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Pimozide, an antipsychotic drug, is a potent inhibitor of the hERG channel. A case of death due to cardiac arrest has been reported in a boy who received pimozide together with sertraline and aripiprazole. In this study, we focused on drug-drug interactions and investigated the relationships between transporter-mediated intracellular accumulation and the hERG inhibitory effect of pimozide. The accumulation of pimozide in cardiomyocyte-derived AC16 cells was significantly increased by sertraline and aripiprazole, which are thought to have a P-glycoprotein (P-gp) inhibitory effect, and under P-gp siRNA conditions. These results suggest P-gp inhibition increases pimozide accumulation in AC16 cells. We introduced the hERG plasmid into AC16 cells and investigated the concentration-dependent hERG inhibitory effect of pimozide from within AC16 cells. Addition of 10 nM or more pimozide significantly inhibited the hERG current with concentration dependence. These results indicate P-gp-mediated pharmacokinetic interaction increases pimozide accumulation in AC16 cells, and the subsequent elevated pimozide levels within the cells may result in an increased risk of hERG channel inhibition. Our present study calls attention to the risks associated with the combined use of cardiotoxic P-gp substrate(s) and P-gp inhibitory medicines.

In this work, a novel environment-friendly stability indicating capillary zone electrophoresis (CZE) method has been developed and validated for assaying the aripiprazole (ARP) in tablet dosage form. The separation of ARP from its degradation products and internal standard was achieved using a fused silica capillary column (30.2 cm x 75 μm ID), a background electrolyte containing 6 mmol L

Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities.Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression.Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine.With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety.31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25μl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma.Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (rIn this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.

Corticosteroid-based drugs are widely used in the general population to treat several acute and chronic inflammatory conditions. However, the therapeutic efficacy of these drugs is often accompanied by severe psychiatric adverse effects through a yet unknown mechanism. To further complicate this situation, therapeutic strategies to counteract psychotic symptoms associated with these agents have yet to be devised. We report a case of a young white male Jehovah's Witness admitted to the psychiatry ward of the Maggiore della Carità Hospital, Novara, Italy. At admission, the patient presented with psychomotor agitation, auditory hallucinations, and thought disturbances, resulting in the working diagnosis of a manic episode with psychotic features. During the 16 days of his hospital admission, the patient was treated with antipsychotic medications (aripiprazole and haloperidol) and with benzodiazepines (lorazepam), and he achieved a complete remission of all psychotic symptoms. While his psychiatric history was negative, his medical records revealed a recent discharge from the infectious disease ward with a diagnosis of infectious mononucleosis treated with intravenous betamethasone. Thus, at discharge, a diagnosis of steroid-induced psychosis was made. In conclusion, our findings are suggestive of a potential role played by corticosteroids in the development of psychotic symptoms, for which routine screening protocols and therapeutic guidelines are still lacking.

Drugs used to treat psychotic disorders (‘antipsychotics’) have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation (‘conventional’) vs second generation (‘atypical’)). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a ‘subway map’ of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses.

Pharmacological treatment of major depressive disorder is often inefficient, and multiple strategies are used for inadequate response to antidepressants. Second-generation antipsychotics are used as augmentation measures in clinical practice; evidence of their efficacy and acceptability is insufficient, and it remains confusing as to which drug should be selected first. In this systematic review and network meta-analysis, we included randomised controlled trials of second-generation antipsychotics used as adjunctive treatment in patients with suboptimal responses. Outcome measures were efficacy (response and remission) and acceptability (dropout due to any reason and adverse events). Thirty-three trials comprising 10 602 participants were included. Regarding efficacy, response rates indicated that all antipsychotics except for ziprasidone were more efficacious than the placebo, with the odds ratios (ORs) ranging from 1.34 for olanzapine and cariprazine [95% credible interval (CrI) 1.04–1.73 and 1.07–1.67, respectively] to 2.17 for risperidone (95% CrI 1.38–3.42). When considering remission, cariprazine was not effective (OR 1.21, 95% CrI 0.96–1.54). For acceptability, quetiapine (OR 0.68, 95% CrI 0.50–0.91), brexpiprazole (OR 0.69, 95% CrI 0.55–0.86), and cariprazine (OR 0.61, 95% CrI 0.46–0.82) were worse than the placebo. With regards to tolerability, only olanzapine (OR 0.51, 95% CrI 0.25–1.07) and risperidone (OR 0.48, 95% CrI 0.10–2.21) showed no significant differences compared with placebo. The administration of adjunctive antipsychotics is associated with high effectiveness and low acceptability. Risperidone and aripiprazole are more efficacious and accepted than other atypical antipsychotics.

Background: Concurrent disorder or dual diagnosis refers to a combination of substance use disorders and mental disorders that occur in the same patient simultaneously. These conditions pose significant clinical and healthcare impacts and are often underdiagnosed, undertreated, and complex to manage. Objective: We assessed the quality of current pharmacological recommendations for the management of dual diagnosis, particularly by evaluating the use of second-generation antipsychotics (SGA). Method: A literature search was performed using the PubMed and Scopus databases for publications up to September 21, 2021, without any time restrictions. The following search strings were used: (aripiprazole OR brexpiprazole OR cariprazine OR paliperidone OR risperidone OR quetiapine OR clozapine OR olanzapine) AND (psychosis OR schizophrenia OR schizoaffective) AND (“substance use disorder” OR cocaine OR alcohol OR cannabis OR heroin OR “double diagnosis” OR “dual diagnosis”)) NOT (animal OR rat OR mouse) NOT (review or meta-analysis). Results: The search produced a final set of 41 articles. Most patients were males and were affected by schizophrenia, with cannabis the most abused substance, followed by alcohol. Aripiprazole was the most used drug, either orally or by long-acting formulations, followed by risperidone with oral and long-acting formulations, clozapine, olanzapine, and quetiapine. Conclusion: The findings highlight the use of SGA for the treatment of psychotic symptoms in comorbidity with substance use. Future studies on people with dual diagnosis and focused on long-term evaluations are warranted and need to investigate the efficacy of newly introduced molecules, such as partial D2 agonists and long-acting injectable antipsychotics.

Introduction An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. Methods The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. Results Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p Discussion Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

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.

Switching antipsychotic medication must be done carefully to ensure patient safety and a successful response. Here, we present two major psychotic decompensations that occurred following a switch to aripiprazole in two patients with schizophrenia. Mr. X was treated with paliperidone and experienced residual anxiety. Thus, a switch to aripiprazole was planned with risperidone and a gradual decrease in paliperidone. Initially, an increase in aripiprazole resulted in remission of his residual symptoms. However, two weeks later, he presented an anxiety relapse with persecutory ideas which required hospitalization. Mr. Y, who was treated for many years with risperidone, presented with a treatment resistant psychotic episode. A switch to aripiprazole enhanced his clinical condition. Despite the initial improvement, soon after discharge from the hospital, the patient presented psychotic symptoms requiring home intervention. Ultimately, the patient in the midst of a delusional recrudescence, had killed himself when the health care team arrived. A strong dopamine antagonist may lead to the development of dopaminergic upregulation. The addition of a partial agonist to these hypersensitive neurotransmitter pathways could explain these episodes. We agree with previous reports and recommend careful management when switching from strong dopamine antagonists to aripiprazole.

Post-traumatic stress disorder (PTSD), previously known as battle fatigue syndrome or shell shock, is a severe mental disturbance condition that is normally triggered by the experience of some frightening/scary events or trauma where a person undergoes some serious physical or mental harm or threatened. PTSD is a long-life effect of the continuous occurrence of traumatic conditions, leading to the production of feelings of helplessness, intense fear, and horror in the person. There are various examples of events that can cause PTSD, such as physical, mental, or sexual assault at home or working place by others, unexpected death of a loved one, an accidental event, war, or some kind of natural disaster. Treatment of PTSD includes the removal or reduction of these emotional feelings or symptoms with the aim to improve the daily life functioning of a person. Problems which are needed to be considered in case of PTSD like ongoing trauma, abusive or bad relationships. Various drugs which are used for the treatment of PTSD include selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluvoxamine, fluoxetine, etc.); tricyclic antidepressants (amitriptyline and isocarboxazid); mood stabilizers (Divalproex and lamotrigine); atypical antipsychotics (aripiprazole and quetiapine), etc. In this review, we have covered the different risk factors, case studies related to various treatment options with different age group of peoples with PTSD and their effects on them. We have also covered the symptoms and associated disorders which can play a key role in the development of PTSD.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

First- and second-generation antipsychotics are highly accountable for causing a plethora of medical side effects, ranging from metabolic imbalances to sexual dysfunction (SD), that frequently undermine patient-doctor relationships. Nevertheless, to date antipsychotics are one of the best treatment options for dealing with numerous either acute or chronic conditions like agitation, suicidality, depression, dementia, and of course psychosis. For these reasons, clinicians need to handle them wisely to preserve patients' sexual health, avoid poor therapeutic adherence and prevent high rates of therapy drop-out.This article reviews the literature on pharmacologic approaches for management strategies in men who are administered with antipsychotics and developed SD. The etiology of antipsychotic-induced SD is also discussed.Clinicians must consider sexual life as a major health domain. To do so, a first step would be to measure and monitor sexual function by means of psychometric tools. Secondly, primary prevention should be conducted when choosing antipsychotics, i.e. picking sex-sparing compounds like aripiprazole or brexpiprazole. Thirdly, if sexolytic compounds cannot be dismissed, such as first-generation antipsychotics, risperidone, paliperidone, or amisulpride, then aripiprazole 5-20 mg/day adjunctive therapy has proven to be most effective in normalizing prolactin levels and consequently treating antipsychotic-induced SD.

Background: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. Aims: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. Methods: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% ( N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 ( p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% ( p = 0.61). Conclusion: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

Antipsychotic-induced hypothermia is an uncommon type of secondary hypothermia resulting from neurotransmitter derangements within the nervous system thermoregulation pathway. The most common causative medications include olanzapine, haloperidol, and risperidone, with one published report of aripiprazole. Most individuals who develop antipsychotic-induced hypothermia receive neuroleptic treatment for psychiatric disorder management, with significantly fewer occurrences in those with neurologic disorders. There are currently no reports of antipsychotic-induced hypothermia after a traumatic brain injury (TBI), where antipsychotics are used for the off-label management of posttraumatic agitation.A retrospective chart review of the patient's medical record was performed.We present a case of a 56-year-old man with a moderate TBI who developed recurrent episodes of antipsychotic-induced hypothermia after starting aripiprazole for posttraumatic agitation management.To our knowledge, this is the first publication detailing antipsychotic-induced hypothermia occurring in a TBI patient. Clinicians who initiate antipsychotics for posttraumatic agitation in a TBI patient should be aware of this potential adverse effect, as well as clinical presentation, evaluation, and management strategies.

ObjectiveThere is little evidence for finding optimal antipsychotic treatment for schizophrenia, especially in paediatrics. To evaluate the performance and clinical benefit of several prediction methods for 1-year treatment continuation of antipsychotics.Design and SettingsPopulation-based prognostic study conducting using the nationwide claims database in Korea.Participants5109 patients aged 2–18 years who initiated antipsychotic treatment with risperidone/aripiprazole for schizophrenia between 2010 and 2017 were identified.Main outcome measuresWe used the conventional logistic regression (LR) and common six machine-learning methods (least absolute shrinkage and selection operator, ridge, elstic net, randomforest, gradient boosting machine, and superlearner) to derive predictive models for treatment continuation of antipsychotics. The performance of models was assessed using the Brier score (BS), area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). The clinical benefit of applying these models was also evaluated by comparing the treatment continuation rate between patients who received the recommended medication by models and patients who did not.ResultsThe gradient boosting machine showed the best performance in predicting treatment continuation for risperidone (BS, 0.121; AUROC, 0.686; AUPRC, 0.269). Among aripiprazole models, GBM for BS (0.114), SuperLearner for AUROC (0.688) and random forest for AUPRC (0.317) showed the best performance. Although LR showed lower performance than machine learnings, the difference was negligible. Patients who received recommended medication by these models showed a 1.2–1.5 times higher treatment continuation rate than those who did not.ConclusionsAll prediction models showed similar performance in predicting the treatment continuation of antipsychotics. Application of prediction models might be helpful for evidence-based decision-making in antipsychotic treatment.

Tourette syndrome (TS) is a frequently observed developmental neuropsychological disorder occurring in children. The pathophysiology involves both genetic and environmental factors. In this review, clinical characteristics, pathophysiology, and treatment approaches based on the pathophysiology of TS are presented. The pathophysiology is the acceleration of developmental decrement of dopamine (DA) activity at the terminal of nigro-striatal (NS)-DA system causing DA D2 receptor up-ward regulation. Serotonergic neurons involving in development of the biphasic sleep-wake-rhythm, and locomotion may be involved. Pharmacological treatments constitute an important part in managing TS. Small dose of levodopa and aripiprazole showed the good effect controlling the tics, without side effects. Intervention with enhancing the day time activity and keeping the regular sleep-wake-rhythm, and encouraging locomotion are important. The data from Yoshiko Nomura Neurological Clinic for Children regarding the clinical features and outcomes, medication effects, and OCD and outcomes are shown. To discuss about the environmental factor, how the COVID-19 pandemic affected the TS patients is also presented.

The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the residual rate of ARIP in the mixed solution decreased to 15.7-17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (-)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.

To evaluate the effect of aripiprazole on psychosis and motor function in Japanese Parkinson's disease patients.Patients with Parkinson's disease and hallucinations and/or delusions were enrolled. They were administered aripiprazole 3 mg/day, with dosage increased or reduced as needed. Patients were evaluated using the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression-Severity (CGI-S) scale, and Clinical Global Impression-Improvement scale for psychiatric response; HoehnYahr staging and Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor response; Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive response; and Schwab and England Activities of Daily Living scale for daily activities of patients, before and at 2, 4, and 12 weeks after initiation of open-label aripiprazole administration. This study was registered at the University Hospital Medical Information Network Center (registration number: UMIN000007711).Nine of the 24 enrolled patients discontinued the study. Among them, eight patients discontinued the trial on account of their worsening parkinsonian symptoms. There were no differences in age, disease duration, disease severity, and MMSE and FAB scores at baseline between patients who continued and discontinued the study. However, in patients who continued aripiprazole administration at 3 mg/day or less significantly improved BPRS, CGI-S scale, and UPDRS parts I and III scores.Significant improvements in hallucinations and delusions can be expected, although aripiprazole may aggravate parkinsonism in Parkinson's disease patients. Low-dose use of aripiprazole may be useful for managing Parkinson's disease patients with psychosis, but only with close observation of extrapyramidal symptoms.

Aripiprazole, structurally considered a third-generation antipsychotic agent, is an effective adjuvant strategy for managing treatment-resistant depression. It has been used successfully as an add-on agent in late-life depression (LLD), but there are no controlled trials on its use as first-line therapy, either alone or in combination with an antidepressant.This is a case note review of aripiprazole prescribed to outpatients with LLD as a first-line therapy either in combination with an antidepressant or as a monotherapy. The local ethics committee approved the audit. Case notes of subjects with Hamilton Rating Scale for Depression scores of ≥11 and with at least 1 follow-up visit were included in the review. Remission was defined as the first occurrence of achieving a Hamilton Rating Scale for Depression score of10.Case notes of 54 subjects (mean age, 68.6 ± 6.9 years) were included, 52 of whom had unipolar depression. Aripiprazole alone was prescribed in 21 subjects, and with an antidepressant in the remaining subjects. The overall remission rate was 59% over 21 weeks, and in the remitted subjects (n = 32), the cumulative remission rate increased from 22% at week 2 to 82% at week 10. No subject discontinued treatment because of poor tolerability or serious adverse events.Aripiprazole was found to be an effective first-line antidepressant in LLD. The remission rates in the present study were considerably higher than the published literature on antidepressant monotherapy in fresh episodes of LLD. This warrants controlled trials of aripiprazole as a first-line antidepressant for this disease entity.

Objective: The youngest children in a classroom have a higher risk of attention-deficit/hyperactivity disorders (ADHDs) and depression than their relatively older peers. However, there has been a lack of research on how relative age is related to second-generation antipsychotic (SGA) medication use. Methods: This study used the Finnish National Prescription Register data and comprised all 669,726 Finnish children and adolescents aged 7-17 in 2018. We extracted data for those who were dispensed SGAs (risperidone, quetiapine, aripiprazole, and olanzapine) and ADHD medication (methylphenidate, atomoxetine, dexamphetamine, and lisdexamfetamine). Odds ratios (OR) and 95% confidence intervals (CI) were calculated for medication dispensed to schoolchildren born from January to April (the relatively oldest), May to August, and September to December (the relatively youngest). Dispensed prescriptions were a proxy for medication use. Results: SGAs were dispensed to 9146 (1.4%) individuals in 2018. Their use was lower among girls aged 12-17 years born from September to December than January to April (OR 0.89; 95% CI 0.83-0.97), with no association between SGA use and birth month among boys. However, younger relative age was associated with combined SGA and ADHD medication, which was used by 2556 (0.4%) of the cohort: 2074 (0.6%) boys and 482 (0.1%) girls. The OR was 1.27 for boys aged 12-17 born from September to December (95% CI 1.10-1.46), compared with January to April. The OR for girls born from May to August was 1.35 (95% CI 1.04-1.76) and from September to December it was 1.33 (95% CI 1.02-1.74), compared with January to April. Conclusions: A novel discovery of this study was that using both SGA and ADHD medication at the age of 12-17 years was more common among the youngest subjects in a school year than their relatively older peers.

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.In this study, 50 patients with bipolar I disorder, manic episode, were divided into two groups receiving aripiprazole (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 (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 POINTSAripiprazole 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.

The present study aimed to evaluate the efficacy and safety of aripiprazole once-monthly (AOM) compared to oral aripiprazole in treating acute schizophrenia.This randomized, double-blind, non-inferiority study recruited patients from 15 trial sites across China from May 2017 to April 2019. Patients with an acute psychotic episode received AOM at 400 mg or oral aripiprazole at 10-20 mg for 12 weeks. The primary and secondary efficacy endpoints were the difference in scores from baseline to week 10, as assessed on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively.A total of 436 patients were randomized. Among them, 159/218 (72.9%) and 165/218 (75.7%) in the AOM and oral aripiprazole groups completed 10 weeks of treatment, respectively. The least-squares (LS) mean changes from baseline to endpoint (week 10) in PANSS were - 33.6 for the AOM group and - 34.8 in the oral aripiprazole group, respectively, with a difference of - 1.2 (95% CI: - 4.1, 1.7). The non-inferiority margin of AOM to oral aripiprazole was - 4.1, which was above the lower limit of the pre-defined margin. The altered CGI-S score was - 2.2 and - 2.3 in the AOM and oral aripiprazole groups, respectively. The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups. The rate of discontinuation due to TEAEs was 2.3% and 3.2% in the AOM and oral aripiprazole groups, respectively.This study confirmed the efficacy and safety of AOM for the treatment of Chinese patients with acute schizophrenia. The non-inferiority of AOM to oral aripiprazole was established, with comparable efficacy and tolerability. These findings suggested that AOM could be used as a treatment option for patients experiencing an acute episode of schizophrenia.ClinicalTrials.gov identifier: NCT03172871.

Uncertainty remains regarding the relative efficacy of maintenance pharmacotherapy for bipolar disorder (BD), and available data require updating. The present systematic review and meta-analysis aims to consolidate the evidence from the highest quality randomized controlled trials (RCTs) published up to July 2021, overcoming the limitations of earlier reviews. The PubMed and the Cochrane Central Register of Controlled Trials were searched for double-blind RCTs involving lithium, mood stabilizing anticonvulsants (MSAs), antipsychotics, antidepressants, and other treatments. Rates of new mood episodes with test vs. reference treatments (placebo or alternative active agent) were compared by random-effects meta-analysis. Polarity index was calculated for each treatment type. Eligible trials involved ≥6 months of maintenance follow up. Of 2,158 identified reports, 22 met study eligibility criteria, and involved 7,773 subjects stabilized for 1-12 weeks and followed-up for 24-104 weeks. Psychotropic monotherapy overall (including lithium, MSAs, and second generation antipsychotics (SGA) was more effective in preventing new BD episodes than placebo (odds ratio, OR=0.42; 95% confidence interval, CI 0.34-0.51, p

Risperidone and aripiprazole are increasingly used for behavioural indications in children and adolescents with intellectual disabilities, including autism. Although there are some reports in literature, the side effect profile in this population remains poorly defined and there is a need to raise awareness among clinicians across specialties. We present two patients with significant intellectual disabilities who developed extrapyramidal side effects (EPSE) including oculogyric crisis following risperidone and aripiprazole use. The onset of these side effects can be insidious and the non-specific nature of the presentation, for example, poor mobility and increased drooling on a background of severe intellectual disability, can lend itself to delay in recognition and reporting by families. There is also reduced awareness among paediatricians, which can further delay the treatment of this reversible condition. There needs to be ongoing vigilance for EPSE as they can develop years after treatment has been initiated.

[Aims/hypothesis]: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. [Methods]: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. [Results]: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p, This work was funded by H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission). We also acknowledge grants RTI2018-094052-B-100/ AEI/10.13039/501100011033 (Ministerio de Ciencia e Innovación y Fondo Europeo de Desarrollo Regional [FEDER]) and S2017/BMD-3684 (Comunidad de Madrid, Spain), and grants from Fundación Ramón Areces (Spain) and CIBERDEM (ISCIII, Spain).

Dopamine supersensitivity psychosis is a clinical concept characterized by an unstable psychotic state and tardive dyskinesia in schizophrenia patients at the chronic stage. This state is thought to be induced by compensatory upregulation of dopamine D2 receptors, which is provoked by long-term and/or high-dose medications. Recent clinical data suggest that patients who responded well to medication but later exhibit dopamine supersensitivity develop tolerance to antipsychotics’ effects and eventually transit to treatment-resistant schizophrenia, indicating that dopamine supersensitivity could be an etiology contributing to treatment-resistant schizophrenia. However, clinicians and researchers consider dopamine supersensitivity psychosis a minor phenomenon during the clinical course and do not make much of it. This opinion is often based on numerous clinical data indicating that dopamine supersensitivity psychosis is a relatively rare event. This review examines the data dealing with dopamine supersensitivity with the five themes of frequency, severity, withdrawal studies, switching to aripiprazole, and tardive dyskinesia. These effects of these themes on discussions of the clinical meaning of dopamine supersensitivity psychosis are then reviewed. The present review will help clinicians speculate about the background of severe psychopathology in a given patient; to make diagnoses of treatment-resistant schizophrenia and dopamine supersensitivity psychosis; and plan antipsychotic medication regimens with the goal of achieving better long-term prognosis.

Background ReLiAM, Real-Life Assessment of Abilify Maintena, was the first reported long-term prospective non-interventional study for patients with schizophrenia treated with aripiprazole once-monthly injectable formulation (AOM) under real-life conditions. ReLiAM’s primary aim was to evaluate the evolution of global functional status in patients treated with AOM for 12 months in Canada. Methods The objective of this post hoc analysis of the ReLiAM study is to investigate the treatment effects of real-life use of AOM over a 1-year period in the subgroup of patients with reported substance use compared with patients without substance use. Results The results of this post hoc analysis demonstrate that treatment with AOM for 12 months in patients with schizophrenia was comparably effective in improving global functioning in subgroups of patients with and without concomitant substance use. Conclusions These results support the use of AOM for the treatment of schizophrenia in patients with or without concomitant substance use. Trial registration ClinicalTrials.gov NCT02131415, first posted on May 6, 2014. Overall trial status: Terminated.

The aim of this study was to improve the solubility of aripiprazole (ARP) by fabricating binary and ternary inclusion complexes with methyl-β-cyclodextrin (MβCD) and L-Arginine (LA). Physical mixing and lyophilization were used in the following molar ratios: 1:1, 1:2.5, 1:4, 1:9, 1:1:1, 1:1:0.27, 1:4:1, 1:9:1, 1:3.6:3.6. The developed formulations were analyzed by solubility and dissolution. They were characterized by FTIR, XRD, DSC, SEM and TGA. Ternary formulations prepared by the lyophilization method showed improved dissolution rates in simulated gastric fluid (SGF). The results showcased that the addition of MβCD and LA in inclusion complexes enhanced the solubility and decreased crystallinity. The amorphous nature of Aripiprazole in lyophilization was confirmed by XRD diffractograms. Drug release was dominated by the first-order kinetics (R2 = 0.9932) with the Fickian type of diffusion mechanism (n0.450). LY18, LY19, LY20 and LY21 have the highest solubility (30, 35, 43 and 48 times higher than the pure drug respectively). Furthermore, it was observed that the method of preparation, as well as a specific drug to polymer and amino acid ratio, are critical for achieving high drug solubility and stability. These complexes appeared to be a promising product for the development of new drug delivery systems.

BackgroundAripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear.AimsTo find the optimal dosage of aripiprazole augmentation.MethodMultiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose–effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4–12 weeks).ResultsTen studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose–efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15–1.85) and 5 mg (OR = 1.93, 95% CI 1.33–2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52–2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate.ConclusionsLow-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.

What is known and objective Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. Case summary An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. What is new and conclusion Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.

Introduction: Catatonia is a psychomotor syndrome that presents with severe symptoms which can lead to dangerous and lethal conditions if not diagnosed and treated properly. SARS-- CoV-2 is a positive-sense single-stranded RNA virus that can occur in severe cases with acute pneumonia, ARDS, sepsis and septic shock. In these cases, ICU admission is necessary. Case Summary: A 59-year-old Caucasian man with septic shock and bilateral interstitial pneumonia from SARS-CoV-2 and schizotypal personality disorder presented with catatonic behaviour manifested by soporous state, response to intense painful stimuli with the opening of the eyes, execution of simple verbal commands, maintenance of the same position, catalepsy, immobility, rigidity and mutism. At the same time, there were symptoms of septic shock and catatonic symptoms, causing greater difficulty in the correct formulation of the diagnosis. During the course of his hospitalization, he was treated with asenapine 20 mg/day. The catatonia responded rapidly and significantly to the asenapine. Discussion: To date, the pathophysiology of catatonia is unclear, and few guidelines are available for the treatment of catatonia. In the literature, studies have reported the efficacy of benzodiazepines such as lorazepam and diazepam, GABAA agonists such as zolpidem, NMDA receptor antagonists such as memantine, antidepressant SSRIs such as fluoxetine and paroxetine, and antipsychotics such as olanzapine, clozapine and aripiprazole. We demonstrate that the antipsychotic asenapine is also effective in treating catatonic symptoms in psychiatric disorders. Conclusion: Asenapine produced a rapid and significant reduction in catatonic symptoms in our patient with schizotypal personality disorder.

Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Purpose/background The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). Methods/procedures Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. Findings/results One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. Implications/conclusions Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

BACKGROUND Parkinson's disease-related psychosis increases patients' risk of falls. Pimavanserin is an atypical antipsychotic approved in the USA in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease-related psychosis. OBJECTIVE We aimed to compare the risk of falls/fractures among patients with Parkinson's disease-related psychosis treated with pimavanserin vs other atypical antipsychotics. PATIENTS AND METHODS We identified a cohort of patients with Parkinson's disease-related psychosis aged ≥ 40 years initiating either pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) in US commercial insurance and supplementary Medicare claims (2015-2019). Comparators were propensity score matched 2:1 with pimavanserin initiators; incidence rates of falls/fractures were compared using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS We identified 112 eligible pimavanserin initiators and 982 comparators. Pimavanserin initiators were younger and had fewer severe comorbidities, indicators of impairment, and healthcare encounters, though they had higher Parkinson's disease medication use. The crude incidence rates [cases/100 person-years] (95% CI) for composite falls/fractures were 17.8 (7.7-35.0) for pimavanserin and 40.8 (35.0-47.4) for comparators. Matching retained 108 pimavanserin initiators and 216 comparators-all characteristics were well balanced after matching-with a matched IRR (pimavanserin vs comparator) of 0.71 (95% CI 0.27-1.67). Sensitivity analysis IRR estimates were consistently below 1.00, with a sensitivity analysis not requiring a diagnosis of psychosis resulting in an IRR estimate of 0.55 (95% CI 0.34-0.86). CONCLUSIONS The results of this study do not suggest an increase in the risk of falls or fractures associated with pimavanserin compared with other antipsychotics in patients with Parkinson's disease-related psychosis. Sensitivity analyses suggest a decreased risk.

Background: The evaluation of long-term effectiveness and tolerability of aripiprazole once-monthly (AOM) is yet scarce, and severely ill patients have not been specifically studied. Objective: The aim of the study was to explore the long-term adherence, effectiveness and tolerability of AOM in the treatment of patients with severe (Clinical Global Impression-Severity, CGI-S ≥ 5) schizophrenia, and whether high-dose therapy may benefit patients inadequately controlled on standard doses. Methods: Six-year mirror-image study, with a 36-month prospective follow-up, was conducted on patients with severe schizophrenia who underwent treatment with AOM (n = 60). The assessment included the CGI-S, the WHO Disability Assessment Schedule (WHO- DAS), the Medication Adherence Report Scale (MARS), the laboratory tests, the assessment of weight and adverse effects reported. Reasons for treatment discontinuation, hospital admissions and psychiatric medications in the previous three years and during the follow-up were recorded. Results: The average dose was found to be 780 (120) mg/28 days. Tolerability was good, with fewer side effects or biological parameters alterations reported. There were three discharges due to adverse effects, two due to lack of effectiveness and one treatment abandoning. Weight and prolactin levels were decreased. CGI-S and WHO-DAS were decreased (p Conclusion: Treatment adherence and tolerability of AOM were found to be remarkable, even in those patients on high doses. AOM showed effectiveness in patients with severe schizophrenia, who recorded less hospitalizations and clinical severity and disability, although a considerable percentage of them required higher doses than labeled.

Background Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common. Methods We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications. Results Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher. Conclusions The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs.

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.

BACKGROUND: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective. METHODS: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated. RESULTS: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity. CONCLUSIONS: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.

La Esquizofrenia de Inicio Precoz es un cuadro infrecuente pero muy grave, que requiere de la instauración temprana de un tratamiento eficaz. La Clozapina es el estándar en el tratamiento de la psicosis refractaria y su eficacia en niños y en adolescentes es similar a la de los adultos, aunque esta población tiene más riesgo de sufrir efectos adversos potencialmente graves que comprometan su funcionamiento y calidad de vida. Una estrategia para sortear estos inconvenientes habitualmente utilizada en la práctica clínica, es la combinación de antipsicóticos que se sustenta en que al disminuir la dosis de los fármacos respecto a la monoterapia se disminuyen los efectos adversos que se producen a dosis más altas. Presentamos el caso de un paciente varón, de 13 años, diagnosticado de Esquizofrenia Paranoide de Inicio Muy Precoz, resistente a tratamiento, en el que se utilizó la combinación de Clozapina+Aripiprazol con buenos resultados a nivel de eficacia y tolerancia. El paciente presentaba, además, sintomatología obsesivo-compulsiva que se relacionó con la Clozapina, que remitió tras la adición al tratamiento de Aripiprazol.

KlasJakub, Kluz Natalia,MakaryczewMikołaj, Piwowar Klaudia. Treatment of schizophrenia and bipolar disorder (ChAD) - a review of the literature. Journal of Education, Health and Sport. 2021;11(9):473-483. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2021.11.09.061 https://apcz.umk.pl/JEHS/article/view/JEHS.2021.11.09.061 https://zenodo.org/record/5524184 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2021; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 15.09.2021. Revised: 20.09.2021. Accepted: 23.09.2021. Treatment of schizophrenia and bipolar disorder (ChAD) - a review of the literature Jakub Klas1, Natalia Kluz1, Mikołaj Makaryczew1, Klaudia Piwowar1 1Medical University of Lublin ORCID ID and E-mail: Jakub Klas https://orcid.org/0000-0002-4795-1909jakubklas99@gmail.com Natalia Kluz https://orcid.org/0000-0002-5801-5913nataliakluz99@gmail.com Mikołaj Makaryczew https://orcid.org/0000-0003-4735-8221mo7655010@gmail.com Klaudia Piwowar https://orcid.org/0000-0001-8232-003Xklaudiaklaudia66@gmail.com ABSTRACT Introduction and aims of the study: The aim of this study is to present recent reports on the treatment and therapy of schizophrenia and bipolar disorder (ChAD). The current treatment of patients affected by these diseases is difficult and unsatisfactory, therefore it is necessary to find new therapeutic options that will improve the effectiveness of treatment For the purpose of this study, scientific papers were reviewed using the Google Scholar search engine covering studies from 2016 to 2021. A dozen papers covering the scope of the publication were selected. Results: In the treatment of schizophrenia, the use of cannabinoids is of greatest interest due to the action of the preparations on the endocannabinoid system. In the treatment of ChaD, promising reports have been published on the therapy with aripiprazole and the need to improve its use in the treatment of both akathisia and agitation. Furthermore, from the fact that abnormalities of calcium signalling are considered a possible pathophysiological process in ChAD, it has been suggested that calcium channel L antagonists may be potential therapeutic agents in bipolar affective disorder. One study also demonstrated the potential use of vortioxetine in the treatment of patients with a depressive episode. Conclusions: The results of recent studies on the treatment of schizophrenia and ChAD cited in this paper offer the prospect of creating treatment regimens that are more effective and targeted in the aforementioned diseases. However, further randomised trials are needed to confirm the effective use of the cited drugs in the treatment of these diseases. Keywords: schizophrenia, ChAD, bipolar disorder

Although existing guidelines have discouraged use of antipsychotics for general clinical high-risk (CHR) individuals, it is unclear if antipsychotics can prevent psychosis in higher-risk population. We aimed to study the comparative real-world effectiveness of antipsychotic treatments for preventing psychosis in higher-risk CHR individuals. A total of 300 CHR individuals were identified using the structured interview for prodromal syndromes (SIPS) and followed the participants for 3 years. In total, 228(76.0%) individuals completed baseline assessments using the NAPLS-2 risk calculator (NAPLS-2-RC), and 210(92.1%) completed the follow-up. The sample was further stratified according to risk level. “Higher-risk” was defined based on the NAPLS-2-RC risk score (≥ 20%) and SIPS positive symptom total scores (≥ 10). The main outcome was conversion to psychosis and poor functional outcomes, defined as a global assessment of function (GAF) score lower than 60 at follow-up. In higher-risk CHR individuals, we found no significant difference in the rate of conversion to psychosis or poor functional outcomes between the antipsychotic and no-antipsychotic groups. Low-risk individuals treated with antipsychotic drugs were more likely exhibit poor functional outcomes compared with the no-antipsychotics group(NAPLS-2-RC estimated risk: χ2 = 8.330, p = 0.004; Positive symptom severity: χ2 = 12.997, p

SUMMARYAripiprazole, brexpiprazole and cariprazine are partial dopamine (and serotonin) agonists developed as novel antipsychotics. This article discusses their pharmacology, evidence on their licensed and off-licence uses (including psychosis, mania, bipolar depression, Tourette syndrome and autism spectrum disorder) and side-effects. In schizophrenia, they have a low risk of Parkinsonism or hyperprolactinaemia, cause modest increases in body weight and are of moderate efficacy.

Aripiprazole, an atypical antipsychotic, is a metabolic substrate for cytochrome P450 (CYP)3A4 and 2D6. Terbinafine, an antifungal agent used for onychomycosis, is a CYP2D6 inhibitor and could theoretically reduce the metabolism of aripiprazole. However, there are no published reports describing this interaction. We present 2 female patients hospitalized in a psychiatric unit who were both taking aripiprazole 15 mg daily and terbinafine 250 mg daily prior to admission. The first patient was a 58-year-old female who was prescribed aripiprazole and terbinafine concomitantly for approximately 5 months prior to admission. A commercial pharmacogenetic testing platform classified this patient as a normal metabolizer for CYP3A4 and 2D6. The first patient's serum trough aripiprazole concentration at steady-state concentration (Css) was 207.5 ng/mL. The second patient was a 43-year-old female who was taking aripiprazole and terbinafine concomitantly for approximately 2 weeks prior to admission who had a Css aripiprazole concentration of 278.9 ng/mL. Aripiprazole has a wide therapeutic range (100 to 350 ng/mL) and a reference dose-related drug concentration of 11.7 (mean) ± 5.6 (SD) ng/mL/mg/d. Our patients had Css aripiprazole concentrations 18% and 59% higher than guideline-supported dose-related drug concentrations. Through the use of therapeutic drug monitoring, pharmacogenetic data, electronic pharmaceutical claims data, and the Drug Interaction Probability Scale, we suggest terbinafine possibly increases aripiprazole concentrations 18% to 59%. Further reports are needed to confirm these findings prior to using this information in clinical practice.

Medication-induced weight gain can be frustrating to patients and health care providers. Drug-induced weight gain is a profound side effect of numerous commonly used medications. The present study aimed to investigate FAERS reports about drug-induced weight gain in the last ten years. Using the US FDA Adverse Event Reporting System (FAERS) between 2012 and 2021, a retrospective, descriptive analysis was conducted to analyze the major reported Adverse Events about weight gain. During the last ten years, 137370 reports were submitted to FAERS about drug-induced weight gain. The most common drugs that are reported by the patients and that are associated with weight gain were risperidone (11.55%), adalimumab (3.94%), pregabalin (3.86%), aripiprazole (3.1%), etanercept (2.72%), and prednisone (2.70%). In conclusion, the present study showed that drug-induced weight gain is a common side effect of several medications frequently used to treat chronic diseases. Healthcare providers should educate their patients about the medicines that may cause weight gain.