Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Reduction in Multiple Cardiometabolic Risk Factors With Combined Olanzapine/Samidorphan Compared With Olanzapine: Post Hoc Analyses From a 24-Week Phase 3 Study.

BACKGROUND AND HYPOTHESES: Weight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine. STUDY DESIGN: This phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids. RESULTS: After 24 weeks' treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, -2.63 mm Hg; 95% CI: -4.78, -0.47), diastolic blood pressure (LSM difference, -0.75 mm Hg; 95% CI: -2.31, 0.80), and BMI (LSM difference, -0.65 kg/m2; 95% CI: -1.01, -0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia. CONCLUSIONS: OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.

Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression.

BACKGROUND: Negative stress significantly impacts major depressive disorder (MDD), given the shared brain circuitry between the stress response and mood. Thus, interventions that target this circuitry will have an important impact on MDD. The aim of this study was to evaluate the acute effects of a novel respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique in the modulation of brain activity and connectivity in women with MDD in response to negative stressful stimuli. METHODS: Twenty premenopausal women with recurrent MDD in an active episode were included in a cross-over experimental study that included two functional MRI visits within one week, randomized to receive exhalatory- (e-RAVANS) or inhalatory-gated (i-RAVANS) at each visit. Subjects were exposed to a visual stress challenge that preceded and followed RAVANS. A Factorial analysis was used to evaluate the effects of RAVANS on brain activity and connectivity and changes in depressive and anxiety symptomatology post-stress. RESULTS: Compared with i-RAVANS, e-RAVANS was significantly associated with increased activation of subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices and increased connectivity between hypothalamus and dorsolateral prefrontal cortex, and from nucleus tractus solitarii to locus coeruleus and ventromedial prefrontal cortex. Changes in brain activity and connectivity after e-RAVANS were significantly associated with a reduction in depressive and anxiety symptoms. CONCLUSIONS: Our study suggests exhalatory-gated RAVANS effectively modulates brain circuitries regulating response to negative stress and is associated with significant acute reduction of depressive and anxiety symptomatology in women with recurrent MDD. Findings suggest a potential non-pharmacologic intervention for acute relief of depressive symptomatology in MDD.

Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies.

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and -10 versus placebo: -1.5, P = 0.018; -1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder.

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, "drug withdrawal" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3).

BACKGROUND: The endogenous opioid system is a fundamental regulator of mood in humans. Previously reported clinical trials have demonstrated the efficacy of the investigational agent buprenorphine/samidorphan (BUP/SAM) combination, an opioid-system modulator, for the adjunctive treatment of major depressive disorder. We present here a third phase III study of different design. METHODS: Adult patients with major depressive disorder and inadequate response to antidepressant therapy were enrolled in this double-blind, placebo-controlled, placebo run-in study to evaluate the efficacy, safety, and tolerability of adjunctive BUP/SAM 2 mg/2 mg. Patients with baseline Hamilton Depression Rating Scale score $20 received double-blind placebo in addition to background antidepressant therapy for 4 weeks. Nonresponders were randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period. RESULTS: Least-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], P=0.782). There were no differences in MADRS-based response or remission rates. Overall, 42.9% of the BUP/SAM 2 mg/2 mg group and 34.5% of the placebo group experienced at least one treatment-emergent adverse event during the 6-week treatment period, most of which were mild or moderate in severity. There were no clinically important changes in laboratory parameters, weight, or vital signs and no evidence of abuse potential during treatment or opiate-withdrawal symptoms post treatment. CONCLUSION: Efficacy results in FORWARD-3 measured by change in MADRS-10 score did not meet the primary end point, but postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was consistent with that seen in previously reported trials. BUP/SAM 2 mg/2 mg was well tolerated.

Social and functional outcomes with two doses of aripiprazole lauroxil vs placebo in patients with schizophrenia: a post-hoc analysis of a 12-week phase 3 efficacy study.

To assess the effect of the long-acting antipsychotic aripiprazole lauroxil (AL) on social and functional outcomes compared with placebo in patients with acute schizophrenia, a post-hoc analysis was conducted. Patients with acute schizophrenia were enrolled in a 12-week, double-blind, placebo-controlled efficacy trial, and randomized 1:1:1 to receive AL 441 mg, AL 882 mg, or placebo every 4 weeks. Changes in social functioning using the 6- and 4-item Positive and Negative Syndrome Scale (PANSS) Prosocial subscales were evaluated. The Personal and Social Performance (PSP) total score evaluated patients' global improvement. Changes from baseline were analyzed using mixed-effect models repeat measurements. PANSS Prosocial subscale scores and PSP total score improved significantly with AL vs. placebo, without any dose-related difference in magnitude of response. Significant mean ± SE improvements in 6-item PANSS Prosocial scores from baseline to Day 85 were observed for both individual active treatment groups (e.g., AL 441 mg and AL 882 mg groups) vs. placebo. There were significant changes in PSP total score from baseline to Day 85 for both AL doses vs. placebo. This post-hoc analysis demonstrated a significant improvement in social functioning with AL vs. placebo, as assessed by the PANSS Prosocial subscale and PSP total score.

Long-term safety and tolerability of aripiprazole lauroxil in patients with schizophrenia.

OBJECTIVE: Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia. METHODS: This was an international, multicenter, phase 3, 52-week safety study of 2 fixed doses of AL (441 mg or 882 mg intramuscular every 4 weeks). Safety endpoints included adverse events (AEs) and extrapyramidal symptoms (EPS) including akathisia, injection-site reactions (ISRs), and clinically relevant changes in metabolic and endocrine values. RESULTS: Of 478 patients entering this study, 236 (49%) continued from a previous 12-week, phase 3 efficacy study of AL, and 242 (51%) were newly enrolled. Overall, 77% and 23% of patients received AL 882 mg (N = 368) and 441 mg (N = 110), respectively. AEs occurred in 50.4% of patients; most were mild (28.7%) or moderate (18.2%). The most common AEs were insomnia (8.4%) and increased weight (5.0%). Akathisia was reported as an AE in 3.8% of the overall population, with higher rates in patients initiating AL on study entry than those continuing on AL. EPS-related AEs occurred in 9.4% of patients, and AEs related to metabolic parameters were reported in 4.6% of patients. Weight gain was minimal (0.8 kg), and no clinically relevant changes were observed for metabolic parameters. The overall incidence of ISRs was 3.8%; most were associated with the initial injections in patients receiving their first injection in this study. CONCLUSION: Long-term treatment with AL is generally well tolerated, with a safety profile consistent with that of oral aripiprazole. It is a suitable option for patients with schizophrenia.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial.

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a µ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2 mg/2 mg), at 4-fold (8 mg/8 mg) and 8-fold (16 mg/16 mg) the therapeutic dose, and buprenorphine alone (8 mg and 16 mg). The primary end point was maximum effect (Emax ) on the visual analog scale for "at the moment" Drug Liking. Emax of Drug Liking for the BUP/SAM 2 mg/2 mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking Emax compared to placebo. Drug Liking Emax for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period.

OBJECTIVE: Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). METHODS: This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. RESULTS: In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. CONCLUSION: Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.

Abuse Potential of Samidorphan: A Phase I, Oxycodone-, Pentazocine-, Naltrexone-, and Placebo-Controlled Study.

Samidorphan is a µ-opioid receptor antagonist in development for the treatment of schizophrenia, in combination with olanzapine, and major depressive disorder, in combination with buprenorphine, at proposed therapeutic doses of samidorphan 10 mg and 2 mg, respectively. A double-blind, double-dummy, active- and placebo-controlled, crossover study evaluated the abuse potential of samidorphan in healthy, nondependent, recreational opioid users. Following a qualification phase, participants were randomized to 1 of 6 treatment sequences of study drugs: placebo, samidorphan (10 or 30 mg), oxycodone (40 mg), pentazocine (30 mg), and naltrexone (100 mg) in a 6 × 6 Williams design. The primary end point was maximum effect (Emax ) for "at-the-moment" Drug Liking visual analog scale scores. Secondary end points included Emax visual analog scale scores for Take Drug Again and Overall Drug Liking and safety assessments. Among 47 participants, at-the-moment Emax Drug Liking scores for positive study controls oxycodone and pentazocine were significantly higher than placebo (P < .001) and samidorphan (both doses; P < .001). Both samidorphan doses had Emax Drug Liking scores similar to placebo and naltrexone (median within-subject differences of 0.0). Emax Take Drug Again scores for samidorphan (both doses) were higher than placebo, but similar to naltrexone, an unscheduled µ-opioid receptor antagonist. Adverse events to evaluate abuse potential occurred less frequently with samidorphan, naltrexone, and placebo than with oxycodone and pentazocine. Findings from this study support a lack of abuse potential with samidorphan at doses up to 30 mg and a safety profile consistent with previous samidorphan clinical studies.

Long-range gamma phase synchronization as a compensatory strategy during working memory in high-performing patients with schizophrenia.

Working memory deficits in schizophrenia may be associated with impairments in the integration of neural activity across a distributed network of cortical areas. However, evaluation of the contribution of this integration to working memory impairments in patients is severely confounded by behavioral performance. In the present multidimensional-neuroimaging study, measures of neural oscillations at baseline and during a working memory task, baseline gamma-aminobutyric acid (GABA) level in the left dorsolateral prefrontal cortex (DLPFC), and behavioral performance were obtained. Controlling behavioral performance by recruiting only "high-performing" patients with schizophrenia, we investigated whether the strength of cross-area communications differs between patients with schizophrenia and healthy participants under accurate and equivalent behavioral performance. Results of phase-locking value indicated that these high-performing patients recruited significantly more between frontal and occipital regions in the left hemisphere, t(13) = -2.16, p = .05, Cohen's d = -1.20, and between frontal and temporal regions in the right hemisphere, t(13) = -2.63, p = .02, Cohen's d = -1.46. These cross-area communication patterns may be associated with visuoverbal and visuospatial working memory networks of the left and right hemispheres, respectively. Moreover, correlations of patient's cross-area communication with in vivo GABA levels of the left DLPFC revealed a significant positive relationship (r = .77, p = .04), demonstrating that the critical role of GABA functions in gamma band oscillations may go beyond local neuronal assemblies in the left DLPFC. Altogether, these exploratory findings point to the heterogeneity among schizophrenia patients and highlight the notion that high-performing patients may engage in potential compensatory mechanisms and may represent a subgroup of patients that may be categorically or dimensionally divergent in psychopathology.

Durability of Therapeutic Response With Long-Term Aripiprazole Lauroxil Treatment Following Successful Resolution of an Acute Episode of Schizophrenia.

OBJECTIVE: To evaluate durability of therapeutic effect of long-term treatment with aripiprazole lauroxil in patients with schizophrenia following successful treatment of an acute psychotic episode. METHODS: This post hoc analysis assessed long-term outcomes for a subgroup of patients who entered a 52-week extension study after being successfully stabilized with one of 2 doses of aripiprazole lauroxil (441 or 882 mg) in a pivotal 12-week, placebo-controlled, randomized clinical trial. Durability of therapeutic effect was measured by the proportion of patients completing the 1-year course of aripiprazole lauroxil, the trajectories of the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity (CGI-S) item scores beyond the first 12 weeks, and the likelihood of remission at any follow-up point. RESULTS: In total, 181 patients treated with aripiprazole lauroxil entered the extension study; 73% and 66% of patients from the 441 mg and 882 mg groups, respectively, completed all 13 aripiprazole lauroxil treatments scheduled every 4 weeks over 52 weeks. Both groups continued on a positive trajectory of symptom improvements (P < .0001 for reductions in PANSS total and CGI-S scores from week 12 to end of follow-up). Most patients (74% and 68% in the aripiprazole lauroxil 441 mg and 882 mg groups, respectively) achieved remission during follow-up. CONCLUSIONS: These post hoc analyses of a subgroup of patients demonstrate the continued therapeutic efficacy of aripiprazole lauroxil after successful treatment of an acute episode of schizophrenia. Both the 441 mg and 882 mg groups had similar retention rates, degree of symptom improvement, and likelihood of remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; European Clinical Trials Database (EudraCT) numbers: 2012-003445-15 and 2012-003996-20​​​​.

Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

BACKGROUND: We assessed long-term metabolic and endocrine profiles of outpatients with schizophrenia participating in a one-year open-label extension study of monthly aripiprazole lauroxil (AL), a long-acting injectable antipsychotic. METHODS: Patients (N = 478) were enrolled in a 52-week, open-label extension study of AL monotherapy administered by intramuscular injection every 4 weeks. Of these, most (368) received AL 882 mg and the remainder AL 441 mg as their fixed-dose regimen. Among the patients entering the long-term study, 181 (38%) had already received three prior AL injections. The baseline values for this analysis were obtained from the visit before the first AL injection. Patients were followed for the full year of the extension study unless they discontinued early. Changes in metabolic parameters (weight, fasting blood sugar, lipids) and serum prolactin were assessed over the duration of AL exposure, which could extend to a total of 16 AL injections. Data presented are last observation carried forward from baseline to last visit. RESULTS: Most patients remained for most of the follow-up period, with 409 (86%) remaining at 6 months and 326 (68%) completing the one-year treatment period. The mean (standard deviation) changes from baseline in the overall population were: +1.1 (27.5) mg/dL for glucose, +0.07 (0.6)% for glycated hemoglobin (HbA1c), -3.3 (35.8) mg/dL for total cholesterol and -5.3 (101.9) mg/dL for triglycerides. Prolactin change from baseline was -8.7 ng/mL (14.7) for men and -14.9 (43.4) ng/mL for women. Overall, the mean weight change was +0.8 (5.9) kg. In terms of categorical weight change, 88 patients (18%) gained ≥7% body weight, and 59 (12%) lost ≥7% body weight. Overall, there was no clinically meaningful difference between any of these variables and AL dose. CONCLUSION: Long-term treatment with AL in outpatients with schizophrenia was associated with a modest lowering of serum prolactin for both genders and relatively modest changes in average weight, fasting glucose, and HbA1c values. There appeared to be little net change in lipid parameters. This presentation extends a recently published report on the short-term metabolic and endocrine effects of AL over a period of 12 weeks. The present study increased the follow-up period to more than a year and was careful to use the first exposure to AL as the baseline. Limitations include lack of a comparison group and difficulty disentangling effects of medication treatment versus factors. Overall, the metabolic, weight, and endocrine effects reported here are consistent with other long-term effects of oral aripiprazole treatment. This study was funded by Alkermes, Inc.

Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy.

AIM: To determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more-affected motor cortex in children with unilateral spastic cerebral palsy (CP). METHOD: Twenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I-III). We used DTI tractography to reconstruct the CST projecting from the more-affected motor cortex. We mapped the motor representation of the more-affected hand by stimulating the more- and the less-affected motor cortex measured with single-pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI. RESULTS: DTI tractography successfully identified the CST controlling the more-affected hand (sensitivity=82%, specificity=78%). INTERPRETATION: Contralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI-identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures.

Skilled Bimanual Training Drives Motor Cortex Plasticity in Children With Unilateral Cerebral Palsy.

Background Intensive bimanual therapy can improve hand function in children with unilateral spastic cerebral palsy (USCP). We compared the effects of structured bimanual skill training versus unstructured bimanual practice on motor outcomes and motor map plasticity in children with USCP. Objective We hypothesized that structured skill training would produce greater motor map plasticity than unstructured practice. Methods Twenty children with USCP (average age 9.5; 12 males) received therapy in a day camp setting, 6 h/day, 5 days/week, for 3 weeks. In structured skill training (n = 10), children performed progressively more difficult movements and practiced functional goals. In unstructured practice (n = 10), children engaged in bimanual activities but did not practice skillful movements or functional goals. We used the Assisting Hand Assessment (AHA), Jebsen-Taylor Test of Hand Function (JTTHF), and Canadian Occupational Performance Measure (COPM) to measure hand function. We used single-pulse transcranial magnetic stimulation to map the representation of first dorsal interosseous and flexor carpi radialis muscles bilaterally. Results Both groups showed significant improvements in bimanual hand use (AHA; P < .05) and hand dexterity (JTTHF; P < .001). However, only the structured skill group showed increases in the size of the affected hand motor map and amplitudes of motor evoked potentials (P < .01). Most children who showed the most functional improvements (COPM) had the largest changes in map size. Conclusions These findings uncover a dichotomy of plasticity: the unstructured practice group improved hand function but did not show changes in motor maps. Skill training is important for driving motor cortex plasticity in children with USCP.

GABA level, gamma oscillation, and working memory performance in schizophrenia.

A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case-control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.

Deep brain stimulation and ablation for obsessive compulsive disorder: evolution of contemporary indications, targets and techniques.

Surgical therapy for treatment-resistant obsessive compulsive disorder (OCD) remains an effective option for well-selected patients managed within a multidisciplinary setting. Historically, lesions within the limbic system have been used to control both obsessive thoughts and repetitive compulsions associated with this disease. We discuss classical targets as well as contemporary neuromodulatory approaches that have been shown to provide symptomatic relief. Recently, deep brain stimulation (DBS) of the anterior limb of the internal capsule/ventral striatum received Conformité Européene (CE) mark and Food and Drug Administration (FDA) approvals for treatment of intractable OCD. Remarkably, this is the first such approval for neurosurgical intervention in a strictly psychiatric indication in modern times. This target is discussed in detail along with alternative targets currently being proposed. We close with a discussion of gamma knife capsulotomy, a modality with deep historical roots. Further directions in the surgical treatment of OCD will require better preoperative predictors of postoperative responses, optimal selection of individualized targets, and rigorous reporting of adverse events and standardized outcomes. To meet these challenges, centers must be equipped with a multidisciplinary team and patient-centered approach to ensure adequate screening and follow up of patients with this difficult-to-treat condition.

Single pulse TMS differentially modulates reward behavior.

Greater knowledge of cortical brain regions in reward processing may set the stage for using transcranial magnetic stimulation (TMS) as a treatment in patients with avolition, apathy or other drive-related symptoms. This study examined the effects of single pulse (sp) TMS to two reward circuit targets on drive in healthy subjects. Fifteen healthy subjects performed the monetary incentive delay task (MID) while receiving fMRI-guided spTMS to either inferior parietal lobe (IPL) or supplemental motor area (SMA). The study demonstrated decreasing reaction times (RT) for increasing reward. It also showed significant differences in RT modulation for TMS pulses to the IPL versus the SMA. TMS pulses during the delay period produced significantly more RT slowing when targeting the IPL than those to the SMA. This RT slowing carried over into subsequent trials without TMS stimulation, with significantly slower RTs in sessions that had targeted the IPL compared to those targeting SMA. The results of this study suggest that both SMA and IPL are involved in reward processing, with opposite effects on RT in response to TMS stimulation. TMS to these target cortical regions may be useful in modulating reward circuit deficits in psychiatric populations.

Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.

CONTEXT: Postmortem studies have found evidence of γ-aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. OBJECTIVE: To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. DESIGN: Case-control study. SETTING: Inpatient psychiatric research unit and associated outpatient clinic. PARTICIPANTS: Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. METHODS: Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. MAIN OUTCOME MEASURES: The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy. RESULTS: In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found. CONCLUSIONS: To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.