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Treatment-resistant bipolar depression (TRBD) is defined by non-remission after 2 8-week trials of recommended medications, including combination therapy, at therapeutic doses, and associated with increased psychiatric hospitalizations and disability, and poorer quality of life.

 The prevalence of type 2 diabetes and insulin resistance in patients with bipolar disorder is approximately 22% and 32%, respectively, and these conditions may worsen illness course.

“Mr Joseph” is a 60-year-old Caucasian male with a history of chronic bipolar I disorder, whose most recent episode included depression without psychotic features. He failed a previous trial of lithium due to adverse effects on renal function. He had improved mood with treatment with ziprasidone, titrated to 40 mg qAM and 80 mg qPM, although he has residual depressive symptoms. He gained weight with ziprasidone, with an increase in BMI from 28 to 32. He maintained a normal fasting glucose. He requested to continue ziprasidone, and 3 months ago was started on metformin, which was titrated to 1000 mg BID. At his most recent outpatient clinic visit, his BMI had decreased to 29.5, and he also noted mild improvements in mood and anxiety.

Calkin and colleagues hypothesized that patients with TRBD who met criteria for insulin resistance would exhibit a favorable response to metformin, which has insulin-sensitizing properties.

 They performed a randomized quadruple-masked (patient, investigator, outcomes assessor, statistician) trial of adjunctive metformin at 2 sites in Canada and the United States. They included adults aged 18 and older with DSM-5 bipolar disorder and unremitting depressive symptoms (Montgomery-Asberg Depression Rating Score [MADRS] score ≥15) for at least 4 weeks despite optimal treatment.

Subjects were screened for insulin resistance using the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) equation, which is based on fasting blood glucose and insulin. Subjects were excluded if they did not have insulin resistance (HOMA-IR <1.8), had manic symptoms (Young Mania Rating Scale score ≥15), had a suicidal ideation rating of 5 on the Columbia Suicide Severity Rating Scale, were already receiving or were allergic to metformin, or had liver function tests ≥3 times the upper limit of normal.

Subjects received metformin 500 mg (or placebo) twice daily for 1 week, then titrated to 1000 mg BID for up to 25 additional weeks. The minimum maintenance dose of metformin was 1500 mg daily. The MADRS was administered, and insulin resistance was measured at baseline, week 2, and every 4 weeks thereafter (primary outcomes). Secondary outcomes included the Clinical Global Impressions Scale (bipolar disorders version; CGI-BP) and the Global Assessment of Functioning (GAF) scale. Returned pill counts were used to determine study medication adherence. The primary hypothesis that metformin would reverse insulin resistance (conversion) was tested using Fisher’s exact test. Improvements in MADRS scores (and other outcomes) in converters were tested using mixed-effects linear models.

The authors consented and screened 88 subjects, of whom 50 were randomized. Efficacy and safety data were reported for 45 subjects (20 metformin and 25 placebo). Thirty-nine subjects (87%) completed the study to the week-14 primary outcome endpoint, and 28 subjects completed the full 26 weeks. Medication adherence was 97% in both treatment groups. Mean subject age was 48, 76% were women, and the mean illness duration was 26 years. There were no significant between-group differences in weight, BMI, glucose, insulin, or blood levels of lithium or lamotrigine.

Ten metformin-treated patients no longer met insulin resistance criteria (converters) at week 14, versus 1 placebo-treated patient (Fisher’s exact p=0.0009). Converters had a significantly greater reduction in MADRS total scores beginning at week 6 and continuing through week 26, with large effect sizes (1.04 to 1.17). There were concordant improvements in GAF, Hamilton anxiety scale, and, to a lesser extent, CGI-BP scores in converters. The most common adverse events were diarrhea and vomiting, which were expected in the metformin group. At week 14, metformin-treated patients lost 1.7 kg and placebo-treated patients gained 1.4 kg, and this difference was statistically significant.

The authors concluded that reversal of insulin resistance by metformin resulted in statistically and clinically significant sustained improvements in depression, with no changes in mania, in patients with TRBD. No serious adverse events occurred, and the most common adverse events were gastrointestinal symptoms. Study limitations included the modest sample size, and whether a higher rate of conversion from insulin resistance could be achieved with either higher doses or extended-release preparations of metformin.

Reversal of insulin resistance by metformin improves depression, anxiety, and general functioning in a large proportion of patients with TRBD. These findings warrant replication in a larger trial.

is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

1. Fountoulakis KN, Yatham LN, Grunze H, et al. 

The CINP guidelines on the definition and evidence-based interventions for treatment-resistant bipolar disorder.

2. Calkin CV, Ruzickova M, Uher R, et al.

 Insulin resistance and outcome in bipolar disorder, 2015.

3. Calkin CV, Chengappa KNR, Cairns K, et al. 

Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial.

Adjunctive metformin in bipolar disorder. Researchers performed a randomized clinical trial of treating insulin resistance to improve clinical outcomes in treatment-resistant bipolar depression. 

Metformin in Treatment-Resistant Bipolar Depression

Biogen and Sage Therapeutics announced positive results from the phase 3 SKYLARK study of 

, an investigational oral drug being evaluated in women with postpartum depression (PPD).

 as rapidly and effectively as possible to restore maternal mental health is of the utmost importance for moms and their babies,” said Kristina Deligiannidis, MD, principal investigator of the SKYLARK Study and associate professor at the Feinstein Institutes for Medical Research in Manhasset, New York. “These encouraging results are another important step in efforts to develop a novel treatment option for patients who suffer from this prevalent condition.”

SKYLARK investigators evaluated 200 women who had a Hamilton Depression Rating Scale (HAMD-17) score of 26 or greater in a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of zuranolone 50 mg dosed once daily for 14 days compared to placebo. Participants were followed for up to 45 days. The study population included approximately 22% Black or African American women and 38% Hispanic or Latina women. Women treated with zuranolone 50 mg (n=98) demonstrated a statistically significant and clinically meaningful improvement in symptoms of depression at day 15—the primary endpoint.

 also surpassed placebo on HAMD-17 at 3 other time points. A difference was detectable on day 3, when the HAMD-17 score in the treatment arm had fallen by 9.5 and lasted through assessments on days 28 and 45. The scores improved in both arms over the course of the trial.

“Postpartum depression is frequently under-recognized, and it can take time for women to be clinically diagnosed and treated,” said Katherine Dawson, MD, head of the Therapeutics Development Unit at Biogen. “Our hope is to be able to offer an innovative treatment option to potentially reduce the overwhelming impact 

 can have on women and their families.”

The study also met key secondary endpoints: Zuranolone 50 mg demonstrated statistically significant improvement in change from baseline in the Clinical Global Impression Severity (CGI-S) scale at day 15 as compared to placebo (zuranolone -2.2 vs. placebo -1.6, p= 0.0052). The CGI-S is a clinician-administered 7-point scale that rates the severity of an individual’s disease at the time of assessment.

“The positive outcomes of the SKYLARK Study are a critical step in our mission to help women suffering with postpartum depression find rapid relief from their depressive symptoms so they can get back to feeling like themselves,” said Barry Greene, chief executive officer at Sage. “Postpartum depression can be devastating for women and their families. If approved, zuranolone would be the first oral medication specifically indicated to treat PPD.”

Sage and Biogen have already begun a rolling submission for zuranolone in major depressive disorder (MDD) and aim to complete it in the second half of the year. An associated filing for zuranolone in PPD is planned for early next year.

1. Sage Therapeutics and Biogen announce that the phase 3 SKYLARK study of zuranolone in postpartum depression met its primary and all key secondary endpoints. Biogen. News release. June 1, 2022. Accessed June 2, 2022. 

https://investors.biogen.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-phase-3-skylark-study

Zuranolone, an investigational oral drug being evaluated in women with postpartum depression, sees positive phase 3 study results. 

Positive Results From SKYLARK for Patients With Postpartum Depression

Axsome Therapeutics announced the publication of the results from the pivotal ASCEND phase 2 clinical trial of dextromethorphan-bupropion (AXS-05) in major depressive disorder (MDD).

 Dextromethorphan-bupropion is an oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity.

“Major depressive disorder is highly prevalent, debilitating and potentially life-threatening. There is an urgent need for mechanistically new treatments that are effective and well tolerated,” said Dan Iosifescu, MD, professor of psychiatry at the New York University School of Medicine, Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research, and coauthor of the publication. “Due to its novel mechanism of action targeting glutamate and sigma-1 receptors, and to its robust antidepressant efficacy demonstrated in this study, AXS-05 has the potential to become an important and very useful new treatment for patients with major depressive disorder.”

The trial assessed the efficacy and safety of dextromethorphan-bupropion versus bupropion in 80 participants with moderate to severe MDD. Participants were randomized to receive dextromethorphan-bupropion (45 mg dextromethorphan/105 mg bupropion tablet) (n=43), or bupropion (105 mg tablet) (n=37), once daily for the first 3 days and then twice daily for the following 6 weeks. The primary endpoint was overall treatment effect on the Montgomery-Åsberg Depression Rating Scale (MADRS) score.

Dextromethorphan-bupropion demonstrated rapid, statistically significant improvement in depressive symptoms and remission compared with bupropion. The mean change from baseline in MADRS score over weeks 1 to 6 was significantly better with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; p<0.001). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs 16.2%; least-squares mean difference=30.3%; p=0.004).

“We are very pleased with the publication of the ASCEND trial results in 

, the most widely read psychiatric journal in the world,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “ASCEND is one of the pivotal efficacy trials that forms the basis of our NDA for AXS-05 in depression, which is currently under review by the FDA. Axsome is positioned to move expeditiously to make this product available to patients as quickly as possible, should it be approved.”

AXS-05 was generally well tolerated in the trial. Common adverse effects included dizziness, nausea, dry mouth, decreased appetite, and anxiety. AXS-05 was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

The article, “Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized, Double-Blind, Controlled Trial,” can be found in 

1. Tabuteau H, Jones A, Anderson A, et al. 

Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial.

. 2022;appiajp21080800. Online ahead of print.

2. Axsome Therapeutics announces publication of pivotal ascend phase 2 trial of AXS-05 in major depressive disorder in the American Journal of Psychiatry. 

 News release. May 18, 2022. Accessed May 19, 2022. 

https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-publication-pivotal-ascend-phase-2

Axsome Therapeutics announced the robust antidepressant efficacy demonstrated in this latest study.

Positive Results for Dextromethorphan-Bupropion ASCEND Phase 2 Clinical Trial

Depression is the leading cause of disability and a major contributor to the overall global burden of disease.

 highlights, despite how common depression is across the life course, critical barriers have prevented depression from receiving sufficient resources and global attention.

 Depression has historically been stigmatized and misunderstood, and it arises due to a combination of biological, social, and psychological factors. Limited access to treatment and lack of cross-disciplinary, collaborative research and care has hindered progress. Additionally, women are disproportionately affected by depression and are twice as likely to have a diagnosis of depression as men, likely due to the combination of health inequities, gender biases, and biological factors.

 when elderly, and it might be a reason more women have dementia than men.

 Developing innovative solutions for depression—especially those focused on women that account for sex and gender differences—are critical to improving individual and collective resilience.

To develop women-focused solutions for depression, it is important to understand the various factors that contribute to women’s greater risk for depression. A health equity and public health lens is imperative. The distinction between sex and gender also needs to be clear, with sex referring to biological differences and gender encompassing socially constructed and enacted roles and behaviors shaped by historical and cultural contexts. Additionally, diagnostic tools, symptom screeners, medications, and other health tools must not have sex or gender bias.

Women in their reproductive years undergo cycle changes in steroid hormones (progesterone/estrogen) over the menstrual cycle. The role of these changes as a factor contributing to depression and mood changes is seen in women with premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS). The estimated prevalence in reproductive women is 5% (PMDD) and 20% (PMS). There is growing evidence that the rise in ovarian steroid hormone production and the effect of their metabolites (in particular allopregnanolone) on central brain receptors as progesterone receptor modulators contribute to the mood symptoms in 

 More research is needed to understand the long-term neurological impacts of birth control and hormone therapy.

 Treatments are now being developed to target these newer proposed actions of hormones on the central brain systems with either 

 (removing the natural fluctuations in hormones) or “correcting” the neurotransmitter or 

 with the use oftargeted specific antidepressants.

The female preponderance in depression occurs largely during the reproductive years, is not evident before puberty, and is less marked after menopause. Societal factors may also play an important role; even in developed countries, women still often take a greater responsibility for child rearing and domestic activities while still being expected to progress their careers—known as a “double day.” Women worldwide are also the majority of caregivers for family members needing health care; often this role is unpaid.

Depression is also linked to intimate partner violence (IPV). 

 globally have experienced physical or sexual IPV.

 Since the outbreak of COVID-19, IPV has escalated and been called the 

 of COVID-19. In numerous countries, there has been a 

, likely fueled by effects and mitigation strategies of COVID-19.

 would be affected by IPV for every 3 months of lockdown.

One particularly devastating yet unaddressed and long neglected impact is the mental and brain health effects—

including traumatic brain injury (TBI) and depression

—resulting from IPV. Numerous studies have found that women exposed to IPV are more likely to develop depression than women who are not exposed.

 This finding is not surprising, given that mental health issues are common sequelae of brain injury that may emerge and worsen years after injury. However, IPV is too often left out of conversations around prevention and treatment of depression.

It is also important to note the connection between depression and chronic health conditions in women, such as heart disease. Since 1989, heart disease has been 

 Women are also more likely than men to die after a heart attack.

Women are more likely to be undiagnosed, misdiagnosed, or poorly treated for their heart disease due to pervasive bias and the male body being the default for biomedical care and research. Additionally, 

the Guidelines for the Prevention of Cardiovascular Disease in Women

 by the American Heart Association show the profound impact of hypertension, diabetes, and depression on women’s hearts.

 It is imperative to understand the huge impact of psychosocial risk factors on women’s hearts and address problems including depression and social isolation.

Understanding the role of depression in dementia for women is also imperative. 

The WHAM Report (Women’s Health Access Matters)

 found that women are 66% of the nearly 7 million people in the United States with Alzheimer disease, and yet just 12% of 2019 NIH Alzheimer disease fund went to projects focused on women.

 Even more, the report showed the following: (1) Doubling the funds for women’s Alzheimer disease research pays for itself 3 times over; (2) this 224% return on investment adds 15% more to our economy than general Alzheimer disease research; and (3) adding $300 million for research on women generates $930 million in economic gains, adds back 4000 years of life, eliminates 6500 Alzheimer disease and related dementias, and saves 3500 years of nursing home care and costs. Depression is 

one of the largest modifiable risk factors

 Thus, understanding the link between depression and dementia and accounting for depression in dementia prevention strategies in women is essential.

Novel, women-focused solutions can reduce the impact of depression and increase global resilience. As a recent 

 finds, women’s health solutions often remain siloed to pregnancy and reproductive-related issues.

There is a dearth of women-focused solutions for chronic health and behavioral health and an even larger gap for solutions at the intersection of both.

 Women-focused solutions that include technology, drug development, and devices are urgently needed. Additionally, convergence solutions that combine multiple domains and technologies, such as blending platform and frontier technologies, are key.

Developing women-focused solutions is not only a medical and moral imperative—there is also significant economic and commercial upside. Emergen Research projects that the global market for women’s health will reach $60 billion in 2027.

 Additionally, women are the chief medical officers of society, controlling 80% of health care decisions in the United States and spending 29% more per capita on health care compared to men.

By developing women-focused solutions for depression that account for various factors, including the relationship between depression with heart disease and dementia in women, we can build a more resilient society and world.

is an Atlantic Fellow for Equity in Brain Health at Global Brain Health Institute, a Thiel Fellow at Stanford University, and a Steering Committee member for OECD-PRODEO Institute Neuroscience-inspired Policy Initiative.

is CEO of PRODEO and cofounder of the PRODEO Institute.

is founder and chief director of the Center for BrainHealth at UT Dallas. She is a distinguished professor at UT Dallas.

is a reproductive endocrinologist at Baylor College of Medicine. He is an active member of the American Society of Reproductive Medicine and the North American Menopause Society, with a special interest in the role of steroid hormones on cognitive function. 

is deputy secretary of public health in the Victorian Department of Health and Honorary Melbourne Enterprise Professor with the University of Melbourne. 

is a NHMRC senior principal research fellow, Alfred Deakin professor of psychiatry at Deakin University, and director of the Institute for Mental and Physical Health and Clinical Translation 

is CEO and cofounder of the Women’s Brain Project.

is colead of the OECD-PRODEO Institute NIPI.He is a senior fellow in brain capital for the Meadows Mental Health Policy Institute. He holds adjunct or advisory roles with IMPACT at Deakin University, the Heka Fund, Brain Health Nexus at Cohen Veterans Bioscience, GBHI, Baylor College of Medicine, Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Chile, University of Texas Health Sciences Center at Houston, the Davos Alzheimer’s Collaborative and the Euro-Mediterranean Economists Association.

1. Herrman H, Patel V, Kieling C, et al. 

Time for united action on depression: a Lancet-World Psychiatric Association Commission.

Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia.

4. Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, et al. 

Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study.

5. Schmidt PJ, Martinez PE, Nieman LK, et al. 

Premenstrual dysphoric disorder symptoms following ovarian suppression: triggered by change in ovarian steroid levels but not continuous stable levels.

6. Hantsoo L, Grillon C, Sammel M, et al. 

Response to sertraline is associated with reduction in anxiety-potentiated startle in premenstrual dysphoric disorder.

7. Breiding MJ, Smith SG, Basile KC, et al. 

Prevalence and characteristics of sexual violence, stalking, and intimate partner violence victimization--national intimate partner and sexual violence survey, United States, 2011.

When pandemics clash: gendered violence-related traumatic brain injuries in women since COVID-19.

9. Mlambo-Ngcuka P. Gender-based violence: we must flatten the curve of this shadow pandemic. November 25, 2020. Accessed May 12, 2022. 

https://www.un.org/africarenewal/magazine/november-december-2020/gender-based-violence-we-must-flatten-curve-shadow-pandemic

10. Ellsberg M, Jansen HAFM, Heise L, et al. 

Intimate partner violence and women’s physical and mental health in the WHO multi-country study on women’s health and domestic violence: an observational study.

11. Mehta LS, Beckie TM, DeVon HA, et al. 

Acute myocardial infarction in women: a scientific statement from the American Heart Association.

12. Mosca L, Benjamin EJ, Berra K, et al. 

Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association.

Societal Impact of Research Funding for Women’s Health in Alzheimer’s Disease and Related Dementias

14. Livingston G, Huntley J, Sommerlad A, et al. 

Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.

15. DeSilva J, Krasniansky A. Building comprehensive women+ digital health: Eight sectors serving women+ needs. Rock Health. September 27, 2021. Accessed May 12, 2022. 

https://rockhealth.com/insights/building-comprehensive-women-digital-health-eight-sectors-serving-women-needs/

16. Femtech Market By Type (Devices, Software, Services), By End-Use (Direct-to-Consumer, Hospitals, Fertility Clinics, Surgical Centers, Diagnostic Centers), By Application (Reproductive Health, Pregnancy & Nursing Care, Pelvic & Uterine Healthcare), By Region, Forecasts to 2027. EMERGEN Research. June 2021. Accessed May 12, 2022. 

https://www.emergenresearch.com/industry-report/femtech-market

17. Femtech—time for a digital revolution in the women’s health market. Frost & Sullivan. January 31, 2018. Accessed May 12, 2022. 

https://www.frost.com/frost-perspectives/femtechtime-digital-revolution-womens-health-market/

18. Gambon E, Stotz C, Sandhu N. Femtech is expansive—it’s time to start treating it as such. Rock Health. August 3, 2020. Accessed May 12, 2022. 

https://rockhealth.com/femtech-is-expansive-its-time-to-start-treating-it-as-such/

Here’s why we should be paying special attention to women's depression treatment.  

Mind-Body Resilience for Women: A Focus on Depression

A study on best practices in the identification and management of perinatal depression raised more questions than answers.

The study aimed to examine the guidelines for managing perinatal depression in obstetric and pediatric settings, as well as the evidence supporting these guidelines. To do this, the investigators conducted a search for best practices in the Guideline International Network using the term 

; conducted additional searches on Google and other websites; and had discussions with experts in perinatal depression. To be included, guidelines had to describe the management of perinatal depression in obstetric or pediatric care settings; be written in English; and have been published between 1990 and 2021. The investigators found 25 guidelines published by 17 organizations—with 6 organizations publishing more than 1 guideline—that met the aforementioned criteria for inclusion. They then examined the research supporting these guidelines through searches in PubMed and Google Scholar, and conducted a literature review.

The investigators found that most guidelines (n =18, 72%) made recommendations for screening for perinatal depression, and 16 (89%) made several recommendations, including for screening timeframe, setting, and instrumentation. Just over one-third of the guidelines (n = 9, 36%) recommended assessment by severity and instrumentation to confirm depression after screening, and 3 (33%) made several recommendations. Suicide assessment was also analyzed, with 13 guidelines (52%) addressing suicide assessment, 6 (46%) of which recommended immediate evaluation. More than 50% of the guidelines (n = 7, 54%) recommended referring the patient to a psychiatrist or other mental health clinician to monitor the patient’s well-being.

The majority of guidelines (n = 21, 84%) made recommendations for treatment, with most (n = 20, 95%) offering several recommendations and 14 (67%) making recommendations by severity. Most (90%) recommended psychosocial interventions such as cognitive behavioral therapy or psychodynamic therapy; 60% recommended pharmacological treatment such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs); 40% recommended psychoeducation throughout the perinatal period; and 19% recommended alternative treatments like bright light therapy and electronic mental health support (ie, self-guided applications). The investigators also noted that literature on reassessment, remission, and care management was limited, and that they identified no literature discussing treatment adjustments for perinatal depression that was unresponsive to psychotherapy or pharmacology.

Overall, the investigators noted that evidence was inadequate or contradictory across all areas, and that of the limited number of studies available, most include small sample sizes or are not of sufficient quality to meaningfully inform clinical practice.

“Clinicians may use these recommendations to guide their practice, but they should be aware of the limitations of the evidence supporting these guidelines and remain alert to new evidence. There is a clear need for researchers and policymakers to prioritize this area in order to develop evidence-based guidelines for managing perinatal depression.”

Management of depression during the perinatal period: state of the evidence

Recommendations are often vague, contradictory, according to investigators.

Study Examines Best Practices for Managing Perinatal Depression

According to the results of a new study, individuals seeking treatment for depression with lower incomes, lower education levels, and those who identify as minorities tend to have worse outcomes even when receiving equal access to treatment.

 Jeffrey Mills, PhD, and Jeffrey Strawn, MD, led the University of Cincinnati cross-college collaborative research.

Investigators analyzed data from a large clinical trial, the Combining Medications to Enhance Depression Outcomes study, that enrolled 665 participants seeking treatment for depression. All participants had the same access to treatment without differences due to health insurance or income. The study also controlled for sex, age, and treatment type. Following 12 weeks of antidepressant medication treatment, participants who were nonwhite improved 11.3% less compared to white patients. Participants who were unemployed saw 6.6% less improvement compared to employed patients. Participants the 25th percentile of income distribution had 4.8% reduced improvement when compared to participants in the 75th percentile. Patients who were nonwhite, unemployed, without degree, and in the 25th income percentile had 26% less improvement compared to patients who were white, employed, with a college degree, and in the 75th income percentile.

“We think about these things in terms of access, we think about them in terms of income inequality, and I realize that education does track with those, but just having a college degree while controlling for all of these other factors still had a significant impact,” said Strawn, professor in the Department of Psychiatry and Behavioral Neuroscience in UC’s College of Medicine and a UC Health adolescent psychiatrist.

Strawn also noted that while the findings are still preliminary, results suggest that participants without a college degree had 9.6% less improvement compared to college graduates. Furthermore, previous research indicates that individuals seeking treatment for depression with lower income and less education have worse outcomes because of a lack of access to quality health care, but socioeconomic factors are hard to isolate.

Mills, professor of economics in UC’s Carl H. Lindner College of Business, said that the findings do not negate the fact that a lack of access makes an impact on treatment outcomes, but it does show the importance of including a patients’ home environment when analyzing the effectiveness of treatment.

“If you’re going home to a wealthy neighborhood with highly educated parents or spouse, then you’re arguably in a much better environment for the treatment to be effective than if you’re going to a poor neighborhood with other problems,” said Mills.

Strawn believes future studies should consider socioeconomic variables that may have been previously overlooked.

“When we don’t control for these variables, which we often do not in our clinical trials because of differences in populations, we may miss detecting an effective treatment because its effect is obscured,” Strawn said. “It can potentially jeopardize our treatment development by not accounting for these factors.”

Moving forward, the investigators want to combine data from other depression trials to produce more powerful results with a larger dataset.

Socioeconomic predictors of treatment outcomes among adults with major depressive disorder.

2. Socioeconomic factors affect response to depression treatment. News release. April 15, 2022. Accessed May 6, 2022. 

https://www.newswise.com/articles/socioeconomic-factors-affect-response-to-depression-treatment

Home environments have a clear impact on depression treatment outcomes. 

The Effect of Socioeconomic Factors on Depression Treatment

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

Consider novel, promising strategies for treatment-resistant depression in order to help guide discussions with patients about appropriate treatments.

1. Understand novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

2. Understand currently available and promising neurostimulation treatment options for treatment-resistant depression.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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Treatment-resistant depression (TRD), which is broadly defined as “the failure to achieve and sustain euthymia with adequate antidepressant treatment,”

 remains a commonly encountered clinical challenge. Treatment response in depression has been characterized by a response curve that demonstrates diminished improvement of symptoms over successive adequate courses of treatment (

 Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study confirm what we know from clinical practice—namely that the chances of adequate symptom resolution are very low (single digits) after 2 initial unsuccessful treatment trials. Approximately one-third of patients do not achieve remission after trials with 4 different conventional treatments. In this context, one definition of TRD is nonresponse to 2 or more antidepressant trials, reflecting this sharp drop-off in response after the second treatment.

A number of organizations (eg, the Canadian Network for Mood and Anxiety Treatments, the National Institute of Health and Care Excellence, and the American Psychiatric Association) have put forth clinical algorithms for the treatment of 

. Current standard treatment options across these guidelines include conventional antidepressant medications (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), other antidepressant drugs (eg, 

, mirtazapine, vilazodone, and vortioxetine), combining antidepressants (eg, bupropion [Wellbutrin, Forfivo] or mirtazapine [Remeron] added to an SSRI or SNRI, augmentation strategies that target associated symptoms such as sleep or anxiety (eg, second-generation antipsychotics, 

, lamotrigine [Lamictal], buspirone [Buspar], and thyroid hormone), and psychotherapy. Furthermore, new and developing advances in depression therapeutics now offer the prospect of significant improvement when administered in conjunction with, or as alternatives to, standard treatments. These promising therapies include rapid-acting novel antidepressant drugs as well as neurostimulation interventions.

, a glutamatergic modulator, has antidepressant properties has led to a mechanistically new treatment option for individuals with TRD.

 Furthermore, its rapid antidepressant effects manifest within hours compared with weeks for conventional antidepressants. Currently, intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as 

, available off-label) and intranasal esketamine (FDA approved with a required risk evaluation and mitigation strategy [REMS] monitoring protocol) are the only routes of administration that have sufficient evidence to support their use. The initial controlled trials of IV ketamine (a single infusion of 0.5 mg/kg over 40 minutes) for TRD found that ketamine exerted rapid (typically within hours) antidepressant effects that peaked at 24 hours, with about 70% of patients demonstrating response.

 Response typically lasted 3 to 7 days postinfusion. Ketamine appears to have broad therapeutic properties, demonstrating particular effectiveness for anxious depression, depression with anhedonic features, and suicidal ideation.

Preliminary evidence also suggests its usefulness in treating other disorders comorbid with major depressive disorder (MDD), including obsessive-compulsive disorder (OCD), posttraumatic stress disorder, social anxiety disorder, and 

 Notably, ketamine has also proven effective for difficult-to-treat atypical features.

 Adverse events associated with subanesthetic-dose ketamine (0.5 mg/kg) are typically transient (eg, somnolence/sedation, hypertension, nausea, dissociation), although risk of abuse and/or dependence have not been sufficiently studied. One key limitation is the short duration of antidepressant effects in response to a single administration, which has prompted use of repeat doses of IV ketamine. Such repeat infusions are typically administered twice per week, and treatments are tapered when maximal response has been reached, which appears to maintain remission.

Esketamine is the S-enantiomer of ketamine and demonstrates greater potency at the glutamate NMDA receptor than the R-enantiomer. In clinical trials, intranasal esketamine (twice weekly, 56 or 84 mg) added to conventional antidepressant therapy significantly improved symptoms compared with placebo.

 Intranasal esketamine (Spravato) received FDA approval for the treatment of adults with TRD in March 2019 and for the treatment of adults with MDD with acute suicidal ideation or behavior in August 2020. Given concerns about adverse events, the FDA approved 

 under a REMS, requiring administration and observation in a medically supervised setting. In terms of adverse effects, reports to the FDA through 2020 noted that esketamine was significantly associated with increased risk of dissociation, sedation, and “feeling drunk.”

In this CME, review novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

Depression

Metformin in Treatment-Resistant Bipolar Depression

Positive Results From SKYLARK for Patients With Postpartum Depression

Positive Results for Dextromethorphan-Bupropion ASCEND Phase 2 Clinical Trial

Mind-Body Resilience for Women: A Focus on Depression

Study Examines Best Practices for Managing Perinatal Depression

The Effect of Socioeconomic Factors on Depression Treatment

Promising Strategies for Treatment-Resistant Depression

Rolling NDA Submission of Zuranolone for Treatment of Major Depressive Disorder

From the Pages of Psychiatric Times: April 2022

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