The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway.

There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham [n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72) = 11.73,p < .001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = -229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.

Yoga-Based Interventions in Low-Income Populations: A Scoping Review.

Introduction: The popularity of yoga has surged in recent years; however, yoga practitioners have remained a largely homogenous population. Research reflects that most practitioners are of a higher socioeconomic status. There are access barriers to yoga for lower income individuals, likely due to factors such as financial constraints and logistical challenges. The primary goal of this review was to synthesize literature on yoga research among low-income populations and better understand the feasibility and acceptability of such interventions. A secondary goal was to assess the consistency of metrics for reporting feasibility and acceptability across such studies using the CheckList Standardizing the Reporting of Interventions for Yoga (CLARIFY) guidelines as a framework. Third, the authors sought to propose additional standardized CLARIFY guidelines that may enhance reporting on the diversity of yoga research populations, adherence, and retention. Methods: The electronic databases PubMed, PsycINFO, Cochrane Central Register of Controlled Trials, and Google Scholar were searched in May 2022 using a prespecified search string. Articles assessing a yoga intervention in predominantly low-income adult populations were deemed eligible for inclusion. Results: The search resulted in 512 potential articles. Eleven were deemed eligible for inclusion. The included studies reported mostly positive effects of yoga on the target outcome (i.e., pain/disability, quality of life/wellness, and psychiatric symptoms). Recruitment and retention data showed generally good attendance and high study completion rates. Common study design components included recruitment embedded within preexisting medical settings, proximal yoga locations, and mitigation of yoga-related costs. Finally, the authors noted inconsistency in the reporting of adherence, retention, and other sociodemographic characteristics of participants and yoga instructors (e.g., race, ethnicity, and income). Discussion: Yoga may promote physical and mental health for low-income individuals. Important facilitators to access are noted, such as proximal study settings, as well as barriers such as the need for childcare that can be addressed in future research. In addition, several study design considerations could help address the specific needs of low-income participants in yoga research, such as compensating participants, recruiting within existing medical settings, and providing yoga-related equipment at no cost. Finally, the authors suggest specific ways to enhance reporting of study metrics related to socioeconomic diversity, by adding to the preexisting CLARIFY guidelines.

Elevated body temperature is associated with depressive symptoms: results from the TemPredict Study.

Correlations between altered body temperature and depression have been reported in small samples; greater confidence in these associations would provide a rationale for further examining potential mechanisms of depression related to body temperature regulation. We sought to test the hypotheses that greater depression symptom severity is associated with (1) higher body temperature, (2) smaller differences between body temperature when awake versus asleep, and (3) lower diurnal body temperature amplitude. Data collected included both self-reported body temperature (using standard thermometers), wearable sensor-assessed distal body temperature (using an off-the-shelf wearable sensor that collected minute-level physiological data), and self-reported depressive symptoms from > 20,000 participants over the course of ~ 7 months as part of the TemPredict Study. Higher self-reported and wearable sensor-assessed body temperatures when awake were associated with greater depression symptom severity. Lower diurnal body temperature amplitude, computed using wearable sensor-assessed distal body temperature data, tended to be associated with greater depression symptom severity, though this association did not achieve statistical significance. These findings, drawn from a large sample, replicate and expand upon prior data pointing to body temperature alterations as potentially relevant factors in depression etiology and may hold implications for development of novel approaches to the treatment of major depressive disorder.

A Brief Resilience-Enhancing Intervention and Loneliness in At-Risk Young Adults: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial assesses whether a behavioral intervention focused on resilience is associated with feelings of loneliness among young adults.

A Randomized Controlled Trial of Community-Delivered Heated Hatha Yoga for Moderate-to-Severe Depression.

Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression.Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019.Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8).Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d = 1.04, P < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews.Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions.Trial Registration: ClinicalTrials.gov identifier: NCT02607514.

The descriptive analysis of depressive symptoms and White Blood Cell (WBC) count between the sexual minorities and heterosexual identifying individuals in a nationally representative sample: 2005-2014.

BACKGROUND: Sexual minorities are at a higher risk of suffering from depressive symptoms compared with heterosexual individuals. Only a few studies have examined the conditions of having depressive symptoms within different sexual minority groups, especially people with sexual orientation uncertainty in a nationally representative sample. Furthermore, few studies have explored whether the mean white blood count (WBC) is different between people with and without depressive symptoms among different sexual minority groups in a nationally representative sample. METHODS: We analyzed the National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2014 with a sample of 14,090 subjects. We compared the prevalence of depressive symptoms in subpopulations stratified by sex, sexual minority status, and race. We also examined the difference in mean WBC count between depressed and non-depressed people among heterosexual individuals and different sexual minority groups. Additionally, two multivariable logistic regression models were used to explore the association between sexual minority status and depressive symptoms, treating sexual minority status as both a binary and categorical variable. RESULTS: Female sex (OR: 1.96, 95% CI: 1.72-2.22) and sexual minority status (OR: 1.79, 95% CI: 1.47-2.17) were both independently associated with depressive symptoms. Within the sexual minority population, subjects who were unsure about their sexual identities had the highest odds of having depressive symptoms (OR: 2.56, 95% CI: 1.40-4.68). In the subgroup analysis considering intersectionality, black sexual minority females had the highest rate of depressive symptoms (19.4%, 95% CI: 7.72-40.98). Finally, the mean WBC count differed significantly between people with and without depressive symptoms among male heterosexual individuals, female heterosexual individuals, and female sexual minorities, but not among male sexual minorities. CONCLUSIONS: Based on sex, race, and sexual minority status, black females of sexual minority status had the highest rate of depressive symptoms. Within sexual minority groups, participants who were unsure about their sexual identities had the highest odds of having depressive symptoms. Finally, the mean WBC count was significantly higher among people with depressive symptoms than those without depressive symptoms only among male heterosexuals, female heterosexuals, and female sexual minorities, but not among male sexual minorities. Future research should investigate the social and biological mechanisms of the differences.

Does the association between Herpes Simplex 2 infection and depressive symptoms vary among different sexual minority statuses and sex groups? Findings from a nationally representative sample.

BACKGROUND: Herpes Simplex Virus Type 2 (HSV-2) has been associated with depression, but the relationship has yet to be explored with respect to gender and sexual orientation in a nationally representative sample to help identify individuals at higher risk for depression. METHODS: A dataset from National Health and Nutrition Examination Survey 2009-2014 was used in this study. Multivariable logistic regression models were constructed to test effect modification on both the multiplicative and additive scale using a sample of 57,684 subjects. RESULTS: Effect modification by sexual minority status was not significant on either the multiplicative scale (Ratio of ORs: 0.74, 95 % CI: 0.37-1.50, p = 0.395) or the additive scale (RERI: -0.22, 95%CI: -2.27-1.84, p = 0.833). Meanwhile, biological sex assigned at birth was a significant modifier only on the additive scale (RERI: 0.82, 95 % CI: 0.004-1.64, P = 0.049). Specifically, females (OR: 1.43, 95 % CI: 1.03-1.97, P = 0.032) had greater odds of having depressive symptoms compared with males (OR: 1.20, 95 % CI: 0.69-2.08, p = 0.509) after the HSV-2 infection. LIMITATIONS: The analysis was based on a cross-sectional study; further investigation using longitudinal datasets might be beneficial. CONCLUSIONS: Sexual minority status did not modify the association between HSV-2 infection and having depressive symptoms. However, biological sex assigned at birth was a modifier only on the additive but not the multiplicative scale. Health workers should be alert for depression symptoms in females with HSV-2 infection.

Efficacy of a transdiagnostic, prevention-focused program for at-risk young adults: a waitlist-controlled trial.

BACKGROUND: Prevention programs that are 'transdiagnostic' may be more cost-effective and beneficial, in terms of reducing levels of psychopathology in the general population, than those focused on a specific disorder. This randomized controlled study evaluated the efficacy of one such intervention program called Resilience Training (RT). METHODS: College students who reported mildly elevated depressive or subclinical psychotic symptoms ('psychotic experiences' (PEs)) (n = 107) were randomized to receiving RT (n = 54) or to a waitlist control condition (n = 53). RT consists of a four-session intervention focused on improving resilience through the acquisition of mindfulness, self-compassion, and mentalization skills. Measures of symptoms and these resilience-enhancing skills were collected before and after the 4-week RT/waitlist period, with a follow-up assessment 12-months later. RESULTS: Compared to the waitlist control group, RT participants reported significantly greater reductions in PEs, distress associated with PEs, depression, and anxiety, as well as significantly greater improvements in resilience, mindfulness, self-compassion, and positive affect, following the 4-week RT/waitlist period (all p < 0.03). Moreover, improvements in resilience-promoting skills were significantly correlated with symptom reductions (all p < 0.05). Lastly, the RT-related reductions in PEs and associated distress were maintained at the 12-month follow-up assessment. CONCLUSIONS: RT is a brief, group-based intervention associated with improved resilience and reduced symptoms of psychopathology, with sustained effects on PEs, in transdiagnostically at-risk young adults. Follow-up studies can further assess the efficacy of RT relative to other interventions and test whether it can reduce the likelihood of developing a serious mental illness.

How family dementia caregivers perceive benefits of a 4-week Mentalizing Imagery Therapy program: a pilot study.

Background: Family caregivers of dementia patients experience high levels of interpersonal stress that often results in elevated anxiety, and depression, and negative impacts on interpersonal relationships. Changes in behaviors and the structure of relationships with the care recipient (CR) and others in the social milieu challenge the caregivers' ability to mentalize, or understand the links between mental states and behaviors. This study investigates the experiences and perceived benefits of family dementia caregivers who underwent Mentalizing Imagery Therapy (MIT), a treatment aiming to improve balanced self-other mentalizing and reduce psychological symptoms. Methods: Purposeful sampling was used to select 11 family dementia caregivers who underwent a 4-week pilot trial of MIT. Semi-structured interviews were completed post-intervention to identify subjective benefits, putative psychological mediators and perceived active components. Results: Caregivers reported improvements in well-being, mood, anxiety, and sleep, and a majority stated MIT helped with forming and maintaining healthier relationships. Some participants noted benefits extending to how they reacted to their social environment and perceived themselves more objectively from others' perspectives. Specific elements of MIT, including self-compassion, self-care, and the ability to reflect on emotionally arousing challenges, might have mediated these improvements. Conclusion: Family dementia caregivers perceived salutary benefits of MIT on multiple domains of well-being. The self reports suggest MIT holds promise for improving well-being, reducing non-mentalizing patterns of thought, and facilitating improvements in balanced mentalization within the caregivers' relationships.

Diminished frontal pole size and functional connectivity in young adults with high suicidality.

BACKGROUND: Suicide rates among young people have been increasing in recent years, yet no validated methods are available for identifying those who are at greatest risk for suicide. Abnormalities in the medial prefrontal cortex have been previously observed in suicidal individuals, but confounding factors such as treatment and chronic illness may have contributed to these findings. Thus, in this study we tested whether the size of the medial prefrontal cortex is altered in suicidal young adults who have received no treatment with psychotropic medications. METHODS: Suicidality was evaluated using the Suicide Behaviors Questionnaire-Revised (SBQ-R) and surface areas of four regions-of-interest (ROIs) within the medial prefrontal cortex were measured using magnetic resonance imaging (MRI) in a cohort of college students (n = 102). In addition, a secondary seed-based functional connectivity analysis was conducted using resting-state functional MRI data. Areas and functional connectivity of the medial prefrontal cortex of young adults with high suicidality (HS; SBQ-R score > 7; n = 20) were compared to those with low suicidality (LS; SBQ-R score = 3, n = 37). RESULTS: Compared to the LS group, the HS group had a significantly lower surface area of the right frontal pole (p < 0.05, Bonferroni-corrected) and significantly lower functional connectivity of the right frontal pole with the bilateral inferior frontal cortex (p < 0.001, Monte-Carlo corrected). LIMITATION: These findings require replication in a larger sample and extension in younger (adolescent) populations. CONCLUSION: Diminished frontal pole surface area and functional connectivity may be linked to elevated levels of suicidality in young people.

Four-Week Mentalizing Imagery Therapy for Family Dementia Caregivers: A Randomized Controlled Trial with Neural Circuit Changes.

INTRODUCTION: Family caregivers of patients with dementia suffer a high burden of depression and reduced positive emotions. Mentalizing imagery therapy (MIT) provides mindfulness and guided imagery skills training to improve balanced mentalizing and emotion regulation. OBJECTIVE: Our aims were to test the hypotheses that MIT for family caregivers would reduce depression symptoms and improve positive psychological traits more than a support group (SG), and would increase dorsolateral prefrontal cortex (DLPFC) connectivity and reduce subgenual anterior cingulate cortex (sgACC) connectivity. METHODS: Forty-six caregivers participated in a randomized controlled trial comparing a 4-week MIT group (n = 24) versus an SG (n = 22). Resting state neuroimaging was obtained at baseline and post-group in 28 caregivers, and questionnaires completed by all participants. The primary outcome was change in depression; secondary measures included anxiety, mindfulness, self-compassion, and well-being. Brain networks with participation of DLPFC and sgACC were identified. Connectivity strengths of DLPFC and sgACC with respective networks were determined with dual regression. DLPFC connectivity was correlated with mindfulness and depression outcomes. RESULTS: MIT significantly outperformed SG in improving depression, anxiety, mindfulness, self-compassion, and well-being, with moderate to large effect sizes. Relative to SG, participants in MIT showed significant increases in DLPFC connectivity - exactly replicating pilot study results - but no change in sgACC. DLPFC connectivity change correlated positively with mindfulness and negatively with depression change. CONCLUSIONS: In this trial, MIT was superior to SG for reducing depression and anxiety symptoms and improving positive psychological traits. Neuroimaging results suggested that strengthening DLPFC connectivity with an emotion regulation network might be mechanistically related to MIT effects.

Mentalizing imagery therapy to augment skills training for dementia caregivers: Protocol for a randomized, controlled trial of a mobile application and digital phenotyping.

More than 50 million people worldwide live with a dementia, and most are cared for by family members. Family caregivers often experience chronic stress and insomnia, resulting in decreased mental and physical health. Accessibility of in-person stress reduction therapy is limited due to caregiver time constraints and distance from therapy sites. Mentalizing imagery therapy (MIT) provides mindfulness and guided imagery tools to reduce stress, promote self and other understanding, and increase feelings of interconnectedness. Combining MIT with caregiver skills training might enable caregivers to both reduce stress and better utilize newly learned caregiving skills, but this has never been studied. Delivering MIT through a smartphone application (App) has the potential to overcome difficulties with scalability and dissemination and offers caregivers an easy-to-use format. Harnessing passive smartphone data provides an important opportunity to study behavioral changes continuously and with higher granularity than routine clinical assessments. This protocol describes a randomized, controlled, superiority trial in which 120 family dementia caregivers, aged 60 years or older, will be assigned to smartphone App delivery of caregiver skills with MIT (experimental condition) or without MIT (control condition). The primary objectives of the trial are to assess whether the experimental condition is superior to control on reducing family caregiver stress, insomnia and related outcomes and to demonstrate the feasibility of developing behavioral markers from passive smartphone data that predict health outcomes in older adults. Trial outcomes may inform the suitability of our intervention for caregivers and provide new methods for assessment of older adults.

A Patient With Electroconvulsive Therapy-resistant Major Depressive Disorder With a Full Response to Heated Yoga: A Case Report.

Depression remains difficult to treat as a result of less than optimal efficacy and troublesome side effects of antidepressants. The authors present the case of a patient with treatment-resistant depression with melancholic features who had previously been unresponsive to electroconvulsive therapy (ECT) plus an antidepressant regimen but whose condition fully remitted with the addition of a standardized form of heated hatha yoga (HY; Bikram yoga) practiced in a room heated to 105°F. The patient was a 28-year-old woman who underwent 8 weeks of HY as part of a randomized controlled trial of HY for depression while continuing her antidepressant treatment. The patient was asked to attend a minimum of 2 weekly, 90-minute HY classes. After 8 weeks (12 classes in total), the patient no longer met the criteria for a major depressive episode with melancholic features, per Mini-International Neuropsychiatric Interview (MINI) criteria. Her depressive symptoms had improved dramatically, with Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30), and Hamilton Depression Rating Scale (HAM-D28) scores decreasing from 28 at baseline to 3, and from 28 at baseline to 4, respectively, indicating remission. This patient's ECT-resistant depression remitted with the addition of HY to her antidepressant regimen. Because of her youth and athleticism, this patient was likely well suited to this rigorous form of yoga. Further research is needed to explore HY as a potential intervention for treatment-resistant depression.

Transitioning From In-Person to Remote Clinical Research on Depression and Traumatic Brain Injury During the COVID-19 Pandemic: Study Modifications and Preliminary Feasibility From a Randomized Controlled Pilot Study.

BACKGROUND: Telehealth has provided many researchers, especially those conducting psychosocial research, with the tools necessary to transition from in-person to remote clinical trials during the COVID-19 pandemic. A growing body of research supports the effectiveness of telemental health for a variety of psychiatric conditions, but few studies have examined telemental health for individuals with comorbid medical diagnoses. Furthermore, little is known about the remote implementation of clinical trials examining telemental health interventions. OBJECTIVE: This paper outlines the procedural modifications used to facilitate conversion of an in-person randomized controlled trial of cognitive behavioral therapy (CBT) for depression in individuals with traumatic brain injury (TBI; CBT-TBI) to a telemental health study administered remotely. METHODS: Given the nature of remote implementation and specific challenges experienced by individuals with TBI, considerations related to treatment delivery, remote consent, data management, neuropsychological assessment, safety monitoring, and delivery of supportive material have been discussed. Feasibility, acceptability, and safety were evaluated by examining attendance and participant responses on self-report measures of treatment satisfaction and suicidal behavior. RESULTS: High rates of treatment attendance, assessment completion, study retention, and satisfaction with the intervention and modality were reported by participants who completed at least one telemental health CBT-TBI session. CONCLUSIONS: Study modifications are necessary when conducting a study remotely, and special attention should be paid to comorbidities and population-specific challenges (eg, cognitive impairment). Preliminary data support the feasibility, acceptability, and safety of remotely conducting a randomized controlled trial of CBT-TBI. TRIAL REGISTRATION: ClinicalTrials.gov NCT03307070; https://clinicaltrials.gov/ct2/show/NCT03307070.

Relationship between cannabis use and psychotic experiences in college students.

BACKGROUND: Emerging data suggest cannabis use is a component cause of psychotic disorders; however, the sequence of processes accounting for this association is poorly understood. Some clues have come from studies in laboratory settings showing that acute cannabis intoxication is associated with subclinical hallucinations and delusional thinking, i.e., "psychotic experiences". Although psychotic experiences are relatively common, those that are severe and distressing are linked to an increased risk of developing a psychotic disorder. This study aimed to investigate the association between the frequency of cannabis use and psychotic experiences in young adults. METHODS: 1034 U.S. college students completed questionnaires to assess: cannabis use in the past week, delusional ideation (Peters Delusions Inventory), hallucinations (Launay-Slade Hallucinations Scale-Extended), and depression (Beck Depression Inventory). RESULTS: Participants reporting higher rates of weekly cannabis use were more likely to report hallucinatory experiences and delusional ideation. The relationship between cannabis use and hallucinatory experiences, but not the relationship between cannabis use and delusional ideation, remained significant after controlling for levels of depression. Moreover, those who reported greater amounts of cannabis use had more distressing delusional ideas, that were held with more conviction. CONCLUSIONS: Cannabis use is linked to the presence of subclinical hallucinations and delusional ideation in U.S. college students.

Change processes in cognitive behavioral therapy and motivational interviewing for depression and heavy alcohol use: A network approach.

Objective: Both cognitive behavioral therapy for depression (CBT-D) combined with brief motivational interviewing (CBT-D + BMI) and alone are associated with symptom improvement among college students with co-occurring depression and heavy episodic drinking (HED). However, little is known about change processes underlying these different treatments.The current study uses a network approach to examine change process that may differentially underlie CBT-D + BMI relative to CBT alone. Methods: Participants included 94 college students with depression and HED who were randomized to either eight weeks of CBT-D + BMI or CBT alone. A network approach was adopted to examine how treatment condition influenced changes in the network structure of depression symptoms, heavy drinking, drinking motives, and consequences of alcohol. Network analyses were conducted using change scores representing the eight-week difference from pre-treatment to post-treatment assessments. Results: Relative to CBT-D alone, the combined CBT-D + BMI treatment influenced the symptom network structure by preferentially targeting reductions in drinking to cope motives and in the depression symptom 'loss of interest'. Conclusion: The current study revealed that combined CBT-D + BMI may confer therapeutic benefit through different network structure pathways than CBT-D alone. Specifically, augmenting CBT-D with BMI may influence change processes related to drinking motives, such as drinking to cope.

Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study.

OBJECTIVE: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. METHODS: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity. RESULTS: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo. CONCLUSIONS: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.

Effects of Open-Label, Adjunctive Ganaxolone on Persistent Depression Despite Adequate Antidepressant Treatment in Postmenopausal Women: A Pilot Study.

OBJECTIVE: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women. METHOD: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper. RESULTS: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. CONCLUSIONS: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02900092.