Depression is characterised by negative views of the self. Antidepressant treatment may remediate negative self-schema through increasing processing of positive information about the self. Changes in affective processing during social interactions may increase expression of prosocial behaviours, improving interpersonal communications.

To examine whether acute administration of citalopram is associated with an increase in positive affective learning biases about the self and prosocial behaviour.

Healthy volunteers (n = 41) were randomised to either an acute 20 mg dose of citalopram or matched placebo in a between-subjects double-blind design. Participants completed computer-based cognitive tasks designed to measure referential affective processing, social cognition and expression of prosocial behaviours.

Participants administered citalopram made more cooperative choices than those administered placebo in a prisoner's dilemma task (β = 20%, 95% CI: 2%, 37%). Exploratory analyses indicated that participants administered citalopram showed a positive bias when learning social evaluations about a friend (β = 4.06, 95% CI: 0.88, 7.24), but not about the self or a stranger. Similarly, exploratory analyses found evidence of increased recall of positive words and reduced recall of negative words about others (β = 2.41, 95% CI: 0.89, 3.93), but not the self, in the citalopram group.

Participants administered citalopram showed greater prosocial behaviours, increased positive recall and increased positive learning of social evaluations towards others. The increase in positive affective bias and prosocial behaviours towards others may, at least partially, be a mechanism of antidepressant effect. However, we found no evidence that citalopram influenced self-referential processing.

The safety and tolerability of aripiprazole as adjunctive treatment was examined in patients with major depressive disorder (MDD) without psychotic features who had a major depressive episode and who did not respond adequately to standard antidepressant therapy (ADT).

Data from three identical short-term, double-blind, placebo-controlled studies (CN138139, CN138163, CN138165) were pooled. After a prospective phase with placebo plus ADT, patients without adequate response entered a 6-week, double-blind phase with placebo or aripiprazole plus ADT. Safety endpoints included death, serious adverse events (SAEs), treatment-emergent adverse events (AEs), Simpson-Angus Scale (SAS), Barnes Akathisia Global Clinical Assessment, Abnormal Involuntary Movement Scale (AIMS), clinical laboratory tests, vital signs and electrocardiograms.

In total, 538 patients were randomized to adjunctive placebo and 547 to adjunctive aripiprazole. AEs with an incidence ≥5% and at least twice the rate of placebo were akathisia (adjunctive aripiprazole, 22.7%; adjunctive placebo, 4.1%), restlessness (12.4% vs 2.2%), fatigue (8.6% vs 4.3%), insomnia (8.2% vs 3.2%), vision blurred (6.2% vs 1.5%), somnolence (5.9% vs 2.6%), and constipation (4.9% vs 2.4%). AEs that had a treatment difference of ≥2% included akathisia, somnolence, sedation, dizziness, disturbance in attention, extrapyramidal disorder, restlessness, insomnia, constipation, dyspepsia, fatigue, feeling jittery, vision blurred, weight increased, and dyspnea. SAEs occurred in 0.7% of patients in each treatment group. There were no deaths during the studies.

In this pooled analysis of patients with MDD and an inadequate response to ADT, adjunctive aripiprazole showed consistently high study completion rates and low discontinuation rates resulting from adverse events.

To evaluate the safety of aripiprazole as adjunctive treatment in major depressive disorder (MDD) without psychotic features within different patient subgroups.

Data were pooled from three multicentre, randomized, double-blind, placebo-controlled studies (CN138-139, CN138-163 and CN138-165). Patients who did not respond adequately to an 8-week course of standard ADT were randomized to receive adjunctive aripiprazole or placebo for a further 6 weeks. To assess differences in the adverse events (AE) profile of aripiprazole for demographic subgroups, the incidence of AEs was presented for the pooled placebo-controlled MDD studies by gender, age, and race. An odds ratio (OR) estimate was calculated and the ORs compared across all categories using the Breslow-Day test for AEs with incidence ≥5% in the pooled aripiprazole group.

In total, 14.3% of aripiprazole-treated patients and 12.5% of placebo-treated patients discontinued treatment. Treatment-emergent AEs were reported by 65.4% and 82.3% in the adjunctive placebo and adjunctive aripiprazole groups, respectively. Most aripiprazole-related AEs were, however, mild to moderate in severity. With the exception of blurred vision, which occurred in white patients only (p=0.002), there were no significant differences in the incidence of treatment-emergent AEs across different age groups, racial groups or between the genders in the aripiprazole- and placebo-treated groups.

Adjunctive aripiprazole was generally well tolerated and most treatment-emergent AEs were of mild to moderate severity. The AEs profile of adjunctive aripiprazole did not show significant variation in relation to age, gender or race, compared with that of placebo.

Aripiprazole has demonstrated efficacy for the treatment of paediatric patients (10–17 years) with a manic or mixed episode associated with bipolar I disorder in a clinical trial that utilised the Young Mania Rating Scale (YMRS) Total score as the primary outcome measure.

This analysis evaluated the profile of discrete symptom response using the YMRS and other measures.

Post-hoc analysis of individual items of the YMRS and the parent or subject version of the General Behaviour Inventory (GBI) Mania and Depression scales using data from a 4-week, double-blind, randomised trial that compared aripiprazole (10 or 30 mg/day, n = 197) with placebo (n = 99).

In total, 296 patients were randomised; 80% completed the study. Significant decreases at Week 4 (p < 0.05) were seen in eight YMRS items: elevated mood, increased motor activity/energy, need for sleep, irritability, speech (rate and amount), language/thought disorder, abnormal thought content and disruptive/aggressive behaviour. For the GBI, effect sizes for parent-reported mania items were medium to large (for example, 0.41 for ‘depressed but high energy’ to 0.78 for ‘rage combined with unusually happy’) but were consistently small on subject self-reported items of mania and depression and, for the overall scale, had the poorest agreement with clinician ratings.

Aripiprazole demonstrated improvements in some of the more troublesome symptoms of paediatric patients with bipolar I disorder experiencing an acute manic or mixed episode. Of note, irritability and aggression showed large treatment effects on both clinician and parent-reported measures, but less so for subject-reported measures.

Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.

This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.

Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.

10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.

There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.

296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.

Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.

Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.

Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.

Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.

710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.

ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.

Brexpiprazole is a serotonin-noradrenaline-dopamine agent that binds with high affinity to multiple serotonin, norepinephrine and dopamine receptors. In particular, Brexpiprazole is a partial agonist at dopamine D2/D3 and 5-HT1A receptors and an antagonist at 5-HT2A and norepinephrine alpha1B receptors.

We assessed the efficacy and safety of brexpiprazole versus placebo as adjunctive therapy to anti-depressant therapy (ADT) in subjects with MDD who demonstrated inadequate response to ADT.

This trial had 3 phases: a screening phase (7-28 days); a prospective phase (Phase A): 8-week, single-blind placebo plus an investigator-determined, open-label ADT; a randomized phase (Phase B): 6-week, double-blind, adjunctive brexpiprazole (2 mg/day) vs. placebo in patients with an inadequate response to ADT.

The primary efficacy endpoint was the change from the end of Phase A (Week 8) to the end of Phase B (Week 14) in MADRS Total Score. The key secondary endpoint was the change in mean SDS score. Other secondary endpoints were mean change in CGI-S, IDS-R, HAMD and HAMA.

Of 379 randomized patients, completion rates at Week 14 were high (92.9%). Statistically significant improvements in mean MADRS Total score were observed for subjects receiving adjunctive brexpiprazole 2mg/day compared with placebo (p=0.0001) at endpoint. In addition, on all secondary endpoints Brexpiprazole showed a statistically significant advantage over placebo.

Commonly reported adverse events in the brexpiprazole group (>5% and more than twice placebo) were weight gain (8.0%), akathisia (7.4%).

Brexpiprazole was effective and well tolerated as adjunctive treatment for MDD patients with an inadequate response to ADT.

Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.

Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.

710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).

Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.