A Systematic, Updated Review on the Antidepressant Agomelatine Focusing on its Melatonergic Modulation

To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine

Psychotic and nonpsychotic mood disorders in autoimmune encephalitis: diagnostic issues and research implications

Recent research on autoimmune disorders suggests additional links between systemic and central nervous system (CNS) pathophysiology, among which the identification of antibody-induced limbic encephalitis provided the strongest evidence for the potential involvement of autoimmunity in the pathogenesis of severe mood and psychotic symptoms. In these illnesses, psychiatric symptoms predominate in the initial phase of the disorder in up to 70% of the cases, and they often lead patients to early psychiatric evaluation. For this reason, it is very important to increase the limited knowledge among psychiatrists about these autoimmune neuropsychiatric diseases, which can mimic psychiatric syndromes, in particular, those typically presented in severe mood disorders and schizophrenia. On the other hand, similarities in clinical presentation suggest that neuroinflammation and systemic immune dysregulation may play a role in the pathophysiology of severe mood and psychotic disorders. A complex interaction between periphery and immune cells of the CNS may result in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. These pathways are possibly shared between comorbid medical disorders and severe mood and psychotic disorders and may reflect common underlying vulnerability

Increase in IL-6 levels among major depressive disorder patients after a 6-week treatment with duloxetine 60 mg/day: a preliminary observation

Immune modifications, including changes in interleukin (IL)-6 levels, have often been observed in major depressive disorder (MDD) during treatment with selective serotonin reuptake inhibitors (SSRIs) or the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine. Nevertheless, no equivalent observation for the SNRI duloxetine has been made to date

An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects

Background: Despite multiple antidepressant options, major depressive disorder (MDD) still faces high non-response rates, eventually requiring anticonvulsant augmentation strategies too. The aim of this study was to explore such a potential role for zonisamide.Methods: A total of 40 MDD outpatients diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, fourth edition criteria entered a 24 week open trial receiving duloxetine 60 mg/day for the first 12 weeks and subsequently (weeks 12 to 24) augmentation with zonisamide 75 mg/day if they did not respond to the initial monotherapy. Efficacy and tolerability were assessed using the Hamilton Scales for Anxiety and Depression (a 12 week score 6550% vs baseline defined 'non-response'), the Arizona Sexual Experience Scale, the Patient Rated Inventory of Side Effects and the Young Mania Rating Scale.Results: At week 12, 15 patients out of 39 (38.5%) were responders, and 1 had dropped out; remarkably, 14 patients out of 24 (58.3%) had achieved response by week 24. Poor concentration and general malaise were associated with non-response both at week 12 and 24 (P = 0.001), while loss of libido and reduced energy were prominent among final timepoint non-responders. Patients receiving zonisamide also experienced weight reduction (2.09 \ub1 12.14 kg; P = 0.001) independently of the outcome.Conclusions: Although only a preliminary study due to strong methodological limitations, and thus requiring confirmation by further controlled investigations, the current results indicate zonisamide may be a potential augmentation option for some depressed patients receiving low doses of duloxetine. \ua9 2011 Fornaro et al; licensee BioMed Central Ltd

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

AbstractAn increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was −0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (−0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (−0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (−0.345). Study characteristics that resulted in low signal detection in our database were: 5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy

Anxiety Disorders in Children and Adolescents with Bipolar Disorder: A Neglected Comorbidity

Objective: We describe a consecutive clinical sample of children and adolescents with bipolar disorder to define the pattern of comorbid anxiety and externalizing disorders (attention-deficit hyperactivity disorder [ADHD] and conduct disorder [CD]) and to explore the possible influence of such a comorbidity on their cross-sectional and longitudinal clinical characteristics. Methods: The sample comprised 43 outpatients, 26 boys and 17 girls, (mean age 14.9 years, SD 3.1; range 7 to 18), with bipolar disorder type I or II, according to DSM-IV diagnostic criteria. All patients were screened for psychiatric disorders using historical information and a clinical interview, the Diagnostic Interview for Children and Adolescents-Revised (DICA-R). To shed light on the possible influence of age at onset, we compared clinical features of subjects whose bipolar onset was prepubertal or in childhood (< 12 years) with those having adolescent onset. We also compared different subgroups with and without comorbid externalizing and anxiety disorders. Results: Bipolar disorder type I was slightly more represented than type II (55.8% vs 44.2%). Only 11.6% of patients did not have any other psychiatric disorder; importantly, 10 subjects (23.5%) did not show any comorbid anxiety disorder. Comorbid externalizing disorders were present in 12 (27.9%) patients; such comorbidity was related to the childhood onset of bipolar disorder type II. Compared with other subjects, patients with comorbid anxiety disorders more often reported pharmacologic (hypo)mania

Insomnia symptoms predict emotional dysregulation, impulsivity and suicidality in depressive bipolar II patients with mixed features

Abstract Introduction Insomnia symptoms are very common in Bipolar Disorder. Our aim was to assess the potential association between insomnia, emotion dysregulation and suicidality in subjects with Bipolar Disorder. Methods Seventy-seven subjects with Bipolar Disorder type II with a depressive episode with mixed features were recruited. Patients were assessed with SCID-DSM-5, the Insomnia Severity Index (ISI), the Difficulties in Emotion Regulation Scale (DERS), the Scale for Suicide Ideation (SSI) while evaluating manic and depressive symptoms. Results Subjects with insomnia symptoms compared to those without showed higher scores in the DERS scale and subscales, including impulsivity, and in the SSI scale. Insomnia symptoms significantly predicted the severity of depressive symptoms, emotion dysregulation, and suicidality in subjects with bipolar disorder. In particular, insomnia was related to difficulties in some areas of emotion regulation including impulsivity. Emotion dysregulation significantly mediated the association between insomnia and depressive symptoms (Z = 2.9, p = 0.004). Furthermore, emotional impulsivity mediated the association between insomnia symptoms and suicidality (Z = 2.2, p = 0.03). Conclusion In our study, subjects with bipolar disorder suffering from insomnia experienced a greater severity of depressive symptoms and suicidality compared to subjects without insomnia. Insomnia was associated with emotion dysregulation, impulsivity and suicidality. Further research is necessary to investigate if these latter features may benefit from early insomnia treatment in subjects with bipolar disorder

Phenomenology and Comorbidity of Dysthymic Disorder in 100 Consecutively Referred Children and Adolescents: Beyond DSM-IV

Objective: Diagnostic criteria and nosological boundaries of juvenile dysthymic disorder (DD) are underresearched. Two different sets of diagnostic criteria are still discussed in the DSM-IV, the first giving major weight to somatic and vegetative symptoms and the second, included in the appendix, to more affective and cognitive symptoms. The aim of this study was to describe prototypical symptomatology and comorbidity of DD, according to DSM-IV criteria, in a consecutive series of referred children and adolescents, as a function of age and sex. Method: One hundred inpatients and outpatients (36 children and 64 adolescents, 57 males, 43 females, age range 7 to 18 years, mean age 13.3 years) received a diagnosis of DD without comorbid major depressive disorder (MDD), using historical information, the Diagnostic Interview for Children and Adolescents-Revised (DICA-R), and symptoms ratings according to the DSM-IV criteria. Results: Irritability, low self-esteem, fatigue or loss of energy, depressed mood, guilt, concentration difficulties, anhedonia, and hopelessness were present in more than 50% of subjects. Differences in symptomatic profile between male and female patients were not significant. Anxiety disorders were commonly comorbid with DD, mainly generalized anxiety disorder, simple phobias, and in prepuberal children, separation anxiety disorder. Externalizing disorders were reported in 35% of the patients, with higher prevalence in male patients. Adolescents showed more suicidal thoughts and anhedonia than children. Conclusions: The clinical picture of early-onset DD we found, based entirely on a pure sample without current and past MDD, is not totally congruent with the diagnostic criteria according to DSM-IV. A more precise definition of the clinical picture may help early diagnosis and prevention of superimposed mental disorders

Adult separation anxiety in patients with complicated grief versus healthy control subjects: relationships with lifetime depressive and hypomanic symptoms

<p>Abstract</p> <p>Background</p> <p>Around 9% to 20% of bereaved individuals experience symptoms of complicated grief (CG) that are associated with significant distress and impairment. A major issue is whether CG represents a distinctive nosographic entity, independent from other mental disorders, particularly major depression (MD), and the role of symptoms of adult separation anxiety. The purpose of this study was to compare the clinical features of patients with CG versus a sample of healthy control subjects, with particular focus on adult separation anxiety and lifetime mood spectrum symptoms.</p> <p>Methods</p> <p>A total of 53 patients with CG and 50 healthy control subjects were consecutively recruited and assessed by means of the Structured Clinical Interview for DSM-IV Axis-I disorders (SCID-I/P), Inventory of Complicated Grief (ICG), Adult Separation Anxiety Questionnaire (ASA-27), Work and Social Adjustment Scale (WSAS) and Mood Spectrum-Self Report (MOODS-SR) lifetime version.</p> <p>Results</p> <p>Patients with CG reported significantly higher scores on the MOODS-SR, ASA-27, and WSAS with respect to healthy control subjects. The scores on the ASA-27 were significantly associated with the MOODS-SR depressive and manic components amongst both patients and healthy control subjects, with a stronger association in the latter.</p> <p>Conclusions</p> <p>A major limitation of the present study is the small sample size that may reduce the generalizability of the results. Moreover, lifetime MOODS-SR does not provide information about the temporal sequence of the manic or depressive symptoms and the loss. The frequent comorbidity with MD and the association with both depressive and manic lifetime symptoms do not support the independence of CG from mood disorders. In our patients, CG is associated with high levels of separation anxiety in adulthood. However, the presence of lifetime mood instability, as measured by the frequent presence of depressive and hypomanic lifetime symptoms, suggests that cyclothymia might represent the common underlying feature characterizing the vulnerability to both adult separation anxiety and CG.</p