René Ernst Nielsen

Increasing mortality gap for patients diagnosed with schizophrenia over the last three decades — A Danish nationwide study from 1980 to 2010

OBJECTIVE The objective of this study is to describe secular trends in the average age of death in patients with schizophrenia and to compare these with the general population. METHODS This is a longitudinal linkage study from 1 January 1980 to 31 December 2010 using the Danish Psychiatric Research Register and the Danish Cause of Death Register. Data were analyzed using descriptive statistics and survival analysis. RESULTS The average age of death in the schizophrenia population (62.2 years; 95% CI, 61.9-62.5) was lower compared to the general population (73.4 years; 95% CI, 73.4-73.4), P<0.001. In the general population we found, for men, an average increase in the age of death of 0.28 years (95% CI, 0.27-0.28) per calendar year, and for women an increase in age of death of 0.31 years (95% CI, 0.31-0.32) per calendar year (both P<0.001). In contrast, age of death decreased in the schizophrenia population: the change in average age of death for males was 0.04 years (95% CI, -0.09 to 0.00) per calendar year (P<0.05), and the comparable estimate for females was -0.05 years (95% CI, -0.09 to 0.01) per calendar year (P<0.05). A similar pattern existed after acts of self-harm as cause of death were excluded from the analyses. Patients diagnosed with schizophrenia had an increased mortality rate compared with the general population (hazard ratio, 2.05; 95% CI, 2.01-2.09). CONCLUSIONS On average, patients with schizophrenia die younger than the general population, independent of intentional self-harm as cause of death.

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

To investigate the effect of second‐generation antipsychotics on cognitive function in patients diagnosed with schizophrenia or schizoaffective disorder.

Type 2 Diabetes Mellitus in Youth Exposed to Antipsychotics: A Systematic Review and Meta-analysis

IMPORTANCE Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern. OBJECTIVE To assess T2DM risk associated with antipsychotic treatment in youth. DATA SOURCES Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015. STUDY SELECTION Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months. DATA EXTRACTION AND SYNTHESIS Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk. MAIN OUTCOMES AND MEASURES The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls. RESULTS Thirteen studies were included in the meta-analysis, including 185,105 youth exposed to antipsychotics and 310,438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1,342,121 patients and 2,071,135 patient-years), and 8 studies included healthy controls (298,803 patients and 463,084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-52.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r(2) = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P ≤ .050) and less autism spectrum disorder diagnosis (P = .048) (r(2) = 0.21, P = .044). CONCLUSIONS AND RELEVANCE Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively.

Predictors of Clozapine Response in Patients With Treatment-Refractory Schizophrenia: Results From a Danish Register Study

Abstract We aimed to identify factors associated with greater clozapine response to guide targeted clozapine use. The study was based on data from the Danish Psychiatric Central Research Register and the National Prescription Database including schizophrenia patients initiating clozapine from 1997 to 2006. Cox regression was used to identify predictors of time to psychiatric hospitalization and all-cause discontinuation from first clozapine prescription. In a 2-year mirror-image design, multiple logistic regression models were used to identify predictors of psychiatric hospitalization. Among 633 schizophrenia patients starting clozapine, shorter time to admission was predicted by increasing number of different antipsychotics (hazard ratio [HR], 1.08/trial; confidence interval [CI], 1.01–1.15/trial) and admissions (HR, 1.04/admission; CI, 1.03–1.05/admission) before first clozapine prescription, earlier onset of schizophrenia (HR, 0.98/y; CI, 0.96–0.99/y), and lower clozapine dose (HR, 0.07/100 mg; CI, 0.03–0.13/100 mg). In the 2-year mirror-image model, during clozapine treatment, there was a significant reduction in bed-days (269.9 days [CI, 238.3–287.8 days] to 64.2 days [CI, 53.0–79.3 days], P < 0.001) and admissions (3.4 [CI, 3.1–3.6] to 2.2 [CI, 1.9–2.5], P < 0.011). Being admitted during clozapine treatment was also associated with more antipsychotic trials (odds ratio [OR], 1.11; CI, 1.00–1.22) and admissions before clozapine initiation (OR, 1.08; CI, 1.04–1.11) and female sex (OR, 1.84; CI, 1.31–2.58). Although the study design does not allow any causal inferences, all 3 models suggested a lower number of psychiatric hospitalizations and antipsychotic trials before clozapine initiation to be associated with greater clozapine response.

Characteristics and predictors of long-term institutionalization in patients with schizophrenia.

BACKGROUND Patients with schizophrenia requiring long-term institutionalization represent those with the worst outcome, leading to personal costs for patients and relatives and constituting a large economical burden for society. AIM To identify characteristics and predictors of outcome of institutionalized patients with schizophrenia. METHOD One-year follow-up cohort study, utilizing the Danish national registers, of all institutionalized and non-institutionalized patients with schizophrenia in Denmark with an ICD-10 lifetime diagnosis of schizophrenia (F20.0-F20.9) since 1969 and alive at the index date of January 1st 2006 (total number 22,395). RESULTS Compared with non-institutionalized patients, institutionalized patients (n=2188; 9.8%) had earlier onset of schizophrenia and lower scholastic achievements, were more often diagnosed with a hebephrenic subtype (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.95-2.80; p<0.001), received higher dosages of antipsychotics, more antipsychotic polypharmacy and more concomitant medications, and had more substance misuse and early retirement pension. In a logistic regression model adjusted for sex and age, institutionalized patients with schizophrenia had an increased risk of type II diabetes (AOR, 1.22; CI, 1.01-1.42; p<0.001), but the mean age of onset of type II diabetes did not differ. The mean patient age was higher in the institutionalized group (62.7 vs. 58.7 years; p=0.027), which was mainly driven by absence of death from suicide in the institutionalized group. Multivariate predictors of institutionalization included hebephrenic subtype, a diagnosis of epilepsy, early retirement pension, male sex, a greater proportion of prior hospitalization, and substance misuse. CONCLUSIONS Institutionalized patients with schizophrenia had a more complex and worse outcome of the disorder, except for less suicide, illustrated by lower scholastic achievement, receiving higher dosages of antipsychotic medications, more concomitant medications and more prior bed-days.

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.

Use of psychotropic drugs during pregnancy and breast-feeding

To write clinical guidelines for the use of psychotropic drugs during pregnancy and breast‐feeding for daily practice in psychiatry, obstetrics and paediatrics.

Neuroleptic malignant syndrome-an 11-year longitudinal case-control study.

Objective: To describe patients with neuroleptic malignant syndrome (NMS), to establish occurrence of NMS, to investigate risk factors of NMS, and to investigate mortality associated with NMS. Method: We conducted a longitudinal register linkage case-control study of NMS. Result: In health care registers covering the period from 1996 to 2007, we identified, among 224 372 patients with organic, psychotic, affective, or neurotic diagnosis, 83 patients with NMS, equivalent to an occurrence of 0.04%. Treatment with second-generation antipsychotics (SGAs) in the 3 months preceding admission increased the NMS risk (OR 4.66; 95% CI 1.96 to 11.10) and also first-generation antipsychotics (FGAs) of high potency (OR 23.41; 95% CI 5.29 to 103.61) and mid potency (OR 4.81; 95% CI 1.96 to 11.79), and depot antipsychotics (OR 4.53; 95% CI 1.60 to 12.80). Benzodiazepines (BDZs) also increased the risk of NMS (OR 3.43; 95% CI 1.68 to 12.80). NMS was associated with an increased mortality (HR 1.88; 95% CI 1.19 to 2.98) in patients, compared with sex-, age-, and diagnosis-matched control subjects, but no significant difference in mortality between patients and control subjects was observed after the initial 30 days (P = 0.27). Conclusions: The occurrence of NMS is low, and the prediction of NMS is difficult. Previous treatment with FGAs, SGAs, and BDZs was identified as a risk factor for developing NMS. NMS increased mortality within 30 days after NMS.

Pharmacological treatment of unipolar depression during pregnancy and breast-feeding—A clinical overview

Background: This overview is aimed at clinicians working with patients in the fertile age who suffer from depressive disorders. The study of adverse effects of antidepressants on the foetus is hampered by difficulty in distinguishing between the behavioural changes that are related to the disorder itself and changes that accompany its treatment with antidepressants. The current lack of solid scientific knowledge and the implications, mainly emotional, of treating pregnant or breast-feeding women often raise anxiety and cause concern among patients and clinicians. Methods: Currently available data are evaluated and clinical recommendations given. Results and Conclusions: Citalopram and sertraline can be used during pregnancy, while some controversy remains over in utero exposure to paroxetine and fluoxetine, which might be associated with an increased risk of foetal cardiovascular malformation. Less data is available concerning fluvoxamine and escitalopram use but current data does not indicate a specific risk. Citalopram, paroxetine and sertraline can be used during breast-feeding, while fluoxetine probably should be avoided. Nortriptyline, amitriptyline and clomipramine can be used during pregnancy and lactation, although data are more abundant for SSRI treatment. Venlafaxine can be used during pregnancy, while caution is advised during breast-feeding. Other antidepressants should be avoided because of lack of data on their effect. A strongly indicated lithium therapy should be continued. Close monitoring of lithium levels throughout pregnancy is mandatory, as is detailed foetal echocardiography in weeks 18–22 of gestation. Lithium should not be used during breast-feeding. Electroconvulsive therapy (ECT) is a valid option if indicated, both during pregnancy and breast-feeding.

Lithium and renal tumors: a critical comment to the report by Zaidan et al

To the Editor: Zaidan et al.1 reported a high prevalence of renal tumors in tertiarily referred patients previously treated with lithium and suffering from impaired renal function, as compared to the prevalence in patients who had similar renal impairment but who had not been treated with lithium. The authors concluded that their study provided clear evidence for a potential association between long-term lithium treatment and an increased risk of renal solid tumors. Owing to methodological shortcomings this interpretation is questioned by the members of the International Group for the Study of Lithium (IGSLi), an association of experts on long-term treatment with lithium (http://www.igsli.org).