Atypical Antipsychotics Research Articles

Pharmacogenomics in Sri Lanka: a comprehensive systematic review of the research landscape and clinical implications.

Aim: Pharmacogenomics is emerging in South Asia, including Sri Lanka, with potential to optimize drug therapy and reduce adverse effects. This review evaluates the state of pharmacogenomics research in Sri Lanka, emphasizing population-specific factors to guide future advancements.Materials & methods: A literature search was performed across PubMed/Web-of-Science/SciVerse-Scopus/Embase, and Sri Lanka Journals Online, along with searches for relevant theses in local health repositories/university databases. Studies were categorized into clinical correlational, descriptive or novel assay development studies.Results: Eleven published articles and eight theses were included. One study examined somatic variants (KRAS gene), while all others focused on germline variants. There were two clinical correlational studies: tamoxifen adverse effects and CYP2D6 variants and FTO gene rs9939609 variants and weight gain caused by second-generation antipsychotics. Eight descriptive studies evaluated prevalence of CYP2D6 variants, HLA-B*15:02 allele, KRAS gene mutations and variants related to statin, warfarin and anticancer drug metabolism. Additionally, nine studies developed, validated and tested novel assays for detecting key pharmacogenomically important variants.Conclusion: While pharmacogenomics research in Sri Lanka has made strides, more clinical studies and broader genomic research are needed. Overcoming challenges related to funding, public awareness and regional collaboration is essential to advance personalized medicine and improve therapeutic outcomes in Sri Lanka and South Asia.

Healthcare resource utilization and costs associated with first versus subsequent use of cariprazine for bipolar I disorder

Aims To evaluate the healthcare resource utilization (HRU) and costs of patients who initiated cariprazine as their first versus subsequent atypical antipsychotic (AA) following a bipolar I disorder (BP-I) diagnosis. Methods Adults with a BP-I diagnosis (first claim = index), commercial, Medicare Supplemental, or Medicaid insurance, and ≥1 outpatient cariprazine dispensing were identified from Merative MarketScan database. Cohorts included patients who initiated cariprazine as either their first or subsequent AA after initial BP-I diagnosis. Characteristics were balanced between cohorts using inverse probability of treatment weighting (IPTW). Outcomes evaluated post-index included all-cause and mental health (MH)–related HRU (hospitalizations, emergency department [ED] visits, outpatient visits), total healthcare costs (medical + pharmacy), and treatment patterns. HRU and healthcare costs were reported per patient-year (PPY) and compared between cohorts using rate ratios and 95% CIs estimated using nonparametric bootstrap procedures. Treatment patterns were analyzed descriptively, with standardized differences ≥10% considered important. Results After IPTW, cohorts included 1,409 patients who initiated cariprazine first and 1,621 patients who initiated cariprazine subsequently; the average (standard deviation, SD) observation period was 678 (373) and 758 (389) days for first and subsequent initiators, respectively. Patients who initiated cariprazine first had 23% fewer all-cause hospitalizations and 28% fewer MH-related hospitalizations PPY (each comparison, p < 0.001). Rates of all-cause and MH-related outpatient visits were significantly lower in patients who initiated cariprazine first versus subsequently (each comparison, p < 0.001), while rates of ED visits were similar. Relative to subsequent initiators, first initiators incurred $2,587 and $2,130 lower all-cause and MH-related total healthcare costs PPY, respectively (each comparison, p < 0.05). Before starting cariprazine, first initiators used fewer BP-I–related medications on average than subsequent initiators (2.6 vs 3.9; standardized difference = 23.9%). Limitations Potential coding inaccuracies and residual confounding. Conclusions In this real-world database analysis, patients with BP-I who initiated cariprazine as their first AA had lower rates of HRU and incurred lower costs than patients who initiated cariprazine as a subsequent AA.

2001-2021 Comparative Persistence of Oral Antipsychotics in Patients Initiating Treatment: Superiority of Clozapine in Time-to-Treatment Discontinuation.

Continuous antipsychotic (AP) therapy is crucial for managing psychotic disorders, and its early interruption reflects the drug's failure. Real-world epidemiological research is essential for confirming experimental data and generating new research hypotheses. The persistence of oral APs in a large population sample from 2000 to 2021 was analyzed by comparing AP prescriptions over this period across four Italian provinces, using dispensing data linked via a record-linkage procedure among regional healthcare utilization databases. We calculated personalized daily dosages and assessed time-to-treatment discontinuation over a 3-month period for patients initiating AP treatment. Treatment persistence was evaluated using Kaplan-Meier curves and Cox regression, with adjustments for age and sex. Second-generation antipsychotics (SGAs) were favored over first-generation antipsychotics (FGAs), with olanzapine as the most prescribed. Within the study time frame, 42,434 individuals were prescribed a new continuous AP regimen. The analysis revealed 24 significant differences within 28 comparisons. As a class, SGAs demonstrated better treatment persistence than FGAs (HR: 0.76; 95%CI: 0.73, 0.79). Clozapine stood out for its superior persistence, surpassing all other SGAs, notably olanzapine (HR: 0.85; 95%CI: 0.79-0.91) and risperidone (HR: 0.80; 95%CI: 0.74-0.87). Olanzapine and aripiprazole showed better results than both risperidone and quetiapine. Quetiapine showed inferior 3-month persistence in all pairwise comparisons. The study results provide insight into the performance dynamics among SGAs: clozapine, despite being one of the less frequently dispensed APs in our sample, emerged as a significant prescription choice. The significance of pharmacoepidemiological studies in complementing experimental findings is also underscored.

Cariprazine in Hospital Treatment of Acute Psychotic Conditions Due to Comorbid Schizophrenia and Chemical Addictions

Background: endogenous psychoses complicated with different addictions have special psychopathological structure including delirious episodes, true hallucinations combined with typical positive symptoms of schizophrenia. These cases are difficult for treatment due to non-compliance of patients and their bad tolerance to drugs. The aim was to study the most effective psychopharmacological treatment using cariprazine for acute psychotic states in paranoid schizophrenia combined with chemical addictions. Patients and Methods: the study was conducted at psychiatric hospitals of Tomsk region, St. Petersburg, Nizhnevartovsk and Noyabrsk from 2018 to 2024. 208 men aged 18 to 45 years suffering from paranoid schizophrenia and dependent on psychoactive substances were examined. The main group made up 104 in-patients, who took cariprazine alone or in combination with haloperidol or chlorpromazine. The control group included 104 in-patients treated with other antipsychotics (aripiprazole, risperidone, olanzapine). Research methods: clinical and psychopathological, psychometric (PANSS, SANS, CGI, GAF), statistical (Python 3.11.0; R version 3.2.4; SPSS Statistics Base 22.0). Results: It was revealed that when comparing the control group with the main group, similar indicators were observed on the CGI and GAF scales on the 2nd week of the study, and on the 4th week of the study, compared with the control group, an improvement in indicators on the PANSS, SANS, CGI, GAF scales was observed. Conclusions: Cariprazine, compared with other atypical antipsychotics (risperidone, olanzapine, aripiprazole), showed a distinct antipsychotic effect in the treatment of acute psychotic states in patients with schizophrenia dependent on psychoactive substances. By the end of the 2nd week after hospitalization, when treating with cariprazine at an average dose of 3 to 6 mg/day in combination with typical neuroleptics (haloperidol, chlorpromazine) or a tranquilizer, the most pronounced antipsychotic effect is achieved. Subsequent isolated use of cariprazine at a therapeutic dose of 3–4.5 mg/day has an effect similar to that of leading atypical antipsychotics by the end of the 4th week of treatment. Unlike other atypical antipsychotics, cariprazine was more effective in the treatment of negative symptoms of schizophrenia, which made it possible to achieve an improvement in overall functioning, increase the duration of remission, and reduce the risk of rehospitalization and the development of hospitalism.

Challenges in the Management of Tuberous Sclerosis-associated Neuropsychiatric Disorders

Abstract Tuberous sclerosis is a rare autosomal dominant multisystem disorder of genetic origin affecting TSC1 and TSC2 genes. Individuals with tuberous sclerosis are affected by a broad range of behavioral, academic, intellectual, psychiatric, and psychosocial problems, typically underidentified and undertreated. We are presenting the case of a young male with tuberous sclerosis presented with seizures followed by the development of behavioral and dermatological manifestations. We faced difficulties in the management due to the lack of appropriate guidelines. Initially, no response was seen with atypical antipsychotics and antidepressants, and when some improvement was noticed with typical antipsychotics, extrapyramidal symptoms intervened in the progress and caused more distress to the patient. Hence, one should focus on early recognition and prompt treatment of the individual suffering from TSC. The lack of proper guidelines for managing neuropsychiatric manifestation poses a significant challenge. More research is needed in this area.

Antipsychotic Prescribing Practices for In-patients with Schizophrenia

Results: consumption of antipsychotics in hospital for the period 2015–2022 characterized by a decrease in the proportion of typical antipsychotics (TA) to 12.8% due to an increase in the proportion of atypical antipsychotics (AA) to 61.0% and long-acting antipsychotics (LA) to 26.2%. The administration of antipsychotics by hospital treatment units was relatively uniform. Clozapine (26.9%), zuclopenthixol (20.0%), haloperidol (10.3%), olanzapine (10.3%), risperidone (9.3%), quetiapine (8.2%), paliperidone (4.1%) accounted for 89.1% of all antipsychotics consumed. The total proportion of cariprazine, pericyazine, aripiprazole, ziprasidone, levomepromazine, chlorprothixene, chlorpromazine, tiapride and trifluoperazine, sertindole, lurasidone, sulpiride, flupenthixol and brexpiprazole was 10.9%. Among the medications prescribed to patients with schizophrenia, the leading ones were risperidone (36.2%), haloperidol (17.1%), olanzapine (15.6%), and clozapine (10.8%). The frequency of prescription of other drugs was less than 10.0%. The share of TA was 26.3%, AA — 73.7%. In the vast majority of cases (98.1%), patients received monotherapy. Conclusion: the data obtained on the structure of antipsychotic prescriptions indicate that our approaches correspond to the global trend of the predominant use of second-generation antipsychotics in the in-patient treatment of schizophrenia.

Responses to clinical treatment of bipolar versus unipolar depressive episodes in women versus men.

Whether responses to treatment of major depressive episodes differ between women and men or with bipolar (BD) and major depressive disorders (MDD) remains unresolved. To test for diagnostic and sex differences in responses to treatment of depression. We compared changes in the 21-item Hamilton Depression Rating Scale (HDRS21) ratings of depression (n = 3243) between women (64.7%) and men, and between DSM-5-TR BD ([n = 253] and subtypes I [BD1] vs II [BD2]) and MDD (n = 2990), using bivariate comparisons and multivariate modeling. Treatments included clinically individualized use of antidepressants (by 92.4%, in doses averaging 90.0 mg/day imipramine-equivalent), sometimes with mood-stabilizing agents (32.1%), second-generation antipsychotics (18.8%), or psychotherapy (38.6%). Depression ratings decreased by 60.6% to a final mean HDRS score of 7.44; response rate (⩾50% reduction in HDRS) averaged 63.7%. Outcomes were very similar in women and men as well as with BD versus MDD, and between BD subtypes. Moreover, age, duration of illness, initial HDRS score, dose of antidepressant, and weeks of treatment, as well as sex and diagnosis were not associated with improvement of HDRS with treatment. Only 6/42 comparisons involving 21 individual HDRS items differed significantly in improvement between sexes or diagnoses. Results were very similar to the Montgomery-Åsberg Depression Rating Scale depression ratings. Only 2.0% of the subjects experienced mood-switching into clinical (hypo)mania and the final Young Mania Rating Scale ratings averaged 0.63. Responses to clinical treatment (as % reduction of HDRS score, response rate, or final HDRS score) of depressed women versus men, and BD (including BD1 vs BD2) versus MDD were substantial and very similar.

The Optimal Dosage and Duration of Metformin for Prevention and Treatment of Antipsychotic-Induced Weight Gain: An Updated Systematic Review and Meta-Analysis.

Weight gain and metabolic complications are substantial adverse effects associated with second-generation antipsychotics. However, comprehensive guidelines for managing antipsychotic-induced weight gain are lacking. This review included all double-blind, placebo-controlled studies investigating metformin's effectiveness in addressing antipsychotic-related weight gain. We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov for relevant studies from the inception to 2024. A random-effects model was used for the meta-analysis. This meta-analysis, including 20 studies with 1070 patients, revealed that metformin significantly surpassed placebo in attenuating weight gain in patients receiving antipsychotics. The mean weight change with metformin was -3.32kg [95% confidence interval (CI): -4.57 to -2.07]. Additionally, metformin use resulted in a marked decrease in body mass index [-1.24kg/m2 (95% CI: -1.70 to -0.77)]. Metformin could maintain the effects from 12 to 24 weeks. This updated meta-analysis investigated the durations and dosages of metformin use in patients with schizophrenia experiencing antipsychotic-induced weight gain. The findings highlight the need for additional large-scale research to validate our findings.

Antipsychotic drugs for anorexia nervosa.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of antipsychotic drugs (both first- and second-generation antipsychotics) compared to placebo on body weight gain, psychological symptoms, acceptability, and adverse events for people with anorexia nervosa.

The Effect of Adjuvant Therapy on Metabolic Syndrome in Schizophrenia Patients at Madani Hospital

Background: Schizophrenia is a mental disorder that impacts behavior, emotions, and communication. In recent years, atypical antipsychotics have been increasingly prescribed because they significantly reduce both positive and negative symptoms. However, the long-term effects of atypical can cause metabolic syndrome. Additional therapy is provided to maximize the primary therapy and reduce the side effects. Method: This study used a quasi-experimental design with a single-blind, pretest-posttest approach. Patients who had been using atypical antipsychotics, either monotherapy or combination therapy, for more than 3 were examined pretest to determine metabolic syndrome levels. Group A received adjuvant therapy, while Group B did not receive adjuvant therapy. Based on this data, an analysis of the reduction in metabolic syndrome categories was conducted. Result: The percentage of schizophrenia patients by gender was dominated by males (60%). By age, the majority were adults (87%). In Group A, the incidence of metabolic syndrome decreased from 53% in the pretest to 40% in the posttest after being given vitamin A, B, and folic acid therapy. The most commonly used other medication was THP (38%). Conclusion: The administration of adjuvant therapy with vitamins A, B, E, and folic acid can reduce the value of one or two of the five metabolic syndrome criteria for schizophrenia patients (p = 0.052) compared to the group of patients who did not receive vitamins A, B, E, and folic acid adjuvant therapy. Future research should use a longer duration to observe the effects of vitamins A, B, E, and folic acid and evaluate their therapeutic doses. Additionally, it should narrow down the criteria for medication use, focusing solely on the atypical antipsychotic’s clozapine or olanzapine.

Treatment satisfaction and effectiveness of Lurasidone on quality of life and functioning in adult patients with schizophrenia in the real-world Italian clinical practice: a prospective 3-month observational study.

Although second-generation antipsychotics (SGAs) have proven to be effective therapeutic options for patients with schizophrenia, there is a notable lack of evidence on patients' subjective perspectives regarding their well-being, quality of life, and satisfaction with these medications. This study aimed to evaluate the treatment satisfaction and effectiveness of lurasidone on quality of life and functioning in adult patients with schizophrenia in real-world Italian clinical practice. This was a multicentre, national, non-interventional, single-arm, 3-month prospective study. Patients who were naive to lurasidone treatment and whose treating physician had decided to start them on this medication were enrolled and evaluated over a 3-month period. Eligible patients were adults (≥ 18 years of age) with a primary diagnosis of schizophrenia who were being treated with lurasidone (for the first time [i.e., they were lurasidone naive]) as part of routine clinical practice. Efficacy endpoints were changes in patient/caregiver treatment satisfaction (seven-point Likert scale from the Treatment Satisfaction Questionnaire for Medication), patient quality of life and functioning (QLS), investigator-rated global assessment of functioning (CGI-S, IAQ) after 6 weeks and 3 months of lurasidone, and number of relapses and hospitalizations. Sixty-one patients were enrolled and 59 completed the study. The median dosage of lurasidone at baseline was 37.00mg/day. The median duration of titration was 86.0 days (Min 28; Max 115 days); the median number of dosage changes was 1.0. At the end of 3-month observation period, the median dose of lurasidone was 74.00mg/day. QoL and Functioning Score showed a trend of improvement over time, reaching a mean change from baseline of 9.8 at the end of the study. According to the CGI-S, the percentage of patients who were "markedly or severely ill" showed a continuous decrease from baseline to 3 months, from 62.29% to 8.20%. Patient satisfaction increased over time, with 80.32% of patients reporting that they were somewhat, fairly, or very satisfied (including 63.93% who were completely or very satisfied) at the end of the study. No relapses/hospitalizations for psychiatric reasons were reported. Lurasidone was well tolerated with no safety concerns or discontinuations due to AEs. Lurasidone represents a valid option for the treatment of schizophrenia and positively affects subjective well-being, quality of life and satisfaction. NCT06527885 retrospectively registered (01/08/2024).

Preclinical Evaluation of MK-8189: A Novel Phosphodiesterase 10A Inhibitor for the Treatment of Schizophrenia.

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits sub-nanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cGMP and pGluR1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P (Sub P) and enkephalin (ENK) after MK-8189 administration. The PDE10A tracer [3H]MK-8193 was used determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ~48%. MK-8189 significantly reversed an MK-801-induced deficit in pre-pulse inhibition at PDE10A EO of ~47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [11C]MK-8193 in PET studies and plasma concentrations of 127nM MK-8189 yielded ~50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ~29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. Significance Statement We describe the primary pharmacology of MK-8189 a PDE10A inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients.

Pharmacologic prophylaxis of postoperative delirium in elderly patients: A network meta-analysis of randomized controlled trials

BackgroundThe high incidence and mortality rates of postoperative delirium (POD) among elderly patients highlights the pressing need for tailored prophylactic strategies. Despite various pharmacologic prophylactic strategies have been reported effective, their overall benefit and safety remain unclear in the geriatric population. Our network meta-analysis (NMA) aimed to systematically evaluate and rank the effectiveness of various pharmacological interventions in preventing POD in elderly patients. MethodsWe conducted an extensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar for randomized controlled trials (RCTs) published up to August 1, 2023. We included RCTs examining pharmacological prophylactic effects of POD in elderly patients. To extract data in alignment with predefined areas of interest, we employed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The primary outcome was the incidence of POD. For secondary outcomes, we evaluated tolerability through all-cause discontinuation or drop-out rates, as well as all-cause mortality. ResultsOur analysis encompassed a total of 44 RCTs involving 11,178 patients. Out of these, 26 RCTs involved comparisons with placebo only. For delirium prevention, the treatment groups receiving atypical antipsychotics (odds ratio (OR) of 0.27 and 95% confidence interval (CI) of 0.12-0.58), haloperidol (OR of 0.42; 95% CI of 0.25-0.71), dexmedetomidine (OR of 0.51 and 95% CI of 0.37-0.71 and melatonergic agents (MMA) (OR of 0.57 and 95% CI of 0.33-0.98) had significantly lower rates of delirium compared to the placebo group. Notably, the atypical antipsychotics ranked as the most effective treatment. For tolerability, no statistically differences in rates of dropout discontinuation and all-cause mortality among groups allocated to the placebo or individual pharmacological treatments. ConclusionsBased on indirect evidence, our network meta-analysis identified atypical antipsychotics, dexmedetomidine, MMA, and haloperidol as effective in preventing POD in the elderly, with atypical antipsychotics ranking highest. However, it is essential to note that these findings should be confirmed through further RCTs.

Atypical antipsychotics improve dendritic spine pathology in temporal lobe cortex neurons in a developmental rodent model of schizophrenia.

"Dendritic spine pathology" refers to alterations in density and morphology of dendritic spines, crucial in corticolimbic neurons in schizophrenia. These structural neuroplasticity changes contribute to the disease's neurobiological underpinnings, alongside alterations in other brain regions, such as temporal lobe cortices like the auditory cortex (Au1) and the entorhinal cortex (Ent), involved in sensory processing, memory, and learning. The neonatal ventral hippocampus lesion (NVHL) in rats exhibits behavioral abnormalities akin to schizophrenia symptoms and corticolimbic dendritic spine pathology, mitigated by atypical antipsychotic drugs (AADs) like risperidone (RISP) and olanzapine (OLZ). This study investigated NVHL-induced dendritic spine pathology in Au1 and Ent, evaluating RISP and OLZ effects. NVHL induced dendritic spine pathology mainly by reducing the dendritic spine density in Au1 and Ent neurons; both RISP and OLZ mitigated it, increasing dendritic spine density and mushroom spine population, the ones related with synaptic strengthening, while decreasing stubby spine population. These findings underscore the role of impaired neuroplasticity in the temporal lobe cortices in schizophrenia pathophysiology and highlight the relevance of the NVHL model for studying neuroplasticity mechanisms in the disease. They also contribute to the growing understanding of targeting structural and functional neuroplasticity for novel drugs in the pharmacotherapy of the disease.

Neuropsychiatric Symptoms in Corticosteroid Induced Systemic Lupus Erythematosus (Sle) Patients: a Case Report

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with an unknown etiology and various clinical manifestations, course, and prognosis. Classes of medication used in the management of SLE include non-biological immunosuppressives, corticosteroids, biologic therapy, and immunoglobulins. The effect of using corticosteroids in the management of SLE still evokes debate regarding the emergence of mental health disorders. Case: A 24-year-old female patient was admitted to the hospital with an initial diagnosis of acute confusional stage, anemia, chronic disease, and systemic lupus erythematosus (SLE). Anticonvulsants, corticosteroids, and packed red blood transfusions had been given to the patient. The course of the disease during the hospitalization the next days, the patient experienced slurred speech, giggling, place and time disorientation, and visual hallucinations. The patient was consulted to a psychiatrist, got atypical antipsychotics and benzodiazepines, and then experienced improvement. Discussion: Patients with moderate SLE, in this case characterized by lupus nephritis, were given corticosteroids. Administration of corticosteroids to SLE patients will increase the risk of developing neuropsychiatric symptoms such as acute confusional state, anxiety, mood disorders, cognitive disorders, and seizures. This can occur due to increased permeability of the blood-brain barrier mediated by pro-inflammatory cytokines, resulting in the formation of autoantibodies against neural antigens, in which phospholipid proteins appear intracranially. Conclusion: Corticosteroid administration in SLE will cause neuropsychiatric symptoms such as slurred speech, giggling to herself, delirium, and visual hallucinations. Further design studies are needed to address the neuropsychiatric effects of corticosteroids in SLE.

Long-term stability of five atypical antipsychotics (risperidone, olanzapine, paliperidone, clozapine, quetiapine) and the antidepressant mirtazapine in human serum assessed by a validated SPE LC-MS/MS method.

Long-term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid-phase extraction and liquid chromatography-tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation. We assessed analyte stability on long-term storage in serum samples at 25°C, 5°C, -20°C and -80°C, and during five freeze-thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at -20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at -80°C. Furthermore, all analytes were stable for five freeze-thaw cycles. We recommend storage at -80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of -20°C is sufficient for storage less than 60 days.

Treatment With Long-Acting Injectable Aripiprazole During Pregnancy in Bipolar Disorder: A Scoping Review

Background: The management of bipolar disorder during pregnancy presents a significant challenge, particularly regarding the safety and effectiveness of long-acting injectable (LAI) antipsychotics like aripiprazole. Despite the growing use of LAI antipsychotics in psychiatric disorders, data on their use during pregnancy are limited, especially for bipolar disorder. This study aimed to shed light on this issue through a scoping review. Areas of Uncertainty: The level of evidence concerning the safety of second-generation antipsychotics during pregnancy is limited. Data on LAI aripirazole are even more limited. Data Sources: We conducted a scoping review following the PRISMA-ScR guidelines, systematically searching multiple electronic databases for studies published between January 2008 and February 2024. The review focused on the administration of aripiprazole during pregnancy among patients with psychiatric disorders, examining outcomes related to maternal health, fetal well-being, and neonatal outcomes. Results: The scoping review identified 11 case reports that met the inclusion criteria and 4 additional studies (prospective and retrospective cohort studies). Conclusions: The scoping review emphasizes the need for further research to confirm its safety and efficacy. The limited data underscore the importance of individualized treatment plans and informed decision-making, considering the unique risks and benefits of LAI antipsychotic use during pregnancy. Further studies are imperative to provide more definitive guidance for managing bipolar disorder with LAI antipsychotics in pregnant patients.

Atypical Antipsychotics Use and Neuroleptic Malignant Syndrome: A Review With a Clinical Perspective

Neuroleptic malignant syndrome (NMS) is a potentially life-threatening idiosyncratic reaction associated with the use of antipsychotic medications, characterized by hyperthermia, muscle rigidity, and alterations in consciousness. Despite a reduction in its incidence due to the predominance of atypical antipsychotics in contemporary treatment regimens, NMS remains a critical neuropsychiatric emergency that warrants vigilant attention. There is a hypothesis proposing that catatonia and NMS may exist along a continuum of the same disorder, and evidence suggests that lorazepam may offer therapeutic benefits for both conditions. It is potential for the concurrent occurrence of NMS and serotonin syndrome when antipsychotics and antidepressants are administered concomitantly. This paper presents a case of NMS following the reinitiation of antipsychotic treatment over an extended duration, a scenario inadequately addressed in existing reports, and discusses strategies for its management in clinical practice.

Clozapine impaired glucose-stimulated insulin secretion partly by increasing plasma 5-HT levels due to the inhibition of OCT1-mediated hepatic 5-HT uptake in mice.

Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR3 antagonist tropisetron or by silencing 5-HTR3a. The 5-HTR2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR2a or the 5-HTR2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [2H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [2H]5-HT and MPP+ uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [2H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR3a. The antagonistic effect of clozapine on islet 5-HTR2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs.

The association between drugs and vaccines commonly prescribed to older people and bullous pemphigoid: a case-control study.

Bullous pemphigoid (BP) is an autoimmune skin disease that affects mainly older people. Numerous drugs have been previously associated with BP based on case series and small hospital-based studies. More reliable and precise estimates of associations between a broad selection of drugs/vaccines and BP will enable greater awareness of potential increased risk of BP following certain medicines and help identify clinical, histological and genomic characteristics of drug-induced BP for different types of culprit drugs. Greater awareness could lead to earlier recognition or suspicion of BP and referral to a dermatologist for diagnosis. Earlier diagnosis may lead to less aggressive treatment and improved well-being. To determine the association between drugs/vaccines commonly prescribed to older people and BP risk. We conducted a population-based nested case-control study between 1998-2021 using electronic primary care records from the Clinical Practice Research Datalink. We matched BP cases with up to 5 controls. Exposures were drugs/vaccines commonly prescribed to older people. We used multivariable conditional logistic regression adjusting for multiple drug use. For antibiotics, we considered prescriptions may be prescribed for undiagnosed symptoms of BP which resemble skin infection (protopathic bias) in a sensitivity analysis. Antibiotics were the therapeutic group associated with the highest risk of BP (OR: 4.60; 95%CI 4.40-4.80). However, after adjusting for protopathic bias, the OR reduced to 2.08 (95%CI 1.99-2.17). After adjusting for protopathic bias, of all antibiotic classes and subclasses, penicillins and penicillinase-resistant penicillins had the strongest associations with BP risk (OR: 3.44; 95%CI 3.29-3.60; sensitivity analysis OR; 1.74; 1.66-1.84 and OR: 7.56; 95%CI 7.15-8.00; sensitivity analysis OR: 2.64; 95%CI 2.45-2.85, respectively). Other drugs strongly associated with increased risk were gliptins (OR: 2.77; 95% CI 2.37-3.23), and second-generation antipsychotics (OR: 2.58; 95%CI 2.20-3.03). Healthcare professionals need to be aware of BP risk in older people particularly when prescribing penicillinase-resistant penicillins, gliptins, and second-generation antipsychotic drugs to recognise and manage BP early. Due to the low prevalence of disease, we do not suggest avoidance of drugs/vaccines to prevent BP. Further research should consider recency, dosage, and duration of antibiotic treatments.