Who benefits from digital interventions for bipolar disorder? Stage of illness characteristics as predictors of changes in quality of life.

OBJECTIVES: This study explored the potential role of stage-related variables in intervention outcomes in bipolar disorder (BD). Specifically, we aimed to identify which subgroups of individuals were most likely to experience improved quality of life following digitally delivered psychosocial interventions for BD. METHODS: The study involved a secondary analysis of combined data from two randomised control trials (RCTs). Each trial assessed the effectiveness of digitally delivered interventions for improving quality of life, in late-stage (ORBIT RCT) or early-stage (BETTER RCT) BD. Three iterations of cluster analyses were performed, identifying subgroups of individuals based on (i) current phenomenology, (ii) course of illness and (iii) medication response. The resultant subgroups were compared with regard to changes in quality of life pre-post intervention, via repeated measures ANOVAs. RESULTS: In each cluster analysis, two clusters were found. The current phenomenology clusters reflected two impairment levels, 'moderate impairment' and 'low impairment'. The course of illness clusters reflected 'more chronicity' and 'less chronicity' and the medication response clusters reflected 'good medication response' and 'poor medication response'. Differences in changes in quality of life over time were observed between the two current phenomenology clusters and between the medication response clusters, while the course of illness subgroups did not respond differently. CONCLUSIONS: There are at least two distinct groups of treatment-seeking individuals with established BD, based on illness features with previously established links to different illness stages. Clusters within the current phenomenology and medication response domains demonstrated significantly different trajectories of QoL change over time in the context of our interventions, highlighting potential implications for treatment selection aligned with precision psychiatry.

Active components and mechanisms of action of psychological interventions in bipolar disorder: A systematic literature review.

OBJECTIVE: The efficacy of psychological interventions for bipolar disorder (BD) is well established, but much remains unknown about how change occurs. The primary objective of this exploratory study was to audit what is known about active components and mechanisms of action of psychological interventions for BD. METHOD: We conducted a systematic review (PROSPERO CRD42022323276). Two independent reviewers screened references from four databases and extracted data from eligible studies. RESULTS: We included four component studies, six studies with mediation analyses and 26 studies presenting subjective experiences of how psychological interventions bring change. Ten mediators were examined across six studies, with only one putative mediator, medication adherence, tested in more than one study. Some initial support for mediation of varied outcomes by control over thoughts, positive non-verbal behaviour, self-esteem, post-trauma growth and medication adherence. Some preliminary support was found in two components, human support and IPT. Studies exploring participant experiences of therapeutic change enumerated a range of potential active components, mechanisms of action and contextual factors potentially warranting investigation in future research. However, the evidence base for active components and mechanisms of action in psychological interventions for BD is unsatisfactory. Findings were inconsistent, studies homogenous with significant methodological limitations and statistical approaches failed to meet quality criteria. CONCLUSIONS: Preliminary identification of potential components and mechanisms via qualitative analyses and the insights emerging from this review will inform future research aimed at investigating how psychological interventions work in BD.

A randomized controlled trial to compare the effects of time-restricted eating versus Mediterranean diet on symptoms and quality of life in bipolar disorder.

BACKGROUND: The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep-wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. METHODS: This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. DISCUSSION: The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06188754.

The management of depression: the evidence speaks for itself.

Comparing the recommendations of two recently published national clinical practice guidelines for depression, this editorial highlights the concordance of advice concerning the selection and sequencing of therapies. Lifestyle and psychological interventions feature prominently and there is broad agreement regarding medication choice and optimisation strategies. The guidelines are therefore a useful resource.

Positioning of psychodynamic psychotherapy in the treatment of depression: A comparison of the RANZCP 2020 and NICE 2022 guidelines.

OBJECTIVE: To compare the 2022 NICE guidelines (NG222) and 2020 RANZCP clinical practice guidelines (MDcpg2020) recommendations for the treatment of depression using psychodynamic psychotherapy. CONCLUSIONS: Both guidelines recommend psychological interventions first-line. However, only short-term psychodynamic psychotherapy (STPP) is recommended, and in the NG222 it is ranked last for less severe depression and 7th for more severe depression. In contrast, cognitive behavioural therapy and behavioural activation are deemed the more clinically effective and cost-effective psychological therapies. And antidepressants play a significant role - largely in more severe depression.

Using a digital personal recovery resource in routine mental health practice: feasibility, acceptability and outcomes.

BACKGROUND: Digital technologies enable the dissemination of multimedia resources to support adults with serious mental illness in their self-management and personal recovery. However, delivery needs to accommodate engagement and accessibility challenges. AIMS: We examined how a digital resource, designed for mental health workers and consumers to use together in session, would be used in routine practice. METHODS: Thirty consumers and their workers participated. The web-based resource, Self-Management And Recovery Technology (SMART), was available to use within and between sessions, for a 6-month period. Workers initiated in-session use where relevant. Feasibility was explored via uptake and usage data; and acceptability and impact via questionnaires. A pre-post design assessed recovery outcomes for consumers and relationship outcomes for consumers and workers. RESULTS: In participating mental health practitioner-consumer dyads, consumers gave strong acceptability ratings, and reported improved working relationships. However, the resource was typically used in one-third or fewer appointments, with consumers expressing a desire for greater in-session use. Improvements in self-rated personal recovery were not observed, possibly contributed to by low usage. CONCLUSIONS: In-session use was found helpful by consumers but may be constrained by other demands in mental health care delivery: collaborative use may require dedicated staff time or more formal implementation.

Understanding familial liability for emotion regulation difficulties in bipolar disorder.

BACKGROUND: There has been relatively limited work focused on understanding whether relatives of individuals with bipolar disorder (BD) have difficulties in the regulation of emotion, particularly in relation to perceptions about whether emotions can be effectively regulated, or trait behaviours that acknowledge emotions as self-regulators themselves. In this study, we assessed the presence and extent of difficulties in these dimensions of emotion regulation in individuals with BD compared to unaffected first-degree biological relatives (FDR) for the first time. METHODS: In total, 161 participants, including euthymic individuals with BD, unaffected FDRs, and healthy controls, were compared on the Difficulties in Emotion Regulation Scale (DERS) - a multi-dimensional measure of habitual emotion regulation. Clinical data were also collected and examined in relation to DERS scores in a secondary analysis. RESULTS: In the BD group, difficulties were evident for most dimensions of emotion regulation as measured by the DERS; and correlated with an earlier onset of illness and more mood episodes. FDRs displayed generally normal emotion regulation, except in terms of their beliefs that emotions can be effectively regulated; on this dimension, their reported difficulty was intermediate to the BD group and controls. CONCLUSION: Habitual emotion regulation difficulties in BD persist irrespective of mood state, are related to the course of illness, and should be targeted in psychological interventions. Further, the perception that emotions cannot be effectively regulated during times of distress seems to represent an endophenotype for BD.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

Social Rhythm Disruption is Associated with Greater Depressive Symptoms in People with Mood Disorders: Findings from a Multinational Online Survey During COVID-19.

OBJECTIVES: Societal restrictions imposed to prevent transmission of COVID-19 may challenge circadian-driven lifestyle behaviours, particularly amongst those vulnerable to mood disorders. The overarching aim of the present study was to investigate the hypothesis that, in the routine-disrupted environment of the COVID-19, amongst a sample of people living with mood disorders, greater social rhythm disruption would be associated with more severe mood symptoms. METHODS: We conducted a two-wave, multinational survey of 997 participants (MAge=39.75±13.39,Female=81.6%) who self-reported a mood disorder diagnosis (i.e., major depressive disorder or bipolar disorder). Respondents completed questionnaires assessing demographics, social rhythmicity (The Brief Social Rhythm Scale), depression symptoms (Patient Health Questionnaire-9), sleep quality and diurnal preference (The Sleep, Circadian Rhythms and Mood questionnaire) and stressful life events during the COVID-19 pandemic (The Social Readjustment Rating Scale). RESULTS: The majority of participants indicated COVID-19-related social disruption had affected the regularity of their daily routines to at least some extent (n = 788, 79.1%). As hypothesised, lower social rhythmicity was associated with greater depressive symptoms when tested cross-sectionally (standardised ß = -.25, t = -7.94, P = 0.000) and when tested using a 2-level hierarchical linear model across two time points (b = -0.14, t = -3.46, df = 264, P ≤ 0.001). CONCLUSIONS: These results are consistent with the social zeitgeber hypothesis proposing that mood disorders are sensitive to life events that disrupt social rhythms.

Ustekinumab in the Management of Hidradenitis Suppurativa: A Retrospective Study.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by the formation of recurrent abscesses in apocrine-bearing areas. In advanced stages, chronic inflammation leads to sinus tract formation and cicatrization.

Pterygoid muscle activity in speech: A preliminary investigation.

BACKGROUND: Speaking depends on refined control of jaw opening and closing movements. The medial pterygoid muscle (MPT), involved in jaw closing, and the lateral pterygoid muscle (LPT), involved in jaw opening, are two key mandibular muscles in mastication and are likely to be recruited for controlled movements in speech. OBJECTIVES: Three hypotheses were investigated, that during speech the MPT and LPT: (1) were both active, (2) but exhibited different patterns of activity, (3) which fluctuated with the vowels and consonants in speech. METHODS: Intramuscular EMG recordings were made from the right inferior head of the LPT and/or the right MPT in five participants during production of 40 target nonsense words (NWs) consisting of three syllables in the form /V1 C1 V2 C2 ə/ (V = vowel; C = consonant; ə = unstressed, reduced vowel), spoken by each participant 10 times per NW; analysis focussed on the target syllable, C1 V2 . RESULTS: Both MPT and LPT exhibited robust increases in EMG activity during utterance of most NWs, relative to rest. Peak LPT activation was time-locked to the final part of the target consonant (C1 ) interval when the jaw begins opening for the target vowel (V2 ), whereas peak MPT activation occurred around the temporal midpoint of V2 , when the jaw begins closing for C2 . EMG amplitude peaks differed in magnitude between "high" vowels, i.e., for which the tongue/jaw are high (e.g., in SEEK), and "low" vowels, i.e., for which the tongue/jaw are low (e.g., in SOCK). CONCLUSIONS: These novel findings suggest a key role for the LPT and MPT in the fine control of speech production. They imply that speech may impose major synergistic demands on the activities of the MPT and the LPT, and thereby provide insights into the possible interactions between speech activities and orofacial activities (e.g. mastication) and conditions (e.g. Temporomandibular Disorders) that involve the masticatory muscles.

An Evidence-Based Perspective on The 2020 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines.

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.

Conceptualizing the later stage of bipolar disorder: Descriptive analyses from the ORBIT trial.

OBJECTIVES: This study aimed to investigate the features of later stage bipolar disorder (BD) and specifically, factors underlying later stage BD and potential subgroups within this stage, to understand more about the later stage group and contribute to the measurement of stage. METHODS: An exploratory factor analysis was conducted using variables relating to current phenomenological aspects of illness, followed by cluster analyses based on the identified factors. Finally, the resultant clusters were compared based on course of illness variables. RESULTS: Fourteen extracted factors explained 57 percent of the variance. Latent structures aligned with current depressive symptoms, energy and interest, independence, occupational functioning, symptoms of anxiety, pain, elevated symptoms, interpersonal functioning, anger, perceptions of social connections, and perceptions of current medication effectiveness, cognitive issues, sleep issues, and sense of isolation. Two clusters were identified which differed significantly on each of these factors, and on a range of course of illness features including lifetime number of episodes, duration of illness and number of depressive hospitalizations. CONCLUSIONS: Latent phenomenological features relevant to individuals in the later stage of BD were identified. Two clusters of individuals in later stage BD differ based on these features as well as course of illness, suggesting that there are distinct subgroups of individuals in the later stage of BD, distinguishable based on current phenomenology and illness history. However, findings are exploratory and therefore require confirmation before they can be applied clinically.

The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders.

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.

Medicinal psychedelics for mental health and addiction: Advancing research of an emerging paradigm.

The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the 'Clinical Memorandum on Psychedelics' recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down-scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field.

Functional properties of single motor units in the human medial pterygoid muscle: Thresholds.

BACKGROUND: Little is known regarding the functional properties of single motor units (SMUs) in the medial pterygoid muscle (MPt) during jaw movements. OBJECTIVES: The aims are (a) to report the thresholds of onset of MPt SMUs during 4 goal-directed jaw movement tasks, and (b) to determine whether the threshold of onset of SMU activation varies with the velocity of jaw movement and the location within the muscle. METHODS: Intra-muscular electrodes were inserted in the right MPt of 18 participants performing ipsilateral (right), contralateral, protrusive and opening-closing jaw movements recorded at 2 velocities. Task phases were as follows: BEFORE, OUT, HOLDING, RETURN and AFTER. SMU onset thresholds were determined from the displacement (mm) of the lower mid-incisor point. Electrode location within 4 arbitrary muscle divisions was determined with computer tomography. Statistical tests: Spearman's correlations, Kruskal-Wallis tests; significance accepted at P < .05. RESULTS: A significant inverse relation occurred between velocity and threshold for the RETURN of the ipsilateral movement (n = 62 SMU thresholds), while a significant positive relation occurred for the OUT of the contralateral movement (n = 208); there were no significant associations for the protrusive (n = 131) and opening-closing (n = 58) tasks. Significant threshold differences occurred across the 4 muscle divisions only during the OUT of the contralateral and protrusive movements. Some evidence was provided for gender differences in MPt SMU properties. CONCLUSIONS: The absence of a significant inverse relation between velocity and SMU threshold for most recorded movements suggests the MPt acts as a stabilizer of the jaw in horizontal and opening-closing jaw movements.

Threshold variations of medial pterygoid single motor units during vertical or horizontal force tasks.

OBJECTIVES: To test the hypotheses that (a) the force thresholds at onset of medial pterygoid muscle single motor unit (SMU) activity do not decrease with an increase in the rate of force generation in standardised vertical or horizontal jaw-force tasks, and (b) there is evidence for functional heterogeneity within the medial pterygoid muscle. METHODS: In 14 healthy participants, electromyographic recordings of the right medial pterygoid muscle were performed with intramuscular fine-wire electrodes during four isometric force tasks: vertical, horizontal contralateral, horizontal protrusion and horizontal ipsilateral, performed at two rates of force development (slow ramp, fast ramp). Computer tomography scans confirmed electrode location within the muscle, which was divided into medial and lateral parts. Force thresholds of onset of discriminated SMUs were compared between rates in each task; significance accepted at p < 0.05. RESULTS: Of 45 SMU force thresholds studied in one or more tasks, there was no significant difference between slow and fast ramp within each force task, except slow ramp thresholds from the lateral part during the vertical force task were significantly higher than fast ramp thresholds. Reversals of recruitment order between tasks provided evidence for functional heterogeneity within the muscle. Force thresholds of the vertical tasks (range: 1-292.6 N) were mostly higher than for the horizontal tasks (range: 0.1-12.5 N). CONCLUSION: The data are consistent with the proposal that the medial pterygoid muscle stabilises the jaw in the vertical plane during isometric force generation in the jaw closing, as well as horizontal directions.

A narrative review of cross-sectional and prospective associations between self-schemas and bipolar disorder.

The role of self-concept in bipolar disorder (BD) has not been well understood. The present review utilizes the notion of self-schema and interrogates existing research concerning evidence for cross-sectional and prospective associations between four schema-like constructs (i.e. trait self-esteem, dysfunctional beliefs concerning contingent self-worth, early maladaptive schemas and implicit self-esteem) and various facets of BD. Existing findings demonstrate various types of involvement of self-schemas in BD. Of particular clinical relevance, the present review suggests that low trait self-esteem and dysfunctional beliefs concerning contingent self-worth are risk factors for ongoing BD symptoms and mood episodes. The present review also yields important yet unaddressed questions with respect to the evaluative content of self-schemas associated with the hypo/manic phase of BD.

Number of episodes in bipolar disorder: The case for more thoughtful conceptualization and measurement.

OBJECTIVES: Number of mood episodes (NoE) may be an important prognostic indicator in bipolar disorder, with implications for treatment. However, NoE has been conceptualized and measured inconsistently throughout the literature. This review examines the construct of NoE in bipolar disorder, with the aim of enhancing its conceptualization and measurement. METHODS: A critical evaluation of literatures on important correlates of NoE, conceptually and phenomenologically overlapping features, and previous studies considering and measuring this construct was undertaken. RESULTS: The literature indicates that despite frequent use, NoE has been inconsistently defined and measured. Multiple studies have linked NoE with important clinical factors, including relapse, functioning, cognitive impairment and the effectiveness of both pharmacological and psychosocial interventions, yet conclusions are limited by its inconsistent treatment. Additionally, it seems evident that that NoE may best be treated as a fuzzy construct (rather than precise figure), with yet to be defined overlaps with clinical variables such as age at onset and severity. Attempts to measure this construct have varied in comprehensiveness and structure. CONCLUSIONS: The NoE construct may have important implications for individuals with bipolar disorders. However, more consistent and systematic definition and assessment of NoE is required to advance this literature and clarify its role. Recommendations aimed at advancing the conceptualization and the measurement of NoE are provided. Conceptualization may be advanced by considering and exploring relationships between NoE and factors with which it overlaps, while measurement may best be improved with increased consistency and balancing accuracy with feasibility.

The influence of stage of illness on functional outcomes after psychological treatment in bipolar disorder: A systematic review.

OBJECTIVES: The aim of this study was to advance understanding of stage of illness in bipolar disorder (BD), by interrogating the literature for evidence of an influence of stage of illness on functional (ie non-symptom) outcomes following psychosocial intervention. METHODS: A systematic literature search following PRISMA guidelines was conducted to identify empirical studies of psychosocial interventions for established BD. To investigate stage as a predictor of three functional outcomes (general/social functioning, cognitive functioning and quality of life [QoL]), study samples were dichotomised into earlier and later stage using proxy measures identified in existing staging models. Findings were integrated using data-based convergent synthesis. RESULTS: A total of 88 analyses from 62 studies were identified. Synthesis across studies suggested that psychosocial intervention was more likely to be effective for general functioning outcomes earlier in the course of established BD. No stage-related differences were found for cognitive or QoL outcomes. Exploratory investigations found some evidence of an interaction between specific intervention type and stage of illness in predicting outcomes. CONCLUSIONS: A novel systematic review provided preliminary evidence that benefits general/social functioning may be more pronounced in earlier versus later stages of established BD. The review also generated hypotheses about a potential three-way interaction, whereby specific psychosocial interventions may be best placed to target functional outcomes in earlier versus later stage BD. The strength of conclusions is limited by the overall low-quality and significant heterogeneity of studies. Further research is urgently required to understand the impact of illness stage on the effectiveness of psychosocial interventions.