The Management of Posttraumatic Stress Disorder and Acute Stress Disorder: Synopsis of the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against. METHODS: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed. RECOMMENDATIONS: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Recycling N-acetylcysteine: A review of evidence for adjunctive therapy in schizophrenia.

INTRODUCTION: All symptoms in schizophrenia may impact functioning. Although Food and Drug Administration-approved medications typically benefit positive symptoms, negative symptoms are generally refractory to medication interventions. N-acetylcysteine's (NAC) influence on glutamatergic neurotransmission has been established. An emerging body of research has attempted to correlate this action with reduction in symptom severity, evaluating response in positive, negative, and cognitive symptom domains. METHODS: A literature review was performed to analyze available data on NAC intervention and improvement in the positive, negative, and cognitive symptom domains in patients with schizophrenia. Quality of evidence was systematically assessed to determine level of certainty in results. RESULTS: Three randomized controlled trials were identified. Across studies, negative symptoms decreased more with NAC compared to placebo; ranging between 11.9% and 24.1%. The assessment determined a low level of certainty regarding benefit of NAC on negative and cognitive symptoms and moderate certainty for NAC regarding findings of side effects and lack of benefit on positive symptoms. DISCUSSION: Consistent reporting of benefit in negative symptoms is found across studies of NAC intervention. These improvements are notable for symptoms that have generally remained refractory to medication intervention. Inconsistent benefit was reported in positive and cognitive symptoms. GRADE (grading of recommendations assessment, development and evaluation) assessment of current evidence indicates a low certainty of benefit for negative symptoms with standard use of NAC in patients with schizophrenia. However, a trial of this low-risk intervention may be warranted in patients with resistant negative symptoms and subsequent impaired functioning despite appropriate antipsychotic therapy as they may experience additional benefit in this symptom domain.

Evaluation of adherence in patients prescribed long-acting injectable antipsychotics: A comparison of biweekly versus monthly administered neuroleptics.

BACKGROUND: Long-acting injectable antipsychotics (LAIAs) have been developed to decrease medication nonadherence. LAIAs are usually given biweekly or monthly, with the exception of new 3-month and 6-week formulations. There has been no known evaluation regarding whether the frequency of LAIA formulation affects adherence. The purpose of this study is to evaluate whether there is a difference in adherence between LAIAs administered biweekly or monthly. METHODS: Eligible participants were identified from the Louis Stokes Cleveland VA electronic medical record as having an active prescription for a LAIA between September 1, 2009, and September 1, 2014. Participants were then evaluated using inclusion and exclusion criteria to determine study entrance. Medication possession ratios (MPRs) were calculated for each participant to determine adherence for comparison of objectives. Descriptive statistics and t tests were used to identify significant differences between groups. RESULTS: There were 128 participants enrolled based on eligibility criteria. There were no differences in MPRs for biweekly versus monthly administered LAIAs (0.98 versus 0.97, respectively; P = .691). No differences in adherence were observed between first- and second-generation LAIAs (0.98 versus 0.98, respectively; P = .975), or for risperidone LAI versus paliperidone palmitate (0.97 versus 0.99, respectively; P = .269). Hospitalizations were observed to decrease by 61% after LAIA initiation (P = .021). DISCUSSION: Based on the findings of this retrospective cohort review, there was no difference in adherence in patients prescribed biweekly versus monthly injected LAIAs. Patient preference and response, safety, tolerability, cost, and availability of follow-up appointments should be other factors to take into consideration for agent selection.

Dalfampridine: a medication to improve walking in patients with multiple sclerosis.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of dalfampridine. DATA SOURCES: A search of PubMed (1966-March 2012) was conducted using the words dalfampridine and Ampyra. Bibliographies of retrieved articles were reviewed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: All identified studies published in English involving the efficacy and safety of dalfampridine were reviewed. DATA SYNTHESIS: Dalfampridine (Ampyra) is a broad-spectrum potassium channel blocker that is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). Dalfampridine is the only medication approved for this indication. Efficacy has been demonstrated in 2 Phase 3 trials involving patients with MS. Dalfampridine 10 mg twice daily improved walking, as shown by a higher proportion of timed walk responders in the dalfampridine-treated group (42.9% and 35%) versus the placebo-treated group (9.3% and 8%) during the 2 studies (p < 0.001). The maximum recommended dose of dalfampridine is 10 mg twice daily; higher doses are associated with an increased risk of seizures. At doses greater than 10 mg twice daily, the frequency of other adverse reactions and discontinuations was greater and showed no additional benefit. The average wholesale price of a 10-mg dalfampridine tablet is $21.12, which would make a 1-month supply of therapy cost $1267.20. CONCLUSIONS: In clinical trials, dalfampridine improved walking speed in approximately one third of patients with MS. The risk of seizures appears to be dose-related and the incidence is low at doses of 10 mg twice daily. Because of the cost, dalfampridine should be reserved for patients who meet criteria for the drug and continued only if they have an adequate response.

Lurasidone: an atypical antipsychotic for schizophrenia.

OBJECTIVE: To provide a clinical overview of the antipsychotic lurasidone. DATA SOURCES: Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and EBSCO databases (through February 2012) using the key word lurasidone. The manufacturer provided information on unpublished Phase 2 and 3 trials. The Clinicaltrials.gov database was reviewed for the status of ongoing and upcoming trials. STUDY SELECTION AND DATA EXTRACTION: All clinical trials lasting longer than 3 weeks and published in the English language were selected for review. Additional documentation, including the product dossier, package insert, and poster presentations supplied by the publisher, was also evaluated. DATA SYNTHESIS: Lurasidone hydrochloride is an atypical antipsychotic that is approved for the treatment of schizophrenia. It is under investigation for treatment of bipolar I disorder. It should be administered with food, is pregnancy category B, is contraindicated for coadministration with strong CYP3A4 inducers and inhibitors, and requires dose adjustments with certain medications and in renal and hepatic impairment. Like other atypical antipsychotics, lurasidone possesses dopamine D(2) and serotonin 5-HT(2A) antagonism but exhibits little affinity for histamine H(1), α(1)-adrenergic, or cholinergic M1 receptors. Additionally, it is a potent 5-HT(7) antagonist, which may impact depression and cognition. Phase 3 trial results revealed that 40-80 mg administered once daily resulted in statistically significant improvements in schizophrenia symptomatology compared with placebo. Lurasidone's rate of metabolic adverse events is low relative to other atypical antipsychotics; however, this is offset by dose-dependent increases in somnolence, akathisia, and parkinsonism. CONCLUSIONS: Lurasidone has shown efficacy when compared to placebo in acute schizophrenia. Full characterization of the adverse effect profile and cognitive and affective benefits requires publication of trials with longer durations.

Pilot study to assess subjective and objective reporting of potential adverse drug reactions in older versus younger HIV-infected patients using antiretroviral therapy.

Limited data exist on tolerability of antiretroviral therapy (ART) in older HIV-infected patients compared to their younger counterparts. There is also concern for overlap of ART toxicities with concomitant conditions potentially leading to an increased burden of ART-related adverse drug reactions (ADRs). A prospective, descriptive-comparative study was conducted to compare incidence and severity of ADRs secondary to ART in older (≥ 50 years) versus younger (<50 years) HIV-infected patients. No differences were found in the presence or severity of subjective or objective ADRs between groups. The burden of intolerance appeared to be high for certain ADRs in both age groups. Regardless of age, subjects with certain concomitant illnesses had higher rates of potential ADRs. Providers need to be aware of patient characteristics that lead to increased rates of ART intolerance; for patients with an increased comorbidity burden, providers need to be attentive to the potential impact on ART tolerability.

Asenapine: a new antipsychotic option.

Asenapine is a new psychopharmacologic agent approved for the acute and maintenance treatment of schizophrenia and the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder. The efficacy of asenapine in treating schizophrenia was evaluated in four 6-week studies in which placebo and active controls (risperidone, olanzapine, and haloperidol) were used. Two 3-week placebo-controlled trials examined the efficacy of asenapine and active control (olanzapine) in the treatment of bipolar I disorder. Asenapine demonstrated efficacy in relation to placebo for 2 of the acute schizophrenia trials and both trials examining the acute treatment of bipolar I disorder. Several factors should be examined when considering asenapine therapy in relation to other antipsychotics including efficacy, atypicality of receptor binding, obstacles to administration and compliance, and finally cost. No efficacy advantage is evident with asenapine over other antipsychotic agents. Barriers to achieving compliance with asenapine include the recommendations of twice daily dosing, the need to avoid food and liquids for at least 10 minutes postadministration, the need for patient cooperation with sublingual administration, and the low bioavailability of the tablet if swallowed. Finally, no cost advantage is evident for using asenapine in comparison to the already available generic risperidone or other soon-to-be generic atypical antipsychotics.

Practical considerations for carbamazepine use in bipolar disorder.

Carbamazepine (CBZ) has a long history of successful use in epilepsy and, therefore, has a safety profile that is well characterised. Additionally, an extended-release formulation of CBZ (CBZ-ERC; Equetro, Shire US) has recently been approved for use in bipolar disorder. The most frequent adverse events associated with CBZ are somnolence, fatigue, dizziness and headache. Rash and leukopoenia may occur in approximately 10% of patients, but are benign and transient in most cases. Rare serious adverse effects include agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although changes in lipid profiles have been noted, hyperglycaemia does not occur with CBZ, and clinically significant weight gain is uncommon. Proper monitoring and careful titration of the extended-release formulation should allow for successful use of CBZ in psychiatric patients.

Catatonic schizophrenia and the use of memantine.

OBJECTIVE: To report a case of catatonic schizophrenia treated with memantine that resulted in a rapid reduction of catatonic symptoms. CASE SUMMARY: A 68-year-old male with catatonic schizophrenia presented with bizarre and catatonic behavior manifested by mutism, waxy flexibility, immobility, staring, nonresponsiveness to verbal commands, grimacing, rigidity, and posturing. During the course of his hospitalization, he was treated with memantine up to 10 mg/day. The catatonia responded rapidly and significantly to memantine. DISCUSSION: Few treatment options are available for the management of catatonia. Lorazepam is generally the agent that has been used most often and has had varying degrees of success. Our report adds to a recently published case that also suggested that memantine might be useful for the management of catatonic behaviors in a patient with schizophrenia. While its mechanism of action is unknown, it has been thought that glutamate antagonists, such as memantine, may be beneficial in catatonic schizophrenia due to a glutamatergic dysfunction present in catatonic patients. It also has been hypothesized that there is a decrease in gamma-aminobutyric acid released to the supplementary motor areas, resulting in less glutamate inhibition. This results in a net effect of glutamatergic hyperfunction in the striatum, which may produce catatonia. Based on this hypothesis, memantine would be beneficial as an N-methyl-D-aspartic acid antagonist to decrease the amount of glutamate in the striatum and thereby relieve symptoms of catatonia. However, these potential benefits must be weighed against recently reported adverse reactions associated with memantine use, namely, psychosis and seizures. CONCLUSIONS: Memantine produced a rapid and significant reduction in catatonic symptoms in our patient with catatonic schizophrenia.

Risperidone in the treatment of bipolar mania.

Atypical antipsychotic medications have assumed growing importance for the treatment of bipolar disorder, an illness that affects approximately 1.2%-3.7% of the general population in a given year. Current practice guidelines for the treatment of bipolar mania support the use of atypical antipsychotic medications as monotherapy or as a component of polytherapy, and in clinical settings the use of atypical antipsychotics to treat bipolar disorder is widespread. Risperidone is an atypical antipsychotic, sometimes referred to as a second-generation antipsychotic. The receptor-binding profile of risperidone, which includes potent antagonism of the serotonin 5-HT2(A), dopamine D(2), and alpha-adrenergic receptors, is believed to be related to positive effects on mood. The FDA-approved bipolar indications for risperidone include: 1) monotherapy for short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and 2) combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. This review of risperidone for bipolar mania will address the chemistry, pharmacodynamics, pharmacokinetics, and metabolism of risperidone, use with concomitant medications, clinical trials in bipolar mania, as well as safety and tolerability issues. Finally, dosing and administration are addressed as well as use for bipolar mania in geriatric, child, or adolescent patients.

Reassessing carbamazepine in the treatment of bipolar disorder: clinical implications of new data.

This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions. Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

Risperidone for bipolar disorders.

Atypical antipsychotic medications are a relatively new, increasingly prominent component of the treatment armamentarium for bipolar disorder -- a development that provides more options for potentially improved outcomes for patients and families affected by bipolar disorder. The US Food and Drug Administration-approved bipolar indications for risperidone include monotherapy for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Risperidone is also approved in over 30 countries worldwide for bipolar mania either as monotherapy, adjunct therapy, or both monotherapy and adjunct therapy. A number of controlled and open-label treatment trials have shown risperidone's efficacy and tolerability in the manic phase of bipolar disorder. Risperidone has also been reported to be useful in the longer-term treatment of bipolar disorder. This drug profile of risperidone for bipolar disorder will address the chemistry, pharmacodynamics, pharmacokinetics and metabolism of risperidone, clinical trials in bipolar disorder, postmarketing surveillance, safety, tolerability and regulatory issues. Finally, a discussion of potential future directions, a summary of key issues and information resources are provided.

Pharmacokinetics of quetiapine in elderly patients with selected psychotic disorders.

OBJECTIVE: To assess the pharmacokinetics and tolerability of quetiapine in elderly patients with selected psychotic disorders. STUDY DESIGN: This was a multicentre, open-label, 27-day, rising multiple-dose trial. Descriptive statistics summarised plasma quetiapine concentrations and pharmacokinetic parameters by trial day. A two-way analysis of variance was used to evaluate all pharmacokinetic parameters, and 90% confidence intervals of the mean differences were calculated. METHODS: Antipsychotic drugs taken prior to the study period were discontinued on day 1. Quetiapine treatment began on day 3. Doses were increased stepwise, starting at 25mg three times daily and reaching 250mg three times daily by day 21. PATIENTS: Twelve patients (age 63-85 years) with schizophrenia, schizoaffective disorder or bipolar disorder. MAIN OUTCOME MEASURES AND RESULTS: Key assessments included quetiapine plasma concentrations, and neurological and safety evaluations. Under steady-state conditions, the 100 and 250mg doses of quetiapine were not significantly different in terms of dose-normalised area under the plasma concentration-time curve within an 8-hour dose administration interval, or in dose-normalised minimum plasma concentration (C(min)) at the end of a dose administration interval. The morning C(min) values for the seven discrete dose amounts evaluated also increased linearly with dose. The apparent oral clearance, volume of distribution and half-life did not change as a function of dose. There were no serious adverse events. The most common adverse events were postural hypotension (n = 6), dizziness (n = 5) and somnolence (n = 4). CONCLUSIONS: While quetiapine was well tolerated at doses up to 250mg three times daily, the potential for reduced clearance, as well as the adverse effects of postural hypotension and dizziness, indicated that quetiapine should be introduced at lower doses and titrated at a relatively slower rate in patients > or =65 years.

Long-acting injectable risperidone.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of long-acting (LA) risperidone for the treatment of schizophrenia. DATA SOURCES: Information was selected from PubMed (1965-July 2004). Applicable scientific posters were also used. STUDY SELECTION AND DATA EXTRACTION: All published information on risperidone LA was considered. Material providing a comprehensive description was considered. DATA SYNTHESIS: Risperidone LA is the first long-acting, injectable atypical antipsychotic. It is dosed at 25-50 mg every 2 weeks. Adverse effects are similar to those seen with oral risperidone. A short-term study showed that risperidone LA is better than placebo in reducing the signs and symptoms of schizophrenia, and a long-term trial showed that stable schizophrenic patients can be switched from either oral or other injectable antipsychotic medications to risperidone LA. CONCLUSIONS: Risperidone LA is efficacious and safe in the treatment of schizophrenia.

Duloxetine: a dual reuptake inhibitor.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of duloxetine for the treatment of major depressive disorder (MDD). DATA SOURCES: Searches using MEDLINE and PsycINFO were conducted (1966 to November 2003). STUDY SELECTION AND DATA EXTRACTION: All duloxetine MDD information gathered was considered. Articles containing comprehensive information regarding duloxetine use for MDD were evaluated. DATA SYNTHESIS: Duloxetine is a serotonin-norepinephrine reuptake inhibitor being considered for treatment of MDD and stress urinary incontinence. While approved dosing ranges have not yet been determined, studies support the efficacy and safety of 40-60 mg twice daily for the treatment of acute MDD. Adverse effects have been of mild to moderate severity and are considered to be transient. Cardiovascular effects (increased heart rate or blood pressure), while present, do not appear to be clinically significant. Overall, duloxetine appears to be well tolerated. CONCLUSIONS: Duloxetine is a safe and effective antidepressant. Approval of this agent provides another treatment option for the management of MDD.

Comparative study of the development of diabetes mellitus in patients taking risperidone and olanzapine.

OBJECTIVES: A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk. METHODS: We conducted a retrospective analysis of the Veteran's Integrated Service Network 10 Veterans Affairs (VA) database. Data for patients receiving olanzapine, risperidone, haloperidol, or fluphenazine from January 1, 1997-December 31, 2000, were included. Diabetes was defined as any health system encounter associated with the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis for diabetes (250.xx) or prescription for a hypoglycemic agent. Data of patients with markers for diabetes within 1 year before their index date, female patients, racial groups other than Caucasian or African-American, and patients receiving clozapine were not analyzed. We performed a Cox regression, with antipsychotic therapy as a time-dependent covariate. Other covariates considered for inclusion in the final model were number of days supply of antipsychotic drug, age, race, psychiatric diagnoses, substance abuse, lithium, valproic acid, and other typical or atypical antipsychotic agents. RESULTS: Data for 5837 patients were analyzed. Overall rate of developing diabetes in the study population was 6.3% (368 of 5837 patients). Olanzapine therapy was associated with a significantly higher risk of development of diabetes compared with risperidone (hazard ratio [HR] 1.37, 95% confidence interval 1.06-1.76, p=0.016) while controlling for race, age, diagnosis, substance abuse, lithium, valproic acid, and other atypical antipsychotic agents. No differences in the rate of developing diabetes were detected between fluphenazine and risperidone (HR 1.11, p=0.69), or haloperidol and risperidone (HR 0.89, p=0.41). CONCLUSIONS: Olanzapine was associated with a 37% (HR 1.37) increased risk of development of diabetes compared with risperidone in a VA population, even after adjusting for other factors associated with the development of diabetes and temporal exposure to study drug. Because of limitations associated with database research, prospective studies should be conducted to corroborate these findings.