Met Responder Criteria Research Articles

Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study.

BackgroundPegloticase, a PEGylated uricase for uncontrolled gout, rapidly lowers serum urate (SU). Not all patients complete a full-therapy course because anti-pegloticase antibodies can develop, causing efficacy loss and infusion reactions. The literature and clinical trial data indicate that methotrexate co-administration markedly improves pegloticase response rates from the established monotherapy response rate of 42%. Unfortunately, methotrexate use is restricted by kidney disease, which is often present in uncontrolled gout patients. Leflunomide is less restricted in patients with renal dysfunction. This study examined the treatment response rate of pegloticase co-administered with leflunomide.MethodsPatients co-treated with pegloticase (8 mg biweekly infusion) and oral leflunomide (20 mg/day) were included. Patient/treatment characteristics and safety parameters (adverse events [AEs], laboratory parameters) were examined. Pre-infusion prophylaxis was administered (day of infusion: IV solumedrol, night before and morning of infusion: oral fexofenadine or diphenhydramine). Patients were considered treatment responders if ≥ 12 pegloticase infusions were administered and pre-infusion SU < 6 mg/dl at infusion-12.ResultsTen patients (five male, 72.7 ± 12.5 years) were included. The most common comorbidities were chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), and congestive heart failure (50%). Baseline SU was 7.1 ± 2.4 mg/dl and nine patients (90%) had subcutaneous tophi noted. Seven patients (70%) met responder criteria, receiving 26.6 ± 14.0 infusions (range 13–55) with a pre-infusion-12 SU of 0.9 ± 1.5 mg/dl. The three non-responders received < 12 infusions because of unrelated AEs or loss of follow-up. Three patients (30%) experienced AEs. One had unrelated cardiac disease worsening and three gout flares, one had a pre-infusion solumedrol reaction (wooziness/loss of consciousness), and one had two mild, transient increases in liver enzymes.ConclusionsThis study supports leflunomide as co-therapy to pegloticase in uncontrolled gout patients. Heterogeneity and high comorbidity burden in uncontrolled gout patients makes having a variety of immunomodulators options important.

Transcranial Photobiomodulation in Adults with High-Functioning Autism Spectrum Disorder: Positive Findings from a Proof-of-Concept Study

Objective: To assess the efficacy and safety of transcranial photobiomodulation (tPBM) in adults with autism spectrum disorder (ASD). Methods: Adults with high-functioning-ASD, between 18 and 59 years of age, were enrolled to receive twice a week tPBM for 8 weeks in an open-label single group design. ASD symptom severity was assessed at baseline, midpoint, and end-point, by clinician-, self-, and informant-rated measures. Treatment response was defined as a ≥30% reduction in Social Responsiveness Scale-2nd Edition (SRS-2) total score and ASD Clinical Global Impression-Improvement score ≤2. Any possible adverse events were recorded at each visit. Paired-samples t-test analyses were performed. Results: Eleven participants were enrolled, and 10 participants (9 males; 30.0 ± 11.9 years) completed the study. One participant withdrew consent before baseline. All 10 completers were included in efficacy and safety analyses. Five participants (50%) met responder criteria at end-point. Overall, 8-week tPBM was associated with significant reduction in SRS-2 total scores at end-point (SRS-2: -30.6 ± 23, p < 0.001) particularly in Social Awareness (-3.0 ± 1.9, p < 0.001), Social Communication (-10.3 ± 6, p < 0.001), Social Motivation (-5.0 ± 2.4, p < 0.001), and Restricted/Repetitive Behaviors (-7.4 ± 4.1, p < 0.001). There were statistically significant improvements at end-point in Global Assessment of Functioning scores (+12.8 ± 4.2, p < 0.001) and Quality of Life Enjoyment and Satisfaction Questionnaire scores (+6.0 ± 7.9, p = 0.02). Three participants experienced transient, mild side effects (insomnia, headache, and warmth at treatment application site). No adverse events required changes in tPBM protocol. Adherence rate was 98%. Conclusions: tPBM is a safe and feasible treatment approach that has the potential to treat core features of ASD. Further research is necessary and warranted. ClinicalTrials.gov Identifier: NCT03724552.

Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial

ObjectivesThe purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF). BackgroundThere are no proven effective treatments for patients with PH-HFpEF. MethodsPatients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages. ResultsThirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (−1.4 mm Hg; 95% confidence interval [CI]: −7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (−3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo. ConclusionsSix weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603)

Benefits Beyond Headache Days With OnabotulinumtoxinA Treatment: A Pooled PREEMPT Analysis.

IntroductionThe double-blind, phase 3 PREEMPT trials demonstrated the efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis evaluated the effect of onabotulinumtoxinA on clinically meaningful changes in headache severity, headache-related impact, and quality of life.MethodsPooled, 24-week data were used to determine percentages of patients meeting responder criteria for the change in headache days (≥ 50% reduction in headache-day frequency), Headache Impact Test (HIT-6; ≥ 5-point improvement), MSQ Role Function-Restrictive (MSQ-RFR; ≥ 10.9-point improvement), and Average Daily Headache Severity (ADHS; ≥ 1-point improvement on a 4-point ordinal scale [0 = no pain, 3 = severe pain]).ResultsIn the pooled analysis population (N = 1384; onabotulinumtoxinA, n = 688; placebo, n = 696), significantly more patients treated with onabotulinumtoxinA compared with placebo were responders on HIT-6 (40.8 vs. 25.3%), MSQ-RFR (59.0 vs. 40.2%), and ADHS (35.5 vs. 22.4%) measures, and achieved traditional ≥ 50% reduction in headache days (44.8 vs. 34.2%; all P < 0.001). At least one responder criterion was met by 72.1% and 56.6% of onabotulinumtoxinA- and placebo-treated patients, respectively; all four were met by 20.4% and 8.6%, respectively (P < 0.001). Linear regression analysis showed that approximately 20% of the variance in HIT-6 and MSQ-RFR improvement was explained by improvement in headache days.ConclusionsTreatment with onabotulinumtoxinA for 24 weeks was associated with clinically meaningful benefits beyond reduction in headache days; including reductions in headache severity and headache-related impact, and improved quality of life. While 45% of patients met responder criteria for monthly headache days, over 70% had clinically meaningful improvements on at least one outcome measure.Trial RegistrationClinicalTrials.gov identifier, NCT00156910 (PREEMPT 1) and NCT00168428 (PREEMPT 2)

Efficacy and Safety of Lurasidone in Adolescents with Schizophrenia: A 6-Week, Randomized Placebo-Controlled Study.

Objective: To evaluate the efficacy and safety of lurasidone in acutely symptomatic adolescent patients with schizophrenia.Methods: Patients aged 13–17 years were randomly assigned to 6 weeks of double-blind, fixed-dose lurasidone (40 or 80 mg/day) or placebo. Primary and key secondary efficacy measures were change from baseline to week 6 in the Positive and Negative Symptom Scale (PANSS) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively, using mixed model for repeated measurement (MMRM) analysis. The proportion of patients achieving treatment response at endpoint, based on ≥20% reduction in PANSS total score, was analyzed using a logistic regression model.Results: Least-squares (LS) mean change in PANSS total score from baseline to week 6 was −18.6 with lurasidone 40 mg/day (N = 108; p < 0.001 vs. placebo; effect size = 0.51), −18.3 with lurasidone 80 mg/day (N = 106; p < 0.001 vs. placebo; effect size = 0.48), and −10.5 with placebo (N = 112). Similarly, LS mean change in CGI-S score from baseline to week 6 was significantly greater with lurasidone 40 mg/day (−1.0; p < 0.001; effect size = 0.49) and 80 mg/day (−0.9; p = 0.0015; effect size = 0.45) compared with placebo (−0.5). A significantly higher proportion of patients met responder criteria on lurasidone 40 and 80 mg/day versus placebo (63.9% and 65.1% vs. 42.0%; p < 0.001 for both comparisons). The rate of study discontinuation was 10.3% in lurasidone-treated and 17.7% in placebo-treated patients. The most common adverse events (incidence ≥5% in either lurasidone dose group and at least twice the rate of placebo) for lurasidone 40 mg/day, 80 mg/day, and placebo, respectively, were nausea (12.7%, 14.4%, and 2.7%), somnolence (9.1%, 11.5%, and 5.4%), akathisia (9.1%, 8.7%, and 1.8%), vomiting (8.2%, 6.7%, and 1.8%), and sedation (5.5%, 1.9%, and 1.8%). Treatment with lurasidone was not associated with clinically meaningful effects on body weight, lipids, measures of glycemic control, or prolactin.Conclusions: In this 6-week study, lurasidone at doses of 40 and 80 mg/day demonstrated statistically significant and clinically meaningful symptom improvement in adolescent patients with schizophrenia. Lurasidone was generally well tolerated with few effects on weight and metabolic parameters, consistent with findings in adult patients with schizophrenia.

PLACEBO-CONTROLLED TRIAL OF DONEPEZIL FOLLOWING ANTIDEPRESSANT TREATMENT IN PATIENTS WITH COMORBID DEPRESSION AND COGNITIVE IMPAIRMENT

In patients with comorbid depression and cognitive impairment, antidepressants are commonly used but the utility of cholinesterase inhibitors (CheI) as cognitive enhancers is not established. Eighty elderly (55–95 years old) depressed, cognitively impaired (DEP-CI) patients participated in the DOTCODE study at two sites: Columbia and Duke University Medical Centers. 40 of 79 patients who received antidepressant medication in the initial phase met criteria for amnestic mild cognitive impairment (MCI). After 16 weeks of open-label antidepressant treatment with antidepressants, primarily citalopram or venlafaxine, 61 patients were randomized to receive 62 weeks of the CheI donepezil 5–10 mg daily or placebo in a randomized, double-blind trial. Linear mixed effects models with random subject-specific intercepts were used to model ADAS-Cog13 and Selective Reminding Test (SRT) Total Immediate Recall over the course of the study. All models include baseline value of the outcome, age, study site, treatment, visit week, and the interaction between treatment and visit week (and interaction terms to test for moderators). In the first 16 weeks, depression improved in most patients and 39 of 61 randomized patients (64%) met responder criteria. In the 61 randomized patients, donepezil did not differ from placebo in change in the co-primary measures of ADAS-Cog13 (F=0.18, p=0.83) and SRT total recall (F=0.06, p=0.9). Four patients were diagnosed with probable Alzheimer's disease by end-trial. Apolipoprotein E e4 allele and MRI hippocampal volume were unrelated to differences in outcomes between donepezil and placebo. Periventricular hyperintensities (PVH) did not distinguish changes in cognition on donepezil from placebo on ADAS-Cog13 (F1,39 = 0.14, p = 0.71) but did on SRT total recall (F1,39 = 4.23, p = 0.04); less PVH was associated with greater improvement with donepezil on SRT total recall. In patients with comorbid depression and cognitive impairment, the addition of donepezil following antidepressant medication treatment did not improve cognition compared to placebo, though donepezil treatment was associated with better cognition in patients with less cerebrovascular disease. The findings add to those from studies in mild cognitive impairment without depression that have not demonstrated superiority for CheI over placebo in improving cognition.

Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder.

This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9. Analyses evaluated effects of XR-NTX + BRP to determine the number of "responders" according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield ≥3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2). Under the statistical analysis plan, study "success" required ≥9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study.

Guanfacine extended release for children and adolescents with attention-deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment.

Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized-withdrawal study (RWS). Participants were 6–17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores ≥32 and Clinical Global Impressions – Severity scores ≥4. RCT participants received dose-optimized GXR (1–7 mg/day), ATX (10–100 mg/day), or placebo for 10–13 weeks. RWS participants received dose-optimized GXR (1–7 mg/day) for 13 weeks. Participants’ last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, −9.8, P<0.001, effect size [ES] 0.85; stimulant-naïve, −7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naïve (−5.0, P=0.022, ES 0.43) but not prior MPH-treated (−1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naïve participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments.

The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study.

This study examined the effects of milnacipran on polysomnographic (PSG) measures of sleep and subjective complaints in patients with fibromyalgia and disturbed sleep. This was a single-site, double-blind, placebo-controlled, two-period crossover PSG study. Eligible subjects (aged 28-72 y) were randomized (1:1) to milnacipran (100 mg/d) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-escalation and dose-maintenance phase, with a 2-w taper/washout between periods. In-laboratory PSGs were collected at baseline, and at the end of each treatment period. The primary endpoints were the difference in PSG-recorded wake after sleep onset (WASO), number of awakenings after sleep onset (NAASO), and sleep efficiency (SE) between 4 w of maintenance treatment with milnacipran and placebo. Other PSG measures, subject-rated sleep, fatigue, physical functioning, and pain were assessed. Post hoc analysis was performed in subjects showing at least 25% reduction in pain from baseline in the Brief Pain Inventory Score (responders). Of 19 subjects randomized, 15 completed both periods. Subjects treated with milnacipran showed no significant improvements in WASO and NAASO, but showed reduced SE (p = 0.049). Milnacipran did not show significant improvement in other PSG parameters or subjective endpoints. Two thirds of completers met responder criteria and additionally showed a significant improvement in daily effect of pain (p = 0.043) and subjective sleep quality (p = 0.040). The data suggest that milnacipran is not sedating in most patients with fibromyalgia and improvements in sleep are likely a result of pain improvement. ClinicalTrials.gov, identifier: NCT01234675.

Modular Cognitive-Behavioral Therapy for Body Dysmorphic Disorder: A Randomized Controlled Trial

There are few effective treatments for body dysmorphic disorder (BDD) and a pressing need to develop such treatments. We examined the feasibility, acceptability, and efficacy of a manualized modular cognitive-behavioral therapy for BDD (CBT-BDD). CBT-BDD utilizes core elements relevant to all BDD patients (e.g., exposure, response prevention, perceptual retraining) and optional modules to address specific symptoms (e.g., surgery seeking).Thirty-six adults with BDD were randomized to 22 sessions of immediate individual CBT-BDD over 24 weeks (n=17) or to a 12-week waitlist (n=19). The Yale-Brown Obsessive-Compulsive Scale Modified for BDD (BDD-YBOCS), Brown Assessment of Beliefs Scale, and Beck Depression Inventory–II were completed pretreatment, monthly, posttreatment, and at 3- and 6-month follow-up. The Sheehan Disability Scale and Client Satisfaction Inventory (CSI) were also administered. Response to treatment was defined as ≥30% reduction in BDD-YBOCS total from baseline. By week 12, 50% of participants receiving immediate CBT-BDD achieved response versus 12% of waitlisted participants (p=0.026). By posttreatment, 81% of all participants (immediate CBT-BDD plus waitlisted patients subsequently treated with CBT-BDD) met responder criteria. While no significant group differences in BDD symptom reduction emerged by Week 12, by posttreatment CBT-BDD resulted in significant decreases in BDD-YBOCS total over time (d=2.1, p<0.0001), with gains maintained during follow-up. Depression, insight, and disability also significantly improved. Patient satisfaction was high, with a mean CSI score of 87.3% (SD=12.8%) at posttreatment. CBT-BDD appears to be a feasible, acceptable, and efficacious treatment that warrants more rigorous investigation.

Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder

The objective of this study was to evaluate the efficacy and safety of pregabalin in preventing relapse in generalized social anxiety disorder (SAD). Patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) generalized SAD, who met responder criteria after 10 weeks of open-label treatment with fixed-dose pregabalin (450 mg/day; n=153), were randomly assigned to 26 weeks of double-blind treatment with pregabalin (450 mg/day) or placebo. The primary a-priori outcome of time to relapse was analyzed using the Kaplan-Meier method and the log-rank test. Double-blind treatment with pregabalin was associated with significant delay in time to relapse versus placebo (P=0.035), and with significantly greater maintenance of symptomatic improvement over 26 weeks on the Liebowitz Social Anxiety Scale total (P=0.012) and subscale scores and on the Marks Fear Questionnaire total phobia (P=0.010) and social phobia (P=0.014) subscales. Pregabalin was generally well tolerated. During the double-blind phase, the adverse events that occurred more frequently with pregabalin compared with placebo were dizziness (11.3 vs. 4.1%) and infection (21.3 vs. 16.4%). The results of this study suggest that pregabalin (450 mg/day) is safe, well tolerated, and has significant relapse-prevention efficacy over 26 weeks in patients with SAD who responded to an initial course of the pregabalin treatment.

P.1.g.015 A cognitive behavioural therapy group treatment program for body dysmorphic disorder: preliminary results

There are few effective treatments for body dysmorphic disorder (BDD) and a pressing need to develop such treatments. We examined the feasibility, acceptability, and efficacy of a manualized modular cognitive-behavioral therapy for BDD (CBT-BDD). CBT-BDD utilizes core elements relevant to all BDD patients (e.g., exposure, response prevention, perceptual retraining) and optional modules to address specific symptoms (e.g., surgery seeking).Thirty-six adults with BDD were randomized to 22 sessions of immediate individual CBT-BDD over 24 weeks (n = 17) or to a 12-week waitlist (n = 19). The Yale-Brown Obsessive-Compulsive Scale Modified for BDD (BDD-YBOCS), Brown Assessment of Beliefs Scale, and Beck Depression Inventory–II were completed pretreatment, monthly, posttreatment, and at 3- and 6-month follow-up. The Sheehan Disability Scale and Client Satisfaction Inventory (CSI) were also administered. Response to treatment was defined as ≥ 30% reduction in BDD-YBOCS total from baseline. By week 12, 50% of participants receiving immediate CBT-BDD achieved response versus 12% of waitlisted participants (p = 0.026). By posttreatment, 81% of all participants (immediate CBT-BDD plus waitlisted patients subsequently treated with CBT-BDD) met responder criteria. While no significant group differences in BDD symptom reduction emerged by Week 12, by posttreatment CBT-BDD resulted in significant decreases in BDD-YBOCS total over time (d = 2.1, p < 0.0001), with gains maintained during follow-up. Depression, insight, and disability also significantly improved. Patient satisfaction was high, with a mean CSI score of 87.3% (SD = 12.8%) at posttreatment. CBT-BDD appears to be a feasible, acceptable, and efficacious treatment that warrants more rigorous investigation.

Adjunctive zonisamide for treatment refractory anxiety

The aim of the study was to assess the use of a novel anticonvulsant, zonisamide, in patients with treatment refractory anxiety. Pilot and open study of a cohort of patients with anxiety (n = 10), who were deemed partial or non-responders to anxiolytic therapy, and received adjunctive zonisamide in a naturalistic fashion. The primary outcome measures were the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impression of Severity (CGI-S) and the Clinical Global Impression of Improvement (CGI-I). Patients included were markedly ill with a mean number of previous medication trials of 4.9 +/- 1.9, a baseline HAM-A score of 27.9 +/- 3.8, and a baseline CGI-S score of 5.7 +/- 0.5. Patients improved significantly with an end-point HAM-A score of 12.6 +/- 7.4 (p < 0.001), CGI-S score of 3.6 +/- 1.3 (p < 0.002) and CGI-I score of 2.5 +/- 1.3. Zonisamide at a mean +/- SD dose of 160 +/- 70 mg/day for 9.2 +/- 4.5 weeks was generally well tolerated. Adverse events were generally mild, and no patients discontinued zonisamide because of side effects. Six patients (60%) met responder criteria at end-point (CGI-I <or= 2). Results from this pilot and open naturalistic study suggest that zonisamide may effectively augment response to anxiolytic medications in patients with treatment refractory anxiety. Larger and controlled studies are warranted to confirm these preliminary findings.

N-Acetyl Cysteine, a Glutamate-Modulating Agent, in the Treatment of Pathological Gambling: A Pilot Study

Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. N-acetyl cysteine (NAC), an amino acid, seems to restore extracellular glutamate concentration in the nucleus accumbens and therefore offers promise in reducing addictive behavior. Twenty-seven subjects (12 women) with DSM-IV PG were treated in an 8-week open-label trial of NAC with responders (defined as a > or = 30% reduction in Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score at end point) randomized to 6 weeks of double-blind NAC or placebo. The PG-YBOCS scores decreased from a mean of 20.3 +/- 4.1 at baseline to 11.8 +/- 9.8 at the end of the open-label phase (p < .001). Sixteen of 27 subjects (59.3%) met responder criteria. The mean effective dose of NAC was 1476.9 +/- 311.3 mg/day. Of 16 responders, 13 entered the double-blind phase. Of those assigned to NAC, 83.3% still met responder criteria at the end of the double-blind phase, compared with only 28.6% of those assigned to placebo. The efficacy of NAC lends support to the hypothesis that pharmacological manipulation of the glutamate system might target core symptoms of reward-seeking addictive behaviors such as gambling. Larger, longer, placebo-controlled double-blind studies are warranted.

Levetiracetam for Treatment-Refractory Posttraumatic Stress Disorder

To assess the use of levetiracetam, a novel anticonvulsant agent, in the treatment of refractory posttraumatic stress disorder (PTSD). Retrospective analysis was conducted of 23 patients with DSM-IV diagnosis of PTSD who, after being deemed partial or nonresponders to antidepressant therapy, received levetiracetam in a naturalistic fashion. The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). Secondary outcome measures included the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impressions-Severity of Illness scale (CGI-S), and Clinical Global Impressions-Improvement scale (CGI-I). Levetiracetam at a mean+/-SD dose of 1967+/-650 mg/day for 9.7+/-3.7 weeks was generally well tolerated. Nineteen patients (83%) were taking at least 1 concomitant medication. Patients were severely ill with a mean baseline PCL-C score of 67.2+/-9.4, CGI-S score of 6.0+/-0.7, and HAM-A score of 26.8+/-4.9. Patients improved significantly on all measures (p<.001). Thirteen patients (56%) met responder criteria at endpoint (PCL-C mean change=23.5, CGI-I score<or=2), and 6 (26%) met remission criteria (CGI-S score<or=2). Adverse events were generally mild, and no patients discontinued levetiracetam because of side effects. These preliminary data suggest that levetiracetam may be an effective treatment in combination with antidepressant therapy for patients with PTSD who remain symptomatic after initial intervention.

Effectiveness of chromium in atypical depression: a placebo-controlled trial

Background Chromium picolinate (CP) has been reported to benefit patients with symptoms of atypical depression. Methods A placebo-controlled, double-blind, pilot study of CP was conducted in 15 patients with DSM-IV major depressive disorder, atypical type. Patients received 600 μg of CP or matching placebo (PBO) for 8 weeks. Results Seven (70%) CP and zero (0%) PBO patients met responder criteria ( p = .02). Other outcomes were consistent with greater effect of CP. Three patients on CP failed to show any improvement. Chromium picolinate was well tolerated. Conclusions Chromium picolinate shows promising antidepressant effects in atypical depression. Its mechanism of action may relate to 5HT 2A downregulation, increased insulin sensitivity, or to other effects.

Sertraline maintenance treatment reduced relapse and dropouts in post-traumatic stress disorder

Davidson J, Pearlstein T, Londborg P, et al. Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28- week double-blind, placebo-controlled study . Am J Psychiatry2001...

Sertraline maintenance treatment reduced relapse and dropouts in post-traumatic stress disorder

(2001) Am J Psychiatry 158, 1974; Davidson J, Pearlstein T, Londborg P, et al. . Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind,...

The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial

A previous report suggested that 5 weeks of continued treatment with 20 mg of fluoxetine was approximately as effective as double-blind titration to a dose of 60 mg in patients who had failed to respond to 3 weeks of initial treatment at 20 mg. The current study was undertaken to evaluate whether 150 mg of sertraline was any more effective than 50 mg in treating depressed patients who were non-responders at 3 weeks. Ninety-one outpatients with DSM-IV major depressive disorder who had a 17-item Hamilton Depression Rating Scale (HAM-D) score > or = 18 were treated with open label sertraline for 3 weeks. Patients who did not achieve remission (defined as 17-item HAM-D total score < or = 8 by week 3) were then randomized to 5 more weeks of double-blind treatment with either 50 mg of sertraline or immediate titration to 150 mg of sertraline. Efficacy was assessed at each visit with the HAM-D, Clinical Global Impressions (CGI)-severity and improvement scale, and the Hopkins Symptom Checklist. There were no significant between-group differences in clinical or demographic features at baseline for the three treatment groups. After 3 weeks of open-label treatment, 16 patients were not randomized, of whom 11 (69%) met responder criteria. The remaining patients were randomized, double-blind, to 50 mg of sertraline (n = 37; HAM-D = 19.2 +/- 5.0) or 150 mg of sertraline (n = 38; HAM-D = 18.4 +/- 5.0). PROC-Mixed analyses found no significant difference in slopes for any outcome measure when comparing 50 mg and 150 mg sertraline treatment groups. At week 8 (LOCF), the overall remission rate (HAM-D < or = 8) for 3-week non-responders was 40%, with no statistically significant between-group difference for the 50 mg versus 150 mg doses of sertraline (P > 0.10). A completer analysis yielded similar results. Adverse events were mostly mild on both doses of sertraline and led to few treatment discontinuations. The results suggest that for most patients continued treatment with 50 mg dose of sertraline yields a rate of antidepressant response that is comparable to what is achieved by dose escalation from 50 mg to 150 mg of sertraline after 3 weeks of treatment. While some patients clearly benefit from higher doses, the results of the current study are consistent with the lack of any evidence for a dose-response curve with sertraline in the treatment of depression.