A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention.

BACKGROUND: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. METHODS: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. RESULTS: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. CONCLUSIONS AND RECOMMENDATIONS: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort.

BACKGROUND: Depression frequently co-occurs with disorders of glucose and insulin homeostasis (DGIH) and obesity. Low-grade systemic inflammation and lifestyle factors in childhood may predispose to DGIH, obesity and depression. We aim to investigate the cross-sectional and longitudinal associations among DGIH, obesity and depression, and to examine the effect of demographics, lifestyle factors and antecedent low-grade inflammation on such associations in young people. METHODS: Using the Avon Longitudinal Study of Parents and Children birth cohort, we used regression analyses to examine: (1) cross-sectional and (2) longitudinal associations between measures of DGIH [insulin resistance (IR); impaired glucose tolerance] and body mass index (BMI) at ages 9 and 18 years, and depression (depressive symptoms and depressive episode) at age 18 years and (3) whether sociodemographics, lifestyle factors or inflammation [interleukin-6 (IL-6) at age 9 years] confounded any such associations. RESULTS: We included 3208 participants. At age 18 years, IR and BMI were positively associated with depression. These associations may be explained by sociodemographic and lifestyle factors. There were no longitudinal associations between DGIH/BMI and depression, and adjustment for IL-6 and C-reactive protein did not attenuate associations between IR/BMI and depression; however, the longitudinal analyses may have been underpowered. CONCLUSIONS: Young people with depression show evidence of DGIH and raised BMI, which may be related to sociodemographic and lifestyle effects such as deprivation, smoking, ethnicity and gender. In future, studies with larger samples are required to confirm this. Preventative strategies for the poorer physical health outcomes associated with depression should focus on malleable lifestyle factors.

A systematic review of the psychometric properties, usability and clinical impacts of mobile mood-monitoring applications in young people.

BACKGROUND: Mobile mood-monitoring applications are increasingly used by mental health providers, widely advocated within research, and a potentially effective method to engage young people. However, little is known about their efficacy and usability in young populations. METHOD: A systematic review addressing three research questions focused on young people: (1) what are the psychometric properties of mobile mood-monitoring applications; (2) what is their usability; and (3) what are their positive and negative clinical impacts? Findings were synthesised narratively, study quality assessed and compared with evidence from adult studies. RESULTS: We reviewed 25 articles. Studies on the psychometric properties of mobile mood-monitoring applications were sparse, but indicate questionable to excellent internal consistency, moderate concurrent validity and good usability. Participation rates ranged from 30% to 99% across studies, and appeared to be affected by methodological factors (e.g. payments) and individual characteristics (e.g. IQ score). Mobile mood-monitoring applications are positively perceived by youth, may reduce depressive symptoms by increasing emotional awareness, and could aid in the detection of mental health and substance use problems. There was very limited evidence on potential negative impacts. CONCLUSIONS: Evidence for the use of mood-monitoring applications in youth is promising but limited due to a lack of high-quality studies. Future work should explicate the effects of mobile mood-monitoring applications on effective self-regulation, clinical outcomes across disorders and young people's engagement with mental health services. Potential negative impacts in this population should also be investigated, as the adult literature suggests that application use could potentially increase negativity and depression symptoms.

Short-term outcome of substance-induced psychotic disorder in a large UK first episode psychosis cohort.

OBJECTIVE: The incidence and outcome of first-episode substance-induced psychotic disorder (SIPD) are unclear. The study aimed to compare the 1-year outcomes of those given a SIPD diagnosis by clinicians compared to other psychosis diagnoses in a first-episode cohort. METHOD: Data were from a large (n = 1027) cohort of first-episode psychosis (FEP) patients admitted to early intervention services in the UK (National EDEN). Diagnosis, including that of SIPD, was made by treating psychiatrists at baseline using ICD10 criteria. Details on symptoms, functioning, quality of life, relapse and recovery were available at baseline and 12 months. RESULTS: There were 67 cases of SIPD (6.5% of the cohort). At baseline, SIPD patients were no different to other psychoses on symptoms, functioning and quality of life. At 12 months, there was no difference in SIPD and other psychoses on functioning, quality of life or relapse and recovery rates. Levels of psychotic and general symptomatology were similar but depressive symptoms were higher in the SIPD group. CONCLUSIONS: First-episode psychosis patients with a diagnosis of SIPD do not appear to have better outcomes than those with other primary psychotic diagnoses. The higher levels of depressive symptoms may be a specific marker in these patients.

Non-pharmacological interventions for reducing aggression and violence in serious mental illness: A systematic review and narrative synthesis.

BACKGROUND: For people with mental illness that are violent, a range of interventions have been adopted with the aim of reducing violence outcomes. Many of these interventions have been borrowed from other (offender) populations and their evidence base in a Serious Mental Illness (SMI) population is uncertain. AIMS: To aggregate the evidence base for non-pharmacological interventions in reducing violence amongst adults with SMI and PD (Personality Disorder), and to assess the efficacy of these interventions. We chose to focus on distinct interventions rather than on holistic service models where any element responsible for therapeutic change would be difficult to isolate. METHODS: We performed a systematic review and narrative synthesis of non-pharmacological interventions intended to reduce violence in a SMI population and in patients with a primary diagnosis of PD. Five online databases were searched alongside a manual search of seven relevant journals, and expert opinion was sourced. Eligibility of all returned articles was independently assessed by two authors, and quality of studies was appraised via the Cochrane Collaboration Tool for Assessing Risk of Bias. RESULTS: We included 23 studies of diverse psychological and practical interventions, with a range of experimental and quasi-experimental study designs that included 7 Randomised Controlled Trials (RCTs). The majority were studies of Mentally Disordered Offenders. The stronger evidence existed for patients with a SMI diagnosis receiving Cognitive Behavioural Therapy or modified Reasoning & Rehabilitation (R&R). For patients with a primary diagnosis of PD, a modified version of R&R appeared tolerable and Enhanced Thinking Skills showed some promise in improving attitudes over the short-term, but studies of Dialectical Behaviour Therapy in this population were compromised by high risk of experimental bias. Little evidence could be found for non-pharmacological, non-psychological interventions. CONCLUSIONS: The evidence for non-pharmacological interventions for reducing violence in this population is not conclusive. Long-term outcomes are lacking and good quality RCTs are required to develop a stronger evidence base.

Affective instability, childhood trauma and major affective disorders.

BACKGROUND: Affective instability (AI), childhood trauma, and mental illness are linked, but evidence in affective disorders is limited, despite both AI and childhood trauma being associated with poorer outcomes. Aims were to compare AI levels in bipolar disorder I (BPI) and II (BPII), and major depressive disorder recurrent (MDDR), and to examine the association of AI and childhood trauma within each diagnostic group. METHODS: AI, measured using the Affective Lability Scale (ALS), was compared between people with DSM-IV BPI (n=923), BPII (n=363) and MDDR (n=207) accounting for confounders and current mood. Regression modelling was used to examine the association between AI and childhood traumas in each diagnostic group. RESULTS: ALS scores in descending order were BPII, BPI, MDDR, and differences between groups were significant (p<0.05). Within the BPI group any childhood abuse (p=0.021), childhood physical abuse (p=0.003) and the death of a close friend in childhood (p=0.002) were significantly associated with higher ALS score but no association was found between childhood trauma and AI in BPII and MDDR. LIMITATIONS: The ALS is a self-report scale and is subject to retrospective recall bias. CONCLUSIONS: AI is an important dimension in bipolar disorder independent of current mood state. There is a strong link between childhood traumatic events and AI levels in BPI and this may be one way in which exposure and disorder are linked. Clinical interventions targeting AI in people who have suffered significant childhood trauma could potentially change the clinical course of bipolar disorder.

Mood instability: significance, definition and measurement.

Mood instability is common, and an important feature of several psychiatric disorders. We discuss the definition and measurement of mood instability, and review its prevalence, characteristics, neurobiological correlates and clinical implications. We suggest that mood instability has underappreciated transdiagnostic potential as an investigational and therapeutic target.

Clinical and psychosocial outcomes of borderline personality disorder in childhood and adolescence: a systematic review.

BACKGROUND: While there is a growing body of research on borderline personality disorder (BPD) in children and adolescents, controversy remains regarding the validity and diagnosis of the disorder prior to adulthood. METHOD: MEDLINE, EMBASE, Psych INFO and PubMed databases were systematically searched for articles pertaining to the clinical and psychosocial outcomes (i.e. predictive validity) of BPD first diagnosed in childhood or adolescence (i.e. prior to 19 years of age). All primary empirical studies were included in the review. A narrative synthesis of the data was completed. RESULTS: A total of 8200 abstracts were screened. Out of 214 full-text articles, 18 satisfied the predetermined inclusion criteria. Quality assessment indicated that most studies had high risk of bias in at least one study domain. Consistent with the adult literature, the diagnostic stability of BPD prior to the age of 19 years was low to moderate, and mean-level and rank-order stability, moderate to high. Individuals with BPD symptoms in childhood or adolescence had significant social, educational, work and financial impairment in later life. CONCLUSIONS: Studies indicate that borderline pathology prior to the age of 19 years is predictive of long-term deficits in functioning, and that a considerable proportion of individuals continue to manifest borderline symptoms up to 20 years later. These findings provide some support for the clinical utility of the BPD phenotype in younger populations, and suggest that an early intervention approach may be warranted. Further prospective studies are needed to delineate risk (and protective) factors pertinent to the chronicity of BPD across the lifespan.

Mood as a mediator of the link between child sexual abuse and psychosis.

The significance of affective changes in psychosis is increasingly acknowledged, as is the role of early traumatic events. In a previous paper, using data from the English Adult Psychiatric Morbidity Survey 2007 (APMS2007), strong associations between child sexual abuse (CSA) and psychosis were demonstrated, with some evidence of mediation by affect. In the current paper, we subjected the same dataset to formal tests of mediation. For CSA involving sexual intercourse, 38.5% of the link was mediated, 30.0% by depression and 8.5% by anxiety. For all forms of contact abuse, 38.2% was mediated, 29.1% by depression and 9.1% by anxiety.

How is affective instability defined and measured? A systematic review.

BACKGROUND: Affective instability (AI) is poorly defined but considered clinically important. The aim of this study was to examine definitions and measures of AI employed in clinical populations. METHOD: This study was a systematic review using the PRISMA guidelines. MEDLINE, Embase, PsycINFO, PsycArticles and Web of Science databases were searched. Also five journals were hand searched. Primary empirical studies involving randomized controlled trials (RCTs), non-RCTs, controlled before and after, and observational investigations were included. Studies were selected, data extracted and quality appraised. A narrative synthesis was completed. RESULTS: A total of 11 443 abstracts were screened and 37 studies selected for final analysis on the basis that they provided a definition and measure of AI. Numbers of definitions for each of the terms employed in included studies were: AI (n = 7), affective lability (n = 6), affective dysregulation (n = 1), emotional dysregulation (n = 4), emotion regulation (n = 2), emotional lability (n = 1), mood instability (n = 2), mood lability (n = 1) and mood swings (n = 1); however, these concepts showed considerable overlap in features. A total of 24 distinct measures were identified that could be categorized as primarily measuring one of four facets of AI (oscillation, intensity, ability to regulate and affect change triggered by environment) or as measuring general emotional regulation. CONCLUSIONS: A clearer definition of AI is required. We propose AI be defined as 'rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences'. No single measure comprehensively assesses AI and a combination of current measures is required for assessment. A new short measure of AI that is reliable and validated against external criteria is needed.

A systematic review and meta-regression analysis of aggression during the first episode of psychosis.

OBJECTIVE: The First Episode of Psychosis (FEP) represents a period of heightened risk for aggression. However, it is not known whether this risk is significantly altered following contact with mental health services. METHOD: Meta-analytic methods were used to estimate pooled prevalence of 'any' and 'serious' aggression during FEP, while meta-regression analyses were conducted to explore reasons for heterogeneity between studies. RESULTS: Fifteen studies comprising 3, 294 FEP subjects were analysed. Pooled prevalence of 'any aggression' before service contact was 28% (95% CI: 22-34) and following contact 31% (95% CI: 20-42). Pooled prevalence of 'serious aggression' was 16% (95% CI: 11-20) before service contact and 13% (95% CI: 6-20) following contact. Four studies reporting repeated assessments within the same cohort revealed that aggression rates did not significantly differ post and pre service contact: Odds Ratios for any aggression: 1.18 (95% CI: 0.46-2.99) and serious aggression: 0.61 (95% CI: 0.31-1.21). CONCLUSION: Rates of aggression are high during FEP, both before and following initial service contact, and seem not to alter following contact. This conclusion remains tentative due to considerable heterogeneity between studies and a lack of prospective cohort studies.

Employment outcomes in people with bipolar disorder: a systematic review.

OBJECTIVE: Employment outcome in bipolar disorder is an under investigated, but important area. The aim of this study was to identify the long-term employment outcomes of people with bipolar disorder. METHOD: A systematic review using the Medline, PsychInfo and Web of Science databases. RESULTS: Of 1962 abstracts retrieved, 151 full text papers were read. Data were extracted from 25 papers representing a sample of 4892 people with bipolar disorder and a mean length of follow-up of 4.9 years. Seventeen studies had follow-up periods of up to 4 years and eight follow-up of 5-15 years. Most studies with samples of people with established bipolar disorder suggest approximately 40-60% of people are in employment. Studies using work functioning measures mirrored this result. Bipolar disorder appears to lead to workplace underperformance and 40-50% of people may suffer a slide in their occupational status over time. Employment levels in early bipolar disorder were higher than in more established illness. CONCLUSION: Bipolar disorder damages employment outcome in the longer term, but up to 60% of people may be in employment. Whilst further studies are necessary, the current evidence provides support for extending the early intervention paradigm to bipolar disorder.

The nature and correlates of paid and unpaid work among service users of London Community Mental Health Teams.

Aims. Little is known about how the rates and characteristics of mental health service users in unpaid work, training and study compare with those in paid employment. Methods. From staff report and patient records, 1353 mental health service users of seven Community Mental Health Teams in two London boroughs were categorized as in paid work, unpaid vocational activity or no vocational activity. Types of work were described using Standard Occupational Classifications. The characteristics of each group were reported and associations with vocational status were explored. Results. Of the sample, 5.5% were in paid work and 12.7% were in unpaid vocational activity, (including 5.3% in voluntary work and 8.1% in study or training). People in paid work were engaged in a broader range of occupations than those in voluntary work and most in paid work (58.5%) worked part-time. Younger age and high educational attainment characterized both groups. Having sustained previous employment was most strongly associated with being in paid work. Conclusions. Rates of vocational activity were very low. Results did not suggest a clear clinical distinction between those in paid and unpaid activity. The motivations for and functions of unpaid work need further research.

Side-effects of antipsychotic medication and health-related quality of life in schizophrenia.

OBJECTIVE: This analysis used data from the large (n = 1208) European Schizophrenia Cohort to examine the association between subjective side-effects of antipsychotic medication and the Mental and Physical Composite Scores (MCS; PCS) of the SF-36 scale. METHOD: Relationships between the subjective evaluation of side-effects identified from the Subjective Side-Effects Scale and the adjusted mean score on the PCS and MCS were examined. Where appropriate, these associations of subjective side-effects were compared with those of the same side-effects measured objectively. RESULTS: In this study, subjective side-effects of antipsychotic medication were linked either to both the PCS and the MCS or, in a few instances, to neither. Subjective evaluations of sexual side-effects were associated only with the MCS, those of sialorrhoea only with the PCS. Objective ratings of extrapyramidal side-effects were related neither to PCS nor to MCS. CONCLUSION: These data suggest that side-effects, whether subjective or objective, may need to be considered individually in relation to their impact on quality of life.

The importance of the dose of etoposide in the initial treatment of metastatic germ cell tumors and advances in management of patients that relapse.

OBJECTIVE: The primary objective was to evaluate the effect of etoposide dose in a 3-day cisplatin/etoposide/bleomycin (PEB) regimen on progression free survival (PFS) and overall survival (OS). Secondary objectives were to determine the impact of a paclitaxel-based salvage regimen on OS and to compare the risk distribution of germ cell patients seen at a tertiary care center to that quoted in the International Germ Cell Consensus Classification (IGCCC). METHODS: A retrospective chart review of all 302 metastatic germ cell patients requiring cisplatin-based chemotherapy between January 1980 and December 2004 was conducted. Data collected on initial treatment included the dose of etoposide: 500 mg/m2/cycle (E500) or 360 mg/m2/cycle (E360) and whether the salvage treatment contained paclitaxel or not. PFS and OS were calculated. Patients were risk stratified as per IGCCC variables. RESULTS: The relapse rate and overall survival for E500 was 3% and 97% respectively compared to a relapse rate and OS rate of 29% and 80% respectively for E360. The addition of paclitaxel to salvage chemotherapy regimens for patients that relapsed results were 1/5 (20%) of patients dying compared to 26/39 (67%) for those who received a non-paclitaxel based salvage regimen. Ninety percent of seminoma patients were good risk and 10% were intermediate risk. Non-seminoma (NSGCT) patients were skewed to the good-risk category: 71% good risk, 10% intermediate risk and 18% poor risk as compared to 56%, 28% and 16% respectively as reported by the IGCCC. Five-year PFS and OS were comparable to those documented by the IGCCC with the exception of the intermediate risk NSGCT patients. CONCLUSION: This review demonstrated that PEB treatment containing higher dose etoposide was superior in terms of PFS and OS. Although the sample size was small, it appeared that paclitaxel containing salvage regimens resulted in superior outcomes compared to previously used salvage regimens. Our center had a similar risk distribution of patients as that quoted by the IGCCC.

Role of MAP kinase pathways in primitive neuroectodermal tumors.

Mitogen-activated protein kinase and Phosphatidylinositol-3 kinase/Akt-mediated signaling pathways play a major role in controlling cell proliferation, differentiation and cell death. Phosphorylation and dephosphorylation of their specific Thr/Tyr residues is critical in determining their activity. We determined the expression pattern and activity of MAP kinases and Akt in Primitive Neuroectodermal Tumors (PNETs). The kinase activity of extracellular signal-regulated kinase (ERK) was higher in both primary tumors and cell lines, as evident from the increased phosphorylation of ERK1 and ERK2. We did not observe the activation of C-jun N-terminal kinase (JNK) or p38 MAPK The expression of Raf-1, a kinase acting upstream of ERK, was significantly increased in primary tumors compared to normal brain. The PI-3 kinase-activated phosphorylation of Akt was also higher in primary tumors. These results suggest that activation of the Raf-1/ERK module of the MAP kinase pathway play an important role in PNETs.

Age-related differences in acute physiologic response to focal traumatic brain injury in piglets.

INTRODUCTION: The goal of the present study was to determine whether age-related differences in the acute physiologic response to scaled cortical impact injury contribute to differences in vulnerability to traumatic brain injury (TBI). METHODS: Heart rate (HR), mean arterial pressure (MAP), brain temperature (BrT) and cerebral blood flow (CBF) were measured in 22 piglets (7 of age 5 days, 8 of age 1 month, 7 of age 4 months) at baseline and for 3 h following scaled cortical impact injury. RESULTS: There were no age-dependent variations from baseline in HR, MAP or BrT following injury. CBF increased in the 5-day-old animals following injury while CBF in the 1- and 4-month-old animals decreased following injury (p = 0.0049). CONCLUSION: CBF was shown to have a significant age-dependent response to TBI with the youngest animals exhibiting increased CBF following injury.

Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression.

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.

Maturation-dependent response of the piglet brain to scaled cortical impact.

OBJECT: The goal of this study was to investigate the relationship between maturational stage and the brain's response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages. METHODS: To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018). CONCLUSIONS: These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages.

Advances in enzymatic transformation of penicillins to 6-aminopenicillanic acid (6-APA).

This article elaborates on the important recent developments in the enzymatic transformation of penicillins to 6-aminopenicillanic acid (6-APA), which is the basic raw material for the industrial production of semisynthetic penicillins such as amoxycillin and ampicillin. Particular emphasis is placed on the improvements in purification, stability, and immobilization of the enzymes, (i.e. penicillin acylases) used for these transformations.