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Adjunctive antipsychotic therapy can be prescribed to patients with depression who have inadequate response to antidepressants. This study aimed to describe the use of adjunctive antipsychotics over a time period that includes the authorization in 2010 of prolonged-release quetiapine as the first adjunct antipsychotic to be used in major depressive disorder in the UK.Adults with an episode of depression between January 1, 2005 and July 31, 2013 were identified from antidepressant prescriptions and depression diagnoses in the UK Clinical Practice Research Datalink. Patients with prior records of bipolar disorder, schizophrenia, or antipsychotic prescriptions were excluded.Rates of adjunct antipsychotic initiation and characteristics and management of patients with adjunct antipsychotics.Of 224,353 adults with depression, 5,807 (2.6%) initiated adjunct antipsychotic therapy. Overall incidence of antipsychotic initiation was 7.4 per 1,000 patient-years (95% CI = 7.2-7.6). Between 2005-2013, the overall rate did not change, although initiation of typical antipsychotic prescribing decreased (57.7% to 29.1%), while atypical antipsychotics, especially quetiapine (14.1% to 49.7%), increased. Of those who initiated antipsychotics, 59.4% were women (typical antipsychotics = 62.8%, atypical antipsychotics = 56.1%) and median age was 46 years (typicals = 49 years, atypicals = 44 years).Antipsychotics were rarely used to treat depression between 2005-2013 in UK primary care. The choice of adjunctive antipsychotic therapy changed over this time, with atypical antipsychotics now representing the preferred treatment choice. However, information on patients strictly cared for in other settings, such as by psychiatrists or in hospitals, potentially more severe patients, was unavailable and may differ. Nonetheless, the high off-label use in primary care, even after the authorization of quetiapine, suggests that there is a need for more licensed treatment options for adjunctive antipsychotic therapy in major depressive disorder.

PurposeThe aim of this study is to evaluate the effectiveness of 12-week treatment with aripiprazole in a broad range of patients suffering from schizophrenia by using a variety of physicians, caregivers and patients scales.Subjects and methodsA total of 361 in- or outpatients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia received open-label aripiprazole (10–30mg per day) in this 12-week, prospective, multicentre, uncontrolled study. The primary endpoint was the Clinical Global Impression-Improvement (CGI-I) scale which measured effectiveness of study medication, including efficacy, safety and tolerability. A variety of physician-, patient- and caregiver-rated parameters were measured to gain a complete view of the effectiveness of aripiprazole.ResultsThe effectiveness of aripiprazole treatment was demonstrated in a broad range of schizophrenia patients (CGI-I score of 3.0; 95% confidence interval: 2.8, 3.2: last observation carried forward [LOCF]) as the upper bound of the 95% CI was less than 4 (score of “no change”). Both patient and caregiver PGI-I scores (LOCF: 95% CI: 2.79, 3.09 and, 95% CI: 2.74, 3.17, respectively) corroborate this finding. Aripiprazole had a positive effect on disease severity by study end, as assessed by an increase of the (physician-rated) CGI-S scores, with 57.3% of patients having improved disease, one-third maintaining their condition (30.8%) and 11.3% with worsening symptoms (LOCF). The Investigator Assessment Questionnaire (IAQ) showed a great improvement (>50% of patients). Patients reported significantly improved quality of life and overall, 71% of patients and 67% of caregivers preferred aripiprazole to their previous antipsychotic medication (LOCF; PConclusionAripiprazole was effective in a broad range of patients with schizophrenia.

AIM: One of the aims of the TEMPPO study was to describe the sociodemographic and clinical characteristics of a cohort of adult outpatients with type I or type II bipolar disorders (as defined by DSM-IV criteria) in France. METHODS: TEMPPO is a multicenter, cross-sectional, non-interventional study conducted in France between November 2008 and May 2009, with a random sample of academic and private practice psychiatrists. Each psychiatrist who agreed to participate in the study had to: complete a register with data on all consecutive patients (up to 20 patients) consulting during a 2-month period and fulfilling inclusion criteria; include in the study the first five patients of the register with an on-going consultation for at least 6 months; for each of which a detailed questionnaire had been assessed, notably their sociodemographic and bipolar clinical characteristics. Adult outpatients diagnosed with bipolar disorders (BD) were enrolled if fulfilling the following inclusion criteria: man or woman, aged 18 and above, diagnosed bipolar type I or II according to DSM-IV criteria, treated (whatever the treatment strategy) or not, and followed-up for at least 6 months by the participating psychiatrist. RESULTS: One hundred and thirty-five psychiatrists included 619 patients with bipolar disorder (197 and 422 followed-up in public and private practice respectively). The estimated prevalence of patients with bipolar disorders consulting psychiatrists was 0.43%. Type I bipolar disorder was the most frequent condition (58% of the patients). As a whole, bipolar disorder was associated with severe handicap (mean global disease Clinical Global Impression [CGI]-Severity score of 4.4 and mean GAF [Global Assessment of Functioning] score of 59), with more depressive episodes than manic episodes (6 vs. 4) or hypomania (6 vs. 3), a high proportion of rapid cycles (11%), psychiatric comorbidities (45% of patients), obesity (16% of patients), libido dysfunction and associated psychotic symptoms. Current manic phase was associated with more pronounced illness severity and lowest functioning. More than half of the patients (57%) had a family history of psychiatric disorders. CONCLUSION: This study could shed some light for a better understanding of demographics and clinical patterns of patients with bipolar disorders consulting psychiatrists in France. The results emphasize the severity of bipolar disorders with mainly depressive episodes, a high proportion of rapid-cycling, comorbidities and associated psychotic symptoms; these characteristics being more marked in patients suffering from BD I. Furthermore, this study confirms the strong negative impact on social and professional life of French bipolar patients, requiring specific management in addition to the symptomatic treatment.

Resume TEMPPO est une etude observationnelle, transversale, multicentrique initiee sur le territoire de la France metropolitaine en 2009. Mise en place aupres d’un echantillon aleatoire de 135 psychiatres, elle a permis d’observer les modalites de prise en charge therapeutique d’une population (n = 619) de leurs patients ambulatoires (respectivement 197 et 422 en secteur public et prive) souffrant de troubles bipolaires de type I ou II (criteres du DSM-IV). Les patients suivis, majoritairement malades a tres malades, beneficiaient tous d’un traitement pharmacologique. La prescription comportait au moins un thymoregulateur ou un antipsychotique (71 % atypique) dans respectivement 78 % et 56 % des cas. Les changements therapeutiques etaient frequents (61 % des patients ont beneficie au moins d’une modification du traitement lors des 12 derniers mois). Une seule molecule par classe therapeutique est generalement prescrite. La presence d’un antipsychotique dans une polytherapie est souvent associee a la gravite ou a la difficulte de prise en charge du patient (etats mixtes, severite de l’atteinte du fonctionnement global, etats maniaques, nombre eleve d’hospitalisations, antecedents de tentative de suicide). L’association de deux antipsychotiques n’est retrouvee que dans les situations difficiles d’etats maniaques. Les patients severes en phase depressive sont ceux qui beneficient de la combinaison antipsychotique + thymoregulateur + antidepresseur (16 % de l’echantillon). Dans cette etude, la prescription d’antidepresseurs est celle qui differe le plus des recommandations de bonnes pratiques de prescription. Elle est, en effet, frequente en phase mixte (63 %), particulierement en monotherapie dans 5 % des cas, et retrouvee chez 48 % des patients en phase euthymique, 12 % des patients en phase maniaque et 29 % des patients en phase hypomaniaque. La prescription des antipsychotiques atypiques (en monotherapie ou association) est, desormais, parfaitement etablie dans la prise en charge de l’ensemble des phases de la maladie. L’importance d’un traitement non pharmacologique est reconnue et proposee par les psychiatres qu’il s’agisse d’une prise en charge psychotherapeutique, de conseils sur la maladie et/ou hygienodietetiques. Les donnees recueillies dans cette etude ont permis de mettre en evidence que les psychiatres participants ont une prise en charge pharmacologique des patients souffrant de troubles bipolaires majoritairement en accord avec les recommandations nationales et internationales.

It is becoming clear to clinicians that functional prognosis is the issue that should be guiding their choice of therapeutic strategy offered to people with schizophrenic disorders. An individual's degree of social autonomy is one of the principal factors determining functional prognosis, and it has become essential to identify the variables that influence it. The ESPASS survey was set up to follow a cohort of 6000 schizophrenic patients in a naturalistic setting, and was conducted over six months by 1170 psychiatrists. Patients were required to meet DSM-IV TR criteria for schizophrenia, with the exception of those suffering from an acute psychotic episode, and to either need a change in their antipsychotic treatment or its initiation. Data collected included patients' sociodemographical characteristics, types of treatment (pharmacological and non-pharmacological), illness characteristics (as determined by the DSM-IV TR criteria), degree of social autonomy (EAS), effectiveness (IAQ scale), overall severity of the illness (CGI - S scale) and patient satisfaction with medical treatment (PASAP self-questionnaire). Concerning the non-pharmacological aspects of treatment that offer patients programmes to increase their autonomy, the survey made it possible to collect data describing real practices and to measure the actual availability of rehabilitation services. It has been verified that the sample of psychiatrists included in this survey, as well as the schizophrenic patients under evaluation, were representative of the French psychiatrist and patient populations. Most importantly, the survey made it possible to objectively evaluate the healthcare services available in France. It seems that the vast majority of public-service psychiatrists have access to hospital and ambulatory facilities for treatment (medical-psychological centers, day-care hospitals and rest centers), as well as access to facilities providing simulated real-life activities. Psychiatrists who are private practitioners have less access to such arrangements for their patients. The vast majority of psychiatrists in both categories are unable to offer their patients active rehabilitation techniques: training in social skills (25%), cognitive remediation (16%), cognitive-behavioral therapies (20%), even though psychoeducation is quite widespread (44%). However, the survey demonstrated that the actual use of these methods was much lower still (2%, 1% and 2%, respectively), although the use of alternative facilities to hospitalization was quite high (day-care hospitals 9%, rest-centers 8%). In total, at the end of the study, the proportion of patients benefiting from some kind of programme to increase their level of autonomy was 41%. These results have demonstrated a link between the evolution of patients' clinical symptoms and their social autonomy. Within the findings, the items that varied most were patient's level of personal care and relations with others, whereas the ability to manage resources seems difficult to influence. Moreover, the results have shown that better development of social autonomy is significantly correlated with the prescription of second-generation antipsychotics. Regarding non-pharmacological treatment, better development of social autonomy is significantly correlated with setting up programmes to achieve this objective, including the use of active rehabilitation techniques. Overall, the survey confirmed the results of earlier work to validate the scale of social autonomy (EAS), and confirmed the robustness of its objective measurements.

Resume EPICTA est une etude ouverte et prospective qui a ete menee en 1994 aupres de 1 702 psychiatres liberaux. Les objectifs etaient de preciser leurs habitudes de prescription des antidepresseurs, en monotherapie, selon qu’ils etaient prescrits en premiere intention ou apres l’echec d’un premier antidepresseur, d’en comparer les effets therapeutiques et de rechercher des facteurs pronostiques. Ont ete inclus 6 537 patients. Les resultats montrent qu’en premiere ou en seconde intention, le choix des psychiatres s’est majoritairement porte sur les ISRS avec des taux de reponse therapeutique satisfaisants. Les antidepresseurs tricycliques, bien que moins frequemment prescrits, donnent de meilleurs resultats que les autres antidepresseurs en seconde intention ( p = 0,008). Les facteurs pronostiques retrouves dans cette enquete confirment les donnees deja existantes. Ainsi, l’âge superieur a 45 ans, une duree d’evolution de l’acces superieure a un an, la presence d’antecedents depressifs remontant a plus de cinq ans, la presence d’un trouble psychiatrique ou somatique associe et la co-prescription de neuroleptiques sont associes a un moindre taux de reponse therapeutique.

International audience; AIM: One of the aims of the TEMPPO study was to describe the sociodemographic and clinical characteristics of a cohort of adult outpatients with type I or type II bipolar disorders (as defined by DSM-IV criteria) in France. METHODS: TEMPPO is a multicenter, cross-sectional, non-interventional study conducted in France between November 2008 and May 2009, with a random sample of academic and private practice psychiatrists. Each psychiatrist who agreed to participate in the study had to: complete a register with data on all consecutive patients (up to 20 patients) consulting during a 2-month period and fulfilling inclusion criteria; include in the study the first five patients of the register with an on-going consultation for at least 6 months; for each of which a detailed questionnaire had been assessed, notably their sociodemographic and bipolar clinical characteristics. Adult outpatients diagnosed with bipolar disorders (BD) were enrolled if fulfilling the following inclusion criteria: man or woman, aged 18 and above, diagnosed bipolar type I or II according to DSM-IV criteria, treated (whatever the treatment strategy) or not, and followed-up for at least 6 months by the participating psychiatrist. RESULTS: One hundred and thirty-five psychiatrists included 619 patients with bipolar disorder (197 and 422 followed-up in public and private practice respectively). The estimated prevalence of patients with bipolar disorders consulting psychiatrists was 0.43%. Type I bipolar disorder was the most frequent condition (58% of the patients). As a whole, bipolar disorder was associated with severe handicap (mean global disease Clinical Global Impression [CGI]-Severity score of 4.4 and mean GAF [Global Assessment of Functioning] score of 59), with more depressive episodes than manic episodes (6 vs. 4) or hypomania (6 vs. 3), a high proportion of rapid cycles (11%), psychiatric comorbidities (45% of patients), obesity (16% of patients), libido dysfunction and associated psychotic symptoms. Current manic phase was associated with more pronounced illness severity and lowest functioning. More than half of the patients (57%) had a family history of psychiatric disorders. CONCLUSION: This study could shed some light for a better understanding of demographics and clinical patterns of patients with bipolar disorders consulting psychiatrists in France. The results emphasize the severity of bipolar disorders with mainly depressive episodes, a high proportion of rapid-cycling, comorbidities and associated psychotic symptoms; these characteristics being more marked in patients suffering from BD I. Furthermore, this study confirms the strong negative impact on social and professional life of French bipolar patients, requiring specific management in addition to the symptomatic treatment.

International audience; TEMPPO is an observational, cross-sectional and multicentre study, initiated in the French metropolitan territory in 2009. Set up from a random sample of 135 psychiatrists, it has observed the procedures for therapeutic management of a population (n=619) of their outpatients (respectively 197 and 422 in public and private practice) with bipolar disorder type I or II disorders (DSM-IV). The patients who were followed were mostly very sick. Every patient received a pharmacological treatment. The prescription included at least one mood stabilizer or an antipsychotic (71 % atypical) in 78 % and 56 % of cases respectively. Treatment regimen changes were frequent (61 % of patients had at least one change in treatment during the last 12 months). A single molecule by therapeutic class was generally prescribed. The presence of an antipsychotic in combination therapy was often associated with the severity or difficulty of care of the patient (mixed states, severity of the global functioning impairment, manic states, high number of hospitalizations and history of suicide attempt). The combination of two antipsychotics is found only in the difficult situations of manic states. Patients with severe depressive phase are those who benefit from the combination mood stabilizer+antipsychotic+antidepressant (16 % of the sample). In this study, the prescription of antidepressants significantly differs from recommendations for good prescribing practices. Indeed antidepressants were commonly prescribed in mixed-phase (63 %), particularly as a monotherapy in 5 % of cases. It was also found in patients in euthymic phase (48 %), manic phase (12 %) and hypomanic phase (29 %). The prescription of atypical antipsychotics (monotherapy or combination) is now fully established in the management of all phases of the disease. The importance of non-pharmacological treatment is acknowledged by psychiatrists and proposed whether a psychotherapeutic support, information about the disease and/or lifestyle changes. The data collected in this study allowed to demonstrate that the participant psychiatrists have a pharmacological management of patients with bipolar disorder mostly in line with national and international guidelines.

It is becoming clear to clinicians that functional prognosis is the issue that should be guiding their choice of therapeutic strategy offered to people with schizophrenic disorders. An individual's degree of social autonomy is one of the principal factors determining functional prognosis, and it has become essential to identify the variables that influence it. The ESPASS survey was set up to follow a cohort of 6000 schizophrenic patients in a naturalistic setting, and was conducted over six months by 1170 psychiatrists. Patients were required to meet DSM-IV TR criteria for schizophrenia, with the exception of those suffering from an acute psychotic episode, and to either need a change in their antipsychotic treatment or its initiation. Data collected included patients' sociodemographical characteristics, types of treatment (pharmacological and non-pharmacological), illness characteristics (as determined by the DSM-IV TR criteria), degree of social autonomy (EAS), effectiveness (IAQ scale), overall severity of the illness (CGI - S scale) and patient satisfaction with medical treatment (PASAP self-questionnaire). Concerning the non-pharmacological aspects of treatment that offer patients programmes to increase their autonomy, the survey made it possible to collect data describing real practices and to measure the actual availability of rehabilitation services. It has been verified that the sample of psychiatrists included in this survey, as well as the schizophrenic patients under evaluation, were representative of the French psychiatrist and patient populations. Most importantly, the survey made it possible to objectively evaluate the healthcare services available in France. It seems that the vast majority of public-service psychiatrists have access to hospital and ambulatory facilities for treatment (medical-psychological centers, day-care hospitals and rest centers), as well as access to facilities providing simulated real-life activities. Psychiatrists who are private practitioners have less access to such arrangements for their patients. The vast majority of psychiatrists in both categories are unable to offer their patients active rehabilitation techniques: training in social skills (25%), cognitive remediation (16%), cognitive-behavioral therapies (20%), even though psychoeducation is quite widespread (44%). However, the survey demonstrated that the actual use of these methods was much lower still (2%, 1% and 2%, respectively), although the use of alternative facilities to hospitalization was quite high (day-care hospitals 9%, rest-centers 8%). In total, at the end of the study, the proportion of patients benefiting from some kind of programme to increase their level of autonomy was 41%. These results have demonstrated a link between the evolution of patients' clinical symptoms and their social autonomy. Within the findings, the items that varied most were patient's level of personal care and relations with others, whereas the ability to manage resources seems difficult to influence. Moreover, the results have shown that better development of social autonomy is significantly correlated with the prescription of second-generation antipsychotics. Regarding non-pharmacological treatment, better development of social autonomy is significantly correlated with setting up programmes to achieve this objective, including the use of active rehabilitation techniques. Overall, the survey confirmed the results of earlier work to validate the scale of social autonomy (EAS), and confirmed the robustness of its objective measurements.

Objective Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day). Methods Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint. Results At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea. Conclusions The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.

IntroductionMajor Depressive Disorder (MDD) patients experience different levels of response and functionality impairments.Objectives/aimsEvaluate levels of response for adjunctive aripiprazole therapy (AA) and effects of AA on patient functioning.MethodsData were pooled from three similar, randomized, double-blind, placebo-controlled trials with aripiprazole in MDD. Quartile response categories were defined by reduction (%) in MADRS >6 weeks of treatment: Minimal response (≤25%), Partial response (>25% to < 50%), Moderate response (≥50% to < 75%), and Robust response (≥75%). Proportions of placebo (AP) vs. AA patients achieving a response were compared (Cochran-Mantel-Haenszel test) for each category. Functionality was assessed using mean changes in Sheehan Disability Scale (SDS) scores. Changes in scores were compared (ANCOVA) between AA and AP.ResultsAA had more patients (%) compared with AP achieving partial (23.9% vs. 17.9%, p = 0.017), moderate (23.1% vs. 15.0%, p< 0.001), and robust responses (14.3% vs. 7.4%, p< 0.001). AA had less (%) achieving minimal response compared with AP (38.7% vs. 59.6%, p< 0.001). Mean changes are below.[Mean changes in SDS and domain scores]ConclusionsMost inadequate responders who continued on AP were minimal responders (60%). 60% of aripiprazole patients rapidly achieved partial, moderate or robust response status. AA significantly improved social and family life domains of functioning.

IntroductionAripiprazole 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.Objectives/aimThis analysis evaluated the profile of discrete symptom response using the YMRS and other measures.MethodsPost-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).ResultsIn 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.ConclusionsAripiprazole 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.

ObjectiveEvaluate the time-course, severity and resolution patterns of adverse events (AEs) occurring with long-term aripiprazole treatment for irritability associated with autistic disorder.MethodsParticipants were treated with aripiprazole in a 52-week, open-label, flexibly dosed (2–15 mg/day) study. Subjects had either completed one of two 8-week randomised trials or were de novo. AEs with an incidence of ≥10% were evaluated by incidence, peak first onset, severity, percent resolved and time to resolution.ResultsA total of 330 subjects entered open-label treatment; 199 completed 52 weeks. Mean dose for the population stabilised at around 10 mg/day after approximately 4 months. Thirteen AEs had an incidence of ≥10%; most were mild or moderate in severity. Vomiting, diarrhoea and headache had an early first onset and tended to resolve fairly quickly.Sedation, fatigue and insomnia also appeared early and resolved in a majority of cases, but not as quickly. Increased appetite appeared early (followed by increased weight) and fewer weight-related AEs resolved. More than half of the subjects increased their weight by at least one percentile category rank; nevertheless, only a small proportion of subjects with normal baseline metabolic or glucose measures had a treatment-emergent, clinically relevant laboratory abnormality. Nasopharyngitis, upper respiratory infection, cough, nasal congestion and pyrexia all had peak onset at variable times during the study, resolving in nearly all cases, with short time to resolution.ConclusionAEs were mostly mild or moderate and of variable duration. Increased weight was observed.

ObjectivesThe 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).MethodsData 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.ResultsIn 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.ConclusionsIn 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.

AimsTo evaluate the efficacy of aripiprazole as adjunctive treatment in patients with major depressive disorder (MDD) without psychotic features and an inadequate response to standard antidepressant therapy (ADT).MethodsData were collected from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165). After a single-blind prospective phase with placebo plus ADT, patients with inadequate response were randomized to 6-weeks’ treatment with adjunctive aripiprazole or placebo. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score during the double-blind phase. Secondary endpoints were response (≥50% reduction in MADRS total score), remission (MADRS total score ≤10 and ≥50% reduction in MADRS total score), and mean change in Hamilton Depression Rating Scale (HAM-D17) total score.ResultsIn all three studies, adjunctive aripiprazole was associated with a significantly greater reduction in MADRS total score than adjunctive placebo, with a treatment difference ranging between -3.73 and -2.84 (p≤0.001 in each study). Response and remission rates with adjunctive aripiprazole (32.4-46.6% and 25.4-36.8%, respectively) were also significantly higher than with adjunctive placebo (17.4-26.6% [p< 0.05 in each study] and 15.2-18.9% [p< 0.05 in each study]). Mean change in HAM-D17 total score ranged from -7.64 to -6.77 with adjunctive aripiprazole and from -5.12 to -4.41 with adjunctive placebo (p< 0.001 for each study).ConclusionsResults of the three studies indicate that treatment with adjunctive aripiprazole and ADT is effective in improving the symptoms of MDD in patients who have had an inadequate response to ADT.

ObjectiveTo evaluate the efficacy of aripiprazole adjunctive antidepressant therapy (ADT) with regard to functioning in patients with major depressive disorder (MDD) who did not achieve an adequate response with standard ADT.MethodsPooled data were analyzed from three nearly identically designed randomized, double-blind, placebo-controlled trials: CN138-139, CN138-163 and CN138-165. These included patients with MDD, without psychotic features, who had failed at least one ADT treatment in the present episode. Patients completing an 8-week prospective ADT phase with inadequate response were randomized to 6-weeks’ treatment with adjunctive aripiprazole (n=508) or placebo (n=494). Functioning was assessed using the Sheehan Disability Scale (SDS). Comparisons of mean change from baseline in total SDS score, and domains of family life, social life and work/school were performed using ANCOVA.ResultsAdjunctive aripiprazole produced significant improvements in total SDS (-1.2 on an adjusted scale of 1-10, with 10=worst level of functioning/1=best) vs adjunctive placebo (-0.7, p< 0.001). Adjunctive aripiprazole produced significant changes in the family life domain (-1.4 for adjunctive aripiprazole vs -0.7 for adjunctive placebo, p< 0.001) and the social life domain (-1.4 for adjunctive aripiprazole vs -0.7 for adjunctive placebo, p< 0.001). No difference between groups was observed on the work/school domain (-0.8 for adjunctive aripiprazole and -0.6 for adjunctive placebo, p=0.34).ConclusionsAdjunctive aripiprazole showed significant improvements in overall SDS scores, and family and social life domains. Less change was observed in the work/school domain. The results emphasize that assessment of patient functioning may have utility both in clinical trials and clinical practice.

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

IntroductionAvailable data suggest that sex hormone levels during puberty may affect symptom onset and expression, treatment responsiveness and outcomes in schizophrenia, whereas post-pubertal adolescents may have a similar clinical presentation and treatment response compared to adults with schizophrenia.ObjectivesPost-hoc analyses were conducted to assess the similarity of short- and long-term efficacy between post-pubertal adolescents and adults with schizophrenia treated with aripiprazole.MethodsBased on available European epidemiologic data, a cut-off age of 15 years was used to isolate a subgroup of mostly post-pubertal adolescents with schizophrenia in aripiprazole clinical studies. Outcome measures from this subgroup (ages 15-17; n=147) were then compared to outcomes from one adult study (n=853) on short and long-term measures of efficacy, including PANSS scores, response rates, and remission rates.ResultsComparable short and long-term treatment effects were observed on the PANSS total and subscale scores, demonstrated by overlapping 95% confidence intervals (mean change from baseline in PANSS total score (OC dataset): at week 6 in adults: -27,7; in adolescents 15-17 yr: -29,6; at week 30 in adults: -39,2; in adolescents 15-17 yr: -36). Percent of adolescents achieving response (defined as ≥ 30% decrease in PANSS total score from baseline) at 32 weeks (80,2%) on open label treatment was similar to that in adult studies at week 34 (80%) on double blind treatment (OC dataset).ConclusionsAdolescents with schizophrenia (ages 15-17, mostly post-pubertal) demonstrate a positive treatment response in short-term and long-term studies which is similar to that observed in the adult patient population.

AimsTo conduct a subgroup analysis of the efficacy of adjunctive aripiprazole as treatment in patients with major depressive disorder (MDD) who demonstrated an inadequate response to standard antidepressant therapy (ADT).MethodsData were pooled from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165) with an 8-week phase of placebo plus ADT and a 6-week double-blind phase with ADT plus adjunctive placebo or aripiprazole. Only MDD patients without psychotic features were eligible for entry. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score in the double-blind phase. Subgroup analyses of the primary efficacy endpoint were performed for age, race, ethnicity, MADRS response, number and choice of previous ADTs, episode duration, and use of selective serotonin re-uptake inhibitors (SSRI).ResultsCompared with the adjunctive placebo group, adjunctive aripiprazole was associated with greater reductions in MADRS total score in all subgroups. Mean change in MADRS total score ranged from -10.71 to -5.89 with adjunctive aripiprazole and -7.57 to -4.10 with adjunctive placebo. No statistically significant treatment-by-subgroup interaction effects were observed for any subgroup except gender (p=0.039). This difference is, however, primarily because of results from study CN138-139 results; consistent results between men and women were reported in CN138-163 and CN138-165.ConclusionsPooled data indicate that in patient populations with similar baseline characteristics, treatment with adjunctive aripiprazole and ADT is efficacious in improving the symptoms of MDD in subgroups of patients having an inadequate response to ADT.

IntroductionAssessing impact of treatment from the patient perspective provides additional information about treatment efficacy in major depressive disorder (MDD) trials.ObjectivesPooled data from three identically designed clinical trials showed aripiprazole adjunctive to antidepressant therapy (ADT) was effective in treating MDD.1MethodsPatients who completed an 8-week prospective ADT phase with inadequate response were randomized double-blind to 6-weeks adjunctive treatment with aripiprazole or placebo. The Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) is a 16-item, self-report measure to evaluate daily functioning, with higher scores indicating better satisfaction. Comparisons of mean change from baseline (Week 8) to Week 14 in Q-LES-Q-SF items and general subscores were performed using ANCOVA (LOCF).ResultsThere was significant improvement in the Q-LES-Q-SF Overall-General subscore (total of items 1-14 expressed as a percentage of the maximum possible score) in the aripiprazole-treatment group (9.49% [n=507]) vs placebo (5.71% [n=492] p< 0.001). Placebo was significantly higher than aripiprazole in Physical Ability (placebo 0.13 vs aripiprazole 0.02, p=0.020). Aripiprazole was significantly higher than placebo in all other items except Physical Health and Vision. Aripiprazole also produced significant increases in both the Satisfaction with Medication (Item 15) (aripiprazole 0.36 vs placebo 0.20, p< 0.01) and Overall Satisfaction (Item 16) (aripiprazole 0.61 vs placebo 0.35, p< 0.001) scores.ConclusionsResults emphasize that assessment of patient functioning and quality of life may have utility both in clinical trials and clinical practice.2

ObjectiveTo evaluate the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in bipolar mania.MethodsCompleters of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to monotherapy were followed up over 46-weeks on open-label aripiprazole plus lithium (ARI+LI) or valproate (ARI+VAL).Results283 (ARI+LI n=108; ARI+VAL n=175) patients entered and 146 (ARI+LI n=55; ARI+VAL n=91) completed the 46-week extension. Safety results for both combinations were consistent with the known tolerability profile of aripiprazole, lithium and valproate. No clinically significant changes in lipids or glucose were observed with either ARI+LI or ARI+VAL. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI+LI and 2.0 (0.4) kg with ARI+VAL. Temporal analysis of the time of first onset of adverse events showed that akathisia and insomnia tended to occur early in treatment, with few new cases in patients previously treated with aripiprazole during the 6-week study.Significant improvements from baseline in YMRS total score and MADRS total score were sustained over the 52 weeks with both ARI+LI and ARI+VAL treatment.Mean reduction from baseline at Week 52 LOCF[95%CI], p value vs baselineARI+LIARI+VALYMRS total score-16.5 [-18.1; -14.8], p-17.6 [-18.9; -16.3] pMADRS total score-1.7 [-3.3; -0.1] p-2.7 [-4.0; -1.4] pConclusionsLong-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well-tolerated. Improvements in manic and depressive symptoms observed during the first 6 weeks of treatment were maintained.

Aims:To evaluate dyslipidaemia risk among patients with schizophrenia treated with aripiprazole or olanzapine.Methods:Pooled analysis of the aripiprazole clinical database, including studies of ≥7 days with at least an oral aripiprazole monotherapy arm. Mean changes from baseline to endpoint and shifts from normal to abnormal lipid levels were calculated.Results:Seventeen placebo- and five olanzapine-controlled studies (3 weeks->3 years) of adult patients (≥18 years) were included. Mean changes (LOCF) in lipids were similar between aripiprazole and placebo for all lipid parameters; aripiprazole showed significant improvements versus olanzapine (p≤0.01). the incidence (OC) of switching to abnormal lipid levels from baseline normal was similar between placebo and aripiprazole, and significantly lower with aripiprazole than olanzapine for most measures.Conclusion:Despite limitations inherent to pooled analyses, these findings lend further support to the differential profile of atypicals, with aripiprazole showing effects on lipids comparable with placebo.

Background:Metabolic syndrome - a significant risk factor for cardiovascular morbidity and mortality - is twice as prevalent among psychiatric patients (21-63%) as general populations (20-24%). Although there is an inherent illness-associated metabolic risk, medications do contribute. Atypicals vary in metabolic risk from high (clozapine, olanzapine), moderate (risperidone, quetiapine) to low (aripiprazole, ziprasidone) (ADA, 2004). Few studies have comprehensively measured cardiovascular risk or directly compared antipsychotics. Limited controlled data show that antipsychotic-induced metabolic abnormalities may be reversible, rationalizing the switch to a lower-risk agent (DeNayer, 2004). Non-HDL-cholesterol encompasses all atherogenic cholesterols and provides a marker of CV risk: an increase of 29ng/dL in diabetics is associated with 50% increased risk (Jiang, 2004). Non-HDL-cholesterol is independently associated with increased risk of non-fatal myocardial infarction and angina.Aim:This study will provide cross-European data from 13 countries on MS rates in schizophrenia and will assess antipsychotic metabolic profiles and benefits of antipsychotic switching.Methods:In this ongoing, 16-week, open-label, European multicentre study, 258 schizophrenia patients treated for ≥3 months with olanzapine, risperidone or quetiapine and who have MS will be randomized to switch to aripiprazole (Week 1: 5mg/day; Week 2: 10mg/day; flexible 10-30mg/day after Week 2) or continue with previous antipsychotic. the primary objective is to demonstrate superiority of aripiprazole versus atypicals on mean percentage change of fasting non-HDL-cholesterol from baseline to Week 16.Conclusion:This study will provide the first direct and comprehensive comparison of metabolic risk with various atypicals in Europe and should impact the future management of schizophrenia.