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Recent developments and current controversies in depression.
In this review of the last 5 years' developments in research into depression we focus on recent advances and current controversies. We cover epidemiology and basic science as well as the treatment of depression in adults in all its forms. Depression in , as well as in has been covered in recent Seminars in The Lancet. Depression in adulthood remains a very common and under-treated condition, resulting in a high degree of disability. Increasingly detailed knowledge about impairment of information processing in depression is being supplemented by quantitative studies of the brain processes underlying these impairments. Most patients improve with present treatments. The mechanisms of action of antidepressants are not fully understood; the hypothesis that reversing hippocampal cell loss in depression may be their active principle is a fascinating new development. Moral panic about the claim that antidepressant serotonin reuptake inhibitors cause patients to commit suicide and become addicted to their medication may have disconcerted the public and members of the medical profession. We will try to describe the considerable effort that has gone into collecting evidence to enlighten this debate.
Obstetric complications in DSM-III schizophrenics and their siblings.
Blind to the adult diagnosis, the birth records of 27 patients fulfilling DSM-III criteria for schizophrenia and those of their healthy siblings were examined. A significant excess of obstetric complications was seen in the schizophrenic subjects.
Transcranial direct current stimulation in the treatment of major depression: a meta-analysis.
BACKGROUND: So far, no comprehensive answer has emerged to the question of whether transcranial direct current stimulation (tDCS) can make a clinically useful contribution to the treatment of major depression. We aim to present a systematic review and meta-analysis of tDCS in the treatment of depression. METHOD: Medline and Embase were searched for open-label and randomized controlled trials of tDCS in depression using the expressions ('transcranial direct current stimulation' or 'tDCS') and ('depression' or 'depressed'). Study data were extracted with a standardized data sheet. For randomized controlled trials, effect size (Hedges' g) was calculated and the relationships between study variables and effect size explored using meta-regression. RESULTS: A total of 108 citations were screened and 10 studies included in the systematic review. Six randomized controlled trials were included in the meta-analysis, with a cumulative sample of 96 active and 80 sham tDCS courses. Active tDCS was found to be more effective than sham tDCS for the reduction of depression severity (Hedges' g=0.743, 95% confidence interval 0.21-1.27), although study results differed more than expected by chance (Q=15.52, df=6, p=0.017, I2=61.35). Meta-regression did not reveal any significant correlations. CONCLUSIONS: Our study was limited by the small number of studies included, which often had small sample size. Future studies should use larger, if possible representative, health service patient samples, and optimized protocols to evaluate the efficacy of tDCS in the treatment of depression further.
Postexercise motor evoked potentials in depressed patients, recovered depressed patients, and controls.
We hypothesized that impaired postexercise motor evoked potential (MEP) facilitation in depressed patients would reverse with recovery from depression. Transcranial magnetic stimulation and exercise of the thenar muscles were used to examine the 10 controls, 10 medicated depressed patients, and 10 medicated recovered patients. Depressed patients showed reduced mean postexercise facilitation compared to both controls (p = 0.005) and recovered patients (p = 0.012). Controls and recovered patients had similar mean postexercise MEPs (p = 0.45). This is consistent with other evidence of reversibility of abnormal findings following recovery from depression.
Psychiatry of Parkinson's Disease
This book assembles short reviews from experts in the field to chart the various psychiatric syndromes known in Parkinson's disease, their presentation, etiology and management. - (1) Epidemiology of Psychiatric Symptoms in Parkinson’s Disease - Leentjens, A.F.G. (Maastricht) - (2) Depression, Apathy and Anxiety Disorders - Brockman, S.; Jayawardena, B.; Starkstein, S.E. (Crawley, W.A.) - (3) Apathy in Parkinson’s Disease - Leroi, I. (Manchester/Blackburn); David, R. (Palo Alto, Calif./Nice); Robert, P. (Nice) - (4) Disorders of Visual Perception in Parkinson’s Disease and Other Lewy Body Disorders - Collerton, D. (Gateshead); Mosimann, U.P. (Bern); Archibald, N. (Newcastle upon Tyne) - (5) Psychosis and Parkinson’s Disease - Jakel, R.J.; Stacy, M.A. (Durham, N.C.) - (6) Sleep in Parkinson’s Disease and Dementia with Lewy Bodies - Ferman, T.J. (Jacksonville, Fla.); Boeve, B.F. (Rochester, Minn.) - (7) Sexual Problems in Parkinson’s Disease - Sakakibara, R. (Sakura/Chiba); Uchiyama, T.; Yamamoto, T. (Chiba); Kishi, M.; Ogawa, E.; Tateno, F. (Sakura) - (8) An Update on Impulse Control Disorders in Parkinson’s Disease - Voon, V.; Mehta, A.R. (Cambridge) - (9) Neuropsychological Features of Early Cognitive Impairment in Parkinson’s Disease - Williams-Gray, C.H.; Mason, S.L. (Cambridge) - (10) Parkinson’s Disease with Dementia - Taylor, J.-P.; O’Brien, J.T. (Newcastle upon Tyne) - (11) Somatoform Disorders in Parkinson’s Disease and Dementia with Lewy Bodies Evidence Underlying Psychotic Traits - Onofrj, M.; Thomas, A.; Bonanni, L.; di Giannantonio, M.; Gambi, F.; Sepede, G. (Chieti) - (12) Drug-Induced Parkinsonism and Abnormal Involuntary Movements - Ritchie, C.W. (London)
Timing of onset of cognitive decline: results from Whitehall II prospective cohort study.
OBJECTIVES: To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. DESIGN: Prospective cohort study. At study inception in 1985-8, there were 10,308 participants, representing a recruitment rate of 73%. SETTING: Civil service departments in London, United Kingdom. PARTICIPANTS: 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. MAIN OUTCOME MEASURE: Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. RESULTS: All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test × 100, in reasoning was -3.6% (95% confidence interval -4.1% to -3.0%) in those aged 45-49 at baseline and -9.6% (-10.6% to -8.6%) in those aged 65-70. In women, the corresponding decline was -3.6% (-4.6% to -2.7%) and -7.4% (-9.1% to -5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by -3.6% (-4.5% to -2.8%) but the cross sectional effects suggested a decline of -11.4% (-14.0% to -8.9%). CONCLUSIONS: Cognitive decline is already evident in middle age (age 45-49).
A systematic review of diffusion tensor imaging studies in affective disorders.
White matter abnormalities constitute one element of the network dysfunction that underlies affective disorders: differences between the white matter of subjects with affective disorders and control subjects have been identified using a range of neuroimaging and histological techniques. Diffusion tensor imaging (DTI) can uniquely study the orientation and integrity of white matter tracts and is thus an ideal tool to shed light on white matter abnormalities in subjects with affective disorders. Here, we systematically review DTI studies of affective disorders. We identified DTI studies of affective disorders from EMBASE and MEDLINE and searched the reference lists of relevant papers. Twenty-seven articles comparing subjects with affective disorders with control subjects were included in the review, with eight studies included in a meta-analysis of superior frontal regions. Twenty-one of 27 studies found significantly lower anisotropy in subjects with affective disorders compared with control subjects, more specifically within the frontal and temporal lobes or tracts. A large effect size was detected within the superior frontal gyrus, although heterogeneity and one index of publication bias were significant. Although there is significant heterogeneity of acquisition and analysis methods and subject properties, DTI studies of affective disorders consistently identify reduced anisotropy in the frontal and temporal lobes and tracts of subjects with affective disorders relative to control subjects.
Functional imaging as a predictor of schizophrenia.
BACKGROUND: Prospective studies of young individuals at high risk of schizophrenia allow the investigation of whether neural abnormalities predate development of illness and, if present, have the potential to identify those who may become ill. METHODS: We studied young individuals with at least two relatives with the disorder. At baseline functional magnetic resonance imaging (fMRI) scan, none met criteria for any psychiatric disorder, but four subjects subsequently developed schizophrenia. We report the baseline functional imaging findings in these subjects performing a sentence completion task compared with normal control subjects (n = 21) and those at high risk with (n = 21) and without (n = 41) psychotic symptoms who have not developed the disorder. RESULTS: High-risk subjects who became ill demonstrated increased activation of the parietal lobe, decreased activation of the anterior cingulate, and smaller increases in activation with increasing task difficulty in the right lingual gyrus and bilateral temporal regions. The hypothesized predictive power of parietal activation was supported only in combination with lingual gyrus activity, which gave a positive predictive value in this sample of .80. CONCLUSIONS: Although these findings should be considered cautiously, as only four subjects who had an fMRI scan subsequently became ill, they suggest functional abnormalities are present in high-risk subjects who later became ill, which distinguish them not only from normal control subjects but also those at high risk who had not developed the disorder. These differences are detectable with fMRI and may have clinical utility.
Single-photon emission computed tomography with 99mTc-exametazime in unmedicated schizophrenic patients.
We examined 20 actively psychotic unmedicated schizophrenic patients and 20 matched control subjects by using single-photon emission, computed tomography (SPECT) with 99mtechnetium-exametazime. Patients showed a hyperfrontal pattern of tracer uptake with significant relative increases in superior prefrontal cortex. This abnormality was less pronounced in patients with higher symptom scores for psychomotor poverty. In addition, patients showed associations between certain schizophrenic syndrome scores, such as psychomotor poverty, disorganization, and reality distortion, and tracer uptake to a number of cortical and subcortical brain regions. This syndrome-related pattern of tracer uptake was, at least in part, consistent with similar associations previously reported in chronically medicated schizophrenic patients. SPECT therefore provides a readily available method to examine the relationship between symptom pattern and regional brain metabolism in psychotic patients. Any observed patterns of association will depend on the current mental and medication status of the patients examined.
Differential effects of the APOE genotype on brain function across the lifespan.
Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.
Limbic over-activity in depression during preserved performance on the n-back task.
The profile of cognitive dysfunction observed in patients with major depressive disorder (MDD) may be partially attributed to a deficit in the central executive component of working memory (WM). This could be the consequence of a functional deficit in regions of cortex that are associated with WM function in healthy adults. In order to investigate this assertion, ten patients with a diagnosis of MDD and ten matched healthy controls undertook a parametric WM task (i.e. the n-back task) during the acquisition of blood oxygen level dependent echo planar magnetic resonance images (BOLD EPI fMRI). There was no significant difference in the behavioral performance of depressed patients and controls. This was true for both accuracy and reaction time on the n-back task. Random effects analysis of the functional imaging data (using SPM99) revealed a significant difference in load-dependent activation in the medial orbitofrontal cortex/rostral anterior cingulate between patients and controls (cluster size (K(E))/volume = 128/1024 mm3, P(corrected) = 0.025). While both participant groups exhibited a significant decrease in activation in this region with increased task difficulty, the magnitude of this decrease was smaller in patients with MDD than in controls. Therefore, this study implies that the performance of WM tasks is associated with a dysfunctional activation of the medial orbitofrontal and rostral anterior cingulate cortex in MDD. The study thus offers a rationale for explaining depressive cognitive impairment by the abnormal fronto-limbic activation found in clinical depression.
White matter hyperintensities classified according to intensity and spatial location reveal specific associations with cognitive performance.
White matter hyperintensities (WMHs) on T<sub>2</sub>-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impairments. WMHs that appear as hypointense in T<sub>1</sub>-weighted images (T<sub>1</sub>w) may also indicate the most severe component of WMHs. We developed an automatic method that sub-classifies WMHs into four categories (periventricular/deep and T<sub>1</sub>w-hypointense/nonT<sub>1</sub>w-hypointense) using MRI data from 684 community-dwelling older adults from the Whitehall II study. To test if location and intensity information can impact cognition, we derived two general linear models using either overall or subdivided volumes. Results showed that periventricular T<sub>1</sub>w-hypointense WMHs were significantly associated with poorer performance in the trail making A (p = 0.011), digit symbol (p = 0.028) and digit coding (p = 0.009) tests. We found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in T<sub>1</sub>w reveals specific associations with cognitive performance.