Non-antipsychotic Medications Research Articles

Antipsychotic agents in anxiety disorders: An umbrella review.

Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale. The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.

Psychiatric and non-psychiatric polypharmacy among older adults with schizophrenia: Trends from a population-based study between 2000 and 2016.

Background: Schizophrenia is a severe psychiatric disorder associated with multiple psychiatric and non-psychiatric comorbidities. As adults with schizophrenia age, they may use many medications, i.e., have polypharmacy. While psychiatric polypharmacy is well documented, little is known about trends and patterns of global polypharmacy. This study aimed to draw a portrait of polypharmacy among older adults with schizophrenia from 2000 to 2016. Methods: This population-based cohort study was conducted using the data of the Quebec Integrated Chronic Disease Surveillance System of the National Institute of Public Health of Quebec to characterize recent trends and patterns of medication use according to age and sex. We identified all Quebec residents over 65years with an ICD-9 or ICD-10 diagnosis of schizophrenia between 2000 and 2016. We calculated the total number of medications used by every individual each year and the age-standardized proportion of individuals with polypharmacy, as defined by the usage of 5+, 10+, 15+, and 20+ different medications yearly. We identified the clinical and socio-demographic factors associated with polypharmacy using robust Poisson regression models considering the correlation of the responses between subjects and analyzed trends in the prevalence of different degrees of polypharmacy. Results: From 2000 to 2016, the median number of medications consumed yearly rose from 8 in 2000 to 11 in 2016. The age-standardized proportion of people exposed to different degrees of polypharmacy also increased from 2000 to 2016: 5+ drugs: 76.6%-89.3%; 10+ drugs: 36.9%-62.2%; 15+: 13.3%-34.4%; 20+: 3.9%-14.4%. Non-antipsychotic drugs essentially drove the rise in polypharmacy since the number of antipsychotics remained stable (mean number of antipsychotics consumed: 1.51 in 2000 vs. 1.67 in 2016). In the multivariate regression, one of the main clinically significant factor associated with polypharmacy was the number of comorbidities (e.g., Polypharmacy-10+: RR[2 VS. 0-1] = 1.4; 99% IC:1.3-1.4, RR[3-4] = 1.7 (1.7-1.8); RR[5+] = 2.1 (2.1-2.2); Polypharmacy-15+: RR[2 VS 0-1] = 1.6; 99% IC:1.5-1.7, RR[3-4] = 2.5 (2.3-2.7); RR[5+] = 4.1 (3.8-4.5). Conclusion: There was a noticeable increase in polypharmacy exposure among older adults with schizophrenia in recent years, mainly driven by non-antipsychotic medications. This raises concerns about the growing risks for adverse effects and drug-drug interactions in this vulnerable population.

An umbrella review on the use of antipsychotics in anxiety disorders: A registered report protocol.

Anxiety disorders, including panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), agoraphobia, and specific phobia, are among the most common psychiatric disorders. Although the traditional pharmacologic treatments for anxiety included barbiturates and then benzodiazepines, the introduction of tricyclic antidepressants, followed by the selective serotonin reuptake inhibitors (SSRIs), marked a tidal shift in the treatment of anxiety. Although not approved for treatment of anxiety disorders (with the exception of trifluoperazine) there is ongoing off-label, unapproved use of both first-generation “typical” antipsychotics (FGAs) and second-generation or “atypical” antipsychotics (SGAs) for anxiety. Although there have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of these reviews focused on SGAs, primarily the use of quetiapine in GAD. Given that there is little known about the potential benefits and short-and long-term risks of using antipsychotics in anxiety, there is a need for an umbrella review of systematic reviews and meta-analyses of the use of both FGAs and SGAs in anxiety disorders. The specific aims of this study are as follows: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) and other non-antipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects; and (3) Evaluate the short- and long-term risks and side effects of prescribing antipsychotics in anxiety disorders. The review is registered on PROSPERO (CRD42021237436). Since data extraction has not begun, there is not preliminary data to share.

Pharmacotherapy for elderly patients with delirium in a general ward setting: A retrospective study

Antipsychotic medications are widely used in patients with delirium. However, antipsychotics may lead to various adverse events including cardiac arrythmias, extrapyramidal side effects, and oversedation. This study aimed to investigate whether non-antipsychotic medications including ramelteon, suvorexant, and trazodone are useful for the treatment of elderly inpatients with delirium in a general ward setting. This was a retrospective cohort study using medical chart reviews of all consecutive inpatients with hyperactive forms of delirium who were admitted to a regional general hospital. The primary outcome of this study was to evaluate whether non-antipsychotic medication (ramelteon, suvorexant, and trazodone) is inferior, in terms of efficacy and safety, to antipsychotic medication in delirium treatment. Of 154 patients who consulted psychiatrists during the study period, 33 patients were diagnosed with hyperactive delirium. Of these patients, 21 were categorized into the antipsychotic medication group, and 12 were categorized into the non-antipsychotic medication group. The duration of delirium after pharmacological treatments was not statistically different between the two groups. However, the rates of adverse events related to psychotropic medications in the antipsychotic medication group were significantly higher than that in the non-antipsychotic medication group. This study demonstrated that, in the treatment of elderly patients with delirium, non-antipsychotic drugs, such as suvorexant, ramelteon, and trazodone, could be more useful than antipsychotics in terms of efficacy and safety.

Impact of Medicaid prescription copayments on use of antipsychotics and other medications in patients with schizophrenia

Objective: To assess the impact of Medicaid prescription copayment policies on anti-psychotic and other medication use among patients with schizophrenia.Method: The study sample included fee-for-service adult Medicaid patients with schizophrenia. Medicaid claims records from 2003–2005 from 42 states and D.C. were linked with county-level data from the Area Resource File and findings from a state Medicaid policy survey. Patient-level fixed-effects regression models examined the impact of increases in generic copayments and generic/brand copayment differentials on monthly use of anti-psychotic (overall and by generic/brand status) and other non-antipsychotic medications. Medications for hypertension, hyperlipidemia, and diabetes in sub-groups of patients with these comorbidities were also examined.Results: Prescription copayment changes had a statistically significant but small impact on anti-psychotic use. For instance, for every $1 increase in the minimum or generic copayment per prescription, there was a reduction of 1.4 anti-psychotic drug fills per 100 patient months (relative reduction = 1.9%). The generic/brand copayment differential increases also had a minimal impact in changing utilization of first-generation (generic) and second-generation (brand) anti-psychotics. Effects of copayment changes on non-anti-psychotic medication use were substantially higher; for each $1 generic copayment increase, there was a reduction of 23 non-anti-psychotic drug fills per 100 patient months (relative reduction = 10.1%). Similarly, for each $1 increase in the generic/brand copayment differential, there was a reduction of 15 non-anti-psychotic drug fills (relative reduction = 5.6%). Reductions in the number of prescriptions filled for antidiabetics, antihypertensives, and lipid-lowering agents were 4–11-fold higher than corresponding reductions for anti-psychotics.Limitations: Because federal law requires pharmacists to fill medications for Medicaid patients regardless of the ability to pay, these results may under-estimate the true impact of copayment increases.Conclusions: Medicaid prescription copayment increases resulted in only a minimal decline in anti-psychotic medication use, but much larger reductions in use of other medications, particularly cardiometabolic medications.

Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia

Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing. To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia. Systematic search of PubMed and PsycInfo until May 13, 2016. Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia. Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine. The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities. Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, -1.27 [95% CI, -2.35 to -0.19] to -0.23 [95% CI, -0.44 to -0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001), yet effect sizes were inversely correlated with study quality (correlation coefficient, -0.06; 95% CI, 0.01 to -0.12; P = .02). Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature.

Attitudes towards and rationale for antipsychotic polypharmacy among psychiatrists in Nigeria: Characteristics associated with high reported antipsychotic polypharmacy

Antipsychotic polypharmacy (APP) is commonplace despite lacking evidence of its effectiveness. We aimed to identify psychiatrists’ rationale for and attitudes towards APP and to determine if attitudes influence antipsychotic polypharmacy prescription rates in a survey of a nationally representative sample of Nigerian psychiatrists (of which a majority were senior trainees: 74.2%). Prescriber characteristics, practices and attitudes were compared in ‘high’ (>30%) vs. ‘low’ (≤30%) antipsychotic polypharmacy prescribers and results were adjusted for multiple comparisons. Altogether, prescribers reported utilizing antipsychotic polypharmacy in 36.2% of their patients. Compared to ‘low’ antipsychotic polypharmacy prescribers, ‘high’ prescribers were significantly more likely using first-generation antipsychotics (FGA) combination, to have attempted a switch to monotherapy in less patients, or been successful in doing so. ‘High’ and ‘low’ antipsychotic polypharmacy prescribers were equally moderately concerned about the effects of antipsychotic polypharmacy and also did not differ regarding reasons not justifying antipsychotic polypharmacy. In a multivariable, backward elimination logistic regression model, ‘low’ antipsychotic polypharmacy was associated with having successfully switched patients to monotherapy, whereas the ‘high’ antipsychotic polypharmacy was associated with preferring FGA+FGA combinations and aiming for a reduction of non-antipsychotic medications. Antipsychotic polypharmacy is common among psychiatrists in Nigeria, with ‘high’ and ‘low’ antipsychotic polypharmacy prescribers sharing similar concerns/attitudes, but differing regarding their primary aim for antipsychotic polypharmacy and in their specific antipsychotic polypharmacy use characteristics.

A Study of the Impact of Cannabis on Doses of Discharge Antipsychotic Medication in Individuals with Schizophrenia or Schizoaffective Disorder.

Patients with schizophrenia or schizoaffective disorder have a high prevalence of comorbid cannabis use disorder (CUD). CUD has been associated with poorer outcomes in patients. We compared doses of antipsychotic medications at the time of discharge from hospital among inpatients with schizophrenia or schizoaffective disorder with or without concurrent cannabis use. We reviewed the medical records of patients (N=8157) with schizophrenia or schizoaffective disorder discharged from the hospital between 2008 and 2012. The patients were divided into two groups; those with urine drug tests positive for cannabis and those negative for cannabis. Doses of antipsychotic medications were converted to chlorpromazine equivalents. Bivariate analyses were done with Student's t test for continuous variables and χ 2 test for categorical variables. Linear regression was carried out to adjust for potential confounders. Unadjusted analysis revealed that the cannabis positive group was discharged on lower doses of antipsychotic medication compared with the cannabis negative group (geometric mean chlorpromazine equivalent doses 431.22±2.20 vs 485.18±2.21; P<0.001). However, the difference in geometric mean chlorpromazine equivalent doses between the two groups was no longer significant after adjusting for sex, age, race, and length of stay (geometric mean difference 0.99; 95% CI 0.92-1.10). Though limited by lack of information on duration, amount and severity of cannabis use, as well as inability to control for other non-antipsychotic medications, our study suggests that cannabis use did not significantly impact on doses of antipsychotics required during the periods of acute exacerbation in patients with schizophrenia or schizoaffective disorder.

Comparative treatment patterns, resource utilization, and costs in stimulant-treated children with ADHD who require subsequent pharmacotherapy with atypical antipsychotics versus non-antipsychotics.

Although not indicated for attention-deficit/hyperactivity disorder (ADHD), atypical antipsychotics (AAPs) are commonly prescribed for children with ADHD. The treatment patterns, resource utilization, and costs associated with AAPs relative to non-antipsychotic medications have not been evaluated for children with ADHD. To compare treatment patterns, resource utilization, and costs to U.S. third party payers between stimulant-treated ADHD children who switch to or augment their stimulant treatment with AAPs (risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, paliperidone, and clozapine) compared with non-antipsychotic medications (atomoxetine, clonidine immediate-release (IR), guanfacine IR, dexmethylphenidate, mixed amphetamine salts, methylphenidate, lisdexamfetamine, and dextroamphetamine). Patients with at least one ADHD diagnosis (ICD-9-CM codes 314.00 or 314.01) and at least one stimulant medication claim between January 1, 2005 and December 31, 2009, were identified from a large U.S. commercial medical/pharmacy claims database. Patients were classified into the AAP cohort if they had a claim for an AAP following a stimulant fill or into the non-antipsychotic cohort if they had a claim for a non-antipsychotic medication after a stimulant fill and no AAP claims. The index date was defined as the date of the first fill of the AAP or a randomly selected eligible non-antipsychotic medication. Patients were eligible for inclusion if they were aged 6-12 as of the index date and had at least 18 months of continuous eligibility. Patients were excluded if they had a psychiatric diagnosis for which AAPs were approved by the U.S. Food and Drug Administration (FDA) or commonly used. Patients in the non-antipsychotic group were matched 1:1 to patients in the AAP group using a propensity score generated from a logistic regression that included demographics, treatments, resource utilization, and comorbidities during the 6 months prior to the index date. All outcomes were measured during the 12 months following the index date. Treatment patterns were compared using Kaplan-Meier (KM) estimates and Cox proportional hazards models. Annual resource utilization was compared using McNemar's test and Poisson regression. Costs were estimated from the perspective of U.S. third-party payers and were adjusted to 2010 dollars using the medical component of the Consumer Price Index. Both all-cause and mental health-related costs were examined and compared using Wilcoxon signed-rank tests. Of the 22,622 patients with ADHD identified to have used AAPs after a stimulant, 15,664 (69%) patients did not have a psychiatric diagnosis for which AAPs were FDA-indicated or commonly used. Among the 84,558 patients using non-antipsychotics after a stimulant, 81,397 (96%) did not have such psychiatric diagnoses. A total of 2,127 children in the AAP cohort and 16,508 children in the non-antipsychotic cohort met all of the study inclusion criteria. After propensity score matching, 1,857 children (358 switchers and 1,499 augmenters) were included in each of the matched cohorts. The baseline characteristics were well balanced between the matched cohorts. In the 12 months post-index date, children treated with AAPs were more likely to experience switching (KM: 17.2% vs. 10.4% at 12 months; HR = 1.75) and augmentation (KM: 43.4% vs. 22.4% at 12 months; HR = 2.62) than the non-antipsychotic group (both P less than 0.001). Rates of discontinuation were similar between groups (KM: 71.8% vs. 71.7% at 12 months; HR = 0.98, P = 0.600). The AAP cohort also had higher mean numbers of hospitalizations, emergency room visits, and outpatient visits (0.08 vs. 0.03, 0.34 vs. 0.25, 14.1 vs. 12.7 per patient, respectively; event rate ratios = 2.61, 1.33, and 1.11, respectively; all P less than 0.001). The AAP group also incurred higher all-cause mean medical, prescription drug, and total health care costs compared with the non-antipsychotic group ($3,090 vs. $2,238; $3,844 vs. $2,509; $6,934 vs. $4,748, respectively; all P less than 0.001). Patients in the AAP group also incurred higher mean total, medical, and drug costs related to mental health ($5,057 vs. $2,859; $1,555 vs. $964; $3,502 vs. $1,895, respectively; all P less than 0.001). Stimulant-treated children with ADHD who switched to or augmented with AAPs versus non-antipsychotics had significantly greater rates of subsequent augmentation and health care resource utilization as well as higher total health care costs. Further research and/or drug utilization reviews may be warranted to fully evaluate the clinical and economic outcomes of pediatric ADHD patients who are receiving AAPs.

Differences in Body Mass Index z-Scores and Weight Status in a Dutch Pediatric Psychiatric Population With and Without Use of Second-Generation Antipsychotics

Weight gain and metabolic adverse effects of second-generation antipsychotics (SGAs) have become a major concern, particularly in youth. However, the specific contribution of SGAs versus other medications or the underlying illness is unclear. In a chart review study of psychiatric outpatients aged ≤ 18 years treated with SGAs and psychiatric controls without lifetime SGA, use body mass index (BMI) z-scores between patients and controls were compared in the entire sample, patients without co-medications, diagnostic subgroups, and age subgroups. In patients with follow-up data, weight z-score change was calculated. Altogether, 592 Caucasian patients aged 4-18 (mean: 10.0) years with a psychiatric diagnosis were included. BMI z-scores in 96 youth treated with SGAs for 9.0 ± 6.1 months were significantly higher than in 496 patients without lifetime SGA use (0.81 ± 1.1 vs. 0.05 ± 1.2; p<0.0001). BMI z-score differences remained significant in all age groups <16 years old. In sub-analyses, results remained the same after eliminating patients on any co-medication (0.82 ± 1.2 vs. 0.23 ± 1.2; p<0.0001) and in patients with (0.75 ± 1.2 vs. 0.17 ± 1.1, p<0.0001) or without autism spectrum disorders (1.1 ± 1.0 vs. -0.02 ± 1.2, p<0.0001). Significantly more SGA-treated youth were obese (27.1% vs. 9.5%, odds ratio [OR]: 3.55, 95% confidence interval [CI]:2.07-6.08) or overweight (21.9% vs. 8.3%, OR: 3.11, 95%CI: 1.75-5.52). In 24 patients (92.3% antipsychotic-naïve) with 6.6 months follow-up, weight z-score increased significantly from -0.17 ± 1.5 to 0.25 ± 1.4 (p<0.0001) with 12.5% transitioning to overweight or obese status. These data show robust and significant differences in sex- and age-adjusted body weight and weight status in young pediatric Caucasian samples with and without use of SGAs independent of Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000 ) diagnosis and nonantipsychotic medications. Weight status and metabolic effects of SGAs require careful attention, especially in youth.

Polypharmacy With Second-Generation Antipsychotics: A Review of Evidence

The objective of this study was to review the prevalence of polypharmacy with second-generation antipsychotics (SGAs) in clinical practice, pharmacological reasons for such practice, and the evidence for and against such polypharmacy. Clinical trial reports, case reports, and reviews were identified by a PubMed literature search from 1966 through October 2006, with retrieved publications queried for additional references. We excluded reports on augmentation with non-antipsychotic medications and polypharmacy involving combinations of SGAs and first-generation (conventional) antipsychotics (FGAs) or combinations of two FGAs. We identified 75 reports concerning SGA polypharmacy, from which we extracted data on study design, sample size, medications, rating scales, outcome, and conclusions. Data from randomized controlled trials and larger case series are presented in detail and case reports are briefly discussed. Polypharmacy with SGAs is not uncommon, with prevalence varying widely (3.9% to 50%) depending on setting and patient population, despite limited support from blinded, randomized, controlled trials or case reports that employed an A-B-A (monotherapy-combination therapy-monotherapy) design and adequate dosing and duration of treatment. Rather than prohibiting or discouraging co-prescription of SGAs, needs of patients and clinicians should be addressed through evidence-based algorithms. Based on unmet clinical needs and modest evidence from case reports, combinations of two SGAs may merit future investigation in efficacy trials involving patients with schizophrenia who have treatment-resistant illness (including partial response) or who are responsive to treatment but develop intolerable adverse effects. Other areas that may merit future research are efficacy of SGA polypharmacy for schizophrenia accompanied by comorbid conditions (eg, anxiety, suicidal or self-injurious behavior, aggression) and for reducing length of stay in acute care settings.

Mortality Risk in Patients With Dementia Treated With Antipsychotics Versus Other Psychiatric Medications

Mortality rates in the year following new antipsychotic medication starts for neuropsychiatric symptoms of dementia were compared with rates after starts of other psychiatric medications. The retrospective, cohort study used national data from the Department of Veterans Affairs (fiscal years 2001-2005) on patients older than 65 years who began outpatient treatment with psychiatric medication following a dementia diagnosis (N=10,615). Twelve-month mortality rates were compared in patients taking antipsychotics and those taking other psychiatric medications. The authors controlled for confounding by using multivariate models and propensity-scoring methods. Secondary analyses included a no-medication group and examination of mortality causes. All groups taking antipsychotics had significantly higher mortality rates (22.6%-29.1%) than patients taking nonantipsychotic medications (14.6%). Adjusted mortality risks for atypicals and for combined atypical and conventional antipsychotics were similar to those for conventional antipsychotics. The mortality risk was significantly lower for nonantipsychotic medications than conventional antipsychotics. Except for anticonvulsants, the adjusted risks for all individual classes of nonantipsychotics were significantly lower than the risk for antipsychotics. Mortality risks did not change over 12 months. The proportions of patients taking antipsychotics who died from cerebrovascular, cardiovascular, or infectious causes were not higher than rates for those taking nonantipsychotic psychiatric medications. Antipsychotic medications taken by patients with dementia were associated with higher mortality rates than were most other medications used for neuropsychiatric symptoms. The association between mortality and antipsychotics is not well understood and may be due to a direct medication effect or the pathophysiology underlying neuropsychiatric symptoms that prompt antipsychotic use.