Efficacy and safety of Lu AF35700 in treatment-resistant schizophrenia: A randomized, active-controlled trial with open-label extension.

INTRODUCTION: Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D1 and D2 receptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile. METHODS: This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine). RESULTS: 1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was -10.1 ± 0.96 for Lu AF35700 10 mg, -8.22 ± 0.98 for Lu AF35700 20 mg, and - 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (-0.12 [-2.37; 2.13] and 1.67 [-0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700. CONCLUSIONS: Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.

The safety and tolerability of aripiprazole once-monthly as maintenance treatment for bipolar I disorder: A double-blind, placebo-controlled, randomized withdrawal study.

BACKGROUND: Aripiprazole once-monthly 400 mg (AOM 400), an atypical long-acting injectable antipsychotic, has demonstrated efficacy and safety in maintenance treatment of bipolar I disorder (BP-I). We further assess safety and tolerability and characterize adverse events (AEs) across the duration of aripiprazole exposure. METHODS: Patients with BP-I were stabilized on oral aripiprazole (2-8 weeks), AOM 400 (12-28 weeks), followed by 1:1 randomization of patients meeting stability criteria to a 52-week, double-blind, placebo-controlled withdrawal phase. Treatment-emergent AEs (TEAEs) were collected across study phases. AEs were counted in a phase if they were drug-related and continued from the baseline of that phase. A separate analysis on new-onset akathisia was conducted. RESULTS: Among TEAEs occurring in ≥10% of patients during all study phases were akathisia (23.3%) and weight increased (10.6%). Median time to akathisia onset was 20 days after starting oral aripiprazole; median duration was 29 days for the first occurrence; 21/168 patients (12.5%) reporting akathisia experienced >1 episode. Episodes of new-onset akathisia decreased over time, with few events reported in the randomized phase. Weight gain was minimal with oral aripiprazole, generally starting within 3 months after the first AOM 400 injection, and appearing to plateau at 36 weeks. The mean weight gain within any study phase was ≤1.0 kg. Potentially clinically significant changes in metabolic parameters were uncommon. LIMITATIONS: Patients on placebo had AOM 400 exposure before randomization. CONCLUSION: These findings suggest that AEs with AOM 400 treatment were time-limited and support AOM 400 as a well-tolerated maintenance treatment of BP-I.

Aripiprazole once-monthly as maintenance treatment for bipolar I disorder: a 52-week, multicenter, open-label study.

BACKGROUND: The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. METHODS: This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder-Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified. RESULTS: Of 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (< 10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications. CONCLUSION: AOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment. Trial registration ClinicalTrials.gov, NCT01710709.

Symptoms and functioning with aripiprazole once-monthly injection as maintenance treatment for bipolar I disorder.

BACKGROUND: Effects of maintenance treatment with aripiprazole once-monthly 400mg (AOM 400) on symptoms and functioning were assessed in adults with bipolar I disorder (BP-I) after a manic episode. METHODS: Patients were stabilized on oral aripiprazole, cross-titrated to AOM 400, then randomized in a 52-week, double-blind, placebo-controlled, withdrawal phase. Prespecified secondary outcomes are reported: time to hospitalization for mood episode, Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Bipolar scale, Functioning Assessment Short Test (FAST), and Brief Quality of Life in Bipolar Disorder questionnaire. Time to hospitalization for mood episode was analyzed using log-rank test and changes from baseline using mixed model for repeated measures or analysis of covariance. RESULTS: AOM 400 significantly increased time to hospitalization for any mood episode versus placebo (P=0.0002). YMRS total scores decreased with oral aripiprazole; improvements were maintained with AOM 400. After randomization, YMRS scores changed little with AOM 400 but worsened with placebo (P=0.0016), and MADRS scores, already low at trial initiation, did not differ between groups. FAST score improvements were maintained with AOM 400 but not placebo (P=0.0287). LIMITATIONS: Results are generalizable to patients with BP-I stabilized on aripiprazole following a manic episode. CONCLUSIONS: Patients with BP-I experiencing an acute manic episode exhibited symptomatic and functional improvements during stabilization with oral aripiprazole and AOM 400 that were maintained with continued AOM 400 treatment but not placebo. AOM 400 is the first once-monthly long-acting injectable antipsychotic to demonstrate efficacy in maintenance treatment of the manic phase of BP-I.

Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study.

OBJECTIVE: To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400mg (AOM 400) in patients with schizophrenia. METHODS: Patients who completed the QUALIFY study (NCT01795547) in the AOM 400 arm were eligible for 6 additional once-monthly injections of AOM 400 during an open-label, 24-week extension (NCT01959035). Safety data were collected at each visit. Effectiveness measures included change from baseline in health-related qualify of life and functioning on the Heinrichs-Carpenter Quality of Life scale (QLS) and Clinical Global Impression - Severity (CGI-S) scale. RESULTS: Of the 88 patients enrolled, 77 (88%) completed the extension study. Most common treatment-emergent adverse events (incidence ≥2%) were weight increased (6/88, 7%), toothache (3/88, 3%) and headache (3/88, 3%). Effectiveness was maintained during the extension study, with small but continued improvements from baseline: the least squares mean (LSM) change (95% CI) from baseline to week 24 was 2.32 (-1.21 to 5.85) for the QLS total score and -0.10 (-0.26 to 0.06) for the CGI-S score. The aggregated LSM change (95% CI) from baseline of the lead-in study to week 24 of the extension study was 11.54 (7.45 to 15.64) for the QLS total score and -0.98 (-1.18 to -0.79) for the CGI-S score. CONCLUSIONS: AOM 400 was well tolerated in patients continuing AOM treatment during the extension phase of the QUALIFY study. Robust and clinically meaningful improvements in health-related quality of life and functioning were maintained, further supporting the long-term clinical benefits of AOM 400 for the treatment of patients with schizophrenia.

Relationship between response to aripiprazole once-monthly and paliperidone palmitate on work readiness and functioning in schizophrenia: A post-hoc analysis of the QUALIFY study.

Schizophrenia is a chronic disease with negative impact on patients' employment status and quality of life. This post-hoc analysis uses data from the QUALIFY study to elucidate the relationship between work readiness and health-related quality of life and functioning. QUALIFY was a 28-week, randomized study (NCT01795547) comparing the treatment effectiveness of aripiprazole once-monthly 400 mg and paliperidone palmitate once-monthly using the Heinrichs-Carpenter Quality-of-Life Scale as the primary endpoint. Also, patients' capacity to work and work readiness (Yes/No) was assessed with the Work Readiness Questionnaire. We categorized patients, irrespective of treatment, by work readiness at baseline and week 28: No to Yes (n = 41), Yes to Yes (n = 49), or No at week 28 (n = 118). Quality-of-Life Scale total, domains, and item scores were assessed with a mixed model of repeated measures. Patients who shifted from No to Yes in work readiness showed robust improvements on Quality-of-Life Scale total scores, significantly greater than patients not ready to work at week 28 (least squares mean difference: 11.6±2.6, p<0.0001). Scores on Quality-of-Life Scale instrumental role domain and items therein-occupational role, work functioning, work levels, work satisfaction-significantly improved in patients shifting from No to Yes in work readiness (vs patients No at Week 28). Quality-of-Life Scale total scores also significantly predicted work readiness at week 28. Overall, these results highlight a strong association between improvements in health-related quality of life and work readiness, and suggest that increasing patients' capacity to work is an achievable and meaningful goal in the treatment of impaired functioning in schizophrenia.

Aripiprazole Once-Monthly in the Treatment of Acute Psychotic Episodes in Schizophrenia: Post Hoc Analysis of Positive and Negative Syndrome Scale Marder Factor Scores.

BACKGROUND: Long-acting injectable antipsychotics are treatment options for acute and long-term treatment of patients with schizophrenia. In a previously published 12-week randomized, double-blind, placebo-controlled clinical trial of patients with schizophrenia experiencing an acute psychotic episode, aripiprazole once-monthly 400 mg (AOM 400) produced significantly greater improvement than placebo on the primary endpoint, Positive and Negative Syndrome Scale (PANSS) total score at week 10. METHODS: To examine the efficacy of AOM 400 across a broader representation of schizophrenia symptoms, including agitation, a post hoc analysis of this trial was carried out to assess the change in PANSS Marder factor domains (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression) and the PANSS excited component (equivalent to Marder factor domain uncontrolled hostility/excitement plus the tension item) by comparing differences in change from baseline between AOM 400 and placebo using a mixed model for repeated measures. RESULTS: The differences between treatment and placebo for all factors were statistically significant, with improvements seen as early as week 1 or 2, and maintained through week 12. Thus, AOM 400, supplemented with oral aripiprazole in the first 2 weeks, showed significantly greater efficacy versus placebo in acutely ill patients with schizophrenia in all 5 Marder illness domains, as well as in agitation as conceptualized by the PANSS excited component score. CONCLUSIONS: These findings indicate that AOM 400 is efficacious across the spectrum of schizophrenia symptoms in acutely ill patients, with implications for both short-term and, by extension, long-term patient outcomes.

Reduced sexual dysfunction with aripiprazole once-monthly versus paliperidone palmitate: results from QUALIFY.

Sexual dysfunction, a common side effect of antipsychotic medications, may be partly caused by dopamine antagonism and elevation of prolactin. In QUALIFY, a randomized study, aripiprazole once-monthly 400 mg (AOM 400), a dopamine D2 receptor partial agonist, showed noninferiority and subsequent superiority versus paliperidone palmitate (PP), a dopamine D2 receptor antagonist, on the Heinrichs-Carpenter Quality-of-Life Scale (QLS) in patients with schizophrenia aged 18-60 years. Sexual dysfunction (Arizona Sexual Experience Scale) and serum prolactin levels were also assessed. Odds for sexual dysfunction were lower with AOM 400 versus PP [week 28 adjusted odds ratio (95% confidence interval), 0.29 (0.14-0.61); P=0.0012] in men [0.33 (0.13-0.86); P=0.023], women [0.14 (0.03-0.62); P=0.0099], and patients aged 18-35 years [0.04 (<0.01-0.34); P=0.003]. Among patients shifting from sexual dysfunction at baseline to none at week 28, there was a trend toward greater improvement in the QLS total score. The mean (SD) prolactin concentrations decreased with AOM 400 [-150.6 (274.4) mIU/l] and increased with PP [464.7 (867.5) mIU/l] in both men and women. Six PP-treated patients experienced prolactin-related adverse events. In addition to greater improvement on QLS, patients had a lower risk for sexual dysfunction and prolactin elevation with AOM 400 versus PP in QUALIFY.

Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) as maintenance treatment for bipolar I disorder (BP-I). METHODS: In a double-blind, placebo-controlled, 52-week randomized withdrawal study conducted from August 2012 to April 2016, patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and AOM 400 and then randomized to AOM 400 or placebo. The primary end point was time from randomization to recurrence of any mood episode. Other end points included proportion of patients with recurrence of any mood episode and recurrence by mood episode type. RESULTS: Of 266 randomized patients, 64 (48.1%) of 133 in the AOM 400 group and 38 (28.6%) of 133 in the placebo group completed the study. AOM 400 significantly delayed the time to recurrence of any mood episode compared with placebo (hazard ratio: 0.45; 95% CI, 0.30 to 0.68; P < .0001). Significantly fewer patients (P < .0001) experienced recurrence of any mood episode with AOM 400 (35/132; 26.5%) compared with placebo (68/133; 51.1%), with the effects observed predominantly on manic episodes (P < .0001). Patients were not depressed at study entry, and between-group differences in depressive episodes were not significant (P < .864). The treatment-emergent adverse events (incidence > 5%) that were reported at higher rates with AOM 400 than placebo were weight increase, akathisia, insomnia, and anxiety. CONCLUSIONS: AOM 400 delayed the time to and reduced the rate of recurrence of mood episodes and was generally safe and well tolerated. These findings support the use of AOM 400 for maintenance treatment of BP-I. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01567527.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration.

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.

Multidimensional Assessment of Functional Outcomes in Schizophrenia: Results From QUALIFY, a Head-to-Head Trial of Aripiprazole Once-Monthly and Paliperidone Palmitate.

Background: QUALIFY was a 28-week, randomized, open-label, head-to-head trial that assessed improvements across multiple measures in stable patients with schizophrenia with aripiprazole once-monthly 400 mg vs paliperidone palmitate. Methods: Secondary effectiveness assessments included physician-rated readiness for work using the Work Readiness Questionnaire, the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales, and quality of life with the rater-blinded Heinrichs-Carpenter Quality of Life Scale. Patients assessed their treatment satisfaction and quality of life with Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life questionnaires. Results: Odds of being ready for work at week 28 were significantly higher with aripiprazole once-monthly 400 mg vs paliperidone palmitate (adjusted odds ratio, 2.67; 95% CI, 1.39-5.14; P=.003). Aripiprazole once-monthly 400 mg produced numerically or significantly greater improvements from baseline vs paliperidone palmitate in all Quality of Life Scale items. With aripiprazole once-monthly 400 mg vs paliperidone palmitate at week 28, there were significantly more Clinical Global Impression-Severity and Clinical Global Impression-Improvement responders (adjusted odds ratio, 2.26; P=.010, and 2.51; P=.0032) and significantly better Clinical Global Impression-Improvement scores (least squares mean treatment difference, -0.326; 95% CI, -0.60 to -0.05; P=.020). Numerically larger improvements with aripiprazole once-monthly 400 mg vs paliperidone palmitate were observed for patient-rated scales Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life. Partial correlations were strongest among clinician-rated and among patient-rated scales but poorest between clinician and patient-rated scales. Conclusions: Consistently greater improvements were observed with aripiprazole once-monthly 400 mg vs paliperidone palmitate across all measures. Partial correlations between scales demonstrate the multidimensionality of various measures of improvement. More patients on aripiprazole once-monthly 400 mg were deemed ready to work by the study end. Trial registry: National Institutes of Health registry, NCT01795547, https://clinicaltrials.gov/ct2/results?id=NCT01795547).

Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia.

OBJECTIVE: To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of-Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. METHOD: This 28-week, randomized, non-inferiority, open-label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. RESULTS: Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigator's Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients ≤35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. CONCLUSION: Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547.

Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate aripiprazole once-monthly (AOM), a long-acting injectable suspension of aripiprazole, as acute treatment in patients with schizophrenia (DSM-IV-TR). METHOD: Adults experiencing an acute psychotic episode were randomized to 12 weeks of double-blind treatment with AOM 400 mg or placebo (October 2012-August 2013). The primary efficacy outcome was change from baseline to endpoint (week 10) in Positive and Negative Syndrome Scale (PANSS) total score. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Secondary efficacy outcomes included change from baseline in PANSS positive and negative subscale and Personal and Social Performance Scale (PSP) scores. The study took place from October 2012 through August 2013. RESULTS: Patients (N = 340; 79% male, 66% black) were randomized to AOM (n = 168) or placebo (n = 172). Least squares (LS) mean change from baseline to endpoint (week 10) favored AOM versus placebo in PANSS total (treatment difference, -15.1 [95% CI, -19.4 to -10.8]; P < .0001) and CGI-S (treatment difference, -0.8 [95% CI, -1.1 to -0.6]; P < .0001) scores, as it did at all other timepoints through 12 weeks (all P ≤ .0005). LS mean change from baseline in PANSS positive and negative subscale and PSP scores favored AOM versus placebo (P < .0001). Common (> 10%) treatment-emergent adverse events (AOM vs. placebo) were increased weight (16.8% vs 7.0%), headache (14.4% vs. 16.3%), and akathisia (11.4% vs 3.5%). CONCLUSIONS: Symptoms and functioning improved with AOM 400 mg versus placebo in patients with acute schizophrenia, with acceptable safety and tolerability. These data suggest that AOM 400 mg is a viable treatment option for patients experiencing an acute schizophrenia episode. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01663532.

Outcomes and risks of operative treatment of rupture of the anterior cruciate ligament in children and adolescents.

PURPOSE: The aim of this meta-analysis was to evaluate the clinical outcomes and risks of anterior cruciate ligament (ACL) surgery in children and adolescents. METHODS: We electronically searched Medline, the Cochrane Controlled Trial Database, Embase, and Medpilot for studies on surgical treatment for ACL ruptures in skeletally immature patients. We extracted baseline demographics, follow-up intervals, surgical details (i.e., ligament suture or reconstruction, physeal-sparing or transphyseal techniques, type of transplant, and methods of fixation). Endpoints comprised rates of growth disturbances and reruptures, as well as knee function (measured by the International Knee Documentation Committee's documentation system and the Lysholm score). Unweighted overall effect sizes (risks, risk ratios [RRs], and means of functional scores) were estimated by use of crude nominators and denominators, and random-effects meta-regression analysis was used for weighted data synthesis. RESULTS: A total of 55 articles reporting on 935 patients (median age, 13 years; range, 1.5 to 16 years) were suitable for the study. After a median follow-up of 40 months (range, 14 to 89 months), the weighted rate of leg-length differences or axis deviations was 1.8% (95% confidence interval [CI], 0% to 3.9%] and that of reruptures was 4.8% (95% CI, 2.9% to 6.7%). Excellent or good function (International Knee Documentation Committee grade A or B) was achieved in 84.2% (95% CI, 75.8% to 92.6%) of all knees, and Lysholm scores averaged 96.3 (95% CI, 95.5 to 97.2). Transphyseal reconstruction was associated with a significantly lower risk of leg-length differences or axis deviations compared with physeal-sparing techniques (1.9% v 5.8%; RR, 0.34; 95% CI, 0.14 to 0.81) but had a higher risk of rerupture (4.2% v 1.4%; RR, 2.91; 95% CI, 0.70 to 12.12). Sutures did not result in any growth disturbances, with a weighted rerupture rate of 4.6% (95% CI, 2.6 to 6.7). Fixation far from the joint line fared better than close fixation with regard to this endpoint (1.4% v 3.2%; RR, 0.42; 95% CI, 0.09 to 1.93). Bone-patellar tendon-bone grafts, which are also less likely to fail, were associated with higher risks of leg-length differences or axis deviations than were hamstrings (3.6% v 2.0%; RR, 1.82; 95% CI, 0.66 to 5.03). Meta-regression did not show a significant impact of the publication year on event rates. CONCLUSIONS: This meta-analysis showed low rates of leg-length differences or axis deviations and graft failures after ACL reconstruction in skeletally immature patients. Hamstring transplants may lower the risk of leg-length differences or axis deviations, and physeal-sparing techniques may increase the risk. Randomized controlled trials are needed to clarify important issues in managing ACL ruptures in children and adolescents. LEVEL OF EVIDENCE: Level IV, meta-analysis of case series.

Relevance of dorsal raphe nucleus firing in serotonin 5-HT(2C) receptor blockade-induced augmentation of SSRIs effects.

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT(2C) receptors significantly potentiates the effect of citalopram, a selective serotonin reuptake inhibitor, on serotonin efflux in the hippocampus and prefrontal cortex (Cremers, T.I.F.H., Giorgetti, M., Bosker, F.J., Hogg, S., Arnt, J., Mork, A., Honig, G., Bøgesø, K.P., Westerink, B.H.C., den Boer, J.A., Wikstrøm, H.V., Tecott, L.H., 2004. Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29, 1782-1789; Cremers, T.I.F.H., Rea, K., Bosker, F.J., Wikström, H.V., Hogg, S., Mørk, A., Westerink, B.H.C., 2007. Augmentation of SSRI effects on serotonin by 5-HT(2C) antagonists: mechanistic studies. Neuropsychopharmacology 32, 1550-1557.). Using in vivo electrophysiology, we show in the present study that the purported selective 5-HT(2C) receptor antagonist, SB242,084, dose-dependently counteracts citalopram-induced inhibition of serotonin cell firing. Even though the effect of SB242,084 is significant at a dose found in vivo to also partially occupy 5-HT(2A) receptors, indicating a possible contribution of a partial blockade of 5-HT(2A) receptors together with 5-HT(2C) receptors, we suggest that high occupancy at 5-HT(2C) receptors is essential for the blockade of the inhibitory effect of citalopram on 5-HT cell firing. Using microdialysis, we also show that the potentiation by SB242,084 on serotonin efflux requires an action of citalopram outside the terminal, most likely at the somato-dendritic level (i.e., on serotonin cell firing). Further experiments using local 5-HT(2C) receptor blockade indicate a role of 5-HT(2C) receptors located in the prefrontal cortex. Modulation of short or long feedback loops originating in the prefrontal cortex by 5-HT(2C) receptors could directly inhibit serotonin efflux, or alternatively, regulate serotonin cell firing in the dorsal raphe nucleus, thereby modulating serotonin efflux indirectly.

Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential.

The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.

Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action.

The effects of acute administration of sertindole on DA output were examined in the shell part of the nucleus accumbens (NACS) and the striatum (STR), areas which are associated with limbic functions and motor control, respectively, by using in vivo differential normal pulse voltammetry in rats. The effect of sertindole was compared to those obtained with the reference antipsychotic drugs clozapine and haloperidol, new generation antipsychotics represented by risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole, as well as, with those of preferential D2/3, D4, 5-HT1A, 5-HT2A, 5-HT2C, alpha1, and alpha2 receptor ligands. In similarity with the new generation antipsychotics, sertindole preferentially increase DA output in the NACS as compared to the STR whereas the opposite was true for haloperidol. The regional specific effect of the partial D2 receptor agonist aripiprazole was mainly driven by a decrease in striatal rather that by an increase in accumbal DA output. The selective 5-HT2A and D4 receptor antagonists MDL100,151 and Lu 38-012, respectively, both preferentially increased DA output in the NACS. Thus, the present results are in line with the hypothesis that 5-HT2A receptor antagonism is of importance for the observed limbic selectivity of new generation antipsychotics and, in turn, to their favorable clinical profile especially as regards extrapyramidal side effects (EPS) liability. For some compounds, blockade of D4 receptors may also play a role in this regard.

Inhibition of the glycine transporter GlyT-1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex.

Clinical studies suggest that the efficacy of the atypical antipsychotic drug (APD) risperidone (but not clozapine) can be augmented by adjunctive treatment with agonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. By using intracellular recording, we have investigated the effect of the glycine transporter-1 (GlyT-1) inhibitor N [3-(4'-fluorophenyl)-3-(4'phenylphenylphenoxy) propyl] sarcosine (NFPS) on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex (mPFC), both when given alone and in combination with either risperidone or clozapine. Both risperidone and clozapine enhanced the NMDA-induced currents. The concentration-response curves were biphasic, and the maximal effect of clozapine on the NMDA-induced currents was significantly larger than the maximal effect of risperidone. NFPS also significantly potentiated the NMDA-induced currents, when given alone. Moreover, NFPS (1 microM) augmented the effect of both the maximal (20 nM), and a submaximal (10 nM), concentration of risperidone. In contrast, NFPS did not potentiate either the effect of the maximal (100 nM) or a submaximal (80 nM) concentration of clozapine on the NMDA-induced currents. These data may explain the beneficial clinical results of using glycine reuptake antagonists as adjuvant treatment to risperidone. Our findings also suggest that risperidone and clozapine may affect NMDA receptor-mediated neurotransmission differently in the mPFC.

Combined alpha2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat.

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Tensile properties of an anterior cruciate ligament graft after bone-patellar tendon-bone press-fit fixation.

Hardware used for fixation of ACL autografts in bone tunnels frequently complicates revision surgery, requiring two-stage procedures when a bone-patellar tendon-bone (B-PT-B) autograft is used for ACL reconstruction. Therefore alternative procedures that eliminate hardware have been advocated. This study compared the mechanical behavior of two fixation procedures: a widely used interference screw (IFS) fixation and a press-fit fixation that is hardware free. Twenty hind limbs from skeletally mature Saanen breed goats were used in this study, ten each in IFS and press-fit groups. After ACL reconstruction the specimens were dissected, leaving a femur-ACL graft-tibia complex (FATC) for uniaxial tensile testing. The tests included a series of three cyclic creep tests (C1-C3) for the evaluation of residual elongation followed by a tensile load to failure test to obtain linear stiffness and ultimate load of the FATCs. Four of ten specimens failed during the cyclic creep test for the press-fit group, compared to one for the IFS group. For the remaining specimens residual elongation following three cyclic creep tests (C1-C3) was 1.7+/-0.5 mm in the press-fit group compared to 1.3+/-0.6 mm in the IFS group, and there was no statistical significant difference between the two fixations. In the load to failure test there was also no statistical significant difference in linear stiffness between the two fixations. However, the ultimate load for the press-fit group (215+/-75 N) was significantly lower than that for the IFS group (328+/-103 N). These results provide the basis for future studies involving the time course of healing of these two procedures using the goat model.