Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encoded in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.

XOB: A novel phenylalkylamine antagonist of 5-HT2A receptors and voltage-gated sodium channels.

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. Significance Statement We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels (VGSCs), in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Efficacy difference of antipsychotics in Alzheimer's disease and schizophrenia: explained with network efficiency and pathway analysis methods.

Approximately 50% of Alzheimer's disease (AD) patients will develop psychotic symptoms and these patients will experience severe rapid cognitive decline compared with those without psychosis (AD-P). Currently, no medication has been approved by the Food and Drug Administration for AD with psychosis (AD+P) specifically, although atypical antipsychotics are widely used in clinical practice. These drugs have demonstrated modest efficacy in managing psychosis in individuals with AD, with an increased frequency of adverse events, including excess mortality. We compared the differences between the genetic variations/genes associated with AD+P and schizophrenia from existing Genome-Wide Association Study and differentially expressed genes (DEGs). We also constructed disease-specific protein-protein interaction networks for AD+P and schizophrenia. Network efficiency was then calculated to characterize the topological structures of these two networks. The efficiency of antipsychotics in these two networks was calculated. A weight adjustment based on binding affinity to drug targets was later applied to refine our results, and 2013 and 2123 genes were identified as related to AD+P and schizophrenia, respectively, with only 115 genes shared. Antipsychotics showed a significantly lower efficiency in the AD+P network than in the schizophrenia network (P < 0.001) indicating that antipsychotics may have less impact in AD+P than in schizophrenia. AD+P may be caused by mechanisms distinct from those in schizophrenia which result in a decreased efficacy of antipsychotics in AD+P. In addition, the network analysis methods provided quantitative explanations of the lower efficacy of antipsychotics in AD+P.

Isolated central hypothyroidism: Underlying pathophysiology and relation to antidepressant and antipsychotic medications-A multi-centre South Wales study.

OBJECTIVE: Isolated biochemical central hypothyroidism is a presentation we are experiencing more frequently as endocrinologists, with variation in levels of investigation between physicians. We therefore conducted research to investigate the final diagnosis and clinical outcome of patients across multiple hospitals in South Wales with biochemical isolated central hypothyroidism; namely to establish whether this isolated biochemical picture was clinically significant. We also analysed whether there is an association between this biochemical picture and treatment with antidepressant and antipsychotic medications, and how common this is. DESIGN: We performed a retrospective observational study of patients across nine different hospitals in South Wales. We analysed patients referred to endocrinology at each site over a 6-year period with unexplained isolated biochemical central hypothyroidism. MATERIALS AND METHODOLOGY: 1022 individual patients' thyroid function test results were identified from our biochemical database using our inclusion criteria. After exclusion criteria were applied, 71 patients' results were analysed as to the final pathophysiology of their central hypothyroidism. RESULT: Of the 71 patients included in the study, none were found to have any clinically significant pathology on pituitary imaging. On reviewing their medications, 46/71 (65%) were found to be taking psychotropic medications. CONCLUSIONS: Our study strongly suggests isolated central hypothyroidism, in the absence of other pituitary hormone dysfunction or visual field defect, does not require further investigation, saving resources as well as sparing patients unnecessary anxiety. It also strongly supports a relationship between patients taking psychotropic medications and biochemical isolated central hypothyroidism, an association only described in a very limited amount of literature before this, and further supporting our previous single-centre study findings. The mechanism behind this is likely to be the suppression of thyrotropin secretion via antagonism of the dopamine-serotoninergic pathway. In our opinion, patients found to have isolated biochemical central hypothyroidism who are taking psychotropic medications can therefore be regarded to have a recognised cause for this biochemical finding and do not require further radiological investigation.

Outpatient Antipsychotic Use and Severe COVID-19: Avoiding the Impact of Age in a Real-World Data Study.

BACKGROUND: The association between use of antipsychotics and COVID-19 outcomes is inconsistent, which may be linked to use of these drugs in age-related diseases. Furthermore, there is little evidence regarding their effect in the nongeriatric population. We aim to assess the association between antipsychotic use and risk of disease progression and hospitalization due to COVID-19 among the general population, stratifying by age. METHODS: We conducted a population-based, multiple case-control study to assess risk of hospitalization, with cases being patients with a PCR(+) test who required hospitalization and controls being individuals without a PCR(+) test; and risk of progression to hospitalization, with cases being the same as those used in the hospitalization substudy and controls being nonhospitalized PCR(+) patients. We calculated adjusted odds-ratios (aOR) and 95% confidence intervals (CI), both overall and stratified by age. RESULTS: Antipsychotic treatment in patients younger than 65 years was not associated with a higher risk of hospitalization due to COVID-19 (aOR 0.94 [95%CI = 0.69-1.27]) and disease progression among PCR(+) patients (aOR 0.96 [95%CI = 0.70-1.33]). For patients aged 65 years or older, however, there was a significant, increased risk of hospitalization (aOR 1.58 [95% CI = 1.38-1.80]) and disease progression (aOR 1.31 [95% CI = 1.12-1.55]). CONCLUSIONS: The results of our large-scale real-world data study suggest that antipsychotic use is not associated with a greater risk of hospitalization due to COVID-19 and progression to hospitalization among patients younger than 65 years. The effect found in the group aged 65 years or older might be associated with off-label use of antipsychotics.

The incidence risk of gynecological cancer by antipsychotic use: a meta-analysis of 50,402 patients.

BACKGROUND: Female gynecological cancers represent a serious public health problem, with 1,398,601 new diagnoses and 671,875 deaths per year worldwide. Antipsychotics are often used in psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. It is estimated that the prescription of these drugs is linked to 1,800 deaths a year in the United States, but their association with cancer remains controversial. METHODS: We searched PubMed, Scopus, and Web of Science databases for studies reporting the correlation in the incidence risk of gynecological cancer by antipsychotic use. We used DerSimonian and Laird random-effect models to compute logit transformed odds ratio (OR) for the primary binary endpoint with 95% confidence interval (CI). Heterogeneity was assessed through effect size width along with I-squared and Tau-squared statistics. Review Manager 5.4.1. was used for statistical analyses. A p-value of < 0.05 denoted statistically significant. RESULTS: 50,402 patients were included, of whom 778 (1,54%) took antipsychotic medication for at least 1 year. 1,086 (2,15%) with ovarian cancer and 49,316 (97,85%) with endometrial cancer. Antipsychotic use (OR 1.50; 1.06 to 2.13 95% CI; p-value 0.02), hypertension (OR 1.50; 95% CI 1.06 to 2.13; p-value < 0.01), nulliparity (OR 1.98; 95% CI 1.53 to 2.57; p-value < 0.01) and multiparity (OR 0.53; 95% CI 0.41 to 0.69; p-value < 0.01) showed significantly different distributions between groups of cancer and cancer-free patients. The primary endpoint of incidence risk of gynecological cancer by antipsychotic therapy showed a statistically significant difference (OR 1.67; 95% CI 1.02 to 2.73; p-value < 0.05) against the use of antipsychotic drugs. CONCLUSIONS: Our meta-analysis showed that the use of antipsychotic drugs increases the risk of gynecological cancers, particularly endometrial cancer. This result should be weighed against the potential effects of treatment for a balanced prescribing decision.

Measuring the impact of therapy on medication use: data-linkage study.

BACKGROUND: The psychological therapies service (PTS) in the Northern Health and Social Care Trust, in Northern Ireland, provides therapies to adults with moderate or severe mental health difficulties. Psychometric outcomes data are routinely collected to assess if a patient demonstrates significant improvement in their main presenting problem area following therapy. The wider impact of therapy is not fully measured in the outcomes database as this would be disproportionately burdensome for both patient and therapist. The present study, to our knowledge, is the first to use data linkage to link patient therapy outcomes data with prescriptions data. AIMS: To widen our understanding of patient medication use before and after therapy. METHOD: Using Health and Care Number as a unique identifier, the Psychological Therapies Service - Routine Outcome Measurement Database (n = 3625) and data from 72 500 controls were linked with data from the Enhanced Prescribing Database (EPD). The EPD data were sourced from the Honest Broker Service. RESULTS: Key findings from the study were: (a) the odds of PTS clients using antipsychotics in the year before therapy were 25 times greater compared with controls (odds ratio (OR) = 24.53, 95% CI 20.16-29.84); (b) in the 1st year post discharge, PTS clients who clinically improved post therapy discharge were more likely than 'non-engagers' and 'non-improvers' to come off antianxiety medication (OR = 0.61, 95%, CI 0.38-0.98); and (c) therapy did not have an impact on antidepressant use. CONCLUSIONS: The results highlight the need for discussion between therapy services, GPs and psychiatry about whether more engagement and collaboration is needed to plan phased reduction in medication.

Use of antipsychotic medication, benzodiazepines, and psychiatric hospitalization in cannabis-related versus cannabis-unrelated schizophrenia - a nationwide, register-based cohort study.

BACKGROUND: Evidence suggests that cannabis may be a causal factor for development of schizophrenia. We aimed to investigate whether use of antipsychotic medication, benzodiazepines, and psychiatric service use differs among patients with schizophrenia depending on whether psychosis was precipitated by a diagnosis of cannabis use disorder (CUD). METHODS: We utilized the nationwide Danish registries to identify all individuals with an incident diagnosis of schizophrenia from 1995 to 2016. We also collected information on whether first CUD diagnosis preceded schizophrenia and thus defined a group of potentially cannabis-related schizophrenia. We compared the cannabis-related schizophrenia group both with all non-cannabis-related patients with schizophrenia and with non-cannabis-related patients with schizophrenia that were propensity-score matched to cases using a range of potentially confounding variables. RESULTS: We included 35 714 people with incident schizophrenia, including 4116 (11.5%) that were cannabis-related. In the unmatched-comparison analyses, there were no clear differences over time in use of antipsychotics and benzodiazepines related to whether the diagnosis of schizophrenia was cannabis-related. After propensity-score matching, use of antipsychotics and benzodiazepines was significantly lower among cannabis-related cases of schizophrenia. In the unmatched comparison, the cannabis-related group had significantly more days admitted than the non-cannabis-related group. This was markedly attenuated after propensity-score matching. CONCLUSIONS: Our findings indicate the importance of considering cannabis-related cases of schizophrenia as a potentially distinct disorder in terms of prognosis. It is unclear, however, if these differences are due to different biological types of schizophrenia being compared or if they rather indicate behavioral differences such as reduced adherence and treatment-seeking.

Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors.

Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.

Differential Effects of Neonatal Ventral Hippocampus Lesion on Behavior and Corticolimbic Plasticity in Wistar-Kyoto and Spontaneously Hypertensive Rats.

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Modulatory effect of olanzapine on neuronal nitric oxide synthase (nNOS) expression in the rat striatum.

Nitric oxide (NO) has been thought to be a novel factor involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about potential crosstalk between neuronal NO signaling and neuroleptics action. The present work was, therefore, focused on gene expression of neuronal NO synthase (nNOS) in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain, and for both descriptive and quantitative analysis of nNOS protein distribution in selected brain structures. Long-term treatment with olanzapine is reflected in different changes in the number of enzyme-expressing cells in the rat brain. Olanzapine decreased the number of nNOS-expressing cells and possibly reduced NO synthesis in the rat striatum. Olanzapine can be taken into account as a potential inhibitor of NO synthesis in the rat striatum.

Emerging therapies for treatment of agitation, psychosis, or apathy in Alzheimer's disease.

INTRODUCTION: Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS. AREAS COVERED: This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD. EXPERT OPINION: Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis, while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.

Antipsychotics in the maintenance phase for psychotic depression.

OBJECTIVE: This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. METHODS: Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007-2016. The participants collected antidepressants with or without antipsychotics from a pharmacy within 14 days after discharge and were followed up for 2 years. The primary outcome was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. Cox regression was used to analyze the data, which were adjusted for sex, age, prior admissions, comorbidity, electroconvulsive therapy, and other pharmacological treatments. RESULTS: We identified 4391 patients, of which 2972 were in the antidepressant + antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. After 2 years, 42.3% and 36.6% of patients were readmitted or committed suicide in the combination therapy and monotherapy group, respectively. Monotherapy was significantly associated with a lower risk of reaching the outcome in the main analysis (hazard ratio = 0.86; 95% confidence interval: 0.77-0.95). The results went in the same direction in all sensitivity analyses. CONCLUSION: Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted.

Prescription patterns in unipolar depression: A nationwide Danish register-based study of 113,175 individuals followed for 10 years.

BACKGROUND: Evidence-based use of antidepressant medications is of major clinical importance. We aimed to uncover precription patterns in a large cohort of patients with unipolar depression. MATERIAL AND METHODS: Using Danish nationwide registers, we identified individuals with a first-time hospital diagnosis of unipolar depression between January 1st, 2001, and December 31st, 2016. Redemeed prescriptions of antidepressants from five years before to five years after diagnosis were retreived. Lithium and relevant antipsychotics were included. Data were analyzed with descriptive statistics including sunburst plots. Cox regressions were used to rank the risk of treatment failure according to antidepressant category and depression severity, as measured by hazard ratios of drug shift. RESULTS: The full study population consisted of 113,175 individuals. Selective Serotonin Reuptake Inhibitors was the predominantly prescribed first-line group, both before (55.4%) and after (47.7%) diagnosis and across depression severities. Changes of treatment strategy were frequent; 60.8%, 33.7%, and 17.1% reached a second, third, and fourth treatment trial after the hospital diagnosis, respectively. More than half of patients continued their pre-diagnosis antidepressant after diagnosis. The risk of change of treatment strategy was generally lower in mild-moderate depression and higher in severe depression, with tricyclic antidepressants carrying the highest risk in the former and the lowest risks in the latter. Overall, prescribing were often not in accordance with guidelines. CONCLUSION: These findings uncover a potential for improving the clinical care for patients with unipolar depression through optimization of the use of marketed antidepressants.

Who is at risk for weight gain after weight-gain associated treatment with antipsychotics, antidepressants, and mood stabilizers: A machine learning approach.

BACKGROUND: Weight gain is a common side effect in psychopharmacology; however, targeted therapeutic interventions and prevention strategies are currently absent in day-to-day clinical practice. To promote the development of such strategies, the identification of factors indicative of patients at risk is essential. METHODS: In this study, we developed a transdiagnostic model using and comparing decision tree classifiers, logistic regression, XGboost, and a support vector machine to predict weight gain of ≥5% of body weight during the first 4 weeks of treatment with psychotropic drugs associated with weight gain in 103 psychiatric inpatients. We included established variables from the literature as well as an extended set with additional clinical variables and questionnaires. RESULTS: Baseline BMI, premorbid BMI, and age are known risk factors and were confirmed by our models. Additionally, waist circumference has emerged as a new and significant risk factor. Eating behavior next to blood glucose were found as additional potential predictor that may underlie therapeutic interventions and could be used for preventive strategies in a cohort at risk for psychotropics induced weight gain (PIWG). CONCLUSION: Our models validate existing findings and further uncover previously unknown modifiable factors, such as eating behavior and blood glucose, which can be used as targets for preventive strategies. These findings underscore the imperative for continued research in this domain to establish effective preventive measures for individuals undergoing psychotropic drug treatments.

Effect of severity of depression on augmentation of antidepressant medication in young adults with depression.

BACKGROUND: Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment-resistant depression. In this study we examined factors (including severity of depression and initial antidepressant) affecting AP augmentation, as well as which APs were initiated as augmentation in young adults. METHODS: Data were extracted from Finnish nationwide registers. Of persons aged 18-29 years diagnosed with a depression during 2004-2017 we focused on incident AD users (who initiated AD 6 months before and after the diagnosis) whose severity level of depression was recorded (N = 21,966). AP augmentation was studied during 1 year after diagnosis of depression. Persons diagnosed with severe depression with psychotic features (n = 1486) were excluded from main analyses and analyzed separately. RESULTS: Overall, 8.4% of new antidepressant users initiated AP augmentation. Risk of augmentation increased with severity of depression as 3.9%, 5.8%, and 14.0% of persons with mild, moderate, and severe depression, respectively, initiated augmentation. Male sex, comorbid anxiety and personality disorders, substance abuse and selfharm/suicide attempt were positively associated with augmentation. Compared to citalopram, use of tricyclic antidepressant, paroxetine and venlafaxine were associated with increased risk of augmentation, while use of bupropion was associated with a decreased risk. Quetiapine and risperidone were the most common APs used in augmentation. Among persons with severe depression with psychotic features, use of sertraline was associated with AP augmentation, whereas use of fluoxetine decreased risk of augmentation. CONCLUSIONS: Use of APs as augmentation of AD therapy was common in severe depression. Comorbidities had only a small effect to augmentation, but selection of initial AD was more closely associated to risk of augmentation. Interestingly, use of bupropion decreased risk of augmentation, which warrants further studies, as well as the decrease in risk of augmentation when fluoxetine in case of psychotic depression was used.