Increased mortality from somatic multimorbidity in patients with schizophrenia: a Danish nationwide cohort study.

OBJECTIVE: To investigate the association of single- and multimorbidity with mortality rates in patients with schizophrenia compared to the general population. METHOD: A nationwide cohort study including residents in Denmark between 1995 and 2015. The cohort was dichotomously divided by a diagnosis of schizophrenia. Somatic diseases included infections, cancer, endocrine, neurologic, cardiovascular, respiratory, digestive, skin, musculoskeletal, and urogenital diseases. Hazard ratios (HRs) and population attributable fractions (PAFs) were calculated. RESULTS: The cohort included 30 210 patients with schizophrenia [mean age (SD) = 32.6 (11.4), males = 57.2%], and 5 402 611 from the general population [mean age (SD) = 33.0 (14.5), males = 50.4%]. All number of somatic diseases were associated with an increased mortality in schizophrenia [HR = 16.3 (95% CI = 15.4-17.3) for 1 disease to 21.0 (95% CI = 19.1-23.0) for ≥5 diseases], using the general population with no somatic disease as reference. Across all somatic diseases, patients with schizophrenia showed a HR > 2, compared to the general population, and respiratory (PAF = 9.3%), digestive (PAF = 8.2%), and cardiovascular (PAF = 7.9%) diseases showed largest contributions to death. CONCLUSIONS: Patients with schizophrenia showed higher mortality on all levels of multimorbidity, and a doubled mortality rate across all somatic diseases, compared to the general population. The findings suggest that the clusters and trajectories of symptoms associated with schizophrenia is the main driver of the excess mortality.

Antipsychotic treatment effects on cardiovascular, cancer, infection, and intentional self-harm as cause of death in patients with Alzheimer's dementia.

BACKGROUND: Alzheimer's disease (AD), the most common disease causing dementia, is linked to increased mortality. However, the effect of antipsychotic use on specific causes of mortality has not yet been investigated thoroughly. METHODS: Utilizing the Danish nationwide registers, we defined a cohort of patients diagnosed with AD. Utilizing separate Cox regressions for specific causes of mortality, we investigated the effects of cumulative antipsychotic dosage after diagnosis and current antipsychotic exposure in the time period 2000-2011. RESULTS: In total, 45,894 patients were followed for 3,803,996 person-years. A total of 6129 cardiovascular related deaths, 2088 cancer related deaths, 1620 infection related deaths, and 28 intentional self-harm related deaths are presented. Current antipsychotic exposure increased mortality rate with HR between 1.92 and 2.31 for cardiovascular, cancer, and infection related death. Cumulative antipsychotic dosages were most commonly associated with increased rates of mortality for cardiovascular and infection as cause of death, whereas the associations were less clear with cancer and intentional self-harm as cause of death. CONCLUSIONS: We showed that cumulative antipsychotic drug dosages increased mortality rates for cardiovascular and infection as cause of death. These findings highlight the need for further investigations of long-term effects of treatment and of possible sub-groups who could benefit from treatment.

Modality shift effect in psychiatric disorders - a new look at an old paradigm.

BACKGROUND: There is a long tradition of reaction time studies in experimental psychopathology. Even though a diminishing interest in this paradigm has been seen over the last years, it is in line with more recent biological approaches to examine psychiatric disorders cross-diagnostically. METHODS: Patients (n=95) with a positive subtype of schizophrenia (n=22), a negative subtype of schizophrenia (n=18), a full major depressive episode (n=19), a full manic episode (n=16), or a mood disorder in remission (n=20) and subjects with no known psychiatric disorder (n=30), respectively, participated in a computer-based reaction time test consisting of four trials with 55 short visual and auditory stimuli presented in a random sequence. Each participant's median reaction time in milliseconds to light stimuli ipsimodal (light preceded by light) and cross-modal (light preceded by tone) and the difference between the two conditions (i.e. cross-modal retardation (CMR) to light) were recorded. Likewise, the median reaction time to tone stimuli ipsimodal and cross-modal and the difference between the two (CMR to tone) were recorded. RESULTS: Patient groups performed worse than the control group, with the exception of the group of patients with mood disorders in remission in both CMRs. When comparing patient groups, the schizophrenia negative subtype performed worse than the remission group in both CMRs. CONCLUSIONS: Our data support newer theories about underlying pathophysiological mechanisms and observable behavioural phenomena occurring across the different diagnostic categories, thereby supporting a dimensional approach in the diagnosis and clinical management.

Risk of psychiatric disorders, self-harm behaviour and service use associated with bariatric surgery.

OBJECTIVE: To investigate psychiatric outcomes after bariatric surgery, including suicide, self-harm, psychiatric service use and substance misuse. METHOD: Retrospective study on a Danish nationwide register-based cohort of 22 451 patients followed for 1 029 736 person-years. Data were analysed utilizing single- and multi-event Cox regression with non-operated controls with obesity and mirror-image analyses with the operated patient serving as their own controls. RESULTS: We showed an increased ratio of self-harm (hazard ratio [HR] 3.23, P < 0.001; incidence rate ratio [IRR] 1.71, P < 0.001), psychiatric service use (admissions IRR 1.52, P < 0.001; emergency room visits IRR 1.70, P < 0.001), psychiatric diagnosis (organic psychiatric disorders HR 1.78, P < 0.001; substance use HR 2.06, P < 0.001; mood disorders HR 2.66, P < 0.001; neurotic, stress-related and somatoform disorders HR 2.48, P < 0.001; behavioural syndromes HR 3.15, P < 0.001; disorders of personality HR 2.68, P < 0.001; behavioural and emotional disorders HR 6.43, P < 0.001), as well as substance misuse utilizing Cox regression as well as mirror-image analyses, as compared to non-operated. We did not find an increased suicide rate (HR 1.35, P = 0.658) among operated as compared to non-operated. CONCLUSION: Our study shows that undergoing bariatric surgery is associated with increases in self-harm, psychiatric service use and occurrence of mental disorders.

Cumulative dosages of antipsychotic drugs are associated with increased mortality rate in patients with Alzheimer's dementia.

OBJECTIVE: We wished to investigate the effects of cumulative dosages of antipsychotic drug in Alzheimer's dementia, when controlling for known risk factors, including current antipsychotic exposure, on all-cause mortality. METHOD: We utilized a nationwide, population-based, retrospective cohort study design with mortality as outcome in individual patients diagnosed with Alzheimer's dementia. RESULTS: We included a total of 45 894 patients and followed them for 3 803 996 person-years in total, presenting 27 894 deaths in the study population. Cumulative antipsychotic exposure increased mortality: more than 0 Daily Defined Dosage (DDDs) but less than 90: HR 2.20, 95% CI (2.14-2.27), P < 0.001; more than or equal to 90 DDDs but less than 365: HR 1.81, 95% CI (1.74-1.89), P < 0.001; more than or equal to 365 DDDs but less than 730: HR 1.38, 95% CI (1.428-1.49), P < 0.001; and more than or equal to 730 DDDs: HR 1.06, 95% CI (0.95-1.18), P = 0.322, when controlling for proxy markers of severity, somatic and mental comorbid disorders. CONCLUSION: In this nationwide cohort study of 45 894 patients diagnosed with Alzheimer's dementia, we found that cumulative dosages of antipsychotic drugs were associated with increased mortality rates.

Use of psychotropic drugs during pregnancy and breast-feeding.

OBJECTIVE: To write clinical guidelines for the use of psychotropic drugs during pregnancy and breast-feeding for daily practice in psychiatry, obstetrics and paediatrics. METHOD: As we wanted a guideline with a high degree of consensus among health professionals treating pregnant women with a psychiatric disease, we asked the Danish Psychiatric Society, the Danish Society of Obstetrics and Gynecology, the Danish Paediatric Society and the Danish Society of Clinical Pharmacology to appoint members for the working group. A comprehensive review of the literature was hereafter conducted. RESULTS: Sertraline and citalopram are first-line treatment among selective serotonin reuptake inhibitor for depression. It is recommended to use lithium for bipolar disorders if an overall assessment finds an indication for mood-stabilizing treatment during pregnancy. Lamotrigine can be used. Valproate and carbamazepin are contraindicated. Olanzapine, risperidone, quetiapine and clozapine can be used for bipolar disorders and schizophrenia. CONCLUSION: It is important that health professionals treating fertile women with a psychiatric disease discuss whether psychotropic drugs are needed during pregnancy and how it has to be administered.

Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials.

OBJECTIVE: To investigate the effect of second-generation antipsychotics on cognitive function in patients diagnosed with schizophrenia or schizoaffective disorder. METHOD: Multiple-treatments meta-analysis model. RESULTS: On cognitive composite score, sertindole was superior to clozapine, effect size (ES) 0.87; 95% CI: 0.12-1.63, quetiapine, ES 0.75; 95% CI: 0.00-1.49, and first-generation antipsychotics (FGAs), ES 0.89; 95% CI: 0.14-1.64. Analyses on each cognitive domain showed clozapine, ES 0.37; 95% CI: 0.00-0.74, olanzapine, ES 0.31; 95%CI: 0.02-0.59, quetiapine, ES 0.34; 95% CI: 0.03-0.64, and FGAs, ES 0.51; 95% CI: 0.18-0.83 performing poorer on verbal working memory than ziprasidone, as well as FGAs performing poorer than risperidone, ES 0.31; 95% CI: 0.04-0.58. On executive function, sertindole performed better than clozapine, ES 0.82; 95% CI: 0.06-1.58, olanzapine, ES 0.81; 95% CI: 0.07-1.55, quetiapine, ES 0.76; 95% CI: 0.02-1.51, ziprasidone, ES 0.90; 95% CI: 0.14-1.67, and FGAs, ES 0.83; 95% CI: 0.08-1.58. On processing speed, FGAs performed poorer than sertindole, ES 0.97; 95% CI: 0.02-1.91, and quetiapine, ES 0.36; 95% CI: 0.01-0.72. On long-term verbal working memory, clozapine performed poorer than olanzapine, ES 0.41; 95% CI: 0.06-0.76. On verbal fluency, FGAs performed poorer than olanzapine, ES 0.26; 95% CI: 0.01-0.50, and clozapine, ES 0.44; 95% CI: 0.06-0.81. Lastly, FGAs, ES 0.41; 95% CI: 0.04-0.78, and clozapine, ES 0.44; 95% CI: 0.05-0.83, performed poorer on visuospatial skill compared to olanzapine. CONCLUSION: The meta-analysis was able to detect some trends in the data analyzed, but did not show any drug having a uniform positive cognitive profile.

Changes in the diagnosed incidence of early onset schizophrenia over four decades.

OBJECTIVE: To explore changes in the diagnosed incidence of early onset schizophrenia (EOS) from 1971 to 2010. METHOD: Examination of incidence rates of schizophrenia in patients under 18 years of age, using a nationwide, population-based, mental health register. RESULTS: The age-standardized incidence rate (IR) of EOS in the period 1971-2010 was 3.17 (95% CI: 3.16, 3.18) per 100 000 person years in the age group 0-18 years, and 9.10 (95% CI: 9.00, 9.21) in the age group 12-18 years. In the period 1971-1993, the age-standardized IR of EOS was 1.80 (95% CI: 1.79, 1.82) per 100 000 person years in the age group 0-18 years, and 5.02 (95% CI: 4.92, 5.11) in the age group 12-18 years. In the period 1994-2010, the age-standardized IR of EOS was 5.15 (95% CI: 5.10, 5.20) per 100 000 person years in the age group 0-18 years, and 15.73 (95% CI: 15.22, 16.22) in the age group 12-18 years. The IR was higher for males than females in the periods 1971-1993 and 1971-2010, but in the period 1994-2010 the IR was higher for females than males. CONCLUSION: In recent years, the diagnosed incidence of EOS has increased and the usual male excess has disappeared. The changes in IR could be a result of changes in the diagnostic system, increased awareness of early psychosis or a reflection of actual underlying incidence of the disorder.

Effects of sertindole on cognition in clozapine-treated schizophrenia patients.

OBJECTIVE: To assess the cognitive effects of sertindole augmentation in clozapine-treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial. METHOD: A 12-week, double-blinded, randomized, placebo-controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of sertindole or placebo as adjunctive treatment to clozapine. RESULTS: Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF-F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF-F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations. CONCLUSION: The clozapine-treated patients displayed marked cognitive deficits at baseline. Adding sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.

Effect of the Palmaz balloon-expandable metallic stent in the trachea of pigs.

Endoscopically placed airway stents offer a viable option in primary or adjunctive treatment of severe pediatric tracheobronchial stenoses. Optimistic clinical reports substantiate the need for experimental studies to more effectively evaluate their clinical role. Development of an animal model comparable with the pediatric airway, amenable to endoscopic instrumentation, and capable of assessing effect on growth was the purpose of this pilot project. Nine 4-week-old piglets underwent endoscopic midtracheal placement of the balloon-expandable Palmaz metallic stent. Initial expansion and stent position were verified fluoroscopically and by direct videobronchoscopy. Serial endoscopic examination and stent reexpansion were performed 2 and 4 weeks after stent insertion. Animal weight, clinical tolerance, tracheal growth, and stent integrity were observed. Tracheal inflammation was evaluated grossly and by objective histopathologic criteria. Successful endotracheal stent placement and expansion were accomplished in all piglets. One pig died of anesthesia complications less than 24 hours after stent insertion. The remaining pigs exhibited excellent clinical tolerance through experiment completion. No detrimental effect on growth was noted, and effective dilatation of the stented tracheal region was observed. Stent incorporation was evident with significant mucosal ingrowth. Inflammation in the form of nonobstructing granulation tissue was present, and no evidence of necrosis or cartilage invasion was evident. The piglet trachea appears to be an excellent model for evaluation of expandable metallic airway stents in management of congenital and acquired tracheobronchial stenoses.