Christoph U. Correll

Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care

The lifespan of people with severe mental illness (SMI) is shorter compared to the general population. This excess mortality is mainly due to physical illness. We report prevalence rates of different physical illnesses as well as important individual lifestyle choices, side effects of psychotropic treatment and disparities in health care access, utilization and provision that contribute to these poor physical health outcomes. We searched MEDLINE (1966 - August 2010) combining the MeSH terms of schizophrenia, bipolar disorder and major depressive disorder with the different MeSH terms of general physical disease categories to select pertinent reviews and additional relevant studies through cross-referencing to identify prevalence figures and factors contributing to the excess morbidity and mortality rates. Nutritional and metabolic diseases, cardiovascular diseases, viral diseases, respiratory tract diseases, musculoskeletal diseases, sexual dysfunction, pregnancy complications, stomatognathic diseases, and possibly obesity-related cancers are, compared to the general population, more prevalent among people with SMI. It seems that lifestyle as well as treatment specific factors account for much of the increased risk for most of these physical diseases. Moreover, there is sufficient evidence that people with SMI are less likely to receive standard levels of care for most of these diseases. Lifestyle factors, relatively easy to measure, are barely considered for screening; baseline testing of numerous important physical parameters is insufficiently performed. Besides modifiable lifestyle factors and side effects of psychotropic medications, access to and quality of health care remains to be improved for individuals with SMI.

Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents

CONTEXT Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic medication. OBJECTIVE To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure. DESIGN, SETTING, AND PATIENTS Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients [corrected] completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group. INTERVENTION Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks. MAIN OUTCOME MEASURES Weight gain and changes in lipid and metabolic parameters. RESULTS After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval [CI], 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, -1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL [95% CI, 6.9 to 24.3 mg/dL] P < .001 and 9.1 mg/dL [95% CI, 0.4 to 17.7 mg/dL] P = .046), triglycerides (24.3 mg/dL [95% CI, 9.8 to 38.9 mg/dL] P = .002 and 37.0 mg/dL [95% CI, 10.1 to 63.8 mg/dL] P = .01), non-high-density lipoprotein (HDL) cholesterol (16.8 mg/dL [95% CI, 9.3 to 24.3 mg/dL] P < .001 and 9.9 mg/dL [95% CI, 1.4 to 18.4 mg/dL] P = .03), and ratio of triglycerides to HDL cholesterol (0.6 [95% CI, 0.2 to 0.9] P = .002 and (1.2 [95% CI, 0.4 to 2.0] P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL [95% CI, 0.5 to 19.0 mg/dL]; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group. CONCLUSIONS First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.

Metabolic and cardiovascular adverse effects associated with antipsychotic drugs

Antipsychotic medications can induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. Although some drug receptor-binding affinities correlate with specific cardiovascular and metabolic abnormalities, the exact pharmacological mechanisms underlying these associations remain unclear. Antipsychotic agents with prominent metabolic adverse effects might cause abnormalities in glucose and lipid metabolism via both obesity-related and obesity-unrelated molecular mechanisms. Despite existing guidelines and recommendations, many antipsychotic-drug-treated patients are not assessed for even the most easily measurable metabolic and cardiac risk factors, such as obesity and blood pressure. Subsequently, concerns have been raised over the use of these medications, especially pronounced in vulnerable pediatric patients, among whom their use has increased markedly in the past decade and seems to have especially orexigenic effects. This Review outlines the metabolic and cardiovascular risks of various antipsychotic medications in adults and children, defines the disparities in health care and finally makes recommendations for screening and monitoring of patients taking these agents.

Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level

Physical disorders are, compared to the general population, more prevalent in people with severe mental illness (SMI). Although this excess morbidity and mortality is largely due to modifiable lifestyle risk factors, the screening and assessment of physical health aspects remains poor, even in developed countries. Moreover, specific patient, provider, treatment and system factors act as barriers to the recognition and to the management of physical diseases in people with SMI. Psychiatrists can play a pivotal role in the improvement of the physical health of these patients by expanding their task from clinical psychiatric care to the monitoring and treatment of crucial physical parameters. At a system level, actions are not easy to realize, especially for developing countries. However, at an individual level, even simple and very basic monitoring and treatment actions, undertaken by the treating clinician, can already improve the problem of suboptimal medical care in this population. Adhering to monitoring and treatment guidelines will result in a substantial enhancement of physical health outcomes. Furthermore, psychiatrists can help educate and motivate people with SMI to address their suboptimal lifestyle, including smoking, unhealthy diet and lack of exercise. The adoption of the recommendations presented in this paper across health care systems throughout the world will contribute to a significant improvement in the medical and related psychiatric health outcomes of patients with SMI.

Antipsychotic Combinations vs Monotherapy in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

CONTEXT Despite lacking evidence for its safety and efficacy, antipsychotic cotreatment is common in schizophrenia. OBJECTIVE To evaluate therapeutic and adverse effects of antipsychotic cotreatment vs monotherapy in schizophrenia. DATA SOURCES Cochrane Schizophrenia Group register and hand searches of relevant journals/conference proceedings. STUDY SELECTION Randomized controlled trials comparing antipsychotic monotherapy to cotreatment with a second antipsychotic. DATA EXTRACTION AND ANALYSIS Two authors independently extracted data. For homogenous dichotomous data, we calculated random effects, relative risk (RR), 95% confidence intervals (CIs), and numbers needed to treat (NNT). For continuous data, weighted mean differences were calculated. RESULTS In 19 studies (1229 patients) with 28 monotherapy and 19 cotreatment arms, antipsychotic cotreatment was superior to monotherapy regarding 2 a priori defined coprimary outcomes: less study-specific defined inefficacy (N = 22, n = 1202, RR = 0.76, CI = 0.63-0.90, P = .002, NNT = 7, CI = 4-17, P = .0008, I(2) = 78.9%) and all-cause discontinuation (N = 20, n = 1052, RR = 0.65, CI = 0.54-0.78, P < .00001). Results were consistent using Clinical Global Impressions thresholds of less than much (P = .006) and less than minimally (P = .01) improved. Specific psychopathology and adverse event data were insufficient to yield meaningful results. In sensitivity analyses, 5 efficacy moderators emerged: concurrent polypharmacy initiation, clozapine combinations, trial duration >10 weeks, Chinese trials, and second-generation + first-generation antipsychotics. In a meta-regression, similar dose combinations, second-generation + first-generation antipsychotics and concurrent polypharmacy initiation remained significant. CONCLUSIONS In certain clinical situations, antipsychotic cotreatment may be superior to monotherapy. However, the database is subject to possible publication bias and too heterogeneous to derive firm clinical recommendations, underscoring the need for future research.

Tardive dyskinesia and new antipsychotics.

Purpose of review To provide an update on tardive dyskinesia rates in patients treated with first-generation or second-generation antipsychotics in studies published since the last systematic review in 2004. Recent findings Across 12 trials (n = 28 051, age 39.7 years, 59.7% male, 70.9% white, followed for 463 925 person-years), the annualized tardive dyskinesia incidence was 3.9% for second-generation antipsychotics and 5.5% for first-generation antipsychotics. Stratified by age, annual tardive dyskinesia incidence rates were 0.35% with second-generation antipsychotics in children, 2.98% with second-generation antipsychotics versus 7.7% with first-generation antipsychotics (P < 0.0001) in adults, and 5.2% with second-generation antipsychotics versus 5.2% with first-generation antipsychotics (P = 0.865) in the elderly (based almost exclusively on one retrospective cohort study). In four adult studies (n = 2088, age 41.2 years, 71.2% male, 62.0% white), tardive dyskinesia prevalence rates were 13.1% for second-generation antipsychotics, 15.6% for antipsychotic-free patients, and 32.4% for first-generation antipsychotics (P < 0.0001). Summary Current evidence supports a lower tardive dyskinesia risk for second-generation antipsychotics than for first-generation antipsychotics. Tardive dyskinesia incidence was higher with second-generation antipsychotics than previously reported, possibly due to recent studies with relatively short mean durations and use of nonstandard tardive dyskinesia definitions.

Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = −3.6, p = 0.0003, r2 = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.

Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice

Second-generation antipsychotics (SGA) are being used more often than ever before in children and adolescents with psychotic and a wide range of non-psychotic disorders. Several SGA have received regulatory approval for some paediatric indications in various countries, but off-label use is still frequent. The aim of this paper was to perform a systematic review and critically evaluate the literature on cardiometabolic and endocrine side-effects of SGA in children and adolescents through a Medline/Pubmed/Google Scholar search of randomized, placebo controlled trials of antipsychotics in children and adolescents (<18 years old) until February 2010. In total, 31 randomized, controlled studies including 3595 paediatric patients were identified. A review of these data confirmed that SGA are associated with relevant cardiometabolic and endocrine side-effects, and that children and adolescents have a high liability to experience antipsychotic induced hyperprolactinaemia, weight gain and associated metabolic disturbances. Only weight change data were sufficiently reported to conduct a formal meta-analysis. In 24 trials of 3048 paediatric patients with varying ages and diagnoses, ziprasidone was associated with the lowest weight gain (-0.04kg, 95% confidence interval [CI]: -0.38 to +0.30), followed by aripiprazole (0.79kg, 95% CI: 0.54 to 1.04], quetiapine (1.43kg, 95% CI: 1.17 to 1.69) and risperidone (1.76kg, 95% CI: 1.27 to 2.25) were intermediate, and olanzapine was associated with weight gain the most (3.45kg, 95% CI: 2.93 to 3.97). Significant weight gain appeared to be more prevalent in patients with autistic disorder who were also younger and likely less exposed to antipsychotics previously. These data clearly suggest that close screening and monitoring of metabolic side effects is warranted and that the least cardiometabolically problematic agents should be used first whenever possible. A good collaboration between child- and adolescent psychiatrists, general practitioners and paediatricians is essential to maximize overall outcomes and to reduce the likelihood of premature cardiovascular morbidity and mortality.

Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices

BACKGROUND Despite increased cardiometabolic risk in individuals with mental illness taking antipsychotic medication, metabolic screening practices are often incomplete or inconsistent. METHOD We undertook a systematic search and a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) meta-analysis of studies examining routine metabolic screening practices in those taking antipsychotics both for patients in psychiatric care before and following implementation of monitoring guidelines. RESULTS We identified 48 studies (n=290 534) conducted between 2000 and 2011 in five countries; 25 studies examined predominantly schizophrenia-spectrum disorder populations; 39 studies (n=218 940) examined routine monitoring prior to explicit guidelines; and nine studies (n=71 594) reported post-guideline monitoring. Across 39 studies, routine baseline screening was generally low and above 50% only for blood pressure [69.8%, 95% confidence interval (CI) 50.9-85.8] and triglycerides (59.9%, 95% CI 36.6-81.1). Cholesterol was measured in 41.5% (95% CI 18.0-67.3), glucose in 44.3% (95% CI 36.3-52.4) and weight in 47.9% (95% CI 32.4-63.7). Lipids and glycosylated haemoglobin (HbA1c) were monitored in less than 25%. Rates were similar for schizophrenia patients, in US and UK studies, for in-patients and out-patients. Monitoring was non-significantly higher in case-record versus database studies and in fasting samples. Following local/national guideline implementation, monitoring improved for weight (75.9%, CI 37.3-98.7), blood pressure (75.2%, 95% CI 45.6-95.5), glucose (56.1%, 95% CI 43.4-68.3) and lipids (28.9%, 95% CI 20.3-38.4). Direct head-to-head pre-post-guideline comparison showed a modest but significant (15.4%) increase in glucose testing (p=0.0045). CONCLUSIONS In routine clinical practice, metabolic monitoring is concerningly low in people prescribed antipsychotic medication. Although guidelines can increase monitoring, most patients still do not receive adequate testing.

Antipsychotic Use in Children and Adolescents: Minimizing Adverse Effects to Maximize Outcomes

In children and adolescents, antipsychotics are being used in large and increasing quantities for a wide range of disorders and psychopathology, including psychotic, mood, and disruptive behavior disorders (1). Moreover, antipsychotics are also being used in children and adolescents to treat irritability associated with autism, tic disorders, obsessive-compulsive disorder, posttraumatic stress disorder and aggression; (2–4) however, the widespread use exceeds the database regarding efficacy as well as safety and tolerability in this population. At the time of this writing, only three antipsychotics— haloperidol, thioridazine, and risperidone—have been approved for use in children and adolescents by the U.S. Food and Drug Administration, with most randomized controlled data being available for risperidone. To appropriately use this potent class of medications, clinicians need to actively weigh the potential risks and benefits of individual agents. The present article aims to succinctly review available data on antipsychotic-related adverse effects in children and adolescents and provide a practical guide for the evaluation and management of antipsychotic-related adverse effects in this vulnerable population.