-
Scientific Reports Jun 2024One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive...
One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.
Topics: Humans; Prefrontal Cortex; Male; Female; Psychotic Disorders; Adult; Magnetic Resonance Imaging; Cognition; Young Adult; Glutamic Acid; Antipsychotic Agents; Gyrus Cinguli
PubMed: 38839828
DOI: 10.1038/s41598-024-63474-1 -
The Mental Health Clinician Jun 2024Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal...
INTRODUCTION
Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated.
METHODS
A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient's cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring.
RESULTS
Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal.
DISCUSSION
Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.
PubMed: 38835819
DOI: 10.9740/mhc.2024.06.204 -
Therapeutic Advances in... 2024Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological...
BACKGROUND
Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological treatments to mitigate initial weight gain is limited. Metformin has been shown to be effective in reducing weight among people on antipsychotic medications who are already overweight, but the potential benefits of metformin co-commencement in mitigating antipsychotic-induced weight gain has not been systematically reviewed.
METHOD
We conducted a systematic review of PubMed, EMBASE, PsychInfo, CINAHL, the Cochrane database, and China National Knowledge Infrastructure from inception to 18 November 2023. We undertook a meta-analysis of concomitant commencement of metformin placebo for attenuation of weight gain and metabolic syndrome for people with schizophrenia commencing a new antipsychotic.
RESULTS
Fourteen studies from Australia, United States, Venezuela, and China with 1126 participants were included. We found that metformin was superior to placebo in terms of attenuating weight gain (-3.12 kg, 95% CI -4.22 to -2.01 kg). Metformin also significantly attenuated derangement of fasting glucose levels, total cholesterol, and total triglyceride levels. Sensitivity analysis on study quality, duration, and antipsychotic agent did not impact the results. Meta-analysis was also conducted on adverse drug reactions (ADR) reported in each study which showed no significant difference in ADR incidence between metformin and placebo groups. Subgroup analysis on antipsychotic-naïve participants and participants switching to new antipsychotic did not impact the results.
CONCLUSION
Metformin led to statistically significant and clinically meaningful attenuation of weight gain as well as attenuation of several other metabolic parameters when commenced concomitantly with antipsychotic medications. Co-commencement of metformin with antipsychotic medications, where tolerated, should be considered in the clinical setting with aim to improve long-term cardiometabolic outcomes for patients with long-term need of antipsychotic treatments.
PubMed: 38827016
DOI: 10.1177/20451253241255476 -
Cureus May 2024Hyperprolactinemia is an endocrinological disorder that might arise from various physiologic or pathologic conditions, as well as from pharmacologic sources. These...
Hyperprolactinemia is an endocrinological disorder that might arise from various physiologic or pathologic conditions, as well as from pharmacologic sources. These pharmacologic sources include antidepressants, antipsychotics, and dopamine receptor-blocking agents. Amitriptyline is classified as a tricyclic antidepressant. While it is FDA-approved primarily for the treatment of depression, amitriptyline also demonstrates efficacy in managing various other conditions, such as anxiety, post-traumatic stress disorder, insomnia, chronic and neuropathic pain, and migraine prevention. We present a case of a 10-year-old patient with a history of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and migraine headaches who was incidentally found to have elevated prolactin levels while taking amitriptyline for migraine prophylaxis. While risperidone, an antipsychotic that can be used for ASD management, is commonly known to induce hyperprolactinemia, the association between amitriptyline and elevated prolactin is less frequently described in the literature. This case underscores the necessity for healthcare providers across various specialties to be aware of amitriptyline-induced hyperprolactinemia.
PubMed: 38826982
DOI: 10.7759/cureus.59604 -
Scientific Reports May 2024Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by...
Association between voriconazole-induced visual hallucination and dopamine in an analysis of the food and drug administration (FDA) adverse event reporting system database.
Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.
Topics: Humans; Voriconazole; Hallucinations; United States; United States Food and Drug Administration; Male; Female; Aged; Middle Aged; Dopamine; Levodopa; Adult; Antifungal Agents; Adverse Drug Reaction Reporting Systems; Chlorpromazine; Risperidone; Dopamine Antagonists; Parkinson Disease; Young Adult; Adolescent; Databases, Factual
PubMed: 38822123
DOI: 10.1038/s41598-024-63504-y -
Nature Communications May 2024Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the...
Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.
Topics: Magnetic Resonance Imaging; Male; Animals; Prefrontal Cortex; Amygdala; Neural Pathways; Frontal Lobe; Limbic System; Brain Mapping; Rest; Macaca mulatta; Designer Drugs; Clozapine; Nerve Net
PubMed: 38821963
DOI: 10.1038/s41467-024-49140-0 -
Molecular Pharmacology May 2024Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical...
Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin (5-HT) 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-HT receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT receptors and blocks sodium current. The new compound, -(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, G-mediated, calcium flux at 5-HT receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT, 5-HT, and 5-HT 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. We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT 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.
PubMed: 38821630
DOI: 10.1124/molpharm.123.000837 -
The Primary Care Companion For CNS... May 2024
Topics: Humans; Antipsychotic Agents; Muscular Atrophy, Spinal; Spinal Curvatures; Male; Female
PubMed: 38815273
DOI: 10.4088/PCC.23br03678 -
Scientific Reports May 2024General practitioners (GPs) are often unaware of antipsychotic (AP)-induced cardiovascular risk (CVR) and therefore patients using atypical APs are not systematically...
General practitioners (GPs) are often unaware of antipsychotic (AP)-induced cardiovascular risk (CVR) and therefore patients using atypical APs are not systematically monitored. We evaluated the feasibility of a complex intervention designed to review the use of APs and advise on CVR-lowering strategies in a transmural collaboration. A mixed methods prospective cohort study in three general practices in the Netherlands was conducted in 2021. The intervention comprised three steps: a digital information meeting, a multidisciplinary meeting, and a shared decision-making visit to the GP. We assessed patient recruitment and retention rates, advice given and adopted, and CVR with QRISK3 score and mental state with MHI-5 at baseline and three months post-intervention. GPs invited 57 of 146 eligible patients (39%), of whom 28 (19%) participated. The intervention was completed by 23 (82%) and follow-up by 18 participants (64%). At the multidisciplinary meeting, 22 (78%) patients were advised to change AP use. Other advice concerned medication (other than APs), lifestyle, monitoring, and psychotherapy. At 3-months post-intervention, 41% (28/68) of this advice was adopted. Our findings suggest that this complex intervention is feasible for evaluating health improvement in patients using AP in a trial.
Topics: Humans; Antipsychotic Agents; Feasibility Studies; Male; Female; Middle Aged; Cardiovascular Diseases; Netherlands; Prospective Studies; Adult; Aged
PubMed: 38811680
DOI: 10.1038/s41598-024-62349-9 -
Scientific Reports May 2024Dysfunction of subcortical D2-like dopamine receptors (DRs) can lead to positive symptoms of schizophrenia, and their analog, the increased locomotor activity in...
Dysfunction of subcortical D2-like dopamine receptors (DRs) can lead to positive symptoms of schizophrenia, and their analog, the increased locomotor activity in schizophrenia model MAM-E17 rats. The ventral pallidum (VP) is a limbic structure containing DRs. The DR antagonist sulpiride is a widespread antipsychotic drug, which can alleviate positive symptoms in human patients. However, it is still not known how sulpiride can influence positive symptoms via VP DRs. We hypothesize that the microinjection of sulpiride into the VP can normalize hyperactivity in MAM-E17 rats. In addition, recently, we showed that the microinjection of sulpirid into the VP induces place preference in neurotypical rats. Thus, we aimed to test whether intra-VP sulpiride can also have a rewarding effect in MAM-E17 rats. Therefore, open field-based conditioned place preference (CPP) test was applied in neurotypical (SAL-E17) and MAM-E17 schizophrenia model rats to test locomotor activity and the potential locomotor-reducing and rewarding effects of sulpiride. Sulpiride was microinjected bilaterally in three different doses into the VP, and the controls received only vehicle. The results of the present study demonstrated that the increased locomotor activity of the MAM-E17 rats was caused by habituation disturbance. Accordingly, larger doses of sulpiride in the VP reduce the positive symptom-analog habituation disturbance of the MAM-E17 animals. Furthermore, we showed that the largest dose of sulpiride administered into the VP induced CPP in the SAL-E17 animals but not in the MAM-E17 animals. These findings revealed that VP DRs play an important role in the formation of positive symptom-like habituation disturbances in MAM-E17 rats.
Topics: Animals; Sulpiride; Schizophrenia; Antipsychotic Agents; Rats; Basal Forebrain; Disease Models, Animal; Male; Microinjections; Habituation, Psychophysiologic; Locomotion; Receptors, Dopamine D2
PubMed: 38811614
DOI: 10.1038/s41598-024-63059-y