Identifying subgroups with differential response to CBASP versus Escitalopram during the first eight weeks of treatment in outpatients with persistent depressive disorder.

There exists little empirical evidence helping clinicians to select the most effective treatment for individual patients with persistent depressive disorder (PDD). This study identifies and characterizes subgroups of patients with PDD who are likely to benefit more from an acute treatment with psychotherapy than from pharmacotherapy and vice versa. Non-medicated outpatients with PDD were randomized to eight weeks of acute treatment with the Cognitive Behavioral Analysis System of Psychotherapy (CBASP; n = 29) or escitalopram plus clinical management (ESC/CM; n = 31). We combined several baseline variables to one composite moderator and identified two subgroups of patients: for 56.0%, ESC/CM was associated with a greater reduction in depression severity than CBASP, for the remaining 44.0%, it was the other way around. Patients likely to benefit more from ESC/CM were more often female, had higher rates of moderate-to-severe childhood trauma, more adverse life events and more previous suicide attempts. Patients likely to benefit more from CBASP were older, had more often an early illness onset and more previous treatments with antidepressants. Symptomatic response, remission, and reductions in symptom severity occurred more often in those patients treated with their likely more effective treatment condition. The findings suggest that the baseline phenotype of patients with PDD moderates their benefit from acute treatment with CBASP relative to ESC/CM. Once confirmed in an independent sample, these results could serve to guide the choice between primarily psychotherapeutic or pharmacological treatments for outpatients with PDD.

Precuneus connectivity and symptom severity in chronic depression✰.

Although abnormal resting state connectivity within several brain networks has been repeatedly reported in depression, little is known about connectivity in patients with early onset chronic depression. We compared resting state connectivity in a homogenous sample of 32 unmedicated patients with early onset chronic depression and 40 healthy control participants in a seed-to-voxel-analysis. According to previous meta-analyses on resting state connectivity in depression, 12 regions implicated in default mode, limbic, frontoparietal and ventral attention networks were chosen as seeds. We also investigated associations between connectivity values and severity of depression. Patients with chronic depression exhibited stronger connectivity between precuneus and right pre-supplementary motor area than healthy control participants, possibly reflecting aberrant information processing and emotion regulation deficits in depression. Higher depression severity scores (Hamilton Rating Scale for Depression) were strongly and selectively associated with weaker connectivity between the precuneus and the subcallosal anterior cingulate. Our findings correspond to results obtained in studies including both episodic and chronic depression. This suggests that there may be no strong differences between subtypes of depression regarding the seeds analyzed here. To further clarify this issue, future studies should directly compare patients with different courses of depression.

Impact of Baseline Characteristics on the Effectiveness of Disorder-Specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Supportive Psychotherapy in Outpatient Treatment for Persistent Depressive Disorder.

Importance: In the treatment of persistent depressive disorder (PDD), disorder-specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been shown to be superior to Supportive Psychotherapy (SP) in outpatients. It remains to clear which subgroups of patients benefit equally and differentially from both psychotherapies. Objective: To identify those patient-level baseline characteristics that predict a comparable treatment effectiveness of CBASP and SP and those that moderate the differential effectiveness of CBASP compared to SP. Design, setting and participants: In this analysis of a 48-week multicenter randomized clinical trial comparing CBASP to SP in adult antidepressant-free outpatients with early-onset PDD, we evaluated baseline variables from the following domains as potential predictors and moderators of treatment effectiveness: socio-demography, clinical status, psychosocial and global functioning, life quality, interpersonal problems, childhood trauma, treatment history, preference for psychotherapy, and treatment expectancy. Interventions: A 48-week treatment program with 32 sessions of either CBASP or SP. Main outcomes and measures: Depression severity measured by the 24-item Hamilton Rating Scale for Depression (HRSD-24) at week 48. Results: From N = 268 randomized outpatients, N = 209 completed the 48-week treatment program. CBASP completers had significantly lower post-treatment HRSD-24 scores than SP completers (meanCBASP=13.96, sdCBASP= 9.56; meanSP= 16.69, sdSP= 9.87; p = 0.04). A poor response to both therapies was predicted by higher baseline levels of clinician-rated depression, elevated suicidality, comorbid anxiety, lower social functioning, higher social inhibition, moderate-to-severe early emotional or sexual abuse, no preference for psychotherapy, and the history of at least one previous inpatient treatment. Moderator analyses revealed that patients with higher baseline levels of self-rated depression, comorbidity of at least one Axis-I disorder, self-reported moderate-to-severe early emotional or physical neglect, or at least one previous antidepressant treatment, had a significantly lower post-treatment depression severity with CBASP compared to SP (all p < 0.05). Conclusions and relevance: A complex multifactorial interaction between severe symptoms of depression, suicidality, and traumatic childhood experiences characterized by abuse, social inhibition, and anxiety may represent the basis of non-response to psychotherapy in patients with early onset PDD. Specific psychotherapy with CBASP might, however, be more effective and recommendable for a variety of particularly burdened patients compared to SP.

Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort.

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Combining baseline characteristics to disentangle response differences to disorder-specific versus supportive psychotherapy in patients with persistent depressive disorder.

Does the pre-treatment profile of individuals with persistent depressive disorder (PDD) moderate their benefit from disorder-specific Cognitive Behavioral System of Psychotherapy (CBASP) versus supportive psychotherapy (SP)? We investigated this question by analyzing data from a multi-center randomized clinical trial comparing the effectiveness of 48 weeks of CBASP to SP in n  =  237 patients with early-onset PDD who were not taking antidepressant medication. We statistically developed an optimal composite moderator as a weighted combination of 13 preselected baseline variables and used it for identifying and characterizing subgroups for which CABSP may be preferable to SP or vice versa. We identified two distinct subgroups: 58.65% of the patients had a better treatment outcome with CBASP, while the remaining 41.35% had a better outcome with SP. At baseline, patients responding more favorably to CBASP were more severely depressed and more likely affected by moderate-to-severe childhood trauma including early emotional, physical, or sexual abuse, as well as emotional or physical neglect. In contrast, patients responding more favorably to SP had a higher pre-treatment global and social functioning level, a higher life quality and more often a recurrent illness pattern without complete remission between the episodes. These findings emphasize the relevance of considering pre-treatment characteristics when selecting between disorder-specific CBASP and SP for treating PDD. The practical implementation of this approach would advance personalized medicine for PDD by supporting mental health practitioners in their selection of the most effective psychotherapy for an individual patient.

Two-Year Follow-Up after Treatment with the Cognitive Behavioral Analysis System of Psychotherapy versus Supportive Psychotherapy for Early-Onset Chronic Depression.

BACKGROUND: Evidence on the long-term efficacy of psychotherapeutic approaches for chronic depression is scarce. OBJECTIVE: To evaluate the effects of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared to Supportive Psychotherapy (SP) 1 year and 2 years after treatment termination. METHODS: In this study, we present 1- and 2-year follow-up assessments of a prospective, multicenter, evaluator-blinded, randomized clinical trial of outpatients with early-onset chronic major depression (n = 268). The initial treatment included 32 sessions of CBASP or SP over 48 weeks. The primary outcome was the rate of "well weeks" (Longitudinal Interval Follow-Up Evaluation; no/minimal symptoms) after 1 year and 2 years. The secondary outcomes were, among others, clinician- and self-rated depressive symptoms, response/remission rates, and quality of life. RESULTS: Of the 268 randomized patients, 207 (77%) participated in the follow-up. In the intention-to-treat analysis, there was no statistically significant difference between CBASP and SP patients in experiencing well weeks (CBASP: mean [SD] of 48.6 [36.9] weeks; SP: 39.0 [34.8]; rate ratio 1.26, 95% CI 0.99-1.59, p = 0.057, d = 0.18) and in remission rates (CBASP: 1 year 40%, 2 years 40.2%; SP: 1 year 28.9%, 2 years 33%) in the 2 years after treatment. Statistically significant effects were found in favor of CBASP 1 year after treatment termination regarding the rate of well weeks, self-rated depressive symptoms, and depression-related quality of life. CONCLUSIONS: CBASP lost its superiority over SP at some point between the first and the second year. This suggests the necessity of maintenance treatment for early-onset chronically depressed patients remitted with CBASP during the acute therapy phase, as well as the sequential integration of other treatment strategies, including medication for those who did not reach remission.

The impact of childhood maltreatment on the differential efficacy of CBASP versus escitalopram in patients with chronic depression: A secondary analysis.

Childhood maltreatment (CM) has been indicated as a predictor of a differential response to antidepressant treatment with psychotherapy compared to medication. In this secondary analysis, we investigated whether the presence of CM results in a differential indication for the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) or escitalopram plus clinical management (ESC). Sixty patients with chronic depression were randomized to either 22 sessions of CBASP or ESC over the course of 8 weeks of acute and 20 weeks of extended treatment at 2 German treatment sites. CM was assessed using the Childhood Trauma Questionnaire and the clinician rated Early Trauma Inventory. Intention-to-treat analyses were used to examine the impact of CM on depression, global functioning, and quality of life. The presence of CM did not result in significant differences in treatment response to CBASP or ESC on any outcome measure after 28 weeks of treatment independent of the type of CM assessment. After 8 weeks, a significant CM × treatment interaction was found for scores on the Montgomery-Asberg Depression Rating Scale. Patients with a history of CM receiving CBASP had a significantly lower response rate compared to patients without CM and to those receiving ESC after 8 weeks. Conclusively, CBASP and ESC are equally effective treatment options for the difficult to treat subgroup of patients with chronic depression and a history of CM. CM may be a predictor of a longer latency of treatment response in the case of psychotherapy. KEY PRACTITIONER MESSAGE: CBASP and escitalopram are equally effective treatment options for chronic depression. Both treatments are also equally effective for the difficult to treat subgroup of patients with chronic depression and a history of childhood maltreatment. Childhood maltreatment may result in a longer latency of treatment response in the case of psychotherapy.

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.

Functional Correlates of childhood maltreatment and symptom severity during affective theory of mind tasks in chronic depression.

Among multiple etiological factors of depressive disorders, childhood maltreatment (CM) gains increasing attention as it confers susceptibility for depression and predisposes to chronicity. CM assumedly inhibits social-cognitive development, entailing interactional problems as observed in chronic depression (CD), especially in affective theory of mind (ToM). However, the extent of CM among CD patients varies notably as does the severity of depressive symptoms. We tested whether the extent of CM or depressive symptoms correlates with affective ToM functions in CD patients. Regional brain activation measured by functional magnetic resonance imaging during an affective ToM task was tested for correlation with CM, assessed by the Childhood Trauma Questionnaire (CTQ), and symptom severity, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS), in 25 unmedicated CD patients (mean age 41.52, SD 11.13). Amygdala activation during affective ToM correlated positively with CTQ total scores, while (para)hippocampal response correlated negatively with MADRS scores. Our findings suggest that differential amygdala activation in affective ToM in CD is substantially modulated by previous CM and not by the pathophysiological equivalents of current depressive symptoms. This illustrates the amygdala's role in the mediation of CM effects. The negative correlation of differential (para)hippocampal activation and depressive symptom severity indicates reduced integration of interactional experiences during depressive states.

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.

Cognitive Behavioral Analysis System of Psychotherapy versus Escitalopram in Chronic Major Depression.

BACKGROUND: A specific psychotherapy for chronic depression, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), was compared to escitalopram (ESC). METHODS: Sixty patients with chronic major depression were randomized to 'CBASP' (22 sessions) or 'ESC plus clinical management' (ESC/CM) at two treatment sites. The primary outcome measure was the score on the Montgomery-Asberg Depression Rating Scale (MADRS) after 8 weeks of acute treatment assessed by blinded raters. In the case of nonimprovement (<20% reduction in the MADRS score), the other condition was augmented for the following 20 weeks of extended treatment. Secondary end points were, among others, depressive symptoms, remission (MADRS score of ≤9) and response rates (reduction of MADRS score of ≥50%) 28 weeks after randomization. RESULTS: An intent-to-treat analysis revealed that clinician-rated depression scores decreased significantly after 8 and 28 weeks with no significant differences between the groups. The response rates after 28 weeks of treatment were high (CBASP: 68.4%, ESC/CM: 60.0%), and the remission rates were moderate (CBASP: 36.8%, ESC/CM: 50.0%) with neither group being superior. Nonimprovers to the initial treatment caught up with the initial improvers in terms of depression scores and response and remission rates by the end of the treatment after being augmented with the respective other condition. CONCLUSIONS: CBASP and ESC/CM appear to be equally effective treatment options for chronically depressed outpatients. For nonimprovers to the initial treatment, it is efficacious to augment with medication in the case of nonresponse to CBASP and vice versa.

Anxiety disorders and physical comorbidity: increased prevalence but reduced relevance of specific risk factors for hospital-based mortality during a 12.5-year observation period in general hospital admissions.

Anxiety disorders (AD) are associated with an increase in physical comorbidities, but the effects of these diseases on hospital-based mortality are unclear. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital-based mortality differed between individuals with and without AD during a 12.5-year observation period in general hospital admissions. During 1 January 2000 and 30 June 2012, 11,481 AD individuals were admitted to seven General Manchester Hospitals. All comorbidities with a prevalence ≥ 1 % were compared with those of 114,810 randomly selected and group-matched hospital controls of the same age and gender, regardless of priority of diagnoses or specialized treatments. Comorbidities that increased the risk of hospital-based mortality (but not mortality outside of the hospital) were identified using multivariate logistic regression analyses. AD individuals compared to controls had a substantial excess comorbidity, but a reduced hospital-based mortality rate. Twenty-two physical comorbidities were increased in AD individuals compared with controls, which included cardiovascular diseases and their risk factors. The most frequent physical comorbidities in AD individuals were hypertension, asthma, cataract, and ischaemic heart disease. Risk factors for hospital-based mortality in AD individuals were lung cancer, alcoholic liver disease, respiratory failure, heart failure, pneumonia, bronchitis, non-specific dementia, breast cancer, COPD, gallbladder calculus, atrial fibrillation, and angina. The impact of atrial fibrillation, angina, and gallbladder calculus on hospital-based mortality was higher in AD individuals than in controls. In contrast, other mortality risk factors had an equal or lower impact on hospital-based mortality in sample comparisons. Therefore AD individuals have a higher burden of physical comorbidity that is associated with a reduced risk of general hospital-based mortality. Atrial fibrillation, angina, and gallbladder calculus are major risk factors for general hospital-based mortality in AD individuals.

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.

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.

Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions.

Schizophrenia is a major psychotic disorder with significant comorbidity and mortality. Patients with schizophrenia are said to suffer more type-2 diabetes mellitus (T2DM) and diabetogenic complications. However, there is little consistent evidence that comorbidity with physical diseases leads to excess mortality in schizophrenic patients. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital mortality differed between patients with and without schizophrenia in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 31 June 2012, 1418 adult patients with schizophrenia were admitted to three General Manchester NHS Hospitals. All comorbid diseases with a prevalemce ≥1% were compared with those of 14,180 age- and gender-matched hospital controls. Risk factors, i.e. comorbid diseases that were predictors for general hospital mortality were identified using multivariate logistic regression analyses. Compared with controls, schizophrenic patients had a higher proportion of emergency admissions (69.8 vs. 43.0%), an extended average length of stay at index hospitalization (8.1 vs. 3.4 days), a higher number of hospital admissions (11.5 vs. 6.3), a shorter length of survival (1895 vs. 2161 days), and a nearly twofold increased mortality rate (18.0 vs. 9.7%). Schizophrenic patients suffered more depression, T2DM, alcohol abuse, asthma, COPD, and twenty-three more diseases, many of them diabetic-related complications or other environmentally influenced conditions. In contrast, hypertension, cataract, angina, and hyperlipidaemia were less prevalent in the schizophrenia population compared to the control population. In deceased schizophrenic patients, T2DM was the most frequently recorded comorbidity, contributing to 31.4% of hospital deaths (only 14.4% of schizophrenic patients with comorbid T2DM survived the study period). Further predictors of general hospital mortality in schizophrenia were found to be alcoholic liver disease (OR = 10.3), parkinsonism (OR = 5.0), T1DM (OR = 3.8), non-specific renal failure (OR = 3.5), ischaemic stroke (OR = 3.3), pneumonia (OR = 3.0), iron-deficiency anaemia (OR = 2.8), COPD (OR = 2.8), and bronchitis (OR = 2.6). There were no significant differences in their impact on hospital mortality compared to control subjects with the same diseases except parkinsonism which was associated with higher mortality in the schizophrenia population compared with the control population. The prevalence of parkinsonism was significantly elevated in the 255 deceased schizophrenic patients (5.5 %) than in those 1,163 surviving the study period (0.8 %, OR = 5.0) and deceased schizophrenic patients had significantly more suffered extrapyramidal symptoms than deceased control subjects (5.5 vs. 1.5 %). Therefore patients with schizophrenia have a higher burden of physical comorbidity that is associated with a worse outcome in a 12-year follow-up of mortality in general hospitals compared with hospital controls. However, schizophrenic patients die of the same physical diseases as their peers without schizophrenia. The most relevant physical risk factors of general hospital mortality are T2DM, COPD and infectious respiratory complications, iron-deficiency anaemia, T1DM, unspecific renal failure, ischaemic stroke, and alcoholic liver disease. Additionally, parkinsonism is a major risk factor for general hospital mortality in schizophrenia. Thus, optimal monitoring and management of acute T2DM and COPD with its infectious respiratory complications, as well as the accurate detection and management of iron-deficiency anaemia, of diabetic-related long-term micro- and macrovascular complications, of alcoholic liver disease, and of extrapyramidal symptoms are of utmost relevance in schizophrenia.