Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression.

The dominant ('general') version of the diathesis-stress theory of depression views stressors and genetic vulnerability as independent risks. In the Australian Genetics of Depression Study (N = 14,146; 75% female), we tested whether polygenic scores (PGS) for major depression, bipolar disorder, schizophrenia, anxiety, ADHD, and neuroticism were associated with reported exposure to 32 childhood, past-year, lifetime, and accumulated stressful life events (SLEs). In false discovery rate-corrected models, the clearest PGS-SLE relationships were for the ADHD- and depression-PGSs, and to a lesser extent, the anxiety- and schizophrenia-PGSs. We describe the associations for childhood and accumulated SLEs, and the 2-3 strongest past-year/lifetime SLE associations. Higher ADHD-PGS was associated with all childhood SLEs (emotional abuse, emotional neglect, physical neglect; ORs = 1.09-1.14; p's < 1.3 × 10-5), more accumulated SLEs, and reported exposure to sudden violent death (OR = 1.23; p = 3.6 × 10-5), legal troubles (OR = 1.15; p = 0.003), and sudden accidental death (OR = 1.14; p = 0.006). Higher depression-PGS was associated with all childhood SLEs (ORs = 1.07-1.12; p's < 0.013), more accumulated SLEs, and severe human suffering (OR = 1.17; p = 0.003), assault with a weapon (OR = 1.12; p = 0.003), and living in unpleasant surroundings (OR = 1.11; p = 0.001). Higher anxiety-PGS was associated with childhood emotional abuse (OR = 1.08; p = 1.6 × 10-4), more accumulated SLEs, and serious accident (OR = 1.23; p = 0.004), physical assault (OR = 1.08; p = 2.2 × 10-4), and transportation accident (OR = 1.07; p = 0.001). Higher schizophrenia-PGS was associated with all childhood SLEs (ORs = 1.12-1.19; p's < 9.3-8), more accumulated SLEs, and severe human suffering (OR = 1.16; p = 0.003). Higher neuroticism-PGS was associated with living in unpleasant surroundings (OR = 1.09; p = 0.007) and major financial troubles (OR = 1.06; p = 0.014). A reversed pattern was seen for the bipolar-PGS, with lower odds of reported physical assault (OR = 0.95; p = 0.014), major financial troubles (OR = 0.93; p = 0.004), and living in unpleasant surroundings (OR = 0.92; p = 0.007). Genetic risk for several mental disorders influences reported exposure to SLEs among adults with moderately severe, recurrent depression. Our findings emphasise that stressors and diatheses are inter-dependent and challenge diagnosis and subtyping (e.g., reactive/endogenous) based on life events.

Effects of ethnic density on the risk of compulsory psychiatric admission for individuals attending secondary care mental health services: evidence from a large-scale study in England.

BACKGROUND: Black, Asian and minority ethnicity groups may experience better health outcomes when living in areas of high own-group ethnic density - the so-called 'ethnic density' hypothesis. We tested this hypothesis for the treatment outcome of compulsory admission. METHODS: Data from the 2010-2011 Mental Health Minimum Dataset (N = 1 053 617) was linked to the 2011 Census and 2010 Index of Multiple Deprivation. Own-group ethnic density was calculated by dividing the number of residents per ethnic group for each lower layer super output area (LSOA) in the Census by the LSOA total population. Multilevel modelling estimated the effect of own-group ethnic density on the risk of compulsory admission by ethnic group (White British, White other, Black, Asian and mixed), accounting for patient characteristics (age and gender), area-level deprivation and population density. RESULTS: Asian and White British patients experienced a reduced risk of compulsory admission when living in the areas of high own-group ethnic density [odds ratios (OR) 0.97, 95% credible interval (CI) 0.95-0.99 and 0.94, 95% CI 0.93-0.95, respectively], whereas White minority patients were at increased risk when living in neighbourhoods of higher own-group ethnic concentration (OR 1.18, 95% CI 1.11-1.26). Higher levels of own-group ethnic density were associated with an increased risk of compulsory admission for mixed-ethnicity patients, but only when deprivation and population density were excluded from the model. Neighbourhood-level concentration of own-group ethnicity for Black patients did not influence the risk of compulsory admission. CONCLUSIONS: We found only minimal support for the ethnic density hypothesis for the treatment outcome of compulsory admission to under the Mental Health Act.

Does circadian dysrhythmia drive the switch into high- or low-activation states in bipolar I disorder?

OBJECTIVES: Emerging evidence suggests a role of circadian dysrhythmia in the switch between "activation" states (i.e., objective motor activity and subjective energy) in bipolar I disorder. METHODS: We examined the evidence with respect to four relevant questions: (1) Are natural or environmental exposures that can disrupt circadian rhythms also related to the switch into high-/low-activation states? (2) Are circadian dysrhythmias (e.g., altered rest/activity rhythms) associated with the switch into activation states in bipolar disorder? (3) Do interventions that affect the circadian system also affect activation states? (4) Are associations between circadian dysrhythmias and activation states influenced by other "third" factors? RESULTS: Factors that naturally or experimentally alter circadian rhythms (e.g., light exposure) have been shown to relate to activation states; however future studies need to measure circadian rhythms contemporaneously with these natural/experimental factors. Actigraphic measures of circadian dysrhythmias are associated prospectively with the switch into high- or low-activation states, and more studies are needed to establish the most relevant prognostic actigraphy metrics in bipolar disorder. Interventions that can affect the circadian system (e.g., light therapy, lithium) can also reduce the switch into high-/low-activation states. Whether circadian rhythms mediate these clinical effects is an unknown but valuable question. The influence of age, sex, and other confounders on these associations needs to be better characterised. CONCLUSION: Based on the reviewed evidence, our view is that circadian dysrhythmia is a plausible driver of transitions into high- and low-activation states and deserves prioritisation in research in bipolar disorders.

Digital cognitive behaviour therapy for insomnia in individuals with self-reported insomnia and chronic fatigue: A secondary analysis of a large scale randomized controlled trial.

Insomnia is associated with fatigue, but it is unclear whether response to cognitive behaviour therapy for insomnia is altered in individuals with co-occurring symptoms of insomnia and chronic fatigue. This is a secondary analysis using data from 1717 participants with self-reported insomnia in a community-based randomized controlled trial of digital cognitive behaviour therapy for insomnia compared with patient education. We employed baseline ratings of the Chalder Fatigue Questionnaire to identify participants with more or fewer symptoms of self-reported chronic fatigue (chronic fatigue, n = 592; no chronic fatigue, n = 1125). We used linear mixed models with Insomnia Severity Index, Short Form-12 mental health, Short Form-12 physical health, and the Hospital Anxiety and Depression Scale separately as outcome variables. The main covariates were main effects and interactions for time (baseline versus 9-week follow-up), intervention, and chronic fatigue. Participants with chronic fatigue reported significantly greater improvements following digital cognitive behaviour therapy for insomnia compared with patient education on the Insomnia Severity Index (Cohen's d = 1.36, p < 0.001), Short Form-12 mental health (Cohen's d = 0.19, p = 0.029), and Hospital Anxiety and Depression Scale (Cohen's d = 0.18, p = 0.010). There were no significant differences in the effectiveness of digital cognitive behaviour therapy for insomnia between chronic fatigue and no chronic fatigue participants on any outcome. We conclude that in a large community-based sample of adults with insomnia, co-occurring chronic fatigue did not moderate the effectiveness of digital cognitive behaviour therapy for insomnia on any of the tested outcomes. This may further establish digital cognitive behaviour therapy for insomnia as an adjunctive intervention in individuals with physical and mental disorders.

Clinical staging and the differential risks for clinical and functional outcomes in young people presenting for youth mental health care.

BACKGROUND: Clinical staging proposes that youth-onset mental disorders develop progressively, and that active treatment of earlier stages should prevent progression to more severe disorders. This retrospective cohort study examined the longitudinal relationships between clinical stages and multiple clinical and functional outcomes within the first 12 months of care. METHODS: Demographic and clinical information of 2901 young people who accessed mental health care at age 12-25 years was collected at predetermined timepoints (baseline, 3 months, 6 months, 12 months). Initial clinical stage was used to define three fixed groups for analyses (stage 1a: 'non-specific anxious or depressive symptoms', 1b: 'attenuated mood or psychotic syndromes', 2+: 'full-threshold mood or psychotic syndromes'). Logistic regression models, which controlled for age and follow-up time, were used to compare clinical and functional outcomes (role and social function, suicidal ideation, alcohol and substance misuse, physical health comorbidity, circadian disturbances) between staging groups within the initial 12 months of care. RESULTS: Of the entire cohort, 2093 young people aged 12-25 years were followed up at least once over the first 12 months of care, with 60.4% female and a baseline mean age of 18.16 years. Longitudinally, young people at stage 2+ were more likely to develop circadian disturbances (odds ratio [OR]=2.58; CI 1.60-4.17), compared with individuals at stage 1b. Additionally, stage 1b individuals were more likely to become disengaged from education/employment (OR=2.11, CI 1.36-3.28), develop suicidal ideations (OR=1.92; CI 1.30-2.84) and circadian disturbances (OR=1.94, CI 1.31-2.86), compared to stage 1a. By contrast, we found no relationship between clinical stage and the emergence of alcohol or substance misuse and physical comorbidity. CONCLUSIONS: The differential rates of emergence of poor clinical and functional outcomes between early versus late clinical stages support the clinical staging model's assumptions about illness trajectories for mood and psychotic syndromes. The greater risk of progression to poor outcomes in those who present with more severe syndromes may be used to guide specific intervention packages.

An ecological study of objective rest-activity markers of lithium response in bipolar-I-disorder.

BACKGROUND: Despite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest-activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR). METHODS: Seventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR). RESULTS: Twenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06). CONCLUSIONS: To our knowledge, this is the largest actigraphy study of rest-activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups.

Predicting the emergence of full-threshold bipolar I, bipolar II and psychotic disorders in young people presenting to early intervention mental health services.

BACKGROUND: Predictors of new-onset bipolar disorder (BD) or psychotic disorder (PD) have been proposed on the basis of retrospective or prospective studies of 'at-risk' cohorts. Few studies have compared concurrently or longitudinally factors associated with the onset of BD or PDs in youth presenting to early intervention services. We aimed to identify clinical predictors of the onset of full-threshold (FT) BD or PD in this population. METHOD: Multi-state Markov modelling was used to assess the relationships between baseline characteristics and the likelihood of the onset of FT BD or PD in youth (aged 12-30) presenting to mental health services. RESULTS: Of 2330 individuals assessed longitudinally, 4.3% (n = 100) met criteria for new-onset FT BD and 2.2% (n = 51) met criteria for a new-onset FT PD. The emergence of FT BD was associated with older age, lower social and occupational functioning, mania-like experiences (MLE), suicide attempts, reduced incidence of physical illness, childhood-onset depression, and childhood-onset anxiety. The emergence of a PD was associated with older age, male sex, psychosis-like experiences (PLE), suicide attempts, stimulant use, and childhood-onset depression. CONCLUSIONS: Identifying risk factors for the onset of either BD or PDs in young people presenting to early intervention services is assisted not only by the increased focus on MLE and PLE, but also by recognising the predictive significance of poorer social function, childhood-onset anxiety and mood disorders, and suicide attempts prior to the time of entry to services. Secondary prevention may be enhanced by greater attention to those risk factors that are modifiable or shared by both illness trajectories.

Chronotypes and circadian rest-activity rhythms in bipolar disorders: a meta-analysis of self- and observer rating scales.

OBJECTIVE: Chronobiological models postulate that abnormalities in circadian rest/activity rhythms (CRAR) are core phenomena of bipolar disorders (BDs). We undertook a meta-analysis of published studies to determine whether self- or observer ratings of CRAR differentiate BD cases from comparators (typically healthy controls [HCs]). METHOD: We undertook systematic searches of four databases to identify studies for inclusion in random effects meta-analyses and meta-regression analyses. Effect sizes (ES) for pooled analyses of self- and observer ratings were expressed as standardized mean differences with 95% confidence intervals (CIs). RESULTS: The 30 studies meeting eligibility criteria included 2840 cases and 3573 controls. Compared with HC, BD cases showed greater eveningness (ES: 0.33; 95% CI: 0.12-0.54), lower flexibility of rhythms (ES: 0.36; 95% CI: 0.06-0.67), lower amplitude of rhythms (ES: 0.55; 95% CI: 0.39-0.70) and more disturbances across a range of CRAR (ES of 0.78-1.12 for general and social activities, sleep and eating patterns). Between study heterogeneity was high (I2  > 70%) and evidence indicated a potential publication bias for studies using the Biological Rhythms Interview of Assessment in Neuropsychiatry. Meta-regression analyses suggested significantly larger ES were observed in studies using observer ratings or including BD cases with higher levels of depressive symptoms. CONCLUSION: This meta-analysis demonstrates that BD is associated with higher levels of self- or observer-rated CRAR disturbances compared with controls. However, further studies should examine the respective performance of individual instruments when used alone or in combination, to clarify their applicability and utility in clinical practice.

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.

Do self-ratings of the Pittsburgh Sleep Quality Index reflect actigraphy recordings of sleep quality or variability? An exploratory study of bipolar disorders versus healthy controls.

Sleep disturbances are typical symptoms of acute episodes of bipolar disorder (BD) and differentiate euthymic BD cases from healthy controls (HC). Researchers often employ objective recordings to evaluate sleep patterns, such as actigraphy, whilst clinicians often use subjective ratings, such as the Pittsburgh Sleep Quality Index (PSQI). As evidence suggests the measures may disagree, we decided to compare subjective (PSQI) and objective (3 weeks of actigraphy) sleep profiles in BD cases and HC (n = 154). We examined whether a dimensional approach helps to illustrate different patterns of sleep disturbances and whether the concordance between subjective and objective recordings varies according to clinical status (BD versus HC). Principal component analysis (PCA) extracted two factors from the PSQI, and separate PCAs of actigraphy recordings extracted two factors for mean values of sleep parameters and one factor for intra-individual variability. Correlational and linear regression analyses of PCA-derived dimensions demonstrated that, in both BD and HC, a PSQI "Sleep duration-efficiency" factor was significantly correlated with an actigraphy "Sleep initiation-duration" factor. Furthermore, in BD cases only, the PSQI total score and a PSQI "Sleep Impairments" factor were each significantly correlated with an actigraphy "Sleep Variability" factor. Overall, we found that subjective experiences of sleep may be modulated by different components of objectively recorded sleep in BD compared with HC. Also, the use of PCA enabled us to consider the multi-dimensional nature of subjective sleep, whilst the inclusion of intra-individual sleep variability afforded a more subtle evaluation of objective sleep.

Digital cognitive behaviour therapy for insomnia (dCBT-I): Chronotype moderation on intervention outcomes.

Using data from 1721 participants in a community-based randomized control trial of digital cognitive behavioural therapy for insomnia compared with patient education, we employed linear mixed modelling analyses to examine whether chronotype moderated the benefits of digital cognitive behavioural therapy for insomnia on self-reported levels of insomnia severity, fatigue and psychological distress. Baseline self-ratings on the reduced version of the Horne-Östberg Morningness-Eveningness Questionnaire were used to categorize the sample into three chronotypes: morning type (n = 345; 20%); intermediate type (n = 843; 49%); and evening type (n = 524; 30%). Insomnia Severity Index, Chalder Fatigue Questionnaire, and Hospital Anxiety and Depression Scale were assessed pre- and post-intervention (9 weeks). For individuals with self-reported morning or intermediate chronotypes, digital cognitive behavioural therapy for insomnia was superior to patient education on all ratings (Insomnia Severity Index, Chalder Fatigue Questionnaire, and Hospital Anxiety and Depression Scale) at follow-up (p-values ≤ 0.05). For individuals with self-reported evening chronotype, digital cognitive behavioural therapy for insomnia was superior to patient education for Insomnia Severity Index and Chalder Fatigue Questionnaire, but not on the Hospital Anxiety and Depression Scale (p = 0.139). There were significant differences in the treatment effects between the three chronotypes on the Insomnia Severity Index (p = 0.023) estimated difference between evening and morning type of -1.70, 95% confidence interval: -2.96 to -0.45, p = 0.008, and estimated difference between evening and intermediate type -1.53, 95% confidence interval: -3.04 to -0.03, p = 0.046. There were no significant differences in the treatment effects between the three chronotypes on the Chalder Fatigue Questionnaire (p = 0.488) or the Hospital Anxiety and Depression Scale (p = 0.536). We conclude that self-reported chronotype moderates the effects of digital cognitive behavioural therapy for insomnia on insomnia severity, but not on psychological distress or fatigue.

A systematic review and meta-analysis of delayed help-seeking, delayed diagnosis and duration of untreated illness in bipolar disorders.

OBJECTIVES: To examine the time delay between the age at onset of symptoms or episodes of bipolar disorders (BD) and the age at diagnosis of and/or receipt of clinical practice guideline recommended interventions for BD. METHODS: Systematic search of five databases to identify publications from January 2000 to July 2022 that reported one or more of the following reliable and valid estimates of latency: delay in help seeking (DHS), delay in diagnosis (DD) and duration of untreated BD (DUB). Eligible studies were included in random effects meta-analyses and multivariate meta-regression was used to assess factors associated with each latency construct. RESULTS: Screening of 1074 publications identified 59 eligible studies (reported in 66 publications) of >40,000 individuals that estimated DHS (8 studies), DD (20 studies) and/or DUB (45 studies). The median DHS, DD and DUB were 3.5 (IQR: 2.8, 8.48), 6.7 (IQR: 5.6, 8.9) and 5.9 years (IQR: 1.1, 8.2), respectively. Key factors associated with shorter DD included older age and residing outside North America; shorter DUB was associated with psychotic or manic onset and access to early intervention services. CONCLUSIONS: Greater consensus on definitions of latency constructs and better-quality targeted research is required regarding DHS, DD and DUB. This review suggests that, while the peak age at onset of BD is 15-25, diagnosis and guideline recommended interventions (e.g., mood stabilizers) are likely to be delayed until age 25-35 years except for a minority of individuals with access to early intervention services.

Research to Clinical Practice-Youth seeking mental health information online and its impact on the first steps in the patient journey.

BACKGROUND: Online searches about anxiety and depression are recorded every 3-5 s. As such, information and communication technologies (ICT) have enormous potential to enable or impair help-seeking and patient-professional interactions. Youth studies indicate that ICT searches are undertaken before initial mental health consultations, but no publications have considered how this online activity affects the first steps of the patient journey in youth mental health settings. METHODS: State-of-the-art review using an iterative, evidence mapping approach to identify key literature and expert consensus to synthesize and prioritise clinical and research issues. RESULTS: Adolescents and young adults are more likely to seek health advice via online search engines or social media platforms than from a health professional. Young people not only search user-generated content and social media to obtain advice and support from online communities but increasingly contribute personal information online. CONCLUSIONS: A major clinical challenge is to raise professional awareness of the likely impact of this activity on mental health consultations. Potential strategies range from modifying the structure of clinical consultations to ensure young people are able to disclose ICT activities related to mental health, through to the development and implementation of 'internet prescriptions' and a youth-focused 'toolkit'.

Sleep and work functioning in nurses undertaking inpatient shifts in a blue-depleted light environment.

BACKGROUND: Blue-depleted light environments (BDLEs) may result in beneficial health outcomes for hospital inpatients in some cases. However, less is known about the effects on hospital staff working shifts. This study aimed to explore the effects of a BDLE compared with a standard hospital light environment (STLE) in a naturalistic setting on nurses' functioning during shifts and sleep patterns between shifts. METHODS: Twenty-five nurses recruited from St. Olavs Hospital in Trondheim, Norway, completed 14 days of actigraphy recordings and self-reported assessments of sleep (e.g., total sleep time/sleep efficiency) and functioning while working shifts (e.g., mood, stress levels/caffeine use) in two different light environments. Additionally, participants were asked to complete several scales and questionnaires to assess the symptoms of medical conditions and mental health conditions and the side effects associated with each light environment. RESULTS: A multilevel fixed-effects regression model showed a within-subject increase in subjective sleepiness (by 17%) during evening shifts in the BDLE compared with the STLE (p = .034; Cohen's d = 0.49) and an 0.2 increase in number of caffeinated beverages during nightshifts in the STLE compared with the BDLE (p = .027; Cohen's d = 0.37). There were no significant differences on any sleep measures (either based on sleep diary data or actigraphy recordings) nor on self-reported levels of stress or mood across the two conditions. Exploratory between-group analyses of questionnaire data showed that there were no significant differences except that nurses working in the BDLE reported perceiving the lighting as warmer (p = .009) and more relaxing (p = .023) than nurses working in the STLE. CONCLUSIONS: Overall, there was little evidence that the change in the light environment had any negative impact on nurses' sleep and function, despite some indication of increased evening sleepiness in the BDLE. We recommend further investigations on this topic before BDLEs are implemented as standard solutions in healthcare institutions and propose specific suggestions for designing future large-scale trials and cohort studies. TRIAL REGISTRATION: The study was registered before data collection was completed on the ISRCTN website ( ISRCTN21603406 ).

A taxonomy of clinical response to mood stabilizers.

INTRODUCTION: Although clinical practice guidelines (CPG) identify first, second- and third-line mood stabilizer (MS) treatments, they rarely define clinical response to prophylaxis or the core issues to be considered. This project aimed to develop a template for describing how clinical response may be classified and a framework to assist decision-making and monitoring of response in day-to-day practice. METHOD: A scoping exercise was undertaken followed by narrative synthesis of (a) qualitative and quantitative definitions of MS response applied in clinical and research practice and (b) potential confounders (eg, non-adherence; tolerability issues) of relevance to routine practice, for example, the concepts are applicable to individuals with bipolar disorder for whom sustained remission is a less realistic goal. Expert consensus was employed to develop a taxonomy of response and key concepts that inform clinical judgements about MS response. RESULTS: Five core constructs can be used to systematize clinical judgements regarding MS response and its monitoring: (a) quantitative, qualitative and/or patient-reported outcome measures (PROMS), (b) personalized assessment of the acceptable benefit-to-harm ratio of a proposed treatment, (c) adequacy of treatment exposure (dose, duration, therapeutic monitoring and adherence), (d) illness activity pre- and post-MS initiation, and (e) other potential confounders (co-prescription of MS; polypharmacy) or protective factors (eg, psychosocial factors). CONCLUSIONS: This heuristic framework might be used as a teaching aid or by clinicians who wish to take a more systematic approach to developing shared criteria for judging MS response that better match patient expectations and preferences. Heuristic approaches also allow seamless introduction of new evidence.

Can network analysis of self-reported psychopathology shed light on the core phenomenology of bipolar disorders in adolescents and young adults?

OBJECTIVES: Network analysis is increasingly applied to psychopathology research. We used it to examine the core phenomenology of emerging bipolar disorder (BD I and II) and 'at risk' presentations (major depression with a family history of BD). METHODOLOGY: The study sample comprised a community cohort of 1867 twin and nontwin siblings (57% female; mean age ~26) who had completed self-report ratings of (i) depression-like, hypomanic-like and psychotic-like experiences; (ii) family history of BD; and (iii) were assessed for mood and psychotic syndromes using the Composite International Diagnostic Interview (CIDI). Symptom networks were compared for recent onset BD versus other cohort members and then for individuals at risk of BD (depression with/without a family history of BD). RESULTS: The four key symptoms that differentiated recent onset BD from other cohort members were: anergia, psychomotor speed, hypersomnia and (less) loss of confidence. The four key symptoms that differentiated individuals at high risk of BD from unipolar depression were anergia, psychomotor speed, impaired concentration and hopelessness. However, the latter network was less stable and more error prone. CONCLUSIONS: We are encouraged by the overlaps between our findings and those from two recent publications reporting network analyses of BD psychopathology, especially as the studies recruited from different populations and employed different network models. However, the advantages of applying network analysis to youth mental health cohorts (which include many individuals with multimorbidity) must be weighed against the disadvantages including basic issues such as judgements regarding the selection of items for inclusion in network models.

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

OBJECTIVES: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. METHODS: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. RESULTS: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. CONCLUSION: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

The Effect of Reducing Insomnia Severity on Work- and Activity-Related Impairment.

OBJECTIVE/BACKGROUND: The effectiveness of Cognitive Behavioral Therapy for Insomnia (CBT-I) for alleviating sleep problems is well established. However, few studies have explored its impact on work productivity and activity. PARTICIPANTS: Seventy-seven currently employed adults with insomnia disorder (59 females) recruited to a randomized trial of digital versus face-to-face CBT-I. METHODS AND MATERIALS: The general health version of the Work Productivity and Activity Impairment questionnaire was used to measure absenteeism, presenteeism, total work impairment, and activity impairment. We assessed changes in work productivity and activity pre-to-post-therapy for the total sample and then for subgroups categorized according to response or remission of insomnia disorder (evaluated using the Insomnia Severity Index). RESULTS: Study participants showed significant improvements in presenteeism (p = .001; Cohen's d= 0.46), total work impairment (p < .001; d= 0.48), and activity (p < .001; d= 0.66), but not absenteeism (p = .51; d= 0.084) between baseline and follow-up assessment. Individuals meeting criteria for remission showed significantly greater improvement in presenteeism (p = .002), total work impairment (p < .001), and activity (p = .006), but not absenteeism (p = .064). CONCLUSION: This study suggests that the benefits of CBT-I extend beyond improvement in sleep to encompass moderate-to-large improvements in work productivity and activity levels particularly for individuals who achieve remission from insomnia. Given the importance of these behaviors, there is a need for future large-scale randomized trials and cohort studies which should strive to include objective measurement of daytime activity and work performance more frequently.

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.

An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes.

OBJECTIVES: The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. METHODS: We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. RESULTS: The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. CONCLUSIONS: This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.