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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.