Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale.

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. METHODS: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. FINDINGS: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. INTERPRETATION: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. FUNDING: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study.

BACKGROUND: The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour. METHODS: The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737. DISCUSSION: The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected. TRIAL REGISTRATION: ISRCTN, ISRCTN33631053 . Retrospectively registered on 8 June 2018 (applied 17 May 2018).

Efficacy of antidepressants over placebo is similar in two-armed versus three-armed or more-armed randomized placebo-controlled trials.

Previous studies have reported that effect sizes of antidepressants were larger in two-armed than in three-armed or more-armed (multiarmed) randomized trials, where the probability of being allocated to placebo is lower. However, these studies have not taken into account the publication bias, differences among antidepressants, or covariance in multiarmed studies, or examined sponsorship bias. We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multiarmed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multivariate meta-analysis. A random-effects model was used throughout. Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multiarmed trials was 1.09 (95% confidence interval: 0.96-1.24). The ROR did not materially change between types of antidepressants, publication year, or sponsorship. The differences between two-armed versus multiarmed studies were much smaller than were suggested in previous studies and were not significant.

Is placebo response in antidepressant trials rising or not? A reanalysis of datasets to conclude this long-lasting controversy.

It had long been believed that placebo response rates in antidepressant trials have been increasing and that they were responsible for rising numbers of so-called failed antidepressant trials. Two recent systematic reviews examined this issue and reached completely opposite findings. Furukawa and colleagues in a paper published in 2016 found that the placebo response rates are stable since 1991 and the apparent increase up to 2000 was confounded by changes in trial design features. By contrast, Khan and colleagues more recently concluded that placebo response rates had grown steadily in the past 30 years. The two reviews differed in the datasets they used, definitions of placebo response and statistical analyses. In this perspective article, we examined if such differences were responsible for the two reviews' contrasting conclusions. Our reanalyses confirmed our previous results. We found that in any dataset and for any placebo response definition, there was no increase in placebo response over the years when the analysis was adjusted for the confounders related to study design features or when it was limited to studies published after 1990s. We conclude that placebo response in antidepressant trials has remained stable for the past 25 years, during which time the large majority of the studies have come to share similar design features.

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.

BACKGROUND: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis.

(Reprinted with permission from Lancet 2018; 391:1357-66).

Implementing tools to support evidence-based practice: a survey and brief intervention study of the National Elf Service across Oxford Health NHS Foundation Trust.

BACKGROUND: Technology and the internet has enabled rapid access to research but most mental health professionals do not have time to keep up with the vast and growing scientific literature. Secondary information sources, such as the National Elf Service (NES), aim to summarise the most important and up-to-date research to improve mental health professionals' access to information to support evidence-based medicine (EBM). OBJECTIVE: To explore mental health professionals' attitudes towards evidence-based practice and methods used to keep up-to-date with research. To promote use of a digital evidence-based platform (the National Elf Service), assess its use and explore its potential to impact clinical practice. METHODS: Baseline and follow-up surveys were distributed among staff of 5 adult mental health community teams and 2 early intervention services (n=331) in Oxford Health Foundation Trust (OHFT) prior to and following an intervention raising awareness of the National Elf Service. FINDINGS: Of 133 baseline survey responders, the majority of staff reported their clinical practice was informed by evidence, mostly using existing clinical guidelines and online resources. Few had used the National Elf Service. 122 staff members completed the follow-up survey. Postintervention, 42 staff members indicated they had used the National Elf Service (compared with 13 preintervention) and that it had improved access to research. Lack of time was most often the barrier restricting evidence-based practice. CONCLUSIONS: Mental health professionals are engaged with EBM and those that used the National Elf Service felt it did, or could have the potential to impact on their clinical practice. CLINICAL IMPLICATIONS: Barriers and challenges to implement EBM more widely suggest targeted efforts should be made to embed evidence-based practice into the working culture.

The effects of medication and current mood upon facial emotion recognition: findings from a large bipolar disorder cohort study.

OBJECTIVES: Emotional processing abnormalities have been implicated in bipolar disorder (BD) but studies are typically small and uncontrolled. Here, facial expression recognition was explored in a large and naturalistically recruited cohort of BD patients. METHODS: 271 patients with BD completed the facial expression recognition task. The effects of current medication together with the influence of current mood state and diagnostic subtype were assessed whilst controlling for the effects of demographic variables. RESULTS: Patients who were currently receiving treatment with lithium demonstrated significantly poorer accuracy in recognising angry faces, an effect that held in a monotherapy sub-analysis comparing those participants on lithium only and those who were medication-free. Accuracy in recognising angry faces was also lower amongst participants currently taking dopamine antagonists (antipsychotics). Higher levels of current depressive symptoms were linked to poorer accuracy at identifying happy faces. CONCLUSION: Use of lithium and possibly dopamine antagonists may be associated with reduced processing of anger cues in BD. Findings support the existence of mood-congruent negative biases associated with depressive symptoms in BD. Observational cohort studies provide opportunities to explore the substantial effects of demographic, psychometric and clinical variables on cognitive performance and emotional processing.

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis.

INTRODUCTION: Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. METHODS AND ANALYSIS: We will include all randomised controlled trials (RCTs) reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model. ETHICS AND DISSEMINATION: This review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal.

Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. METHODS AND ANALYSIS: We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42014008976.

Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies.

BACKGROUND: Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics. METHODS: In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression. FINDINGS: We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk [RR] 1·00, 95% CI 0·97-1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01-1·05 for 1 more week in trial length; 1·32, 1·11-1·57 for multicentre vs single-centre trials). INTERPRETATION: Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view. FUNDING: Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.

Psychoeducation and online mood tracking for patients with bipolar disorder: A randomised controlled trial.

BACKGROUND: Psychoeducation is an effective adjunct to medications in bipolar disorder (BD). Brief psychoeducational approaches have been shown to improve early identification of relapse. However, the optimal method of delivery of psychoeducation remains uncertain. Here, our objective was to compare a short therapist-facilitated vs. self-directed psychoeducational intervention for BD. METHODS: BD outpatients who were receiving medication-based treatment were randomly assigned to 5 psychoeducation sessions administered by a therapist (Facilitated Integrated Mood Management; FIMM; n=60), or self-administered psychoeducation (Manualized Integrated Mood Management; MIMM; n=61). Follow-up was based on patients' weekly responses to an electronic mood monitoring programme over 12 months. RESULTS: Over follow-up, there were no group differences in weekly self-rated depression symptoms or relapse/readmission rates. However, knowledge of BD (assessed with the Oxford Bipolar Knowledge questionnaire (OBQ)) was greater in the FIMM than the MIMM group at 3 months. Greater illness knowledge at 3 months was related to a higher proportion of weeks well over 12 months. LIMITATIONS: Features of the trial may have reduced the sensitivity to our psychoeducation approach, including that BD participants had been previously engaged in self-monitoring. CONCLUSIONS: Improved OBQ score, while accelerated by a short course of therapist-administered psychoeducation (FIMM), was seen after both treatments. It was associated with better outcome assessed as weeks well. When developing and testing a new psychosocial intervention, studies should consider proximal outcomes (e.g., acquired knowledge) and their short-term impact on illness course in bipolar disorder.

Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis.

INTRODUCTION: Many antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct and indirect comparisons; however, these reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. METHODS AND ANALYSIS: We will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework. ETHICS AND DISSEMINATION: This review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42012002291.