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Expert Opinion on Pharmacotherapy 2023Long-acting injectable antipsychotics (LAIs) are an effective, but potentially underutilized treatment option in schizophrenia and other severe mental illnesses.... (Review)
Review
INTRODUCTION
Long-acting injectable antipsychotics (LAIs) are an effective, but potentially underutilized treatment option in schizophrenia and other severe mental illnesses. Prescribing information typically focuses on how to initiate treatment from the corresponding oral formulations. However, in clinical practice other scenarios, such as switching from other oral antipsychotics or other LAIs, occur frequently, requiring guidance.
AREAS COVERED
Pharmacodynamic properties of antipsychotics and their relation to rebound symptoms. Pharmacokinetic properties of LAIs and their implications for switching approaches. Specific approaches to switching to LAIs.
EXPERT OPINION
The LAI landscape has evolved significantly in the last decade with more formulations available, longer dosing intervals, and extended indications. However, currently available LAIs have various shortcomings, e.g. short dosing intervals, need for oral supplementation, loading regimens, deep intramuscular injection and/or restricted indications. Recent improvements include a one-day initiation option for aripiprazole lauroxil, aripiprazole monohydrate once-monthly, risperidone in situ microparticles and subcutaneous risperidone. Future LAI developments should focus on longer dosing intervals, subcutaneous administration, expansion of LAIs beyond currently available antipsychotic agents and indications beyond schizophrenia and bipolar disorder. In the future, LAIs might become a first-line treatment after initial oral stabilization for chronic mental disorders with need for maintenance treatment and presence of significant non-adherence.
Topics: Humans; Antipsychotic Agents; Risperidone; Schizophrenia; Bipolar Disorder; Injections, Intramuscular; Delayed-Action Preparations
PubMed: 37345508
DOI: 10.1080/14656566.2023.2228686 -
Nature Dec 2023Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse... (Comparative Study)
Comparative Study
Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HTR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.
Topics: Animals; Humans; Mice; Amines; Amphetamine; Antipsychotic Agents; Binding Sites; Catecholamines; Cryoelectron Microscopy; GTP-Binding Proteins; Ligands; Molecular Dynamics Simulation; Mutation; Polypharmacology; Receptors, G-Protein-Coupled; Species Specificity; Substrate Specificity
PubMed: 37935376
DOI: 10.1038/s41586-023-06804-z -
Emergency Medicine Clinics of North... Feb 2024Schizophrenia is a chronic condition characterized by positive symptoms (auditory hallucinations, delusion), negative symptoms (avolition, social withdrawal), and... (Review)
Review
Schizophrenia is a chronic condition characterized by positive symptoms (auditory hallucinations, delusion), negative symptoms (avolition, social withdrawal), and disorganized thoughts/behaviors. Although the pathophysiology is incompletely understood, several neurobiological mechanisms have been proposed. Treatment usually involves antipsychotic medication as well as psychotherapy and supportive services. When evaluating patients in the emergency department, acute safety considerations are paramount. Patients should be assessed for suicide risk, violence risk, inability to care for self, and the risk of being the victim of a crime. Persons with schizophrenia are at an increased risk of substance use and a variety of medical problems.
Topics: Humans; Schizophrenia; Hallucinations; Violence; Antipsychotic Agents; Emergency Medicine
PubMed: 37977755
DOI: 10.1016/j.emc.2023.06.012 -
The Lancet. Psychiatry Dec 2023TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria.
BACKGROUND
TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that was approved in April, 2023 for subcutaneous use. The aim of the phase 3 Risperidone Subcutaneous Extended-release (RISE) study was to evaluate the efficacy of TV‑46000 in schizophrenia.
METHODS
The RISE study consisted of two treatment stages: a 12-week, open-label stabilisation phase with oral risperidone (stage 1), and an open-ended, randomised, double-blind, placebo-controlled, relapse-prevention phase with subcutaneous TV-46000 (stage 2) done at 69 clinical sites across the USA and Bulgaria. Patients diagnosed with schizophrenia more than 1 year before screening by DSM-5 criteria and confirmed at screening by the Structured Clinical Interview for DSM-5 and who had at least one relapse within 24 months before screening were eligible for enrolment. Patients who were outpatients and stabilised in stage 1 continued to stage 2 and were randomly assigned 1:1:1 by a computer-generated randomisation list to receive either subcutaneous TV-46000 once monthly, TV-46000 once every 2 months, or placebo until relapse, early discontinuation, or the study was stopped because the prespecified stopping criterion of at least 90 relapse events was met. The primary endpoint was time to impending relapse of the intention-to-treat patient population in stage 2. This study is registered with ClinicalTrials.gov, number NCT03503318, and is complete.
FINDINGS
The study enrolled the first patient on June 1, 2018, and the last patient completed on Dec 3, 2020. 1267 patients were screened, 863 enrolled, and 544 (male, n=332 [61%], female, n=212 [39%]; mean [SD] age, 49·3 [10·98] years; Black or African American, n=322 [59%]; White, n=206 [38%]; Asian, n=7 [1%]; Native Hawaiian or other Pacific Islander, n=2 [<1%]; race not reported, n=3 [<1%]; other race, n=4 [<1%]; Hispanic or Latinx, n=117 [22%]) randomly assigned to subcutaneous TV-46000 once monthly (n=183), TV-46000 once every 2 months (n=180), or placebo (n=181). Time to impending relapse was significantly prolonged by 5·0 times with TV-46000 once monthly (hazard ratio, 0·200 [95% CI 0·109-0·367]; p<0·0001) and by 2·7 times with TV-46000 once every 2 months (0·375 [0·227-0·618]; p<0·0001) versus placebo. Most frequently reported treatment-related adverse events (ie, ≥5% of patients in either TV-46000 group) that occurred more often in patients receiving TV-46000 (once monthly or once every 2 months) versus placebo were injection site nodules (7% for TV-46000 once monthly, 7% for TV-46000 once every 2 months, 3% for placebo), weight increased (4%, 6%, 2%, respectively), and extrapyramidal disorder (5%, 3%, 0% respectively). Serious adverse events were reported for eight (4%) patients in the TV-46000 once-monthly group, ten (6%) patients in the TV-46000 once-every-2-months group, and 14 (8%) patients in the placebo group. The safety profile of TV-46000 was consistent with other approved formulations of risperidone. No new safety signals were identified.
INTERPRETATION
In patients with schizophrenia, subcutaneous TV-46000 once monthly and once every 2 months significantly delayed impending relapse versus placebo. TV-46000 is an effective long-acting, subcutaneous, antipsychotic agent treatment option in adult patients with schizophrenia, with a favourable benefit-risk profile.
FUNDING
Teva Branded Pharmaceutical Products R&D.
Topics: Adult; Humans; Male; Female; Middle Aged; Risperidone; Schizophrenia; Antipsychotic Agents; Bulgaria; Treatment Outcome; Chronic Disease; Double-Blind Method; Recurrence
PubMed: 37924833
DOI: 10.1016/S2215-0366(23)00288-2 -
Aging Cell Nov 2023The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for...
The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.
Topics: Animals; Humans; Olanzapine; Antipsychotic Agents; Aging; Mitophagy; Mitochondria; Caenorhabditis elegans
PubMed: 37828862
DOI: 10.1111/acel.14003 -
Journal of Neuroendocrinology Dec 2023Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits.... (Review)
Review
Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits. Although the use of AAPs is associated with beneficial effects in these patients, they are also associated with undesired metabolic side effects, including metabolic syndrome (MetS). MeS is defined by the presence of metabolic abnormalities such as large waist circumference, dyslipidemia, fasting hyperglycemia and elevated blood pressure, which predispose to type 2 diabetes (T2D) and cardiovascular disease. In this review, the molecular and cellular mechanisms involved in these undesired metabolic abnormalities induced by AAPs are described. These mechanisms are complex as AAPs have multiple cellular targets which significantly affect the activities of several hormones and neuromodulators. Additionally, AAPs affect all the relevant metabolic organs, namely the liver, pancreas, adipose tissue, skeletal muscle and intestine, and the central and peripheral nervous system as well. A better understanding of the molecular targets linking AAPs with MetS and of the mechanisms responsible for clinically different side effects of distinct AAPs is needed. This knowledge will help in the development of novel AAPs with less adverse effects as well as of adjuvant therapies to patients receiving AAPs.
Topics: Humans; Antipsychotic Agents; Diabetes Mellitus, Type 2; Schizophrenia
PubMed: 37866818
DOI: 10.1111/jne.13347 -
The Psychiatric Clinics of North America Sep 2023Men and women, for biologic and sociocultural reasons, differ in the nature of their risks for schizophrenia and also in their care needs. Women with schizophrenia have... (Review)
Review
Men and women, for biologic and sociocultural reasons, differ in the nature of their risks for schizophrenia and also in their care needs. Women with schizophrenia have several reproduction-associated risks and care needs that require special clinical consideration. They also have several specific risks related to antipsychotics and gender-associated needs not necessarily related to biology. These require clinicians' diagnostic acumen, treatment skills, cultural sensitivity, and advocacy know-how. Although this does not pertain to everyone, awareness on the part of clinicians is essential. This article addresses the current evidence for difference.
Topics: Male; Humans; Female; Schizophrenia; Antipsychotic Agents
PubMed: 37500245
DOI: 10.1016/j.psc.2023.04.005 -
MMW Fortschritte Der Medizin May 2024
Topics: Humans; Antipsychotic Agents; Dementia; Aged
PubMed: 38693357
DOI: 10.1007/s15006-024-3895-2 -
Ugeskrift For Laeger May 2024Long-acting injectable antipsychotics (LAI) is a frequently used treatment modality which has advantages over oral antipsychotics regarding hospitalization or relapse... (Review)
Review
Long-acting injectable antipsychotics (LAI) is a frequently used treatment modality which has advantages over oral antipsychotics regarding hospitalization or relapse prevention. However, the pharmacokinetic properties of LAI greatly differ from oral antipsychotics. This necessitates an increased knowledge about LAI among clinicians, especially when commencing treatment, changing doses and discontinuing treatment. In this review, we summarize an array of clinically important characteristics of LAI and give a conceptual framework for understanding the pharmacokinetics of LAI.
Topics: Humans; Antipsychotic Agents; Delayed-Action Preparations; Injections; Injections, Intramuscular
PubMed: 38808759
DOI: 10.61409/V12230776 -
Antipsychotic-Induced Weight Gain in Severe Mental Illness: Risk Factors and Special Considerations.Current Psychiatry Reports Nov 2023Weight gain is a disconcerting issue experienced by patients treated with antipsychotics (APs). This review summarizes current knowledge on the prevalence, etiology, and... (Review)
Review
PURPOSE OF REVIEW
Weight gain is a disconcerting issue experienced by patients treated with antipsychotics (APs). This review summarizes current knowledge on the prevalence, etiology, and risk factors for antipsychotic-induced weight gain (AIWG), and evidence for interventions, including special considerations.
RECENT FINDINGS
Predisposing risk factors for AIWG include lack of prior AP exposure, sex, and age. AP dose and duration of exposure are additional treatment-related factors that may contribute to this issue. Among current approaches to target AIWG, metformin has the most evidence to support its use, and this is increasingly reflected in clinical guidelines. While lifestyle approaches are recommended, cost-effectiveness and scalability represent limitations. More research is needed to identify newer treatment options and inform clinical recommendations for AIWG. Concerns around scope of practice in psychiatry to address AIWG and related comorbidities will require enhanced training opportunities and interdisciplinary collaborations, as well as updated position statements/practice guidelines emphasizing prevention.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Weight Gain; Mental Disorders; Risk Factors
PubMed: 37755655
DOI: 10.1007/s11920-023-01458-0