Claire Chiang

Antipsychotics, Other Psychotropics, and the Risk of Death in Patients With Dementia: Number Needed to Harm

IMPORTANCE Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear. OBJECTIVE To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-control study was conducted in the Veterans Health Administration from October 1, 1998, through September 30, 2009. Participants included 90,786 patients 65 years or older with a diagnosis of dementia. Final analyses were conducted in August 2014. EXPOSURES A new prescription for an antipsychotic (haloperidol, olanzapine, quetiapine, and risperidone), valproic acid and its derivatives, or an antidepressant (46,008 medication users). MAIN OUTCOMES AND MEASURES Absolute change in mortality risk and NNH over 180 days of follow-up in medication users compared with nonmedication users matched on several risk factors. Among patients in whom a treatment with medication was initiated, mortality risk associated with each agent was also compared using the antidepressant group as the reference, adjusting for age, sex, years with dementia, presence of delirium, and other clinical and demographic characteristics. Secondary analyses compared dose-adjusted absolute change in mortality risk for olanzapine, quetiapine, and risperidone. RESULTS Compared with respective matched nonusers, individuals receiving haloperidol had an increased mortality risk of 3.8% (95% CI, 1.0%-6.6%; P < .01) with an NNH of 26 (95% CI, 15-99); followed by risperidone, 3.7% (95% CI, 2.2%-5.3%; P < .01) with an NNH of 27 (95% CI, 19-46); olanzapine, 2.5% (95% CI, 0.3%-4.7%; P = .02) with an NNH of 40 (95% CI, 21-312); and quetiapine, 2.0% (95% CI, 0.7%-3.3%; P < .01) with an NNH of 50 (95% CI, 30-150). Compared with antidepressant users, mortality risk ranged from 12.3% (95% CI, 8.6%-16.0%; P < .01) with an NNH of 8 (95% CI, 6-12) for haloperidol users to 3.2% (95% CI, 1.6%-4.9%; P < .01) with an NNH of 31 (95% CI, 21-62) for quetiapine users. As a group, the atypical antipsychotics (olanzapine, quetiapine, and risperidone) showed a dose-response increase in mortality risk, with 3.5% greater mortality (95% CI, 0.5%-6.5%; P = .02) in the high-dose subgroup relative to the low-dose group. When compared directly with quetiapine, dose-adjusted mortality risk was increased with both risperidone (1.7%; 95% CI, 0.6%-2.8%; P = .003) and olanzapine (1.5%; 95% CI, 0.02%-3.0%; P = .047). CONCLUSIONS AND RELEVANCE The absolute effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported and increases with dose.

Risk of mortality among individual antipsychotics in patients with dementia.

OBJECTIVE The use of antipsychotics to treat the behavioral symptoms of dementia is associated with greater mortality. The authors examined the mortality risk of individual agents to augment the limited information on individual antipsychotic risk. METHOD The authors conducted a retrospective cohort study using national data from the U.S. Department of Veterans Affairs (fiscal years 1999-2008) for dementia patients age 65 and older who began outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its derivatives (as a nonantipsychotic comparison). The total sample included 33,604 patients, and individual drug groups were compared for 180-day mortality rates. The authors analyzed the data using multivariate models and propensity adjustments. RESULTS In covariate-adjusted intent-to-treat analyses, haloperidol was associated with the highest mortality rates (relative risk=1.54, 95% confidence interval [CI]=1.38-1.73) followed by risperidone (reference), olanzapine (relative risk=0.99, 95% CI=0.89-1.10), valproic acid and its derivatives (relative risk=0.91, 95% CI=0.78-1.06), and quetiapine (relative risk=0.73, 95% CI=0.67-0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage revealed similar patterns. The mortality risk with haloperidol was highest in the first 30 days but decreased significantly and sharply thereafter. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during follow-up. CONCLUSIONS There may be differences in mortality risks among individual antipsychotic agents used for treating patients with dementia. The use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.

Trends in Antipsychotic Use in Dementia 1999-2007

CONTEXT Use of atypical antipsychotics for neuropsychiatric symptoms of dementia increased markedly in the 1990s. Concerns about their use began to emerge in 2002, and in 2005, the US Food and Drug Administration warned that use of atypical antipsychotics in dementia was associated with increased mortality. OBJECTIVE To examine changes in atypical and conventional antipsychotic use in outpatients with dementia from 1999 through 2007. DESIGN Time-series analyses estimated the effect of the various warnings on atypical and conventional antipsychotic usage using national Veterans Affairs data across 3 periods: no warning (1999-2003), early warning (2003-2005), and black box warning (2005-2007). SUBJECTS Patients aged 65 years or older with dementia (n = 254 564). MAIN OUTCOME MEASURES Outpatient antipsychotic use (percentage of patients, percentage of quarterly change, and difference between consecutive study periods). RESULTS In 1999, 17.7% (95% confidence interval [CI], 17.2-18.1) of patients with dementia were using atypical or conventional antipsychotics. Overall use began to decline during the no-warning period (rate per quarter, -0.12%; 95% CI, -0.16 to -0.07; P < .001). Following the black box warning, the decline continued (rate, -0.26%; 95% CI, -0.34 to -0.18; P < .001), with a significant difference between the early and black box warning periods (P = .006). Use of atypical antipsychotics as a group increased during the no-warning period (rate, 0.23; 95% CI, 0.17-0.30; P < .001), started to decline during the early-warning period (rate, -0.012; 95% CI, -0.14 to 0.11; P = .85), and more sharply declined during the black box warning period (rate, -0.27; 95% CI, -0.36 to -0.18; P < .001). Olanzapine and risperidone showed declining rates and quetiapine showed an increase during the early-warning period, but rates of use for all 3 antipsychotics declined during the black box warning period. In the black box warning period, there was a small but significant increase in anticonvulsant prescriptions (rate, 0.117; 95% CI, 0.08-0.16; P < .001). CONCLUSIONS Use of atypical antipsychotics began to decline significantly in 2003, and the Food and Drug Administration advisory was temporally associated with a significant acceleration in the decline.

Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease

IMPORTANCE As many as 60% of patients with Parkinson disease (PD) experience psychosis, 80% develop dementia, and the use of antipsychotics (APs) in the population with PD is common. The use of APs by patients with dementia in the general population is associated with increased mortality, but whether this risk extends to patients with PD remains unknown. OBJECTIVE To determine whether AP use in patients with PD is associated with increased mortality. DESIGN, SETTING, AND PARTICIPANTS This retrospective matched-cohort study used data from a Veterans Health Administration database from fiscal years 1999 to 2010 to examine the risk associated with AP use in a cohort of patients with idiopathic PD and recent stable physical health. The rates of 180-day mortality were compared in 7877 patients initiating AP therapy and 7877 patients who did not initiate AP therapy (matched for age ±2.5 years, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new nonpsychiatric medications). Data were analyzed from October 19, 2012, to September 21, 2015. MAIN OUTCOMES AND MEASURES Mortality rates at 180 days in those patients who initiated AP therapy compared with matched patients who did not use APs. Cox proportional hazards regression models were used with intent-to-treat (ITT) and exposure-only analyses. RESULTS The study population included 7877 matched pairs of patients with PD (65 women [0.8%] and 7812 men [99.2%] in each cohort; mean [SD] age, 76.3 [7.7] years for those who initiated AP therapy and 76.4 [7.6] years for those who did not). Antipsychotic use was associated with more than twice the hazard ratio (HR) of death compared with nonuse (ITT HR, 2.35; 95% CI, 2.08-2.66; P < .001). The HR was significantly higher for patients who used typical vs atypical APs (ITT HR, 1.54; 95% CI, 1.24-1.91; P < .001). Among the atypical APs used, HRs relative to nonuse of APs in descending order were 2.79 (95% CI, 1.97-3.96) for olanzapine, 2.46 (95% CI, 1.94-3.12) for risperidone, and 2.16 (95% CI, 1.88-2.48) for quetiapine fumarate. CONCLUSIONS AND RELEVANCE Use of APs is associated with a significantly increased mortality risk in patients with PD, after adjusting for measurable confounders. This finding highlights the need for cautious use of APs in patients with PD. Future studies should examine the role of nonpharmacologic strategies in managing psychosis in PD. In addition, new pharmacologic treatments that do not increase mortality in patients with neurodegenerative diseases need to be developed.

After the Black Box Warning: Predictors of Psychotropic Treatment Choices for Older Patients With Dementia

OBJECTIVES This study aimed to evaluate factors associated with the selection of pharmacological treatments often given as first-line treatments to elderly patients with neuropsychiatric symptoms associated with dementia. It also evaluated patterns of medication usage over time in the year preceding and three years after the U.S. Food and Drug Administration issued a black box warning for antipsychotic usage. METHODS A retrospective cohort consisted of 19,517 Veterans Affairs patients with diagnosed dementia and a new outpatient start with an antipsychotic agent (haloperidol, olanzapine, quetiapine, or risperidone) or valproic acid and its derivatives between May 1, 2004, and September 30, 2008. Patient and facility characteristics were examined for their association with the new starts of these medications. RESULTS Trends in the rate of fills for psychotropic medications varied, with yearly increases in the use of quetiapine, haloperidol, and valproic acid and decreasing use of olanzapine and risperidone. Predictors of haloperidol use included a new start in nonpsychiatric settings, prior benzodiazepine use, and any prior-year hospitalization. Anxiety disorder and major depression were predictive of not receiving haloperidol. Parkinsons disease was predictive of quetiapine use, whereas bipolar disorder was predictive of valproic acid use. Older age was predictive of use of antipsychotics rather than valproic acid. Urban facilities were less likely to use olanzapine, and significant regional variations were seen. CONCLUSIONS Important patient and facility characteristics were associated with initiating different psychotropic agents among elderly dementia patients. In addition, the rate of use and the factors predictive of use varied across the study years.

The association between race and gender, treatment attitudes, and antidepressant treatment adherence

We examined the associations between treatment attitudes and beliefs with race–gender differences in antidepressant adherence.

Adherence to Depression Treatment in Primary Care: A Randomized Clinical Trial

Importance Nonadherence to antidepressant medication is common and leads to poor outcomes. Early nonadherence is especially problematic. Objective To test the effectiveness of a psychosocial intervention to improve early adherence among older patients whose primary care physician newly initiated an antidepressant for depression. Design, Setting, and Participants The Treatment Initiation and Participation Program (TIP) was offered in a 2-site randomized clinical effectiveness study between January 2011 and December 2014 at primary care practices in New York, New York, and Ann Arbor, Michigan. Analyses began in February 2016. All participants were middle-aged and older adults (aged ≥55 years) who received newly initiated depression treatment by their primary care physician and recruited within 10 days of their prescription. Analyses were intention-to-treat. Interventions Participants were randomly assigned to the intervention (TIP) or treatment as usual. Participants in the TIP group identified and addressed barriers to adherence, including stigma, misconceptions, and fears about treatment, before developing a personalized adherence strategy. The Treatment Initiation and Participation Program was delivered in three 30-minute contacts scheduled during a 6-week period just after the antidepressant was prescribed. Main Outcomes and Measures The primary outcome was self-reported adherence on the Brief Medication Questionnaire, with adequate early adherence defined as taking 80% or more of the prescribed doses at 6 and 12 weeks. The secondary outcome was depression severity. Results In total, 231 middle-aged and older adults (167 women [72.3%] and 64 men [27.7%]) without significant cognitive impairment were randomly assigned to the TIP intervention (n = 115) or treatment as usual (n = 116). Participants had a mean (SD) age of 67.3 (8.4) years. Participants in the TIP group were 5 times more likely to be adherent at 6 weeks (odds ratio, 5.54; 95% CI, 2.57 to 11.96; &khgr;21 = 19.05; P < .001) and 3 times more likely to be adherent at both 6 and 12 weeks (odds ratio, 3.27; 95% CI, 1.73 to 6.17; &khgr;21 = 13.34; P < .001). Participants in the TIP group showed a significant earlier reduction (24.9%) in depressive symptoms (95% CI, 13.9 to 35.9; t337 = 4.46; adjusted P < .001). In both groups, participants who were 80% adherent at weeks 6 and 12 had a 15% greater improvement in depressive symptoms from baseline over the course of treatment (95% CI, −0.2 to −30; t369 = 1.93; P = .051). Conclusions and Relevance The Treatment Initiation and Participation Program is an effective intervention to improve early adherence to pharmacotherapy. Improved adherence can promote improvement in depression. Trial Registration clinicaltrials.gov Identifier: NCT01301859

Mortality Risk With the Use of Atypical Antipsychotics in Later-Life Bipolar Disorder:

Introduction: In recent years, concerns about the use of antipsychotic medications in dementia have grown. There is limited data on mortality risk of atypical antipsychotics for other psychiatric disorders of later life such as bipolar disorder. Methods: Data were derived from the national Department of Veterans Affairs registries for older patients with bipolar disorder (>65 years) with a new start of an atypical antipsychotic (risperidone, olanzapine, or quetiapine) or valproic acid and derivatives during fiscal years 2001-2008. Six-month mortality rates were compared for individual drug groups. Results: The sample included 4717 patients. The risperidone cohort had the highest mortality rate (11.8 per 100 person-years) with the quetiapine and valproic acid cohorts having the lowest (5.3 and 4.6 per 100 person-years, respectively). Various methods to adjust for baseline differences including propensity models showed similar patterns. Conclusions: Among older patients with bipolar disorder, there may be differences in mortality risks among individual antipsychotic agents.

Antipsychotic Use and Physical Morbidity in Parkinson Disease

OBJECTIVE To determine if antipsychotic (AP) use in Parkinson disease (PD) patients is associated with increased physical morbidity. METHODS Veterans Health Administration data (1999-2010) was used to examine physical morbidity risk associated with AP use in idiopathic PD patients with stable recent physical health. We compared 180-day morbidity rates in patients initiating an AP with matched non-AP users who survived for 180 days (matched on age, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new non-psychiatric medications; covarying for psychosis). Outcomes were 180-day emergency department (ED), and inpatient and outpatient visits. RESULTS There were 6,679 matched PD pairs. Any AP use was associated with an increased risk of ED visit (HR: 1.64, 95% CI: 1.51, 1.77), inpatient care (HR: 1.58, 95% CI: 1.46, 1.71), and outpatient visits (IRR: 1.08, 95% CI: 1.05, 1.12). The risk was significantly higher for atypical AP use compared with nonuse for all three morbidity outcomes, and was similar for atypical and typical AP use. CONCLUSIONS Any AP use, and atypical AP use, are associated with significantly increased physical morbidity risk in PD patients, as evidenced by increased ED, inpatient, and outpatient visits. These findings, which require replication, extend the risk associated with use of APs in this population from mortality to a broader range of adverse outcomes, and further highlight the need to use APs cautiously in PD patients.

Unintended Consequences of Adjusting Citalopram Prescriptions Following the 2011 FDA Warning

OBJECTIVES In 2011, the U.S. Food and Drug Administration (FDA) issued a safety announcement cautioning providers against prescribing citalopram above 40 mg per day given concerns for QT prolongation. We assessed the impact of a health system quality improvement initiative to identify patients taking higher than the recommended dose of citalopram. DESIGN Retrospective cohort study. SETTING Nine primary care clinics within the University of Michigan from March 2012 to February 2013. PARTICIPANTS Adult patients taking a higher-than-recommended dose of citalopram following the FDA warning in 2011 (N = 199). MEASUREMENTS Frequency of EKG monitoring, clinical factors associated with patients whose citalopram dose or use was adjusted, and potential impact of these changes on overall health care utilization was assessed. RESULTS In patients prescribed higher-than-recommended doses of citalopram and who received a note from a pharmacist regarding the FDA warnings, only 8.5% received electrocardiogram (EKG) monitoring. Patients who were converted to an alternative antidepressant from citalopram were more likely to receive subsequent new prescriptions for benzodiazepines and sedative hypnotics (χ2 = 7.9, p = 0.048). Patients who had any adjustments to their antidepressant medication had greater overall health care utilization (OR: 25.0; 95% CI: 5.7-109.6; p < 0.001) than patients remaining on the same dose of citalopram. CONCLUSIONS Despite a targeted quality intervention to address the FDA warning regarding citalopram, the warning was associated with low levels of EKG monitoring, increased anxiolytic and sedative medication use, and higher healthcare utilization. This finding may represent destabilization of patients on previously therapeutic doses of their antidepressant and an unintended consequence of the FDA warning.