Mean Clinical Global Impressions-Improvement Research Articles

Trofinetide for the treatment of Rett syndrome: Long-term safety and efficacy results of the 32-month, open-label LILAC-2 study

Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study. Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient's experience with RTT and the efficacy of trofinetide during study participation. In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n= 24/25) were satisfied or very satisfied with the benefits of trofinetide. Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves. The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.

P.045 Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC and LILAC-2 studies

Background: Trofinetide significantly improved core symptoms of Rett syndrome (RTT) with an acceptable safety profile in LAVENDER. Here, we report the safety and efficacy results of LILAC and LILAC-2, open-label extension studies of LAVENDER. Methods: Females with RTT, aged 5–21 years, received twice-daily, oral trofinetide in LILAC for 40 weeks. Participants who completed LAVENDER and LILAC continued trofinetide in LILAC-2, a 32-month extension study. Safety assessments included the incidence of adverse events (AEs). Efficacy endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression–Improvement (CGI-I) scale. Results: Overall, 154 patients were enrolled in LILAC. The most common AEs were diarrhea (74.7%) and vomiting (28.6%). The mean (standard error [SE]) change from the LAVENDER baseline to Week 40 in the LILAC study in RSBQ was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean (SE) CGI-I scores compared with the LILAC baseline at Week 40 were 3.1 (0.11) and 3.2 (0.14) for patients treated with trofinetide and placebo in LAVENDER, respectively. Similar safety and efficacy trends were observed in LILAC-2. Conclusions: Trofinetide continued to improve symptoms of RTT in LILAC and LILAC-2 with a safety profile consistent with LAVENDER.

Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study

Objective Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I) (per DSM-5 criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with BP-I. Methods Patients with BP-I were randomized to receive Ari 2MRTU 960 (n = 40) every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400; n = 41) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019–July 2020 across 16 US sites. Primary safety endpoints included reported adverse events (coded by the Medical Dictionary for Regulatory Activities preferred term), injection site reactions (assessments included a Visual Analog Scale [VAS] to evaluate patient-reported injection-site pain), and motoric symptoms. Secondary endpoints for efficacy included change from baseline at Week 32 in the Young Mania Rating Scale (YMRS), Montgomery–Åsberg Depression Rating Scale (MADRS), Clinical Global Impression – Bipolar Version (CGI-BP), and Subjective Well-being under Neuroleptic Treatment – Short Form (SWN-S) scores, and Clinical Global Impression – Improvement (CGI-I) at Week 32. Results The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (82.5% [33/40]) and AOM 400 (87.8% [36/41]; p = .5468). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 25.0% [10/40]; AOM 400: 26.8% [11/41]; p = 1). Injection-site pain was experienced by more patients in the Ari 2MRTU 960 group (25% [10/40]) versus the AOM 400 group (7.3% [3/41]; p = .0622). Mean (standard deviation [SD]) VAS scores for patient-reported injection-site pain following the last injection were 1.2 (2.07) for Ari 2MRTU 960 group and 1.3 (2.19) for AOM 400 (p = .9479) (VAS scale range 0–100 [no pain–extreme pain]). No notable improvement or decline from baseline was observed in motoric symptoms in either treatment group. Patients in both treatment groups remained clinically stable for the entire 32-week trial duration, with minimal difference between treatment groups in the least squares (LS) mean change from baseline at Week 32 in the YMRS Total (p = .8995), MADRS Total (p = .3185), and CGI-BP scores (p = .8485), and in mean CGI-I score (p = .7960). LS mean change from baseline in SWN-S score was greater for Ari 2MRTU 960 than for AOM 400 at Week 32 (p = .0169). Conclusions Ari 2MRTU 960 was well tolerated in patients with BP-I, with efficacy similar to AOM 400. Trial registration ClinicalTrials.gov identifier: NCT04030143.

Safety and Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg in Adult Patients With Bipolar I Disorder

AbstractBackgroundAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole and maintenance monotherapy treatment of BP-I [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with BP-I are reported here.MethodsPatients with BP-I were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale (VAS) scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was assessed at Week 32 by Clinical Global Impression – Improvement (CGI-I), Clinical Global Impression – Bipolar Version (CGI-BP), Subjective Well-being under Neuroleptic Treatment – Short Form (SWN-S), Montgomery–Åsberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS).ResultsStudy completion rate was 72.5% (29/40 patients) in the Ari 2MRTU 960 group and 70.7% (29/41 patients) in the AOM 400 group. Demographics and baseline disease characteristics were generally well balanced between treatment groups. Treatment-emergent AE (TEAE) incidence was 82.5% with Ari 2MRTU 960 and 87.8% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 25.0%; AOM 400, 26.8%) and injection site pain (Ari 2MRTU 960, 25.0%; AOM 400, 7.3%). Mean (standard deviation [SD]) VAS score for pain after last injection was 1.2 (2.07) with Ari 2MRTU 960 and 1.3 (2.19) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was 3.1 [1.2] with Ari 2MRTU 960 and 3.2 [1.5] with AOM 400, and there was minimal mean (SD) change from baseline in CGI-BP score (Ari 2MRTU 960, -0.2 [1.0]; AOM 400, -0.6 [1.2]). Mean (SD) change from baseline in SWN-S Total score was 10.3 (16.1) with Ari 2MRTU 960 and 3.4 (21.4) with AOM 400. There was no clinically meaningful difference between the groups in MADRS Total score or YMRS Total score (difference of least squares mean change from baseline [95% confidence interval]: MADRS Total score -2.1 [-6.3, 2.1], p=0.3185; YMRS Total score 0.1 [-1.8, 2.1], p=0.8995).ConclusionsIn patients with BP-I, Ari 2MRTU 960 was generally well tolerated, and clinical stability was maintained during the study.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Safety And Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg in Adult Patients With Schizophrenia

AbstractBackgroundAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I), versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with schizophrenia are reported here.MethodsPatients with schizophrenia were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale [VAS] scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was evaluated at Week 32 using mean (standard deviation [SD]) Clinical Global Impression – Improvement (CGI-I) score, and mean (SD) change from baseline in Clinical Global Impression – Severity (CGI-S) score, Subjective Well-being under Neuroleptic Treatment – Short Form [SWN-S] Total score, and Positive and Negative Syndrome Scale (PANSS) Total score.ResultsStudy completion rate was 79.3% (73/92 patients) in the Ari 2MRTU 960 group and 67.7% (63/93 patients) in the AOM 400 group. Demographics and disease characteristics were well balanced between groups at baseline (mean [SD] PANSS Total score: Ari 2MRTU 960, 62.0 [13.5]; AOM 400, 61.8 [13.5]; mean (SD) CGI-S score: Ari 2MRTU 960, 3.3 [0.9]; AOM 400, 3.1 [0.9]). Treatment-emergent AE (TEAE) incidence was 66.3% with Ari 2MRTU 960 and 63.4% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 21.7%; AOM 400, 18.3%) and injection site pain (Ari 2MRTU 960, 15.2%; AOM 400, 9.7%). Mean (SD) VAS score for pain after last injection was 1.5 (4.58) with Ari 2MRTU 960 and 1.3 (2.79) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was similar between groups (Ari 2MRTU 960, 3.5 [1.0]; AOM 400, 3.6 [0.9]). Minimal change from baseline was seen at Week 32 in CGI-S score and SWN-S Total score. There was no clinically meaningful difference between the groups for PANSS Total score (difference of least squares mean change from baseline [95% confidence interval]: -0.9 [-3.5, 1.8]; p=0.5154).ConclusionsIn patients with schizophrenia, administration of Ari 2MRTU 960, as compared with AOM 400, was generally well tolerated, and clinical stability was maintained during the study.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Characteristics of patients who were able to switch from benzodiazepine hypnotics to lemborexant.

Objectives:There is little evidence of insomnia treatment, especially exit strategies for hypnotics. We examined on the characteristics of patients who were able to switch from benzodiazepine hypnotics to lemborexant.Methods:Insomnia was assessed using the Athens Insomnia Scale. Efficacy outcome assessment was the Clinical Global Impressions-Improvement scale.Results:Eighty patients switched from benzodiazepine hypnotic monotherapy to lemborexant and 57 patients who continued the use of benzodiazepine hypnotics. The switched group had a significantly lower benzodiazepine hypnotic diazepam equivalent and a significantly shorter dosing period than the continued group (p < 0.001 for all). The mean Athens Insomnia Scale total score of the switched group was a significant improved (5.8 ± 3.3 to 4.0 ± 3.3; p < 0.05). The mean Clinical Global Impressions-Improvement score of the switched group was 3.3 ± 0.7.Conclusion:Our findings suggest that when administering benzodiazepine hypnotics, shortening the administration period, as much as possible, allows a smooth switch to safe long-term maintenance therapy using lemborexant, without exacerbating insomnia.

Pharmacogenetic testing in psychiatric inpatients with polypharmacy is associated with decreased medication side effects but not via medication changes

In psychiatric patients, medication adverse effects are regularly attributed to psychosomatic causes. However, many psychotropic medications are metabolized by cytochrome P450 (CYP450) enzymes. In the setting of polypharmacy, the activity of these enzymes may produce unfavorable drug-drug interactions (DDI) and drug-genotype interactions (DGI) that contribute to morbidity and mortality. This study sought to estimate the risk of adverse DDI and DGI in psychiatric inpatients with polypharmacy. We assessed whether medication changes made after pharmacogenetics (PGx) testing correlated with changes in side effects and overall improvement. Adult psychiatry inpatients with polypharmacy, defined as 5 or more scheduled prescription medications, completed the 24-item Antidepressant Side Effect Checklist (ASEC) questionnaire on enrollment and underwent PGx testing. Analysis of PGx results focused on whether the CYP2D6 and CYP2C19 phenotypes were “extreme,” defined as poor, poor to intermediate, or ultrarapid. Approximately 30 days after PGx results were sent to outpatient providers, patients were contacted to obtain their current medication list and ASEC and Clinical Global Impression Improvement (CGI-I) scores. A total of 80 patients were enrolled, and 52 (65%) completed follow-up. ASEC scores improved from 11.5 (±8.1) to 7.2 (±6.0) (p = 0.0009). Mean CGI-I score was 2.7 (±1.4), between “minimal” to “much improved.” However, linear regression revealed that these improvements were not correlated with whether medications were changed. We concluded that the impact of drug-genotype interactions in this small sample of inpatients with polypharmacy was low, and that patient improvement was related not to PGx-guided medication changes but to other treatments during hospitalization.

When Can We Predict the Outcome of an Electroconvulsive Therapy Course in Adolescents?: A Retrospective Study.

There is a dearth of up-to-date literature regarding electroconvulsive therapy (ECT) in adolescents, and the question of when to pronounce course failure has not been properly addressed. The current study aims to evaluate trajectories of clinical status throughout ECT courses in adolescent patients. We retrieved detailed data of 36 patients who received ECT in our treatment center. Clinical records were retrospectively assessed and evaluated every 6 ECT sessions to quantify Clinical Global Impressions-Improvement (CGI-I) scores. The mean number of sessions per course was 24.4 ± 14.2. The mean CGI-I score at the conclusion of the ECT courses was 2.47 ± 1.19. At the end of the acute treatment stage, 26 patients (72.2%) were much or very much improved, based on CGI-I scores. Only 5 patients exhibited a significant response after 6 sessions or fewer, whereas 21 patients (56.6%) improved after 12 sessions. Pearson correlations between CGI-I scores throughout the course of ECT showed no significant correlation between CGI-I scores after 6 sessions and the final CGI-I scores. However, a significant correlation was found between CGI-I scores after 12 sessions and the final CGI-I score. An improvement in the clinical status of adolescents treated by ECT might occur only after a substantial number of sessions. An early lack of response does not necessarily predict a failed ECT course.

Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12–17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50–800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817.

CBT-based group therapy intervention for nonepileptic attacks and other functional neurological symptoms: A pilot study

Despite the high prevalence and disabling nature of nonepileptic attacks (NEAs) and other types of functional neurological symptoms (FNSs), treatment trials are few. Preliminary evidence supports the efficacy of cognitive behavioral therapy (CBT) approaches, and CBT-based group therapies have the potential to improve cost-effectiveness and deliverability of treatment. This pilot study was undertaken to evaluate whether CBT-based group therapy would offer a feasible treatment option for patients with NEAs and other FNSs. We evaluated the outcomes of an information and management intervention within a neuropsychiatry service, which included weekly CBT-based group therapy sessions for patients with NEAs and other FNSs. Outcomes pertaining to quality of life and physical and emotional well-being were measured using the 36-item Short-Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale (HADS), and the Clinical Global Impression (CGI) scale. Data were collected from 16 patients, of whom 10 presented with NEAs. Significant improvements were selectively reported in the ‘emotional well-being’ (p=0.04) and ‘role limitation due to emotional well-being’ (p=0.04) subscores of the SF-36. Improvements in overall quality-of-life scores (p=0.22), as well as in HADS anxiety (p=0.34) and depression (p=0.46) scores, did not reach statistical significance. These trends were supported by a positive mean CGI improvement scale score of 2.4, indicating minimal-to-considerable improvement. Group therapy intervention with a CBT-based approach is a feasible treatment option in the management of NEAs and other FNSs, as shown by significant improvements in emotional domains of quality of life in this low power pilot study.

Efficacy and Tolerability of Aripiprazole: A 26-Week Switching Study from Oral Antipsychotics

ObjectiveTo determine if the maintenance effectiveness and tolerability of aripiprazole demonstrated in a 12-week study were maintained in an extension phase (up to 26 weeks).MethodsThis study was the extension of our switching study from other antipsychotics to aripiprazole in symptomatically stable patients with schizophrenia or schizoaffective disorder. All the patients were randomly assigned to the aripiprazole group or the non-aripiprazole group. The effectiveness analysis consisted of the comparison of the upper bound of the 95% confidence interval (CI) of the mean Clinical Global Impression-Improvement (CGI-I) score to 4 (no change) at the end of the study.ResultsAt the baseline, the aripiprazole group (n=135) and the non-aripiprazole group (n=31) were comparable with respect to their mean ages, gender distribution, baseline Positive and Negative Syndrome Scale scores, and Clinical Global Impression-Severity (CGI-S) scores. The study showed that the mean CGI-I score was 2.92 (95% CI: 2.72-3.12) in the aripiprazole group and 2.81 (95% CI: 2.35-3.26) in the non-aripiprazole group at 26 weeks. In the aripiprazole group, the remission rates at 12 and 26 weeks were 74.8% and 72.6%, respectively, and 80.2% of the patients with remission at 12 weeks maintained their remission state until the end of the study. About one-fourth of the patients in the aripiprazole group reported one or more spontaneous treatment-emergent adverse events, such as insomnia, headache, and nausea.ConclusionThis study suggested that most clinically stable outpatients with schizophrenia maintain their remission states after being switched to aripiprazole, without serious symptom aggravation and adverse events over a course of 26 weeks.

Efficacy and Safety of OROS Methylphenidate in Adults With Attention-Deficit/Hyperactivity Disorder

To assess the efficacy and safety of OROS methylphenidate (Concerta; McNeil Pediatrics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc, Titusville, NJ) in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. A randomized, 7-week, double-blind, placebo-controlled, dose-escalation, parallel-group study of OROS methylphenidate 36, 54, 72, 90, or 108 mg/d versus placebo was conducted in adults with ADHD. The primary end point was the Adult ADHD Investigator Symptom Report Scale. Other assessments included the Clinical Global Impressions-Improvement scale, a post hoc responder analysis, adverse events, and vital signs. Two hundred twenty-six subjects (56.2% male; mean age, 39.0 years; range, 18-65 years) were included in the intention-to-treat population (110 subjects on OROS methylphenidate; 116 subjects on placebo). OROS methylphenidate resulted in greater ADHD symptom improvement than placebo as demonstrated by a statistically significantly lower least squares mean change from baseline in Adult ADHD Investigator Symptom Report Scale total score at the final visit (last observation carried forward [LOCF]; P = 0.012). Subjects on OROS methylphenidate also had a significantly lower least squares mean Clinical Global Impressions-Improvement score at the final visit (LOCF; P = 0.008). A significantly greater proportion of subjects on OROS methylphenidate (36.9%, 38/103 subjects) were responders at the final visit (LOCF) compared with placebo (20.9%, 24/115 subjects; P = 0.009). OROS methylphenidate was well tolerated. Adverse events were reported by 93 (84.5%) of the 110 OROS methylphenidate-treated subjects versus 74 (63.8%) of the 116 placebo-treated subjects. No serious treatment-emergent adverse events and no deaths were reported. Similar mean changes from baseline to final visit (LOCF) for systolic and diastolic blood pressures for the OROS methylphenidate and placebo groups were observed. In a dose escalation ranging from 36 to 108 mg/d, OROS methylphenidate is effective and well tolerated in the management of ADHD in adults.

A Multicenter, Randomized, Double-Blind Study of the Effects of Aripiprazole in Overweight Subjects With Schizophrenia or Schizoaffective Disorder Switched From Olanzapine

Major mental disorders are associated with an increased risk for obesity-related cardiovascular mortality, leading to interest in risk-reduction approaches that target weight and risk-related plasma lipids, including use of antipsychotic agents with low metabolic risk. This multicenter, randomized, double-blind study compared the metabolic effects of aripiprazole versus olanzapine in overweight persons with schizophrenia or schizoaffective disorder who were previously on olanzapine treatment. In total, 173 subjects with DSM-IV-TR-defined schizophrenia or schizoaffective disorder were randomly assigned to receive aripiprazole (N = 88) or olanzapine (N = 85) for 16 weeks in a study conducted from March 30, 2004, to August 8, 2006. Primary and secondary endpoints were mean weight change from baseline and percentage change from baseline in fasting triglyceride levels, respectively. At week 16, weight decreased significantly with aripiprazole versus olanzapine (-1.8 vs. +1.41 kg; p < .001). Significant differences in percentage change in triglyceride levels were observed with aripiprazole (decreases) versus olanzapine (increases) at all time-points. In addition, significantly more subjects receiving aripiprazole had clinically relevant (> or = 7%) weight loss versus olanzapine (11.1% vs. 2.6%; p = .038), and a lower percentage of subjects receiving aripiprazole had clinically relevant weight gain (2.5% vs. 9.1%; p = .082). Mean percentage changes in fasting total cholesterol and high-density lipoprotein cholesterol at week 16 were significantly different with aripiprazole versus olanzapine, with no significant effects on glycemic laboratory measures. Mean Clinical Global Impressions-Improvement (CGI-I) scores for both groups were in the range of "no change" to "minimal improvement." CGI-I endpoint scores were statistically significantly better with olanzapine (mean +/- SE = 3.09 +/- 0.16) versus aripiprazole (mean +/- SE = 3.74 +/- 0.15; p < .001), and more subjects discontinued aripiprazole (N = 32/88; 36%) than olanzapine (N = 22/85; 26%). Significant improvements in weight and lipids observed during discontinuation of olanzapine and switch to aripiprazole treatment occurred with limited evidence of negative psychiatric effects, relative to uninterrupted continuation of olanzapine treatment. The results suggest that the potential value of therapeutic substitutions involving specific antipsychotic medications should be considered in overall efforts to reduce cardiovascular risk in this population.

Outcomes and Length of Treatment With Carbamazepine Extended-Release Capsules in Bipolar Disorder

This analysis was a retrospective chart review evaluating the relationship between outcomes and length of treatment with carbamazepine extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) in bipolar disorder. The medical records of adult patients (>or=18 years) meeting DSM-IV criteria for bipolar disorder who were treated with CBZ-ERC for 30 days or less, 31 to 180 days, and more than 180 days were reviewed in this study. There were significant differences in mean Clinical Global Impression-Improvement (CGI-I) scores at the best office visit among the three treatment groups. The mean CGI-I scores for the 31- to 180-day (2.3+/-1.1) and >180-day (1.8+/-1.0) groups were significantly lower than the mean score for the <or=30-day treatment group (p<0.0001), and the mean CGI-I score for the >180-day group was significantly lower than that of the 31- to 180-day group (p=0.0027). Significantly fewer patients in the 31- to 180-day (5.4%; p=0.0039) and >180-day groups reported nausea (4.8%; p=0.034) when compared to the <30 day group. The results of this study indicate that future controlled studies are warranted to further explore the safety and efficacy of CBZ-ERC as a long-term therapy for bipolar disorder.

Carbamazepine Extended-Release Capsules Use in Bipolar Disorder: Efficacy and Safety in Adult Patients

Safety, tolerability, and efficacy of carbamazepine (CBZ) have been demonstrated in numerous studies over the last three decades. Until recently, CBZ studies largely involved immediate-release formulations, while long-term studies have been few in number. The recent development of beaded CBZ extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) provides a new formulation with potential advantages in safety, tolerability, and efficacy over earlier formulations. The present study assesses these parameters in patients of various bipolar subtypes (mixed/manic, bipolar I depression, and bipolar II), in a single-site private practice setting. Data were obtained from the charts of 300 patients>or=18 years old who met DSM-IV criteria for bipolar disorder. Clinical response to CBZ-ERC therapy was defined as a score of <or=3 on the Clinical Global Impression-Improvement (CGI-I) scale, while relapse was defined as a change in CGI-I to >or=4 in those subjects who had previously achieved clinical response. Clinical response occurred in 73% of patients, leading to a mean CGI-I score of 2.5 (SD=1.2). Relapse was seen in 33% of responders. Most common adverse events were somnolence, dizziness, and nausea. A high level of treatment response and a low relapse rate were observed in long-term treatment with CBZ-ERC in adults with bipolar disorder. The limited number and nature of the adverse events observed during the course of this study provide evidence of the safety and tolerability of CBZ-ERC. Carbamazepine extended-release capsules appear safe and efficacious for the treatment of bipolar disorder. Controlled studies are warranted to further establish the safety, tolerability, and efficacy of CBZ-ERC for treatment of adult bipolar patients.

Mood stabilizers in hospitalized children with bipolar disorder: a retrospective review.

A paucity of naturalistic data supported a rationale for the present retrospective review of clinical changes during hospitalization in 44 bipolar pre-adolescents, treated with monotherapy lithium, carbamazepine (CBZ) or divalproex sodium (DVP). Daily staff progress notes and discharge summaries on each patient were read by four trained clinicians blind to treatment group, and rated according to the Clinical Global Impression Improvement (CGI-I) scale. Consensus rating was measured by kappa reliability. Data were analyzed using a general linear model (sas mixed) analysis of variance (anova) with repeated measures. The medication groups did not differ in length of hospitalization, overall severity of illness at the time of admission, or comorbidity. Prior treatment was considered as a covariate. Each group approached serum therapeutic levels at day 7 of the medication period. The estimated mean CGI-I scores for CBZ were systematically higher (i.e. worse) than those for lithium and DVP, which overlapped and crossed over time. The difference became increasingly apparent and was statistically significant by week 2 (P = 0.036). The present study was limited in that the sample sizes, particularly in the case of CBZ, were small, commensurate with the low prevalence of the disorder. Lack of structured interviews, as an independent assessment of diagnoses was an intrinsic limitation of the study. Although constrained by its retrospective nature, our findings suggest that by week 2 of hospitalization both lithium and DVP may be more efficacious than CBZ in bipolar pre-adolescents. Any significant finding must be viewed as tentative and subject to confirmation in other studies.

Divalproex in the management of neuropsychiatric complications of remote acquired brain injury.

A retrospective chart review was conducted on 11 patients with a remote history of acquired brain injury (ABI) referred for psychiatric treatment who were treated with divalproex sodium alone or in combination with other psychotropic medications. The patients were highly heterogeneous. They had a variety of psychiatric symptoms and frequently received concomitant psychotropic medications. The mean daily dose of divalproex was 1,818+/-791 mg/day, serum valproic acid level 85.6+/-29.6 microg/ml. Mean Clinical Global Impression improvement score was 1.9+/-0.5. This is the largest postacute case series reported. It demonstrates that divalproex sodium is well tolerated and effective in reducing a broad range of neurobehavioral symptoms in psychiatric patients with a remote history of ABI.

Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial

To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. Paroxetine is generally well tolerated and effective for major depression in adolescents.

An open assessment of the acceptability, efficacy, and tolerance of venlafaxine in usual care settings

An open-label study in 518 outpatients with major depression was performed by a collaborative group involving 105 psychiatrists in 22 cities in Mexico. The objectives of this study were to assess the tolerance and efficacy of venlafaxine, a new antidepressive drug, in outpatients in usual care settings. The two largest psychiatric medical associations approved the proposed protocol, and their chairmen coordinated the study. Patients had to comply with the diagnostic criteria for major depression as stated in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised. The Hamilton Depression rating scale (21 items) and the Clinical Global Impressions (CGI) rating scale were used to assess a patient's clinical response to drug, which was prescribed in different doses (37.5 to 75 mg, 100 to 150 mg, and 175 to 300 mg) according to a patient's status at enrollment. Patients were followed for 6 weeks. A total of 435 patients (84%) completed the study. After 7 days of treatment with venlafaxine, there was a statistically significant improvement in patients with mild-to-moderate depression—those in the 37.5- to 75- mg group (mean CGI improvement, 3.8% to 38.2%) and in the 100- to 150-mg group (mean CGI improvement, 1.3% to 16.7%)—and by day 14 in patients with severe depression—those in the 175- to 300-mg group (mean CGI improvement at day 14, 1.8% to 20.0%). The efficacy of venlafaxine was assessed in all three groups by day 42, with statistically significant improvement observed after treatment with venlafaxine as compared with baseline. The adverse events most frequently associated with the use of venlafaxine were nausea (35.13%) and headache (17.95%), which did not differ in nature and intensity from that reported by other investigators. A total of 83 patients withdrew from the study; 50 of these dropped out due to an adverse event. Although the study design weakened the conclusions drawn from this study, in this 6-week, open-label, uncontrolled trial, venlafaxine appeared to be an efficacious, well-tolerated antidepressant in patients with major depression, with improvement generally detected in about 1 week.