Efficacy of Agomelatine 25-50 mg for the Treatment of Anxious Symptoms and Functional Impairment in Generalized Anxiety Disorder: A Meta-Analysis of Three Placebo-Controlled Studies.

INTRODUCTION: The purpose of this study is to investigate the effects of agomelatine on anxious symptoms and functional impairment in a pooled dataset from randomized placebo-controlled trials for generalized anxiety disorder (GAD). METHODS: Data from three randomized, placebo-controlled trials that evaluated the efficacy of agomelatine 25-50 mg were pooled. The short-term (12 weeks) efficacy of agomelatine was assessed in regards to (1) anxious symptoms using the Hamilton Anxiety Scale (HAM-A), and (2) functional impairment using the Sheehan Disability Scale (SDS). Meta-analysis using a random effect model was used to assess differences between groups. Remission and response rates for the HAM-A and SDS were calculated, and analyses were repeated in participants with more severe anxiety symptoms. RESULTS: In total, 669 patients (340 on agomelatine; 329 on placebo) were included in the analyses. Compared to placebo, the agomelatine group had a significant reduction in HAM-A total score at week 12 (between group difference: 6.30 ± 2.51, p = 0.012). Significant effects were also found for symptom response on the HAM-A (67.1% of patients on agomelatine vs. 32.5% on placebo) and symptom remission (38.8% of patients on agomelatine vs. 17.3% on placebo). Compared to placebo, there was a significant difference in favour of the agomelatine group at week 12 on the SDS total score (5.11 ± 1.81, p = 0.005). Significant effects were also found for functional response on the SDS (79.1% of patients on agomelatine vs. 43.2% of placebo) and functional remission (55.2% of patients on agomelatine vs. 25.4% on placebo). All findings for anxious symptoms and functional impairment were confirmed in the subset of more severely anxious patients. Agomelatine was well tolerated by patients. CONCLUSION: This meta-analysis confirms that agomelatine reduces anxiety symptoms and improves the global functioning of GAD patients.

A clinical approach to treatment resistance in depressed patients: What to do when the usual treatments don't work well enough?

BACKGROUND: Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility. AIM: This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression? METHOD: Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD - World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing. OUTCOMES: The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of 'deconstructing depression'. By this approach, the clinician considers which factors contribute to making this individual both depressed and 'resistant' to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual's hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan. LIMITATIONS: A 'deconstructing depression' qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD. CONCLUSIONS: MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient's depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence.

Efficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial

Objective: Bipolar depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp's properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for bipolar depression. Methods: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment. Conclusion: The findings of this study may have implications for improving treatment outcomes for those with bipolar disorder and may contribute to our understanding of the pathophysiology of bipolar depression. Clinical trial registration: Australian and New Zealand Clinical Trial Registry, ACTRN12616000028404.

The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia.

New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders.

Efficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial.

OBJECTIVE: Bipolar depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp's properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for bipolar depression. METHODS: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment. CONCLUSION: The findings of this study may have implications for improving treatment outcomes for those with bipolar disorder and may contribute to our understanding of the pathophysiology of bipolar depression. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ACTRN12616000028404.

12-week double-blind randomized multicenter study of efficacy and safety of agomelatine (25-50 mg/day) versus escitalopram (10-20 mg/day) in out-patients with severe generalized anxiety disorder.

Treatment of severely symptomatic patients with generalized anxiety disorder (GAD) raises particular concerns for clinicians. This 12-week double-blind study evaluated the efficacy of agomelatine (25-50 mg/day) in the treatment of patients with severe GAD, using escitalopram (10-20 mg) as active comparator. The primary outcome measure was the change from baseline of the total score on the Hamilton Anxiety scale (HAM-A) at week 12. Secondary outcome measures included rate of response to treatment (at least 50% score reduction from baseline) in the HAM-A psychic and somatic anxiety sub-scores, Clinical Global Impression severity and change scores, the Toronto Hospital Alertness Test, the Snaith-Hamilton Pleasure Scale, and the Leeds Sleep Evaluation Questionnaire Scores. Sixty one clinical centers (Australia, Canada, Czech Republic, Finland, Germany, Hungary, Poland, Russia, Slovakia) participated from April 2013 to February 2015. Patient characteristics and demographic data were comparable between treatment groups. Both treatments were associated with a clinically significant decrease in HAM-A total score at week 12; the non-inferiority of agomelatine versus escitalopram was not demonstrated (E(SE) = -0.91(0.69), 95%CI = [-2.26, 0.44], p = 0.195). At week 12, the response rate was 60.9% in the agomelatine group, and 64.8% in the escitalopram group. In both treatment arms, HAM-A psychic and somatic anxiety scores decreased, alertness and sleep parameters improved, and ability to experience pleasure increased. In these secondary outcome measures, there were no significant differences between the treatment groups. Agomelatine was well-tolerated, with a lower incidence of adverse events than escitalopram. Agomelatine and escitalopram are efficacious in treating GAD patients with severe symptoms.

The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013.

OBJECTIVES: We present the global burden of bipolar disorder based on findings from the Global Burden of Disease Study 2013 (GBD 2013). METHODS: Data on the epidemiology of bipolar disorder were obtained from a systematic literature review and assembled using Bayesian meta-regression modelling to produce prevalence by country, age, sex and year. Years lived with disability (YLDs) were estimated by multiplying prevalence by disability weights quantifying the severity of the health loss associated with bipolar disorder. As there were no years of life lost (YLLs) attributed to bipolar disorder, YLDs equated to disability-adjusted life years (DALYs) as a measure of total burden. RESULTS: There were 32.7 million cases of bipolar disorder globally in 1990 and 48.8 million in 2013; equivalent to a 49.1% increase in prevalent cases, all accounted for by population increase and ageing. Bipolar disorder accounted for 9.9 million DALYs in 2013, explaining 0.4% of total DALYs and 1.3% of total YLDs. There were 5.5 million DALYs recorded for female individuals and 4.4 million for male individuals. DALYs were evident from age 10 years, peaked in the 20s, and decreased thereafter. DALYs were relatively constant geographically. CONCLUSIONS: Despite being relatively rare, bipolar disorder is a disabling illness due to its early onset, severity and chronicity. Population growth and aging are leading to an increase in the burden of bipolar disorder over time. It is important that resources be directed towards improving the coverage of evidence-based intervention strategies for bipolar disorder and establishing strategies to prevent new cases of the disorder.

A consensus statement for safety monitoring guidelines of treatments for major depressive disorder.

OBJECTIVE: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. METHOD: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. RESULTS: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. CONCLUSION: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.