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Mary Mabel Tannahill was the only child of Andrew Robert Tannahill (poet, writer in Scots, and translator) and Mary Reid (artist), members of the cultural elite of Glasgow from the late 1920s to the 60s. However, her mother decided that Mabel was too intellectually gifted to waste her time in the arts and that she should instead study medicine. After qualifying Mabel trained in public health before switching to psychiatry. She was one of the comparatively rare members of her generation to combine raising a family and climbing the ladder to consultant status. She held the post of part time senior lecturer and honorary consultant at St Thomas’ Hospital, London, before her husband’s job as a company doctor for Unilever took him to Liverpool. Mabel opted to stay with her Celtic roots and was appointed consultant at the North Wales Hospital in Denbigh. She was with Clwyd Health Authority from 1975 to 1994.

Individuals with a mental health disorder appear to be at increased risk of medical illness. To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden. Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria. We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset. Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.

Background It has been suggested that clinician‐rated scales and self‐report questionnaires may be interchangeable in the measurement of depression severity, but it has not been tested whether clinically significant information is lost when assessment is restricted to either clinician‐rated or self‐report instruments. The aim of this study is to test whether self‐report provides information relevant to short‐term treatment outcomes that is not captured by clinician‐rating and vice versa. Methods In genome‐based drugs for depression (GENDEP), 811 patients with major depressive disorder treated with escitalopram or nortriptyline were assessed with the clinician‐rated Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (HRSD), and the self‐report Beck Depression Inventory (BDI). In sequenced treatment alternatives to relieve depression (STAR*D), 4,041 patients treated with citalopram were assessed with the clinician‐rated and self‐report versions of the Quick Inventory of Depressive Symptomatology (QIDS‐C and QIDS‐SR) in addition to HRSD. Results In GENDEP, baseline BDI significantly predicted outcome on MADRS/HRSD after adjusting for baseline MADRS/HRSD, explaining additional 3 to 4% of variation in the clinician‐rated outcomes (both P < .001). Likewise, each clinician‐rated scale significantly predicted outcome on BDI after adjusting for baseline BDI and explained additional 1% of variance in the self‐reported outcome (both P < .001). The results were confirmed in STAR*D, where self‐report and clinician‐rated versions of the same instrument each uniquely contributed to the prediction of treatment outcome. Conclusions Complete assessment of depression should include both clinician‐rated scales and self‐reported measures.

White matter abnormalities have been implicated in the aetiology of major depressive disorder; however, the relationship between the severity of symptoms and white matter integrity is currently unclear. To investigate white matter integrity in people with major depression and healthy controls, and to assess its relationship with depressive symptom severity. Diffusion tensor imaging data were acquired from 66 patients with recurrent major depression and a control group of 66 healthy individuals matched for age, gender and IQ score, and analysed with tract-based spatial statistics. The relationship between white matter integrity and severity of depression as measured by the Beck Depression Inventory was examined. Depressive illness was associated with widespread regions of decreased white matter integrity, including regions in the corpus callosum, superior longitudinal fasciculus and anterior corona radiata, compared with the control group. Increasing symptom severity was negatively correlated with white matter integrity, predominantly in the corpus callosum. Widespread alterations in white matter integrity are evident in major depressive disorder. These abnormalities are heightened with increasing severity of depressive symptoms.

Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Studies demonstrating an association between childhood trauma and psychosis in adulthood have not systematically explored gender differences. To investigate gender differences in the prevalence of childhood sexual and physical abuse among people with psychosis in comparison with healthy controls. The Childhood Experiences of Care and Abuse Questionnaire was completed to elicit experiences of sexual and physical abuse during childhood in first-episode psychosis cases and population-based controls. Among women, those in the cases group were twice as likely to report either physical or sexual abuse compared with controls following adjustment for all confounders. In particular, the effect of physical abuse in women was stronger and more robust than that for sexual abuse. A similar trend was found for psychotic-like experiences in the female control group. No association was found in men. Reports of severe childhood physical or sexual abuse were associated with psychosis in women but not in men.

Adverse drug reactions are important determinants of non-adherence to antidepressant treatment, but their assessment is complicated by overlap with depressive symptoms and lack of reliable self-report measures. To evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample. The newly developed self-report Antidepressant Side-Effect Checklist and the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly administered to 811 adult participants with depression in a part-randomised multicentre open-label study comparing escitalopram and nortriptyline. There was good agreement between self-report and psychiatrists' ratings. Most complaints listed as adverse reactions in people with depression were more common when they were medication-free rather than during their treatment with antidepressants. Dry mouth (74%), constipation (33%) and weight gain (15%) were associated with nortriptyline treatment. Diarrhoea (9%), insomnia (36%) and yawning (16%) were more common during treatment with escitalopram. Problems with urination and drowsiness predicted discontinuation of nortriptyline. Diarrhoea and decreased appetite predicted discontinuation of escitalopram. Adverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.

Background Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either ‘reactive’ or ‘endogenous’ subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of ‘reactive’ or ‘endogenous’ subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of ‘reactive’ and ‘endogenous’ depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. Methods Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic ‘stress’ protocols (maternal separation and Unpredictable Chronic Mild Stress) to model ‘reactive’ depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of ‘endogenous’ depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. Results In the mouse ‘reactive’ model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the ‘endogenous’ rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. Conclusions Our results suggest that ‘endogenous’ and ‘reactive’ subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of ‘reactive’ depression caused by early stressors differs considerably from that of ‘reactive’ depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

Background Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD). Methods Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples. Results Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1 ) and on 1q24.1 near the gene TMCO1 , and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling. Conclusions The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1 , as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2 , NCALD , WDR60 , SCN7A and SPAG16 .

There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene. To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor). The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project. The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome. The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.