In the following we comprehensively review approaches to treating schizophrenia that do not primarily involve dopamine antagonism or partial agonism. Following 70 years of broadly similar dopamine D2 receptor antagonist/partial agonist drugs, Cobenfy™ was approved as a novel antipsychotic in September 2024. Cobenfy™ is a combination formulation of xanomeline, a muscarinic cholinergic M1/M4 receptor agonist and trospium, a peripherally restricted muscarinic antagonist included to offset peripheral side effects of xanomeline. This approval has reinvigorated optimism in the field and raised important questions for the future direction of antipsychotic drug development. We review therapeutic strategies beyond dopamine that have been and are currently being investigated to address whether there are a sufficient number of novel approaches to maintain the momentum of this breakthrough and question why it has taken so long. The current pipeline of late-stage compounds is low and potentially constrained by historical setbacks and challenges in clinical trial design for schizophrenia. This success rate has future potential to improve given the range of biomarkers in development designed to enable greater precision in future clinical trials. Cobenfy™ approval demonstrates that with combination formulations designed to improve side effect profiles and optimised clinical trial design it is possible to generate tolerable and efficacious treatment options for patients beyond a solely dopaminergic framework. We conclude that advances in understanding the neurobiology of schizophrenia, while not complete, has generated a diverse and well justified pool of potentially novel and repurpose-ready approaches, with mechanisms beyond simple dopamine D2 antagonism/partial agonism.

Tardive dyskinesia (TD) is a severe and persistent involuntary movement disorder associated with long-term antipsychotic treatment. TD is likely underreported and misdiagnosed in routine practice, and there is a need to understand the proportion of patients who may experience TD but receive no formal diagnosis. This information could support the characterisation of patient populations that may benefit from novel therapeutic interventions. This study aimed to identify and describe patients with diagnosed or undiagnosed TD. Demographic and clinical features associated with an ICD-9/10 diagnosis of TD were explored.

A retrospective study was conducted using de-identified electronic health record (EHR) data captured between 1999 and 2021 in the US. A cohort of 32,558 adults with schizophrenia-spectrum disorders, major depressive disorder with psychosis or bipolar disorder with psychosis who were prescribed antipsychotics was selected. Abnormal movements associated with TD and presence of TD documented in semi-structured EHR data were extracted through manual review of text recorded as part of the mental state examination. Patients with a recorded diagnosis of TD were identified based on the presence ICD-9/10 codes within structured portions of medical records: ICD-9: 333.85; ICD-10: G24.01. Logistic regression was used to assess the association between patient characteristics and an ICD diagnosis.

Altogether, 1,301 (4.0%) patients had either description of abnormal movements associated with TD (n=691) or documented TD (n=610) within semi-structured EHR data. Of those patients, only 64 (4.9%) had an ICD-TD diagnosis in structured EHR data. When the cohort was limited to those with documented TD in semi-structured EHR data, 56 (9.2%) had an ICD-TD diagnosis. Black/African-American race was associated with lower odds of ICD diagnosis compared with white race (OR=0.46, 95%CI=0.20-0.95, p=0.04). Treatment in community mental health centres was associated with increased odds of an ICD diagnosis compared to an academic medical centre (OR=adjusted OR=2.02, 95%CI=1.09-3.74, p=0.03).

This study highlights a pressing need for clinicians to better recognise and diagnose TD, which in turn may contribute to increased access to treatments for patients. A recorded ICD diagnosis of TD may be driven by factors related to both the patient and clinical setting.

Schizophrenia is a chronic and profound mental disorder. Non-adherence to prescribed medication regimens is a major concern in the treatment of schizophrenia. This study aimed to investigate the prevalence, factors, and reasons contributing to non-adherence among Ethiopian patients with schizophrenia who are receiving second-generation antipsychotics (SGAs).

A hospital-based cross-sectional study was done at Amanuel Mental Specialized Hospital (AMSH) from 03/10/2022 to 31/8/2023. Data were collected using the drug attitude inventory-10 (DAI-10) tool. Analysis was conducted using Statistical Package for Social Sciences (SPSS) version 25. Univariate and multivariate binary logistic regression analyses were conducted.

Most participants were male, (90.0%), and aged 26-40 years, (53.5%). Mean doses for risperidone and olanzapine prescribed were 4.9mg (±2.4) and 13.5mg (±5.0), respectively. Close to 40% of patients were khat (Catha edulis) users. The mean Positive and Negative Syndrome Scale (PANSS) total score was 71.1 ± 35.9 and the Clinical Global Impression-Severity (CGI-S) score was 3.42 ± 1.21. Around 31.4% of participants were non-adherent. Forgetfulness (31.73%) and stigma (27.31%) were the primary reasons cited for non-adherence. The multivariate binary logistic regression analysis revealed a significant association between non-adherence and several key factors. Patients with a PANS score equal to or greater than 71 (95% CI: 1.04, 3.80; p = 0.02), Patients categorized as having a moderate to markedly severe illness (95% CI: 1.1, 3.1; p = 0.024), duration of follow-up (DUP) (6-10) years (95% CI: 1.4, 129; p = 0.02), and age (26-40) years (95% CI: 0.3, 0.9; p = 0.04) were found to be statistically significant predictors of non-adherence.

The investigators recommended that counseling of the patients to highlight the importance of adherence, instituting regular and comprehensive symptom monitoring, tailoring interventions to address reasons for non-adherence, promoting early intervention and treatment initiation to reduce the DUP, and customizing interventions based on age-specific needs.

"Tardive syndrome" is an umbrella term for a group of drug-induced movement disorders associated with the prolonged use of mainly dopamine receptor blockers and also other medications. Early recognition followed by gradual withdrawal of the incriminating drug may lead to reversal, although not in all patients. Tardive syndromes are usually mixed movement disorders, with specific phenotypes, which may lead to severe disability. The pathophysiology remains incompletely understood. Treatment ranges from medical options, particularly dopamine-depleting agents and chemodenervation (botulinum toxin), to surgical options (deep brain stimulation and lesioning surgeries). Most studies that focused on treatment are limited by small patient numbers. Unfortunately, tardive syndromes often remain under-recognized in clinical practice. This article reviews the historical aspects, epidemiology and risk factors, pathophysiology, diagnostic criteria, clinical phenotypes, and management of tardive syndromes.

Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register (22/05/2023, pre-defined protocol https://osf.io/b52ae/ ), for randomized controlled trials (RCTs) of pharmacological/brain stimulation interventions for DRA-induced TD in adults with schizophrenia or mood disorders. Primary outcomes were TD symptom change (standardized mean difference/SMD) and all-cause discontinuation (acceptability-risk ratio/RR). Sensitivity analyses were conducted. Global, local inconsistencies, risk of bias (RoB-2 tool), and confidence in evidence (CINeMA) were measured. We included 46 trials (n = 2844, age = 52.89 ± 9.94 years, males = 59.8%, schizophrenia = 84.6%, mood disorders = 15.4%), all testing pharmacological interventions versus placebo. We identified three subnetworks. In network 1, several treatments outperformed placebo on TD symptoms with large effect sizes (k = 34, n = 2269), encompassing 22 interventions versus placebo, but 18 had 1 RCTs only, and 15 had n ≤ 20. High heterogeneity (I2 = 57.1%; tau2 = 0.0797), and global inconsistency (Q = 32.64; df = 14; p = 0.0032) emerged. No significant differences emerged in acceptability. When restricting analyses to treatments with trials with n > 20 and >1 RCT, only valbenazine (k = 5, SMD = -0.69; 95% CI = -1.00, -0.37) and vitamin E (k = 7, SMD = -0.49; 95% CI = -0.87, -0.11) were superior to placebo. Deutetrabenazine outperformed placebo considering AIMS score and in low risk of bias trials only and with a moderate effect size for 24/36 mg (k = 2, SMD = -0.57/-0.60). Confidence in findings was low for deutetrabenazine and valbenazine, very low for all others. In network 2 (k = 2, n = 63), switch to molindone (k = 1, n = 9) versus switch to haloperidol worsened TD (SMD = 1.68; 95% CI = 0.61,2.76). In network 3 (k = 3, n = 194), antipsychotic wash-out+placebo (k = 1, n = 25) versus TAU+placebo (k = 1, n = 27) worsened TD (SMD = 1.30; 95% CI = 0.36,2.23). Despite large effect sizes for some treatments with very low quality/confidence, when considering higher quality evidence only valbenazine or deutetrabenazine are evidence-based first-line treatments for TD, and potentially vitamin E as second-line. Switching to molindone and antipsychotic washout should be avoided. More treatment options and higher-quality trials are needed.

Deutetrabenazine, a selective vesicular monoamine transporter type 2 (VMAT2) inhibitor, has been demonstrated efficacy in treating refractory neurologic disorders such as Tardive Dyskinesia (TD) and Huntington's disease but have potential adverse events (AEs) that require detailed pharmacovigilance. This study aimed to comprehensively assess the safety profile of deutetrabenazine in real-world settings by analyzing AEs reported from the FDA Adverse Event Reporting System (FAERS) database.

We conducted a retrospective pharmacovigilance study using FAERS data from Q3 2017 to Q3 2024, focusing on deutetrabenazine-related AEs. We applied four disproportionality analysis methods-Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Multinomial Gamma Poisson Shrinkage (MGPS)--to identify potential safety signals. Furthermore, we utilized the Weibull distribution model to analyze the temporal risk of AEs.

Among the 10,571,578 reports obtained from the FAERS database, 4,337 AE reports were associated with deutetrabenazine. Using four independent computational methods at the preferred term (PT) level, we identified 1,131 PTs that indicated noteworthy adverse reactions. The drug's label-listed adverse reactions, including depression, somnolence, suicidal ideation, and fatigue, showed remarkable signals. Furthermore, we detected potential adverse reactions that were not specified on the label, such as drug ineffectiveness, dyskinesia, death, falls, and insomnia. The majority of these AEs were reported within the initial month of deutetrabenazine treatment, with a median time to onset of 40.5 days.

This research has yielded initial safety insights into the practical use of deutetrabenazine, validating established adverse reactions and uncovering further possible risks. These findings present essential safety considerations for physicians when prescribing deutetrabenazine for the clinical treatment.

The pathogenesis of tardive dyskinesia (TD) remains unclear, involving multiple biological pathways. This study aimed to explore biomarkers of TD through untargeted metabolomics for the early identification of TD.

This study recruited 84 schizophrenia (SZ) patients with TD and 160 SZ patients without TD. TD diagnosis was based on the Schooler-Kane criteria, and the severity of TD and psychiatric symptoms were assessed using the Abnormal Involuntary Movement Scale and the Positive and Negative Syndrome Scale. Fasting blood samples were collected from all patients and subjected to untargeted metabolomics analysis using Ultra-high-performance liquid chromatography-high resolution mass spectrometry, allowing for the quantification and profiling of 699 metabolites. Data were analyzed with orthogonal partial least squares discriminant analysis, and receiver-operating characteristic curves.

In TD, 57 metabolites exhibited significant changes (variable importance of projection > 1, false discovery rate-adjusted P < .05), primarily involving amino acids and lipids. These changes predominantly affected the phenylalanine, tyrosine, and tryptophan pathway (impact = 0.5, P = .0252), as well as the phenylalanine metabolism pathway (impact = 0.36, P = .0498). N-Acetyl-l-phenylalanine (B = 2.249, t = 4.56, P < .001, 95% CI, 1.302-3.286) and Succinylcarnitine (AcCa(4:0-DC)) (B = 1.009, t = 3.07, P = .002, 95% CI, 0.362-1.656) are negatively related to the total abnormal involuntary movement scale score. Additionally, 5 differential metabolites had area under the curve (AUC) values greater than 0.7 for diagnosing TD, with the combined diagnostic capability exceeding 0.8 (AUC = 0.817, 95% CI, 0.759-0.875).

In TD, disruptions in amino acid and lipid metabolism were predominantly observed. Amino acids and lipid metabolites may be involved in the development of TD. Additionally, a biomarker panel composed of amino acids and lipids can be used for the differential diagnosis of TD.

Sensori- and psychomotor abnormalities are an inherent part of schizophrenia-spectrum disorders (SSD) pathophysiology and linked to psychopathological symptoms as well as cognitive and global functioning. However, how these different symptom clusters simultaneously interact with each other is still unclear. Here, we examined 192 SSD patients (37.75 ± 12.15 years, 73 females). First, we investigated the cross-sectional prevalence and overlap of individual sensori- and psychomotor abnormalities. Second, we applied network analysis methods to simultaneously model the associations between Neurological Soft Signs (NSS), level of akathisia, parkinsonism symptoms, tardive dyskinesia (TD) and catatonia signs as well as cognition, psychopathology, global functioning and daily antipsychotic dose. The largest centralities were exhibited by NSS (0.90), catatonia signs (0.82) and global functioning (0.79). NSS showed strong partial correlations with cognition and parkinsonism symptoms (edge weight, ew = 0.409 and ew = 0.318, respectively). Catatonia signs showed strong connections with global functioning (ew = 0.333). In contrast, TD, akathisia and daily antipsychotic dose were weakly connected with other variables (e.g., largest ew=0.176 between TD and akathisia). In conclusion, NSS and cognition, parkinsonism symptoms and NSS as well as catatonia signs and global functioning seem to be preferentially connected in SSD. The daily medication had little influence on sensori- and psychomotor abnormalities, indicating that they are features of core SSD pathophysiology. Future studies should incorporate these relationships to enhance the understanding of SSD.

Chronic use of typical antipsychotics can lead to varying motor effects depending on the timing of analysis. Acute treatment typically induces hypokinesia, resembling parkinsonism, while repeated use can result in tardive dyskinesia, a hyperkinetic syndrome marked by involuntary orofacial movements, such as vacuous chewing movements in mice. Tardive dyskinesia is particularly concerning due to its potential irreversibility and associated motor discomfort. One prevailing theory suggests that tardive dyskinesia arises from hypersensitivity of D2-type dopaminergic receptors caused by continuous blockade from typical antipsychotics like haloperidol. Additionally, increased inflammation, oxidative stress, and elevated FosB protein expression in the dorsolateral striatum are implicated in its pathophysiology. Current treatments for tardive dyskinesia often lack clear efficacy and may lead to significant side effects. Cannabigerol, a non-psychotomimetic cannabinoid with antioxidant and anti-inflammatory properties, has been investigated for its potential antidyskinetic effects. In this study, mice were treated with cannabigerol at doses of 3 and 10 mg/kg to evaluate its ability to prevent, ameliorate, or reverse haloperidol-induced vacuous chewing movements. Cannabigerol successfully reduced vacuous chewing movements without affecting normal motor activity, exacerbating haloperidol-induced hypokinesia, or inducing dyskinetic effects on its own. However, no significant reversal of the haloperidol-induced motor effects was observed under the current protocol. Furthermore, cannabigerol did not alter FosB expression or microglia morphology. These findings underscore the need for further research to explore cannabigerol's therapeutic potential and contribute to our understanding of its possible clinical applications in managing tardive dyskinesia.

Schizophrenia treatment with antipsychotics often results in side effects that impact adherence and quality of life. Managing these effects remains challenging, as it requires balancing efficacy and tolerability. The Schizophrenia Technological Evaluation of Patient Side Effects (STEP-SE) app aims to aid side effects monitoring and management through shared decision-making (SDM).

This study aimed to evaluate the usability of the STEP-SE app for patients and clinicians in managing antipsychotic side effects.

Sixteen stable outpatients and 14 psychiatrists participated in semi-structured interviews after using the STEP-SE app. Questions explored ease of use, information clarity, user needs fulfilment, patient-clinician collaboration, treatment adherence improvement, patient empowerment and clinical utility. Data were analysed thematically.

Overall satisfaction with STEP-SE was high. Both groups found that the tool improved patient involvement, provided reliable information to enhance therapeutic alliance, posed low risks of misunderstanding and had an intuitive interface. Patients felt more motivated and empowered. Clinicians appreciated guideline consistency. Preferences differed regarding data visualization formats.

STEP-SE shows potential for aiding SDM on antipsychotic side effects. Patients gained motivation, and clinicians felt reassured. Refinements around mobile access, graphics and features could augment utility. Generalizability is limited given the stable patient sample.

Preliminary findings suggest that STEP-SE effectively engages patients, empowers them and supports clinicians in collaborative side effect management. Further testing with diverse user groups is warranted.

The current study was designed to gather patient and public feedback for the development of our decision aid tool, STEP-SE. Participants interacted with the tool's prototype in interactive sessions, providing insights and identifying technical issues. Their feedback was crucial for enhancing the tool, with each suggestion and bug report carefully considered for future iterations. The participants' contributions were key in optimizing STEP-SE's features and ensuring its relevance and reliability. We thank all who shared their time and perspectives, significantly shaping the tool's user-centred design.

We report the case of a 23-year-old man who developed orofacial dyskinesia secondary to aripiprazole whilst being treated for psychosis in the hospital. He was known to mental health services and had suffered a relapse of bipolar affective disorder. Upon cessation of aripiprazole and commencement of quetiapine, there was a rapid reversal of his movement disorder. He also did not have any notable risk factors associated with developing orofacial dyskinesia beyond having an affective disorder, which highlights the unusual and rare occurrence of this side effect with the use of aripiprazole. Unlike many first-generation antipsychotics, aripiprazole had been previously reported to be protective against and also treat extrapyramidal side effects (EPSE) due to its mixed mechanism of action, which includes being a partial dopamine receptor 2 (DR2) agonist.

Tardive dyskinesia (TD) is a persisting, and potentially irreversible, movement disorder associated with treatment with dopamine receptor antagonists. Few data are available on the risk of TD in children and adolescents treated with antipsychotic medication.

To review the literature on incidence, risk factors, and treatment options for antipsychotic-associated TD in children and adolescents (aged < 18 years).

Relevant articles were identified through a systematic search of Embase and Medline performed in January 2024. Methodological quality was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute Critical Appraisal tools.

Thirteen studies were identified. The reported TD point prevalence was 5-20%, with higher rates in studies involving typical antipsychotics. Lower estimates (around 1%) emerged from analyses of clinical database data suggesting underdiagnosis in clinical practice. Risk factors included treatment with typical antipsychotics, higher doses, longer duration of exposure, older age, female gender, higher baseline Abnormal Involuntary Movements Scale (AIMS) scores, intellectual impairment, and perinatal complications.

Although relatively few cases have been reported in children and adolescents, TD remains a risk in this population. Individuals receiving antipsychotics should be monitored carefully for the emergence of abnormal movements. Other than dose reduction, discontinuation, or switch to a lower-risk antipsychotic, few interventions have demonstrated efficacy. The strongest evidence for pharmacological treatment is for VMAT-2 inhibitors (valbenazine and deutetrabenazine), but these drugs are not licensed for use in children. To reduce risk, antipsychotics should be prescribed only if necessary, at the minimum effective dose and for the minimum necessary duration.

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis.

For bipolar disorder (BD), the inconsistency of treatment guidelines and the long phases of pharmacological adjustment remain major challenges. BD is known to be comorbid with many medical and psychiatric conditions and they may share inflammatory and stress-related aetiologies, which could give rise to this association. The integrated stress response (ISR) responds to various stress conditions that lead to alterations in cellular homeostasis. However, as a causative mechanism underlying cognitive deficits and neurodegeneration in a broad range of brain disorders, the impact of ISR on BD is understudied. Mendelian randomization has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for BD and analyze their pathophysiological mechanisms, using the summary data-based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the summary-level data of the GWAS on BD and the expression quantitative trait locus (eQTL) study in blood. We utilized the GWAS data including 41,917 BD cases and 371,549 controls from the Psychiatric Genomics Consortium and the eQTL data from 31,684 participants of predominantly European ancestry from the eQTLGen consortium. The SMR analysis identified the EIF2B5 gene that was associated with BD due to no linkage but pleiotropy or causality. The COLOC analysis strongly suggested that EIF2B5 and the trait of BD were affected by shared causal variants, and thus were colocalized. Utilizing data in EpiGraphDB we find other putative causal BD genes (EIF2AK4 and GSK3B) to prioritize potential alternative drug targets.

Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID).

The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER.

Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020.

The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age.

The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively.

In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner.

Schizophrenia is a complex neuropsychiatric disorder with significant morbidity. Treatment options that address the spectrum of symptoms are limited, highlighting the need for innovative therapeutic approaches. Gamma Entrainment Using Sensory Stimulation (GENUS) is an emerging treatment for neuropsychiatric disorders that uses sensory stimulation to entrain impaired oscillatory network activity and restore brain function. Aberrant oscillatory activity often underlies the symptoms experienced by patients with schizophrenia. We propose that GENUS has therapeutic potential for schizophrenia. This paper reviews the current status of schizophrenia treatment and explores the use of sensory stimulation as an adjunctive treatment, specifically through gamma entrainment. Impaired gamma frequency entrainment is observed in patients, particularly in response to auditory and visual stimuli. Thus, sensory stimulation, such as music listening, may have therapeutic potential for individuals with schizophrenia. GENUS holds novel therapeutic potential to improve the lives of individuals with schizophrenia, but further research is required to determine the efficacy of GENUS, optimize its delivery and therapeutic window, and develop strategies for its implementation in specific patient populations.

Effective side effects management present a challenge in antipsychotic treatment with second-generation antipsychotics (SGAs). In recent years, most of the commonly used SGAs, except for clozapine, have been shown to differ only slightly in their effectiveness, but considerably regarding perceived side effects, safety profiles, and compatibility to preexisting medical conditions.

The current state of available evidence on side-effect management in SGA treatment of patients with schizophrenia spectrum disorders (SSD) is reviewed. In addition, current guideline recommendations are summarized, highlighting evidence gaps.

SGA safety and side effects needs to be considered in treatment planning. Shared decision-making assistants (SDMA) can support patients, practitioners and relatives to orient their decisions toward avoiding side effects relevant to patients' adherence. Alongside general measures like psychosocial and psychotherapeutic care, switching to better tolerated SGAs can be considered a relatively safe strategy. By contrast, novel meta-analytical evidence emphasizes that dose reduction of SGAs can statistically increase the risk of relapse and other unfavorable outcomes. Further, depending on the type and severity of SGA-related side effects, specific treatments can be used to alleviate induced side effects (e.g. add-on metformin to reduce weight-gain). Finally, discontinuation should be reserved for acute emergencies.

Clonazepam has some evidence in the treatment of tardive dyskinesia. It can be used as an alternative treatment option in situations where vesicular monoamine transporter 2 inhibitors are not available or when it is not feasible to use them.

Antipsychotics are recommended for prevention of relapse in schizophrenia. It is unclear whether increased risk of relapse following antipsychotic discontinuation is predominantly associated with an absolute magnitude of dose reduction or rate of antipsychotic reduction. Establishing the responsible mechanism is important because prolonged withdrawal schedules have been suggested to reduce risk of relapse.

Individual patient data from antipsychotic discontinuation studies were obtained. We estimated the occupancy of receptors over time using half-lives and median effective dose ED50 values obtained from pharmacokinetic and receptor occupancy studies. Hazard ratios for relapse events were calculated using Cox proportional hazards models to assess the influence of formulation (oral, 1-monthly, and 3-monthly injections). The change in hazard ratio over time was estimated, and the effect of time-varying covariates was calculated, including rate of occupancy reduction and absolute receptor occupancy.

Five studies including 1388 participants with schizophrenia were identified (k = 2: oral, k = 2: 1-monthly injection, k = 1: 3-monthly injection). Withdrawal of long-acting injectable medication did not lead to a lower hazard ratio compared with withdrawal of oral medication, and this included the period immediately following randomization. Hazard ratios were not associated with the rate of decline of receptor occupancy; however, they were associated with reduced absolute occupancy in trials of long-acting injections (P = .038).

Antipsychotic discontinuation is associated with an increased risk of psychotic relapse, related to receptor occupancy. Although relapse does not appear to be related to the rate of discontinuation, gradual discontinuation strategies may allow for easier antipsychotic reinstatement in case of symptomatic worsening.

Schizophrenia poses significant societal challenges, including interpersonal tension, an increased risk of suicide, and soaring medical costs. Although antipsychotics can prevent relapses, they often give rise to adverse effects and do not provide lasting relief. Mindfulness-based interventions (MBI) emerge as a hopeful avenue for improving outcomes. However, existing research and meta-analyses of the efficacy of MBI in schizophrenia remain limited. This study aimed to evaluate the efficacy of MBI as an adjunctive therapy for schizophrenia. Relevant randomized controlled trials (RCTs) were searched across PubMed, Embase, Web of Science, and Cochrane Library from inception dates up to January 12, 2023. Statistical analyses were conducted using Stata software (version 15.0) and Review Manager 5.4. The quality of the included RCTs was assessed using the revised Cochrane risk of bias tool. A total of 18 RCTs were included, with 675 patients and 704 health controls. Our meta-analysis revealed that MBI significantly improved psychosocial function, insight, and mindfulness in individuals with schizophrenia. The quality of the included RCTs had a low to moderate risk of bias. These findings suggest that MBI holds promise for improving the mental health of individuals with schizophrenia.

Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection.

This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations.

Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients' outcomes.

AimThe aim of this study is to summarize the spontaneous reports of tardive dyskinesia (TD) and extrapyramidal symptoms (EPSs) that occurred in Japan over the past decade. MethodsThe study analyzed TD and EPS cases reported in the Japanese Adverse Drug Event Report database between April 2011 and March 2021. The cases were stratified by the diagnoses of schizophrenia, bipolar disorders, and depressive disorders. ResultsIn total, 800 patients including a total of 171 TD cases and 682 EPS cases were reported in the JADER database across psychiatric diagnosis. The cases were caused by first-generation antipsychotics (FGA, TD: n = 105, EPS: n = 245) and second-generation antipsychotics (SGA, TD: n = 144, EPS: n = 598). The SGA were categorized based on Neuroscience-based Nomenclature (NbN) regarding pharmacological domain and mode of action, which were reported evenly as the offending agents. Among reported treatment and outcome in TD cases (n = 67, 37.6%) and EPS cases (n = 405, 59.3%), the relatively limited number of TD cases were reported as recovered/improved was also limited (n = 32, 47.8%) compared to those of EPS cases (n = 266, 65.7%). Some cases still had residual symptoms or did not recover fully (TD: n = 21, 31.3%, EPS: n = 77, 19.0%). CONCLUSION: Tardive dyskinesia and EPS have been widely reported in Japan over the past decade across psychiatric diagnoses and antipsychotic classes. LIMITATIONS: It is important to acknowledge the presence of reporting bias and the lack of comparators to accurately assess risks. Owing to the nature of spontaneous reporting, the estimation of prevalence is not feasible.

Lysergic acid diethylamide (LSD) is a hallucinogenic agent. In the mid-20th century, it was used to augment psychoanalysis and to treat alcohol use disorder. However, LSD was banned in 1970 in part because of concerns that it could bring about or exacerbate mental illness. Its therapeutic potential remains incompletely understood.

While uncontrolled recreational use of LSD can, in rare instances, lead to long-term psychosis, adverse events in clinical trials of LSD, such as anxiety, headache, and nausea, have almost always been mild and transient. Serious adverse events, such as intense panic, suicidal ideation, and psychosis, were reported in either none or very few of the participants. However, patient selection criteria, optimal dosing strategy, and appropriate clinical follow-up guidelines remain to be established.

Preliminary data suggest that LSD may be effective for the management of alcohol use disorder, anxiety, and depression. In trials of LSD for treating anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrate durable relief at 1 year post-treatment. Top-line data from a large-scale phase IIb trial (n = 198) indicate that 50% of participants experience remission from generalized anxiety disorder after a single 100 μg dose of LSD. According to a meta-analysis of RCTs on LSD from the mid-20th century, single-dose regimens of LSD significantly improve alcohol use disorder (P < 0.0003) with an odds ratio (OR) of 1.96.

Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. Further studies with large sample sizes are needed to explore potential clinical applications.

Preliminary data suggest that LSD may be one of the most potent treatments for anxiety in patients both with and without a life-threatening illness. LSD may also be beneficial for treating depression and substance use disorders.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.

The dichotomies of 'typical/atypical' or 'first/second generation' have been employed for several decades to classify antipsychotics, but justification for their use is not clear. In the current analysis we argue that this classification is flawed from both clinical and pharmacological perspectives. We then consider what approach should ideally be employed in both clinical and research settings.

Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype.

An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls.

EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients.

EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.

The term extrapyramidal disorders is most often used for conditions such as Parkinson's disease or Huntington's disease, but also refers to a group of extrapyramidal side effects of antipsychotics (EPS), such as tardive dyskinesia (TD). After a brief description of some clinical features of TD, this article summarizes the relatively scarce results of research on a possible link between mainly cytokine levels and TD. This data was found by systematically searching Pubmed and Embase. The limitations of these types of studies are a major obstacle to interpretation. After describing relevant aspects of the neuroinflammatory response and the neuroanatomical backgrounds of EPS, a new hypothesis for the origin of TD is presented with emphasis on dysfunctions in the striosomal compartment of the striatum and the dorsal diencephalic connection system (DDCS). It is postulated that (partly immunologically-induced) increase in oxidative stress and the dopamine-dependent immune response in classic TD proceed primarily via the DDCS, which itself is activated from evolutionarily older parts of the forebrain. Neuroinflammatory responses in the choroid plexus of the third ventricle may contribute due to its proximity to the habenula. It is concluded that direct evidence for a possible role of inflammatory processes in the mechanism of TD is still lacking because research on this is still too much of a niche, but there are indications that warrant further investigation.

Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation.

To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS).

Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap.

By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes.

National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

Multiple studies report racial disparities in antipsychotic prescription patterns. This study assessed demographic and clinical factors associated with the utilization of first-generation (FG) versus second-generation (SG) long-acting injectable (LAI) antipsychotics.

This retrospective, observational cohort analysis used claims data from the IBM MarketScan® Multi-State Medicaid database. The study included adults with an LAI claim between 01-January-2009 and 31-December-2018, an ICD-9-CM or ICD-10-CM diagnosis of schizophrenia, race recorded as Black or White, and ≥12 months of continuous enrollment before the index LAI. Descriptive analysis detailed the relationship between race and FG or SG LAI initiation. Multivariate logistic regression was used to assess potential associations with FG vs. SG LAI initiation, including clinical and demographic factors, comorbidities, and index year.

A total of 10,773 patients were included: 6659 (62 %) Black and 4114 (38 %) White. Black patients had a higher utilization of FG LAIs than White patients (46.8 % vs. 38.9 %) over the 10 years analyzed. Black patients were more likely to utilize FG LAIs than White patients (odds ratio: 1.47; 95 % CI: 1.34, 1.62) after controlling for index year and covariates (race, age, gender, insurance plan type, Quan-Charlson Comorbidity index score, comorbidities, prior medications). Significant predictors of FG LAI utilization were older age, type of baseline oral antipsychotic (FG vs SG), type of coverage (managed care vs fee for service), and greater comorbidity burden.

The utilization of FG LAIs was greater in Black compared to White Medicaid beneficiaries with schizophrenia over a 10-year period. These findings suggest that racial disparities exist in LAI initiation, with implications for differential quality of schizophrenia treatment.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Neuronal degeneration and apoptosis may play an important role in the pathogenesis of tardive dyskinesia (TD). Previous studies suggested brain structural and functional abnormalities in patients with TD. We investigated changes in cerebral regional homogeneity (ReHo) in patients with TD using resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were collected from schizophrenia patients with TD (TD group, n=58) and without TD (non-TD group, n=66) and healthy controls (HC group, n=67), processed with SPM, and evaluated at a corrected threshold. Psychopathology and severity of TD were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Results: TD vs. non-TD group showed significantly higher ReHo in the Left Inferior Semilunar Lobule and Right Fusiform Gyrus and lower ReHo in Left Supramarginal Gyrus, Right Inferior Tempotal Gyrus, and Left Medial Frontal Gyrus. The ReHo value in the Left Inferior Semilunar Lobule was negatively correlated with AIMS upper limbs scores. Conclusions: The findings suggest altered regional neural connectivities in association with TD and may inform research of the etiology and monitor the course of TD in patients with schizophrenia and potentially other psychotic disorders.

Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics.

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.

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.

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.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Lumateperone is a novel antipsychotic medication that has recently received approval by the United States Food and Drug Administration for treatment of major depressive episodes of type I and II bipolar disorder. It is approved for use as monotherapy or as an adjunctive treatment to lithium or valproic acid.

Clinical trials performed with lumateperone for bipolar disorder were reviewed. Additionally, pharmacodynamic actions of lumateperone are reviewed. Lumateperone is superior to placebo whether used alone or in combination with a mood stabilizer in patients with type I or type II bipolar disorder. It achieves this effect with minimal dopamine blockade-related side effects due to less than 50% dopamine D2 receptor occupancy. While the pharmacodynamic profile of lumateperone is unique, the mechanism of action in bipolar depression remains obscure.

Lumateperone is an antipsychotic with full antagonist effects at the post-synaptic D2, and partial agonist effects at the presynaptic D2. This unique profile allows for both antipsychotic and antidepressant effects at the same dose, which does not produce dopamine-related side effects. Consequently, lumateperone is exceptionally well tolerated compared to other antidepressant-acting antipsychotic agents. It is now the only agent approved as an adjunct to the mood stabilizer for bipolar II depression.

Since being recognized as an important drug-induced clinical entity during the 1960s, tardive dyskinesia (TD) has generated an extensive body of research seeking to understand its clinical characteristics, epidemiology, pathophysiology and management. Modern scientometric approaches allow interactive visualization of large bodies of literature to identify trends and hotspots within knowledge domains. This study thus aimed to provide a comprehensive scientometric review of the TD literature.

Web of Science was searched for articles, reviews, editorials and letters with the term "tardive dyskinesia" in the title, abstract, or keywords through 12/31/2021. A total of 5,228 publications and 182,052 citations were included. Annual research output, prominent research areas, authors, affiliations and countries were summarized. VOSViewer and CiteSpace were used for bibliometric mapping and co-citation analysis. Structural and temporal metrics were used to identify key publications in the network.

TD-related publications peaked in the 1990s, gradually declined after 2004, and showed a further small increase after 2015. The most prolific authors were Kane JM, Lieberman JA, and Jeste DV overall (1968-2021), and Zhang XY, Correll CU and Remington G in the last decade (2012-2021). The most prolific journal was the Journal of Clinical Psychiatry overall, and the Journal of Psychopharmacology in the last decade. Knowledge clusters in the 1960-1970s dealt with clinical and pharmacological characterization of TD. In the 1980s, epidemiology, clinical TD assessment, cognitive dysfunction and animal models predominated. During the 1990s, research diverged into pathophysiological studies, especially oxidative stress, and clinical trials on atypical antipsychotics, with a focus on clozapine and bipolar disorder. In the 1990-2000s, pharmacogenetics emerged. More recent clusters include serotonergic receptors, dopamine-supersensitivity psychosis, primary motor abnormalities of schizophrenia, epidemiology/meta-analyses, and advances in TD treatment, particularly vesicular monoamine transporter-2 inhibitors since 2017.

This scientometric review visualized the evolution of scientific knowledge on TD over more than five decades. These findings will be useful for researchers to find relevant literature when writing scientific articles, choosing appropriate journals, finding collaborators or mentors for research, and to understand the historical developments and emerging trends in TD research.