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  • Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records.

    29 June 2018

    It is unclear which maintenance treatment for bipolar disorder is superior in clinical practice. Randomized controlled head-to-head trials of available drugs either do not exist or are inconclusive. We aimed to compare rates of monotherapy treatment failure in individuals prescribed lithium, valproate, olanzapine or quetiapine by a population-based cohort study using electronic health records. 5,089 patients with bipolar disorder were prescribed lithium (N=1,505), valproate (N=1,173) olanzapine (N=1,366) or quetiapine (N=1,075) as monotherapy. Treatment failure was defined as time to stopping medication or add-on of another mood stabilizer, antipsychotic, antidepressant or benzodiazepine. In unadjusted analyses, the duration of successful monotherapy was longest in individuals treated with lithium. Treatment failure had occurred in 75% of those prescribed lithium by 2.05 years (95% CI: 1.63-2.51), compared to 0.76 years (95% CI: 0.64-0.84) for those prescribed quetiapine, 0.98 years (95% CI: 0.84-1.18) for those prescribed valproate, and 1.13 years for those prescribed olanzapine (95% CI: 1.00-1.31). Lithium's superiority remained in a propensity score matched analysis; when treatment failure was defined as stopping medication or add-on of a mood stabilizer or antipsychotic; and when treatment failure was restricted to more than three months after commencing the study drug. Lithium appears to be more successful as monotherapy maintenance treatment than valproate, olanzapine or quetiapine. Lithium is often avoided because of its side effect profile, but alternative treatments may reduce the time to being prescribed more than one drug, with potential additive side effects of these treatments.

  • Association between early temperament and depression at 18 years.

    29 June 2018

    BACKGROUND: Early childhood temperament, particularly negative emotionality (high tendency to show distress), may be a risk factor for subsequent depression. METHODS: Using data from a large UK cohort (Avon Longitudinal Study of Parents and Children), we examined the association between temperament on the Emotionality Activity Sociability Questionnaire at age 6 and ICD-10 depression at 18. Results were adjusted for a range of confounders. RESULTS: Children with high emotionality scores at age 6 had a 20% (7-36%) increase in the odds of being diagnosed with depression at age 18. CONCLUSIONS: Depression at 18 years has an early developmental diathesis, which means we may be able to identify children at risk of developing depression in young adulthood.

  • MVPA to enhance the study of rare cognitive events: An investigation of experimental PTSD

    3 July 2018

    Many cognitive processes are challenging to study due to their scarce occurrence. Here we demonstrate how pattern recognition and brain imaging can enhance the study of such processes by providing fast, sensitive, and non-intrusive detection of these events. This can enable efficient experimental and clinical intervention. We focus on the study of traumatic events producing flashbacks associated with post-traumatic stress disorder (PTSD), using an experimental analogue of trauma (a traumatic film). These events are rare and challenging to reliably elicit in experimental settings. We show that a classifier can be built to predict, based upon brain response, which stimuli are likely to induce these rare flashbacks at the point of exposure. An ability to predict these stimuli makes possible the trialing of context-specific preventative clinical interventions. We present results from two independent datasets, outlining key analytic challenges. © 2014 IEEE.

  • Clinically significant fatigue after stroke: a longitudinal cohort study.

    3 July 2018

    OBJECTIVE: Fatigue is often distressing for stroke survivors. The time course of clinically significant fatigue in the first year after stroke is uncertain. We aimed to determine the frequency, severity and time course of clinically significant fatigue in the first 12 months after stroke onset. METHODS: We recruited patients with a recent acute stroke. At about one month, six months and 12 months, we performed a structured interview to identify clinically significant fatigue (case definition), and assessed fatigue severity (Fatigue Assessment Scale (FAS)). RESULTS: Of 157 patients who initially consented, 136 attended at least one assessment. At one month, 43/132 (33%) had clinically significant fatigue. Eighty-six attended all three assessments, of whom clinically significant fatigue was present in 24 (28%) at one month, 20 (23%) at six months and 18 (21%) at 12 months; their median (IQR) FAS scores were 23 (18 to 29), 21 (17 to 25) and 22.5 (17 to 28) at one, six and 12 months respectively. Of 101 patients who attended at least the one and six month assessments, fatigue status did not change in 65 (64%), with 9 (9%) fatigued throughout and 56 (55%) non-fatigued throughout; 15 (15%) became non-fatigued, 9 (9%) became fatigued, and in 12 (12%) fatigue status fluctuated across three assessments. CONCLUSION: Clinically significant fatigue affected a third of patients one month after stroke. About two thirds of these patients had become non-fatigued by six months, most of whom remained non-fatigued at 12months. Fatigue persists in a third at 12 months.

  • Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer.

    3 July 2018

    BACKGROUND: The management of depression in patients with poor prognosis cancers, such as lung cancer, creates specific challenges. We aimed to assess the efficacy of an integrated treatment programme for major depression in patients with lung cancer compared with usual care. METHODS: Symptom Management Research Trials (SMaRT) Oncology-3 is a parallel-group, multicentre, randomised controlled trial. We enrolled patients with lung cancer and major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with lung cancer treatment programme or usual care by a database software algorithm that used stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. Depression care for people with lung cancer is a manualised, multicomponent collaborative care treatment that is systematically delivered by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. The primary outcome was depression severity (on the Symptom Checklist Depression Scale [SCL-20], range 0-4) averaged over the patient's time in the trial (up to a maximum of 32 weeks). Trial statisticians and data collection staff were masked to treatment allocation, but patients and clinicians could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN75905964. FINDINGS: 142 participants were recruited between Jan 5, 2009, and Sept 9, 2011; 68 were randomly allocated to depression care for people with lung cancer and 74 to usual care. 43 (30%) of 142 patients had died by 32 weeks, all of which were cancer-related deaths. No intervention-related serious adverse events occurred. 131 (92%) of 142 patients provided outcome data (59 in the depression care for people with lung cancer group and 72 in the usual care group) and were included in the intention-to-treat primary analysis. Average depression severity was significantly lower in patients allocated to depression care for people with lung cancer (mean score on the SCL-20 1·24 [SD 0·64]) than in those allocated to usual care (mean score 1·61 [SD 0·58]); difference -0·38 (95% CI -0·58 to -0·18); standardised mean difference -0·62 (95% CI -0·94 to -0·29). Self-rated depression improvement, anxiety, quality of life, role functioning, perceived quality of care, and proportion of patients achieving a 12-week treatment response were also significantly better in the depression care for people with lung cancer group than in the usual care group. INTERPRETATION: Our findings suggest that major depression can be treated effectively in patients with a poor prognosis cancer; integrated depression care for people with lung cancer was substantially more efficacious than was usual care. Larger trials are now needed to estimate the effectiveness and cost-effectiveness of this care programme in this patient population, and further adaptation of the treatment will be necessary to address the unmet needs of patients with major depression and even shorter life expectancy. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

  • Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial.

    3 July 2018

    BACKGROUND: Medical conditions are often complicated by major depression, with consequent additional impairment of quality of life. We aimed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer (depression care for people with cancer) with usual care. METHODS: SMaRT Oncology-2 is a parallel-group, multicentre, randomised controlled effectiveness trial. We enrolled outpatients with major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. Depression care for people with cancer is a manualised, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. Outcome data were collected up until 48 weeks. The primary outcome was treatment response (≥50% reduction in Symptom Checklist Depression Scale [SCL-20] score, range 0-4) at 24 weeks. Trial statisticians and data collection staff were masked to treatment allocation, but participants could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN40568538. FINDINGS: 500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37-53), adjusted odds ratio 8·5 (95% CI 5·5-13·4), p<0·0001. Compared with patients in the usual care group, participants allocated to the depression care for people with cancer programme also had less depression, anxiety, pain, and fatigue; and better functioning, health, quality of life, and perceived quality of depression care at all timepoints (all p<0·05). During the study, 34 cancer-related deaths occurred (19 in the depression care for people with cancer group, 15 in the usual care group), one patient in the depression care for people with cancer group was admitted to a psychiatric ward, and one patient in this group attempted suicide. None of these events were judged to be related to the trial treatments or procedures. INTERPRETATION: Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer. It offers a model for the treatment of depression comorbid with other medical conditions. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

  • Novel genetic loci associated with hippocampal volume.

    3 July 2018

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  • Meta-analytic evidence for neuroimaging models of depression: state or trait?

    3 July 2018

    BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. With the rapid growth of neuroimaging research on relatively small samples, meta-analytic techniques are becoming increasingly important. Here, we aim to clarify the support in fMRI literature for three leading neurobiological models of MDD: limbic-cortical, cortico-striatal and the default mode network. METHODS: Searches of PubMed and Web of Knowledge, and manual searches, were undertaken in early 2011. Data from 34 case-control comparisons (n=1165) and 6 treatment studies (n=105) were analysed separately with two meta-analytic methods for imaging data: Activation Likelihood Estimation and Gaussian-Process Regression. RESULTS: There was broad support for limbic-cortical and cortico-striatal models in the case-control data. Evidence for the role of the default mode network was weaker. Treatment-sensitive regions were primarily in lateral frontal areas. LIMITATIONS: In any meta-analysis, the increase in the statistical power of the inference comes with the risk of aggregating heterogeneous study pools. While we believe that this wide range of paradigms allows identification of key regions of dysfunction in MDD (regardless of task), we attempted to minimise such risks by employing GPR, which models such heterogeneity. CONCLUSIONS: The focus of treatment effects in frontal areas indicates that dysregulation here may represent a biomarker of treatment response. Since the dysregulation in many subcortical regions in the case-control comparisons appeared insensitive to treatment, we propose that these act as trait vulnerability markers, or perhaps treatment insensitivity. Our findings allow these models of MDD to be applied to fMRI literature with some confidence.