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Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Diaryltriazene derivatives were synthesized and evaluated for their antimicrobial properties. Initial experiments showed some of these compounds to have activity against both methicillin-resistant strains of Staphylococus aureus (MRSA) and Mycobacterium smegmatis, with MICs of 0.02 and 0.03 μg/mL respectively. Those compounds with potent anti-staphylococcal and anti-mycobacterial activity were not found to act as growth inhibitors of mammalian cell lines or yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at

Summary Background Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. Methods This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18–65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2–10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Asberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. Findings Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2–24·4] in the metyrapone group vs 22·6 points [20·1–24·8] in the placebo group; adjusted mean difference of −0·51 points [95% CI −3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. Interpretation Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic–pituitary–adrenal axis abnormalities. Funding Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

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.

Background Bipolar disorder is associated with both white matter abnormalities and hypothalamo–pituitary–adrenal axis dysfunction. In a post-hoc analysis of diffusion tensor data, the relationship between cortisol levels and white matter structural integrity was explored in healthy controls and in euthymic patients with bipolar disorder. Methods Healthy control subjects and patients with bipolar disorder, prospectively verified as euthymic, underwent diffusion tensor MRI: fractional anisotropy and mean diffusivity data in fifteen regions of interest were obtained. Morning and evening salivary cortisol levels (SCLs) were measured. Results Significant negative partial correlations were found between fractional anisotropy and evening SCLs in control subjects in four periventricular regions. This pattern was absent in bipolar patients, possibly due to the presence of an excess of extracellular fluid manifested as a significant increase in mean diffusivity in those regions. Limitations This is an exploratory, post-hoc analysis of data with relatively small sample sizes. Lithium treatment and past substance abuse in the bipolar group are potentially confounding factors in this study. Conclusions These preliminary data show an inverse relationship between evening cortisol levels and a measure of periventricular white matter integrity in healthy controls. This relationship appears disrupted in bipolar patients, possibly due to periventricular osmoregulatory dysfunction, the effects of medication or past substance use. Future research should further investigate the influences of cortisol on oligodendrocyte function, white matter integrity and brain osmoregulation in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10(-7)) and thalamus (d=-0.148; P=4.27 × 10(-3)) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10(-5)) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.Molecular Psychiatry advance online publication, 9 February 2016; doi:10.1038/mp.2015.227. ispartof: Molecular Psychiatry vol:21 issue:12 pages:1710-1716 ispartof: location:England status: published

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.

Although the relationship between antipsychotic medication, particularly second-generation antipsychotics (SGAs), and metabolic disturbance is increasingly accepted, there is an important, but little recognised, potential interaction between this and the other important serious adverse effect of neuroleptic malignant syndrome (NMS). We report a case of a 35-year old female who developed new onset type II diabetes mellitus with hyperosmolar hyperglycaemic coma and acute renal failure following treatment with a SGA for a first manic episode. The history is strongly suggestive of concurrent NMS. This case raises important questions about non-ketotic, hyperosmolar diabetic coma with antipsychotics, the possible association between hyperglycaemia and hyperthermia, and the direction of causality in this, the recognition of either syndrome when they co-exist and management issues in such patients. These questions are considered in the context of currently available literature.

We describe the case of a 44-year-old woman admitted with mania with psychotic symptoms who presented with delusion of twin pregnancy a month after admission, which temporally correlated with hyperprolactinemia secondary to antipsychotic medication. Modification of antipsychotic medication was associated with fall in serum prolactin and disappearance of delusion of pregnancy. In light of this clinically striking temporal association between hyperprolactinemia and delusion of pregnancy, we review the literature to examine the hypothetical relationship. We highlight the clinical significance of examining the various factors, including antipsychotic-induced hyperprolactinemia, which could trigger the development of delusion of pregnancy.

Objectives: Even when euthymic bipolar disorder patients can have persistent deficits in working memory, but the neural basis of this deficit remains unclear. We undertook an functional magnetic resonance imaging investigation of euthymic bipolar disorder patients performing two working memory paradigms; the two-back and Sternberg tasks, selected to examine the central executive and the phonological loop respectively. We hypothesized that neuronal dysfunction would be specific to the network underlying the executive rather than the phonological loop component of working memory. Methods: Twelve right-handed euthymic bipolar I males receiving lithium carbonate monotherapy were matched with 12 controls. The two-back task comprised a single working memory load contrasted with baseline vigilance condition. The Sternberg paradigm used a parametric design incorporating variable working memory load with fixed delay between presentation of an array of items to be remembered and a target item. Functional activation data were acquired during performance of the tasks and were analysed to produce brain activation maps representing significant group differences in activation (ANOVA). Load–response curves were derived from the Sternberg task data set. Results: There were no significant between-group differences (t-test) in performance of the two-back task, or in 2 × 5 group by memory load ANOVA for the performance data from Sternberg task. In the two-back task, compared with controls bipolar disorder patients showed reductions in bilateral frontal, temporal and parietal activation, and increased activations with the left precentral, right medial frontal and left supramarginal gyri. No between-group differences were observed in the Sternberg task at any working memory load. Conclusions: Our findings support the notion that, in euthymic bipolar disorder, failure to engage fronto-executive function underpins the core neuropsychological deficits.

This study determined whether cognitive impairments and structural brain changes in older depressed subjects, especially in the hippocampus, are related to hypercortisolemia.Sixty-one depressed subjects over age 60 who met DSM-IV criteria for major depression and 40 healthy comparison subjects underwent structural magnetic resonance imaging, neuropsychological testing, apolipoprotein E (APOE) genotyping, and salivary cortisol assessment (over 3 days) with follow-up 6 months later. Hippocampal volume was measured by manual segmentation that was blind to diagnosis. Average area under the curve for salivary cortisol over the 3 days was calculated. Cognitive function was assessed by using a combined memory z score.Depressed subjects showed multiple impairments in attention, working memory, visual memory, verbal memory, new learning, and executive function in relation to comparison subjects. They had hypercortisolemia (53% increase in area under the curve) and a reduction in right hippocampal volume (6% decrease). Hippocampal volume reduction was not associated with increased cortisol levels but was significantly correlated with continuing memory deficits at 6 months. Persisting "mild cognitive impairment" was seen in 20 (41%) of 49 subjects at 6 months and was associated with reduced hippocampal volume but not severity of depression, cortisol levels, or APOE genotype.Older depressed subjects have persisting cognitive impairments associated with hippocampal volume reduction, but the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism. Neuropathological studies are required to investigate the basis for hippocampal changes, while follow-up will determine whether hippocampal atrophy is a risk factor for cognitive decline.

Dementia with Lewy bodies (DLB) is associated with occipital changes in blood flow and metabolism, but structural changes in this region have not previously been assessed. The authors performed volumetric MRI measurement of the occipital lobe blind to the diagnosis in 23 subjects with DLB, 25 with AD, and 24 age-matched control subjects. There were no significant differences between groups in occipital lobe volume. The authors conclude gross structural changes in the occipital lobe do not occur in patients with mild to moderate DLB or AD.

Background Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. Methods/design Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. Discussion Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. Trial registration Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Thiol groups are important components of proteins and their oxidation can lead to a substantial loss of protein function. Patients with two apparently unrelated inborn errors of metabolism, tyrosinaemia type 1 and glutathione synthetase deficiency, have been reported to show reduced cell glutathione concentrations. We have found that not only glutathione but also protein thiol concentrations are reduced in the liver in tyrosinaemia type 1 patients. We also report a case of glutathione synthetase deficiency with a substantial deficiency of liver 4-fumarylacetoacetate hydrolase and provide evidence that glutathione, or some small-molecular-weight thiol, is essential for maintaining stability of this enzyme in vitro. Our results suggest that the availability of thiol groups may modify the phenotype of tyrosinaemia type 1 and that liver 4-fumarylacetoacetate hydrolase deficiency may be a secondary complicating factor in some forms of glutathione synthetase deficiency.

Anomalies of asymmetry and sex differences in brain structure have frequently been described in schizophrenic illnesses but have seldom been explored in bipolar disorder.We measured volumes of the left and right frontal, temporal, parietal, and occipital lobes and computed the magnitude of brain torque (i.e., rightward frontal and leftward occipital asymmetry) for 49 patients with bipolar disorder and 47 healthy controls and performed an exploratory analysis of sex differences in patients and controls.Patients had significantly greater cerebrospinal fluid volume than controls, but no difference in total brain volume. There were no main effects of diagnosis in gray matter lobe volume or brain torque, but when analyses were performed separately for male and female subjects, significant sex-by-diagnosis interactions were found in the volume of the left frontal, left temporal, right parietal, and right occipital lobes, such that male patients with bipolar disorder tend toward larger, more symmetric brains than male controls, whereas female patients tend toward smaller, more asymmetric brains than female controls.The lateralised nature of these interactions was such that the normal sex difference in volume was significantly accentuated, whilst the normal sex difference in asymmetry tended to be diminished in patients with bipolar disorder. We conclude that bipolar disorder in part reflects an interaction between brain growth and sex along the anterior-posterior axis of the human brain.

BackgroundCerebrovascular changes and glucocorticoid mediated hippocampal atrophy are considered relevant for depression-related cognitive deficits, forming putative treatment targets.AimsThis study examined the relative contribution of cortisol levels, brain atrophy and white matter hyperintensities to the persistence of cognitive deficits in older adults with depression.MethodThirty-five people aged ⩾60 years with DSM–IV major depression and twenty-nine healthy comparison controls underwent magnetic resonance imaging (MRI) and were underwent magnetic resonance imaging (MRI) and were followed up for 18 months. We analysed the relationship between baseline salivary cortisol levels, whole brain, frontal lobe and hippocampal volumes, severity of white matter hyperintensities and follow-up cognitive function in both groups by testing the interaction between the groups and these biological measures on tests of memory, executive functions and processing speed in linear regression models.ResultsGroup differences in memory and executive function follow-up scores were associated with ratings of white matter hyperintensities, especially of the deep white matter and periventricular regions. Compared with healthy controls, participants with depression scoring within the third tertile of white matter hyperintensities dropped two and three standard deviations in executive function and memory scores respectively. No biological measure related to group differences in processing speed, and there were no significant interactions between group and cortisol levels, or volumetric MRI measures.ConclusionsWhite matter hyperintensities, rather than cortisol levels or brain atrophy, are associated with continuing cognitive impairments in older adults with depression. The findings suggest that cerebrovascular disease rather than glucocorticoid-mediated brain damage are responsible for the persistence of cognitive deficits associated with depression in older age.

BackgroundAbnormal diffusion parameters are reported in specific brain regions and white matter tracts in bipolar disorder.AimsTo investigate whether these abnormalities are generalised, and thus evident in large regions of white matter.MethodDiffusion parameters were measured at several regions in the corpus callosum and in deep/periventricular white matter in 28 currently euthymic patients with bipolar disorder and controls. White matter hyperintensity loads were assessed.ResultsComparing the whole data-sets using the sign test, in the group with bipolar disorder, mean diffusivity was greater at all 15 sites (PPU-test), prefrontal and periventricular mean diffusivity were significantly increased; callosal and occipital fractional anisotropy were significantly reduced. Former substance use and lithium were possible confounding factors. Periventricular white matter hyperintensities were associated with significantly increased periventricular mean diffusivity in individuals with bipolar disorder.ConclusionsGeneralised white matter microstructural abnormalities may exist in bipolar disorder, possibly exacerbated by past substance use and ameliorated by lithium.

Summary Background Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. Aims To investigate the structure and function of the hypothalamic–pituitary–adrenal axis in euthymic patients with bipolar disorder. Method Euthymic adult patients with bipolar disorder ( n = 49 ) were compared with matched normal control subjects ( n = 47 ). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. Results The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean ± SD (in mm): 3.87 ± 1.96 versus 2.56 ± 1.34; d = 0.76 , ANOVA F = 12.7 , p = 0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups ( F = 16.97 , p 0.001 ). Pituitary volumes did not differ between patients and controls (mean ± SD (in mm3): 632 ± 176 versus 679 ± 159). Overall, females had larger pituitaries than males (703 ± 160 versus 595 ± 161; d = 0.67 , F = 9.65 , p = 0.003 ; all subjects), but female patients had smaller pituitaries compared to female controls (637 ± 178 versus 756 ± 126; d = 0.65 , F = 5.04 , p = 0.03 ). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. Conclusions In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes.

Ligase MurM catalyses the addition of Ala from alanyl-tRNA(Ala), or Ser from seryl-tRNA(Ser), to lipid intermediate II in peptidoglycan biosynthesis in Streptococcus pneumoniae, and is a determinant of high-level penicillin resistance. Phosphorus-based transition state analogues were designed as inhibitors of the MurM-catalysed reaction. Phosphonamide analogues mimicking the attack of a lysine nucleophile upon Ala-tRNA(Ala) showed no inhibition of MurM, but adenosine 3'-phosphonate analogues showed inhibition of MurM, the most active being a 2'-deoxyadenosine analogue (IC50 100 mu M). Structure/function studies upon this analogue established that modi. cation of the amino group of the aminoalkylphosphonate resulted in loss of potency, and modi. cation of the adenosine 5'-hydroxyl group with either a t-butyl dimethyl silyl or a carbamate functional group resulted in loss of activity. A library of 48 aryl sulfonamides was also screened against MurM using a radiochemical assay, and two compounds showed sub-millimolar inhibition. These compounds are the first small molecule inhibitors of the Fem ligase family of peptidyltransferases found in Gram-positive bacteria. (C) 2009 Elsevier Ltd. All rights reserved.

The authors describe 12 patients with antipsychotic-induced hyperprolactinemia. Six patients had erroneous ideas of being pregnant (four delusional and two non-delusional) temporally associated with hyperprolactinemia and resolving as prolactin levels returned to normal. The remaining six patients did not develop such ideas. Contrasting the clinical features of the two groups of patients in the context of existing literature informs on the possible biological and cognitive mechanisms that can be hypothesized to underlie the relationship between hyperprolactinemia due to antipsychotics and the development of inaccurate beliefs and feelings about pregnancy, and the effect of current mental state on the propensity to develop these beliefs.

An increase in white-matter lesions has been previously described in older subjects with depression. The authors investigated whether the regional location varied between depressed and normal subjects and determined the relationship of magnetic resonance (MR) signal hyperintensities to known clinical risk factors for vascular disease.Authors used automated image-processing software to determine volumes of signal hyperintensities from MR brain scans of older people with depression (N=29; mean age: 76 years) and normal subjects of similar age (N=32).Overall, subjects with depression had a significantly greater frontal-lobe white-matter lesion volume than normal subjects (0.35% versus 0.22%). However, after excluding subjects with hypertension, diabetes, or ischemic heart disease (leaving 14 depressed and 15 normal subjects), we found even greater differences between groups, with a larger volume of MR signal hyperintensities in the frontal region of the depressed group, but no difference in the basal ganglia or parietal and occipital lobes.The results support the "vascular depression" hypothesis and suggest that those with depression but without traditional vascular risk factors may be much more susceptible to cerebrovascular disease than normal subjects. The mechanisms for this increased susceptibility remain to be determined.

BackgroundEvidence for structural hippocampal change in depression is limited despite reports of neuronal damage due to hypercortisolaemia and vascular pathology.AimsTo compare hippocampal and white matter structural change in demographically matched controls and participants with early-onset and late-onset depression.MethodHigh-resolution volumetric magnetic resonance imaging (MRI) and rating of MRI hyperintensities.ResultsA total of 51 people with depression and 39 control participants were included. Participants with late-onset depression had bilateral hippocampal atrophy compared with those with early-onset depression and controls. Hippocampal volumes did not differ between control participants and those with early-onset depression. Age of depression onset correlated (negatively) with hippocampal volume but lifetime duration of depression did not. Hyperintensity ratings did not differ between groups.ConclusionsResults suggest that acquired biological factors are of greater importance in late-than in early-onset illness and that pathological processes other than exposure to hypercortisolaemia of depression underlie hippocampal atrophy in depression of late life.

Pharmacological treatment of bipolar affective disorder was examined by case note review of 120 subjects under the care of four hospitals in the North-East of England and compared with that recommended in published consensus opinions and also with the findings of previous surveys. Although the only comparison available is with other geographical regions, it appears that lithium use has remained relatively constant in recent years (53% in this sample). The use of anticonvulsants (62%) was greater than in previous studies, as was use of mood stabilizers in combination (37% overall, 53% in rapid cycling subjects). Antidepressant use was found in 23% of subjects. Eleven percent of subjects taking antidepressants were not prescribed a mood stabilizer and 43% of antidepressants prescribed were tricyclics, possibly increasing the risk of switching to mania. Fifteen percent had no mood stabilizer and antipsychotic use was almost equally split between typical and atypical drugs. Practice in the population studied is nearer than treatment described in previous work to that suggested in the literature. This may result from either, or most probably a combination of, the local availability of a specialist mood disorder service and evolution of overall prescribing practice. However, it still falls short in a number of respects of such recommendations as exist and this requires further examination and monitoring.

Case reports We report two cases of late life depression who became progressively more resistant to treatment, developed cognitive impairment, and began to exhibit neurological abnormalities and evidence of vascular disease. A discussion of the clinical features of the cases is accompanied by reports of neuropathology and neuroimaging findings. Extensive white matter lesions were present on computed tomography in both patients, and basal ganglia infarcts were seen in one. Neuropathology revealed evidence of cerebral atrophy, demyelination and white matter lesions in addition to cerebrovascular and generalised vascular disease. Neither patient exhibited Alzheimer pathology outwith the norm for their age. We believe this to be the first report of neuropathological findings in depression with white matter changes. Literature review The pathological basis of white matter lesions and their relationship to depression, its age of onset and clinical features is addressed in relation to the cases described. Pathological investigation of white matter lesions has not previously been carried out in depression and hypotheses regarding their nature in this illness are based on extrapolation from research in a variety of other disorders. The association of depression with vascular risk factors is considered, as is the relationship between depression and cognitive deficits. There is a need for further investigation in this area. Copyright © 2001 John Wiley & Sons, Ltd.

Curtis VA, Thompson JM, Seal ML, Monks PJ, Lloyd AJ, Harrison L, Brammer MJ, Williams SCR, Murray RM, Young AH, Ferrier IN. The nature of abnormal language processing in euthymic bipolar I disorder: evidence for a relationship between task demand and prefrontal function. Bipolar Disord 2007: 9: 358-369. © Blackwell Munksgaard, 2007 Objectives: Abnormal language processing is a consistent finding in bipolar disorder (BD). We used functional magnetic resonance imaging (fMRI) to investigate the core components of language processing as well as the impact of task demand in a group of bipolar subjects. Methods: Twelve euthymic dextral male BD I participants receiving lithium monotherapy were matched with 12 controls. Groups were matched for age, years of education and estimated premorbid IQ. We employed a factorial design manipulating task demand (decision versus fluency) and task domain (phonetic versus semantic) to investigate differences in language processing between groups and across different task domains and requirements. Data were fitted to haemodynamic response models convolved to the experimental design. Group and task difference maps were generated. Results: During the scanning session bipolar patients demonstrated significantly slower reaction times. However, groups demonstrated the same task accuracy except for one domain (phonetic decision). All participants activated regions known to be engaged by language tasks, but compared to controls the bipolar patients showed altered patterns of prefrontal activation which were related to the nature of the task, language processing, and increasing task demand. Conclusions: We have demonstrated abnormal prefrontal activation in bipolar patients across a range of language tasks with varying task demands.