Tobias Gerhard

Broadened Use Of Atypical Antipsychotics: Safety, Effectiveness, And Policy Challenges

Atypical antipsychotic medications are increasingly used for a wide range of clinical indications in diverse populations, including privately and publicly insured youth and elderly nursing home residents. These trends heighten policy challenges for payers, patients, and clinicians related to appropriate prescribing and management, patient safety, and clinical effectiveness. For clinicians and patients, balancing risks and benefits is challenging, given the paucity of effective alternative treatments. For health care systems, regulators, and policymakers, challenges include developing the evidence base on comparative risks and benefits; defining measures of treatment quality; and implementing policies that encourage evidence-based practices while avoiding unduly burdensome restrictions.

Premature Mortality Among Adults With Schizophrenia in the United States

IMPORTANCE Although adults with schizophrenia have a significantly increased risk of premature mortality, sample size limitations of previous research have hindered the identification of the underlying causes. OBJECTIVE To describe overall and cause-specific mortality rates and standardized mortality ratios (SMRs) for adults with schizophrenia compared with the US general population. DESIGN, SETTING, AND PARTICIPANTS We identified a national retrospective longitudinal cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1, 2001, to December 31, 2007). The cohort included 1,138,853 individuals, 4,807,121 years of follow-up, and 74,003 deaths, of which 65,553 had a known cause. MAIN OUTCOMES AND MEASURES Mortality ratios for the schizophrenia cohort standardized to the general population with respect to age, sex, race/ethnicity, and geographic region were estimated for all-cause and cause-specific mortality. Mortality rates per 100,000 person-years and the mean years of potential life lost per death were also determined. Death record information was obtained from the National Death Index. RESULTS Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100,000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest mortality rate (74.8 per 100,000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5). Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths (119.7 per 100,000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100,000 person-years). Nonsuicidal substance-induced death, mostly from alcohol or other drugs, was also a leading cause of death (95.2 per 100,000 person-years). CONCLUSIONS AND RELEVANCE In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use. Excess deaths directly attributable to alcohol or other drugs highlight threats posed by substance abuse. More aggressive identification and management of cardiovascular risk factors, as well as reducing tobacco use and substance abuse, should be leading priorities in the medical care of adults with schizophrenia.

Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study

Objective To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes. Design Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality. Setting Nursing homes in the United States. Participants 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5. Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders. Results Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine. Conclusions Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Utilization of Pharmacologic Treatment in Youths with Attention Deficit/Hyperactivity Disorder in Medicaid Database:

Background: Little is known about longitudinal changes in drug utilization in attention-deficit/hyperactivity disorder (ADHD). Objective: To describe longitudinal trends in ADHD drug utilization and explore demographic differences among youths eligible for a large Southern state Medicaid program. Methods: A cross-sectional and longitudinal analysis of 10 years of claims data for all Medicaid beneficiaries younger than 20 years of age with 6 months or more of continuous insurance (N = 2,131,953) was conducted. Annual prevalence, incidence, and persistence in ADHD medication use (stimulants and atomoxetine) were estimated based on pharmacy claims and clinician-reported ADHD diagnosis. Results: ADHD prevalence increased 1.70-fold (95% CI 1.67 to 1.73) from 3.10% (21,904 of 705,573 beneficiaries) in fiscal year 1995–1996 to 5.27% (41,661 of 790,338) in 2003–2004, paralleled by a 1.84-fold (95% CI 1.81 to 1.87) increase in drug use to 4.63%. In 2003–2004, 0.69% of youths were diagnosed and newly started on drugs, reflecting a 1.38-fold (95% CI 1.33 to 1.43) increase over 1995–1996. One in five white males between the ages of 10 and 14 years (19.24%; 95% CI 18.81 to 19.67) received ADHD medication in 2003–2004. Males continued to be more likely diagnosed and treated than females (prevalence ratio [PR] in 2003–2004 = 2.96:95% CI 2.90 to 3.03 vs 3.82; 95% CI 3.69 to 3.96 in 1995–1996), as were whites when compared with Hispanics (PR in 2003–2004 = 2.65; 95% CI 2.57 to 2.73 vs 3.78; 95% CI 3.57 to 3.99 in 1995–1996) and blacks (PR in 2003–2004 = 1.81; 95% CI 1.76 to 1.85 vs 2.00; 95% CI 1.93 to 2.07 in 1995–1996). The most common starting age throughout the study period was 5–9 years, with 2.45% (95% CI 2.37 to 2.52) new ADHD drug users in 2003–2004, but largest increases in prevalence were observed in adolescents 15–19 years of age, with 2.47% (95% CI 2.38 to 2.55) in 2003–2004 compared with 0.45% (95% CI 0.41 to 0.49) in 1995–1996. Medication persistence varied, with only 49.9% (95% CI 49.4 to 50.5) of new users receiving drugs after 1 year, with yet another 17.2% (95% CI 16.4 to 18.0) continuing for 5 years or more. Conclusions: ADHD drug utilization continues to increase due to steady increases in diagnosis and chronic use of the drugs over several years. While racial, ethnic, and sex differences persist, the age distribution of drug users has shifted toward older children. These findings emphasize the need for studies that analyze determinants of treatment as well as outcomes, both benefits and risks, associated with long-term medication use.

Cardiac Safety of Central Nervous System Stimulants in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder

OBJECTIVES. Case reports have raised concerns about the risk of cardiac events associated with central nervous system stimulants for the treatment of attention-deficit/hyperactivity disorder. PATIENTS AND METHODS. This was a retrospective cohort study that used 10 years (July 1994 to June 2004) of Florida Medicaid claims data cross-linked to Vital Statistics Death Registry data. The cohort was composed of all youth 3 to 20 years old who were newly diagnosed with attention-deficit/hyperactivity disorder. Each month of follow-up was classified according to stimulant claims (methylphenidate, amphetamines, and pemoline) as current use (active stimulant claim), former use (time after periods of current use), or nonuse (time preceding the first stimulant claim, including follow-up of youth who were never exposed to stimulants). The studys end points were (1) cardiac death, (2) first hospital admission for cardiac causes or (3) first emergency department visit for cardiac causes. Risks were compared with time-dependent Cox regression analysis adjusting for various cardiac risk factors. RESULTS. During 124932 person-years of observation (n = 55383), 73 youth died, 5 because of cardiac causes. No cardiac death occurred during 42612 person-years of stimulant use. Hospital admissions for cardiac cause occurred for 27 children (8 during stimulant use, 11 during 35671 person-years of former use, and 8 during 46649 person-years of nonuse); and 1091 children visited the emergency department for cardiac causes (8.7 per 1000 person-years). Current stimulant use was associated with a 20% increase in the hazard for emergency department visits when compared with nonuse. No increased risk was found for periods of former use when compared with nonuse. CONCLUSIONS. Incidence rates of cardiac events requiring hospitalization were small and similar to national background rates. Stimulants were associated with an increase in cardiac emergency department visits. More evidence is needed that addresses the long-term risk/benefit of the various treatment options and the effect of other cardiac risk factors and comedications.

Comparative Safety of Antipsychotic Medications in Nursing Home Residents

To compare the risk of major medical events in nursing home residents newly initiated on conventional or atypical antipsychotic medications (APMs).

Stimulants and Cardiovascular Events in Youth with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE This study examined associations between stimulant use and risk of cardiovascular events and symptoms in youth with attention-deficit/hyperactivity disorder and compared the risks associated with methylphenidate and amphetamines. METHOD Claims were reviewed of privately insured young people 6 to 21 years old without known cardiovascular risk factors (n = 171,126). A day-level cohort analysis evaluated the risk of cardiovascular events after a diagnosis of attention-deficit/hyperactivity disorder in relation to stimulant exposures. Based on filled stimulant prescriptions, follow-up days were classified as current, past, and no stimulant use. Endpoints included an emergency department or inpatient diagnosis of angina pectoris, cardiac dysrhythmia, or transient cerebral ischemia (cardiac events) or tachycardia, palpitations, or syncope (cardiac symptoms). RESULTS There were 0.92 new cardiac events and 3.08 new cardiac symptoms per 1,000,000 days of current stimulant use. Compared with no stimulant use (reference group), the adjusted odds ratios of cardiac events were 0.69 (95% confidence interval 0.42-1.12) during current stimulant use and 1.18 (95% CI 0.83-1.66) during past stimulant use. The corresponding adjusted odds ratios for cardiac symptoms were 1.18 (95% CI 0.89-1.59) for current and 0.93 (95% CI 0.71-1.21) for past stimulant use. No significant differences were observed in risks of cardiovascular events (2.14, 95% CI 0.82-5.63) or symptoms (1.08, 95% CI 0.66-1.79) for current methylphenidate use compared with amphetamine use (reference group). CONCLUSIONS Clinical diagnoses of cardiovascular events and symptoms were rare and not associated with stimulant use. The results help to allay concerns over the cardiovascular safety of stimulant treatment for attention-deficit/hyperactivity disorder in young people without known pre-existing risk factors.

Cardiac Safety of Methylphenidate Versus Amphetamine Salts in the Treatment of ADHD

OBJECTIVES: Safety concerns about central nervous system stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) include adverse cardiac effects. This study aimed to compare the risk for cardiac events in users of methylphenidate and amphetamine salts. METHODS: A retrospective cohort design using claims data from the Florida Medicaid fee-for-service program representing a total of 2131953 children and adolescents was used. The analysis included all beneficiaries who were between 3 and 20 years of age, enrolled between July 1994 and June 2004, had at least 1 physician diagnosis of ADHD and were newly started on methylphenidate or amphetamine salts. Each month of follow-up was classified according to stimulant use into current use or former use. We defined cardiac events as first emergency department (ED) visit for cardiac disease or symptoms. Risk between current users of methylphenidate versus amphetamine salts and former users of drugs in these categories was compared by using a time-dependent Cox proportional hazard model that adjusted for differences in gender; race; age; year of the index date; disability; congenital anomalies; history of circulatory disease; history of hospital admission; and use of antidepressants, antipsychotics, and bronchodilators. RESULTS: A total of 456 youth visited the ED for cardiac reasons during 52783 years of follow-up. After adjustment for differences in covariates, the risk for cardiac ED visits was similar among current users of methylphenidate or amphetamines. Periods of former use had a similar risk between youth with an exposure history to methylphenidate or amphetamine. CONCLUSION: Exposure to methylphenidate and amphetamines salts showed similar risk for cardiac ED visits. Additional population-based studies that address manifestation of serious heart disease, especially after long-term use, dosage comparisons, and interactions with preexisting cardiac risk factors are needed to inform psychiatric treatment decisions.

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.

Comparative Effectiveness of Clozapine and Standard Antipsychotic Treatment in Adults With Schizophrenia.

OBJECTIVE The authors compared the effectiveness of initiating treatment with either clozapine or a standard antipsychotic among adults with evidence of treatment-resistant schizophrenia in routine clinical practice. METHOD U.S. national Medicaid data from 2001 to 2009 were used to examine treatment outcomes in a cohort of patients with schizophrenia and evidence of treatment resistance that initiated clozapine (N=3,123) and in a propensity score-matched cohort that initiated a standard antipsychotic (N=3,123). Interventions were new initiation of clozapine or a standard antipsychotic medication, defined as no exposure to the new medication in the prior 365 days. The primary outcome was hospital admission for a mental disorder. Secondary outcomes included discontinuation of the index antipsychotic, use of an additional antipsychotic, incidence of serious medical conditions, and mortality. RESULTS Initiation of clozapine was associated with a significantly decreased rate of psychiatric hospital admission (hazard ratio=0.78, 95% CI=0.69-0.88), index antipsychotic discontinuation (hazard ratio=0.60, 95% CI=0.55-0.65), and use of an additional antipsychotic (hazard ratio=0.76, 95% CI=0.70-0.82). Clozapine was associated with significantly increased incidence of diabetes mellitus (2.8% for clozapine vs. 1.4% for standard antipsychotic; hazard ratio=1.63, 95% CI=0.98-2.70), hyperlipidemia (12.9% for clozapine vs. 8.5% for standard antipsychotic; hazard ratio=1.40, 95%CI=1.09-1.78), and intestinal obstruction (0.9% for clozapine vs. 0.3% for standard antipsychotic; hazard ratio=2.50, 95% CI=0.97-6.44). CONCLUSIONS In adults with schizophrenia and evidence of treatment resistance, initiating clozapine compared with initiating a standard antipsychotic was associated with greater effectiveness on several important outcomes. Increasing the judicious use of clozapine is warranted together with vigilance to prevent and detect serious medical adverse effects.