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To enable greater use of National Institute of Mental Health Research Domain Criteria (RDoC) in real-world settings, we applied large language models (LLMs) to estimate dimensional psychopathology from narrative clinical notes. We conducted a cohort study using health records from individuals age ≤18 years evaluated in the psychiatric emergency department of a large academic medical center between November 2008 and March 2015. Outcomes were hospital admission and length of emergency department stay. RDoC domains were estimated using a Health Insurance Portability and Accountability Act–compliant LLM (gpt-4-1106-preview) and compared with a previously validated token-based approach. The cohort included 3059 individuals (median age 16 years [interquartile range, 13–18]; 1580 [52%] female, 1479 [48%] male; 105 [3.4%] identified as Asian, 329 [11%] as Black, 288 [9.4%] as Hispanic, 474 [15%] as other race, and 1863 [61%] as White), of whom 1695 (55%) were admitted. Correlation between LLM-extracted RDoC scores and the token-based scores ranged from small to medium as assessed by Kendall's tau (0.14–0.22). In logistic regression models adjusting for sociodemographic and clinical features, admission likelihood was associated with greater scores on all domains, with the exception of the sensorimotor domain, which was inversely associated (p <.001 for all adjusted associations). Tests for bias suggested modest but statistically significant differences in positive valence scores by race (p <.05 for Asian, Black, and Hispanic individuals). An LLM extracted estimates of 6 RDoC domains in an explainable manner, which were associated with clinical outcomes. This approach can contribute to a new generation of prediction models or biological investigations based on dimensional psychopathology. [ABSTRACT FROM AUTHOR]

The author reflects on the launch of JAMA+ AI, which aims to centralize and enhance resources on artificial intelligence (AI) in healthcare for clinicians, researchers, and technologists. Topics include the platform's goals to facilitate understanding and collaboration on AI's role in healthcare, the need to address challenges like bias and health disparities in AI applications, and the importance of educating future clinicians on integrating AI into practice.

Background: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Objective: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Design: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Participants: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Main Measures: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Key Results: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.Conclusions: Millions of US adults continue to experience symptoms of post COVID-19 condition (PCC). More data on health service utilization patterns and barriers to care in this population are needed to understand how to care for people with PCC.To evaluate health service utilization and barriers to medical care among individuals with a history of PCC compared with other US adults.Data were analyzed from the 2022 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey of the US population.US adults.Health service utilization and the presence of financial and nonfinancial barriers to care in the preceding 12 months.There were 24,905 individuals included in the analysis, representing approximately 230 million US adults. The weighted prevalence of those with a history of PCC was 6.9% (95%CI, 6.5–7.3). Compared to other US adults, participants with a history of PCC were more likely to have had an urgent care visit (adjusted odds ratio (aOR) 1.52 [95%CI, 1.34–1.72]), emergency room visit (aOR 1.94 [95%CI 1.71–2.21]), hospitalization (aOR 1.48 [95%CI, 1.24–1.77]), rehabilitation services (aOR 1.35 [95%CI, 1.14–1.60]), home care (aOR 1.55 [95%CI, 1.66–2.26]), mental health counseling (aOR 1.39 [95%CI, 1.17–1.65]), and complementary and integrative medicine services (aOR 1.29 [95%CI, 1.13–1.49]). Furthermore, respondents with a history of PCC were more likely to report at least one financial barrier to care (aOR 1.71 [95%CI, 1.48–1.97]) and at least one nonfinancial barrier (aOR 1.77 [95%CI, 1.56–2.00]). A greater proportion of participants with a history of PCC reported a financial barrier and nonfinancial barrier than adults with most other chronic conditions captured by NHIS.Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population. [ABSTRACT FROM AUTHOR]

Introduction: The major stressors associated with the COVID‐19 pandemic provide an opportunity to understand the extent to which protective factors against depression may exhibit gender‐specificity. Method: This study examined responses from multiple waves of a 50 states non‐probability internet survey conducted between May 2020 and January 2021. Participants completed the PHQ‐9 as a measure of depression, as well as items characterizing social supports. We used logistic regression models with population reweighting to examine association between absence of even mild depressive symptoms and sociodemographic features and social supports, with interaction terms and stratification used to investigate sex‐specificity. Results: Among 73,917 survey respondents, 31,199 (42.2%) reported absence of mild or greater depression—11,011/23,682 males (46.5%) and 20,188/50,235 (40.2%) females. In a regression model, features associated with greater likelihood of depression‐resistance included at least weekly attendance of religious services (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16) and greater trust in others (OR: 1.04 for a 2‐unit increase, 95% CI: 1.02–1.06), along with level of social support measured as number of social ties available who could provide care (OR: 1.05, 95% CI: 1.02–1.07), talk to them (OR: 1.10, 95% CI: 1.07–1.12), and help with employment (OR: 1.06, 95% CI: 1.04–1.08). The first two features showed significant interaction with gender (p <.0001), with markedly greater protective effects among women. Conclusion: Aspects of social support are associated with diminished risk of major depressive symptoms, with greater effects of religious service attendance and trust in others observed among women than men. [ABSTRACT FROM AUTHOR]

Background: Cohort and cost-effectiveness studies suggest that measuring variation in genes that influence metabolism of common drugs could improve antidepressant treatment outcomes. Prior randomized trials have yielded inconsistent results.Method: Multicenter randomized double-blind (subject and rater), controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder. Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment in light of the test report. Primary outcome was change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17).Results: For the primary comparison of interest, change in SIGH-D-17, no significant difference was detected between AGT and TAU at Week 8 (p = .53). Rates of study completion also did not differ between the arms (AGT 92.7%, TAU 92.2% (χ2  = 0.03, df = 1, p = .86). Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with greater likelihood of remission.Conclusion: Pharmacogenomic testing using a panel of pharmacokinetic and pharmacodynamic variants was not associated with significant improvement in the primary efficacy outcome when providers were unconstrained by the assay results. Further investigation is needed to understand the discordance with cost-effectiveness results and among randomized trials. [ABSTRACT FROM AUTHOR]

Background: Low rates of medication adherence remain a major challenge across psychiatry. In part, this likely reflects patient concerns about safety and adverse effects, accurate or otherwise. We therefore sought to characterize online information about common psychiatric medications in terms of positive and negative sentiment.Methods: We applied a natural language processing tool to score the sentiment expressed in web search results for 51 psychotropic medications across 3 drug classes (antidepressants, antipsychotics, and mood stabilizers), as a means of seeing if articles referencing these medications were generally positive or generally negative in tone. We compared between medications of the same class, and across medication classes.Results: Across 12,733 web search results, significant within-class differences in positive (antidepressants: F(24,2682) = 2.97, p < 0.001; antipsychotics: F(16,4029) = 3.25, p < 0.001; mood stabilizers: F(8,2371) = 6.88, p < 0.001) and negative sentiment (antidepressants: F(24,6282) = 11.17, p < 0.001; antipsychotics: F(16, 4029)  = 12.13, p < 0.001; mood stabilizers: F(8, 2371) = 13.28, p < 0.001) were identified. Among these were significantly greater negative sentiment for the antidepressants sertraline, duloxetine, venlafaxine, and paroxetine, and for the antipsychotics, quetiapine and risperidone. Conversely, lithium preparations and valproate exhibited less negative sentiment than other mood stabilizing medications.Limitations: While these results provide a novel means of comparing medications, the present analyses cannot be linked to individual patient consumption of this information, or to its influence on their future clinical interactions.Conclusions: Overall, a subset of psychotropic medications were associated with significantly more negative sentiment. Characterizing these differences may allow clinicians to anticipate patient willingness to initiate or continue medications. [ABSTRACT FROM AUTHOR]

Background: Naturalistic and small randomized trials have suggested that pharmacogenetic testing may improve treatment outcomes in depression, but its cost-effectiveness is not known. There is growing enthusiasm for personalized medicine, relying on genetic variation as a contributor to heterogeneity of treatment effects. We sought to examine the relationship between a commercial pharmacogenetic test for psychotropic medications and 6-month cost of care and utilization in a large commercial health plan.Methods: We performed a propensity-score matched case-control analysis of longitudinal health claims data from a large US insurer. Individuals with a mood or anxiety disorder diagnosis (N = 817) who received genetic testing for pharmacokinetic and pharmacodynamic variation were matched to 2,745 individuals who did not receive such testing. Outcomes included number of outpatient visits, inpatient hospitalizations, emergency room visits, and prescriptions, as well as associated costs over 6 months.Results: On average, individuals who underwent testing experienced 40% fewer all-cause emergency room visits (mean difference 0.13 visits; P < 0.0001) and 58% fewer inpatient all-cause hospitalizations (mean difference 0.10 visits; P < 0.0001) than individuals in the control group. The two groups did not differ significantly in number of psychotropic medications prescribed or mood-disorder related hospitalizations. Overall 6-month costs were estimated to be $1,948 (SE 611) lower in the tested group.Conclusions: Pharmacogenetic testing represents a promising strategy to reduce costs and utilization among patients with mood and anxiety disorders. [ABSTRACT FROM AUTHOR]

The author reflects on a users' guide for physicians in reading articles about clinical machine learning. Other topics include the importance of a model's inputs and outputs in assessing the practical value of an algorithm, the importance of replication in the validation process, and the bias introduced in the use of complex machine learning systems pretrained for a certain application but refit to another task.

Background: The U.S. Physician Payments Sunshine Act mandates the reporting of payments or items of value received by physicians from drug, medical device, and biological agent manufacturers. The impact of these payments on physician prescribing has not been examined at large scale. Methods: We linked public Medicare Part D prescribing data and Sunshine Act data for 2013. Physician payments were examined descriptively within specialties, and then for association with prescribing costs and patterns using regression models. Models were adjusted for potential physician-level confounding features, including sex, geographic region, and practice size. Results: Among 725,169 individuals with Medicare prescribing data, 341,644 had documented payments in the OPP data (47.1%). Among all physicians receiving funds, mean payment was $1750 (SD $28336); median was $138 (IQR $48-$394). Across the 12 specialties examined, a dose-response relationship was observed in which greater payments were associated with greater prescribing costs per patient. In adjusted regression models, being in the top quintile of payment receipt was associated with incremental prescribing cost per patient ranging from $27 (general surgery) to $2931 (neurology). Similar associations were observed with proportion of branded prescriptions written. Conclusions: While distribution and amount of payments differed widely across medical specialties, for each of the 12 specialties examined the receipt of payments was associated with greater prescribing costs per patient, and greater proportion of branded medication prescribing. We cannot infer a causal relationship, but interventions aimed at those physicians receiving the most payments may present an opportunity to address prescribing costs in the US. [ABSTRACT FROM AUTHOR]

This study uses public data to examine the nature and extent of health data confidentiality breaches from 2010 through 2017 [ABSTRACT FROM AUTHOR]

Clinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression. A total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non–selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology–Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding. A total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was −4.2% (95% CI, −15.6 to 4.6) for the SD group and −9.7% (−19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively. Using the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants. [ABSTRACT FROM AUTHOR]

The advent of somatic cell reprogramming technologies—which enables the generation of patient-specific, induced pluripotent stem cell and other trans-differentiated human neuronal cell models—provides new means of gaining insight into the molecular mechanisms and neural substrates of psychiatric disorders. By allowing a more precise understanding of genotype-phenotype relationship in disease-relevant human cell types, the use of reprogramming technologies in tandem with emerging genome engineering approaches provides a previously “missing link” between basic research and translational efforts. In this review, we summarize advances in applying human pluripotent stem cell and reprogramming technologies to generate specific neural subtypes with a focus on the use of these in vitro systems for the discovery of small molecule-probes and novel therapeutics. Examples are given where human cell models of psychiatric disorders have begun to reveal new mechanistic insight into pathophysiology and simultaneously have provided the foundation for developing disease-relevant, phenotypic assays suitable for both functional genomic and chemical screens. A number of areas for future research are discussed, including the need to develop robust methodology for the reproducible, large-scale production of disease-relevant neural cell types in formats compatible with high-throughput screening modalities, including high-content imaging, multidimensional, signature-based screening, and in vitro network with multielectrode arrays. Limitations, including the challenges in recapitulating neurocircuits and non-cell autonomous phenotypes are discussed. Although these technologies are still in active development, we conclude that, as our understanding of how to efficiently generate and probe the plasticity of patient-specific stem models improves, their utility is likely to advance rapidly. [ABSTRACT FROM AUTHOR]

Objectives. Treatment-resistant depression is a common clinical occurrence among patients with major depressive disorder (MDD), but its neurobiology is poorly understood. We used data collected as part of routine clinical care to study white matter integrity of the brain's limbic system and its association to treatment response. Methods. Electronic medical records of multiple large New England hospitals were screened for patients with an MDD billing diagnosis, and natural language processing was subsequently applied to find those with concurrent diffusion-weighted images, but without any diagnosed brain pathology. Treatment outcome was determined by review of clinical charts. MDD patients ( n = 29 non-remitters, n = 26 partial-remitters, and n = 37 full-remitters), and healthy control subjects ( n = 58) were analyzed for fractional anisotropy (FA) of the fornix and cingulum bundle. Results. Failure to achieve remission was associated with lower FA among MDD patients, statistically significant for the medial body of the fornix. Moreover, global and regional-selective age-related FA decline was most pronounced in patients with treatment-refractory, non-remitted depression. Conclusions. These findings suggest that specific brain microstructural white matter abnormalities underlie persistent, treatment-resistant depression. They also demonstrate the feasibility of investigating white matter integrity in psychiatric populations using legacy data. [ABSTRACT FROM AUTHOR]

The article offers information on COVID-19 pandemic has dropped the curtain on clinical studies in psychiatry with unprecedented speed. Topics include the investigators has faced strong headwinds a move away from drug discovery by big pharma and a shift in federal funding toward more basic neuroscience at the cost of clinical trials, and the emphasis on dimensional features of illness that conflict with traditional the U.S. Food and Drug Administration indications.

Background: Early identification of depressed individuals at high risk for treatment resistance could be helpful in selecting optimal setting and intensity of care. At present, validated tools to facilitate this risk stratification are rarely used in psychiatric practice. Methods: Data were drawn from the first two treatment levels of a multicenter antidepressant effectiveness study in major depressive disorder, the STAR⁎D (Sequenced Treatment Alternatives to Relieve Depression) cohort. This cohort was divided into training, testing, and validation subsets. Only clinical or sociodemographic variables available by or readily amenable to self-report were considered. Multivariate models were developed to discriminate individuals reaching remission with a first or second pharmacological treatment trial from those not reaching remission despite two trials. Results: A logistic regression model achieved an area under the receiver operating characteristic curve exceeding .71 in training, testing, and validation cohorts and maintained good calibration across cohorts. Performance of three alternative models with machine learning approaches—a naïve Bayes classifier and a support vector machine, and a random forest model—was less consistent. Similar performance was observed between more and less severe depression, men and women, and primary versus specialty care sites. A web-based calculator was developed that implements this tool and provides graphical estimates of risk. Conclusion: Risk for treatment resistance among outpatients with major depressive disorder can be estimated with a simple model incorporating baseline sociodemographic and clinical features. Future studies should examine the performance of this model in other clinical populations and its utility in treatment selection or clinical trial design. [ABSTRACT FROM AUTHOR]

Abstract: For certain research questions related to long-term outcomes or to rare disorders, designing prospective studies is impractical or prohibitively expensive. Such studies could instead utilize clinical and magnetic resonance imaging data (MRI) collected as part of routine clinical care, stored in the electronic medical record (EMR). Using major depressive disorder (MDD) as a disease model, we examined the feasibility of studying brain morphology and associations with remission using clinical and MRI data exclusively drawn from the EMR. Advanced automated tools were used to select MDD patients and controls from the EMR who had brain MRI data, but no diagnosed brain pathology. MDD patients were further assessed for remission status by review of clinical charts. Twenty MDD patients (eight full-remitters, six partial-remitters, and six non-remitters), and 15 healthy control subjects met all study criteria for advanced morphometric analyses. Compared to controls, MDD patients had significantly smaller right rostral-anterior cingulate volume, and level of non-remission was associated with smaller left hippocampus and left rostral-middle frontal gyrus volume. The use of EMR data for psychiatric research may provide a timely and cost-effective approach with the potential to generate large study samples reflective of the real population with the illness studied. [Copyright &y& Elsevier]

Background It has been suggested that clinician-rated scales and self-report questionnaires may be interchangeable in the measurement of depression severity, but it has not been tested whether clinically significant information is lost when assessment is restricted to either clinician-rated or self-report instruments. The aim of this study is to test whether self-report provides information relevant to short-term treatment outcomes that is not captured by clinician-rating and vice versa. Methods In genome-based drugs for depression ( GENDEP), 811 patients with major depressive disorder treated with escitalopram or nortriptyline were assessed with the clinician-rated Montgomery- Åsberg Depression Rating Scale ( MADRS), Hamilton Rating Scale for Depression ( HRSD), and the self-report Beck Depression Inventory ( BDI). In sequenced treatment alternatives to relieve depression ( STAR* D), 4,041 patients treated with citalopram were assessed with the clinician-rated and self-report versions of the Quick Inventory of Depressive Symptomatology ( QIDS- C and QIDS- SR) in addition to HRSD. Results In GENDEP, baseline BDI significantly predicted outcome on MADRS/ HRSD after adjusting for baseline MADRS/ HRSD, explaining additional 3 to 4% of variation in the clinician-rated outcomes (both P < .001). Likewise, each clinician-rated scale significantly predicted outcome on BDI after adjusting for baseline BDI and explained additional 1% of variance in the self-reported outcome (both P < .001). The results were confirmed in STAR* D, where self-report and clinician-rated versions of the same instrument each uniquely contributed to the prediction of treatment outcome. Conclusions Complete assessment of depression should include both clinician-rated scales and self-reported measures. [ABSTRACT FROM AUTHOR]

Background: Suicide is one of the top ten leading causes of death in North America and represents a major public health burden, partcularly for people with Major Depressive disorder (MD). Many studies have suggested that suicidal behavior runs in families, however, identification of genomic loci that drive this efffect remain to be identified. Methodology/Principal Findings: Using subjects collected as part of STAR*D, we genotyped 189 subjects with MD with history of a suicide attempt and 1073 subjects with Major Depressive disorder that had never attempted suicide. Copy Number Variants (CNVs) were called in Birdsuite and analyzed in PLINK. We found a set of CNVs present in the suicide attempter group that were not present in in the non-attempter group including in SNTG2 and MACROD2 -- two brain expressed genes previously linked to psychopathology; however, these results failed to reach genome-wide signifigance. Conclusions: These data suggest potential CNVs to be investigated further in relation to suicide attempts in MD using large sample sizes. [ABSTRACT FROM AUTHOR]

Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients. [ABSTRACT FROM AUTHOR]

Objective: Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. Method: The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, genotyped: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. Results: The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. Conclusions: This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future largescale cross-disorder GWAS analyses. [ABSTRACT FROM AUTHOR]

Background: Recent studies have identified associations of polymorphisms in several target genes with antidepressant treatment response of serotonin reuptake inhibitors and a tricyclic antidepressant. We sought to replicate these associations in a study of a serotonin-norepinephrine reuptake inhibitor. Methods: In 250 outpatients with nonpsychotic major depressive disorder, response to treatment with once-daily duloxetine (60 mg/day) over 6 weeks was examined for associations with polymorphisms in eight candidate genes previously associated with antidepressant response using mixed-effect model repeated-measures analysis. Treatment response was quantified on the basis of changes from baseline using 17-item Hamilton Depression Rating Scale total scores. Results: Polymorphisms in PDE1A, PDE1C, PDE6A, PDE11A, ABCB1, GRIK4, SLC6A4, and OPRM1 genes showed no statistically significant associations (uncorrected, two-tailed p > .05) with duloxetine treatment response. Conclusions: Previously, described associations between polymorphisms in candidate genes and antidepressant treatment response were not replicated in this study. This result may suggest that previous associations are specific to serotonin reuptake inhibitors. [Copyright &y& Elsevier]

Objective: Presymptomatic individuals with the Huntingtin (HIT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established. Method: This was a case-control genetic association study of HTTCAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression. Results: CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats. Conclusions: In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTTCAG alleles. [ABSTRACT FROM AUTHOR]

Objective: Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. Methods: We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. Results: A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. Conclusion: While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder. [ABSTRACT FROM AUTHOR]

The potential of personalized medicine to transform the treatment of mood disorders has been widely touted in psychiatry, but has not been quantified. We estimated the costs and benefits of a putative pharmacogenetic test for antidepressant response in the treatment of major depressive disorder (MDD) from the societal perspective. Specifically, we performed cost-effectiveness analyses using state-transition probability models incorporating probabilities from the multicenter STAR*D effectiveness study of MDD. Costs and quality-adjusted life years (QALYs) were compared for sequential antidepressant trials, with or without guidance from a pharmacogenetic test for differential response to selective serotonin reuptake inhibitors (SSRIs). Likely SSRI responders received an SSRI, whereas likely nonresponders received the norepinephrine/dopamine reuptake inhibitor bupropion. For a 40-year old with MDD, applying the pharmacogenetic test and using the non-SSRI bupropion for those at higher risk for nonresponse cost $93 520 per additional QALY compared with treating all patients with an SSRI first and switching sequentially in the case of nonremission. Cost per QALY dropped below $50 000 for tests with remission rate ratios as low as 1.5, corresponding to odds ratios ∼1.8–2.0. Tests for differential antidepressant response could thus become cost effective under certain circumstances. These circumstances, particularly availability of alternative treatment strategies and test effect sizes, can be estimated and should be considered before these tests are broadly applied in clinical settings.Neuropsychopharmacology (2009) 34, 2227–2236; doi:10.1038/npp.2009.50; published online 3 June 2009 [ABSTRACT FROM AUTHOR]

Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case–control cohort derived from the STAR*D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n=1473) for whom DNA and adverse effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted p<0.05 for each). Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes.Neuropsychopharmacology (2009) 34, 1819–1828; doi:10.1038/npp.2009.4; published online 18 March 2009 [ABSTRACT FROM AUTHOR]

Objective: Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms. Methods: We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry. Results: Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups. Conclusion: Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation. [ABSTRACT FROM AUTHOR]

Background: The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). Methods: We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). Results: After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experimentwide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was −10.8 (1.2), −8.7 (.6), and −6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. Conclusions: Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance. [Copyright &y& Elsevier]

Objective: Little is known about how of- ten bipolar depressive episodes are accompanied by subsyndromal manic symptoms in bipolar I and II disorders. The authors sought to determine the frequency and clinical correlates of manic symptoms during episodes of bipolar depression. Method: From among 4,1 07 enrollees in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 1,380 individuals met criteria for bipolar I or II depressive syndromes at the time of enrollment and were assessed for concomitant manic symptoms. Illness characteristics were compared in patients with pure bipolar depressed episodes and those with mixed depressive presentations. Results: Two-thirds of the subjects with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation. Patients with any mixed features were significantly more likely than those with pure bipolar depressed episodes to have early age at illness onset, rapid cycling in the past year, bipolar I subtype, history of suicide attempts, and more days in the preceding year with irritability or mood elevation. ConcIusions: Manic symptoms often accompany bipolar depressive episodes but may easily be overlooked when they appear less prominent than depressive features. Subsyndromal manic symptoms during bipolar I or II depression demarcate a more common, severe, and psychopathologically complex clinical state than pure bipolar depression and merit recognition as distinct nosologic entity. [ABSTRACT FROM AUTHOR]

Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16) score 5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.Neuropsychopharmacology (2008) 33, 2810–2819; doi:10.1038/npp.2008.6; published online 20 February 2008 [ABSTRACT FROM AUTHOR]

Objective: Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs. Method: The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by ≥2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up. Results: Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model. Conclusions: In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy. [ABSTRACT FROM AUTHOR]

Background: Anger and irritability are prominent in a subset of individuals with major depressive disorder (MDD). Phosphorylation of the transcription factor cyclic adenosine monophosphate (cAMP) Response Element Binding Protein (CREB) has been associated with aggression or reward/aversion in rodents, and markers near CREB1 have been linked to MDD. Therefore, we examined the association between CREB1 polymorphisms and anger expression in MDD. Methods: A clinical sample of 94 Caucasian outpatients with MDD (42 male, 52 female) completed the Spielberger State-Trait Anger Expression Inventory. We examined six tagging single nucleotide polymorphisms (SNPs) spanning CREB1 and flanking regions for association with a summary measure of frequency and intensity of anger expression. We also introduced a novel statistical method to dissect the independent effect of individual SNPs and haplotypes. Results: For the sample as a whole, one of six SNPs tested was significantly associated with anger expression (empirical p = .003). Among the male subsample, this association was particularly marked (empirical p = 8 × 10−5). A global haplotype test of the six SNPs was likewise significant (p = 3.7 × 10−6). No single SNP or haplotype accounted for all of the association observed. Conclusion: These preliminary results suggest a strong, gender-specific association between variation at the CREB1 locus and anger expression in MDD. [Copyright &y& Elsevier]

Although the field of pharmacogenetics has existed for nearly 50 years, it has begun to enter mainstream clinical practice only recently. Researchers and clinicians have now demonstrated that a wide assortment of genetic variants influence how individuals respond to medications. Many of these variants are relevant for psychiatry, affecting how patients respond to most antidepressants, antipsychotics, anxiolytics, and mood stabilizers. Enthusiasts hope that pharmacogenetics will soon usher in a new era of individualized medicine. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication, and in part because a host of nongenetic factors (including age, diet, environmental exposures, and comorbid diseases) also influence how individuals respond to medications. Since individualized pharmacogenetic assessment remains difficult, some researchers have argued that race provides a convenient proxy for individual genetic variation, and that clinicians should choose medications and doses differently for different races. This approach remains extremely controversial because of the complexity of the genetic structure of the human population, the complexity of gene-environment interactions, and the complexity of the meanings of race in the United States. [ABSTRACT FROM AUTHOR]

Objective: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. Method: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP- BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. Results: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416(48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. Conclusions: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence. [ABSTRACT FROM AUTHOR]

Objective: Failure to recognize bipolar disorder in patients who experience a major depressive episode may lead to inappropriate treatment and poorer outcomes. Clinical features that could distinguish bipolar from unipolar depression would facilitate more appropriate treatment selection. Method: The authors used data from nonpsychotic outpatients participating in three large multicenter clinical trials conducted in the United States for the treatment of major depressive episodes to compare 477 subjects with a diagnosis of bipolar disorder and 1,074 with major depressive disorder. Results: Bipolar depression was associated with family history of bipolar disorder, an earlier age at onset, a greater previous number of depressive episodes, and eight individual symptom items on the Montgomery-Åsberg Depression Rating Scale and the Hamilton Anxiety Rating Scale. Fears were more common in patients with bipolar disorder, whereas sadness; insomnia; intellectual (cognitive), somatic (muscular), respiratory, genitourinary com- plaints; and depressed behavior were more common in patients with unipolar depression. A logistic regression model correctly classified 86.9% of the subjects. Conclusions: Bipolar depression and major depressive disorder exhibit subtle differences in presentation, which may help guide the initial diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Financial conflict of interest has been reported to be prevalent in clinical trials in general medicine and associated with a greater likelihood of reporting results favorable to the intervention being studied. The extent and implications of industry sponsorship and financial conflict of interest in psychiatric clinical trials have not been investigated, to the authors' knowledge. Method: The authors examined funding source and author financial conflict of interest in all clinical trials published in the American Journal of Psychiatry, the Archives of Genera! Psychiatry, the Journal of Clinical Psychopharmacology, and the Journal of Clinical Psychiatry between 2001 and 2003. Results: Among 397 clinical trials identified, 239 (60%) reported receiving funding from a pharmaceutical company or other interested party, and 187 studies (47%) included at least one author with a reported financial conflict of interest. Among the 162 randomized, double-blind, placebo-controlled studies examined, those that reported conflict of interest were 4.9 times more likely to report positive results; this association was significant only among the subset of pharmaceutical industry-funded studies. Conclusions: Author conflict of interest appears to be prevalent among psychiatric clinical trials and to be associated with a greater likelihood of reporting a drug to be superior to placebo. [ABSTRACT FROM AUTHOR]

Background: We examined the hypothesis that a first depressive rather than manic episode in bipolar disorder might herald a subsequent course notable for greater burden of depressive symptoms. Methods: We analyzed retrospective data on the polarity of first mood episode obtained from 704 bipolar I subjects entering the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. Subjects with an initial manic or depressive episode and those in whom both poles occurred within the same year were compared. Results: Depressive-onset bipolar disorder was more common in women and those with earlier onset of illness. Adjusting for these differences, it was significantly associated with more lifetime depressive episodes and a greater proportion of time with depression and anxiety in the year prior to study entry. Conclusions: Polarity of first mood episode may be useful in distinguishing subsets of bipolar patients at risk for a more chronic course. [Copyright &y& Elsevier]

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25. [Copyright &y& Elsevier]

: BackgroundEarly onset of mood symptoms in bipolar disorder has been associated with poor outcome in many studies; however, the factors that might contribute to poor outcome have not been adequately investigated.: MethodsThe first consecutive 1000 adult bipolar patients enrolled in the National Institute of Mental Health''s Systematic Treatment Enhancement Program for Bipolar Disorder were assessed at study entry to determine details of their age of onset of mood symptoms. Clinical course, comorbidity, and functional status and quality of life were compared for groups with very early (age < 13 years), early (age 13–18 years), and adult (age > 18 years) onset of mood symptoms.: ResultsOf 983 subjects in whom age of onset could be determined, 272 (27.7%) experienced very early onset, and 370 (37.6%) experienced early onset. Earlier onset was associated with greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, greater likelihood of suicide attempts and violence, and greater likelihood of being in a mood episode at study entry.: ConclusionsVery early or early onset of bipolar disorder might herald a more severe disease course in terms of chronicity and comorbidity. Whether early intervention might modify this risk merits further investigation. [Copyright &y& Elsevier]

Background: Anger attacks, characterized by sudden episodes of intense anger with autonomic arousal, have been described in patients with major depressive disorder (MDD). This study compared the prevalence and clinical significance of anger attacks in unipolar versus bipolar depression. Methods: Using the questionnaire of Fava et al. [Psychopharmacol. Bull. 27(3) (1991) 275–279], we assessed rates of anger attacks among outpatients with MDD (n=50) or bipolar disorder (BPD) (n=29) who were currently in a pure depressive episode. Results: Anger attacks were significantly more common among bipolar (62%) than unipolar (26%) depressed individuals. In a multiple logistic regression, the presence of anger attacks emerged as a significant predictor of bipolarity. Limitations: This preliminary finding should be confirmed in a larger sample. Conclusions: These results suggest that anger attacks may be a common feature of bipolar depression. [Copyright &y& Elsevier]

: BackgroundThe short (S) allele of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been associated with poorer antidepressant response in major depressive disorder (MDD) and with antidepressant-induced mania. This study investigated a possible association with treatment-emergent insomnia or agitation.: MethodsThirty-six outpatients with MDD were genotyped at 5HTTLPR and treated with open-label fluoxetine up to 60 mg/day. Treatment-emergent adverse effects were assessed at each study visit.: ResultsOf nine subjects homozygous for the “S” allele, seven (78%) developed new or worsening insomnia, versus 6 of 27 (22%) non-“S”-homozygous subjects (Fisher’s exact p = .005). Similarly, six of nine subjects homozygous for the “S” allele (67%) developed agitation, versus 2 of 27 (7%) of non-“S”-homozygous subjects (Fisher’s exact p = .001).: ConclusionsThe “S” allele of the 5HTTLPR may identify patients at risk for developing insomnia or agitation with fluoxetine treatment. This preliminary result requires confirmation in larger samples. [Copyright &y& Elsevier]

Effective antidepressant pharmacotherapy began in the 1950s, with the introduction of tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). Unfortunately, these medications have properties that can limit their utility. TCA can produce a variety of side effects and they have a narrow therapeutic index with a high risk of death in overdose. MAOI require dietary restrictions and carry a risk of hyperadrenergic crisis. Moreover, the advent of selective serotonin reuptake inhibitors (SSRI) has significantly affected the treatment of depression. SSRI have become the first-line treatment for depression because they are effective, require minimal dose titration and have fewer side effects with less risk of death in overdose than the traditional agents. In addition, the sexual side effects of SSRI and the older antidepressants can reduce compliance and diminish patient's quality of life.

Investigates the academic psychopharmacology practice of treating selective serotonin-reuptake inhibitor-associated sexual dysfunction in the U.S. Interventions for decreased libido; Interventions for erectile dysfunction or anorgasmia; Magnitude of adverse effects.

Objective: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. Methods: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16–35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. Results: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90–3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54–1.55). Conclusions: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania. [ABSTRACT FROM AUTHOR]

Objective Maternal risk stratification systems are increasingly employed in predicting and preventing obstetric complications. These systems focus primarily on maternal morbidity, and few tools exist to stratify neonatal risk. We sought to determine if a maternal risk stratification score was associated with neonatal morbidity. Study Design Retrospective cohort study of patients with liveborn infants born at ≥24 weeks at four hospitals in one health system between January 1, 2020, and December 31, 2020. The Expanded Obstetric Comorbidity Score (EOCS) is used as the maternal risk score. The primary neonatal outcome was 5-minute Apgar <7. Logistic regression models determined associations between EOCS and neonatal morbidity. Secondary analyses were performed, including stratifying outcomes by gestational age and limiting analysis to "low-risk" term singletons. Model discrimination assessed using the area under the receiver operating characteristic curves (AUC) and calibration via calibration plots. Results A total of 14,497 maternal–neonatal pairs were included; 236 (1.6%) had 5-minute Apgar <7; EOCS was higher in 5-minute Apgar <7 group (median 41 vs. 11, p < 0.001). AUC for EOCS in predicting Apgar <7 was 0.72 (95% Confidence Interval (CI) 0.68, 0.75), demonstrating relatively good discrimination. Calibration plot revealed that those in the highest EOCS decile had higher risk of neonatal morbidity (7.6 vs. 1.7%, p < 0.001). When stratified by gestational age, discrimination weakened with advancing gestational age: AUC 0.70 for <28 weeks, 0.63 for 28 to 31 weeks, 0.64 for 32 to 36 weeks, and 0.61 for ≥37 weeks. When limited to term low-risk singletons, EOCS had lower discrimination for predicting neonatal morbidity and was not well calibrated. Conclusion A maternal morbidity risk stratification system does not perform well in most patients giving birth, at low risk for neonatal complications. The findings suggest that the association between EOCS and 5-minute Apgar <7 likely reflects a relationship with prematurity. This study cautions against intentional or unintentional extrapolation of maternal morbidity risk for neonatal risk, especially for term deliveries. Key Points EOCS had moderate discrimination for Apgar <7. Predictive performance declined when limited to low-risk term singletons. Relationship between EOCS and Apgar <7 was likely driven by prematurity. [ABSTRACT FROM AUTHOR]

Multiple lines of evidence implicate dysregulated microglia-mediated synaptic pruning in the pathophysiology of schizophrenia. In vitro human cellular studies represent a promising means of pursuing this hypothesis, complementing efforts with animal models and postmortem human data while addressing their limitations. The challenges in culturing homogeneous populations of cells derived from postmortem or surgical biopsy brain material from patients, and their limited availability, has led to a focus on differentiation of induced pluripotent stem cells. These methods too have limitations, in that they disrupt the epigenome and can demonstrate line-to-line variability due in part to extended time in culture, partial reprogramming, and/or residual epigenetic memory from the cell source, yielding large technical artifacts. Yet another strategy uses direct transdifferentiation of peripheral mononuclear blood cells, or umbilical cord blood cells, to microglia-like cells. Any of these approaches can be paired with patient-derived synaptosomes from differentiated neurons as a simpler alternative to co-culture. Patient-derived microglia models may facilitate identification of novel modulators of synaptic pruning and identification of biomarkers that may allow more targeted early interventions. [ABSTRACT FROM AUTHOR]

• Risk for treatment resistance in depression can be estimated at time of first antidepressant. • With a sensitivity of 80%, specificity for treatment resistance was 36% in a second health system. • Adding data from early in treatment did not improve prediction. • Even modest improvement in prediction may enable targeted treatments. With the emergence of evidence-based treatments for treatment-resistant depression, strategies to identify individuals at greater risk for treatment resistance early in the course of illness could have clinical utility. We sought to develop and validate a model to predict treatment resistance in major depressive disorder using coded clinical data from the electronic health record. We identified individuals from a large health system with a diagnosis of major depressive disorder receiving an index antidepressant prescription, and used a tree-based machine learning classifier to build a risk stratification model to identify those likely to experience treatment resistance. The resulting model was validated in a second health system. In the second health system, the extra trees model yielded an AUC of 0.652 (95% CI: 0.623–0.682); with sensitivity constrained at 0.80, specificity was 0.358 (95% CI: 0.300–0.413). Lift in the top quintile was 1.99 (95% CI: 1.76–2.22). Including additional data for the 4 weeks following treatment initiation did not meaningfully improve model performance. The extent to which these models generalize across additional health systems will require further investigation. Electronic health records facilitated stratification of risk for treatment-resistant depression and demonstrated generalizability to a second health system. Efforts to improve upon such models using additional measures, and to understand their performance in real-world clinical settings, are warranted. [ABSTRACT FROM AUTHOR]

The author discusses the effectiveness of ondansetron in treating alcohol-dependent patients by determining biomarkers. The author denotes a study concerning the applicability of biomarkers in assessing the efficacy of the said serotonin receptor antagonist to alcoholics. The author cites the drugs ability to exhibit genotype-specific effects on alcoholics. The proper administration of the mentioned drug is also mentioned.

The author reflects on an article published in the "New York Times" which presents public health population-level data indicating that many people are taking antidepressant. He is critical on the potential of the article to readers to make fallacious conclusion that psychiatric disease and the suffering it brings are a failing of character. He also outlines the lack of information on the extent to which treatment of depression can truly change lives for the better.