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In the wake of the COVID-19 pandemic, healthcare systems rapidly embraced technology as a means of providing care while adhering to social distancing protocols. In this brief article, we report on a new telehealth initiative recently implemented in an out-patient psychiatric setting and outline the novel role telehealth may serve in facilitating psychiatric care globally. The uptake of telehealth represents a new and exciting opportunity to increase both access to, and quality of, care for people with mental illness.

Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations.Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L.The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable.This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant's experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants' experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression.report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis.Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm.This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants' experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.

Objective To rebut the claims made in an opinion piece by Anaf and colleagues regarding the recommendations for psychotherapy within the 2020 RANZCP Mood Disorders Clinical Practice Guidelines (CPG). Conclusions The CPG attaches importance to psychological interventions and recommends their administration as first-line in the treatment of depression. The concerns raised by Anaf and colleagues have no basis and are readily dismissed by referring to the guidelines. Therefore, we strongly encourage clinicians to formulate their own views by reading the guidelines for themselves.

SUMMARYDistinguishing the symptoms of antidepressant withdrawal from those of relapse is a complex issue that has an impact on a significant number of clinicians and patients. This commentary expands on several important points made by Horowitz & Taylor in their examination of this critically under-researched area and illustrates the relationships between symptoms, and how their onset may provide insights into their aetiology.

Psychotic episodes occur in a substantial proportion of patients suffering from major mood disorders (both unipolar and bipolar) at some point in their lives. The nature of these episodes is less well understood than the more common, non-psychotic periods of illness and hence their management is also less sophisticated. This is a concern because the risk of suicide is particularly high in this subtype of mood disorder and comorbidity is far more common. In some cases psychotic symptoms may be signs of a comorbid illness but the relationship of psychotic mood to other forms of psychosis and in particular its interactions with schizophrenia is poorly understood. Therefore, our targeted review draws upon extant research and our combined experience to provide clinical context and a framework for the management of these disorders in real-world practice - taking into consideration both biological and psychological interventions.

With advances in technology being applied to the detection and diagnosis of medical disorders we consider the potential role of such innovations in improving the management of mental health, in particular depression.

Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Facial emotion recognition (FER) deficits in depressed mood disorder patients contribute to suicidality. Prior research shows that intrinsic brain activity patterns are altered by attempting suicide. Therefore, we investigated in depressed patients whether differences in FER contribute to their clinical symptoms of suicide.Neural activity in response to an FER task was compared across three groups: healthy controls (HCs, N = 66), suicide non-attempter (SNA, N = 50), suicide attempter (SA, N = 25). Modulation of brain networks by the task and functional connectivity (FC) within (using spatial map, spectral power) and between (using functional network connectivity; FNC) were examined. The contribution of these differences to suicidal symptoms in each group was also examined.Patient groups displayed impaired FC both within and between networks but differed in nature and networks involved. They also showed differential modulation of networks by task, such that compared with both HC and SNA, SA displayed impaired FC within the default-mode network (DMN) and also its task modulation. In the SA group, FC within the DMN and FNC between two lateral prefrontal networks, and its interaction with the basal ganglia network contributed significantly to the clinical symptoms of suicide.This study affirms differences between SA and SNA brain activity patterns and suggests that suicidal activity probably emanates via different mechanisms in these patient groups. Perhaps, over-attribution of emotion impairs one's self-referential thought processes and coupled with diminished emotional control this makes depressed individuals vulnerable to suicide.

Despite homogenous clinical presentations between bipolar and unipolar disorders, there are distinct neurobiological differences. Chronicity of illness may be a factor impacting and sustaining certain neural features. The goal of this study was to investigate common and shared neural mechanisms underlying mood disorders, and possible sustained neural changes relating to illness chronicity by investigating a cohort of euthymic patients with bipolar disorder (BD), unipolar depression who had responded to treatment (treatment-sensitive depression, TSD), and a chronically treatment-resistant depressed (TRD) group.One hundred and seventy-two participants (40 BD, 39 TSD, 40 TRD, and 53 age-gender-matched healthy controls) underwent resting-state fMRI scans. Seed-based and independent component analyses were performed to investigate group differences in resting-state connectivity between the four groups.All three clinical groups had significantly lower connectivity within the frontoparietal network (FPN) relative to controls. TRD and BD were significantly different from TSD (TRD, BD TSD) but were not significantly different from each other. TRDs were also significantly different from both BD and TSD for salience network connectivity with the posterior cingulate (DMN) and the FPN with frontal pole (DMN). Additionally, the BD group exhibited greater DMN-FPN (sgACC-RDLPFC) connectivity relative to TRD, TSD, and controls, which was correlated with a previous number of depressive episodes, in the BD group only.BD demonstrated shared and differential connectivity features relative to symptomatic TRD and euthymic TSD groups. The increased sgACC-RDLPFC connectivity in BD and its correlation with a number of depressive episodes could be a neural feature associated with illness chronicity.

This perspective piece is a detailed analysis of the critique by Gordon Parker of the mood disorders clinical practice guidelines (MDcpg2020), in which he claims that bipolar II disorder has been ‘banished’ despite its formal status in current taxonomies. In this article, I defend the reasoning used by the Committee to adopt a dimensional model for describing and managing mood disorders, in particular bipolar disorder. I also robustly contend the many erroneous inferences made by him in his Viewpoint regarding management recommendations within the MDcpg2020and demonstrate that there is no valid justification for subtyping bipolar disorder – especially in the manner proposed by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Thus, I argue that it was appropriate for the MDcpg2020Committee to pursue an alternative model to the usual subtyping of bipolar disorder into ‘thing one’ and ‘thing two’ and conclude that the now clearly redundant model of Bipolar II should be altogether removed from our lexicon and clinical practice. Indeed, it is time to develop new and alternative models for defining bipolar disorder and among these a dimensional model should be given consideration.

Feeling irritable is a common experience, both in health and disease. In the context of psychiatric illnesses, it is a transdiagnostic phenomenon that features across all ages, and often causes significant distress and impairment. In mood disorders, irritability is near ubiquitous and plays a central role in diagnosis and yet, despite its prevalence, it remains poorly understood. A neurobiological model of irritability posits that, in children and adolescents, it is consequent upon deficits in reward and threat processing, involving regions such as the amygdala and frontal cortices. In comparison, in adults with mood disorders, the few studies that have been conducted implicate the amygdala, orbitofrontal cortices, and hypothalamus; however, the patterns of activity in these areas are at variance with the findings in youth. These age-related differences seem to extend to the neurochemistry of irritability, with links between increased monoamine transmission and irritability evident in adults, but aberrant levels of, and responses to, dopamine in youth. Presently, there are no specific treatments that have significant efficacy in reducing irritability in mood disorders. However, treatments that hold some potential and warrant further exploration include agents that act on serotonergic and dopaminergic systems, especially as irritability may serve as a prognostic indicator for overall clinical responsiveness to specific medications. Therefore, for understanding and treatment of irritability to advance meaningfully, it is imperative that an accurate definition and means of measuring irritability are developed. To achieve this, it is necessary that the subjective experience of irritability, both in health and illness, is better understood. These insights will inform an accurate, comprehensive, and valid interrogation of the qualities of irritability in health and illness, and allow not only a clinical appreciation of the phenomenon, but also a deeper understanding of its important role within the development and manifestation of mood disorders.

The efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression is disputed. This is partly because, to date, insufficient good-quality studies have been conducted, and a definitive clinical profile for which rTMS is best suited is yet to be determined. However, another equally important reason for questioning the efficacy of rTMS is that the clinical response to its application is thought to be the result of predominantly non-specific and placebo effects. Therefore, in this viewpoint we examine this possibility in detail and propose a meaningful way forward for rTMS research.

Background The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2015 and MDcpg2020) provide evidence-based and consensus-based recommendations for managing mood disorders. Aims We examined Australian real-world prescribing habits to determine whether management in clinical practice aligned with MDcpg2015 recommendations. Method A retrospective analysis of a cohort of patients ≥16 years old who had been dispensed a Pharmaceutical Benefits Scheme (PBS)-listed antidepressant between July 2013 and June 2019 was conducted using Australian Commonwealth Department of Human Services PBS 10% sample data. Results Between July 2013 and June 2019, 239 944 patients in Australia commenced antidepressant treatment. Of these, 22% (52 694 patients) received a second treatment (a new class of treatment after a period of discontinuation or additional antipsychotic therapy) and 6% (15 741 patients) received a third treatment. Patients were initially prescribed primarily selective serotonin reuptake inhibitors (SSRIs; 52% of prescriptions) or tricyclic antidepressants (TCAs; 25%), even though TCAs are not recommended for first-line treatment. Fewer than one-quarter of patients were prescribed serotonin–noradrenaline reuptake inhibitors (13%) or other agents (10%). General practitioners (GPs) were more likely to initiate TCAs than psychiatrists (22% v. 7%). Once initiated, the overall median time patients remained on treatment was 4.5 months; this was highest with SSRIs (5.8 months) and lowest with TCAs (0.9 months). Conclusions First-line prescribing broadly follows guidelines. GP and psychiatrist prescribing patterns differ, perhaps reflecting different patient groups and the need to tailor treatment to individuals. Future guidelines should aim to capture the different presentations and complexity of depression.

An increased prevalence of duplicated Heschl’s gyrus (HG) has been repeatedly demonstrated in various stages of schizophrenia as a potential neurodevelopmental marker, but it remains unknown whether other neuropsychiatric disorders also exhibit this macroscopic brain feature. The present magnetic resonance imaging study aimed to examine the disease specificity of the established finding of altered HG patterns in schizophrenia by examining independent cohorts of bipolar disorder (BD) and major depressive disorder (MDD). Twenty-six BD patients had a significantly higher prevalence of HG duplication bilaterally compared to 24 age- and sex-matched controls, while their clinical characteristics (e.g., onset age, number of episodes, and medication) did not relate to HG patterns. No significant difference was found for the HG patterns between 56 MDD patients and 33 age- and sex-matched controls, but the patients with a single HG were characterized by more severe depressive/anxiety symptoms compared to those with a duplicated HG. Thus, in keeping with previous findings, the present study suggests that neurodevelopmental pathology associated with gyral formation of the HG during the late gestation period partly overlaps between schizophrenia and BD, but that HG patterns may make a somewhat distinct contribution to the phenomenology of MDD.

Background Up to 40% of patients with bipolar disorder (BD) are initially diagnosed as having major depressive disorder (MDD), and emotional lability is a key aspect of both sets of mood disorders. However, it remains unknown whether differences in the regulation of emotions through cognitive reappraisal may serve to distinguish BD and MDD. Therefore, we examined this question in euthymic BD and MDD patients. Methods Thirty-eight euthymic BD, 33 euthymic MDD and 37 healthy control (HC) participants, matched for age, gender and depression severity, engaged in an emotion regulation (ER) cognitive reappraisal task during an fMRI scan were examined. Participants either reappraised (Think condition) or passively watched negative (Watch condition) or neutral (Neutral condition) pictures and rated their affect. Activation and connectivity analyses were used to examine group differences in reappraisal (Think vs Watch) and reactivity (Watch vs Neutral) conditions in ER-specific neural circuits. Results Irrespective of group, participants rated most negatively the images during the Watch condition relative to Think and Neutral conditions, and more negatively to Think relative to Neutral. Notably, BD participants exhibited reduced subgenual anterior cingulate activation (sgACC) relative to MDD during reappraisal, but exhibited greater sgACC activation relative to MDD during reactivity, whereas MDD participants elicited greater activation in right amygdala relative to BD during reactivity. We found no group differences in task-related connectivity. Conclusions Euthymic BD and MDD patients engage differential brain regions to process and regulate emotional information. These differences could serve to distinguish the clinical groups and provide novel insights into the underlying pathophysiology of BD.

Objectives: To provide advice and guidance regarding the management of mood disorders, derived from scientific evidence and supplemented by expert clinical consensus to formulate s that maximise clinical utility. Methods: Articles and information sourced from search engines including PubMed, EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (e.g. books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Relevant information was appraised and discussed in detail by members of the mood disorders committee, with a view to formulating and developing consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous consultation and external review involving: expert and clinical advisors, key stakeholders, professional bodies and specialist groups with interest in mood disorders. Results: The Royal Australian and New Zealand College of Psychiatrists mood disorders clinical practice guidelines 2020 (MDcpg2020) provide up-to-date guidance regarding the management of mood disorders that is informed by evidence and clinical experience. The guideline is intended for clinical use by psychiatrists, psychologists, primary care physicians and others with an interest in mental health care. Conclusion: The MDcpg2020 builds on the previous 2015 guidelines and maintains its joint focus on both depressive and bipolar disorders. It provides up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus. Mood disorders committee: Gin S Malhi (Chair), Erica Bell, Darryl Bassett, Philip Boyce, Richard Bryant, Philip Hazell, Malcolm Hopwood, Bill Lyndon, Roger Mulder, Richard Porter, Ajeet B Singh and Greg Murray.

Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility.This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression?Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD - World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing.The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of 'deconstructing depression'. By this approach, the clinician considers which factors contribute to making this individual both depressed and 'resistant' to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual's hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan.A 'deconstructing depression' qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD.MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient's depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence.

OBJECTIVES: To provide a succinct, clinically useful summary of the management of bipolar disorder, based on the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2020 ). METHODS: To develop the MDcpg2020 , the mood disorders committee conducted an extensive review of the available literature to develop evidence-based recommendations (EBR) based on National Health and Medical Research Council (NHMRC) guidelines. In the MDcpg2020 , these recommendations sit alongside consensus-based recommendations (CBR) that were derived from extensive deliberations of the mood disorders committee, drawing on their expertise and clinical experience. This guideline summary is an abridged version that focuses on bipolar disorder. In collaboration with international experts in the field, it synthesises the key recommendations made in relation to the diagnosis and management of bipolar disorder. RESULTS: The bipolar disorder summary provides a systematic approach to diagnosis, and a logical clinical framework for management. It addresses the acute phases of bipolar disorder (mania, depression and mixed states) and its longer-term management (maintenance and prophylaxis). For each phase it begins with Actions, which include important strategies that should be implemented from the outset wherever possible. These include for example, lifestyle changes, psychoeducation and psychological interventions. In each phase, the summary advocates the use of Choice medications for pharmacotherapy, which are then used in combinations along with additional Alternatives to manage acute symptoms or maintain mood stability and provide prophylaxis. The summary also recommends the use of electroconvulsive therapy (ECT) for each of the acute phases but not for maintenance therapy. Finally, it briefly considers bipolar disorder in children and its overlap in adults with borderline personality disorder. CONCLUSIONS: The bipolar disorder summary provides up to date guidance regarding the management of bipolar disorder, as set out in the MDcpg2020 . The recommendations are informed by evidence and clinical expertise and experience. The summary is intended for use by psychiatrists, psychologists and primary care physicians but will be of interest to anyone involved in the management of patients with bipolar disorder.

OBJECTIVES: To provide a succinct, clinically useful summary of the management of major depression, based on the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2020 ). METHODS: To develop the MDcpg2020 , the mood disorders committee conducted an extensive review of the available literature to develop evidence-based recommendations (EBR) based on National Health and Medical Research Council (NHMRC) guidelines. In the MDcpg2020, these recommendations sit alongside consensus-based recommendations (CBR) that were derived from extensive deliberations of the mood disorders committee, who drew on their expertise and clinical experience. Therefore, this guideline summary is an abridged version that focuses on major depression. In collaboration with international experts in the field, it synthesises the key recommendations made in relation to the diagnosis and management of major depression. RESULTS: The depression summary provides a systematic approach to diagnosis, and a logical clinical framework for management. The latter begins with Actions, which include important strategies that should be implemented from the outset. These include lifestyle changes, psychoeducation and psychological interventions. The summary advocates the use of antidepressants in the management of depression as Choices and nominates seven medications that can be trialled as clinically indicated before moving to Alternatives for managing depression. Subsequent strategies regarding Medication include Increasing Dose, Augmenting and Switching (MIDAS). The summary also recommends the use of ECT, and discusses how to approach non-response. CONCLUSIONS: The major depression summary provides up to date guidance regarding the management of major depressive disorder, as set out in the MDcpg2020 . The recommendations are informed by research evidence in conjunction with clinical expertise and experience. The summary is intended for use by psychiatrists, psychologists and primary care physicians, but will be of interest to all clinicians and carers involved in the management of patients with depressive disorders.

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

It has recently been argued that a unidimensional approach to mood disorders, focusing predominantly on emotions is too narrow to capture the full spectrum of symptoms of affective disorders, and that additional symptom domains of activity and cognition are at least equally important - possibly even more so1 . This 'ACE' (Activity, Cognition and Emotion) model provides more clarity in conceptualising mixed states, the existence of which challenges the predominantly dichotomous view promulgated by DSM and ICD, in which mania and depression are deemed to be mutually exclusive and form two poles of mood disorders with little in between. However, in reality, there are symptoms that occur in both depression and mania, and to better understand mixed mood states it has been proposed that these 'overlapping' symptoms form the essence of mixed states, and therefore they should be central to their definition. Furthermore, within these, overlapping symptoms of distractibility, irritability and psychomotor agitation2 are possibly the most important for better defining mixed states and advancing our understanding. Thus, in this brief article we endeavour to further refine our focus, specifically narrowing in on irritability, and argue that perhaps 'it' in particular holds the key to defining these complex presentations and unlocking their secrets.

Background: Randomized controlled clinical trials that have investigated minocycline as an adjunctive treatment for major depressive disorder have proved promising. Data from two studies were pooled to evaluate more definitively whether the addition of minocycline to standard treatment for major depressive disorder leads to an improvement of depressive symptoms when compared with placebo. Methods: Both studies were multi-site, double-blinded, placebo-controlled trials of minocycline 200 mg/day added to treatment as usual during a 12-week period. The primary outcome measure was change in depressive symptoms (Montgomery–Asberg Depression Rating Scale in Dean et al. and Hamilton Depression Rating Scale in Husain et al.). Secondary outcomes were change in depression severity (Montgomery–Asberg Depression Rating Scale for Dean et al. and 9-item Patient Health Questionnaire in Husain et al.), anxiety severity (Hamilton Anxiety Rating Scale in Dean et al. and Generalized Anxiety Disorder 7-item scale in Husain et al.) and functional status, which were also evaluated as potential mediators on the primary outcome. Results: A total of 112 participants were included in the pooled data (Dean et al., n = 71; Husain et al., n = 41). A significant change from baseline to week 12 was noted in depressive symptoms – differential change (Placebo vs Minocycline): 9.0, 95% confidence interval = [4.2, 13.9], Cohen’s D (95% confidence interval): 0.71 [0.29, 1.14], p Conclusion: The improvement of depressive symptoms, anxiety severity and functional status is promising and suggests that minocycline has potential as an adjunctive treatment for major depressive disorder. However, further studies are warranted to confirm therapeutic effects of minocycline in major depressive disorder. Trial registrations: NCT02263872, registered October 2014, and ACTRN12612000283875, registered March 2012.

Objective: Torture adversely influences emotional functioning, but the neurophysiological mechanisms underpinning its impact are unknown. This study examined how torture exposure affects the neural substrates of interpersonal threat and reward processing. Methods: Male refugees with ( N = 31) and without ( N = 27) torture exposure completed a clinical interview and functional magnetic resonance imaging scan where they viewed fear, happy and neutral faces. Between-group activations and neural coupling were examined as moderated by posttraumatic stress disorder symptom severity and cumulative trauma load. Results: Posttraumatic stress disorder symptom severity and trauma load significantly moderated group differences in brain activation and connectivity patterns. Torture survivors deactivated the ventral striatum during happy processing compared to non-torture survivor controls as a function of increased posttraumatic stress disorder symptom severity – particularly avoidance symptoms. The ventral striatum was more strongly coupled with the inferior frontal gyrus in torture survivors. Torture survivors also showed left hippocampal deactivation to both fear and happy faces, moderated by trauma load, compared to controls. Stronger coupling between the hippocampus and frontal, temporoparietal and subcortical regions during fear processing was observed, with pathways being predicted by avoidance and hyperarousal symptoms. Conclusion: Torture exposure was associated with distinct brain activity and connectivity patterns during threat and reward processing, dependent on trauma exposure and posttraumatic stress disorder symptom severity. Torture appears to affect emotional brain functioning, and findings have the potential to guide more targeted interventions for torture survivors.

Background Attentional deficits are common in both symptomatic and symptom-remitted patients with bipolar disorder (BP) and major depressive disorder (MDD). However, whether the level of neurocognitive impairment in attentional processing is different between these two disorders, or not, is still unclear. Thus, we investigated the P300 event-related potential component as a biomarker of cognitive dysfunction to differentiate BP and MDD. Methods Twenty-three age and gender matched BP, 20 MDD and 23 healthy controls (HC) were part of a discovery cohort to identify neurophysiological differences between groups and build a classification model of these disorders. The replication of this model was then tested in an independent second cohort of 17 BP, 19 MDD and 19 HC. All participants were symptom-remitted for at least two weeks. We compared neural responses to target stimuli during an auditory oddball task, computing peak amplitude and latency of the P300 component extracted from the midline centro-parietal electrode. Results BP had significantly smaller P300 amplitudes compared to both MDD and HC, whereas there were no differences between MDD and HC. The differences between groups were replicated in the second cohort, however the accuracy level of the classification model was only 53.5%. Limitations Small sample sizes may have led to low accuracy levels of the classification model. Conclusion Specific neural mechanisms of attention and context updating seem not to recover with symptom remission in BP. These findings contribute to the detection of a potential electrophysiological marker for BP, which may allow its differentiation from unipolar major depressive disorder.