A study of wrist-worn activity measurement as a potential real-world biomarker for late-life depression.

BACKGROUND: Late-life depression (LLD) is associated with a decline in physical activity. Typically this is assessed by self-report questionnaires and, more recently, with actigraphy. We sought to explore the utility of a bespoke activity monitor to characterize activity profiles in LLD more precisely. METHOD: The activity monitor was worn for 7 days by 29 adults with LLD and 30 healthy controls. Subjects underwent neuropsychological assessment and quality of life (QoL) (36-item Short-Form Health Survey) and activities of daily living (ADL) scales (Instrumental Activities of Daily Living Scale) were administered. RESULTS: Physical activity was significantly reduced in LLD compared with controls (t = 3.63, p < 0.001), primarily in the morning. LLD subjects showed slower fine motor movements (t = 3.49, p < 0.001). In LLD patients, activity reductions were related to reduced ADL (r = 0.61, p < 0.001), lower QoL (r = 0.65, p < 0.001), associative learning (r = 0.40, p = 0.036), and higher Montgomery-Åsberg Depression Rating Scale score (r = -0.37, p < 0.05). CONCLUSIONS: Patients with LLD had a significant reduction in general physical activity compared with healthy controls. Assessment of specific activity parameters further revealed the correlates of impairments associated with LLD. Our study suggests that novel wearable technology has the potential to provide an objective way of monitoring real-world function.

Altered hippocampal function in major depression despite intact structure and resting perfusion.

BACKGROUND: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation. METHOD: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed. RESULTS: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow. CONCLUSIONS: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression.

The interrelationship between attentional and executive deficits in major depressive disorder.

OBJECTIVE: Cognitive dysfunction is an established feature of major depressive disorder (MDD). However, it remains unclear whether deficits in different cognitive domains are relatively independent or originate from a circumscribed 'primary deficit'. This study tested the hypothesis that a deficit in attention represents a primary deficit in depression. METHOD: Neuropsychological function was assessed in 30 depressed patients with MDD and 34 control participants. Cognitive composites were derived from a minimum of three tests and included attention, executive function, visuospatial memory and verbal memory. A multivariate analysis of variance was used to assess group differences in overall cognitive performance, and multiple regression models were used to evaluate the role of attention in deficits in other domains. RESULTS: The cognitive deficit in the depressed sample was found to be characterized by poorer performance in attention and executive function. When evaluating the interrelationship between the two deficits, the attentional deficit was found to persist when variability in executive function was statistically accounted for, whilst the executive deficit was eliminated when attention was accounted for. CONCLUSION: The results demonstrated that the attentional deficit could not be explained by deficits in executive function, which provides support for a primary attention deficit in depression.

Neurocognitive intra-individual variability in mood disorders: effects on attentional response time distributions.

BACKGROUND: Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders. METHOD: A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the 'slow tail' of the distribution). RESULTS: Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09-0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07-1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60-1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls. CONCLUSIONS: Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.

Neurocognitive functioning in bipolar depression: a component structure analysis.

BACKGROUND: Previous studies of neurocognitive performance in bipolar disorder (BD) have focused predominantly on euthymia. In this study we aimed to compare the neurocognitive profile of BD patients when depressed with healthy controls and explore the component structure of neurocognitive processes in these populations. METHOD: Cognitive tests of attention and executive function, immediate memory, verbal and visuospatial learning and memory and psychomotor speed were administered to 53 patients with a SCID-verified diagnosis of BD depression and 47 healthy controls. Test performance was assessed in terms of statistical significance, effect size and percentile standing. Principal component analysis (PCA) was used to explore underlying cognitive factor structure. RESULTS: Multivariate analysis revealed an overall group effect, depressed BD patients performing significantly worse than controls. Patients performed significantly worse on 18/26 measures examined, with large effect sizes (d > 0.8) on tests of speed of processing, verbal learning and specific executive/working memory processes. Almost all tests produced at least one outcome measure on which ∼25-50% of the BD sample performed at more than 1 standard deviation (s.d.) below the control mean. Between 20% and 34% of patients performed at or below the fifth percentile of the control group in working memory, verbal learning and memory, and psychomotor/processing speed. PCA highlighted overall differences between groups, with fewer extracted components and less specificity in patients. CONCLUSIONS: Overall, neurocognitive test performance is significantly reduced in BD patients when depressed. The use of different methods of analysing cognitive performance is highlighted, along with the relationship between processes, indicating important directions for future research.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Polygenic dissection of the bipolar phenotype.

BACKGROUND: Recent data provide strong support for a substantial common polygenic contribution (i.e. many alleles each of small effect) to genetic susceptibility for schizophrenia and overlapping susceptibility for bipolar disorder. AIMS: To test hypotheses about the relationship between schizophrenia and psychotic types of bipolar disorder. METHOD: Using a polygenic score analysis to test whether schizophrenia polygenic risk alleles, en masse, significantly discriminate between individuals with bipolar disorder with and without psychotic features. The primary sample included 1829 participants with bipolar disorder and the replication sample comprised 506 people with bipolar disorder. RESULTS: The subset of participants with Research Diagnostic Criteria schizoaffective bipolar disorder (n = 277) were significantly discriminated from the remaining participants with bipolar disorder (n = 1552) in both the primary (P = 0.00059) and the replication data-sets (P = 0.0070). In contrast, those with psychotic bipolar disorder as a whole were not significantly different from those with non-psychotic bipolar disorder in either data-set. CONCLUSIONS: Genetic susceptibility influences at least two major domains of psychopathological variation in the schizophrenia-bipolar disorder clinical spectrum: one that relates to expression of a 'bipolar disorder-like' phenotype and one that is associated with expression of 'schizophrenia-like' psychotic symptoms.

Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype.

Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABA(A) receptor beta1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABA(A) receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (P=3.8 x 10(-6)). Independently, these cases showed strong evidence that variation in GABA(A) receptor genes influences risk for this phenotype (independent system-wide P=6.6 x 10(-5)) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR3. [corrected] Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.

DISC1 exon 11 rare variants found more commonly in schizoaffective spectrum cases than controls.

We previously performed a linkage study using families identified through probands meeting criteria for DSM-IV schizoaffective disorder, bipolar type (SABP) and observed a genome-wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM-IV SABP samples from the linkage study identified 2 non-synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P-value = 0.008, Fisher's exact trend test).

Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept.

BACKGROUND: Psychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological-genetic research. AIMS: To use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case-control bipolar disorder sample. METHOD: We analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant at P<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM-IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type. RESULTS: The RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P = 2.42 x 10(-7)). Biological systems implicated included gamma amniobutyric acid (GABA)(A) receptors. Genes having at least one associated polymorphism at P<10(-4) included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and CDH12. CONCLUSIONS: Our findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.

White matter lesions in euthymic patients with bipolar disorder.

OBJECTIVE: We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls. METHOD: Cerebral hyperintensities on T2, proton density and fluid-attenuated inversion recovery (FLAIR) MRI were compared between 48 bipolar and 47 control subjects using semi-quantitative rating scales. RESULTS: Bipolar subjects had more severe frontal deep white matter lesions (DWML). Hyperintensity load was independent of age in bipolar patients but increased with age in controls. Global prevalence and severity of hyperintensities did not differ between groups. Exploratory analysis showed DWML in excess in the left hemisphere in bipolar subjects but not in controls. CONCLUSION: Findings are consistent with clinical, particularly some neurocognitive, features of bipolar disorder and implicate fronto-subcortical circuits in its neurobiology. They more probably reflect a trait abnormality or illness scar rather than a mood state-dependent finding. Processes other than ageing and vascular factors may underlie their development.

The neurocognitive performance of drug-free and medicated euthymic bipolar patients do not differ.

OBJECTIVE: Although it is established that euthymic bipolar patients have neurocognitive deficits, the influence of medication on their cognitive performance is uncertain and requires investigation. METHOD: Neuropsychological tests of executive function, memory and attention were performed on 44 prospectively verified, euthymic bipolar I patients, 22 of whom were drug-free. Residual mood symptom effects were controlled statistically using ancova. RESULTS: Drug-free and medicated patients differed only in delayed verbal recall (Rey AVLT list A7, drug-free > medicated), and perseverations during the five-point test (drug-free > medicated). When residual mood symptoms were controlled statistically, differences between drug-free and medicated subjects became insignificant. Medication effect sizes were modest. Significant correlations were found between residual depression scores and measures of verbal learning. CONCLUSION: Medications did not have any significant influence on neurocognitive performance, suggesting that neurocognitive deficits are an integral part of bipolar disorder.

A prospective study of glycaemic status in anti-psychotic-treated patients.

Anti-psychotic drugs, particularly the second generation, or ;atypical' agents, have been implicated in the development of metabolic dysfunction such as diabetes mellitus. There is a paucity of longitudinal data on the natural history of glucose homeostasis in anti-psychotic-treated patients, and there are no universally accepted strategies for managing worsening glycaemic control in this population. Notwithstanding, several guidelines recommend switching to a ;lower risk' agent if patients develop worsening glycaemic control during anti-psychotic treatment. We prospectively followed a cohort of 106 anti-psychotic-treated patients from across the diagnostic spectrum, and investigated changes in glycaemic status. Between baseline and follow-up assessment (mean follow-up time, 599.3 [SD+/-235.4] days glycaemic status was unchanged in 78 (86.7%) patients; 5 (5.6%) reverted from impaired fasting glucose (IFG) to normoglycaemia in the absence of any pharmacological or lifestyle intervention and all were taking a ;high risk' drug (clozapine or olanzapine). These preliminary data suggest that progression to overt diabetes mellitus is not inevitable in patients who develop IFG during anti-psychotic treatment. Switching to another agent simply on the basis of the development of IFG may not offer any advantage, especially if the mental state is stable.

Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.

A revision of the 2000 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in May 2006. Key areas in treating depression were reviewed, and the strength of evidence and clinical implications were considered. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is provided, which identifies the quality of evidence to inform the recommendations, the strength of which are based on the level of evidence. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse, and stopping treatment.

Antiglucocorticoid treatments for mood disorders.

BACKGROUND: Antiglucocorticoids may have antidepressant effects and have been reported to be efficacious in the treatment of severe psychiatric disorders. The efficacy and safety of antiglucocorticoid treatments for mood disorders is the subject of this systematic review. OBJECTIVES: To compare the efficacy and safety of antiglucocorticoid agents in the treatment of mood episodes (manic, mixed affective or depressive) with placebo or alternative drug treatment in mood disorders. SEARCH STRATEGY: CCDANCTR-Studies and CCDANCTR-References were searched on 11-9-2007. Additional searches of electronic databases were conducted in December 2006. Conference proceedings were searched. Experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials comparing antiglucocorticoid drugs in the treatment of mood episodes with placebo or alternative drug treatment in mood disorders were selected. DATA COLLECTION AND ANALYSIS: Data were extracted and the methodological quality of each study was assessed independently by two review authors. Meta-analyses were performed using Review Manager software. Relative risk (RR) with 95% confidence intervals (CI) were calculated for dichotomous outcomes. For continuous data, weighted mean differences (WMD) were calculated. MAIN RESULTS: Nine studies met criteria for inclusion. A number of drugs were examined, including mifepristone [RU-486], ketoconazole, metyrapone and DHEA. Three trials were in patients with psychotic major depression (pMDD), five trials in non-psychotic major depression and one trial in bipolar disorder. When examining all trials together across all affective episodes, there was no significant difference in the overall proportion of patients responding to antiglucocorticoid treatment over placebo, although the mean change in HAM-D scores indicated a significant difference in favour of treatment (WMD -4.54, 95%CI -6.78 to -2.29). Of the five trials in non-psychotic depression (unipolar or bipolar), there was a significant difference favouring treatment (HAM-D 50% reduction: RR 0.72, 95%CI 0.56 to 0.91). In pMDD, there was no evidence of an overall antidepressant effect (HAM-D 50% reduction: RR 0.98, 95%CI 0.79 to 1.22) or an effect on overall psychopathology (BPRS 30% reduction: RR 0.96, 95%CI 0.76 to 1.22). In these subtypes, the mean change in HAM-D indicated a significant difference in favour of treatment. AUTHORS' CONCLUSIONS: The use of antiglucocorticoids in the treatment of mood disorders is at the proof-of-concept stage. Considerable methodological differences exist between studies with respect to the compounds used and the patient cohorts studied. Results in some diagnostic subtypes are promising and warrant further investigation to establish the clinical utility of these drugs in the treatment of mood disorders.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Tritiated LSD binding in frontal cortex in schizophrenia.

It has been reported that the binding of tritiated LSD (at 2 or 4 nm) to frontal cortex is reduced in schizophrenia, a finding that has been interpreted as a reduction in the number of serotonin receptors. The present study, however, reveals in a Scatchard analysis of tritiated LSD binding in frontal cortex in the brains of 13 schizophrenic patients that there was no decrease in binding by comparison with eight control brains. Quantities of neuroleptic remaining in the brain after death cannot be readily washed out and could have led to the previous report of reduced LSD binding. A decrease in affinity of LSD binding sites consistent with this possibility has been demonstrated in chlorpromazine-treated rats. In the brains of five patients who had probably been neuroleptic-free for the year before death, tritiated LSD binding was significantly increased. This result needs to be replicated in larger samples.

Anterior pituitary hormone secretion in chronic schizophrenics.

Venous samples were obtained serially from 18 chronic schizophrenics and nine controls before and after the intravenous administration of protirelin and gonadorelin (gonadotropin releasing hormone [GnRH] ) and by venipuncture from 38 controls. Significant reductions in basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were found in the schizophrenic group associated with a reduction in the fluctuation of LH in serial samples. The FSH and prolactin responses to the administration of protirelin and gonadorelin were reduced in the schizophrenic group and abnormal increments of growth hormone secretion were noted in a number of patients, particularly those with reduced basal and stimulated hormone secretion. This pattern of hypothalamic-pituitary dysfunction, which is distinct from that seen in other psychiatric and endocrinological conditions, suggests a reduction in spontaneous GnRH release from the hypothalamus in schizophrenia and may be of potential pathophysiological significance.

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines.

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.