Browsing by Subject "Antipsychotic agents"

Now showing 1 - 5 of 5
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    Advances in Alzheimer therapy: understanding pharmacological approaches to the disease
    (Bentham Science Publishers, 2009-04) Martinez, Ana; Lahiri, Debomoy K.; Giacobini, Ezio; Greig, Nigel H.; Department of Psychiatry, IU School of Medicine
    Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy".
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    Application of machine learning to predict reduction in total PANSS score and enrich enrollment in schizophrenia clinical trials
    (Wiley, 2021-09) Podichetty, Jagdeep T.; Silvola, Rebecca M.; Rodriguez-Romero, Violeta; Bergstrom, Richard F.; Vakilynejad, Majid; Bies, Robert R.; Stratford, Robert E., Jr.; Medicine, School of Medicine
    Clinical trial efficiency, defined as facilitating patient enrollment, and reducing the time to reach safety and efficacy decision points, is a critical driving factor for making improvements in therapeutic development. The present work evaluated a machine learning (ML) approach to improve phase II or proof-of-concept trials designed to address unmet medical needs in treating schizophrenia. Diagnostic data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial were used to develop a binary classification ML model predicting individual patient response as either "improvement," defined as greater than 20% reduction in total Positive and Negative Syndrome Scale (PANSS) score, or "no improvement," defined as an inadequate treatment response (<20% reduction in total PANSS). A random forest algorithm performed best relative to other tree-based approaches in model ability to classify patients after 6 months of treatment. Although model ability to identify true positives, a measure of model sensitivity, was poor (<0.2), its specificity, true negative rate, was high (0.948). A second model, adapted from the first, was subsequently applied as a proof-of-concept for the ML approach to supplement trial enrollment by identifying patients not expected to improve based on their baseline diagnostic scores. In three virtual trials applying this screening approach, the percentage of patients predicted to improve ranged from 46% to 48%, consistently approximately double the CATIE response rate of 22%. These results show the promising application of ML to improve clinical trial efficiency and, as such, ML models merit further consideration and development.
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    Incidence of Corrected QT Prolongation With Concomitant Methadone and Atypical Antipsychotics in Critically Ill Children
    (Allen Press, 2021) Hughes, Kaitlin M.; Thorndyke, Anne; Tillman, Emma M.; Pediatrics, School of Medicine
    Objective: To evaluate the safety of the combination of methadone and an atypical antipsychotic in PICU patients. Methods: This was a retrospective observational cohort pilot study in a single-center PICU in an academic children's hospital. Children 1 month to 18 years of age were included if they received methadone, were then initiated on an atypical antipsychotic (i.e., quetiapine or risperidone), and had EKG monitoring before and after medication initiation. Results: Prolongation of the corrected QT (QTc) interval occurred in 5 of the 34 included patients when an atypical antipsychotic was added to methadone. Of the 5 patients who had a prolonged QTc interval, 4 (80%) were older than 12 years and had a median weight of 91.3 kg. There were statistical differences between age and weight when comparing patients who experienced QTc prolongation, but no differences in sex, ethnicity, electrolyte deficiencies, number of additional QTc-prolonging medications, and number of additional drug-drug interactions were identified. When comparing atypical antipsychotics, 9.5% of patients receiving risperidone had a prolonged QTc interval, versus 23% of patients receiving quetiapine (p = 0.04). The net change in QTc interval after initiation of methadone was 0.19 milliseconds (IQR: -3, 15), which increased after atypical antipsychotic initiation to 4 milliseconds (IQR: -16, 15). Conclusions: Our pilot trial suggests there is no clinically significant difference in incidence of QTc prolongation with addition of atypical antipsychotics to methadone.
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    Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder
    (American Medical Association, 2022) Katz, Ira R.; Rogers, Malcolm P.; Lew, Robert; Thwin, Soe Soe; Doros, Gheorghe; Ahearn, Eileen; Ostacher, Michael J.; DeLisi, Lynn E.; Smith, Eric G.; Ringer, Robert J.; Ferguson, Ryan; Hoffman, Brian; Kaufman, James S.; Paik, Julie M.; Conrad, Chester H.; Holmberg, Erika F.; Boney, Tamara Y.; Huang, Grant D.; Liang, Matthew H.; Li+ plus Investigators; Psychiatry, School of Medicine
    Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main outcomes and measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities.
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    Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia
    (Massachusetts Medical Society, 2021-02-25) Brannan, Stephen K.; Sawchak, Sharon; Miller, Andrew C.; Lieberman, Jeffrey A.; Paul, Steven M.; Breier, Alan; Psychiatry, School of Medicine
    Background: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. Methods: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia.