Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Quetiapine for the treatment of cocaine use disorder.

BACKGROUND: Cocaine addiction continues to be a significant healthcare issue, yet there are no FDA approved medications for the treatment of cocaine use disorder within the United States. METHODS: This 12-week, prospective, double-blind, randomized, placebo-controlled study examined the effectiveness of quetiapine (Seroquel XR™) versus matched placebo for the treatment of DSM-IV cocaine dependence in non-psychotic individuals. Subjects randomized to quetiapine (N = 29) were titrated up to a target dose of 400mg/day of quetiapine, while those in the placebo arm (N = 31) were given a matched placebo. All subjects had weekly clinic visits and a cognitive-behavioral therapy group session. Outcome measures included self-report of cocaine use and money spent on cocaine as well as urine drug screens (UDS). RESULTS: The drop-out rate was substantial at 68%. Logistic regression analysis did not find significant differences between groups in predicting end-of trial abstinence, defined as three consecutive weekly negative UDS (13.7% in the quetiapine group versus 12.9% in the placebo group; p = .92). Based upon a repeated measures analysis of variance, subjects in this study, as a whole, demonstrated reductions in their self-reported use of cocaine, self-reported money spent on cocaine, and number of days per week using cocaine. However, the quetiapine group did not differ significantly from the placebo group. CONCLUSIONS: This study did not find group differences between the quetiapine and placebo arms, suggesting that quetiapine is not an efficacious treatment for DSM-IV cocaine dependence.

The utility of the Dementia Severity Rating Scale in differentiating mild cognitive impairment and Alzheimer disease from controls.

The current study investigated the utility of the Dementia Severity Rating Scale (DSRS) total score to identify individuals at the earliest stage of impairment (ie, mild cognitive impairment/MCI). In addition, the authors sought to investigate how well the measure correlates with an expanded battery of cognitive tests and other measures of functional abilities. Of the 320 participants included in this study, 85 were normal controls, 96 had single-domain or multiple-domain amnestic MCI, and 139 had possible or probable Alzheimer disease (AD). Each participant underwent a thorough cognitive, neurological, and physical examination. Results from this study indicated that the DSRS total scores differed significantly between the 3 groups (P<0.001) and accurately identified 81% of the control group, 60% of the MCI group, and 78% of the AD group in a post hoc discriminant analysis. When combined with a brief cognitive measure (ie, Consortium to Establish a Registry for Alzheimer's Disease Word List 5 min recall test), the DSRS accurately identified 98% of the control group, 76% of the MCI group, and 82% of the AD group. Implications for clinical practice and proposed areas of future research are discussed.

Concomitant psychotropic medication use during treatment of schizophrenia patients: longitudinal results from the CATIE study.

OBJECTIVE: This study is a post hoc analysis of additions of antidepressants, anxiolytics, and sedative/hypnotics in treatment of patients randomized to antipsychotic treatment in the CATIE study, which recruited a chronic, "real world" schizophrenia sample and followed patients for up to eighteen months. We examined baseline predictors of initiation, time until initiation, and duration of treatment with antidepressants, anxiolytics, and sedative/hypnotics in CATIE study participants. METHODS: Psychotropic medication use by 1,449 CATIE study participants was documented at each study visit. Baseline demographic and clinical predictors of initiation, of time to initiation, and of duration of treatment of Concomitant Psychotropic Medications (CPMs) in each category (antidepressant, anxiolytic, and sedative/hypnotics) were identified through multiple regression analyses. RESULTS: Initiation of new CPMs post baseline by CATIE clinicians was moderately frequent, with 14.6% of patients receiving antidepressants, 13.7% receiving anxiolytics, and 11.2% receiving sedative/hypnotics. Predictors of antidepressant initiation (14.6% of group) were being female or white, and having a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence. Predictors of anxiolytic initiation (13.7% of group) were not being of African-American race, being separated/divorced, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse/dependence. CONCLUSIONS: Sedative/hypnotics, anxiolytics, and antidepressants were commonly used CPMs in schizophrenia during the CATIE trial, where patients were being seen frequently and antipsychotic treatment was optimized. Randomized, controlled clinical trials examining adjunctive use of antidepressants, anxiolytics and sedative/hypnotics to target symptoms of anxiety, depression, and insomnia in patients with schizophrenia are needed to adequately address the efficacy of these interventions.

Open trial of injectable risperidone for methamphetamine dependence.

We tested acceptability and tolerability of long-acting injectable risperidone for methamphetamine (MA) dependence in an open trial with the hypothesis that participants would reduce MA use. Participants were also evaluated for changes in neurocognitive function and psychiatric symptomology. Participants with MA dependence (n = 34) entered a 7-day open-label run-in with oral risperidone. Participants who tolerated oral risperidone (n = 22) were begun on long-acting injectable risperidone 25 mg intramuscular medication with subsequent injections q 2 weeks to a total of 4 injections. Participants remained on oral risperidone during the first 3 weeks after initial injection. Participants were offered 8 weekly individual sessions of relapse prevention counseling. At baseline, participants reported using MA an average of 4.1 days per week (SD = 1.9). Estimated mean days of MA use per week while on injections was 1.0 (95% confidence interval = 0.6-1.4), with days of use decreasing significantly from baseline through week 8 (ß = -0.27; 95% confidence interval: - 0.38--0.16; P < 0.001). Mean week 6 risperidone + 9-OH risperidone plasma levels for participants abstinent from MA from weeks 5 to 8 (n = 7, 63.6%) were 18.8 ng/mL (SD = 6.6) compared with 12.3 (SD = 4.0) for those not abstinent (n = 4; P = 0.075). No serious adverse events occurred. Verbal memory improved at week 4 compared with baseline (P < 0.05). Participation in this trial of injectable risperidone was associated with reductions in MA use as well as some positive benefits on verbal memory. However, these results are limited by the use of an open trial design with a high dropout rate. Risperidone deserves further study in controlled trials as a pharmacotherapy for MA dependence.

Quetiapine for the treatment of cocaine dependence: an open-label trial.

The monaminergic properties of second generation antipsychotics are prompting research on their use to treat cocaine dependence, with inconclusive results to date. In preliminary reports, the atypical antipsychotic quetiapine has shown promise for the treatment of substance abuse disorders. The primary objective of the current study was to assess the efficacy of quetiapine in reducing cocaine cravings and use in nonpsychotic subjects with cocaine dependence over 6 weeks of open-label treatment. Twenty-two cocaine-dependent, nonpsychotic men were initiated to open-label treatment with quetiapine (300-600 mg/d). The primary outcome measure was weekly self-report of cocaine cravings as assessed with the Brief Substance Craving Scale. Cocaine use was captured with a self-report Timeline Follow-back calendar, administered every 2 weeks. Side effect monitoring was conducted weekly, and movement disorders were assessed every 2 weeks. Intent-to-treat regression analyses (n = 22) indicated that the Brief Substance Craving Scale total score decreased significantly overtime (P < 0.001). Self-reports also suggested decreased cocaine use. There was no treatment-related increase in movement disorders, and most side effects were mild. However, all subjects did experience sedation, and several subjects dropped out because of it. What is more, weight increased significantly over time (P < 0.001). Open-label quetiapine treatment reduced cravings and improved some aspects of cocaine dependence in nonpsychotic individuals. Additional research is needed to confirm the current findings and to further delineate the role quetiapine may play in the treatment of cocaine use disorders.

Time to discontinuation and self-discontinuation of olanzapine and risperidone in patients with schizophrenia in a naturalistic outpatient setting.

BACKGROUND: Although efficacy of antipsychotic medications is well documented, their effectiveness in real-world practice is less robust. We examined the effectiveness of olanzapine and risperidone in schizophrenia in a naturalistic setting. METHODS: We used an electronic medical records database at a Veterans Affairs Medical Center to conduct a retrospective study of all new outpatient medication trials of olanzapine (n = 221) and risperidone (n = 274) over a 2-year period beginning January 1999 in patients diagnosed with schizophrenia or schizoaffective disorder. We defined medication discontinuation as a switch between the 2 agents (most switches) or self-discontinuation when a patient is without medication supply for longer than 1 month. RESULTS: Sample mean age (+/-SD) was 48.4 (+/-11.6) years; 91% were men. Discontinuation rates were high (73%), trending lower in olanzapine (70%) than risperidone (76%) (P = 0.12). Median time to discontinuation was 120 days (95% confidence interval [CI], 105-135), longer for olanzapine (150 days; 95% CI, 120-180) than risperidone (90 days; 95% CI, 71-109) (P = 0.04). Self-discontinuation was high (48%), with no significant difference between olanzapine (50%) and risperidone (46%). Switching rate was 25% and more likely to occur in risperidone (30%) than olanzapine (20%) (odds ratio, 1.72; 95% CI, 1.13-2.61). CONCLUSIONS: Effectiveness of antipsychotic medications in schizophrenia may be hampered by high rates of medication self-discontinuation in outpatient practice settings. Time to discontinuation suggests that olanzapine may be more effective than risperidone. Strategies to address causes of poor adherence should be incorporated in medication algorithms to optimize their effectiveness.

Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats.

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.

Organizational and unit factors contributing to reduction in the use of seclusion and restraint procedures on an acute psychiatric inpatient unit.

OBJECTIVE: The use of seclusion or restraint (S/R) as an emergency medical intervention to assist patients in regaining behavioral control continues to be an area of interest and concern for the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO), consistent with the ongoing concerns in the medical, patient advocate, legislative and legal communities. This study examined unit characteristics and the use of S/R in a VA facility with a secured, acute mental health unit before and after the promulgation of the JCAHO 2000 standards for utilization of S/R for behavioral health reasons. METHODS: Variables examined include patient acuity, patient census, number of admits, number of discharges, length of stay, number of nursing staff on duty, critical incidents and S/R hours per month. RESULTS: Results indicated S/R use began showing a notable decrease corresponding to the time that senior unit management began discussions of the new JCAHO standards. These reductions maintained statistical significance even after controlling for changes in unit environmental variables.

Abstinence, anticipation, reduction, and treatment (AART): a stepwise approach to the management of atypical antipsychotic side effects.

Antipsychotic medications, specifically the atypical agents, serve as first-line treatment options for patients with psychotic disorders, including individuals with schizophrenia or schizoaffective disorder. Atypical antipsychotics are also often prescribed off-label as either the primary treatment or as an adjunctive treatment for individuals with other disorders, including mood disorders without psychosis, behavioral disorders, and insomnia. Despite the generally superior side-effect profiles of atypical antipsychotics compared with typical antipsychotic agents, the atypicals have been associated with a number of serious side effects, including metabolic disorders, cardiovascular disorders, seizures, hyperprolactinemia, and movement disorders. This article offers a stepwise approach to the management of antipsychotic side effects: Abstinence, Anticipation, Reduction, and Treatment (AART). The steps in AART are hierarchical, but often overlap in the areas of risk prevention and minimization. The authors discuss issues relevant to each level of intervention and provide suggestions for integrating the AART approach into a comprehensive treatment plan. By incorporating this stepwise approach into their clinical decision-making process, prescribers may be able to optimize the risk:benefit ratio associated with the prescription of atypical antipsychotics.

Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial.

OBJECTIVE: This study examined the prevalence and correlates of concomitant psychotropic medications and use of anticholinergic drugs to treat schizophrenia. METHODS: Concomitant medication use was studied at baseline for participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. RESULTS: Of the 1,380 patients with baseline medication data, 82 percent were taking psychotropic medications. Of this group, 6 percent were taking two antipsychotics (one first generation and one second generation); 38 percent, antidepressants; 22 percent, anxiolytics; 4 percent, lithium, and 15 percent, other mood stabilizers. The strongest predictors of taking several medications were having anxiety or depression, being female, and taking second-generation antipsychotics. Conversely, African Americans and those with better neurocognitive functioning were less likely to be taking several concomitant psychotropic medications. In some cases symptoms that were likely targets of polypharmacy, such as depression, remained prominent, suggesting only partial response. CONCLUSIONS: Concomitant use of psychotropic medications to treat people with schizophrenia is common. Empirical data demonstrating the effectiveness of many of these agents for this population are lacking.

Combination antipsychotic therapy in clinical practice.

OBJECTIVE: Surveys have shown that antipsychotic drug combinations are frequently prescribed, yet few clinical studies have examined this practice. Experts have generally recommended antipsychotic combinations, especially those combining an atypical and a conventional antipsychotic, as a measure of last resort. A survey of prescribers was conducted to examine why combination antipsychotic therapy is being used in outpatient clinical practice. METHODS: Antipsychotic prescribing practices in the Department of Veterans Affairs Puget Sound Health System were reviewed for a six-month period during 1998-1999. Data on the use of atypical and conventional antipsychotics in combination were collected. RESULTS: A total of 1,794 patients received prescriptions for at least one antipsychotic medication during the study period, of which 715 (40 percent) received an atypical agent. Ninety-three patients (13 percent) who were treated with an atypical antipsychotic received a prescription for combination antipsychotic therapy for at least 30 days. In cases in which both a conventional and an atypical agent were prescribed, the primary reason given for adding a conventional antipsychotic medication was to treat persistent positive symptoms. The primary reason an atypical agent was added to a conventional agent was to switch medications to the atypical agent; however, a significant number of patients became "stuck" on the combination. CONCLUSIONS: The results of this study support previous reports of the frequent use of combination antipsychotic therapy in clinical practice. Prospective controlled trials are needed to substantiate perceptions that combination antipsychotic therapy is clinically beneficial and to provide guidelines on when and for whom antipsychotic polypharmacy should be considered.

Depression in Kraepelinian schizophrenia.

In order to improve our understanding of depression in chronic schizophrenia, depressive symptoms were assessed in institutionalized, so called Kraepelinian, patients with schizophrenia (N = 43). The patients had been ill and dependent on others for at least 5 years. Depressive symptoms as measured by the Hamilton Depression (HAM-D) scale were less prevalent in this population compared to published data on non-Kraepelinian patients. Only 5% of our Kraepelinian patients had a HAM-D score >/= 16. There was also a low prevalence of core depressive symptoms (depressed mood, suicidal ideation, and guilt). The relationship of depression to other dimensions of schizophrenia was explored. Depression had a modest positive correlation (r = 0.44) with general psychopathology as measured by the Brief Psychiatric Rating Scale (BPRS), but not with positive symptoms as measured by BPRS positive subscale or negative symptoms as measured by the Scale for the Assessment of Negative Symptoms (SANS). Depression also showed a modest positive correlation (r =.48) using the Simpson-Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS). These results indicate that in Kraepelinian schizophrenia, depression is not prevalent, even though patients are severely ill both in symptom and functioning domains. The results of our analysis support that Kraepelinian schizophrenia is a distinct subtype, and raise questions regarding the boundary between schizoaffective disorder and non-Kraepelinian schizophrenia. Finally, the low rate of depression observed revives the notion that preservation of core functional abilities is important for a depressive reaction to evolve in schizophrenia.