A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder.

OBJECTIVE: To determine clinical predictors of lithium response in bipolar disorder. METHODS: Systematic review of studies examining clinical predictors of lithium response was conducted. Meta-analyses were performed when ≥2 studies examined the same potential predictor. RESULTS: A total of 71 studies, including over 12 000 patients, identified six predictors of good response: mania-depression-interval sequence [odds ratio (OR): 4.27; 95% CI: 2.61, 6.97; P < 0.001], absence of rapid cycling (OR for rapid cycling: 0.30; 95% CI: 0.17, 0.53; P < 0.001), absence of psychotic symptoms (OR for psychotic symptoms: 0.52; 95% CI: 0.34, 0.79; P = 0.002), family history of bipolar disorder (OR: 1.61; 95% CI: 1.03, 2.52; P = 0.036), shorter prelithium illness duration [standardised mean difference (SMD): -0.26; 95% CI: -0.41, -0.12; P < 0.001] and later age of onset (SMD: 0.17; 95% CI: 0.02, 0.36; P = 0.029). Additionally, higher body mass index was associated with poor response in two studies (SMD: -0.61; 95% CI: -0.90, -0.32; P < 0.001). There was weak evidence for number of episodes prior to lithium treatment (SMD: -0.42; 95% CI: -0.84, -0.01; P = 0.046), number of hospitalisations before lithium (SMD: -0.40; 95% CI: -0.81, 0.01; P = 0.055) and family history of lithium response (OR: 10.28; 95% CI: 0.66, 161.26; P = 0.097). CONCLUSIONS: The relative importance of these clinical characteristics should be interpreted with caution because of potential biases and confounding.

Variability in phase and amplitude of diurnal rhythms is related to variation of mood in bipolar and borderline personality disorder.

Variable mood is an important feature of psychiatric disorders. However, its measurement and relationship to objective measureas of physiology and behaviour have rarely been studied. Smart-phones facilitate continuous personalized prospective monitoring of subjective experience and behavioural and physiological signals can be measured through wearable devices. Such passive data streams allow novel estimates of diurnal variability. Phase and amplitude of diurnal rhythms were quantified using new techniques that fitted sinusoids to heart rate (HR) and acceleration signals. We investigated mood and diurnal variation for four days in 20 outpatients with bipolar disorder (BD), 14 with borderline personality disorder (BPD) and 20 healthy controls (HC) using a smart-phone app, portable electrocardiogram (ECG), and actigraphy. Variability in negative affect, positive affect, and irritability was elevated in patient groups compared with HC. The study demonstrated convincing associations between variability in subjective mood and objective variability in diurnal physiology. For BPD there was a pattern of positive correlations between mood variability and variation in activity, sleep and HR. The findings suggest BPD is linked more than currently believed with a disorder of diurnal rhythm; in both BPD and BD reducing the variability of sleep phase may be a way to reduce variability of subjective mood.

Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial.

After psychological trauma, recurrent intrusive visual memories may be distressing and disruptive. Preventive interventions post trauma are lacking. Here we test a behavioural intervention after real-life trauma derived from cognitive neuroscience. We hypothesized that intrusive memories would be significantly reduced in number by an intervention involving a computer game with high visuospatial demands (Tetris), via disrupting consolidation of sensory elements of trauma memory. The Tetris-based intervention (trauma memory reminder cue plus c. 20 min game play) vs attention-placebo control (written activity log for same duration) were both delivered in an emergency department within 6 h of a motor vehicle accident. The randomized controlled trial compared the impact on the number of intrusive trauma memories in the subsequent week (primary outcome). Results vindicated the efficacy of the Tetris-based intervention compared with the control condition: there were fewer intrusive memories overall, and time-series analyses showed that intrusion incidence declined more quickly. There were convergent findings on a measure of clinical post-trauma intrusion symptoms at 1 week, but not on other symptom clusters or at 1 month. Results of this proof-of-concept study suggest that a larger trial, powered to detect differences at 1 month, is warranted. Participants found the intervention easy, helpful and minimally distressing. By translating emerging neuroscientific insights and experimental research into the real world, we offer a promising new low-intensity psychiatric intervention that could prevent debilitating intrusive memories following trauma.

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.

Remote mood monitoring for adults with bipolar disorder: An explorative study of compliance and impact on mental health service use and costs.

BACKGROUND: Remote monitoring of mood disorders may be an effective and low resource option for patient follow-up, but relevant evidence remains very limited. This study explores real-life compliance and health services impacts of mood monitoring among patients with bipolar disorder in the UK. METHODS: Patients with a diagnosis of bipolar disorder who were registered users of the True Colours monitoring system for at least 12months at study assessment were included in this retrospective cohort study (n=79). Compliance was measured as the proportion of valid depression and mania scale messages received in comparison to their expected numbers over the first 12months of monitoring. Mental health service use data were extracted from case notes, costed using national unit costs, and compared 12months before (pre-TC period) and 12months after (TC period) patients' engagement with monitoring. Associations with relevant patient factors were investigated in a multiple regression model. RESULTS: Average compliance with monitoring was 82%. Significant increases in the annual use and costs of psychiatrist contacts and total mental health services were shown for patients newly referred to the clinic during the pre-TC period but not for long-term patients of the clinic. Psychiatric medication costs increased significantly between the pre-TC and TC periods (£235, P=0.005) unrelated to patients' referral status. CONCLUSIONS: Remote mood monitoring has good compliance among consenting patients with bipolar disorder. We found no associations between observed changes in mental health service costs and the introduction of monitoring except for the increase in psychiatric medication costs.

Detecting Bipolar Depression From Geographic Location Data.

OBJECTIVE: This paper aims to identify periods of depression using geolocation movements recorded from mobile phones in a prospective community study of individuals with bipolar disorder (BD). METHODS: Anonymized geographic location recordings from 22 BD participants and 14 healthy controls (HC) were collected over 3 months. Participants reported their depressive symptomatology using a weekly questionnaire (QIDS-SR16). Recorded location data were preprocessed by detecting and removing imprecise data points and features were extracted to assess the level and regularity of geographic movements of the participant. A subset of features were selected using a wrapper feature selection method and presented to 1) a linear regression model and a quadratic generalized linear model with a logistic link function for questionnaire score estimation; and 2) a quadratic discriminant analysis classifier for depression detection in BD participants based on their questionnaire responses. R esults: HC participants did not report depressive symptoms and their features showed similar distributions to nondepressed BD participants. Questionnaire score estimation using geolocation-derived features from BD participants demonstrated an optimal mean absolute error rate of 3.73, while depression detection demonstrated an optimal (median ± IQR) [Formula: see text] score of 0.857 ± 0.022 using five features (classification accuracy: 0.849 ± 0.016; sensitivity: 0.839 ± 0.014; specificity: 0.872 ± 0.047). CONCLUSION: These results demonstrate a strong link between geographic movements and depression in bipolar disorder. S ignificance: To our knowledge, this is the first community study of passively recorded objective markers of depression in bipolar disorder of this scale. The techniques could help individuals monitor their depression and enable healthcare providers to detect those in need of care or treatment.

Experiences of remote mood and activity monitoring in bipolar disorder: A qualitative study.

BACKGROUND: Mobile technology enables high frequency mood monitoring and automated passive collection of data (e.g. actigraphy) from patients more efficiently and less intrusively than has previously been possible. Such techniques are increasingly being deployed in research and clinical settings however little is known about how such approaches are experienced by patients. Here, we explored the experiences of individuals with bipolar disorder engaging in a study involving mood and activity monitoring with a range of portable and wearable technologies. METHOD: Patients were recruited from a wider sample of 50 individuals with Bipolar Disorder taking part in the Automated Monitoring of Symptom Severity (AMoSS) study in Oxford. A sub-set of 21 patients participated in a qualitative interview that followed a semi-structured approach. RESULTS: Monitoring was associated with benefits including increased illness insight, behavioural change. Concerns were raised about the potential preoccupation with, and paranoia about, monitoring. Patients emphasized the need for personalization, flexibility, and the importance of context, when monitoring mood. CONCLUSIONS: Mobile and electronic health approaches have potential to lend new insights into mental health and transform healthcare. Capitalizing on the perceived utility of these approaches from the patients' perspective, while addressing their concerns, will be essential for the promise of new technologies to be realised.

Associations between mood instability and emotional processing in a large cohort of bipolar patients.

BACKGROUND: Aberrant emotional biases have been reported in bipolar disorder (BD), but results are inconsistent. Despite the clinical relevance of chronic mood variability in BD, there is no previous research investigating how the extent of symptom fluctuations in bipolar disorder might relate to emotional biases. This exploratory study investigated, in a large cohort of bipolar patients, whether instability in weekly mood episode symptoms and other clinical and demographic factors were related to emotional bias as measured in a simple laboratory task. METHOD: Participants (N = 271, BDI = 206, BDII = 121) completed an 'emotional categorization and memory' task. Weekly self-reported symptoms of depression and mania were collected prospectively. In linear regression analyses, associations between cognitive bias and mood variability were explored together with the influence of demographic and clinical factors, including current medication. RESULTS: Greater accuracy in the classification of negative words relative to positive words was associated with greater instability in depressive symptoms. Furthermore, greater negative bias in free recall was associated with higher instability in manic symptoms. Participants diagnosed with BDII, compared with BDI, showed overall better word recognition and recall. Current antipsychotic use was associated with reduced instability in manic symptoms but this did not impact on emotional processing performance. CONCLUSIONS: Emotional processing biases in bipolar disorder are related to instability in mood. These findings prompt further investigation into the underpinnings as well as clinical significance of mood instability.

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels.

BACKGROUND: Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers. METHOD: Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period. RESULTS: Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness. CONCLUSIONS: Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Clinical and regulatory implications of active run-in phases in long-term studies for bipolar disorder.

OBJECTIVE: The integration of new treatments into the market and routine clinical practice should be dependent on robustness of evidence from randomised controlled trials (RCTs). We assessed study designs of long-term studies for bipolar disorder of all second-generation antipsychotics (SGAs) submitted to the Food and Drug Administration (FDA) and the completeness of evidence submitted to the regulatory agency. METHOD: Systematic review of double-blind RCTs comparing SGAs with placebo or active drugs in adults. FDA website and electronic databases were searched until July 2013. RESULTS: Six placebo-controlled trials comparing aripiprazole, olanzapine, quetiapine and ziprasidone were found in the FDA website. Electronic searches found four additional RCTs about aripiprazole, olanzapine or quetiapine. All RCTs (either submitted to FDA or not) selected patients who responded to acute treatment to increase the treatment effect observed in the long-term phase (enrichment design). By contrast, in the prescribing information sheets for all SGAs, the reported indication was 'maintenance treatment of bipolar disorder'. CONCLUSION: Extrapolation of results from enrichment studies to the more general population of patients should be carried out cautiously because average treatment benefits are likely to be less in unselected patients. Clear guidance for regulatory submission of RCTs is needed.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Use of self-administered instruments to assess psychiatric disorders in older people: validity of the General Health Questionnaire, the Center for Epidemiologic Studies Depression Scale and the self-completion version of the revised Clinical Interview Schedule.

BACKGROUND: Diagnosis of depressive disorder using interviewer-administered instruments is expensive and frequently impractical in large epidemiological surveys. The aim of this study was to assess the validity of three self-completion measures of depressive disorder and other psychiatric disorders in older people against an interviewer-administered instrument. METHOD: A random sample stratified by sex, age and social position was selected from the Whitehall II study participants. This sample was supplemented by inclusion of depressed Whitehall II participants. Depressive disorder and other mental disorders were assessed by the interviewer-administered structured revised Clinical Interview Schedule (CIS-R) in 277 participants aged 58-80 years. Participants also completed a computerized self-completion version of the CIS-R in addition to the General Health Questionnaire (GHQ) and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: The mean total score was similar for the interviewer-administered (4.43) and self-completion (4.35) versions of the CIS-R [95% confidence interval (CI) for difference -0.31 to 0.16]. Differences were not related to sex, age, social position or presence of chronic physical illness. Sensitivity/specificity of self-completion CIS-R was 74%/98% for any mental disorder and 75%/98% for depressive episode. The corresponding figures were 86%/87% and 78%/83% for GHQ and 77%/89% and 89%/86% for CES-D. CONCLUSIONS: The self-completion computerized version of the CIS-R is feasible and has good validity as a measure of any mental disorder and depression in people aged ≥ 60 years. GHQ and CES-D also have good criterion validity as measures of any mental disorder and depressive disorder respectively.

Nonlinear time-series approaches in characterizing mood stability and mood instability in bipolar disorder.

Bipolar disorder is a psychiatric condition characterized by episodes of elevated mood interspersed with episodes of depression. While treatment developments and understanding the disruptive nature of this illness have focused on these episodes, it is also evident that some patients may have chronic week-to-week mood instability. This is also a major morbidity. The longitudinal pattern of this mood instability is poorly understood as it has, until recently, been difficult to quantify. We propose that understanding this mood variability is critical for the development of cognitive neuroscience-based treatments. In this study, we develop a time-series approach to capture mood variability in two groups of patients with bipolar disorder who appear on the basis of clinical judgement to show relatively stable or unstable illness courses. Using weekly mood scores based on a self-rated scale (quick inventory of depressive symptomatology-self-rated; QIDS-SR) from 23 patients over a 220-week period, we show that the observed mood variability is nonlinear and that the stable and unstable patient groups are described by different nonlinear time-series processes. We emphasize the necessity in combining both appropriate measures of the underlying deterministic processes (the QIDS-SR score) and noise (uncharacterized temporal variation) in understanding dynamical patterns of mood variability associated with bipolar disorder.

Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials.

We conducted a systematic review and meta-analysis of randomised and quasi-randomised controlled trials evaluating all clinically relevant pharmacological interventions for the prevention of relapse in people with bipolar disorder. Thirty-four trials were included in the review. Direct comparisons with placebo and with lithium were available for most drugs. In addition, there were direct comparisons of valproate vs. olanzapine, imipramine vs. lithium plus imipramine, olanzapine plus mood stabilisers vs. mood stabilisers and perphenazine plus mood stabilisers vs. mood stabilisers. Methodological quality varied across studies and the strength of evidence was not equal for all treatments or for all comparisons. There is evidence from placebo-controlled trials for the efficacy of lithium, valproate and lamotrigine as maintenance therapy for the prevention of relapse in bipolar disorder. Three drugs have a significant effect in the prevention of manic relapses (lithium, olanzapine and aripiprazole) and three in the prevention of depressive symptoms (valproate, lamotrigine and imipramine). Imipramine is little used in practice, because of concern about adverse effects. The significant effects of olanzapine and aripiprazole were demonstrated in selected responsive bipolar I patients only. Despite widespread use in clinical practice, there is little evidence to support the efficacy of combination therapy.

Oxcarbazepine in the maintenance treatment of bipolar disorder.

BACKGROUND: Some studies have suggested that oxcarbazepine has a role in preventing episode recurrence in bipolar affective disorder. This review attempted to investigate the existing evidence from randomised controlled trials for its use in the maintenance treatment of this illness. OBJECTIVES: To review the efficacy of oxcarbazepine, relative to placebo and other agents, in the prevention of affective episodes of bipolar affective disorder. The efficacy of oxcarbazepine was considered in terms of episode recurrence, general and social functioning. Adverse effects, overall acceptability to participants and mortality were also considered. SEARCH STRATEGY: CCDANCTR-Studies and CCDANCTR-References were searched on 7/11/2007. Medline, CENTRAL, EMBASE and PsycINFO were searched in March 2007. Specialist journals and conference proceedings were handsearched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Authors, experts in the field and pharmaceutical companies were contacted requesting information on published or unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing oxcarbazepine with placebo or alternative agents, where the stated intent of intervention was the maintenance treatment of bipolar affective disorder were sought. Participants with bipolar disorder, male and female, of all ages, were included. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports individually by two review authors. The methodological quality of included studies was assessed individually by two review authors. The main outcomes were the efficacy of oxcarbazepine maintenance treatment in preventing or attenuating further episodes of bipolar affective disorder (including its efficacy in rapid cycling disorder), the acceptability of oxcarbazepine treatment to participants, the prevalence of side-effects, and mortality, if any, on oxcarbazepine treatment. Where appropriate, data concerning outcome measures and adverse effects were to be extracted from the studies and analysed using Review Manager software. MAIN RESULTS: Two randomised controlled trials were found that met the methodological criteria for inclusion in the review. However, they did not report data with sufficient clarity to allow their confident extraction for inclusion in the meta-analysis. Findings from the two studies were presented descriptively. AUTHORS' CONCLUSIONS: There is an insufficient methodologically rigorous evidence base to provide guidance on the use of oxcarbazepine in the maintenance treatment of bipolar disorder. Given the need for more efficacious therapeutic agents, there is a need for good quality randomised controlled trials examining the therapeutic potential of this and related agents in bipolar disorder.

WITHDRAWN: Selective serotonin reuptake inhibitors (SSRIs) versus other antidepressants for depression.

BACKGROUND: The relatively new class of antidepressant, the selective serotonin reputake inhibitors (SSRIs), may be better tolerated than the older tricyclic antidepressants. This review compares the efficacy of SSRIs with other antidepressants. OBJECTIVES: To examine the relative efficacy of selective serotonin reuptake inhibitors (SSRIs) compared to other antidepressants. SEARCH STRATEGY: The search strategy included a search of (a) Electronic bibliographic databases (MEDLINE, EMBASE); (b) reference lists of related reviews (c) reference lists of all located studies (d) contact with the manufacturer and (e) the Cochrane Group register of controlled trials SELECTION CRITERIA: Randomised controlled trials comparing selective serotonin reuptake inhibitors with other kinds of antidepressants in the treatment of patients with depressive disorders. The outcome measures assessed included measures of the severity of depression. DATA COLLECTION AND ANALYSIS: Data were collected from each study the main outcome measurefrom each study. These included: mean Hamilton depression rating scale, mean Montgomery & Asberg depression rating scale, Clinical Global Impression rating scale. An analysis of standardised mean difference of these scales was performed using Review Manager 3.1 software. The presence of heterogeneity of treatment effect was assessed MAIN RESULTS: Ninety-eight trials contributed data to the analysis of the relative efficacy of SSRIs and related drugs with comparator antidepressants (Figure 3 & Appendix 3). Analysis of efficacy was based upon 5044 patients treated with an SSRI or related drug, and 4510 treated with an alternative antidepressant. The standardised effect size for SSRIs and related drugs together versus alternative antidepressants using a fixed effects model was 0.035 (95% CI -0.006 to 0.076; Q = 149.25, df = 97, p < 0.001). AUTHORS' CONCLUSIONS: There are no clinically significant differences in effectiveness between selective serotonin reuptake inhibitors and tricyclic antidepressants. Treatment decisions need to be based on considerations of relative patient acceptability, toxicity and cost.

WITHDRAWN: Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs).

BACKGROUND: Selective serotonin reuptake inhibitors are thought to have better discontinuation rates (i.e. less people dropping out) than tricyclic and heterocyclic antidepressant drugs. It is important to quantify the drop-out rates of different antidepressant drugs in order to have a better understanding of the relative tolerability of these drugs. OBJECTIVES: To assess the comparative tolerability of selective serotonin reuptake inhibitors and tricyclic/heterocyclic antidepressant drugs. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (1997 to 1999), MEDLINE (1966 to 1999), EMBASE (1974 to 1999) We also searched specialist journals, the reference lists of relevant papers and previous systematic reviews, conference abstracts and government documents. Representatives of the pharmaceutical industry were contacted. SELECTION CRITERIA: Parallel group randomised controlled trials comparing selective serotonin reuptake inhibitors with tricyclic or heterocyclic antidepressants in people with depression. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and a third reviewer checked any cases of disagreement. MAIN RESULTS: We included 136 trials. The selective serotonin reuptake inhibitors showed less participants dropping out compared to the tricyclic/heterocyclic group (odds ratio 1.21, 95% confidence interval 1.12 to 1.30). A statistically significant difference was found in total drop-outs between the selective serotonin reuptake inhibitors and the old tricyclics as well as the newer tricyclics. When the selective serotonin reuptake inhibitors were compared to the heterocyclic antidepressants, there was a non significant difference favouring the selective serotonin reuptake inhibitors. The poor tolerability profile of the old tricyclics was explained by differences in drop-outs for side-effects, but not for inefficacy. AUTHORS' CONCLUSIONS: Whilst selective serotonin reuptake inhibitors do appear to show an advantage over tricyclic drugs in terms of total drop-outs, this advantage is relatively modest. This has implications for pharmaco-economic models, some of which may have overestimated the difference of drop-out rates between selective serotonin reuptake inhibitors and tricyclic antidepressants. These results are based on short-term randomised controlled trials, and may not generalise into clinical practice.

Incentives and disincentives to participation by clinicians in randomised controlled trials.

BACKGROUND: Patients and clinicians need reliable, up-to-date information from randomised controlled trials (RCTs) on the costs and benefits of treatments. Recruitment difficulties arise when clinicians do not invite patients to participate in trials. OBJECTIVES: Primary: to assess the evidence for the effect of disincentives and incentives on the extent to which clinicians invite eligible patients to participate in RCTs of healthcare interventions. Secondary: to assess the evidence in relation to stated willingness to invite participation. SEARCH STRATEGY: 1. The Cochrane Methodology Register and Cochrane Database of Methodology Reviews were searched in May 2006 and Cochrane Central Register of Controlled Trials, National Research Register and ClinicalTrialsGov in April 2005.2. EMBASE, MEDLINE, CINAHL, PsycINFO and AMED were searched in April 2005.3. Reference lists of included studies were checked. SELECTION CRITERIA: Studies exploring the effect of (dis)incentives on clinicians' views and recruitment-related activity. DATA COLLECTION AND ANALYSIS: The information about included studies was insufficient for a full assessment of quality. Data on (dis)incentives were extracted and association with recruitment tested. MAIN RESULTS: No RCTs of interventions were identified. Eleven observational studies were included - two medical records reviews, one matched pair study, one clinician interview study, two studies documenting clinicians' decisions and five postal surveys. Three measures of recruitment were used, invitation to participate, entry into RCT and reported entry to RCT. Five studies explored the effect of patient characteristics. The effect of age and prognosis varied between trials. Six studies considered the association between clinicians' views and recruitment. Clinicians who agreed to participate because they were acquainted with the researchers were less likely to participate than those otherwise motivated (1 study, 2-sided p = 0.04 Fisher's exact test) and (Odds Ratio [OR] 0.4, 95% Confidence Interval [CI] 0.2 to 0.9, 1 study). Clinicians who had recruited were more likely to report some difficulties including "trials involve extra work" (OR 92.94, 95% CI 4.54 - 1902.11; p