The Journal of Clinical Psychiatry

Published by Physicians Postgraduate Press
Online ISSN: 1555-2101
Publications
Article
Our mental health care system fails to serve the very people whose suffering that system ostensibly exists to alleviate. This article relates the stories of 3 people who fell through the cracks of this system. An alternative approach, the Integrated Services Agency (ISA), has been implemented in California and offers hope to persons with schizophrenia. The ISA approach focuses on the expressed needs of the members it exists to serve, and both members and staff have experienced changes in their roles and expectations. Staff and members have learned that engagement with the "outside world" involves taking risks but that risk avoidance only perpetuates the status quo. The ISA approach rewards growth and patients' being well rather than rewarding docility and illness. Medication is neither ordered nor assigned, but chosen in a collaboration between staff and members. ISAs have returned care to the mental health care system.
 
Article
It has been suggested that the histamine subtype 3 receptor inverse agonists such as MK-0249 might be effective in treating attention-deficit/hyperactivity disorder (ADHD). We evaluated the effects of MK-0249 in adults with ADHD. A randomized, double-blind, placebo-controlled, incomplete block, 2-period crossover study of MK-0249 5-10 mg/d and osmotic-release oral system (OROS) methylphenidate 54-72 mg/d (active comparator) was performed in 72 men and women aged ≥ 18 to ≤ 55 years who met DSM-IV criteria for ADHD of either inattentive or combined subtype and who had a chronic course of behavior disorder. The study was conducted from August 2007 through April 2008 at 6 US sites. Primary efficacy was assessed by the mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score after 4 weeks of treatment. Change from baseline in AISRS at week 4 for MK-0249 was not different from placebo (P = .341), whereas a significant benefit was seen for OROS methylphenidate versus placebo (P < .001). Analysis of secondary end points, including the Conners Adult ADHD Rating Scales, showed results consistent with the AISRS. A similar percentage of patients reported adverse events for MK-0249 compared with placebo (73% versus 69%, respectively). However, a greater percentage of patients reported insomnia as an adverse event with MK-0249 treatment compared with placebo (32% versus 11%, respectively). MK-0249 10 mg/d is not effective for the treatment of adult ADHD. ClinicalTrials.gov identifier: NCT00475735.
 
Article
ABT-089, an α4β2 neuronal nicotinic receptor partial agonist (generic name pozanicline), has demonstrated efficacy in adults with attention-deficit/hyperactivity disorder (ADHD) at doses of 40 mg once daily and 40 mg twice daily. The purpose of this exploratory pilot study was to obtain initial safety, tolerability, and efficacy data for an ABT-089 80-mg once-daily regimen to inform a decision of whether to include an 80-mg once-daily dose regimen in subsequent, definitive (phase 3) efficacy studies. This phase 2, randomized, double-blind, parallel-group, placebo-controlled pilot study was conducted at 12 sites from March to August 2008. A screening/washout period of up to 4 weeks was followed by an 8-week double-blind treatment period. Eligible subjects met DSM-IV-TR criteria for ADHD and were randomized in a 1:1:1 ratio to ABT-089 40 mg once daily, ABT-089 80 mg once daily, or placebo. The primary efficacy variable was reduction from baseline to the final evaluation in the investigator-rated Conners' Adult ADHD Rating Scale for each active treatment group versus placebo. Safety assessments and pharmacokinetic sampling were also conducted. A total of 160 subjects were randomized, with 137 (86%) completing the trial. No statistically significant treatment effects were observed with either ABT-089 dose for any efficacy measures. The most commonly reported adverse events in the active treatment groups were nasopharyngitis (6.6%), upper respiratory tract infection (6.6%), and somnolence (5.7%). The incidence of adverse events did not differ significantly between active groups and placebo. There were no clinically significant laboratory, electrocardiogram, or physical examination findings. ABT-089 was generally well tolerated at doses up to 80 mg. Because ABT-089 is a weak partial neuronal nicotinic receptor agonist, the results may not predict the potential efficacy for other, more potent neuronal nicotinic receptor agonists. ClinicalTrials.gov identifier: NCT00640185.
 
Article
Depression is common in many chronic physical health disorders, but the nature and extent of physical health comorbidities in depression, particularly within large population-based samples of patients, and how these comorbidities relate to factors such as age, sex, and social deprivation, are unknown. We aimed to assess the nature and extent of multiple physical health comorbidities in primary care patients with depression within a large and representative Scottish dataset. This study was a cross-sectional secondary data analysis of 314 primary care practices in Scotland (from the Primary Care Clinical Informatics Unit at the University of Aberdeen, Scotland, March 31, 2007), including 143,943 people with depression and 1,280,435 controls. The outcomes assessed were 32 common chronic physical health conditions, adjusted for age, sex, and social deprivation. Depression was defined as a Read code for depression recorded within last year and/or 4 or more antidepressant prescriptions (excluding low-dose tricyclic antidepressants) within the last year. Individuals in primary care with depression were more likely than individuals without depression to have every one of the 32 comorbid physical conditions we assessed, even after adjusting for age, sex, and deprivation. The depression group was also significantly more likely to have multiple levels of comorbidity, including 2 physical health conditions (OR = 1.55; 95% CI, 1.53-1.58), 3 physical health conditions (OR = 1.84; 95% CI, 1.81-1.87), 4 physical health conditions (OR = 2.06; 95% CI, 2.01-2.11; P < .001), and 5 or more physical health conditions (OR = 2.65; 95% CI, 2.59-2.71; P < .001). Depression in primary care is associated with a very wide range of physical health comorbidities and considerable medical burden. The nature and extent of this multimorbidity and the important association with social deprivation have not been previously described within a large and representative dataset of routine primary care data. Our findings have important implications for the integrated management of depression and physical health problems in the United Kingdom and throughout the world. © Copyright 2014 Physicians Postgraduate Press, Inc.
 
Article
A 26-week, double-blind, placebo-controlled relapse prevention study of aripiprazole was designed a priori with a prospective, 74-week, double-blind, placebo-controlled extension phase. Efficacy and tolerability of aripiprazole for relapse prevention in bipolar I disorder was, therefore, evaluated for 100 weeks. Patients with DSM-IV bipolar I disorder, recent manic or mixed episode, received open-label aripiprazole 15 or 30 mg/day (started at 30 mg/day) for 6 to 18 weeks. Patients achieving stabilization (Young Mania Rating Scale score <or= 10 and Montgomery-Asberg Depression Rating Scale score <or= 13 for 6 consecutive weeks) entered the double-blind phase, at which point they were randomly assigned to double-blind treatment with aripiprazole or placebo for 26 weeks. The primary endpoint was time to relapse for any mood episode. Patients who completed the 26-week stabilization continued in a double-blind fashion with aripipra-zole or placebo for an additional 74 weeks and were monitored for relapse, efficacy, and tolerability. The study was conducted from March 2000 to June 2003. In total, 161 patients met the stabilization criteria and were randomly assigned to aripiprazole (N = 78) or placebo (N = 83). At 100 weeks, time to relapse was significantly longer with aripiprazole (N = 7) than placebo (N = 5; hazard ratio = 0.53 [p = .011; 95% CI = 0.32 to 0.87]); however, a further 24 patients had discontinued due to study closure. Aripiprazole was superior to placebo in delaying time to manic relapse (p = .005; hazard ratio = 0.35 [95% CI = 0.16 to 0.75]); however, no significant differences were observed in time to depressive relapse (p = .602; hazard ratio = 0.81 [95% CI = 0.36 to 1.81]). The adverse events reported during 100 weeks of treatment with aripiprazole versus placebo (>or= 5% incidence and twice placebo rate) were tremor, akathisia, dry mouth, hypertension, weight gain, vaginitis, abnormal thinking, pharyngitis, and flu syndrome. Mean weight change from baseline to 100 weeks (last observation carried forward) was +0.4 +/- 0.8 kg with aripiprazole and -1.9 +/- 0.8 kg with placebo. Over a 100-week treatment period, aripiprazole monotherapy was effective for relapse prevention in patients who were initially stabilized on aripiprazole for 6 consecutive weeks, and it maintained a good safety and tolerability profile. ClinicalTrials.gov identifier NCT00036348.
 
Article
During the course of a family-interview study of probands with psychotic disorders, the authors encountered two pedigrees in which schizophrenic individuals had first-degree relatives with bipolar disorder. The authors describe the members of both families in detail and discuss several hypotheses that might account for the co-occurrence of schizophrenia and bipolar disorder in the same family.
 
Article
We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication. Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003. In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms. Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.
 
Article
Sir: Schizophrenia is associated with increased prevalence of smoking, heavy smoking, and smoking-related morbidity and mortality. Standard nicotine dependence treatments have been associated with modest efficacy in patients with schizophrenia and high rates of relapse to smoking upon their discontinu- ation. 1-3 These reports prompted the authors to review clinical nico- tine dependence treatment with varenicline in smokers with schizophrenia at an urban community mental health clinic with attention to clinical efficacy for nicotine dependence and to signs of clinical worsening that may have occurred secondary to varenicline treatment. Method. From October 2006 to October 2007, 19 patients with schizophrenia, most of whom had quit smoking in the past but had relapsed to smoking after discontinuation of nicotine dependence treatment with bupropion or nicotine replacement therapy, requested nicotine dependence treatment with the newly available medication, varenicline. These 19 outpatients with schizophrenia were on stable antipsychotic medication regimens and received a standard titration of varenicline as fol- lows: 0.5 mg/day for 3 days, 0.5 mg b.i.d. for 4 days, then 1 mg b.i.d. Each received brief individual counseling at medication visits. Visits were weekly for 2 weeks, then approximately monthly. Results. All 19 patients reported reduced craving to smoke after initiating varenicline treatment. Four patients discontinued varenicline treatment due to nausea and vomiting. One patient subsequently restarted varenicline and was able to tolerate treat- ment without vomiting on the second exposure. Thirteen pa- tients tolerated the medication, quit smoking within 10 to 21 days of starting varenicline, and maintained self-reported absti- nence for ≥ 12 weeks, verified with periodic expired air carbon monoxide measurements of < 9 ppm at clinical visits. In the pe- riod between 12 and 24 weeks, 4 patients had occasional "slips" in which they smoked < 5 cigarettes per day for a period of < 7 days and then regained abstinence. All 13 patients in this series who quit smoking elected to continue to take varenicline beyond the standard 24-week regi- men to prevent relapse to smoking. Patients in this series have remained clinically stable with no clinical evidence of psy- chotic relapse or significant worsening of psychiatric symptoms or side effects of antipsychotic medications. None of the 19 pa- tients had a psychiatric hospitalization within 24 weeks of start- ing varenicline. No clinical rating scales were performed as part of this treatment. Likewise, no cognitive tests were performed to assess the effect of varenicline on cognitive performance in these patients. Varenicline is a partial α 4β2 and full α 7 nicotinic acetylcho- line receptor (nAChR) agonist.
 
Article
This trial was conducted to determine the incidence of seizures associated with the use of bupropion. A total of 3341 depressed patients from 102 sites were enrolled in this 8-week, prospective, open trial. Following the 8-week treatment phase, patients could elect to enroll in a humanitarian continuation phase of unlimited duration. Dosing was initiated at 225 mg/day and increased to 450 mg/day as tolerated. Investigators carefully monitored seizure occurrences and rated their patients' response to and tolerance of bupropion. A total of 1986 patients (61%) completed the 8-week treatment phase, and 1616 (81%) of these elected to be maintained on bupropion treatment in the humanitarian continuation phase. The observed seizure rate was 0.24% for the treatment phase and 0.40% for the entire study. An 8-week survival analysis performed on patients with a dosing regimen of 300 to 450 mg/day yielded a cumulative rate of 0.36%. Patients, including those previously resistant to antidepressant treatment, responded to and tolerated bupropion well. These rates confirm earlier seizure estimates and fall within accepted parameters for antidepressant drugs. This trial enhances bupropion's position as a valuable alternative for the management of depression.
 
Article
BL-1020 is a γ-aminobutyric acid (GABA)-enhanced antipsychotic that combines dopamine antagonism with GABA agonist activity. On the basis of animal models, we tested the hypotheses that BL-1020 would be effective in ameliorating both psychotic symptoms and cognitive impairments, with a favorable safety profile in acutely ill schizophrenia patients. 363 hospital-based psychiatric patients in India, Romania, and United States aged 18 to 65 years and meeting criteria for DSM-IV-TR diagnosis of chronic schizophrenia were randomized double-blind to receive BL-1020 10 mg/d, BL-1020 20-30 mg/d, placebo, or risperidone (2-8 mg/d) for 6 weeks. The main outcome measures were the Positive and Negative Syndrome Scale (PANSS), Brief Assessment of Cognition in Schizophrenia, Readiness for Discharge Questionnaire, Clinical Global Impressions Scale (CGI) , and Extrapyramidal Symptom Rating Scale. The study ran from July 2008 to June 2009. BL-1020 20-30 mg was significantly better than placebo on PANSS (P = .02) and CGI (P < .001) measurements, with no significant differences noted between BL-1020 20-30 mg and risperidone. There were no significant differences in the maximum change on Extrapyramidal Symptom Rating Scale between risperidone and BL-1020 20-30 mg, and both were significantly worse (P < .001) than placebo. BL-1020 20-30 mg was associated with significantly greater improvements on cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia composite score when compared to placebo (effect size = 0.50, P = .009), risperidone (effect size = 0.43, P = .019), and BL-1020 10 mg (effect size = 0.42, P = .013) after 6 weeks. BL-1020 appears to be an effective antipsychotic with possible procognitive effects that will need to be further tested for short- and long-term effects. A further randomized controlled trial using the US Food and Drug Administration-recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive battery is ongoing. ClinicalTrials.gov identifier: NCT00567710.
 
Comparative incidence of sexual dysfunction with selective serotonin reuptake inhibitors (SSRIs) . 
Diagnostic Distribution ( N = 344) Diagnosis Male Female ( n = 152) ( n = 192) Total 
Seventy of sexual dysfunction with selective serotonin reuptake inhibitors (SSRIs). 
Article
Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and clomipramine, are frequently associated with sexual dysfunction. Other antidepressants (nefazodone, mirtazapine, bupropion, amineptine, and moclobemide) with different mechanisms of action seem to have fewer sexual side effects. The incidence of sexual dysfunction is underestimated, and the use of a specific questionnaire is needed. The authors analyzed the incidence of antidepressant-related sexual dysfunction in a multicenter, prospective, open-label study carried out by the Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. The group collected data from April 1995 to February 2000 on patients with previously normal sexual function who were being treated with antidepressants alone or antidepressants plus benzodiazepines. One thousand twenty-two outpatients (610 women, 412 men; mean age = 39.8 +/- 11.3 years) were interviewed using the Psychotropic-Related Sexual Dysfunction Questionnaire, which includes questions about libido, orgasm, ejaculation, erectile function, and general sexual satisfaction. The overall incidence of sexual dysfunction was 59.1% (604/1022) when all antidepressants were considered as a whole. There were relevant differences when the incidence of any type of sexual dysfunction was compared among different drugs: fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction. The incidence of sexual dysfunction with SSRIs and venlafaxine is high, ranging from 58% to 73%, as compared with serotonin-2 (5-HT2) blockers (nefazodone and mirtazapine), moclobemide, and amineptine.
 
Article
Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. PubMed was searched for trials published in English up to January 2008 evaluating modafinil's effects on fatigue, negative symptoms, and cognition in schizophrenia with combinations of the following terms: schizophrenia, modafinil, cognition, negative symptoms, and fatigue. Six trials were identified: 2 randomized, prospective, double-blind placebo-controlled trials; 3 randomized, prospective, double-blind placebo-controlled crossover trials; and 1 open-label pilot study. Case series and case reports were excluded in the data analysis, except to identify potential adverse reactions to modafinil. Studies were examined for number of subjects, trial duration, design, dosing, and outcomes with respect to sedation, negative symptoms, cognitive function, and tolerability. One of 4 reviewed studies found a significant effect of modafinil as an alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 reviewed studies found modafinil to improve negative symptoms of schizophrenia. Three of 6 reviewed studies showed that modafinil may improve short-term memory, attention, and the ability to shift mental sets. Two neuroimaging studies identified functional correlates in areas associated with working memory functions. The main adverse effect was found to be a small risk of psychosis exacerbation, which was seen in 5 of 83 patients (6.0%) in the active treatment groups as compared to 2 of 70 patients (2.9%) in the placebo groups. While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. Well-powered, prospective, randomized placebo-controlled trials using the MATRICS battery concomitantly with functional outcome measures are necessary to elucidate modafinil's efficacy and effectiveness as an adjunctive treatment for sedation, negative symptoms, and cognitive deficits in schizophrenia. Hence, before prescribing modafinil to a schizophrenia patient, the possible risks and benefits of each particular case should be evaluated.
 
Article
To ascertain the prevalence of mood disorders among consecutively evaluated prepubertal children presenting for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a community mental health clinic. 104 children received systematic assessments designed to identify individuals meeting the DSM-IV criteria for major depressive disorder (MDD), mania, and ADHD. "Standard" and "modified" criteria for mania were employed. Modified criteria, in an effort to minimize false-positive diagnoses of mania, required the presence of euphoria and/or flight of ideas. A child meeting the criteria for MDD or either set of criteria for mania was categorized as having a mood disorder. Mood disorders in first-degree relatives were assessed using a systematic interview. Data were gathered from 2000 to 2002. Sixty-two children (59.6%) had a mood disorder. Compared with those who did not have a mood disorder, they were 3.3 times more likely (54.8% vs. 16.7%) to have a family history of any affective disorder (p <.0001) and 18.3 times more likely (43.5% vs. 2.4%) to have a family history of bipolar disorder (p <.0001). Twenty (32.3%) of the children with and none without a mood disorder had psychotic features (p <.0001). Compared with those meeting only the standard criteria for mania, those meeting the modified criteria were 9.1 times more likely (69.8% vs. 7.7%) to have a family history of an affective disorder (p <.0001) and 7.3 times more likely (55.8% vs. 7.7%) to have a family history of bipolar disorder (p =.002). Children who presumably have ADHD often have unrecognized affective illness. Our findings support the view that children meeting the modified criteria for mania have veritable bipolar disorder. These findings, which were derived in the course of delivering routine clinical services in a community mental health clinic, are consistent with those obtained in research settings suggesting that children presenting with ADHD often have occult mood disorders, especially unrecognized bipolarity. We suggest that clinicians encountering children with prominent features of ADHD inquire about the presence of euphoria and flight of ideas. We submit that the presence of these "classic" manifestations of mania strongly suggests the presence of occult bipolarity, even if course of illness otherwise markedly deviates from "classic" descriptions.
 
Article
To evaluate the efficacy and tolerability of gepirone extended-release (ER) tablets in patients with major depressive disorder (MDD) and high ratings of anxiety (anxious depression). This subgroup analysis was derived from an 8-week, double-blind, placebo-controlled study of gepirone ER in patients with MDD. Male and female patients 18 to 69 years of age who met DSM-IV criteria for MDD and had high ratings of anxiety (Hamilton Rating Scale for Depression [HAM-D-17] total score > or = 20 and HAM-D-17 factor I [anxiety/somatization] score > 6) were included in this subgroup analysis. Eligible patients with anxious depression were randomly assigned to receive either placebo or gepirone ER, 20 mg to 80 mg daily. Patient assessments were performed at weeks 1, 2, 3, 4, 6, and 8. Treatment efficacy was evaluated by mean HAM-D-17 total scores and mean changes from baseline in (1) HAM-D-17 total scores, (2) HAM-D-17 factor I (anxiety/somatization) scores, and (3) HAM-D-17 item 12 (anxiety, psychic) scores. All statistical tests were 2-sided and considered statistically significant if the p value was <.05. Between-group comparisons were analyzed using least-squares analysis of variance on the change from baseline at each visit with the last observation carried forward (LOCF). The Cochran-Mantel-Haenszel test adjusting for center was also performed on the percentage of patients in each treatment group at each visit (LOCF) who met the response criterion on the HAM-D-17 (> or = 50% decrease from baseline) or remission criterion (HAM-D-17 total score < or = 7). Gepirone ER-treated patients (N = 58) experienced a statistically significant (p <.05) reduction in mean HAM-D-17 total score at week 3, 6, and 8 compared with placebo-treated patients (N = 75). A statistically significant effect (p <.05) in favor of gepirone ER was observed in mean change from baseline in HAM-D-17 total scores and for HAM-D factor I (anxiety/somatization) scores from week 2 onward. A statistically significant (p < or =.01) effect in favor of gepirone ER was observed in HAM-D-17 item 12 (anxiety, psychic) scores throughout the 8-week trial. There were significantly more patients in the gepirone ER group compared with the placebo group who were HAM-D-17 responders (p <.05) at endpoint and who met the criteria for HAM-D-17 remission at week 3 (p <.05) and weeks 6 and 8 (p <.01). Overall, gepirone ER was well tolerated, with rates of weight gain and sexual dysfunction comparable to placebo. Adverse events were generally mild to moderate. The most commonly reported adverse events were dizziness and nausea. Gepirone ER is an effective and well-tolerated treatment for patients with anxious depression.
 
Article
In a naturalistic study, the treatment response and outcome of 1087 patients with nonbipolar primary (N = 763) and secondary (N = 324) depression were compared by a chart review. The patients were divided into four treatment groups, based on the primary mode of therapy received during the index hospitalization: ECT, adequate antidepressant, inadequate antidepressant, and neither treatment. Primary depressives were more likely to have received ECT, and secondary depressives were more likely to have received inadequate antidepressant or neither treatment. A total of 436 (57.1%) primary depressives received adequate therapy, but only 113 (34.9%) secondary depressives did (p less than .001). Overall, primary depressives responded better to treatment (both ECT and antidepressants) than did secondary depressives. A total of 470 (61.6%) primary depressives but only 140 (43.2%) secondary depressives were recovered at discharge (p less than .001). The conclusion is that secondary depressives are more likely to receive inadequate treatment and are less likely to respond to adequate treatment than are primary depressives.
 
Article
Combination therapy (risperidone and a mood stabilizer) for patients with a history of bipolar disorder (DSM-IV) and hospitalized for treatment of a manic episode was assessed in a 13-week study. Subjects received flexible doses of a mood stabilizer (lithium or divalproex) plus placebo, risperidone, or haloperidol in a 3-week double-blind study. They could then enter a 10-week open-label study during which they received risperidone combined with a mood stabilizer. Of the 156 patients enrolled in the 3-week study, 85 entered the 10-week open-label extension, of whom 48 completed 10 weeks of treatment. The mean +/- SE doses of risperidone were 3.8 +/- 0.3 mg/day during the 3-week study and 3.1 +/- 0.2 mg/day during the 10-week study. At double-blind endpoint, mean reductions in Young Mania Rating Scale (YMRS) scores were significantly greater in patients receiving risperidone plus mood stabilizer than in those receiving placebo plus mood stabilizer (-14.3 vs. -8.2, p <.001). Further significant (p <.001) reductions were seen during the 10 weeks of treatment with risperidone plus mood stabilizer. Symptom remission (YMRS score <or= 12) was seen in 38 patients (79%) at the end of the 10-week study. Scores on the Brief Psychiatric Rating Scale, Hamilton Rating Scale for Depression, and Clinical Global Impressions scale improved significantly (p <.05) during both the 3-week and 10-week studies. Treatment was well tolerated, and modest weight gain was observed during the 13-week study period. The combination of risperidone and a mood stabilizer was efficacious and well tolerated in the continuation treatment of patients initially hospitalized for the management of an acute manic episode.
 
The Ccx Proportional Odds Model for Cardiovascular Disease-Related Death and for Diabetes Mellitus in Clozapine-Teated Patients With Schizophrenia Over a 10-Year Period 
Article
The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease. Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals. At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus. These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia.
 
Article
This preliminary study endeavored to evaluate the use of virtual reality (VR) enhanced exposure therapy for the treatment of posttraumatic stress disorder (PTSD) consequent to the World Trade Center attacks of September 11, 2001. Participants were assigned to a VR treatment (N = 13) or a waitlist control (N = 8) group and were mostly middle-aged, male disaster workers. All participants were diagnosed with PTSD according to DSM-IV-TR criteria using the Clinician-Administered PTSD Scale (CAPS). The study was conducted between February 2002 and August 2005 in offices located in outpatient buildings of a hospital campus. Analysis of variance showed a significant interaction of time by group (p < .01) on CAPS scores, with a between-groups posttreatment effect size of 1.54. The VR group showed a significant decline in CAPS scores compared with the waitlist group (p < .01). Our preliminary data suggest that VR is an effective treatment tool for enhancing exposure therapy for both civilians and disaster workers with PTSD and may be especially useful for those patients who cannot engage in imaginal exposure therapy.
 
Article
A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.
 
Article
A number of medications are now available or are in development as antimanic and/or mood-stabilizing agents. We reviewed the clinical pharmacodynamics and pharmacokinetics of these agents to provide a summary of these properties relevant to clinical practice. We conducted a MEDLINE search augmented by a manual search of bibliographies and a review of textbooks to identify articles regarding the clinical pharmacology of lithium, valproate, carbamazepine, oxcarbazepine, olanzapine, clozapine, risperidone, ziprasidone, quetiapine, lamotrigine, and topiramate. Not surprisingly, there are a number of clinically relevant pharmacodynamic and pharmacokinetic differences among these medications, and these differences are discussed. Knowledge of the clinical pharmacology of established and putative antimanic and mood-stabilizing medications is important in administering these agents safely and effectively.
 
Article
Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD). Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding. There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001). Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC.
 
Article
Clinicians and researchers who work with mentally retarded subjects have reported on the frequent exhibition of mental disorders and behavioral problems in this population. Rituals are often among the disturbances described. We decided to treat disabling cleaning and collecting compulsions in mentally retarded adults with clomipramine 75 mg/day, sustained release (SR) preparation. The 8-week trial included 11 subjects, mean age of 24.1 years (range, 21-27) with a mean +/- SD I.Q. of 65.0 +/- 11.0. The majority of subjects (N = 9) were occupied with washing rituals that took hours to complete. Subjects were started on a schedule of 32.5 mg of clomipramine SR once daily for 1 week, then received 75 mg SR once daily for an additional 7 weeks. Improvement was assessed by using the National Institute of Mental Health Global Obsessive Compulsive Scale and the Global Improvement score of the Yale-Brown Obsessive Compulsive Scale. Statistically significant reduction in severity of rituals (p < .05) was found at the trial's completion. Once-daily clomipramine SR 75 mg is effective in treating adults with mental retardation and disabling rituals.
 
Article
Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) dopamine transporter occupancies. Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007. For all doses, plasma dexmethylphenidate levels and CNS dopamine transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001). These results confirm the study hypothesis that central dopamine transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration. clinicaltrials.gov Identifier: NCT00593138.
 
Article
This study evaluated the relationship between resilience and psychological functioning in military veterans deployed to a region of military conflict in support of Operation Enduring Freedom or Operation Iraqi Freedom. 497 military veterans completed a structured psychiatric interview and questionnaires measuring psychological symptoms, resiliency, and trauma exposure. The study had 2 primary aims: (1) to examine whether the association between trauma exposure and PTSD was moderated by resilience and (2) to examine whether resilience was uniquely associated with functional outcomes after accounting for PTSD. Measures included the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (for PTSD diagnosis), the Connor-Davidson Resilience Scale, and the Traumatic Life Events Questionnaire. Data were collected between June 2005 and February 2009. Evaluating the association of resilience and trauma exposure with PTSD revealed main effects for combat exposure, lifetime trauma exposure, and resilience. Additionally, there was a significant (P < .05) interaction between combat exposure and resilience such that higher levels of resilience were particularly protective among individuals with high combat exposure. After controlling for age, gender, minority status, trauma exposure, and PTSD diagnosis, resilience was uniquely associated with decreased suicidality, reduced alcohol problems, lower depressive symptom severity, and fewer current health complaints and lifetime and past-year medical problems. These results suggest that resilience is a construct that may play a unique role in the occurrence of PTSD and severity of other functional correlates among deployed veterans. Future studies in this area would benefit from a prospective design, the evaluation of other possible protective processes (e.g., social support), and specific examination of particular aspects of resilience and how resilience may be increased.
 
Article
We examined the development of posttraumatic stress disorder (PTSD) following indirect exposure to the September 11, 2001, terrorist attacks in a cohort at high risk for adverse trauma-related sequelae as a result of having bipolar disorder. Subjects (N = 137) were participants in the ongoing, naturalistic, longitudinal study Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) prior to September 11, 2001. The present study examined prospectively collected pre-event information about bipolar disorder and other potential predictors of PTSD, along with assessment of the level of indirect trauma exposure (i.e., via media) and peritraumatic distress in the aftermath of September 11, and their association with 9/11-related, new-onset PTSD as assessed by a self-report measure, the Posttraumatic Stress Diagnostic Scale. Posttrauma assessments were completed a mean +/- SD of 430.6 +/- 78.7 days (range, 0.5-1.5 years) after September 11. Twenty percent (N = 27) of patients reported development of new-onset PTSD in response to the September 11 attacks. Rates of PTSD were significantly associated with the presence of a hypomanic, manic, or mixed mood state at the time of trauma (chi(2) = 4.25; p < .05); 62% of patients in these states developed PTSD. Mania/hypomania remained a significant predictor of PTSD in response to the September 11 attacks after controlling for peritraumatic exposure and distress variables, suggestive of a substantial increase in risk compared with those in recovery (OR = 17; 95% CI = 2.6 to 115.6; p = .0034). Rates of persistent new-onset PTSD among bipolar patients were elevated in the aftermath of the September 11 attacks. Our findings suggest that the presence of a manic state may be the most critical risk factor for adverse sequelae following indirect traumatic exposure in bipolar individuals.
 
Article
Clinical trials of risperidone, a recently approved novel antipsychotic, included elderly healthy patients, but more data are needed on the effects of risperidone in this population, especially those with comorbid medical illnesses. Risperidone was used to treat 11 elderly hospitalized patients between 61 and 79 years of age who manifested signs of psychoses related to schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia. All patients had been treated previously with classic antipsychotics. Response was assessed by clinical observation of the patients' behavior. Eight patients responded to treatment, 1 did not respond, and 2 had treatment discontinued because of hypotension or dizziness. Positive and negative symptoms decreased markedly in 7 of the responding patients. Four patients had preexisting extrapyramidal symptoms (EPS) and symptoms of tardive dyskinesia that also decreased in response to risperidone treatment. In addition, 4 patients were able to discontinue anti-parkinsonian medications, and 2 were able to discontinue antihypertensive medications. Side effects related to blockade of dopamine, histamine, and serotonin were negligible. No adverse consequences occurred when electroconvulsive therapy, carbamazepine, or lithium was given concurrently. The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, and anticholinergic side effects indicate that risperidone is a safe and effective medication for the elderly.
 
Article
There is a paucity of data on the long-term course and outcome of obsessive-compulsive disorder (OCD). Available data suggest that OCD runs a chronic course with waxing and waning severity. However, most previous studies included severely ill patients who were often clinically referred and hospitalized. The present study reports the course and outcome of OCD in patients who were largely outpatient, self-referred, and drug-naive. Seventy-five of the 105 subjects (71%) with DSM-IV-diagnosed OCD were followed up 11 to 13 years after initial consultation in 1991 and 1992 at a major psychiatric hospital in India. A majority were self-referred (N = 63, 84%), drug-naive (N = 54, 72%), and outpatients (N = 60, 80%). The follow-up evaluations were carried out by experienced clinicians using various scales and structured instruments. The course and outcome were determined according to predefined criteria. Multinomial logistic regression analysis was performed to identify potential predictors of outcome. A majority of subjects were adequately treated with medications (N = 57, 76%). Out of 75 subjects, only 18 subjects (24%) had clinical OCD. Overall, 57 subjects (76%) had a favorable outcome: 32 subjects (43%) had no OCD and 25 (33%) had subclinical OCD. Mixed OCD and any Axis I lifetime comorbidity predicted "clinical OCD" outcome. Outcome of OCD is better than generally assumed, and the findings of this study offer a new perspective on the long-term outcome of OCD. Poor outcome in previous studies may have been due to the inclusion of severely and chronically ill patients.
 
Article
Reactions to the September 11 attacks across the United States were pervasive, and persons throughout the country reported experiences akin to posttraumatic stress disorder (PTSD) in the first week following the attacks. In the New York area, 2 major surveys conducted 4 to 8 weeks after the attacks found that approximately 1 in 10 persons probably met full criteria for PTSD related to September 11. Although tobacco, alcohol, and marijuana use did increase, it was largely among persons already using these substances. The greatest increase, not surprisingly, occurred among persons with PTSD and major depressive disorder. Nationwide during the same time period, rates of PTSD related to September 11 were estimated at 2.7% to 4.3%, a striking finding in that the attacks were witnessed primarily on television outside the New York area. In all studies, having anxiety symptoms or meeting criteria for PTSD was strongly associated with number of hours of television watched on September 11 and in the days afterward. A number of explanations for this new finding are possible. These data can inform our understanding of trauma-related diagnoses, further the evolving diagnostic definitions of the Diagnostic and Statistical Manual of Mental Disorders, and contribute to etiologic models of PTSD. Future directions for postdisaster survey research are briefly discussed.
 
Article
To determine whether severity of obsessive-compulsive symptoms (OCS) differs during treatment with olanzapine or risperidone and to establish whether duration of antipsychotic treatment is related to severity of OCS. We conducted a prospective study of consecutively hospitalized young patients (mean age = 22.4 years) with DSM-IV schizophrenia or related disorders (N = 113) who were treated with olanzapine or risperidone. Olanzapine or risperidone was randomly prescribed for patients who were drug-naive or were treated with typical antipsychotics before admission (N = 36). Patients who had started olanzapine (N = 39) or risperidone treatment (N = 23) prior to admission continued with that medication if they showed initial clinical response. Patients who prior to admission started olanzapine (N = 6) or risperidone (N = 9) but showed no response or suffered from adverse effects switched at admission to risperidone or olanzapine, respectively. Medical records, parents, and patients revealed information on duration of treatment and compliance with olanzapine or risperidone prior to admission. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was administered at admission and 6 weeks thereafter. At baseline and 6-week assessments, OCS were found in about 30% of 106 evaluable cases and 15% met DSM-IV criteria for obsessive-compulsive disorder. No differences in OCS were found in the patients randomly assigned to olanzapine or risperidone. The 35 subjects treated with olanzapine at both assessments had significantly (p = .01) more severe OCS at week 6 than the 20 subjects treated with risperidone at both assessments. Duration of treatment with olanzapine was significantly (p < .01) related to severity of OCS. There are no differences in the short-term propensity of olanzapine or risperidone to induce or exacerbate OCS. However, severity of OCS was associated with duration of treatment with olanzapine.
 
Article
Despite a surge of interest and literature on depersonalization disorder in recent years, a large series of individuals with the disorder has not been described to date. In this report, we systematically elucidate the phenomenology, precipitants, antecedents, comorbidity, and treatment history in such a series. 117 adult subjects with depersonalization disorder (DSM-III-R/DSM-IV criteria) consecutively recruited to a number of depersonalization disorder research studies were administered structured and semistructured diagnostic interviews and the Dissociative Experiences Scale. Data were gathered from 1994 to 2000. The illness had an approximately 1:1 gender ratio with onset around 16 years of age. The course was typically chronic and often continuous. Illness characteristics such as onset, duration, and course were not associated with symptom severity. Mood, anxiety, and personality disorders were frequently comorbid, but none predicted depersonalization severity. The most common immediate precipitants of the disorder were severe stress, depression, panic, marijuana ingestion, and hallucinogen ingestion, and none of these predicted symptom severity. Negative affects, stress, perceived threatening social interaction, and unfamiliar environments were some of the more common factors leading to symptom exacerbation. Conversely, comforting interpersonal interactions, intense emotional or physical stimulation, and relaxation tended to diminish symptom intensity. There were no significant gender differences in the clinical features of the disorder. In this sample, depersonalization tended to be refractory to various medication and psychotherapy treatments. The characteristics of depersonalization disorder found in this sample, the largest described to date, are in good accord with previous literature. The study highlights the need for novel therapeutic approaches to treat depersonalization disorder. Novel medication classes, as well as novel psychotherapeutic techniques that build on the reported symptom fluctuation factors, may prove helpful in the future.
 
Article
The importance of the therapist's education and experience for the successful behavior treatment of obsessive-compulsive disorder (OCD) has not been investigated. Data on the relative effectiveness of self-controlled versus therapist-controlled in vivo exposure with response or ritual prevention (ERP) have yielded conflicting results. The present study compared the effectiveness of 4 different modes of delivery of ERP in a referred sample of OCD patients. Of the 146 eligible OCD outpatients, 118 patients enrolled in this randomized controlled trial and were randomly assigned to (1) therapist-controlled ERP performed by experienced behavior therapists; (2) therapist-controlled ERP performed by master's students of clinical psychology; (3) self-controlled ERP performed by experienced behavior therapists; and (4) self-controlled ERP performed by master's students of clinical psychology. This trial was performed from January 1999 to January 2005. Our analyses revealed no significant differences in clinical outcome between any of the different modes of delivery of ERP at posttreatment. The different ERP modes of delivery were associated with significant pretreatment to posttreatment improvement on all measurements, with large effect sizes on the primary outcome measure, the Yale-Brown Obsessive Compulsive Scale. Our results indicate that clinically inexperienced master's students with no postgraduate training can be as capable as experienced and certified behavior therapists in treating OCD patients, as long as therapists adhere to a standardized treatment manual and adequate training and supervision is provided. In contrast to other studies, we did not find a supposed benefit of therapist-controlled ERP versus self-controlled ERP in patients with OCD. www.trialregister.nl Identifier: NTR1444.
 
Article
Antipsychotic medications differ in their sedative potential, which can affect cognitive performance. The primary objective of this double-blind study was to compare the effects of treatment initiation with risperidone and quetiapine on cognitive function in subjects with stable bipolar disorder. Subjects had a DSM-IV diagnosis of bipolar I disorder in partial or full remission and a Young Mania Rating Scale score <or= 8 at screening. Subjects were randomly assigned to 1 of 2 treatment sequences: risperidone-quetiapine or quetiapine-risperidone. Subjects in the risperidone-quetiapine sequence received 2 mg of risperidone with dinner and placebo with breakfast during period 1 and 100 mg of quetiapine with dinner and 100 mg with breakfast during period 2. Subjects in the quetiapine-risperidone sequence received the same treatments in reverse order. The 2 treatment periods were separated by a 6- to 14-day washout period. Cognitive function, including attention, working memory, declarative memory, processing speed, and executive functions, was measured before and after dosing. The Visual Analog Scale for Fatigue was also completed. The primary endpoint was a neurocognitive composite score (NCS). The study was conducted from November 2004 through August 2005. Thirty subjects were randomly assigned; 28 took all doses of study medication and completed a baseline and at least 1 postbase-line assessment in each treatment. On the NCS, significantly better overall cognitive function was seen after risperidone than after quetiapine at each time point after dosing. Subjects performed significantly better after risperidone than after quetiapine (p < .05) on 9 of the 18 individual cognitive outcome measures and significantly better after quetiapine than after risperidone on 1 measure. Sleeping or the need for sleep during the test days was reported in significantly more patients after receiving quetiapine than risperidone. The results indicate that initiation of quetiapine treatment was associated with more immediate adverse cognitive effects and increased somnolence than risperidone treatment. ClinicalTrials.gov identifier NCT00097032.
 
Article
Comorbid alcohol use disorders (AUDs) in schizophrenia are associated with increased morbidity, more inpatient treatment, and violent offending. It is of clinical importance to identify those with schizophrenia who may go on to develop an alcohol use disorder; however, the risk factors are not well understood. The aim of this study was to identify risk factors for the development of an AUD in patients after they had been diagnosed with schizophrenia. We conducted a retrospective case-control study of 12,653 individuals diagnosed with ICD-defined schizophrenia in Sweden in 1973-2004, using data from national registers. We tested the associations between individual factors (marital status, immigrant status, and previous violent offending), sociodemographic factors (income and education), and parental risk factors (AUDs, psychosis, and violent offending) ICD-defined and AUD development using logistic regression modeling. Over a median follow-up of 17.3 years, 7.6% of patients had at least 1 hospital diagnosis of AUD. After adjustment for gender and age at diagnosis in a multivariate regression model, previous violent offending (OR = 2.1; 95% CI, 1.8-2.5), low education (OR = 1.3; 95% CI, 1.1-1.5), maternal AUD (OR = 1.9; 95% CI, 1.4-2.7), and paternal AUD (OR = 1.9; 95% CI, 1.5-2.3) remained independently associated with increased risk of patient AUD. AUDs are a common sequela of schizophrenia. Risk factors that could be identified at the time of first presentation include low educational attainment, previous violent offending, and parental history of AUDs and may inform clinical treatment and follow-up of those most at risk.
 
Article
This investigation was performed to assess the efficacy and safety of zolpidem extended-release in patients with insomnia associated with major depressive disorder (MDD). Patients (N = 385) received open-label escitalopram 10 mg/d and were randomized to concomitant zolpidem extended-release 12.5 mg/night or placebo for 8 weeks (phase 1) in a randomized, parallel-group, multicenter trial. Responders (≥ 50% in 17-item Hamilton Depression Rating Scale [HDRS(17)] score) continued 16 weeks of double-blind treatment (phase 2); escitalopram only was given during a 2-week run-out period. The study was conducted between February 2006 and June 2007. The primary efficacy measure was change from baseline in subjective total sleep time. Secondary efficacy measures included subjective sleep-onset latency, number of awakenings, wake time after sleep onset, sleep quality, sleep-related next-day functioning, HDRS(17), Sleep Impact Scale score, Patient and Clinical Global Impressions of Insomnia Treatment, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, and the Quality of Life Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study; sleep measures were also evaluated during the run-out period. Throughout phase 1, zolpidem extended-release led to significantly greater improvements in total sleep time (P < .0001), wake time after sleep onset, sleep onset latency, number of awakenings, and sleep quality (P ≤ .0003), and some measures of sleep-related next-day functioning but not in depressive symptoms or quality of life. During phase 2, improvements with the zolpidem extended-release/escitalopram group occurred for total sleep time (significant [P < .05] at weeks 12 and 16), as well as for a few other secondary efficacy measures but not in depressive symptoms or quality of life. The most common adverse events associated with combination treatment included nausea, somnolence, dry mouth, dizziness, fatigue, and amnesia. Zolpidem extended-release administered concomitantly with escitalopram for up to 24 weeks was well tolerated and improved insomnia and some sleep-related next-day symptoms and next-day functioning in patients with MDD but did not significantly augment the antidepressant response of escitalopram. clinicaltrials.gov Identifier: NCT00296179.
 
Article
This phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fixed-dose levomilnacipran sustained release (SR) compared with placebo in patients with major depressive disorder (MDD); the study was conducted from September 2009-May 2011. Outpatients met DSM-IV-TR criteria for MDD with an ongoing major depressive episode ≥ 8 weeks' duration. After a 1-week placebo lead-in, patients were randomly assigned to receive placebo (n = 179) or levomilnacipran SR 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment, followed by a 2-week double-blind down-taper. The primary efficacy parameter was change from baseline on the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) total score. The prespecified secondary efficacy parameter was change from baseline in Sheehan Disability Scale (SDS) total score. Additional efficacy measures included the 17-item Hamilton Depression Rating Scale (HDRS17) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I). Safety and tolerability were also evaluated. The least squares mean difference (LSMD) for change from baseline in MADRS total score was significantly superior to placebo for all dose groups: -3.23 (P = .0186), -3.99 (P = .0038), and -4.86 (P = .0005) for levomilnacipran SR 40, 80, and 120 mg, respectively. The LSMD was significantly different for levomilnacipran SR 80 mg and 120 mg versus placebo on the SDS (-2.51 and -2.57, respectively, P < .05 for both doses), HDRS17 (-2.09 and -2.34, respectively, P < .05 for both doses), CGI-S (-0.43 [P < .01] and -0.35 [P < .05], respectively), and CGI-I (-0.34 and -0.32, respectively, P < .05 for both doses) assessments. The most common treatment-emergent adverse events (≥ 10% of any treatment group) were headache, nausea, constipation, dry mouth, increased heart rate, and hyperhidrosis. Levomilnacipran SR demonstrated significant improvement in depressive symptoms and functioning relative to placebo. In this study, levomilnacipran SR was generally well tolerated. Trial Registration: ClinicalTrials.gov identifier: NCT00969709.
 
Article
To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily. Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥ 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores ≥ 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) ≥ 4 and hospitalized ≥ 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008. There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea. Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies. clinicaltrials.gov Identifier: NCT00422162.
 
Article
Trichotillomania, characterized by an irresistible urge to pull one's hair, may be more prevalent than previously believed. Despite increasing attention devoted to this topic in the recent literature, there are few studies based on large samples that are potentially generalizable to a community population. Surveys addressing clinical profile, comorbidity, and treatment history were mailed to all responders to a nationally distributed magazine article on trichotillomania. Out of 772 surveys sent, 123 completed surveys were returned. While there was a predominance of females in the whole sample, female-to-male prevalence was lower in children than adults. Onset was predominantly in childhood (mean age = 11 years), most frequently in middle childhood and least frequently before age 6. Subjects pulled hair from a variety of sites, including scalp, eyelashes, eyebrows, pubic region, face, and body, but the highest incidence and severity involved scalp hair. Children under 6 were more likely than other age groups to pull scalp hair and possibly less likely to pull other hair. In adults, symptom profile was not associated with age at onset. While subjects reported high rates of comorbid conditions in both self and family, trichotillomania was reportedly formally diagnosed in only 40% of the subjects. Although subjects reported a range of treatments, the majority (58%) reported no treatment history. Finally, only minimal improvement was reported for all modalities, with no significant difference in response to psychotherapy, behavior therapy, clomipramine, or fluoxetine. Trichotillomania is a chronic illness that may be difficult to treat. Controlled studies on comorbidity, epidemiology, treatment-seeking patterns, and long-term treatment response are needed.
 
Article
Little is known about the evolution of brain perfusion alterations in patients with major depression, and still less about the changes in functional neuroimage produced by different antidepressant biological treatments. Between January 2001 and December 2003, long-term follow-up frontal brain perfusion was compared in 2 subgroups of elderly patients (>or= 60 years) treated for severe unipolar major depression (DSM-IV): one subgroup of 16 patients administered electroconvulsive therapy, and another of 26 patients receiving pharmacologic treatment. All patients were remitters. A medication-free brain single photon emission computed tomography was performed in baseline conditions and after a minimum period of 12 months of euthymia. Twenty-eight age- and sex-matched healthy controls were also assessed. No significant differences were found between the 2 subgroups in frontal uptake ratios after a 12-month follow-up period of euthymia. During the acute episode, patients presented significant anterior hypofrontality; 12 months later the hypofrontality had disappeared. The long-term evolution of frontal perfusion in elderly major depressives who respond to antidepressant biological treatment is essentially the same in those who receive electroconvulsive therapy and in those who receive medication.
 
Article
To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria). The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed. After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (>/= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively). Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients. clinicaltrials.gov Identifier: NCT00094549.
 
Article
To investigate the effectiveness and tolerability of quetiapine for the treatment of adolescents at high risk for developing bipolar I disorder. Twenty adolescents (aged 12-18 years) with mood symptoms that did not meet DSM-IV-TR criteria for bipolar I disorder and who had at least one first-degree relative with bipolar I disorder were recruited from August 2003 to June 2005 to participate in a single-blind, 12-week prospective study of quetiapine. Subjects were diagnosed using the Washington University in St. Louis Kiddie Schedule of Affective Disorders and Schizophrenia and were symptomatic, defined by a Young Mania Rating Scale (YMRS) score > or = 12 or a Childhood Depression Rating Scale-Revised Version (CDRS-R) score > or = 28 at baseline. The primary effectiveness measure was an endpoint Clinical Global Impressions-Improvement scale (CGI-I) score < or = 2 ("much" or "very much" improved). Secondary efficacy measures included change from baseline to endpoint in YMRS and CDRS-R scores. Mood disorder diagnoses in the adolescents consisted of bipolar disorder not otherwise specified (N = 11), dysthymia (N = 3), bipolar II disorder (N = 3), cyclothymia (N = 2), and major depressive disorder (N = 1). The majority of patients (N = 12, 60%) were non-responders to previous trials of psychotropic agents. Fifteen subjects (75%) completed all study visits. Eighty-seven percent of patients were responders (CGI-I < or = 2) to quetiapine at week 12 (mean +/- SD endpoint dose = 460 +/- 88 mg/day). YMRS scores decreased from 18.1 +/- 5.5 at baseline to 8.7 +/- 7.9 at endpoint (p < .0001), and CDRS-R scores decreased from 38.2 +/- 9.8 to 27.7 +/- 9.3, (p = .0003). The most frequently reported adverse events were somnolence, headache, musculoskeletal pain, and dyspepsia. No subjects discontinued study participation due to adverse events. Although these findings are limited by the small sample size and open-label treatment, the results suggest that quetiapine may be an effective treatment for mood symptoms in adolescents with a familial risk for developing bipolar I disorder.
 
Article
Cognitive dysfunction in schizophrenia differs from cognitive dysfunction in neurodegenerative illnesses because it is associated with neuronal dysfunction and not neurodegeneration. Pharmacologically, potential targets for developing treatments may differ from cognition in dementing disorders. Several putative molecular targets for treating cognition in schizophrenia show promise, such as treatments that act on the D(1) receptor of the dopamine system; the 5HT(1A), 5HT(2A), and 5HT(6), receptors of the serotonin system; and ampakines, Glycine/D-cycloserine, D-serine, and mGluR 2/3 agonists of the glutamatergic system. Other receptors associated with improvement in cognition include nicotinic and muscarinic receptors, and the alphalpha2 subunit receptor of the brain GABA system. Domain treatment of schizophrenia is a new method of treating schizophrenia that involves treating a single domain of dysfunction at a time.
 
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The purpose of this study was to examine the reliability and validity of a new multidimensional screening instrument for 13 DSM-IV Axis I disorders. The Psychiatric Diagnostic Screening Questionnaire (PDSQ) is a 90-item self-administered questionnaire that screens for 13 DSM-IV disorders in 5 areas (eating, mood, anxiety, substance use, and somatoform disorders). A consecutive series of 500 psychiatric outpatients completed the PDSQ immediately before their intake evaluation. Seventy-four patients completed the scale a second time less than a week after the initial administration, and 51 patients completed a booklet of questionnaires that included established measures of the same symptom domains assessed by the PDSQ. The PDSQ subscales achieved moderate-to-high levels of internal consistency (mean Cronbach's alpha coefficient = 0.82) and test-retest reliability (mean correlation coefficient = 0.84). Subscale scores were significantly associated with blind clinical diagnoses, and individual PDSQ items correlated much more highly with their own subscale than with other subscales. The PDSQ subscales were much more highly correlated with established measures of the same symptom domain (mean correlation coefficient = 0.72) than with measures of other types of psychopathology (mean correlation = 0.17). The PDSQ is a reliable and valid measure of multiple DSM-IV disorders that is brief enough to be incorporated into routine clinical outpatient practice without disruption, yet lengthy enough to be a psychometrically sound instrument.
 
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To determine risk factors for and prevalence of violent crime in patients with schizophrenia, and in particular, to explore the contribution of familial risk factors. We designed a cohort study that followed up patients with 2 or more hospitalizations for schizophrenia (ICD-8, ICD-9, and ICD-10 criteria) and investigated the risk for a violent conviction using Cox proportional hazards models. All 13,806 patients with 2 hospital discharge diagnoses of schizophrenia from January 1, 1973, through December 31, 2004, in Sweden were followed until violent conviction, emigration, death, or end of follow-up (December 31, 2004), and associations with sociodemographic, individual (substance abuse comorbidity, and previous violence), and familial (parental violent crime and parental alcohol abuse) factors were examined. Over an average follow-up period of 12 years, 17.1% (N = 1519) of the men and 5.6% (N = 273) of the women with 2 or more hospitalizations for schizophrenia had a violent conviction after discharge from hospital. Familial risk factors had moderate effects, increasing the risk for violent convictions by 50% to 150%. After adjustment for sociodemographic and individual risk factors, the associations between parental violent crime and risk of violent convictions remained in men (adjusted hazard ratio [HR] = 1.65, 95% CI = 1.33 to 2.04) and in women (adjusted HR = 1.83, 95% CI = 1.11 to 3.01), whereas parental alcohol abuse was no longer significantly associated with violent crime. Parental violent crime had moderate associations with violent crime in male and female offspring with at least 2 hospitalizations for schizophrenia, which were mostly stronger than the better documented sociodemographic risk factors. This suggests that familial (genetic or early environmental) risk factors have an important role in the etiology of violent offending among individuals with schizophrenia and should be considered in violence risk assessment.
 
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This study was constructed to detail the demographic and phenomenological features of pathological gamblers. One hundred thirty-one subjects with DSM-IV pathological gambling were administered a semistructured interview to elicit demographic data and information on the phenomenology, age at onset, course, associated features, treatment history, and response to treatment of the disorder, followed by the Structured Clinical Interview for DSM-IV. Seventy-eight female (59.5%) and 53 male (40.5%) (mean +/- SD age = 47.7+/-11.0 years) pathological gamblers were studied. The majority of subjects (55.7%) were married. Subjects gambled a mean of 16 hours per week. Slot machines (65%), cards (33%), and blackjack (26%) were the most popular forms of gambling. The mean length of time between first gambling behavior and onset of pathological gambling was 6.3+/-8.9 years. Approximately one half (46%) of the subjects reported that television, radio, and billboard advertisements were a trigger to gamble. Most gamblers had severe financial, social, or legal problems. The majority of the subjects (58%) had at least 1 first-degree relative who also exhibited symptoms of problematic gambling behavior. Pathological gambling is a disabling disorder associated with high rates of social and legal difficulties.
 
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Tardive dyskinesia (TD) has been a source of great concern to the psychiatric community because of the iatrogenic nature of the illness. Little is known about the risk of developing TD if neuroleptic medications are continued. This paper presents long-term risk estimates for TD in a prospective cohort study of 362 chronic psychiatric outpatients who were free of TD at baseline and who were maintained on neuroleptic medications. On the basis of 5 years of follow-up, we estimate the risk of persistent TD to be 32% after 5 years of neuroleptic exposure (95% confidence interval [CI] = 23%-43%), 57% after 15 years of exposure (95% CI = 47%-66%), and 68% after 25 years of exposure (95% CI = 58%-77%). For patients with 10 years of previous neuroleptic exposure, the risk is 15% after 5 more years of exposure (95% CI = 7.2%-27%) and 38% after 15 more years of exposure (95% CI = 24%-53%). Our results fall within the wide range of results found in other studies of TD incidence. Differences in incidence across studies may be explained in terms of patient characteristics and other methodological factors. One implication of this finding is that patients in the first 5 years of exposure could be targeted for prevention programs if resources are limited. A potential methodological problem encountered when studying chronically exposed patients is that they may have acquired TD (persistent) prior to the study and remitted before entry.
 
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Development of biomarkers for early detection of Alzheimer's disease (AD) is a major clinical research goal. On the basis of the hypothesis that cardiovascular risk factors contribute to the pathogenesis of AD, we investigated whether the cardiovascular risk markers midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP) predict a major clinical milestone, ie, conversion from predementia mild cognitive impairment (MCI) to manifest AD. A group of 134 MCI patients, among 137 originally prospectively recruited at the memory disorder clinic at Malmö University Hospital, Malmö, Sweden, between July 1998 and June 2001, was clinically followed for 4-6 years. We determined whether plasma concentrations of MR-proADM and MR-proANP at baseline predicted time to conversion from MCI to clinically diagnosed AD (DSM-III-R). MCI was diagnosed according to Petersen criteria. During follow-up, 41.8% of MCI patients remained cognitively stable, 42.5% converted to possible and probable AD, and 15.7% converted to other forms of dementia (MCI-other). MCI converters and MCI-other patients showed increased concentrations of MR-proANP and MR-proADM compared to the stable MCI patients (P = .0001). At a cutoff of 87 pmol/L, MR-proANP yielded a sensitivity of 73.7% and a specificity of 64.3% for predicting conversion to AD. The survival analysis showed that higher values of MR-proANP and MR-proADM were associated with progression to AD. In a multivariate Cox regression model including known risk factors, MR-proANP and MR-proADM remained independent risk factors for conversion to AD for patients below the age of 72 years. Our study shows that plasma concentrations of MR-proANP and MR-proADM have predictive value in the progression from predementia MCI to clinical AD. Sensitivity was particularly high, which may recommend this test for first-stage screening in patients at risk for AD.
 
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Four cases of sudden death in children 12 years or younger during desipramine treatment were identified between 1986 and 1992. We evaluated whether these events support the hypothesis that exposure to therapeutic doses of desipramine contributes to the risk for sudden death in otherwise healthy children. The National Center for Health Statistics provided the baseline number of sudden unexplained deaths in children 5 to 14 years old. Data from the National Disease and Therapeutic Index were used to estimate the exposure to desipramine in children in the same age group. Since two of the four deaths were identified by 1987, we used the post-1987 experience as if it were a prospective period in which a causal association could be examined. The number of sudden deaths in desipramine-exposed children did not increase from 1986 to 1992 despite a marked increase in exposure. By using 4 to 6 months as the average lifetime of a desipramine prescription and a baseline rate of sudden death of 4.2 deaths/million/year in this population, the post-1987 period would account for 162,000 to 242,000 person-years of desipramine exposure. Although not statistically significant, this level of exposure corresponds to a relative risk of 2.1 (95% CI = 0.5 to 15) to 3.1 (95% CI = 0.8 to 22). Although, based on our estimates, the evidence for an association between desipramine and sudden death in children aged 5 to 14 years appears weak, replication of our findings is needed with a more precise numerator (total number of deaths) and denominator (the appropriate conversion from drug appearance to actual exposure) before a firm conclusion on this subject can be drawn. Until then, even if remote, the possibility of an association between desipramine and sudden death in children stresses the importance of assessing risks and benefits when desipramine is used in pediatric patients.
 
Top-cited authors
David V. Sheehan
  • University of South Florida
Saundra L Stock
  • University of South Florida
Berney J. Wilkinson
  • USF Health Byrd Alzheimer's Institute
Yvonne Bannon
  • University of South Florida
Kathy Harnett-Sheehan
  • University of South Florida