Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence-based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady-state concentration)-response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure-response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease-drug-dropout models were developed using patient-level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure-response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure-response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13-17 years with schizophrenia.

UNASSIGNED: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.
UNASSIGNED: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects.
UNASSIGNED: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively.
UNASSIGNED: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

BACKGROUND: In this cross-sectional study, we compared fasting serum asprosin levels and metabolic parameters between patients receiving one of three atypical antipsychotics (olanzapine, risperidone, or aripiprazole) and healthy subjects.
METHODS: The study population included 62 adult outpatients with schizophrenia and 22 healthy controls, matched for age and gender. Patients were in remission and had been on stable monotherapy with one of these atypical antipsychotics for over 6 months. Body Mass Index (BMI) and fasting serum levels of asprosin, glucose, HA1c, insulin, and lipid profile were compared across the investigated groups. Additionally, the number of participants meeting the insulin resistance criterion, defined as homeostasis model assessment for insulin resistance (HOMA-IR) >2.5, as well as the number of participants with elevated BMI levels (men >27 kg/m2, women >25 kg/m2) were compared among the groups.
RESULTS: We observed statistically significant differences in BMI and fasting serum levels of glucose, HA1c, insulin, triglyceride (TG), high-density lipoprotein cholesterol, and asprosin among patients receiving olanzapine or risperidone, as compared to those receiving aripiprazole and healthy subjects. Patients on aripiprazole exhibited values comparable to healthy subjects, whereas those on risperidone or olanzapine showed significantly higher values, with the highest observed in the olanzapine group. Additionally, the prevalence of participants meeting the insulin resistance criterion and those with elevated BMI was also greater in individuals receiving olanzapine or risperidone compared to those on aripiprazole and healthy subjects. Serum asprosin levels showed a significant positive correlation with BMI and several metabolic parameters, including HbA1c, fasting insulin, HOMA-IR, and TG. No significant differences were observed among the investigated groups in terms of serum levels of total cholesterol and low-density lipoprotein cholesterol.
CONCLUSIONS: Our cross-sectional study highlights the association between elevated asprosin levels, weight gain, and metabolic disorders in patients treated with olanzapine and risperidone. Given the bidirectional nature of the relationship between serum asprosin levels and these metabolic disturbances, further research is warranted to elucidate potential causative pathways.

Clozapine is an atypical antipsychotic that acts by blocking mainly dopamine 4 receptors. It is usually prescribed for treatment-resistant schizophrenia as well as treatment-resistant bipolar disorder. Clozapine has a wide profile of side effects that result from blocking different receptors all over the body. A 42-year-old Middle Eastern female is known to have suffered from schizoaffective disorder for many years and had frequent relapses despite compliance with treatment. She was commenced on Clozapine; the patient started complaining of an electric shock sensation throughout her body that resulted in recurrent falls with bilateral leg fractures. She was started on sodium valproate to exclude the possibility of seizure activity but the electric shock sensation did not subside. The decision was made to switch her to aripiprazole and gradually taper down and stop Clozapine which improved her symptoms. Careful monitoring of patients who receive Clozapine is recommended especially during the tapering phase due to the risky adverse events it can bring about. It is essential to understand the side effects in order to tackle them as soon as they arise.

Microglia are the primary innate immune cells of the central nervous system and extensively contribute to brain homeostasis. Dysfunctional or excessive activity of microglia may be associated with several neuropsychiatric disorders, including schizophrenia. Therefore, we examined whether aripiprazole and risperidone could influence the expression of the Cd200-Cd200r and Cx3cl1-Cx3cr1 axes, which are crucial for the regulation of microglial activity and interactions of these cells with neurons. Additionally, we evaluated the impact of these drugs on microglial pro- and anti-inflammatory markers (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β) and cytokine release (IL-6, IL-10). The research was executed in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those exposed to maternal immune activation (MIA OCCs), which allows for the exploration of schizophrenia-like disturbances in animals. All experiments were performed under basal conditions and after additional stimulation with lipopolysaccharide (LPS), following the \"two-hit\" hypothesis of schizophrenia. We found that MIA diminished the mRNA level of Cd200r and affected the OCCs\' response to additional LPS exposure in terms of this parameter. LPS downregulated the Cx3cr1 expression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increased Cd200 expression in MIA OCCs, while aripiprazole treatment elevated the gene levels of the Cx3cl1-Cx3cr1 dyad in control OCCs. The antipsychotics limited the LPS-generated increase in the expression of proinflammatory factors (Il-1β and Il-6) and enhanced the mRNA levels of anti-inflammatory components (Cd206 and Tgf-β) of microglial polarization, mostly in the absence of the MIA procedure. Finally, we observed a more pronounced modulating impact of aripiprazole on the expression of pro- and anti-inflammatory cytokines when compared to risperidone in MIA OCCs. In conclusion, our data suggest that MIA might influence microglial activation and crosstalk of microglial cells with neurons, whereas aripiprazole and risperidone could beneficially affect these changes in OCCs.

The incidence of major depressive disorder (MDD) after heart transplantation is high; however, there are no reports on treatment options when antidepressant therapy fails to improve the condition. We herein report on the case of a woman with MDD after heart transplantation who partially improved with antidepressant treatment but continued to have a loss of appetite. Augmentation treatment with aripiprazole improved her appetite, and her MDD went into remission. When antidepressant treatment is not sufficiently effective for MDD after heart transplantation, augmentation treatment with antipsychotics, such as aripiprazole, should be considered.

BACKGROUND: Wernicke encephalopathy (WE) is an acute and potentially fatal neuropsychiatric disorder resulting from thiamine deficiency: its etiology and clinical presentation can be heterogeneous and arduously recognized, especially in children and adolescents.
METHODS: An 8-year-old girl arrived to the emergency room with ataxic gait, nystagmus, and mental confusion after a 10-day history of repeated severe vomiting; her recent clinical history was characterized by restricted nutrition due to a choking phobia, which caused substantial weight loss. Brain magnetic resonance imaging revealed a bilaterally increased T2 signal in the medial areas of the thalami and cerebral periaqueductal region. Diagnosis of WE based on clinical and neuroradiological findings was established and confirmed after labwork showing low serum thiamine. Following psychiatric evaluation, the patient was also diagnosed with avoidance-restrictive food intake disorder (ARFID), which required starting cognitive behavioral therapy and introducing aripiprazole. The patient displayed improvement of the radiological findings after one month and complete resolution of her neurological symptoms and signs.
CONCLUSIONS: Eating disorders like ARFID might forerun acute signs of WE; this possibility should be considered even in pediatric patients, especially when atypical neurological pictures or feeding issues come out.

BACKGROUND: Aripiprazole (ARI) is a recently developed antipsychotic medication that belongs to the second generation of antipsychotics. The literature has contradictory information regarding ARI, which has been classified as pregnant use category C by the FDA.
METHODS: 125 pathogen-free fertilized eggs were incubated for 28 h and divided into five groups of 25 eggs each (including the control group), and 18 eggs with intact integrity were selected from each group. After the experimental groups were divided, ARI was administered subblastodermally with a Hamilton micro-injector at 4 different doses (1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg). At the 48th hour of incubation, all eggs were hatched and embryos were removed from the embryonic membranes. And then morphologic (position of the neural tube (open or closed), crown-rump length, number of somites, embryological development status), histopathologic (apoptosis (caspase 3), cell proliferation (PCNA), in situ recognition of DNA breaks (tunnel)), genetic (BRE gene expression) analyzes were performed.
RESULTS: According to the results of the morphological analysis, when the frequency of neural tube patency was evaluated among the experimental groups, a statistically significant difference was determined between the control group and all groups (p < 0.001). In addition, the mean crown-rump length and somite number of the embryos decreased in a dose-dependent manner compared to the control group. It was determined that mRNA levels of the BRE gene decreased in embryos exposed to ARI compared to the control group (p < 0.001).
CONCLUSIONS: Morphologically, histopathologically, and genetically, aripiprazole exposure delayed neurogenesis and development in early chick embryos. These findings suggest its use in pregnant women may be teratogenic. We note that these results are preliminary for pregnant women, but they should be expanded and studied with additional and other samples.

Invasive fungal infections impose an enormous clinical, social, and economic burden on humankind. One of the most common species responsible for invasive fungal infections is Candida albicans. More than 30% of patients with disseminated candidiasis fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 medications that antagonize the activity of the azoles on C. albicans. Although gain-of-function mutations responsible for antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impacts C. albicans physiology, fitness, or virulence. In this study, we examined how exposure to seven azole antagonists affects C. albicans phenotype and capacity to cause disease. Most of the azole antagonists appear to have little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact on C. albicans hyphal growth and increased cell wall chitin content. It also aggravated the disseminated C. albicans infections in mice. This effect was abrogated in immunosuppressed mice, indicating that it is at least in part dependent upon host immune responses. Collectively, these data provide proof of principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.