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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. (c) 2021 Elsevier B.V. and ECNP. 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.

This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP.

Introduction: Lockdowns implemented in response to the COVID-19 pandemic are thought to impact mental health [1,2] Understanding the mechanisms underlying this impact is critical to mitigating it [3] We tested the hypothesis that one such mechanism involves impaired mood homeostasis (i e , failure to stabilize mood via mood-modifying activities) [4,5] Methods: In this ecological momentary assessment cohort study, students in the Netherlands reported their mood and activities 4 times a day between March 16 and 29, 2020 New and immediate lockdown measures were announced on March 23 The average change in mood an individual experienced when engaging in an activity was recorded as its pleasantness Mood homeostasis was defined as the extent to which participants preferentially engaged in pleasant activities at time t+1 when their mood was low at time t, thus stabilizing their mood Participants' history of mental illness was screened at baseline Using linear regressions we assessed (i) changes in mood homeostasis from before to during lockdown, (ii) their moderation by mental illness history, (iii) their association with changes in mood level, and (iv) their mediation by changes in range of activities undertaken How changes in mood homeostasis might impact the risk of depression was estimated using computer simulations Statistical significance was set at 2-sided P< 05 Results: Seventy-eight students were included Mood homeostasis was significantly higher before than during lockdown (0 37 vs 0 28;95% CI of the difference [0 03,0 15];P= 003) For every 0 1 point drop in mood homeostasis, average mood decreased by 1 9 points (95% CI, [1 3,3 6], P< 001) This is enough to bring someone's average mood from the population's mean to its bottom quartile The change in mood homeostasis from before to during lockdown was mediated by a reduction in the range of activities (proportion mediated: 11 9%, P< 001) Mood homeostasis dropped significantly more among people with (vs without) a history of mental illness (P< 001): from similar values before lockdown (0 31 vs 0 36;P= 37) to significantly different values during lockdown (0 13 vs 0 35;95% CI of the difference [0 11,0 33];P< 001) In computer simulations, changes in mood homeostasis attributed to the lockdown led to a 3-fold increase in the the yearly incidence of depressed mood episodes: from 9 0% (95% CI [6 6%,11 4%]) before lockdown to 28 2% (95% CI [23 6%,32 6%]) during lockdown Conclusions: Mood homeostasis appears to decrease during lockdown Larger decreases correlate with larger decreases in mood level The impact was larger for students with a history of mental illness The lack of a control group (as the lockdown was implemented nationally) is the main limitation of our study However, since the same participants were monitored before and during lockdown, the lockdown itself seems to be the most likely explanation for the observed difference Identifying interventions that increase mood homeostasis might be a promising avenue to mitigate the impact of lockdowns on mental health Table 1 No conflict of interest

International audience; 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

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.

In early March 2011 the European College of Neuropsychopharmacology (ECNP) hosted a summit to consider the implications and consequences of the abrupt withdrawal of a number of major pharmaceutical companies from key areas of neuroscience research and development in brain disorders and psychopharmacology in particular. This paper presents the recommendations of the summit plus details of the background and analyses of the problem. It will be widely circulated within Europe and elsewhere.

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.

Bipolar disorder is a devastating and chronic mood disorder, which can require life-long treatment. The vast majority of patients will suffer relapse of symptoms in the absence of effective therapy. Of those patients receiving treatment, compliance to medication regimens is poor. Non-compliance, when associated with lithium treatment in particular, increases the risk of recurrence of illness. Problems associated with withdrawal serve as powerful stimuli to develop alternatives to lithium monotherapy. Conventional placebo-controlled studies of treatments are difficult in patients with bipolar disorder. Large-scale, pragmatic and clinically relevant trials should be employed to assess existing and novel treatments for bipolar disorder. These can only develop out of genuine clinician and patient uncertainty and the creation of a trial culture in everyday practice.