Vortioxetine 5, 10, and 20 mg significantly reduces the risk of relapse compared with placebo in patients with remitted major depressive disorder: The RESET study.

BACKGROUND: Maintenance therapy for major depressive disorder (MDD) is typically recommended at the dose on which the patient was stabilized. However, for some patients, dose alteration may be required. We investigated multiple vortioxetine doses versus placebo for relapse prevention in patients achieving remission with vortioxetine 10 mg daily. METHODS: In this US-based, randomized withdrawal study, outpatients (N = 1106, aged 18-75 years) with recurrent MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥26), a current major depressive episode (MDE) (8 weeks-18 months' duration), and ≥2 previous MDEs were treated with open-label vortioxetine 10 mg once daily orally for 16 weeks. Responders at week 8 (≥50% MADRS score reduction) achieving remission (MADRS score ≤12) at weeks 14 and 16 (N = 580) were randomized to vortioxetine 5, 10, or 20 mg or placebo in a 32-week double-blind period. The primary outcome was time to first relapse over the first 28 weeks; secondary outcomes (relapse, change in total MADRS, Clinician Global Impression-Severity [CGI-S]) were evaluated at 32 weeks. RESULTS: Time to relapse was longer and cumulative relapse rates were lower for vortioxetine 5 mg (19.3%), 10 mg (17.9%), and 20 mg (17.4%) versus placebo (32.5%) over 28 weeks (p<0.05 for all). CGI-S scores remained stable and adverse events were generally mild-to-moderate. LIMITATIONS: Extrapolation of results to patients achieving remission with vortioxetine doses other than 10 mg should be made with caution. CONCLUSION: For patients with MDD achieving symptomatic remission at 10 mg/day, all doses of vortioxetine were effective for relapse prevention, with acceptable tolerability.

Using self-reported vocational functioning measures to identify employed patients with impaired functional capacity in major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) show impairments in cognitive functioning, including deficits on performance-based measures of functional capacity. A proportion of patients with MDD may achieve higher scores at baseline, and may not show a detectable response to treatment. How to identify these cases is the goal of this investigation. METHODS: Retrospective analyses of data from the CONNECT study with vortioxetine were performed to determine whether the Work Limitations Questionnaire (WLQ) can be used to exclude very high-performing patients on the functional capacity outcome measure, University of California San Diego Performance-Based Skills Assessment (UPSA), in studies evaluating cognitive function impairment in MDD, to identify those with greater potential for treatment response. The post-hoc analyses included data on cognitive function assessed with a Digit Symbol Substitution Test (DSST) from vortioxetine-treated patients. RESULTS: WLQ score >13 identified patients with greater impairments in UPSA-Brief (UPSA-B). Patients with WLQ scores >13, but not with scores ≤13, showed statistically significant improvements with vortioxetine treatment in UPSA-B and DSST compared with placebo. LIMITATIONS: Study limitations include small sample size and use of post-hoc analyses. The generalizability of this analysis is limited to working patients with MDD. CONCLUSIONS: The WLQ can be used to identify patients with MDD with high potential for treatment response in studies evaluating cognitive function impairment while excluding patients likely to achieve ceiling scores on UPSA. This approach helps identify higher performers on potential outcomes measures without biasing the study by requiring a specific UPSA cutoff score for eligible participants.

Brain serotonin transporter binding in former users of MDMA ('ecstasy').

BACKGROUND: Animal experimental studies have prompted concerns that widespread use of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') by young people may pose a major public health problem in terms of persistent serotonin neurotoxicity. AIMS: To determine the status of brain serotonin neurons in a group of abstinent MDMA users. METHOD: We assessed the integrity of brain serotonin neurons by measuring serotonin transporter (SERT) binding using positron emission tomography (PET) and [(11)C]DASB in 12 former MDMA users, 9 polydrug users who had never taken MDMA and 19 controls who reported no history of illicit drug use. RESULTS: There was no significant difference in the binding potential of [(11)C]DASB between the groups in any of the brain regions examined. CONCLUSIONS: To the extent that [(11)C]DASB binding provides an index of the integrity of serotonin neurons, our findings suggest that MDMA use may not result in long-term damage to serotonin neurons when used recreationally in humans.

Human 5-HT transporter availability predicts amygdala reactivity in vivo.

The amygdala plays a central role in fear conditioning, emotional processing, and memory modulation. A postulated key component of the neurochemical regulation of amygdala function is the neurotransmitter 5-hydroxytryptamine (5-HT), and synaptic levels of 5-HT in the amygdala and elsewhere are critically regulated by the 5-HT transporter (5-HTT). The aim of this study was to directly examine the relationship between 5-HTT availability and amygdala activity using multimodal [positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)] imaging measures in the same individuals. Healthy male volunteers who had previously undergone an [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]-DASB) PET scan to determine 5-HTT availability completed an fMRI emotion recognition task. [11C]-DASB binding potential values were calculated for the amygdala using arterial input function and linear graphical (Logan) analysis. fMRI was performed on a 3T Philips Intera scanner, and data were analyzed using SPM2 (Wellcome Department Imaging Neuroscience, University College London). Percentage signal change during the task was extracted from the amygdala using MarsBaR (Brett et al., 2002). fMRI analysis revealed significant amygdala activation during the emotion recognition task. Region of interest analyses demonstrated a significant negative correlation between fMRI signal change in the left amygdala and 5-HTT availability in the left amygdala, with 5-HTT availability accounting for approximately 42% of the variability in left amygdala activity. Our novel in vivo data highlight the central importance of the serotonergic system in the responsiveness of the human amygdala during emotional processing.

A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans.

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Diminished brain 5-HT transporter binding in major depression: a positron emission tomography study with [11C]DASB.

BACKGROUND: The serotonin transporter (5-HTT) plays a critical role in the regulation of serotonin neurotransmission and has been implicated in the pathophysiology of major depression. In a previous positron emission tomography study, we found no difference in brain 5-HTT binding between unmedicated recovered depressed patients and healthy controls. AIM: This study aims to assess brain 5-HTT binding in a group of unmedicated acutely depressed patients in comparison to healthy controls. METHODS: We studied 5-HTT binding using [(11)C]DASB in conjunction with positron emission tomography in 12 medication-free depressed patients with a mean duration of illness of about 1 year and 24 healthy controls. RESULTS: The depressed patients had lowered 5-HTT binding in several brain regions including brain stem, thalamus, caudate, putamen, anterior cingulate cortex and frontal cortex. CONCLUSIONS: These results suggest that diminished availability of the 5-HTT in the brain may be a state marker of acute depression. Alternatively, low 5-HTT binding may delineate a group of depressed patients with a poor long-term prognosis.

Autistic-like behaviour profile and psychiatric morbidity in Fragile X Syndrome: a prospective ten-year follow-up study.

In subjects with Fragile X Syndrome (FXS), the mutation of Fragile X Mental Retardation Type 1 ( FMR-1) gene at Xq27.3 predisposes to Mental Retardation (MR), autistic-like behaviour and to a variety of psychiatric syndromes. However, the longitudinal course of autistic-like behaviour profile and psychiatric morbidity is untested. In this study, we followed up people with FXS for 10 years to establish the stability of their autistic- like behaviour profile and psychiatric morbidity. The autisticlike behaviour profile was assessed using Brief Disability Assessment Schedule (B-DAS) and relevant items from Handicaps, Behaviour and Skills (HBS) Schedule. The psychiatric morbidity was assessed using data from the case notes, Mini Psychiatric Assessment Schedule for Adults with Developmental Disability (Mini PAS-ADD) and clinical interview. Our findings suggest that the autistic-like behaviour pattern is a stable phenotypic feature of FXS, but for increase in resistance to change over time. There is a tenfold increase in the prevalence of psychiatric morbidity in FXS compared to the general population, which does not increase significantly over time.