Aswin Ratheesh

The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study

There are no established tools to identify individuals at risk for developing bipolar disorder. We developed a set of ultra‐high‐risk criteria for bipolar disorder [bipolar at‐risk (BAR)]. The primary aim of the present study was to determine the predictive validity of the BAR criteria.

Neurocognitive functioning in the prodrome of mania—an exploratory study

BACKGROUND Cognitive deficits have been well documented in individuals with bipolar disorder (BD) after the first episode of mania. However, little is known about the presence of such deficits prior to the initial manic episode. METHODS Participants were recruited from a cohort of 416 young people who were at ultra-high risk (UHR) for psychosis and were followed up between 4 and 13 years later. The current report is of 16 participants who developed BD over a mean follow-up period of 8.2 years (UHR-BD). Baseline demographic, clinical and neurocognitive assessment scores were compared with those of 46 age and gender matched UHR subjects who did not transition to psychosis or BD over the follow-up period (UHR-NT) and 66 healthy comparison subjects. RESULTS UHR-BD subjects had lower global functioning at baseline compared with UHR-NT subjects. There were no significant differences between UHR-BD and UHR-NT subjects on baseline demographic and neurocognitive characteristics. UHR-BD subjects had lower test performance than HC on picture completion, Trail-Making Tests and measures of global intelligence. LIMITATIONS Small sample size, limited and variable neurocognitive tests utilised and the confounding effects of psychotic symptoms might have impacted on the ability to detect meaningful clinical and neurocognitive differences. CONCLUSIONS In this exploratory study, neurocognition in young people who later develop BD is similar to those of subjects who are at a high risk for psychotic disorders, but there may be certain neurocognitive markers that distinguish this group from unaffected and healthy young people.

Staging in bipolar disorder: from theoretical framework to clinical utility

Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at‐risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end‐stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage‐specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage‐specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at‐risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative‐type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.

Quetiapine v. lithium in the maintenance phase following a first episode of mania: randomised controlled trial

BackgroundLithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other.AimsTo investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania.MethodMaintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.)ResultsIn total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and post hoc comparisons further demonstrated the superiority of lithium treatment over quetiapine.ConclusionsIn people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.

A systematic review and meta-analysis of prospective transition from major depression to bipolar disorder

Some people with major depressive disorder (MDD) may be at a pre‐onset stage for bipolar disorder (BD), where early identification or prevention efforts may be feasible. We aimed to identify rates and characteristics predictive of transition to BD in prospective follow‐up studies of people with MDD.

Instruments that prospectively predict bipolar disorder - A systematic review

BACKGROUND Identification of earlier stages of Bipolar Disorder (BD), even prior to the first manic episode, may help develop interventions to prevent or delay the onset of BD. However, reliable and valid instruments are necessary to ascertain such earlier stages of BD. The aim of the current review was to identify instruments that had predictive validity and utility for BD for use in early intervention (EI) settings for the prevention of BD. METHODS We undertook a systematic examination of studies that examined participants without BD I or II at baseline and prospectively explored the predictive abilities of instruments for BD onset over a period of 6 months or more. The instruments and the studies were rated with respect to their relative validity and utility predicting onset of BD for prevention or early intervention. Odds ratios and area under the curve (AUC) values were derived when not reported. RESULTS Six studies were included, identifying five instruments that examined sub-threshold symptoms, family history, temperament and behavioral regulation. Though none of the identified instruments had been examined in high-quality replicated studies for predicting BD, two instruments, namely the Child Behavioral Checklist - Pediatric BD phenotype (CBCL-PBD) and the General Behavioral Inventory - Revised (GBI-R), had greater levels of validity and utility. LIMITATION Non-inclusion of studies and instruments that incidentally identified BD on follow-up limited the breadth of the review. CONCLUSION Instruments that test domains such as subthreshold symptoms, behavioral regulation, family history, and temperament hold promise in predicting BD onset.

Prospective progression from high-prevalence disorders to bipolar disorder: Exploring characteristics of pre-illness stages

BACKGROUND Identification of risk factors within precursor syndromes, such as depression, anxiety or substance use disorders (SUD), might help to pinpoint high-risk stages where preventive interventions for Bipolar Disorder (BD) could be evaluated. METHODS We examined baseline demographic, clinical, quality of life, and temperament measures along with risk clusters among 52 young people seeking help for depression, anxiety or SUDs without psychosis or BD. The risk clusters included Bipolar At-Risk (BAR) and the Bipolarity Index as measures of bipolarity and the Ultra-High Risk assessment for psychosis. The participants were followed up for 12 months to identify conversion to BD. Those who converted and did not convert to BD were compared using Chi-Square and Mann Whitney U tests. RESULTS The sample was predominantly female (85%) and a majority had prior treatment (64%). Four participants converted to BD over the 1-year follow up period. Having an alcohol use disorder at baseline (75% vs 8%, χ(2)=14.1, p<0.001) or a family history of SUD (67% vs 12.5%, χ(2)=6.0, p=0.01) were associated with development of BD. The sub-threshold mania subgroup of BAR criteria was also associated with 12-month BD outcomes. The severity of depressive symptoms and cannabis use had high effects sizes of association with BD outcomes, without statistical significance. CONCLUSIONS AND LIMITATIONS The small number of conversions limited the power of the study to identify associations with risk factors that have previously been reported to predict BD. However, subthreshold affective symptoms and SUDs might predict the onset of BD among help-seeking young people with high-prevalence disorders.

Predictors of functional status at service entry and discharge among young people with first episode psychosis

ObjectiveMost patients with first episode psychosis (FEP) are neither studying nor employed (have a poor functional status) when first accessing care. Knowledge of the characteristics of patients with poor functioning and the features influencing functional status over time may pave the way to better treatment.MethodA medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics on 661 FEP patients who consecutively attended the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, between 1998 and 2000. Functional status was ascertained using the modified vocational status index and was rated at baseline (poor or good) and according to its evolution over the treatment period (stable good, stable poor, deteriorating or improved functional status).Results52.0% of patients had a poor functional status at service entry. They were more likely to be male with a non-affective psychosis. They also had lower levels of premorbid global functioning and education, and were more likely to have self-reported histories of learning disability, forensic issues, traumatic experiences and substance use. At service entry, they had more severe symptoms and poorer global functioning. 37% of these patients maintained a poor functional status at discharge, and 18% of those with a good functional status at service entry experienced a decline.ConclusionsAlthough psychosocial interventions might assist a young person with FEP with working towards functional goals, for some, the impact of factors such as ongoing substance use and forensic issues on functional status needs to be addressed.

Early psychosis research at Orygen, The National Centre of Excellence in Youth Mental Health

BackgroundSpecialised early intervention (SEI) programs have offered individuals with psychotic disorders and their families new hope for improving illness trajectories and outcomes. The Early Psychosis Prevention and Intervention Centre (EPPIC) was one of the first SEI programs developed in the world, providing services for young people experiencing their first episode of psychosis.MethodsWe conducted a narrative synthesis of controlled and uncontrolled studies that have been conducted at EPPIC.DiscussionThe history of the EPPIC model is first described. This is followed by a discussion of clinical research emerging from EPPIC, including psychopharmacological, psychotherapeutic trials and outcome studies. Neurobiological studies are also described. Issues pertaining to the conduct of clinical research and future research directions are then described. Finally, the impact of the EPPIC model on the Australian environment is discussed.

Ethical considerations in preventive interventions for bipolar disorder.

Early intervention and prevention of serious mental disorders such as bipolar disorder has the promise of decreasing the burden associated with these disorders. With increasing early and preventive intervention efforts among cohorts such as those with a familial risk for bipolar disorder, there is a need to examine the associated ethical concerns. The aim of this review was to examine the ethical issues underpinning the clinical research on pre‐onset identification and preventive interventions for bipolar disorder.