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Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder.
OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for pediatric major depressive disorder (MDD). We conducted a meta-analysis to examine the following: the time-course of response to SSRIs in pediatric depression; whether higher doses of SSRIs are associated with an improved response in pediatric depression; differences in efficacy between SSRI agents; and whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD. METHOD: We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo groups. RESULTS: The meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating that the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data (log[week] = 0.10, 95% CI = 0.06-0.15, p < .0001). There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD. CONCLUSION: Treatment gains in pediatric MDD are greatest early in treatment and are, on average, minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response (e.g., 2-4 weeks) to predict outcomes in short-term pharmacological trials.
Who needs AESOP? Predicting long-term readmission rates from routine Early Intervention team discharge information.
AIM: Prognosis following early psychosis is highly variable. Long-term prognostic information from research studies is available in only a few areas. We sought to understand how well routine discharge information allows prediction of long-term readmission prognosis. METHODS: We reviewed the records of 239 people leaving Early Intervention services, after an average of 2.5 years, and counted the number of relapses. The distribution was modelled and extrapolated to a predicted 10 year outcome. Model predictions were compared with published data. RESULTS: Numbers of relapses varied substantially, with 59% having no relapses before discharge, and 5% having 4 or more. Model predictions for 10-year outcome were close to the observed data. CONCLUSIONS: A simple model can describe the distribution of numbers of relapses among people discharged from EI services, and predict long-term outcomes matching those observed in formal research. This low-cost approach could allow EI services to develop locale-specific prognostic information.
Delays before diagnosis and initiation of treatment in patients presenting to mental health services with bipolar disorder
© 2015 Patel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare. Method: Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay). Results: The median diagnostic delay was 62 days (interquartile range: 17-243) and median treatment delay was 31 days (4-122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18-3.06) and treatment delay (4.40, 3.63-5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33-0.41) and substance misuse disorders (0.44, 0.31-0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay. Conclusions: Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner in order to facilitate improved clinical outcomes, such as developing specialist early intervention services to identify and treat people with bipolar disorder.
Evidence that increased 5-HT release evokes region-specific effects on blood-oxygenation level-dependent functional magnetic resonance imaging responses in the rat brain.
This study aimed to determine the potential of in vivo functional magnetic resonance imaging (fMRI) methods as a non-invasive means of detecting effects of increased 5-HT release in brain. Changes in blood-oxygenation level-dependent (BOLD) contrast induced by administration of the 5-HT-releasing agent, fenfluramine, were measured in selected brain regions of halothane-anesthetized rats. Initial immunohistochemical measurements of the marker of neural activation, Fos, confirmed that in halothane-anesthetized rats fenfluramine (10 mg/kg i.v.) evoked cellular responses in cortical regions which were attenuated by pre-treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (300 mg/kg i.p. once daily for 2 days). Fenfluramine-induced Fos was demonstrated in numerous glutamatergic pyramidal neurons (Fos/excitatory amino acid carrier 1 (EAAC1) co-labeled), but also a small number of GABA interneurons (Fos/glutamic acid decarboxylase (GAD)(67) colabeled). Fenfluramine (10 mg/kg i.v.) evoked changes in BOLD signal intensity in a number of cortical and sub-cortical regions with the greatest effects being observed in the nucleus accumbens (-13.0%+/-2.7%), prefrontal cortex (-10.1%+/-3.2%) and motor cortex (+2.3%+/-1.0%). Pre-treatment with p-chlorophenylalanine, significantly attenuated the response to fenfluramine (10 mg/kg i.v.) in all regions with the exception of the motor cortex which showed a trend. These experiments demonstrate that increased 5-HT release evokes region-specific changes in the BOLD signal in rats, and that this effect is attenuated in almost all regions by 5-HT depletion. These findings support the use of fMRI imaging methods as a non-invasive tool to study 5-HT function in animal models, with the potential for extension to clinical studies.
Antidepressant response and the serotonin transporter gene-linked polymorphic region.
BACKGROUND: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44-base pair-long region gives rise to short "S" and long "L" forms of the promoter region, the "S" form being associated with reduced serotonin transporter expression. METHODS: A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested-SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL. RESULTS: There was no statistically significant effect on antidepressant response. Compared with L carriers, there was an apparent effect of the SS genotype on remission rate (relative risk: .88; 95% confidence interval: .79-.98; p = .02). However, after trim and fill correction for missing data, the effect disappeared (relative risk: .92; 95% confidence interval: .81-1.05; p = .23), indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases. CONCLUSIONS: The 5-HTTLPR biallelic short/long polymorphism by itself does not seem to usefully predict antidepressant response.
A noisy transform predicts saccadic and manual reaction times to changes in contrast
One of the most important factors affecting the time taken to respond to a visual stimulus is contrast, and studies of reaction time can provide precise, quantitative information about the underlying signal processing. In this study we measured both saccadic and manual reaction times to step increments in target contrast. Our results over a range of initial contrasts are consistent with a simple model consisting of a noisy logarithmic transducer followed by a rise-to-threshold accumulator. A systematic comparison with previous contrast-processing models also shows that the commonly used method of linear regression may not be a particularly sensitive tool in deciding between them. We found similar parameters for the contrast processor in both saccadic and manual reaction times, as might be expected if a common target detection stage precedes each type of reaction. © 2006 The Authors. Journal compilation © 2006 The Physiological Society.
Effect of sustained cyclovergence on eye alignment: Rapid torsional phoria adaptation
PURPOSE. To describe adaptive changes in torsional alignment that follow sustained cyclovergence in healthy humans. METHODS. Eye movements were recorded binocularly from four healthy subjects using dual-coil scleral annuli. Cyclovergence movements were evoked over periods of 30 to 150 seconds using a stereoscopic display, presenting gratings of lines arranged horizontally, vertically, or at 45°, subtending angles of up to 48°. In- and excyclodisparities of 5°were introduced and removed in a single-step fashion. After stimulation, the time course and magnitude of the decay in cyclovergence was compared with the subject either in darkness or viewing a baseline stimulus of zero cyclodisparity. RESULTS. As reported previously, the cyclovergence response to incyclodisparities was greater than to excyclodisparities. After sustained excyclovergence, however, in all subjects and in response to all orientations of the gratings, the decay in darkness was incomplete, implying an adaptive change in torsional alignment. In response to the horizontal gratings, for incyclovergence there was also an incomplete decay in darkness but to a lesser degree than in response to excyclovergence, and in only three of four subjects. The incyclovergence evoked by the oblique and vertical gratings was of small magnitude, and its decay was unaffected by the presence or absence of a visual stimulus. CONCLUSIONS. After sustained cyclovergence, its decay in the absence of a visual stimulus may be incomplete. The residual component may be interpreted, by analogy with horizontal and vertical vergence, as reflecting so-called phoria adaptation for torsional alignment.
The CIRCuiTS study (Implementation of cognitive remediation in early intervention services): protocol for a randomised controlled trial.
BACKGROUND: Cognitive problems in people with schizophrenia predict poor functional recovery even with the best possible rehabilitation opportunities and optimal medication. A psychological treatment known as cognitive remediation therapy (CRT) aims to improve cognition in neuropsychiatric disorders, with the ultimate goal of improving functional recovery. Studies suggest that intervening early in the course of the disorder will have the most benefit, so this study will be based in early intervention services, which treat individuals in the first few years following the onset of the disorder. The overall aim is to investigate different methods of CRT. METHODS: This is a multicentre, randomised, single-blinded, controlled trial based in early intervention services in National Health Service Mental Health Trusts in six English research sites. Three different methods of providing CRT (intensive, group, and independent) will be compared with treatment as usual. We will recruit 720 service users aged between 16 and 45 over 3 years who have a research diagnosis of non-affective psychosis and will be at least 3 months from the onset of the first episode of psychosis. The primary outcome measure will be the degree to which participants have achieved their stated goals using the Goal Attainment Scale. Secondary outcome measures will include improvements in cognitive function, social function, self-esteem, and clinical symptoms. DISCUSSION: It has already been established that cognitive remediation improves cognitive function in people with schizophrenia. Successful implementation in mental health services has the potential to change the recovery trajectory of individuals with schizophrenia-spectrum disorders. However, the best mode of implementation, in terms of efficacy, service user and team preference, and cost-effectiveness is still unclear. The CIRCuiTS trial will provide guidance for a large-scale roll-out of CRT to mental health services where cognitive difficulties impact recovery and resilience. TRIAL REGISTRATION: ISRCTN, ISRCTN14678860 , Registered on 6 June 2016.
Measuring Life Events and Their Association With Clinical Disorder: A Protocol for Development of an Online Approach.
BACKGROUND: Severe life events are acknowledged as important etiological factors in the development of clinical disorders, including major depression. Interview methods capable of assessing context and meaning of events have demonstrated superior validity compared with checklist questionnaire methods and arguments for interview approaches have resurfaced because choosing the appropriate assessment tool provides clarity of information about gene-environment interactions in depression. Such approaches also have greater potential for understanding and treating clinical cases or for use in interventions. OBJECTIVE: (1) To argue that life events need sophisticated measurement not satisfactorily captured in checklist approaches. (2) To review life-events measures and key findings related to disorder, exemplifying depression. (3) To describe an ongoing study with a new online measure and to assess its psychometric properties and the association of life events in relation to disorder and educational outcomes. METHODS: The Computerised Life Events Assessment Record (CLEAR) is under development as a tool for online assessment of adult life events. Based on the Life Events and Difficulties Schedule interview, CLEAR seeks to assess life events to self and close others, link these to other events and difficulties, and utilize calendar-based timing, to improve upon checklist approaches. RESULTS: The CLEAR study is in the preliminary stages and its results are expected to be made available by the end of 2015. CONCLUSIONS: There is currently no sophisticated technological application of social risk factor assessment, such as life events and difficulties. CLEAR is designed to gather reliable and valid life-event data while combating the limitations of interviews (eg, time consuming and costly) and life-event checklists (eg, inability to accurately measure severity and independence of life events). The advantages of using such innovative methodology for research, clinical practice, and interventions are discussed.