Dieter Schoepf

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Type-2 diabetes mellitus in schizophrenia: Increased prevalence and major risk factor of excess mortality in a naturalistic 7-year follow-up

OBJECTIVE Physical co-morbidity including type 2 diabetes mellitus is more prevalent in patients with schizophrenia compared to the general population. However, there is little consistent evidence that co-morbidity with diabetes mellitus and/or other diseases leads to excess mortality in schizophrenia. Thus, we investigated whether co-morbidity with diabetes and other somatic diseases is increased in schizophrenics, and if these are equally or more relevant predictors of mortality in schizophrenia than in age- and gender-matched hospitalised controls. METHODS During 2000-2007, 679 patients with schizophrenia were admitted to University Hospital Birmingham NHS Trust. Co-morbidities were compared with 88,778 age- and gender group-matched hospital controls. Predictors of mortality were identified using forward Cox regression models. RESULTS The prevalence of type 2 diabetes mellitus was increased in schizophrenia compared to hospitalised controls (11.3% versus 6.3%). The initial prevalence of type 2 diabetes mellitus was significantly higher in the 100 later deceased schizophrenic patients (24.0%) than in those 579 surviving over 7 years (9.2%). Predictors of mortality in schizophrenia were found to be age (relative risk [RR] = 1.1/year), type 2 diabetes mellitus (RR = 2.2), pneumonia (RR = 2.7), heart failure (RR = 2.9) and chronic renal failure (RR = 3.2). The impact of diabetes mellitus on mortality was significantly higher in schizophrenia than in hospital controls (RR = 2.2 versus RR = 1.1). In agreement, deceased schizophrenics had significantly suffered more diabetes mellitus than deceased controls (24.0 versus 10.5%). The relative risks of mortality for other disorders and their prevalence in later deceased subjects did not significantly differ between schizophrenia and controls. CONCLUSION Schizophrenics have more and additionally suffer more from diabetes: co-morbidity with diabetes mellitus is increased in schizophrenia in comparison with hospital controls; type 2 diabetes mellitus causes significant excess mortality in schizophrenia. Thus, monitoring for and prevention of type 2 diabetes mellitus is of utmost relevance in hospitalised patients with schizophrenia.

Alzheimer's disease and co-morbidity: Increased prevalence and possible risk factors of excess mortality in a naturalistic 7-year follow-up

BACKGROUND Subjects with late-onset Alzheimers disease (AD) have to be sufficiently healthy to live long enough to experience and to be diagnosed with dementia in later life. In contrast, neurodegeneration and cognitive deficits in AD may increase the frequency of co-morbid disorders and their possible influence on mortality. Consequently, we investigated whether the pattern of co-morbidity and its relevance for later death differed between hospitalized AD and age-matched controls subjects. METHODS Co-morbid diseases with a prevalence of more than 1% at hospital admission were compared between 634 hospitalized AD and 72,244 control subjects aged above 70 years admitted to the University of Birmingham NHS Trust between 1 January 2000 to 31 December 2007. Risk factors, i.e. co-morbid diseases that were predictors of mortality within the 7-year follow-up, were identified and compared. RESULTS Subjects with AD suffer more eating disorders, infections, brain diseases and neck of femur fractures than other hospitalized elderly patients. In contrast, some cardiovascular diseases and diabetes mellitus were less prevalent in AD subjects in comparison with hospitalized controls. Diseases that might have contributed to later mortality in AD were pneumonia, ischemic heart disease and gastroenteritis, but there were no significant differences in their impact on mortality compared to other hospitalized elderly subjects with the same co-morbidities in multivariate logistic regression analyses. CONCLUSION Patients with AD have a different pattern of co-morbidity, but die from the same diseases as other hospitalized patients. Infections including pneumonia and diseases that may occur secondary to neurodegeneration and cognitive decline may need special attention in patients with AD who may not be able to identify or report the early symptoms. Preventive measures may be helpful to reduce the high risk and fatal consequences of undetected disease in AD.

Bipolar disorder and comorbidity: Increased prevalence and increased relevance of comorbidity for hospital-based mortality during a 12.5-year observation period in general hospital admissions

BACKGROUND Bipolar disorder (BD) is associated with an increase of psychiatric and physical comorbidities, but the effects of these disorders on general hospital-based mortality are unclear. Consequently, we investigated whether the burden of comorbidity and its relevance on hospital-based mortality differed between individuals with and without BD during a 12.5-year observation period in general hospital admissions. METHODS During 1 January 2000 and 30 June 2012, 621 individuals with BD were admitted to three General Manchester Hospitals. All comorbidities with a prevalence ≥1% were compared with those of 6210 randomly selected and group-matched hospital controls of the same age and gender, regardless of priority of diagnoses. Comorbidities that increased the risk for hospital-based mortality (but not mortality outside of the hospitals) were identified using multivariate logistic regression analyses. RESULTS Individuals with BD had a more severe course of disease than controls that was associated with a higher total number of in-hospital deaths. Individuals with BD compared to controls had a substantial higher burden of comorbidities, the most frequent comorbidities included asthma, type-2 diabetes mellitus (T2DM), and alcohol dependence. 18 other diseases with a surplus of diabetes related complications were also increased. Fourteen comorbidities contributed to the prediction of hospital-based mortality in univariate analyses. Risk factors for hospital-based mortality in multivariate analyses were ischemic stroke, pneumonia, bronchitis, chronic obstructive pulmonary disease, T2DM, and hypertension. The impact of T2DM on hospital-based mortality was higher in individuals with BD than in controls. LIMITATIONS The study design was not assigned to assess the type of BD, the current bipolar status, and if individuals with BD were treated with medication. It was neither possible to compare drug effects, nor to compare the adherence to treatment between samples. CONCLUSION In one of the largest samples of individuals with BD in general hospitals, the excess comorbity in individuals with BD compared to controls is in particular caused by asthma and T2DM. T2DM and its complications cause significant excess hospital-based mortality in individuals with BD.

Effect of Disorder-Specific vs Nonspecific Psychotherapy for Chronic Depression: A Randomized Clinical Trial

Importance Chronic depression is a highly prevalent and disabling disorder. There is a recognized need to assess the value of long-term disorder-specific psychotherapy. Objective To evaluate the efficacy of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared with that of nonspecific supportive psychotherapy (SP). Design, Setting, and Participants A prospective, multicenter, evaluator-blinded, randomized clinical trial was conducted among adult outpatients with early-onset chronic depression who were not taking antidepressant medication. Patients were recruited between March 5, 2010, and October 16, 2012; the last patient finished treatment on October 14, 2013. Data analysis was conducted from March 5, 2014, to October 27, 2016. Interventions The treatment included 24 sessions of CBASP or SP for 20 weeks in the acute phase, followed by 8 continuation sessions during the next 28 weeks. Main Outcomes and Measures The primary outcome was symptom severity after 20 weeks (blinded observer ratings) as assessed by the 24-item Hamilton Rating Scale for Depression (HRSD-24). Secondary outcomes were rates of response (reduction in HRSD-24 score of ≥50% from baseline) and remission (HRSD-24 score ⩽8), as well as self-assessed ratings of depression, global functioning, and quality of life. Results Among 622 patients assessed for eligibility, 268 were randomized: 137 to CBASP (96 women [70.1%] and 41 men [29.9%]; mean [SD] age, 44.7 [12.1] years) and 131 to SP (81 women [61.8%] and 50 men [38.2%]; mean [SD] age, 45.2 [11.6] years). The mean (SD) baseline HRSD-24 scores of 27.15 (5.49) in the CBASP group and 27.05 (5.74) in the SP group improved to 17.19 (10.01) and 20.39 (9.65), respectively, after 20 weeks, with a significant adjusted mean difference of –2.51 (95% CI, –4.16 to –0.86; P = .003) and a Cohen d of 0.31 in favor of CBASP. After 48 weeks, the HRSD-24 mean (SD) scores were 14.00 (9.72) for CBASP and 16.49 (9.96) for SP, with an adjusted difference of –3.13 (95% CI, –5.01 to –1.25; P = .001) and a Cohen d of 0.39. Patients undergoing CBASP were more likely to reach response (48 of 124 [38.7%] vs 27 of 111 [24.3%]; adjusted odds ratio, 2.02; 95% CI, 1.09 to 3.73; P = .03) or remission (27 of 124 [21.8%] vs 14 of 111 [12.6%]; adjusted odds ratio, 3.55; 95% CI, 1.61 to 7.85; P = .002) after 20 weeks. Patients undergoing CBASP showed significant advantages in most other secondary outcomes. Conclusions and Relevance Highly structured specific psychotherapy was moderately more effective than nonspecific therapy in outpatients with early-onset chronic depression who were not taking antidepressant medication. Adding an extended phase to acute psychotherapy seems promising in this population. Trial Registration clinicaltrials.gov Identifier: NCT00970437.

Comorbidity and its relevance on general hospital based mortality in major depressive disorder: A naturalistic 12-year follow-up in general hospital admissions

Major depressive disorder (MDD) is associated with physical comorbidity, but the risk factors of general hospital-based mortality are unclear. Consequently, we investigated whether the burden of comorbidity and its relevance on in-hospital death differs between patients with and without MDD in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 30 June 2012, 9604 MDD patients were admitted to three General Manchester Hospitals. All comorbidities with a prevalence ≥1% were compared with those of 96,040 age-gender matched hospital controls. Risk factors of in-hospital death were identified using multivariate logistic regression analyses. Crude hospital-based mortality rates within the period under observation were 997/9604 (10.4%) in MDD patients and 8495/96,040 (8.8%) in controls. MDD patients compared to controls had a substantial higher burden of comorbidity. The highest comorbidities included hypertension, asthma, and anxiety disorders. Subsequently, twenty-six other diseases were disproportionally increased, many of them linked to chronic lung diseases and to diabetes. In deceased MDD patients, chronic obstructive pulmonary disease and type-2 diabetes mellitus were the most common comorbidities, contributing to 18.6% and 17.1% of deaths. Furthermore, fifteen physical diseases contributed to in-hospital death in the MDD population. However, there were no significant differences in their impact on mortality compared to controls in multivariate logistic regression analyses. Thus in one of the largest samples of MDD patients in general hospitals, MDD patients have a substantial higher burden of comorbidity compared to controls, but they succumb to the same physical diseases as their age-gender matched peers without MDD.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10−3) or a 2.87% smaller volume compared with controls (Cohen’s d=−0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28–0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Behavioral Evidence for an Impairment of Affective Theory of Mind Capabilities in Chronic Depression

Background: The only treatment specifically developed for chronic depression, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), is based amongst others on the hypothesis that chronically depressed patients (CD) show considerable deficits of affective theory of mind (ToM) capabilities. Data are scarce, however, and it remains unclear if ToM deficits are specific or if they arise from global cognitive deficits associated with depression. This study investigates the specific deficits of affective ToM abilities in CD. Sampling and Methods: ToM abilities were assessed in 26 medication-free CD and 26 matched healthy controls (HC) by means of a previously established false-belief ToM cartoon task. Since the task allowed an intern control for cognitive factors - operationalized in a visuospatial ToM task - it was possible to investigate specific affective ToM deficits. Results: As hypothesized, the CD showed a significant specific slowdown of affective ToM compared to cognitive ToM (3rd person perspective) when compared to HC. Simultaneously, we observed a general deterioration of all ToM functions in CD. Conclusions: This study provides evidence that CD have a mentalization deficit, specifically for affective ToM functions. This deficit is combined with a general deterioration of ToM functions, most likely attributable to frequently described cognitive deficits in depression.

Alcohol dependence and physical comorbidity: Increased prevalence but reduced relevance of individual comorbidities for hospital-based mortality during a 12.5-year observation period in general hospital admissions in urban North-West England.

PURPOSE Alcohol dependence (AD) is associated with an increase in physical comorbidities. The effects of these diseases on general hospital-based mortality are unclear. Consequently, we conducted a mortality study in which we investigated if the burden of physical comorbidities and their relevance on general hospital-based mortality differs between individuals with and without AD during a 12.5-year observation period in general hospital admissions. METHODS During 1 January 2000 and 30 June 2012, 23,371 individuals with AD were admitted at least once to seven General Manchester Hospitals. Their physical comorbidities with a prevalence≥1% were compared to those of 233,710 randomly selected hospital controls, group-matched for age and gender (regardless of primary admission diagnosis or specialized treatments). Physical comorbidities that increased the risk of hospital-based mortality (but not outside of the hospital) during the observation period were identified using multiple logistic regression analyses. RESULTS Hospital-based mortality rates were 20.4% in the AD sample and 8.3% in the control sample. Individuals with AD compared to controls had a higher burden of physical comorbidities, i.e. alcoholic liver and pancreatic diseases, diseases of the conducting airways, neurological and circulatory diseases, diseases of the upper gastrointestinal tract, renal diseases, cellulitis, iron deficiency anemia, fracture neck of femur, and peripheral vascular disease. In contrast, coronary heart related diseases, risk factors of cardiovascular disease, diverticular disease and cataracts were less frequent in individuals with AD than in controls. Thirty-two individual physical comorbidities contributed to the prediction of hospital-based mortality in univariate analyses in the AD sample; alcoholic liver disease (33.7%), hypertension (16.9%), chronic obstructive pulmonary disease (14.1%), and pneumonia (13.3%) were the most frequent diagnoses in deceased individuals with AD. Multiple forward logistic regression analysis, accounting for possible associations of diseases, identified twenty-three physical comorbidities contributing to hospital-based mortality in individuals with AD. However, all these comorbidities had an equal or even lower impact on hospital-based mortality than in the comparison sample. CONCLUSION The excess of in-hospital deaths in general hospitals in individuals with AD is due to an increase of multiple physical comorbidities, even though individual diseases have an equal or even reduced impact on general hospital-based mortality in individuals with AD compared to controls.