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Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GRD and JK own shares in the study sponsor (P1vital Products Ltd) which also owns the PReDicT predictive algorithm. ACB, RD, and JK are employees of P1vital Products Ltd. GRD owns shares in P1vital Ltd. ABA and GRD are employees of P1vital Ltd. HGR reports speakers’ bureau honoraria from Janssen, Lundbeck, and received research grants from ZonMW, HersenStichting, EU Horizon 2020, the Dutch Ministry of Health, and an unrestricted Educational grant from Janssen. AR has received honoraria for lectures and/or advisory boards from Janssen, Boehringer Ingelheim, COMPASS, SAGE/Biogen, LivaNova, Medice, Shire/Takeda and cyclerion. Also, he has received research grants from Medice and Janssen. GMG is Chief Medical Officer at Compass pathways, holds shares and options in Compass pathways and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital Ltd., Sage, Servier and Takeda. MB has acted as a consultant for Janssen Research, P1vital Ltd, Boehringer and CHDR, and was previously a paid employee of P1vital Ltd. RM has received payment from Novartis plc but have no other conflicts of interest to report. All other authors declare that they have no conflicts of interest. JS has received research grants from the ECNP, EU Horizon 2020, EU Horizon Europe, FWF, NIHR, WWTF, and academic advisor honoraria from the European Brain Council, (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

Background: Major depressive disorder (MDD) is a highly prevalent psychiatric condition associated with significant disability, mortality and economic burden. A large proportion of MDD patients are treated in primary health care in the local community. Attentional Bias Modification (ABM) training in combination with antidepressants could be an effective treatment. Here we test the hypothesis that adding an ABM procedure to regular treatment with antidepressants in primary health care will result in further improvement of symptoms compared to treatment with antidepressants alone (treatment as usual, TAU) and as compared to an active comparison condition., Methods: A total of 246 patients with a diagnosis of MDD will be included in this study. The study is a three-armed pragmatic randomized controlled trial comparing the efficacy of ABM as add-on to treatment with antidepressants in primary care (ABM condition) compared to standard antidepressant treatment (TAU condition). In a third group participants will complete the same schedule of intermediate assessments as the ABM condition in addition to TAU, but no ABM, thus controlling for the non-training-specific aspects of the ABM condition (Antidepressant active comparison group)., Discussion: The clinical outcome of this study may help develop easily accessible, low-cost treatment of depression in primary health care. Moreover, the study aims to broaden our knowledge of optimal treatment for patients with a MDD by providing adjunct treatment to facilitate recovery and long-term gain., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OAA is consultant to cortechs.ai, and has received speaker's honorarium from Lundbeck, Janssen, Sunovion. Local PI for clinical trials sponsored by BI, Janssen, MAPS, COMPASS. CH has received consultancy payments from P1vital Ltd., Compass Pathways, Lundbeck and Medscape Education. Hold grant income from UCB, J&J and Pfizer. JK is Chief Executive Officer, Director and Shareholder of P1vital Products Ltd. GD is Co-owner and major stockholder in P1vital LTD P1vital Products LTD. GG holds shares in Compass pathways and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital, Sage, Servier and Takeda. The other authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Individuals with mental health disorders (MHDs) have worse physical health than the general population, utilise healthcare resources more frequently and intensively, incurring higher costs. We provide a first comprehensive overview and quantitative synthesis of literature on the magnitude of excess resource use and costs for those with MHDs and comorbid physical health conditions (PHCs). This systematic review (PROSPERO CRD42017075319) searched studies comparing resource use or costs of individuals with MHDs and comorbid PHCs versus individuals without comorbid conditions published between 2007 and 2021. We conducted narrative and quantitative syntheses, using random-effects meta-analyses to explore ranges of excess resource use and costs across care segments, comparing to MHD only, PHC only, or general population controls (GPC). Of 20,075 records, 228 and 100 were eligible for narrative and quantitative syntheses, respectively. Most studies were from the US, covered depression or schizophrenia, reporting endocrine/metabolic or circulatory comorbidities. Frequently investigated healthcare segments were inpatient, outpatient, emergency care and medications. Evidence on lost productivity, long-term and informal care was rare. Substantial differences exist between MHDs, with depressive disorder tending towards lower average excess resource use and cost estimates, while excess resource use ranges between +6% to +320% and excess costs between +14% to +614%. PHCs are major drivers of resource use and costs for individuals with MHDs, affecting care segments differently. Significant physical health gains and cost savings are potentially achievable through prevention, earlier identification, management and treatment, using more integrated care approaches. Current international evidence, however, is heterogeneous with limited geographical representativeness and comparability., Competing Interests: Declaration of Competing Interest JS has received academic expert honoraria from the European Brain Council. ALP and DM have received support from the ECNP. GG has received royalties or licenses from Oxford University Press and Oxford University, payment or honoraria for lecture fees from Evopharma and Johnson & Johnson, provided expert testimony for Johnson & Johnson, participated in the advisory board for H Lundbeck, Medscape, Sage, Johnson & Johnson, Novartis, Beckley Psytech, Clerkenwell Health, Ocean neuroscience, and Boehringer Ingelheim, co-chairs the Bipolar Commission of Bipolar-UK, and has stock and/or stock options for P1vital, P1vital products, and Compass pathways. GG is a NIHR Emeritus Senior Investigator and Chief Medical Officer of Compass pathways. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the ECNP, the NHS, the NIHR or the Department of Health., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular., Competing Interests: Declaration of Competing Interest Guy M. Goodwin is a NIHR Emeritus Senior Investigator, holds shares in P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, P1Vital, Sage, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. Andreas Meyer-Lindenberg has received consultant fees from: Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Röntgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung, American Association for the Advancement of Science, Servier International. Additionally, he has received speaker fees from: Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik für Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry, Siemens Healthineers, Biotest AG -All unrelated to this work. Terence A. Ketter has been a consultant to Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Abbvie, and Alkermes. Joseph Goldberg has been a consultant to BioXCel, Otsuka, Sage Pharmaceuticals, Sunovion, and WebMD, and served on the speaker boards for Allergan, Intracellular Therapies, and Sunovion. Rif S. El-Mallakh is on the speaker bureau of Alkermes, Eisai, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Noven, Otsuka, Sunonvion, and Teva. Lakshmi N Yatham has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, CANMAT, CIHR, DSP, Merck, and Sanofi Rasmus W. Licht has within the preceding three years served an advisory board of Janssen Cilag and Sagw, and received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier and Lundbeck Allan H. Young has been employed by King's College London; Honorary Consultant SLaM (NHS UK). Young has participated in paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Allan H. Young's independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Consultant to Johnson & Johnson and Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova. Prof. Alessandro Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Bo- heringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. Ayşegül Yildiz has nothing to declare. Jean Michel Azorin has received honoraria or research or educational conference grants from Lundbeck and Otsuka. Othman Sentissi has received advisory board honoraria or research or educational conference from Otsuka, Lilly, Lundbeck, Sandoz, Janssen and Sunovion on an institutional account for research and teaching. Prof. Gordon Parker has received lecture fees and board member honoraria from Otsuka, Servier and Lundbeck. Dr. David Bond has received consulting fees and/or research grants from Alkermes, Myriad Genetics, the National Institutes of Health, the University of Minnesota Department of Psychiatry and Behavioral Sciences, and the University of Minnesota Foundation. Prof. Giulio Perugi has received grant/research support from Eli Lilly & Co.; is on the speaker/advisory board of Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, Eli Lilly & Co., Jannsen-Cilag, and Lundbeck; and has acted as consultant of AstraZeneca, Eli Lilly & Co., and Lundbeck. Prof. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB- Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. Dina Popovic has served as a speaker and/or medical writer and/or consultant and/or has participated in advisory boards for Bristol-Myers Squibb, Dexel, Merck Sharp & Dohme, Janssen-Cilag, Lundbeck, Ferrer, and Forum Pharmaceuticals. None of the remaining authors have conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor., Competing Interests: Declaration of Competing Interest As the article is a review on the literature, there is generally no conflict of interest in respect to this article. Nevertheless, some of the authors had relationships with different companies or served as consultants in the last three years. MM has served as consultant, or CME speaker for Angelini. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, AbbVie, Angelini, Boehringer-Ingelheim, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, Sunovion, and Takeda, outside the submitted work. LM declares that he has received lecture honoraria from Lundbeck pharmaceutical. No other equity ownership, profit-sharing agreements, royalties, or patent. CC has been a consultant and/or advisor to or has received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma. AF is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo, Doc Generici, Glaxo Smith Kline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor. MB has received institutional grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and European Commission. He served in advisory boards for GH Research, Janssen-Cilag, neuraxpharm, Novartis, Sandoz, Shire International, Sumitomo Dainippon, Sunovion, and Takeda, and received speaker honoraria for Aristo, Hexal, Janssen Pharmaceutica NV, Janssen-Cilag, and Sunovion, outside the submitted work. REN has received research grants from H. Lundbeck and Otsuka Pharmaceuticals for clinical trials, received speaking fees from Bristol-Myers Squibb, Astra Zeneca, Janssen & Cilag, Lundbeck, Servier, Otsuka Pharmaceuticals, Teva A/S, and Eli Lilly and has acted as advisor to Astra Zeneca, Eli Lilly, Lundbeck, Otsuka Pharmaceuticals, Takeda, and Medivir, and has acted as investigator for Janssen-Cilag, Lundbeck, Boehringer, Compass and Sage. RW Licht has within the preceding three years served an advisory board of Janssen Cilag and Sage and has received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier, Lundbeck and Teva. No known conflicts of interest in respect to this article from all other authors., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30-50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research., (Copyright © 2021. Published by Elsevier B.V.)

Background and Objectives: Cognitive behavioral therapy (CBT) is a first-line treatment for anxiety, but it is not widely available as clinical guidelines recommend. We examined the feasibility and efficacy of a novel smartphone-based fully automated digital CBT intervention, 'Daylight™', to improve symptoms of Generalized Anxiety Disorder (GAD)., Methods: In this multiple-baseline design, 21 adults (20 F; mean age 43yrs. range 19-65yrs.) with moderate-to-severe symptoms of GAD were randomized to one of three baseline durations (2-, 4-, or 6-weeks) and then received access to digital CBT. Participants completed daily ratings of anxiety and worry, weekly measures of anxiety, depressive symptoms, and sleep, and measures of anxiety, worry, wellbeing, quality of life, CBT skill acquisition, and work performance at initial assessment prior to baseline randomization, post-intervention, and follow-up., Results: Digital CBT was found to be feasible in terms of engagement, satisfaction, and safety. For preliminary efficacy, improvements were detected in daily and weekly outcomes of anxiety for most participants. Despite individual differences, significant improvements occurred with the introduction of digital CBT and not during baseline. Overall, 70% of participants no longer had clinically significant symptoms of GAD, 61% no longer had significant depressive symptoms, and 40% no longer had significant sleep difficulty at post-intervention., Limitations: The study sample was recruited using the internet and was mostly female, limiting the generalizability of the findings., Conclusions: Findings support the feasibility and efficacy of Daylight. Further examination in randomized controlled trials is now warranted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Antidepressants must be taken for weeks before response can be assessed with many patients not responding to the first medication prescribed. This often results in long delays before effective treatment is started. Antidepressants induce changes in the processing of emotional stimuli early in the course of treatment. In the current study we assessed whether changes in emotional processing and subjective symptoms over the first week of antidepressant treatment predicted clinical response after 4-8 weeks of treatment. Such a predictive test may shorten the time taken to initiate effective treatment in depressed patients. Seventy-four depressed primary care patients completed measures of emotional bias and subjective symptoms before starting antidepressant treatment and then again 1 week later. Response to treatment was assessed after 4-6 weeks. The performance of classifiers based on these measures was assessed using a leave-one-out validation procedure with the best classifier then tested in an independent sample from a second study of 239 patients. The combination of a facial emotion recognition task and subjective symptoms predicted response with 77% accuracy in the training sample and 60% accuracy in the independent study, significantly better than possible using baseline response rates. The face based measure of emotional bias provided good quality data with high acceptability ratings. Changes in emotional processing can provide a sensitive early measure of antidepressant efficacy for individual patients. Early treatment induced changes in emotional processing may be used to guide antidepressant therapy and reduce the time taken for depressed patients to return to good mental health., (Copyright © 2018. Published by Elsevier B.V.)

Background: Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations., Methods: We did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251., Findings: Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohen's d=1·11; p<0·0001), paranoia (-2·22, -2·98 to -1·45, Cohen's d=0·19; p<0·0001), and hallucinations (-1·58, -1·98 to -1·18, Cohen's d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported., Interpretation: To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision., Funding: Wellcome Trust., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Despite recent research demonstrating associations between violence and depression in adults, links in adolescents are uncertain. This study aims to assess the longitudinal associations between young people's depression and later violent outcomes., Method: We used data from three cohorts with different measurements of depression exposures and subsequent violent outcomes. In a Dutch community cohort Research on Adolescent Development And Relationships (RADAR; N = 623) and a population-based British birth cohort Avon Longitudinal Study of Parents and Children (ALSPAC; N = 4,030), we examined the longitudinal links between adolescent depressive symptoms and violent behaviors from age 13 to 17 years. In a total Finnish birth cohort (FBC 1987; N = 57,526), we estimated risk of violent convictions in individuals clinically diagnosed with depression from age 15 to 27 years., Results: During a mean follow-up period of 4 years, the adjusted odds ratio (aOR) of violent behaviors per unit of increase in depressive symptoms was 1.7 (95% CI = 1.2-2.5) in the Dutch RADAR community sample and 1.8 (95% CI = 1.4-2.3) in the British ALSPAC birth cohort. In the FBC 1987 cohort, the aOR of violent convictions was 2.1 (95% CI = 1.7-2.7) among individuals with a depression diagnosis compared with general population controls without depression. All risk estimates were adjusted for family socioeconomic status and previous violence., Conclusion: Consistent findings across three longitudinal studies suggest that clinical guidelines should consider recommending risk assessment for violence in young people with depression. The benefits of targeting risk management in subgroups by gender need further investigation., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630)., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: Depressive symptoms are a major cause of disability in bipolar disorder and there are few safe and effective treatments. The combination of lamotrigine plus quetiapine potentially offers improved outcomes for people with bipolar depression. We aimed to determine if combination therapy with quetiapine plus lamotrigine leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy plus lamotrigine placebo., Methods: In this double-blind, randomised, placebo-controlled, parallel group, 2 × 2 factorial trial (CEQUEL), patients with DSM-IV bipolar disorder I or II, who were aged 16 years or older, and required new treatment for a depressive episode, were enrolled from 27 sites in the UK. Patients were randomly assigned (1:1) by an adaptive minimisation algorithm to lamotrigine or placebo and to folic acid or placebo. Participants and investigators were masked to the treatment groups. The primary outcome was improvement in depressive symptoms at 12 weeks with the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). Analysis was by modified intention-to-treat. This trial is registered with EUdraCT, number 2007-004513-33., Findings: Between Oct 21, 2008, and April 27, 2012, 202 participants were randomly assigned; 101 to lamotrigine and 101 to placebo. The mean difference in QIDS-SR16 total score between the group receiving lamotrigine versus the placebo group at 12 weeks was -1·73 ([95% CI -3·57 to 0·11]; p=0·066) and at 52 weeks was -2·69 ([-4·89 to -0·49]; p=0·017). Folic acid was not superior to placebo. There was a significant interaction (p=0·028), with folic acid reducing the effectiveness of lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was -4·14 ([95% CI -6·90 to -1·37]; p=0·004) for patients receiving lamotrigine without folic acid compared with 0·12 ([-2·58 to 2·82]; p=0·931) for those receiving lamotrigine and folic acid., Interpretation: Addition of lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of lamotrigine. CEQUEL should encourage clinicians and patients to consider lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness., Funding: Medical Research Council., (Copyright © 2016 Geddes et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Neuroscience based Nomenclature (NbN) is a new system of classifying psychotropic drugs by their pharmacological profile. The NbN was developed to replace the current indication-based nomenclature and to provide an up-to-date and more useful framework to better inform pharmacological decisions. NbN provides updated relevant and specific scientific, regulatory and clinical information, aiming to support rational and lucid prescribing. This pharmacologically driven nomenclature, which highlights pharmacological domains and modes of action, may also increase drug adherence as it clarifies the rationale for selecting a specific psychotropic agent., (Copyright © 2015. Published by Elsevier B.V.)

Bipolar disorder is associated with impaired decision-making. Little is known about how treatment, especially lithium, influences decision-making abilities in bipolar patients when euthymic. We aimed at testing for an association between lithium medication and decision-making performance in remitted bipolar patients. Decision-making was measured using the Iowa Gambling Task in 3 groups of subjects: 34 and 56 euthymic outpatients with bipolar disorder, treated with lithium (monotherapy and lithium combined with anticonvulsant or antipsychotic) and without lithium (anticonvulsant, antipsychotic and combination treatment), respectively, and 152 matched healthy controls. Performance was compared between the 3 groups. In the 90 euthymic patients, the relationship between different sociodemographic and clinical variables and decision-making was assessed by stepwise multivariate regression analysis. Euthymic patients with lithium (p=0.007) and healthy controls (p=0.001) selected significantly more cards from the safe decks than euthymic patients without lithium, with no significant difference between euthymic patients with lithium and healthy controls (p=0.9). In the 90 euthymic patients, the stepwise linear multivariate regression revealed that decision-making was significantly predicted (p<0.001) by lithium dose, level of education and no family history of bipolar disorder (all p≤0.01). Because medication was not randomized, it was not possible to discriminate the effect of different medications. Lithium medication might be associated with better decision-making in remitted bipolar patients. A randomized trial is required to test for the hypothesis that lithium, but not other mood stabilizers, may specifically improve decision-making abilities in bipolar disorder., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Modern neuropsychopharmacology commenced in the 1950s with the serendipitous discovery of first-generation antipsychotics and antidepressants which were therapeutically effective yet had marked adverse effects. Today, a broader palette of safer and better-tolerated agents is available for helping people that suffer from schizophrenia, depression and other psychiatric disorders, while complementary approaches like psychotherapy also have important roles to play in their treatment, both alone and in association with medication. Nonetheless, despite considerable efforts, current management is still only partially effective, and highly-prevalent psychiatric disorders of the brain continue to represent a huge personal and socio-economic burden. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative disengagement by pharmaceutical firms from neuropsychiatry. Nonetheless, interest remains high, and partnerships are proliferating with academic centres which are increasingly integrating drug discovery and translational research into their traditional activities. This is, then, a time of transition and an opportune moment to thoroughly survey the field. Accordingly, the present paper, first, chronicles the discovery and development of psychotropic agents, focusing in particular on their mechanisms of action and therapeutic utility, and how problems faced were eventually overcome. Second, it discusses the lessons learned from past successes and failures, and how they are being applied to promote future progress. Third, it comprehensively surveys emerging strategies that are (1), improving our understanding of the diagnosis and classification of psychiatric disorders; (2), deepening knowledge of their underlying risk factors and pathophysiological substrates; (3), refining cellular and animal models for discovery and validation of novel therapeutic agents; (4), improving the design and outcome of clinical trials; (5), moving towards reliable biomarkers of patient subpopulations and medication efficacy and (6), promoting collaborative approaches to innovation by uniting key partners from the regulators, industry and academia to patients. Notwithstanding the challenges ahead, the many changes and ideas articulated herein provide new hope and something of a framework for progress towards the improved prevention and relief of psychiatric and other CNS disorders, an urgent mission for our Century., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Depression increases the risk of a range of adverse outcomes including suicide, premature mortality, and self-harm, but associations with violent crime remain uncertain. We aimed to determine the risks of violent crime in patients with depression and to investigate the association between depressive symptoms and violent crime in a cohort of twins., Methods: We conducted two studies. The first was a total population study in Sweden of patients with outpatient diagnoses of depressive disorders (n=47,158) between 2001 and 2009 and no lifetime inpatient episodes. Patients were age and sex matched to general population controls (n=898,454) and risk of violent crime was calculated. Additionally, we compared the odds of violent crime in unaffected half-siblings (n=15,534) and full siblings (n=33,516) of patients with the general population controls. In sensitivity analyses, we examined the contribution of substance abuse, sociodemographic factors, and previous criminality. In the second study, we studied a general population sample of twins (n=23,020) with continuous measures of depressive symptoms for risk of violent crime., Findings: During a mean follow-up period of 3·2 years, 641 (3·7%) of the depressed men and 152 (0·5%) of the depressed women violently offended after diagnosis. After adjustment for sociodemographic confounders, the odds ratio of violent crime was 3·0 (95% CI 2·8–3·3) compared with the general population controls. The odds of violent crime in half-siblings (adjusted odds ratio 1·2 [95% CI 1·1–1·4]) and full siblings (1·5, 95% CI 1·3–1·6) were significantly increased, showing some familial confounding of the association between depression and violence. However, the odds increase remained significant in individuals with depression after adjustment for familial confounding, and in those without substance abuse comorbidity or a previous violent conviction (all p<0·0001). In the twin study, during the mean follow-up time of 5·4 years, 88 violent crimes were recorded. Depressive symptoms were associated with increased risk of violent crime and a sensitivity analysis identified little difference in risk estimate when all crimes (violent and non-violent) was the outcome., Interpretation: Risk of violent crime was increased in individuals with depression after adjustment for familial, sociodemographic and individual factors in two longitudinal studies. Clinical guidelines should consider recommending violence risk assessment in certain subgroups with depression., Funding: Wellcome Trust and the Swedish Research Council.

Structural magnetic resonance imaging (MRI) studies using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) have been inconsistent in demonstrating impairments in gray matter (GM) and white matter (WM) structures in bipolar disorder (BD). This may be a consequence of significant confounding effects of medication, illness history and selection of controls in existing studies. Study of bipolar II or not-otherwise-specified (BD II/NOS) disorder provides a solution to these confounds and a bridge to unipolar cases across the affective spectrum. Thirty-eight euthymic, antipsychotic- and mood stabilizer-naïve young adults (mean age = 20.9 years) with BD II/NOS and 37 age-, cognitive ability- and gender-matched healthy controls (HCs) underwent MRI. Voxel-wise and regional gray matter volume comparisons were conducted using voxel-based morphometry (VBM). Tract-based spatial statistics (TBSS) were used to assess whole-brain WM, as indexed using fractional anisotropy (FA), mean diffusivity (MD), parallel and perpendicular diffusion values. No between-group differences were observed for whole-brain VBM comparisons. By contrast, in comparison to HCs, participants with BD II/NOS had significant widespread reductions in FA and increased MD and perpendicular diffusion values in virtually all the major cortical white matter tracts. These data suggest pathophysiological involvement of WM microstructures - but not GM macrostructures - in high functioning BD II/NOS patients at an early age and before significant clinical adversity has been recorded. We propose that white matter development is a valid candidate target for understanding genetic and environmental antecedents to bipolar disorder and mood disorder more generally.

Background: Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium., Methods: We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity., Findings: We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders., Interpretation: Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment., Funding: National Institute for Health Research Programme Grant for Applied Research., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs., Methods: We systematically reviewed 68 randomised controlled trials (16,073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat., Findings: Haloperidol (standardised mean difference [SMD] -0·56 [95% CI -0·69 to -0·43]), risperidone (-0·50 [-0·63 to -0·38), olanzapine (-0·43 [-0·54 to -0·32], lithium (-0·37 [-0·63 to -0·11]), quetiapine (-0·37 [-0·51 to -0·23]), aripiprazole (-0·37 [-0·51 to -0·23]), carbamazepine (-0·36 [-0·60 to -0·11], asenapine (-0·30 [-0·53 to -0·07]), valproate (-0·20 [-0·37 to -0·04]), and ziprasidone (-0·20 [-0·37 to -0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD -0·19 [95% CI -0·36 to -0·01]), quetiapine (-0·19 [-0·37 to 0·01]), aripiprazole (-0·19 [-0·36 to -0·02]), carbamazepine (-0·20 [-0·36 to -0·01]), asenapine (-0·26 [-0·52 to 0·01]), valproate (-0·36 [-0·56 to -0·15]), ziprasidone -0·36 [-0·56 to -0·15]), lamotrigine (-0·48 [-0·77 to -0·19]), topiramate (-0·63 [-0·84 to -0·43]), and gabapentin (-0·88 [-1·40 to -0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin., Interpretation: Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines., Funding: None., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance., Methods: Subjects (N = 317; age range: 18-65 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency., Results: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p < .001, p < .01, and p < .05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p < .001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants., Conclusions: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Gambling can be motivated by both its hedonic value and by attempts to cope with dysphoric or stressful states. Thus, motivations constitute important mechanisms linking mood fluctuations and gambling. However, little is known about how different kinds of affective disturbance, such as mood elevation and dysphoria, motivate gambling behavior., Methods: To estimate relationships between different mood experiences and gambling motivations, we recruited 4125 Internet gamblers via hyperlinks placed on gambling Web sites. Mean (SD) age of respondents was 35.5 (11.8) years, with 79.1% (3263) being male and 68.8% (2838) UK residents. We collected ratings for 11 gambling motivations. We used principal components analysis, followed by hierarchical linear regression, to model the relationships between motivation factor scores and gambling behavior, depressive symptoms, hypomanic experiences, deliberate self-harm, and alcohol and substance misuse., Results: Gambling to regulate mood, gambling for monetary goals, and gambling for enjoyment were enhanced in individuals at heightened risk of problematic gambling, with mood regulation and enjoyment factors being enhanced in female compared with male problem gamblers. Lowered mood reduced the enjoyment motivation, whereas previous mood elevation enhanced it. Gambling problems alongside previous hypomanic experiences or current dysphoria enhanced gambling to regulate emotional states., Conclusions: Recent theorizing argues that mood disorders and pathologic gambling may share aspects of pathophysiology. Different forms of emotional disturbance, such as mood elevation and dysphoric states, which confer heightened risk for bipolar disorder and depression, are associated with divergent motivations that might represent distinct pathways into gambling behavior., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Depressed mood alters the pain experience. Yet, despite its clear clinical relevance, little is known about the cognitive and neural mechanisms underlying this phenomenon. We tested an experimental manipulation to unravel the interaction between depressed mood and pain. We hypothesized that dysregulation of the neural circuitry underlying emotion regulation is the mechanism whereby pain processing is affected during depressed mood., Methods: Using functional magnetic resonance imaging, we compared the effects of sad and neutral cognitive mood inductions on affective pain ratings, pain-specific cognitions, and central pain processing of a tonic noxious heat stimulus in 20 healthy volunteers., Results: The increase in negative pain-specific cognitions during depressed mood predicted the perceived increase in pain unpleasantness. Following depressed mood induction, brain responses to noxious thermal stimuli were characterized by increased activity in a broad network including prefrontal areas, subgenual anterior cingulate cortex, and hippocampus, as well as significantly less deactivation when compared with pain responses in a neutral mood. The participants who reported the largest increase in pain unpleasantness after the sad mood induction showed greater inferior frontal gyrus and amygdala activation, linking changes in emotion regulation mechanisms with enhancement of pain affect., Conclusions: Our results inform how depressed mood and chronic pain co-occur clinically and may serve to develop and translate effective interventions using pharmacological or psychological treatment., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A tendency to orient attention toward threatening stimuli may be involved in the etiology of anxiety disorders. In keeping with this, both psychological and pharmacological treatments of anxiety reduce this negative attentional bias. It has been hypothesized, but not proved, that psychological interventions may alter the function of prefrontal regions supervising the allocation of attentional resources., Methods: The current study examined the effects of a cognitive training regime on attention. Participants were randomly assigned to one of two training conditions: "attend-threat" training, which increases negative attentional bias, or "avoid-threat" training, which reduces it. The behavioral effects of training were assessed using a sample of 24 healthy participants. Functional magnetic resonance imaging data were collected in a further 29 healthy volunteers using a protocol that allowed the influence of both stimuli valence and attention to be discriminated., Results: Cognitive training induced the expected attentional biases in healthy volunteers. Further, the training altered lateral frontal activation to emotional stimuli, with these areas responding specifically to violations of the behavioral rules learned during training. Connectivity analysis confirmed that the identified lateral frontal regions were influencing attention as indexed by activity in visual association cortex., Conclusions: Our results indicate that frontal control over the processing of emotional stimuli may be tuned by psychological interventions in a manner predicted to regulate levels of anxiety. This directly supports the proposal that psychological interventions may influence attention via an effect on the prefrontal cortex., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder., Methods: 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332., Findings: 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death)., Interpretation: For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy., Funding: Stanley Medical Research Institute; Sanofi-Aventis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Bipolar disorder (BD) is associated with high-risk behaviors, such as gambling and impulsivity. However, little is known about the psychological factors that influence these behaviors or their significance for the development of the disorder. In this study, we investigated the effects of highlighting rewards versus highlighting punishments in the risky decision-making of euthymic individuals with bipolar disorder., Methods: Twenty euthymic, medication-free men and women with previously undiagnosed bipolar II or bipolar disorder not otherwise specified and 20 age- and IQ-matched healthy men and women completed a computerized risky decision-making task in which mathematically equivalent dilemmas were presented in terms of opportunities to gain rewards ("positively-framed") or to avoid suffering losses ("negatively-framed"). The dependent measures were the proportion of risk-seeking choices (and deliberation times) when making decisions in positively versus negatively framed dilemmas., Results: As expected, healthy control participants made more risky-seeking choices in response to the negatively framed dilemmas compared with the positively framed dilemmas. However, this effect was significantly attenuated in BD participants who also took significantly longer to make risk-averse responses to the positively framed dilemmas. The BD participants overestimated the number of bad outcomes arising out of positively framed dilemmas., Conclusions: These data demonstrate that risky choice in BD is associated with reduced sensitivity to emotional contexts that highlight rewards or punishments, possibly reflecting altered valuations of prospective gains and losses associated with behavioral options.

TERMINOLOGY AND PRINCIPLES OF COMBINING ANTIPSYCHOTICS WITH A SECOND MEDICATION: The term "combination" includes virtually all the ways in which one medication may be added to another. The other commonly used terms are "augmentation" which implies an additive effect from adding a second medicine to that obtained from prescribing a first, an "add on" which implies adding on to existing, possibly effective treatment which, for one reason or another, cannot or should not be stopped. The issues that arise in all potential indications are: a) how long it is reasonable to wait to prove insufficiency of response to monotherapy; b) by what criteria that response should be defined; c) how optimal is the dose of the first monotherapy and, therefore, how confident can one be that its lack of effect is due to a truly inadequate response? Before one considers combination treatment, one or more of the following criteria should be met; a) monotherapy has been only partially effective on core symptoms; b) monotherapy has been effective on some concurrent symptoms but not others, for which a further medicine is believed to be required; c) a particular combination might be indicated de novo in some indications; d) The combination could improve tolerability because two compounds may be employed below their individual dose thresholds for side effects. Regulators have been concerned primarily with a and, in principle at least, c above. In clinical practice, the use of combination treatment reflects the often unsatisfactory outcome of treatment with single agents. ANTIPSYCHOTICS IN MANIA: There is good evidence that most antipsychotics tested show efficacy in acute mania when added to lithium or valproate for patients showing no or a partial response to lithium or valproate alone. Conventional 2-armed trial designs could benefit from a third antipsychotic monotherapy arm. In the long term treatment of bipolar disorder, in patients responding acutely to the addition of quetiapine to lithium or valproate, this combination reduces the subsequent risk of relapse to depression, mania or mixed states compared to monotherapy with lithium or valproate. Comparable data is not available for combination with other antipsychotics. ANTIPSYCHOTICS IN MAJOR DEPRESSION: Some atypical antipsychotics have been shown to induce remission when added to an antidepressant (usually a SSRI or SNRI) in unipolar patients in a major depressive episode unresponsive to the antidepressant monotherapy. Refractoriness is defined as at least 6 weeks without meeting an adequate pre-defined treatment response. Long term data is not yet available to support continuing efficacy. SCHIZOPHRENIA: There is only limited evidence to support the combination of two or more antipsychotics in schizophrenia. Any monotherapy should be given at the maximal tolerated dose and at least two antipsychotics of different action/tolerability and clozapine should be given as a monotherapy before a combination is considered. The addition of a high potency D2/3 antagonist to a low potency antagonist like clozapine or quetiapine is the logical combination to treat positive symptoms, although further evidence from well conducted clinical trials is needed. Other mechanisms of action than D2/3 blockade, and hence other combinations might be more relevant for negative, cognitive or affective symptoms. OBSESSIVE-COMPULSIVE DISORDER: SSRI monotherapy has moderate overall average benefit in OCD and can take as long as 3 months for benefit to be decided. Antipsychotic addition may be considered in OCD with tic disorder and in refractory OCD. For OCD with poor insight (OCD with "psychotic features"), treatment of choice should be medium to high dose of SSRI, and only in refractory cases, augmentation with antipsychotics might be considered. Augmentation with haloperidol and risperidone was found to be effective (symptom reduction of more than 35%) for patients with tics. For refractory OCD, there is data suggesting a specific role for haloperidol and risperidone as well, and some data with regard to potential therapeutic benefit with olanzapine and quetiapine. ANTIPSYCHOTICS AND ADVERSE EFFECTS IN SEVERE MENTAL ILLNESS: Cardio-metabolic risk in patients with severe mental illness and especially when treated with antipsychotic agents are now much better recognized and efforts to ensure improved physical health screening and prevention are becoming established.

Diagnosis and Epidemiology: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.

Background: The amygdala is believed to play a key role in processing emotionally salient, threat-relevant, events that require further online processing by cortical regions. Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala, but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information., Methods: The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging. A double-blind, between-groups design was used with volunteers randomized to 20 mg/day citalopram versus placebo., Results: Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo. Citalopram also reduced responses within the hippocampus and medial prefrontal cortex (mPFC) specifically during the fear-relevant stimuli. These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan. By contrast, there was no effect of citalopram on the neural or behavioral response to the happy facial expressions., Conclusions: These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans. Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety.

Background: Acute tryptophan depletion can induce a transient reappearance of depressive symptoms in recovered depressed patients. The neurochemical mechanism is thought to be impairment of brain serotonin neurotransmission, but the neuropsychologic mechanisms underlying the effect are unclear., Methods: To assess whether low-dose tryptophan depletion can tease out the psychological mechanisms sensitive to substrate depletion in vulnerable subjects without inducing mood changes, a between-subjects randomized design was used. Recovered depressed patients (n = 24) and healthy volunteers (n = 24) were administered while fasting either a tryptophan-free or a control mixture, containing 31.2 and 33.2 g of amino acids, respectively. Objective and subjective ratings of mood were made before and 5 hours after ingestion; at the latter time point, cognitive and emotional processing were also assessed., Results: Low-dose tryptophan depletion did not affect mood. Significant changes in emotional and cognitive processing occurred in the recovered depressed group, however, and to a lesser extent in the healthy volunteers. The profile of effects seen in the recovered patients suggested a return of the impairments seen in acute depression., Conclusions: Our data suggest that low-dose tryptophan depletion permits investigation of the cognitive correlates of acute reductions in brain serotonin in populations vulnerable to depression and in healthy volunteers, without causing depressive symptoms.