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Background The relationship between irritability as a subjective experience and the behavioural indicators typically used to measure the construct are not known. Its links to mood, and contextual relationships, vary with age and are yet to be thoroughly examined. Aims First, to interrogate the relationship between the subjective experience of irritability and mood, and that with its behavioural indicators. Second, to determine how these relationships vary with age and over time. Method This study examined data from a previous clinical trial of adolescents and young adults (N = 82) with bipolar disorder, who received a psychological intervention over 18 months. Participants completed a battery of questionnaires, which included assessments of irritability. Analyses of covariance were conducted to examine the interaction between mood symptoms, subjective measures of irritability, behavioural measures of irritability and age over time. Results Subjective irritability scores differed significantly over time when controlling for manic, but not depressive, symptom scores. Further, subjective irritability significantly differed when controlling for behavioural measures of irritability (temper outbursts and argumentativeness). There were significant interactions between scores of depressive symptoms, temper outbursts and subjective irritability with age, wherein younger participants showed no correlation between depressive symptoms and temper outbursts. In addition, younger participants showed lower correlations between subjective irritability and both depressive and temper outburst scores, than older participants. Conclusions Subjective irritability is linked to mood morbidity and behavioural outbursts, and these relationships are contingent on age. Our novel findings suggest that subjective irritability should be assessed in greater detail in patients with mood disorders.

The issue of categorical vs. dimensional classification of bipolar disorder continues to generate controversy as it has for generations. Despite the evidence that no psychiatric disorder has discrete boundaries separating pathological and nonpathological states, and within a disorder, no clear differences separate subtypes-which would suggest a more dimensional approach-there are valid reasons to continue with our current categorical system, which distinguishes bipolar I from bipolar II disorder. Complicating the issue, a number of interested constituencies, including patients and their families, clinicians, scientists/researchers, and governmental agencies and insurance companies have different interests and needs in this controversy. This paper reviews both the advantages and disadvantages of continuing the bipolar I/bipolar II split vs. redefining bipolar disorder as one unified diagnosis. Even with one unified diagnosis, other aspects of psychopathology can be used to further describe and classify the disorder. These include both predominant polarity and categorizing symptoms by ACE-activity, cognition and energy. As a field, we must decide whether changing our current classification before we have a defining biology and genetic profile of bipolar disorder is worth the disruption in our current diagnostic system.

Recent conceptualisations of resilience have advanced the notion that it is a dynamic and multifaceted construct. However, its adaptive components, especially those forged by adversity, have not been fully realised, and its neurobiological and psychosocial underpinnings are yet to be meaningfully integrated. In part, this is because a developmental perspective is often neglected in the formulation of resilience. In this review, we consider the findings of resilience research, with a specific emphasis on the developmental period of adolescence. To bridge the gaps in our current understanding, we propose a model of resilience that is predicated on experiencing adversity. Specifically, our model provides a sophisticated insight into the components of resilience, which, together with intrinsic features, involves facilitation of, and skill acquisition via strengthening processes we term tempering and fortification. The model also points to the potential trajectories of adversity-driven resilience and forms the basis of a framework that allows for individual variance in resilience, and the identification of both neurobiological and psychosocial targets for prevention and therapeutic interventions.

Alzheimer's disease (AD) research, treatment, and prevention focus increasingly on developing personalized interventions based on personal genetic, biological, phenotypic data, for early intervention (EI) to limit harm. This approach has much to recommend it, but important ethical and philosophical challenges follow that should be considered, which we analyze here. We argue that advancing understanding of the causes of AD undermines the clarity of the distinction between primary and secondary prevention. This makes it increasingly unclear how primary and secondary categories can be appealed to as the basis for making judgements about what interventions are permissible, and for distinguishing between acceptably vs unacceptably early points in life to intervene. Timely efforts at prevention are vital for limiting harm from AD and given the logic of EI is that, in presence of risk, earlier is better, one might assume that earliest is best. This may or may not be the case; however, the permissibility of intervening in different ways at different stages of life is complex and turns on numerous contextual factors. We consider the particular ethical implications of intervening at different points in the life course, presenting a valuable resource for negotiating clinical and policy implications of EI in AD.

SummaryThe term ‘mood stabiliser’ is ill-defined and lacks clinical utility. We propose a framework to evaluate medications and effectively communicate their mood stabilising properties – their acute and prophylactic efficacy across the domains of mania and depression. The standardised framework provides a common definition to facilitate research and clinical practice.Declaration of interestThe Treatment Algorithm Group (TAG) was supported logistically by Servier who provided financial assistance with travel and accommodation for those TAG members travelling interstate or overseas to attend the meeting in Sydney (held on 18 November 2017). None of the committee were paid to participate in this project and Servier have not had any input into the content, format or outputs from this project.

Abnormal melatonin secretion has been demonstrated in patients with affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). However, magnetic resonance imaging (MRI) studies that previously investigated the volume of the pineal gland, which regulates circadian rhythms by secreting melatonin, in these patients reported inconsistent findings. The present study employed MRI to examine pineal gland volumes and pineal cyst prevalence in 56 MDD patients (29 currently depressed and 27 remitted patients), 26 BD patients, and matched controls (33 for MDD and 24 for BD). Pineal volumes and cyst prevalence in the current MDD, remitted MDD, and BD groups did not significantly differ from those of the healthy controls. However, pineal gland volumes were significantly smaller in the current MDD subgroup of non-melancholic depression than in the melancholic MDD subgroup. Interestingly, pineal volumes correlated negatively with the severity of loss of interest in the current MDD group. Medication and the number of affective episodes were not associated with pineal volumes in the MDD or BD group. While these results do not suggest that pineal volumes reflect abnormal melatonin secretion in affective disorders, they do point to the possibility that pineal abnormalities are associated with clinical subtypes of MDD and its symptomatology.

Background: A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis.\ud \ud \ud Methods: A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes.\ud \ud \ud Results: One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group.\ud \ud \ud Conclusions: These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction.

AIMS: To systematically review existing trials on optimal serum levels for lithium for maintenance treatment of bipolar disorder and to develop clinical recommendations.METHODS: Systematic literature search. Discussion of major characteristics, limitations, methodological quality and results of selected trials. Delphi survey consisting of clinical questions and corresponding statements. For statements endorsed by at least 80% of the members, consensus was considered as having been achieved.RESULTS: With strict inclusion criteria no studies could be selected, making it difficult to formulate evidence-based recommendations. After loosening the inclusion criteria seven trials were selected addressing our aims at least to some extent. Four of these studies suggest better efficacy being associated with lithium serum levels in a range above a lower threshold around 0.45/0.60 and up to 0.80/1.00 mmol/L. These findings support the outcome of the Delphi survey.CONCLUSIONS: For adults with bipolar disorder there was consensus that the standard lithium serum level should be 0.60-0.80 mmol/L with the option to reduce it to 0.40-0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. For children and adolescents there was no consensus, but the majority of the members endorsed the same recommendation. For the elderly there was also no consensus, but the majority of the members endorsed a more conservative approach: usually 0.40-0.60 mmol/L, with the option to go to maximally 0.70 or 0.80 mmol/L at ages 65-79 years, and to maximally 0.70 mmol/L over age 80 years. This article is protected by copyright. All rights reserved.

In November this year, we marked the 100th anniversary of the birthday of Mogens Schou, the great Danish clinical and basic scientist and a true giant of lithium research and treatment. Mogens Schou did more than anybody else in the world to establish lithium therapy, and without his assiduousness lithium may well have been forgotten. To commemorate his achievements a special symposium was organized in Copenhagen dedicated to lithium and the life time contributions of Mogens Schou. The celebration took place on November 23, 2018, the day before Mogens Schou's actual birthday. During the symposium, Janusz Rybakowski highlighted the scientific achievements of Mogens Schou, Marylou Selo focused on what he meant for patients. This article is protected by copyright. All rights reserved.

Posttraumatic Stress Disorder (PTSD) is associated with elevated noradrenergic signaling, which has an impact on emotional learning and memory. Fear extinction is thought to underlie the processes of exposure therapy, however the relationship between noradrenaline and extinction in PTSD is unclear. Participants with PTSD (n = 21), trauma-exposure without PTSD (TC; n = 36), and non-trauma-exposed controls (NTC; n = 27) completed a fear conditioning and extinction paradigm, and conditioned fear was indexed by skin conductance response (SCR). Salivary α-amylase (sAA) collected at baseline and immediately post-fear acquisition was used as an index of noradrenaline, and we examined whether sAA in response to fear acquisition was a moderator between fear extinction and PTSD symptoms. While there was a significant increase in sAA from baseline to post-fear acquisition, this was not modulated by group. Compared to TC and NTC, the PTSD group displayed a slower decline in SCRs during early extinction, which generalized across stimulus type, and was not moderated by sAA. These findings suggest that the relationship between fear extinction and PTSD symptoms does not change as a function of sAA levels; however previous research suggests other processes of fear learning may be associated with noradrenergic activity in PTSD.

Fear reinstatement is one of several paradigms designed to measure fear return following extinction, as a laboratory model for the relapse of Posttraumatic Stress Disorder (PTSD) symptoms. Sleep is a key factor in emotional memory consolidation, and here we examined the relationship between sleep quality and fear reinstatement in PTSD, relative to trauma-exposed and non-exposed controls. The Pittsburgh Sleep Quality Index (PSQI) was used as a subjective measure of sleep quality, and skin conductance responses (SCR) and unconditioned stimulus (US)-expectancy ratings were used to index threat responses during a differential fear conditioning, extinction, and reinstatement paradigm. There were no significant between-group differences in the reinstatement of conditioned responding. Sleep disturbance and sleep onset latency were significant moderators between reinstatement of fear and PTSD symptom severity, such that there was a positive relationship between PTSD symptoms and fear reinstatement for higher levels - but not lower levels - of sleep disturbance and sleep onset latency. To our knowledge, this is the first study to investigate PTSD-specific reinstatement patterns and sleep as a boundary condition of reinstatement. Future research using polysomnographic measures of sleep-wave architecture may further clarify the relationship between fear reinstatement and sleep quality in clinical samples with PTSD relative to controls.

Technological advances have defined our age. Computers, the internet and mobile devices are ubiquitous and virtually essential day-to-day tools. Some would argue that they have expanded our minds—and in doing so created the so-called ‘extended mind’. Irrespective of whether this is the case, they have at the very least permeated every aspect of our lives—to the point that most of us now rely heavily on technology and would be truly lost without our mobile phone, laptop or electronic calendar; and this is particularly true of younger generations. However, though we often refer to these as recent developments, even these technological advances are not that new. Surprisingly, most of these technologies have now been available for at least two decades or more. So what has changed recently? The key advances in recent years have been the increase in reliability and portability of hardware devices, the connectivity between devices and the individuals using them and the power with which software can meaningfully process and store information. This has meant that information that previously required a powerful desktop computer to process and store can now be miniaturised into the smallest of portable equipment, …

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.72.

While current pharmacotherapies are efficacious, there remain a clear shortfall between symptom remission and functional recovery. With the explosion in our understanding of the biology of these disorders, the time is ripe for the investigation of novel therapies. Recently depression is conceptualized as an immune-inflammatory and nitro-oxidative stress related disorder. Minocycline is a tetracycline antibiotic that has anti-inflammatory, pro-oxidant, glutamatergic, neurotrophic and neuroprotective properties that make it a viable target to explore as a new therapy. This double blind, randomised, placebo controlled adjunctive trial will investigate the benefits of 200 mg/day of minocycline treatment, in addition to any usual treatment, as an adjunctive treatment for moderate-severe major depressive disorder. Sixty adults are being randomised to 12 weeks of treatment (with a 4 week follow-up post-discontinuation). The primary outcome measure for the study is mean change on the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcomes including the Social and Occupational Functioning Assessment Scale (SOFAS), Clinical Global Impressions (CGI), Hamilton Rating Scale for Anxiety (HAM-A), Patient Global Impression (PGI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Range of Impaired Functioning Tool (LIFE-RIFT). Biomarker analyses will also be conducted at baseline and week 12. The study has the potential to provide new treatment targets, both by showing efficacy with a new class of 'antidepressant' but also through the analysis of biomarkers that may further inform our understanding of the pathophysiology of unipolar depression.

The original article [1] contained two minor errors.

OBJECTIVES: Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. METHODS: Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. RESULTS: Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. CONCLUSION: Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Objective: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. Method: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. Results: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. Conclusion: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.

SummaryThe classification of mood disorders lacks precision and consequently there has been no recent meaningful advance in their treatment. By virtue of its therapeutic specificity, lithium responsivity offers an opportunity to diagnose a definitive subtype of mood disorders that may provide a platform for the development of targeted therapy.

SummaryThe Royal College of Psychiatrists welcomes you to its newest peer-reviewed research journal, British Journal of Psychiatry Open (BJPsych Open), which has been created to maximise the College's efforts to publish and disseminate the most exciting and progressive research in psychiatry and allied disciplines. BJPsych Open will maintain the same high quality standards established by the British Journal of Psychiatry (BJPsych). As an online journal without print restrictions, BJPsych Open will be able to publish many more excellent articles and article types not currently accommodated within BJPsych. The breadth of BJPsych Open is outlined in ‘What we publish’ and its strength is realised in our first issue, ‘Powerful papers'. As editors, we welcome both your submissions and comments as our new generation journal grows.

The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders.

Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder

A task force report presents 12 recommendations for antidepressant use in bipolar disorder rated by at least 80% of International Society for Bipolar Disorders experts as essential or important. Objective The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. Method An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. Results There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. Conclusions Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Schizophrenia can be conceptualized as a disorder of functional connectivity within the fronto-temporal (FT) and/or default-mode (DM) networks. Recent evidence suggests that dysfunctional integration between these large neural networks may also contribute to the illness, and that the ability to mentalize or have a ‘theory of mind’ (ToM) is discernibly impaired in patients with schizophrenia. Hence in this study, we examined whether impaired functional network connectivity (FNC) contributes to a compromise in the ability to mentalize in patients with schizophrenia. Functional magnetic resonance imaging data were acquired from 20 male schizophrenia patients and 19 matched healthy controls whilst performing a well-known ToM task. The study revealed that relative to non-ToM the engagement of ToM produced reduced neural activity in the lateral FT and insula networks in patients, as compared to healthy subjects. The findings also indicated that in comparison to healthy subjects the DM and medial FT networks are less suppressed in patients irrespective of the task (ToM/non-ToM). Further, FNC analyses showed that the degree of functional connectivity between task-positive (lateral FT and insula) and task-negative (medial FT, posterior DM) networks was significantly reduced in patients as compared to controls. Of note, a significant correlation between the functional connectivity strength of the lateral FT network with the medial FT and the degree to which this is modulated by the ToM task, suggest that mentalizing deficits in male schizophrenia patients may stem from impaired communication between neural networks that comprehend the mental states of self (medial FT) and others (lateral FT).

Objective: The caudate nucleus (CN) is a crucial component of the ventral striatum, which is part of a prefrontal-striatal-thalamic circuit that is modulated by limbic structures to subserve emotional processing. Bipolar disorder is thought to be underpinned by dysfunctional anterior limbic networks, although MRI studies examining the CN have shown equivocal results. As gross volumetric analyses may not detect subtle regional change, we aimed to clarify the role of the CN in bipolar disorder by undertaking shape analysis to detect regional reductions. Methods: The CN was manually traced on MRI scans from 27 patients with bipolar-I disorder and 24 matched controls. A non-parametric spherical harmonic shape analysis was undertaken using the SPHARM toolkit. Results: Whilst the left CN volume was consistently larger in the sample, there was no effect of group or gender or significant interactions between these variables. Volume did not correlate with illness duration or lithium dosage, but was larger in those with a history of psychosis at trend level. However, left caudate shape differed significantly between groups, with deflation in an area along the ventromedial surface (connecting to dorsolateral prefrontal regions) in bipolar patients. Psychotic patients showed increases in the dorsal head and body at trend level overall, in regions connecting to medial and orbitofrontal regions. Conclusions: These findings suggest that subtle rather than gross structural changes occur in the CN, which may not be detectable by volumetric analysis alone, and reflect alterations in specific frontostriatal circuitry in the disorder.

Aim: Morphometric brain imaging studies have revealed regional brain abnormalities in patients with bipolar disorder, which may play a role in illness pathophysiology. It is not known whether such changes are of neurodevelopmental, neurodegenerative, or combined origin. We reviewed the anatomical brain imaging literature in bipolar disorder, in an attempt to determine whether there is evidence to suggest that such abnormalities are progressive.Method: Literature searches were conducted using MEDLINE for the period from 1966 to June 2004, using specific key words; bipolar disorder and the names of the individual brain structures. Papers were selected according to their salience in relation to whether reported changes are progressive.Results: Available findings suggest reduced grey matter in prefrontal brain regions such as anterior cingulate and subgenual prefrontal cortex, and abnormalities in amygdala size in adult and paediatric bipolar patients. White matter hyperintensities, which are non-specific abnormalities, are also common in bipolar patients. Bipolar patients may lose more brain grey matter by ageing. There is also evidence for impaired myelination of the corpus callosum in bipolar disorder. Lithium may reverse or prevent grey matter prefrontal cortex abnormalities in bipolar patients by its neuroprotective effects.Conclusions: Both early developmental and later neurodegenerative processes may play a role in the pathophysiology of bipolar disorder. Findings from anatomical brain imaging studies implicate key regions involved in mood regulation. The evidence for the progressive nature of this illness is tentative, as no follow-up study with bipolar patients has been reported to this date.