All studies are not created equal: A systematic narrative review of bipolar depression clinical trial inclusion/exclusion rules and baseline severity scores.

BACKGROUND: Several bipolar depression treatment guidelines have been designed to assist clinicians with medication selection. When ranking medications, none explicitly considered the inclusion/exclusion criteria or baseline severity scores of the reviewed clinical trials. This article aimed to determine if sufficient differences exist in these variables to justify their consideration when designing treatment guidelines. METHODS: Using Ovid and PubMed databases in May and September 2022, all published, short-term cross-over or parallel-group design studies comparing second generation antipsychotics (SGAs), mood stabilizers, or antidepressants versus placebo in bipolar depressed patients were identified. Included studies must have enrolled adult bipolar I/II depressed patients, randomized patients into two or more treatment groups, utilized a double-blind, prospective design written in English, and had primary outcome results that were statistically significant in favor of the investigational treatment. RESULTS: Thirty studies met eligibility criteria, comprising a total of 8791 patients. Among those studies, there were seventeen antipsychotic trials, six lithium trials, one lamotrigine trial, three valproate trials, two carbamazepine trials, and two antidepressant trials. The analysis revealed substantial differences among the studies. Although this was seen among all the different drug classes, these differences are clearest when comparing the lithium trials to those of the SGAs. LIMITATIONS: Limitations included the selection of severity scores from the treatment arm with the most severe score and the exclusive focus on mood stabilizers, antidepressants, and SGAs. CONCLUSIONS: Severity of the enrolled patient sample and treatment-resistance should be considered in addition to other factors when ranking medications in bipolar depression treatment guidelines.

A preliminary descriptive report of the longevity of the effects of Swedish Massage therapy for subjects with Generalized Anxiety Disorder.

OBJECTIVE: Generalized Anxiety Disorder (GAD) is a prevalent and costly disorder, and many patients may prefer non-traditional treatment. A proof-of-concept study demonstrated the efficacy of Swedish Massage Therapy (SMT) as a monotherapy for treatment of GAD. Subjects were followed-up 6-12 months after study completion to evaluate post-treatment outcome. METHODS: Subjects were enrolled into a randomized, single-masked clinical trial between March of 2012 and May of 2013. Forty-seven untreated subjects with DSM-IV diagnosis of GAD were randomly assigned to 6 weeks of twice-a-week light touch (LT) followed by 6 weeks of twice-a-week SMT, or 12 weeks of twice-a-week SMT. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HAM-A) scores after six weeks of SMT versus LT. Qualifying participants received a follow-up survey to investigate whether the benefits of SMT for GAD were sustained. RESULTS: 28 of 40 subjects completed at least 12 sessions of SMT and were sent the follow-up survey. Of the 19 subjects with follow-up, nine (47%) reported no return of GAD symptoms up to 1 year after study completion. There were no differences between those randomized to 12 weeks SMT and those receiving 6 weeks LT followed by 6 weeks SMT. Of those reporting a return of some symptoms, 50% associated symptom return with a stressful life event. INTERPRETATION: In this first monotherapy trial of SMT for the treatment of GAD, follow-up results suggest that the beneficial effects of SMT may last up to 1 year after end of treatment.

The United States index of socioeconomic deprivation for individuals (USiDep).

Background: Individuals experiencing socioeconomic deprivation consistently demonstrate poorer physical and mental health. Income alone is inadequate as a measure of socioeconomic status (SES); a better measure for assessing the deprivation status of individuals is needed. Methods: The New Zealand Index of Socioeconomic Deprivation for Individuals, a validated, eight-item measure of deprivation, was modified to create the United States Index of Socioeconomic Deprivation for Individuals (USiDep). The questionnaire was administered to patients with major depressive disorder participating in two clinical trials. Spearman's correlation coefficients evaluated associations between USiDep scores with income and other measures associated with deprivation. Results: The USiDep was completed by 118 participants, demonstrating adequate internal consistency (Crohnbach's alpha = 0.766) and strong item-total correlations. USiDep scores were moderately correlated with past-year personal income (Spearman's rho = -0.362, p < .001) and several other measures related to deprivation, including body mass index, level of education, quality of life, severity of childhood traumatic events, self-reported physical health, and negative life events. Patients scoring 5 on the USiDep (the highest possible score, indicating greater deprivation) had significantly lower rates of remission after 12 weeks of treatment than those scoring ≤ 4 (1/12, 8.3% vs 40/98, 40.8%, respectively, p = .03), whereas the lowest income group showed no significant associations with outcomes. Conclusion: The USiDep is a valid, brief questionnaire for assessing SES that has utility for clinical research and may serve as a predictor of treatment outcomes in clinical trials. Validation of the USiDep in healthy controls and other medically and psychiatrically ill populations is warranted.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Psychiatry Residency Directors' Attitudes Toward and Uses of the Medical Student Performance Evaluation and Other Potential Tools for Residency Selection.

OBJECTIVE: A survey was conducted to determine US psychiatry residency directors' attitudes regarding current measures of medical student performance and their preferences for the future. METHODS: A team of psychiatry medical student educators and residency program directors developed a 23-question survey. In July 2021, links to the survey were sent out to all program directors registered with the American Association of Directors of Psychiatric Residency Training. RESULTS: Seventy program directors out of 223 initiated the survey, resulting in a response rate of 31.4%. Forty percent of respondents reported that the most important use of the Medical Student Performance Evaluation (MSPE) is in screening out applicants for interviews, and only 26.1% reported that the MSPE in its current form could be trusted to provide a valid and reliable assessment of a student's medical school performance. Most respondents agreed that in the absence of United States Medical Licensing Examination (USMLE) step 1 numerical scores, the existing MSPE format/content requirements should be modified, use a set of ranking categories that are uniform across all medical schools, and be supplemented with additional measures of the student's character and ability specific to psychiatry. CONCLUSIONS: US psychiatry program directors are eager for change when it comes to the MSPE and how it reports rankings, grades, and professionalism. The transition of the USMLE step 1 score reporting to pass/fail presents an opportunity to pursue this change and for stakeholders from all medical specialties to work together toward a shared goal of an improved residency selection process.

Lithium in the treatment of acute bipolar depression: A systematic review and meta-analysis.

OBJECTIVES: To evaluate lithium in the treatment of acute bipolar depression. METHODS: We conducted a systematic literature review for: 1) cross-over or parallel-group design studies comparing lithium response in bipolar versus unipolar depressed patients, and 2) parallel group studies of bipolar depressed patients comparing lithium versus placebo or other psychotropics. Meta-analyses using response rate as the primary outcome were conducted to evaluate lithium's efficacy. RESULTS: The literature search yielded 947 records. Ultimately, 17 studies were included, totaling 1545 patients, including 676 who received lithium. The overall summary effects reveal that there were no statistically significant differences between lithium versus antidepressants or placebo, however, lithium performed numerically worse than antidepressants (RR = 0.61; 95%CI, 0.37-1.02; p = 0.06) but better than placebo (RR = 1.18; 95%CI, 0.99-1.41; p = 0.07). The specificity of lithium for bipolar versus unipolar depression was not supported in the primary analysis of all trials, though an analysis limited to double-blinded, monotherapy, cross-over studies revealed a statistically significant result supporting lithium's efficacy for those with bipolar depression. LIMITATIONS: Limitations include study selection rules, the use of response rates rather than remission rates or continuous score outcomes, and the small number of studies included in each meta-analysis. CONCLUSIONS: These meta-analyses do not support lithium as a first-line treatment for acute bipolar depression. However, the bipolar vs. unipolar sensitivity analysis and the modest, though non-significant advantage over placebo suggest lithium may still be a viable treatment option. Larger and more rigorously-designed studies are needed to determine lithium's full range of efficacy relative to placebo and other psychotropics.

Establishing Evidence for Clinical Utility of a Neuroimaging Biomarker in Major Depressive Disorder: Prospective Testing and Implementation Challenges.

BACKGROUND: Although a number of neuroimaging biomarkers for response have been proposed, none have been tested prospectively for direct effects on treatment outcomes. To the best of our knowledge, this is the first prospective test of the clinical utility of the use of an imaging biomarker to select treatment for patients with major depressive disorder. METHODS: Eligible participants (n = 60) had a primary diagnosis of major depressive disorder and were assigned to either escitalopram or cognitive behavioral therapy based on fluorodeoxyglucose positron emission tomography activity in the right anterior insula. The overall study remission rate after 12 weeks of treatment, based on the end point Hamilton Depression Rating Scale score, was then examined for futility and benefit of the strategy. RESULTS: Remission rates demonstrated lack of futility at the end of stage 1 (37%, 10/27), and the study proceeded to stage 2. After adjustment for the change in stage 2 sample size, the complete remission rate did not demonstrate evidence of benefit (37.7%, 95% confidence interval, 26.3%-51.4%, p = .38). However, total remission rates (complete and partial remission) did reach significance in post hoc analysis (49.1%, 95% confidence interval, 37.6%-60.7%, p = .020). CONCLUSIONS: The study shows some evidence for a role of the right anterior insula in the clinical choice of major depressive disorder monotherapy. The effect size, however, is insufficient for the use of insula activity as a sole predictive biomarker of remission. The study also demonstrates the logistical difficulties in establishing clinical utility of biomarkers.

Dry Those Crying Eyes: The Role of Depression and Antidepressants in Dry Eye Disease.

PURPOSE/BACKGROUND: Several clinic-based and large population studies have associated a depression diagnosis or depression severity with dry eye disease (DED) or symptoms. On the other hand, several other large population studies have found that antidepressant use was also associated with DED. Unfortunately, many of the studies finding associations between depression and DED did not control for concomitant antidepressant use, whereas the ones that found associations between antidepressant use and DED did not control for severity of depression or other psychiatric indications for selective serotonin inhibitor use. The purpose of this review was to identify whether depression and antidepressants play an independent role from one another in the onset of DED. METHODS/PROCEDURES: A systematic literature review was conducted searching for DED studies that adjusted for concomitant antidepressant use in depressed patients, that adjusted for depressive symptoms in patients taking antidepressants, and that enrolled depressed patients who were not taking psychiatric medications at the time of the study. Additionally, the prescribing information of marketed antidepressants was reviewed to determine rates of dry eyes reported during clinical trials. FINDINGS/RESULTS: The literature review initially identified 43 studies with 13 fitting the inclusion criteria. Although these studies varied in their quality, 7 revealed statistically significant associations between depression and DED, whereas 7, including 1 randomized trial, revealed significant associations between antidepressants and DED. Sixteen percent of the antidepressant package inserts inspected reported DED symptoms as an infrequent risk. IMPLICATIONS/CONCLUSIONS: This review suggests that independent of one another, both depression and antidepressant use are associated with DED.

Efficacy of Vortioxetine Monotherapy for Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

PURPOSE/BACKGROUND: There are few efficacious pharmacological treatments for posttraumatic stress disorder (PTSD) and many patients fail to benefit from existing treatments. Vortioxetine, a recently developed antidepressant, acts as a serotonin modulator through inhibition of the serotonin transporter and actions at multiple types of serotonin receptors. Its unique pharmacodynamic profile suggests it may have efficacy for the treatment of PTSD. METHODS/PROCEDURES: We conducted a 12-week placebo-controlled, randomized clinical trial of vortioxetine (flexibly dosed from 10 to 20 mg/d) versus placebo in adults with PTSD. The primary outcome was change from baseline in the past-month version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), analyzed using a mixed-model repeated-measures analysis of variance. FINDINGS/RESULTS: Forty-one patients were randomized, and 32 (78%) completed the 12 weeks of treatment. The mean reduction in CAPS-5 scores at week 12 did not significantly differ between the 2 arms; the effect size for the difference in changes between vortioxetine and placebo on CAPS-5 total scores at week 12 was Cohen d = 0.29. However, at week 8, the drug-placebo difference was d = 0.78, which met the multivariate criteria for statistical significance, P = 0.014. IMPLICATIONS/CONCLUSIONS: In this study of 41 patients, vortioxetine did not demonstrate superiority over placebo for adults with PTSD. Future PTSD trials may benefit from stratifying the randomization based on number of years since the index traumatic event and a history of failure to respond to treatment.

Six versus twelve weeks of Swedish massage therapy for generalized anxiety disorder: Preliminary findings.

Acute treatment of Generalized Anxiety Disorder often requires 3 months or more of care in order to optimize response. As part of an exploratory grant we have previously demonstrated that six weeks of twice-weekly Swedish Massage Therapy (SMT) was more effective than an active control in decreasing Hamilton Anxiety Rating Scale Scores (HAM-A). An additional goal of this project was to determine if an additional six weeks of twice-weekly SMT led to greater clinical and statistical benefit. We found that HAM-A scores did continue to decrease with an additional six weeks of therapy but that the greatest benefit occurred during the first versus the second 12 sessions (-9.91 vs.-3.09, t = 2.21; df = 10; p = 0.052). These preliminary findings suggest that the majority of benefit in symptom reduction occurs in the first six weeks and that six weeks of twice-weekly SMT may be sufficient for the majority of patients.

A Virtual Standardized Patient-Based Assessment Tool to Evaluate Psychiatric Residents' Psychopharmacology Proficiency.

OBJECTIVES: A virtual standardized patient-based assessment simulator was developed to address biases and practical limitations in existing methods for evaluating residents' proficiency in psychopharmacological knowledge and practice. METHODS: The simulator was designed to replicate an outpatient psychiatric clinic experience. The virtual patient reported symptoms of a treatment-resistant form of major depressive disorder (MDD), requiring the learner to use various antidepressants in order for the patient to fully remit. Test scores were based on the proportion of correct responses to questions asked by the virtual patient about possible side effects, dosing, and titration decisions, which depended upon the patient's tolerability and response to the learner's selected medications. The validation paradigm included a novice-expert performance comparison across 4th year medical students, psychiatric residents from all four post-graduate year classes, and psychiatry department faculty, and a correlational analysis of simulator performance with the PRITE Somatic Treatments subscale score. Post-test surveys evaluated the test takers' subjective impressions of the simulator. RESULTS: Forty-three subjects completed the online exam and survey. Total mean scores on the exam differed significantly across all the learner groups in a step-wise manner from students to faculty (F = 6.10, p = 0.0001). Total mean scores by residency class correlated with PRITE Somatic Therapies subscale scores (p < 0.01). The post-test survey mean Likert results ranged from 3.33 ± 1.20 to 4.4 ± 0.79, indicating neutral to favorable responses for use of the simulator. CONCLUSIONS: This simulator demonstrated strong construct validity and high participant acceptability for assessing proficiency in the psychopharmacologic treatment of MDD.

Millennials in Psychiatry: Exploring Career Choice Factors in Generation Y Psychiatry Interns.

OBJECTIVE: There is a national shortage of psychiatrists. To grow the workforce, educators must understand the factors that influence the choice of psychiatry as a specialty for medical students in the Generation Y cohort. METHODS: Psychiatry residents born between 1981 and 2000 were recruited from six psychiatry training programs across the USA and were interviewed in the fall of their first year. The interviews were coded and analyzed qualitatively for themes. Career Construction Theory (CCT) was applied to relate the themes within the four domains of Career Adaptability (a focus of CCT): concern, control, curiosity, and confidence. RESULTS: The majority of themes mapped onto the four domains. A fifth domain, "contribution," was created to capture additional themes. Themes associated with choosing psychiatry as a career included Practice Concerns and Economic/Lifestyle Concerns (concern), Changes in Stigma and Changes in Legitimacy (control), Exploring Humanity and Exposures to Psychiatry (curiosity), Abilities Called Upon by the Field, Recognized Qualities in the Participant, and Recognized Qualities in the Faculty/Residents (confidence), and Hoping to Make a Difference and Engaging in Research/Technology (contribution). CONCLUSIONS: With the knowledge generated from this study, educators now have a guide for the kinds of learning experiences that may attract Generation Y students to the field, and can identify those with the background, values, or personality traits most likely to find a career in psychiatry to be attractive.

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

Developing medical record-based, healthcare quality indicators for psychiatric hospitals in China: a modified Delphi-Analytic Hierarchy Process study.

OBJECTIVES: To develop a medical record-based, comprehensive system of healthcare quality indicators for psychiatric hospitals in China. DESIGN: A modified Delphi process with analytic hierarchy process (AHP) was used. PARTICIPANTS: Twenty nationally-recognized experts were invited to participate in two rounds of Delphi expert consultation and AHP. METHODS: Fifty potential indicators were included based on literature review, and 20 experts were asked to rate the importance of each indicator using two rounds of email surveys. The AHP was used to determine the relative importance of the finalized quality indicators. RESULTS: The average authoritative coefficient was 0.92 ± 0.07. After two rounds of Delphi consultation, 47 healthcare quality indicators were identified for Chinese psychiatric hospitals. The mean importance ratings ranged from 7.06 to 8.84 on a nine-point scale, with variation coefficients ranging from 0.04 to 0.22. The percentage of full score for potential indicators ranged from 16% to 74%. In two rounds, the Kendall's W coefficients ranged from 0.423 to 0.535. The weights of structure, process and outcome were 0.175, 0.211 and 0.614, respectively. CONCLUSION: We developed the first set of healthcare quality indicators for psychiatric hospitals in mainland China, and it will provide a standardized and meaningful guide to evaluate the healthcare quality of psychiatric hospitals across the country.

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Suicidal ideation and other persisting symptoms after CBT or antidepressant medication treatment for major depressive disorder.

BACKGROUND: Persisting symptoms after treatment for major depressive disorder (MDD) contribute to ongoing impairment and relapse risk. Whether cognitive behavior therapy (CBT) or antidepressant medications result in different profiles of residual symptoms after treatment is largely unknown. METHODS: Three hundred fifteen adults with MDD randomized to treatment with either CBT or antidepressant medication in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study were analyzed for the frequency of residual symptoms using the Montgomery Asberg Depression Rating Scale (MADRS) item scores at the end of the 12-week treatment period. Separate comparisons were made for treatment responders and non-responders. RESULTS: Among treatment completers (n = 250) who responded to CBT or antidepressant medication, there were no significant differences in the persistence of residual MADRS symptoms. However, non-responders treated with medication were significantly less likely to endorse suicidal ideation (SI) at week 12 compared with those treated with CBT (non-responders to medication: 0/54, 0%, non-responders to CBT: 8/30, 26.7%; p = .001). Among patients who terminated the trial early (n = 65), residual MADRS item scores did not significantly differ between the CBT- and medication-treated groups. CONCLUSIONS: Depressed adults who respond to CBT or antidepressant medication have similar residual symptom profiles. Antidepressant medications reduce SI, even among patients for whom the medication provides little overall benefit.