Efficacy Of Aripiprazole Research Articles

Efficacy of Aripiprazole for the Management of Antipsychotic-Induced Hyperprolactinemia: A Retrospective Case Series

Efficacy of Aripiprazole for the Management of Antipsychotic-Induced Hyperprolactinemia: A Retrospective Case Series

Nanogels Based on N,N-Dimethylacrylamide and β-Cyclodextrin Triacrylate for Enhanced Solubility and Therapeutic Efficacy of Aripiprazole.

Aripiprazole (ARZ) is a medication used for the treatment of various diseases such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Despite its therapeutic benefits, ARZ is characterized by a poor water solubility which provoked the development of various delivery systems in order to enhance its solubility. In the present work, a nanoscale drug delivery system based on N,N-dimethylacrylamide (DMAA) and β-cyclodextrin triacrylate (β-CD-Ac3) as potential aripiprazole delivery vehicles was developed. The nanogels were synthesized by free radical polymerization of DMAA in the presence of β-CD-Ac3 as a crosslinking agent and then loaded with ARZ via host-guest inclusion complexation. The blank- and drug-loaded nanogels were evaluated using different methods. Fourier transform infrared (FTIR) spectroscopy was employed to confirm the incorporation of β-CD moieties into the polymer network. Dynamic light scattering (DLS) was used to study the size of the developed systems. The samples exhibited a monomodal particle size distribution and a relatively narrow dispersity index. The hydrodynamic diameter (Dh) of the gels varied between 107 and 129 nm, with a tendency for slightly larger particles as the β-CD-Ac3 fraction increased. Loading the drug into the nanocarrier resulted in slightly larger particles than the blank gels, but their size was still in the nanoscopic range (166 to 169 nm). The release profiles in PBS were studied and a sustained release pattern with no significant burst effect was observed. A cytotoxicity assessment was also conducted to demonstrate the non-toxicity and biocompatibility of the studied polymers.

Application of Antipsychotic Drugs in Mood Disorders.

Since their first application in psychiatry seventy years ago, antipsychotic drugs, besides schizophrenia, have been widely used in the treatment of mood disorders. Such an application of antipsychotics is the subject of this narrative review. Antipsychotic drugs can be arbitrarily classified into three generations. First-generation antipsychotics (FGAs), such as phenothiazines and haloperidol, were mainly applied for the treatment of acute mania, as well as psychotic depression when combined with antidepressants. The second-generation, so-called atypical antipsychotics (SGAs), such as clozapine, risperidone, olanzapine, and quetiapine, have antimanic activity and are also effective for the maintenance treatment of bipolar disorder. Additionally, quetiapine exerts therapeutic action in bipolar depression. Third-generation antipsychotics (TGAs) started with aripiprazole, a partial dopamine D2 receptor agonist, followed by brexpiprazole, lurasidone, cariprazine, and lumateperone. Out of these drugs, aripiprazole and cariprazine have antimanic activity, lurasidone, cariprazine, and lumateperone exert a significant antidepressant effect on bipolar depression, while there is evidence for the efficacy of aripiprazole and lurasidone in the prevention of recurrence in bipolar disorder. Therefore, successive generations of antipsychotic drugs present a diverse spectrum for application in mood disorders. Such a pharmacological overlap in the treatment of schizophrenia and bipolar illness stands in contrast to the dichotomous Kraepelinian division of schizophrenia and mood disorders.

The pharmacogenetics of the new-generation antipsychotics - A scoping review focused on patients with severe psychiatric disorders.

Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i.e., cariprazine, brexpiprazole, aripiprazole, lumateperone, and pimavanserin. Based on the analysis of 25 primary and secondary sources and the review of these agents' summaries of product characteristics, aripiprazole benefits from the most relevant data about the impact of gene variability on its pharmacokinetics and pharmacodynamics, with significant consequences on this antipsychotic's efficacy and tolerability. The determination of the CYP2D6 metabolizer status is important when administering aripiprazole, either as monotherapy or associated with other pharmacological agents. Allelic variability in genes encoding dopamine D2, D3, and serotonin, 5HT2A, 5HT2C receptors, COMT, BDNF, and dopamine transporter DAT1 was also associated with different adverse events or variations in the clinical efficacy of aripiprazole. Brexpiprazole also benefits from specific recommendations regarding the CYP2D6 metabolizer status and the risks of associating this antipsychotic with strong/moderate CYP2D6 or CYP3A4 inhibitors. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations about cariprazine refer to possible pharmacokinetic interactions with strong CYP3A4 inhibitors or inducers. Pharmacogenetic data about cariprazine is sparse, and relevant information regarding gene-drug interactions for lumateperone and pimavanserin is yet lacking. In conclusion, more studies are needed to detect the influence of gene variations on the pharmacokinetics and pharmacodynamics of new-generation antipsychotics. This type of research could increase the ability of clinicians to predict favorable responses to specific antipsychotics and to improve the tolerability of the treatment regimen in patients with SPD.

Third-generation antipsychotics in patients with schizophrenia and non-responsivity or intolerance to clozapine regimen: What is the evidence?

Clozapine is considered « the golden standard » for the management of treatment-resistant schizophrenia, but many patients do not present adequate responsivity even to this antipsychotic. If we add the need to strictly monitor the hematologic and cardiometabolic adverse events during each clozapine trial and the difficulty of preserving therapeutic adherence in patients with low insight, residual negative/positive symptoms, or economic challenges, then the necessity of exploring alternative interventions for these patients becomes obvious. Also, in case of intolerance to clozapine or where clozapine did not induce remission, clinicians have to find new ways to help their patients. Switching to other antipsychotics or using these agents as add-ons to clozapine are the main interventions explored in this review, for patients with schizophrenia resistant to clozapine (ultra-resistant schizophrenia, URS). When clozapine intolerance is detected, conversion to another antipsychotic with distinct pharmacologic properties or formulation (e.g., long-acting intramuscular injectable agents, LAI) may be a useful option. Third-generation antipsychotics (TGA) have been selected for their distinct pharmacodynamically profile, which allows, at a theoretical level, their use in combination with clozapine. This narrative review is based on searching four electronic databases, that retrieved 19 primary and secondary reports on aripiprazole (seven case reports or case series presenting 24 patients; nine clinical trials, and three systematic reviews/meta-analyses), two primary reports on brexpiprazole (case report and case series, N = 3 patients), and six primary reports on cariprazine (case reports and case series, N = 14 patients). Based on the information collected from these reports, which included oral and LAI formulations, the TGA most supported by evidence for the augmentation of clozapine is aripiprazole (high-and medium-quality data), followed by cariprazine (low-quality data). Brexpiprazole has not yet been systematically explored for this indication, and in the case of lumateperone, no report could be found. The efficacy of aripiprazole and cariprazine was supported in the domains of positive, negative, and general symptoms, and aripiprazole may positively impact the metabolic profile in patients with URS. Also, adding TGA may lead to a decrease in the dose of clozapine concomitantly administered. More data derived from good quality research are needed in order to confirm the circumstances of TGAs recommendation in patients with URS, either as monotherapy, or added to clozapine.

Aripiprazole Improved Post-Streptococcal Dyskinesia by Modulating Dopaminergic Activity: A Case Report

This case report aimed to discuss the efficacy of aripiprazole for dyskinesia in patients with functional movement disorder after streptococcal infection, with its biological action of modulating dopamine hyperactivity in the basal ganglia as a dopamine partial agonist. This report has shown that the [18F] N‐(3‐Fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane positron emission tomography findings of the patient revealed that the dopamine hyperactivity in the basal ganglia at baseline was normalized after aripiprazole treatment due to its balancing effect as a dopamine partial agonist.

Pharmacological Treatment of Early-Onset Schizophrenia: A Critical Review, Evidence-Based Clinical Guidance and Unmet Needs

Early-onset schizophrenia (EOS) – onset before age 18 – is linked with great disease burden and disability. Decision-making for EOS pharmacological treatment may be challenging due to conflicting information from evidence and guidelines and unidentified care needs may remain unmet.We searched for systematic reviews, meta-analyses and umbrella reviews of EOS pharmacological treatment published in PubMed over the past 10 years and selected five clinical guidelines from Europe, North-America and Australia. Based on predefined outcomes, we critically compared the evidence supporting EOS-approved drugs in Europe and/or North-America with guidelines recommendations. We also evaluated the coverage of these outcomes to identify unmet needs.One systematic review, nine meta-analyses and two umbrella reviews (k=203 trials, N=81,289 participants, including duplicated samples across selected articles) were retrieved. Evidence supported the efficacy of aripiprazole, clozapine, haloperidol, lurasidone, molindone, olanzapine, quetiapine, risperidone and paliperidone in EOS, all of which obtained approval for EOS either in Europe and/or in North-America. Cognition, functioning and quality of life, suicidal behaviour and mortality and services utilisation and cost-effectiveness were poorly covered/uncovered.Among the antipsychotics approved for EOS, aripiprazole, lurasidone, molindone, risperidone, paliperidone and quetiapine emerged as efficacious and comparably safe options. Olanzapine is known for a high risk of weight gain and haloperidol for extrapyramidal side-effects. Treatment-resistant patients should be offered clozapine. Future long-term trials looking at cognition, functioning, quality of life, suicidal behaviour, mortality, services utilisation and cost-effectiveness are warranted. Closer multi-agency collaboration may bridge the gap between evidence, guidelines and approved drugs.

Antipsychotics for irritability in children with Autism Spectrum Disorders

IntroductionAutism is a neurodevelopmental disorder characterized by qualitative impairments in social interaction, communication, and restricted and repetitive behaviors [1]. Despite of these symptoms, some patients present different manifestations of irritability. These can be expressed in different kinds of disruptive behaviors. Recent studies shown that, at least 20% of children with autism present irritability symptoms, which cause severe social and familiar disturbances [2].ObjectivesThe aim of this study was to evaluate short-term efficacy of aripiprazole in children in comparison with other antipsychotic. We include behaviors related to irritability as all kinds of aggressions, tantrums and self-injuries.Methods90 patients were recruited. 45 of the patients received aripiprazole and 45 received other antipsychotic. The initial doses of aripiprazole was 2,5 mg/day. Doses were increase related to symptoms. The range of the doses were from 2,5 to 15 mg/day.ResultsFrom these 45 patients 12 had a relapse (26,6%) during the next two years. From the second group, 20 (44.4%) of the patients had a relapse during the next two years. Five of the aripiprazole group (11,1%) abandon treatment. From the second group twelve patients (26.6%) also abandon treatment. Prolactin rates with aripiprazole were 28.2 ng/ml for males and 14.1 ng/ml for women.Conclusions In general, the result of our research indicated that Aripiprazole was effective and generally safe and well tolerated in the treatment of irritability associated with ASD. One of the limitations was that we do not use scales in order to measure the changes.DisclosureNo significant relationships.

Place of the partial dopamine receptor agonist aripiprazole in the management of schizophrenia in adults: a Delphi consensus study

BackgroundAripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may be of interest in patients with specific clinical profiles who have not been studied extensively in randomised clinical trials.ObjectivesTo capture experience with aripiprazole in everyday psychiatric practice using the Delphi method in order to inform decision-making on the use of aripiprazole for the treatment of patients with schizophrenia in clinical situations where robust evidence from clinical trials is lacking.MethodsThe scope of the survey was defined as the management of schizophrenia in adults. A systematic literature review was performed to identify the different clinical situations in which aripiprazole has been studied, and to describe the level of clinical evidence. Clinical profiles to include in the Delphi survey were selected if there was a clear interest in terms of medical need but uncertainty over the efficacy of aripiprazole. For each clinical profile retained, five to seven specific statements were generated and included in a questionnaire. The final 41-item questionnaire was proposed to a panel of 406 French psychiatrists with experience in the treatment of schizophrenia. Panellists rated their level of agreement using a Likert scale. A second round of voting on eleven items was organised to clarify points for which a consensus was not obtained in the first round.ResultsFive clinical profiles were identified in the literature review (persistent negative symptoms, pregnancy, cognitive dysfunction, addictive comorbidity and clozapine resistance). Sixty-two psychiatrists participated in the first round of the Delphi survey and 33 in the second round. A consensus was obtained for 11 out of 41 items in the first round and for 9/11 items in the second round. According to the panellists’ clinical experience, aripiprazole can be used as maintenance treatment for pregnant women, is relevant to preserve cognitive function and can be considered an option in patients with a comorbid addictive disorder or with persistent negative symptoms.ConclusionThese findings may help physicians in choosing relevant ways to use aripiprazole and highlight areas where more research is needed to widen the evidence base.

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans.

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

Comparing the efficacy of aripiprazole as an add-on to valproate with other second-generation antipsychotics in acute mania symptoms in manic patients in Iran

Background Given the great importance of treating patients with bipolar disorder, the aim of this study was to compare the efficacy of aripiprazole with other second-generation antipsychotics in relieving acute symptoms of mania. Materials and methods In this study, 50 patients with bipolar I disorder, manic episode, were divided into two groups receiving aripiprazole (n = 25) and other second-generation antipsychotics (risperidone, olanzapine, and quetiapine) (n = 25) for 6 weeks. The disease severity was evaluated and compared according to YMRS and CGI criteria. Results The mean severity of mania according to YMRS and CGI, at week 0 in comparison with weeks 2, 4 and 6 in both groups was significantly different (p < 0.0001) and the treatment with Aripiprazole at week 2 (p < 0.0001) and 4 (p = 0.0002) was significantly better than the other second-generation antipsychotics. The two groups also showed an overall improvement in CGI-based results at weeks 4 and 6 (p = 0.002). In addition, the efficacy index for aripiprazole at weeks 4 (p = 0.011) and 6 (p < 0.0001) as well as disease improvement in the second (p < 0.0001) and fourth (p = 0.026) weeks after treatment were better than the other second-generation antipsychotics. Conclusions Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder, however, aripiprazole seems to be more efficient and faster for controlling mania in patients with bipolar disorder. KEY POINTS Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder. Comparison between the two drugs, aripiprazole showed a more beneficial role in the second and fourth weeks than second-generation antipsychotics. Due to the fact that the possible mechanisms involved in the role of aripiprazole have not been considered compared to other antipsychotics in patients with bipolar disorder, there is a need for more extensive studies in this field.

A head-to-head randomised controlled trial of aripiprazole versus quetiapine as augmenting agents in treatment-resistant depression

Introduction: Almost 30%–50% of the patients with major depressive disorder can be categorised as treatment-resistant depression (TRD). The use of augmenting agents such as aripiprazole (ARI) and quetiapine (QP) to the existing antidepressant (AD) therapy could be a suitable alternative for treating TRD. The superiority of anyone over others is not established in short-term studies. Hence, the present study was performed to compare the safety and efficacy of ARI and QP for the treatment of TRD. Materials and Methods: In the present study, a total of 50 patients with TRD who showed insufficient response to at least two ADs for 12 weeks were enrolled. The participants were assigned randomly in a double-blind trial to receive ARI (10 mg/day; n = 25) or QP (300 mg/day; n = 25) in addition to their standard AD therapy for 12 weeks. Montgomery–Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scale were used to measure treatment efficacy. The safety was evaluated by recording treatment-caused adverse effects (AEF). Results: A significant decrease in MADRS score was observed with ARI groups than in the QP group (‒7.5; ‒4.6, P < 0.001). The CGI scores in the ARI group also exhibit significant improvement compared with the QP group. There was a non-significant change in CGI score recorded in both groups. The AEF was observed in 11% of patients with more incidences in the QP groups. The incidences of AEFs resulting in discontinuation of therapy were found low in both groups (ARI: 1.6%; QP: 3.2%). Conclusion: The findings of this study conclude that TRD patients can be more benefitted by ARI augmentation therapy than QP.

Atypical antipsychotics in the treatment of patients with a dual diagnosis of schizophrenia spectrum disorders and substance use disorders: the results of a randomized comparative study

The article presents the results of a randomized comparative study of Aripiprazole and Quetiapine in the treatment of patients with a dual diagnosis: schizophrenia and substance use disorders. During the study, 90 of the 266 male patients were screened. Among them, 54 individuals (60%) had a previously established diagnosis of mental disorder and 36 patients (40%) had no established psychiatric diagnosis. They were randomly randomized into three groups of 30 patients, each receiving an antipsychotic: Aripiprazole at a dose of up to 20 mg daily, Quetiapine at a dose of up to 600 mg daily, or Haloperidol at a dose of up to 30 mg daily. The efficacy of Aripiprazole and Quetiapine was evaluated using the following scales: PANSS, BPRS, VAS, and Substance Craving Scale (SCS). Drug safety was assessed by the development of adverse events, serious adverse events, or adverse reactions. Study results demonstrated the efficacy of atypical antipsychotics in the three groups. Analysis of independent variables showed significant differences between Aripiprazole and Haloperidol in PANSS and BPRS scores by Visit 4, in VAS scores by Visit 3, and in SCS scores by Visit 2. Intergroup analysis of independent variables showed significant differences between Quetiapine and Haloperidol in PANSS, VAS, and SCS scores by Visit 4. Intergroup analysis of independent variables showed significant differences between Aripiprazole and Quetiapine in the VAS and SCS scores. The correlation analysis allowed drawing conclusions about the close connection of the symptoms of schizophrenia and substance use disorders in patients with a dual diagnosis

Aripiprazole Augmentation to Mood Stabilizers for Obsessive-Compulsive Symptoms in Bipolar Disorder.

Background and Objectives: Aripiprazole is a first-line agent in the treatment of bipolar disorder (BD) and available data demonstrates its efficacy on clinical symptoms in serotonin reuptake inhibitors-resistant obsessive-compulsive disorder (OCD) patients. Therefore, aripiprazole augmentation to mood stabilizers could represent a promising treatment in BD patients with comorbid OCD. The study examined the efficacy and safety of aripiprazole added to lithium or valproate for the treatment of obsessive-compulsive (OC) symptoms in euthymic BD patients with comorbid OCD. Materials and Methods: This is a 12-week prospective observational study. The efficacy of aripiprazole on OC symptoms was assessed through the mean change of Yale–Brown Obsessive-Compulsive (YBOCS) total score. Tolerability was assessed with the Utvalg for Kliniske Undersogelser (UKU) side effect scale and by reporting adverse events. Results: A total of 70 patients were included in the analyses. The withdrawal rate was 21.4%, mainly due to adverse events. Mean ± SD final aripiprazole dose was 15.2 ± 5.3 in the completer sample (N = 55). The Y-BOCS mean score decreased from 24.0 ± 4.1 at baseline to 17.1 ± 4.3 at 12 weeks. Treatment response rate (Y-BOCS reduction ≥ 35%) was 41.8%, while partial response rate (Y-BOCS reduction greater than 25% but less than 35% from baseline) accounted for the other 18.2% of patients. Overall, 91.4% of completers had at least 1 adverse effect (tremor, tension/inner unrest, reduced duration of sleep, akathisia). No significant differences emerged comparing aripiprazole efficacy and tolerability between patients treated with lithium or valproate. Conclusion: Our findings show that aripiprazole addition to lithium or valproate can reduce OC symptoms in real-world BD euthymic patients.

A safety evaluation of aripiprazole in the treatment of schizophrenia

ABSTRACT Introduction Aripiprazole is a third generation antipsychotic approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. Aripiprazole is available as oral and long-acting injectable (LAI) depot formulations, with a unique mechanism of action comprising partial D2 and serotonin 5-HT1A agonism and antagonism at serotonin 5-HT2A receptors. Areas covered We review short-and-long-term clinical trials, meta-analyses of clinical trials and product information pertaining to the safety and efficacy of aripiprazole in adults with schizophrenia. Formulations of aripiprazole reviewed include oral aripiprazole, Aripiprazole monohydrate LAI (Abilify Maintena©) and Aripiprazole lauroxil LAI (Aristada©). Clinical studies and product information were collected from PubMed, Psychinfo, Embase, and other web sources. Expert opinion Aripiprazole is a generally well-tolerated third-generation antipsychotic with low rates of motor side effects and metabolic adverse effects that occur commonly with several alternative antipsychotics. Akathisia and tremor appear to occur at higher rates with aripiprazole compared to placebo but are still generally uncommon with incidences of 10–11% or less. Uniquely, aripiprazole treatment is associated with reduced serum prolactin levels and QTc interval. A variety of LAI options with dosing intervals as infrequent as every 8 weeks provide a compelling reason to select aripiprazole in patients with limited oral treatment adherence.

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation.

Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity. Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2days, over 2weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting RESULTS: Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats. In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation.

Risperidone-induced tardive dystonia in 10 years old boy and efficacy of aripiprazole: a case report

Risperidone-induced tardive dystonia in 10 years old boy and efficacy of aripiprazole: a case report

Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments, and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2, and 7 determines the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism for fine-tuning the intrinsic efficacy of D2R agonists.

Evidence-Based Pharmacological Management and Treatment of Behavioral and Psychological Symptoms of Dementia

Evidence-Based Pharmacological Management and Treatment of Behavioral and Psychological Symptoms of Dementia

Real-life assessment of aripiprazole monthly (Abilify Maintena) in schizophrenia: a Canadian naturalistic non-interventional prospective cohort study

BackgroundWith previously established efficacy of aripiprazole once-monthly injectable formulation (AOM) in pre-registration randomized controlled trials, the current study was designed to evaluate its effectiveness in patients treated for schizophrenia in regular clinical settings in Canada.MethodsFollowing their clinicians’ decision to prescribe AOM, 193 patients with a diagnosis of schizophrenia, were recruited from 17 Canadian community or hospital-based settings. The primary outcome of global functioning was assessed with the Global Assessment of Functioning Scale (GAF) at 3-month intervals for 1 year. Secondary outcomes (social and occupational functioning and illness severity) and adverse drug reactions (ADR) were also assessed.ResultsA majority of the 169 evaluable patients were within the first 5 years of diagnosis (early phase). A linear mixed model analysis showed a significant main effect of time (Type III test p < 0.001) after adjusting for baseline GAF score, with a change in mean GAF scores from 49 at baseline to 61 at 12 months. No differences between early vs late phase were observed. Results on secondary outcome measures of function (Social and Occupational Functioning Scale) and illness severity (Clinical Global Impression-Severity Scale and Brief Psychiatric Rating Scale) were similar. Serious ADRs were observed in 29 (14.6%) patients and akathisia in 18 (9.1%) patients. At month-12, significant (≥7%) weight gain was observed in 25.7% (n = 27/105) of patients.ConclusionsTreatment with AOM is effective in improving symptoms and functioning in schizophrenia patients treated in regular clinical settings. Akathisia was infrequent while one quarter of patients gained clinically significant weight.Trial registrationUnique identifier: NCT02131415. First posted: 06 May 2014.