. Agomelatine is a novel antidepressant drug with melatonergic and serotonergic properties that acts as a full agonist at the melatonin MT1 and MT2 receptors and binds to the serotonin 5-HT2C, 5-HT2B, and 5-HT1A receptors, without causing clinically significant sexual adverse effects or weight gain. Moreover, agomelatine increases dopamine and noradrenaline levels in the frontal cortex and stimulates cell proliferation and neurogenesis. In a recent case series, agomelatine has been reported to lead to a significant improvement in OCD symptoms. In the present case report, we describe the case of a young female patient with severe OCD who remitted as a result of the initiation of agomelatine monotherapy.

Agomelatine Augmentation of Escitalopram Therapy in Treatment-Resistant Obsessive-Compulsive Disorder: A Case Report

Obsessive-compulsive disorder (OCD) is a chronic condition characterized by obsessions or compulsions that cause distress or interfere with functioning. Selective serotonin reuptake inhibitors are the first-line strategy in the treatment of OCD, but approximately 40% to 60% of patients with OCD fail to respond to them. Several augmentation strategies have been proposed, including the use of atypical antipsychotics and antidepressant combinations. In the present paper we describe the case of a young female patient suffering from severe treatment-resistant OCD who remitted as a result of agomelatine augmentation of escitalopram therapy.