Journal of Clinical Psychiatry最新文献

Objective: The primary aim of this study was to examine the association between the different predicted phenotypes of the polymorphic CYP2D6 gene and the prevalence of adverse drug reactions in patients suffering from depressive disorders. The secondary aim was to investigate if comedication with CYP2D6 inhibitors resulted in more adverse drug reactions due to phenoconversion.

Methods: Between January 2012 and December 2021, 415 patients with a depressive disorder and insufficient treatment response in secondary psychiatric care were included in the naturalistic observational study Genes, Depression, and Suicidality (GEN-DS). The patients were subjected to a semistructured interview and diagnosed according to DSM-IV. Patients were also required to complete the self-rating version of the UKU Side Effect Rating Scale. All patients were genotyped for CYP2D6 and assigned a corresponding predicted CYP2D6 phenotype.

Results: Out of the 415 patients, 147 patients with available genotyping and UKU scale results were also prescribed 1 or more drugs metabolized by CYP2D6. We did not find any evidence of an effect of the predicted CYP2D6 phenotype on the total burden of adverse drug reactions or in any of the specific symptom domains as measured with the UKU scale among these patients. We also investigated if comedication with 1 or more substances that inhibited the effect of the CYP2D6 enzyme resulted in more reported adverse drug reactions due to phenoconversion. Even though the rate of phenotypic PMs increased from 13 to 38 patients, we did not find any support for increased adverse drug reactions in this group.

Conclusions: We did not find that CYP2D6 phenotype could predict the occurrence of adverse drug reactions in patients with depressive disorders in this naturalistic setting. However, information about CYP2D6 genotype may still be important in antidepressant treatment for the selection of appropriate drugs, for dosing recommendations of certain medications, or when the patient is suffering from severe adverse reactions.

Objective: To determine if iloperidone, a second-generation antipsychotic, reduces symptoms of bipolar mania.

Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults with bipolar mania at 27 US and international sites between April 2021 and September 2022. Participants were randomized 1:1 to iloperidone (up to 24 mg/d given twice daily) or placebo for 4 weeks. The primary efficacy endpoint was change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score versus placebo. Secondary efficacy endpoints included change from baseline in the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales.

Results: Altogether, 414 participants were randomized and administered at least 1 dose of study medication (iloperidone, n = 206; placebo, n = 208). Overall, 139 (67.1%) iloperidone patients and 153 (72.9%) placebo patients completed the study. Iloperidone demonstrated significant improvement versus placebo at week 4 for the primary and secondary endpoints. Differences in the least-squares mean (95% CI; P value) of change from baseline for YMRS total scores were -4.0 (-5.70 to -2.25; adjusted P = .000008). The most encountered adverse events with iloperidone were tachycardia, dizziness, dry mouth, alanine aminotransferase increased, nasal congestion, increased weight, and somnolence. The incidence of akathisia and extrapyramidal symptom-related treatment-emergent adverse events was low.

Conclusions: Iloperidone is effective in treating patients with bipolar mania. The tolerability and safety profile of iloperidone in bipolar mania is consistent with previous clinical studies of patients with schizophrenia, and no new safety concerns were identified.

Trial Registration: ClinicalTrials.gov identifier: NCT04819776; EudraCT: 2020-000405-83.

Objective/Background: Intravenous (IV) ketamine is effective for reducing symptoms of major depressive disorder in short-term clinical trials; this study characterized clinical outcomes of repeated infusions in routine clinical practice and the frequency and number of infusions used to sustain symptom improvement.

Methods: Records of IV ketamine infusions for depression and associated Patient Health Questionnaire-9 (PHQ-9) scores were identified from Veterans Health Administration (VA) electronic medical records for patients treated in Fiscal Year 2020 and up to 12 months following the date of their first infusion.

Results: Sample patients (n = 215) had a mean baseline PHQ-9 score of 18.6 and a mean of 2.1 antidepressant medication trials in the past year and 6.1 antidepressant trials in the 20 years prior to their first ketamine infusion. Frequency of infusions decreased from every 5 days to every 3-4 weeks over the first 5 months of infusions, with a mean of 18 total infusions over 12 months. After 6 weeks of treatment, 26% had a 50% improvement in PHQ-9 score (response) and 15% had PHQ-9 score ≤ 5 (remission). These improvements were similar at 12 and 26 weeks. No demographic characteristics or comorbid diagnoses were associated with 6-week PHQ-9 scores.

Conclusions: While only a minority of patients treated with IV ketamine for depression experienced response or remission, symptom improvements achieved within the first 6 weeks were sustained over at least 6 months with decreasing infusion frequency. Further study is needed to determine optimal infusion frequency and potential for adverse effects with repeated ketamine infusions for depression.

Objective: This study aims to identify how mental illness severity interacts with oral anticoagulant (OAC) patterns among people with atrial fibrillation (AF).

Methods: AF patients with comorbid mental illness (classified using ICD-10) were identified from the South London and Maudsley Biomedical Research Centre Case Register. CHA₂DS₂-VASc and ORBIT scales were used to calculate stroke and bleeding risks, respectively, whereas Health of the Nation Outcome Scales (HoNOS) assessment was used for functional impairment.

Results: Overall, 2,105 AF patients were identified between 2011 and 2019. Serious mental illness (SMI) was associated with lower prescription of any OAC (adjusted risk ratio [aRR]: 0.94; 95% CI, 0.90-0.99). A total of 62% of SMI patients at risk of stroke were not prescribed an OAC. In the AF cohort, alcohol or substance dependence and activities of daily living (ADL) impairment were associated with lower prescription of warfarin (aRR: 0.92; 95% CI, 0.86-0.98 and aRR: 0.96; 95% CI, 0.93-0.99, respectively). Among people with AF and SMI, warfarin was less likely to be prescribed to people with self-injury (aRR: 0.84; 95% CI, 0.77-0.91), hallucinations or delusions (aRR: 0.92; 95% CI, 0.85-0.99), ADL impairment (aRR: 0.91; 95% CI, 0.84-0.99), or alcohol or substance dependence (aRR: 0.92; 95% CI, 0.87-0.98). Among people with AF and comorbid substance use disorder, self-injury (aRR: 0.78; 95% CI, 0.64-0.96), cognitive problems (aRR: 0.84; 95% CI, 0.70-0.99), and other mental illnesses (aRR: 0.83; 95% CI, 0.70-0.99) were associated with lower prescription of warfarin.

Conclusions: An OAC treatment gap for AF patients with comorbid SMI relative to other mental illnesses was identified. The gap was wider in those with dependence comorbidities, positive symptoms, self-injury, or functional impairment.

J Clin Psychiatry 2024;85(1):23m14824.

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Objective: Studies suggest that people with major depressive disorder (MDD) often receive treatment that is not concordant with practice guidelines. To evaluate this, we (1) developed a guideline concordance algorithm for MDD pharmacotherapy (GCA-8), (2) scored it using clinical data, and (3) compared its explanation of patient-reported symptom severity to a traditional concordance measure.

Methods: This study evaluated 1,403 adults (67% female, 85% non-Hispanic/Latino White, mean age 43 years) with non-psychotic MDD (per ICD-10 codes), from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System (PCARES) registry (visits from February 1, 2015, to April 13, 2021). We (1) scored 1-year concordance using the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines and deviation from 8 pharmacotherapy-related criteria and (2) examined associations between concordance and Patient Health Questionnaire depression module (PHQ-9) scores.

Results: The mean GCA-8 score was 6.37 (standard deviation [SD] = 1.30; 8.00 = perfect concordance). Among those who switched drugs (n = 671), 81% (n = 542) did not have their dose increased to the recommended maximum before switching. In our adjusted analyses, we found that a 1 SD increase in the GCA-8 was associated with a 0.78 improvement in the mean PHQ-9 score (P < .001). The comparison concordance measure was not associated with the mean PHQ-9 score (β = -0.20; P = .20; R² = 0.53), and adding the GCA-8 score significantly improved the model (R² = 0.54; Vuong test P = .008).

Conclusions: By measuring naturalistic MDD pharmacotherapy guideline concordance with the GCA-8, we revealed potential treatment gaps and an inverse association between guideline concordance and MDD symptom severity.

Objective: To identify outcome predictors in hospitalized youth with mental disorders.

Methods: This retrospective analysis of systematically recorded clinical parameters in youth hospitalized for psychiatric treatment in 2004-2015 assessed magnitude and correlates of symptom response (SR), global illness response (GIR), social functioning (SF), out-of-home placement (OOHP), and length of stay (LOS). Backward elimination regression analyses were performed to identify independent baseline correlates of each of the 5 outcomes, with R² representing the variance explained by the independent correlates retained in the final model.

Results: Across 1,189 youth (median age = 14.4 years; interquartile range = 11.6,16.1 years; range, 5-19 years; females = 61.5%), frequencies of coprimary outcomes were as follows: SR = 57.5% (statistically significant correlates = 13, R² = 0.154), GIR = 30.0% (correlates = 5, R² = 0.078), SF = 19.0% (correlates = 8, R² = 0.207), OOHP recommendation = 35.2% (correlates = 13, R² = 0.275), and mean ± SD LOS = 65.0 ± 37.5 days (correlates = 11, R² = 0.219). In multivariable analyses, 11 factors were statistically significantly (P < .05) associated with > 1 poor outcome: 4 with 4 outcomes (disturbed social interaction, substance abuse/dependence symptoms; sole exception for both = LOS; disturbed drive/attention/impulse control, sole exception = OOHP; higher admission BMI percentile [but shorter LOS], sole exception = GIR), 3 with 3 outcomes (higher admission age [but good SF and shorter LOS], more abnormal psychosocial circumstances, more mental health diagnoses), and 4 with 2 outcomes (intelligence level [IQ] < 85, obsessive-compulsive disorder symptoms, disturbed social behavior, somatic findings). Additionally, 17 correlates were statistically significantly (P < .05) associated with 1 outcome, ie, SR = 6, OOHP = 5, LOS = 5, SF = 1.

Conclusions: Higher admission BMI percentile, disturbed social interaction, disturbed drive/attention/impulse control, and substance abuse/dependence symptoms were independently associated with multiple poor outcomes in mentally ill youth requiring inpatient care. Knowledge of global and specific correlates of poor inpatient treatment outcomes may help inform treatment decisions.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.

Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).

Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).

Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.

Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Objective: This study aimed to assess the effectiveness of metformin for antipsychotic-induced weight gain (AIWG) and determine whether the timing of metformin initiation and premorbid obesity moderated metformin effectiveness in children and adolescents on treatment with second-generation antipsychotics (SGAs).

Methods: A cohort of individuals 6 to 17 years of age, from 2016 to 2021, initiating a new SGA treatment and receiving a subsequent metformin prescription during SGA treatment were identified from the IQVIA Ambulatory EMR-US database. The changes in body mass index (BMI) z score before and after metformin initiation were assessed using the piecewise linear mixed-effects regression model.

Results: The results showed that the initiation of metformin was associated with a flattening out of the prior-metformin BMI z score trend. Relative to those who did not use metformin, metformin users had an additional monthly decrease in BMI z score of -0.053 (P = .0008) during the 6-month period after metformin initiation. Specifically, users who were non-obese before the intervention experienced a greater reduction in the BMI z score slope compared to those who were mildly-to-moderately obese and severely obese (non-obese - mildly-to-moderately obese: -0.07631, P = .0001; non-obese - severely obese: -0.09613, P < .0001). A different effect was not observed between patients who initiated metformin within versus beyond 90 days of SGA initiation. Extending the observation period to 12 months yielded comparable findings.

Conclusions: Adjuvant metformin helps manage AIWG in children and adolescents by flattening the upward AIWG trend rather than reversing it. The effect was more prominent before the development of obesity, suggesting that the early introduction of metformin for AIWG management may be warranted.

Objective: To evaluate psychometrically and provide crosswalks between 3 self-report measures of depressive symptomatology in youth in psychiatric care settings. Ratings included the Patient Health Questionnaire for Adolescents (PHQ-A), a widely used 9-item self-report; the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR₁₆); and the 5-item Very Quick Inventory of Depressive Symptomatology-Self-Report (VQIDS-SR₅), a recent effort to create a bridge from the QIDS-SR₁₆ to clinical practice.

Methods: Data from the Texas Youth Depression and Suicide Research Network Registry (August 26, 2020-May 11, 2022) were included in this work. At first visit, 795 depressed or suicidal adolescent (12-20 years of age) psychiatric outpatients completed the PHQ-A, QIDS-SR₁₆, and VQIDS-SR₅. Classical test theory and item-response theory (IRT) analyses were conducted. Crosswalks among total scales were created. Sensitivity to change over 1-month follow-up was assessed for all 3 scales (n = 682).

Results: Cronbach alphas were 0.86 (PHQ-A), 0.80 (QIDS-SR₁₆), and 0.76 (VQIDS-SR₅). Item total correlations were 0.49-0.72, 0.29-0.64, and 0.43-0.61, respectively. All 3 scales were unidimensional and sensitive to change over a 1-month period. IRT analyses revealed satisfactory item performance. Modest but significant associations were found between baseline to 1-month changes in PHQ-A and VQIDS-SR₅ total scores (r = 0.50, P < .0001) and between PHQ-A and QIDS-SR₁₆ total scores (r = 0.56; P < .0001). Categorical thresholds of severity (ie, mild, moderate, severe, and very severe) were comparable between PHQ-A and QIDS-SR₁₆.

Conclusions: The PHQ-A, QIDS-SR₁₆, and VQIDS-SR₅ are unidimensional, psychometrically acceptable self-reports of depressive prevalence or severity in adolescents and young adults in this sample. Total scale scores on any measure can be converted reliably to those on any other.