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According to the results of a phase 2b trial of COMP360 psilocybin therapy for treatment-resistant depression (TRD), the largest study of its kind, patients with TRD could see symptom relief after a single dose of psilocybin.

Investigators gathered 233 participants with TRD and gave them either 1 mg, 10 mg, or 25 mg COMP360 psilocybin, in conjunction with psychological support from specially trained therapists. Approximately 30% of participants with TRD in the randomized, controlled, double-blind phase 2b study were in remission at week 3 after a single 25 mg dose of COMP360 psilocybin therapy. The difference between the 25 mg group and 1 mg group was -6.6 on the MADRS depression scale at week 3 (p<0.001).

“Over 100 million people around the world suffer with [TRD], and haven’t found relief from existing therapies. With every new treatment, the chance of responding decreases significantly, and patients become even more hopeless. Yet in this study, a substantial number of patients in the 25mg group experienced improvement in their symptoms of depression, with the effects lasting for up to 3 months,” said Scott Aaronson, MD, Chief Science Officer of the Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, and a principal investigator on the trial.

Participants who received a 25 mg dose also had double the sustained response at week 12 (20.3%), as compared with those who received 1 mg (10.1%). COMP360 psilocybin was generally well-tolerated; on the day of administration, common adverse events included headache, nausea, and dizziness.

“We saw positive results in a particularly difficult to treat group of patients, and the highest dose of COMP360 psilocybin had the greatest impact on people’s depression. This suggests that COMP360 psilocybin has a true pharmacological effect, a finding that is critical for it to be recognized as a new treatment option in the future,” said Guy Goodwin, MD, DPhil, Chief Medical Officer at COMPASS Pathways. “We look forward to starting our phase 3 program later this year, moving us closer to providing COMP360 psilocybin with psychological support for patients who desperately need it.”

1. Goodwin GM, Aaronson ST, Alvarez O, et al. 

Single-dose psilocybin for a treatment-resistant episode of major depression.

2. COMPASS Pathways announces publication of phase 2b study of COMP360 psilocybin therapy for treatment-resistant depression in The New England Journal of Medicine. News release. November 3, 2022. Accessed November 4, 2022. 

https://compasspathways.com/compass-pathways-announces-publication-of-phase-2b-study-of-comp360-psilocybin-therapy-for-treatment-resistant-depression-in-the-new-england-journal-of-medicine/

A single dose of psilocybin could help patients with treatment-resistant depression, according to a new study. 

A Single Dose of Psilocybin for Treatment-Resistant Depression

According to a new study, treating depression could lower the risk of dementia for certain patients.

Using data collected by the UK Biobank, researchers examined more than 350,000 participants, including 46,280 participants with depression. During the study, 725 of the patients with depression also developed dementia. Participants were categorized into 1 of 4 courses of depression: increasing course, with mild initial symptoms that steadily increase; decreasing course, with moderate- or high-severity symptoms that decrease; chronically high course, with ongoing severe depressive symptoms; and chronically low course, with mild or moderate depressive symptoms that are consistently maintained.

“For subjects with late-life depression, it is crucial to receive timely treatment. The onset of dementia reduced most significantly among patients with an increasing course, while treatment turned out to be disappointing for those with persistent high symptoms. Thus, timely treatment might be essential for subjects [with depression],” study leader Jin-Tai Yu, MD, PhD, exclusively told 

The study results suggested that depression elevated the risk of dementia by 51% as compared with participants without depression. Participants with increasing, chronically high, or chronically low course depression were found to be more prone to dementia, while those with decreasing course faced no greater risk than participants without depression. Participants with depression who received treatment had a 30% reduced risk of dementia compared to untreated participants.

“This indicates that timely treatment of depression is needed among those with late-life depression,” said study lead Wei Cheng, PhD. “Providing depression treatment for those with late-life depression might not only remit affective symptoms but also postpone the onset of dementia.”

As to further research, the study leaders shared with Psychiatric Times that future studies are needed to unravel the effect of different treatment types.

“In our study, we did not find any comparable difference between treatment types. However, since only 725 participants developed dementia, after being stratified by specific treatment types and depression courses, the statistical power might be insufficient to yield significant conclusions,” said Dr Yu. “Therefore, future research should stratify subjects [with depression] by types of treatment, for example, cognitive behavioral therapy, interpersonal therapy, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, etc.”

Depression, depression treatments, and risk of incident dementia: a prospective cohort study of 354,313 participants.

2. Timely interventions for depression might lower the future risk of dementia. Elsevier. News release. October 17, 2022. Accessed November 2, 2022. 

https://www.biologicalpsychiatryjournal.com/pb/assets/raw/Health%20Advance/journals/bps/BPS_221017_PR_Yang_et_al_FINAL-1666034440127.pdf

According to new research, treating depression in older adults could decrease risk of dementia by 51%. 

Treating Depression to Prevent Dementia

“Mr Vern” is a 35-year-old Caucasian male with a history of recurrent major depressive disorder (MDD), with illness onset in his teens. He has a history of anemia. Recently labs ordered by his primary care physician were significantly for mildly elevated high-sensitivity C-reactive protein (hs-CRP)level (5.0 mg/L). He is adherent with a selective serotonin reuptake inhibitor and clinically stable, as evidenced by no psychiatric hospitalizations in the past 5 years. However, he does have some residual symptoms of depression, including low energy and concentration. At his most recent outpatient clinic visit, he asks about taking an omega-3 fatty acid supplement. As his psychiatrist, would you prescribe omega-3 fatty acids for this patient, and if so, at what dose?

There is mixed evidence for adjunctive treatment with omega-3 polyunsaturated fatty acids (PUFA) in MDD.

 The dose and duration of treatment with PUFAs may contribute to heterogeneous findings. Furthermore, it is also possible that subgroups of patients with MDD, such as those with evidence of inflammation in the peripheral blood, may be more likely to respond to treatment with adjunctive PUFAs. There is also evidence that PUFAs decrease inflammation by reducing interleukin-6 (IL-6) and tumor necrosis factor (TNF).

 performed a 12-week, multicenter trial of 3 different doses of PUFAs (versus placebo) in patients with MDD and inflammation (hs-CRP level ≥ 3.0

 and body mass index [BMI] >25). They also investigated the impact of PUFAs on blood markers of inflammation, including plasma interleukin-6 (IL-6) and lipopolysaccharide-stimulated macrophage production of tumor necrosis factor (TNF).

The authors performed a parallel group, double-blind randomized controlled trial at 2 sites in the United States. Inclusion criteria were men and women aged 18 to 80 years with DSM-5 MDD without psychotic features, a BMI > 25, hs-CRP level ≥3.0, and a total Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30), score of ≥ 25 at screening and baseline.

Major exclusion criteria were lifetime neurocognitive disorder, psychotic or bipolar disorder, or anorexia nervosa; substance use disorder in the 3 months prior to screening; current obsessive-compulsive disorder or bulimia nervosa; serious suicidal or homicidal risk; serious or unstable medication illness; malignancy in remission for < 1 year; active autoimmune disorder; concomitant antidepressant use; and scheduled use of anti-inflammatory or other immunomodulating medications. 

Omega-3 PUFA capsules had a ratio of eicosapentaenoic acid (EPA):docosahexaenoic acid (DHA) of about 4:1. After screening, subjects were randomized equally to 1, 2, or 4 g EPA/day or placebo, and took 4 capsules twice daily for 12 weeks. Subjects had biweekly study visits, and fasting blood samples for inflammatory biomarkers were obtained at baseline and weeks 4, 8, and 12.

Data on changes in blood inflammatory markers was analyzed using non-parametric rank-order statistics. Data on changes in depressive symptoms were analyzed using mixed model repeated measures analysis. Data on whether changes in inflammatory markers were associated with changes in depressive symptoms was obtained using Spearman rank order correlations.

Sixty-one subjects were randomized to treatment, and treatment groups were not significantly different on baseline demographic or clinical characteristics. Approximately 51 subjects were evaluable for clinical efficacy, and 45 subjects completed the trial with adequate adherence, depressive symptom, and biomarker data.

In the analyses of biomarker data, after 12 weeks, median blood hs-CRP levels decreased in a dose-dependent manner in the PUFA groups compared to placebo. PUFAs failed to demonstrate a (small-to-moderate) effect size of ≥ 0.40 at weeks 8 and 12 for decrease in blood IL-6 or TNF production.

In the clinically evaluable sample (n=51), there were significant decreases in depressive symptoms in all 4 subject groups from week 4 to 12, with no significant between-group differences. In the completer sample (n=45), the EPA 4g/day group had a 64% response rate at week 12, compared to 36% to 40%, although this finding was not statistically significant. There was a significant correlation between the percent change in blood hs-CRP and depressive symptoms at 12 weeks in the EPA 4g/day group (ρ=0.69). Approximately 59% of subjects reported at least 1 (generally mild) adverse event, and no serious adverse events were reported.

The authors performed the first dose-finding trial of EPA in MDD to focus on inflammatory biomarkers. Although they did not find that EPA decreased blood IL-6 or TNF production, they did find that EPA 4 g/d was associated with increased sustained response rates for depression, with concomitant decreases in hs-CRP. Study limitations include the modest sample size, and the fact that treatment response was dichotomized. Data on baseline red blood cell or plasma lipids were not available. Furthermore, subjects were not taking antidepressants, so the effects of PUFAs in treated patients with depression and inflammation remains unclear.

High-dose (4 g/day) PUFAs may be effective for depression in some overweight or obese patients with inflammation, and reduction in hs-CRP may play a role.

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. Abdelhamid AS, Brown TJ, Brainard JS, et al. 

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease

Efficacy of omega-3 PUFAs in depression: a meta-analysis

 [published correction appears in Transl Psychiatry. 2021 Sep 7;11(1):465]. 

3. Ellulu MS, Khaza'ai H, Abed Y, et al. 

Role of fish oil in human health and possible mechanism to reduce the inflammation

4. Itariu BK, Zeyda M, Hochbrugger EE, et al. 

Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial

 [published correction appears in Am J Clin Nutr. 2020 Nov 11;112(5):1405]. 

5. Mischoulon D, Dunlop BW, Kinkead B, et al. 

Omega-3 fatty acids for major depressive disorder with high inflammation: a randomized dose-finding clinical trial

“Fishing” for novel approaches to depression: Researchers performed randomized dose-finding trial of omega-3 fatty acids for depression with inflammation.

Omega-3 Fatty Acids for Depression With Inflammation

“Mr Brad,” a 46-year-old, employed man, is seen in our clinic for medication management of chronic unipolar depression, generalized anxiety, and 

. At his most recent visit, he proactively shared that he was in the process of starting at-home ketamine through an online health care provider. He has tried various antidepressant and antianxiety medications, including 9 infusions of intravenous ketamine over the years for his mental health symptoms, with mixed results. His current medications include aripiprazole 10 mg, desvenlafaxine 100 mg, clonazepam 0.5 mg QID, and mixed amphetamine salts 20 mg QID. Although his symptoms have improved and he is functioning well, he still reports some mild, low-grade depression and 

Mr Brad underwent a virtual assessment with a multistate licensed online health care provider (HCP) who was physically located in another geographic area. According to the patient, he shared his medical history, medications, and current symptoms. He was not asked to sign a release, and we were not contacted by the HCP. This presented a clinical dilemma as to our role, responsibility, and liability if we continued to treat the patient with these medicines while he was receiving at-home ketamine though another provider.

There has been a recent proliferation of online health care businesses that offer at-home ketamine through virtual visits to patients suffering from a variety of mental health conditions. 

 is FDA approved for anesthesia and pain management but not for depression or any other psychiatric disorder.

 HCPs in many countries, however, can prescribe ketamine off label for nonapproved indications.

Ketamine can be rapid acting and studies have shown effectiveness in treatment-resistant depression (TRD), suicidal ideation, and other psychiatric conditions.

 The therapeutic effects are often attributed to its antagonistic effects on the NMDA receptor, 1 of 4 subtypes of inotropic glutamate receptors located throughout the central nervous system.

. The dissociative and altered state seen with ketamine may play an important role in its therapeutic benefits. Increased attention in the lay literature and on social media on ketamine as a psychiatric treatment alternative, as well as a tool to facilitate psychotherapy through its mind-expanding properties, has led more patients to seek out this potential therapy, with or without their HCP’s consent.

Simultaneously, there has been an uptick in utilization of online telehealth providers, particularly in mental health. This has been accelerated with technology advances, increased investor interest in this business model, and COVID-19 limiting in-office health care. These businesses claim to make mental health care more convenient, affordable, and accessible by offering care in locations with few mental health care providers.

Access to ketamine as a treatment option can be challenging to interested patients. Many HCPs are reluctant to suggest or use ketamine since it is not approved for psychiatric conditions. Psychiatrists more accepting of ketamine as a treatment option may not have the staff, space, training, or equipment to administer the medication in their offices. Nonpsychiatric health care practitioners including anesthesiologists, mid-level anesthetists, and other HCPs may be skilled at ketamine administration but not in managing patients with 

treatment-resistant psychiatric disorders

. Ketamine therapy can be costly since it is often not covered by insurance.

Esketamine has some similar pharmacokinetic and pharmacodynamic properties to ketamine since it is an isomer of the medication and is FDA approved for TRD and major depression with 

. Access to esketamine is limited since many insurances are reluctant to approve this treatment. Few mental health practitioners offer this treatment since they do not have the office space, comfort level, or ability to navigate the complex insurance obstacles restricting payment.

Recently, several telehealth companies have emerged offering virtual assessments and at-home ketamine delivery, including but not limited to Mindbloom, My Ketamine Home, and Smith Family MD.

 These companies specifically market to those looking for ketamine treatment. While promoting at-home ketamine for treatment of psychiatric disorders, many of these companies are led by medical directors without mental health training. Mindbloom, one of the largest such virtual, at-home services, does have psychiatric physicians on its leadership team, including 2 chairmen and vice chairmen of psychiatric hospital departments and a former chief medical officer of the US Department of Health and Human Services.

In 2008, the Ryan Haight Online Pharmacy Consumer Protection Act was passed after a 17-year-old boy died of an opiate 

 prescribed through a telemedicine consult.

 This law limited the prescribing of controlled substances through telemedicine consult without a face-to-face encounter and an adequate medical evaluation. In 2021, with COVID-19 affecting in-person health care, the Drug Enforcement Administration temporarily loosened the prescribing restrictions of Scheduled II-V controlled substances (CS).

 There is a legislative push to continue these lessened restrictions post-COVID.

“Mr Ryan” is a 65-year-old man who agreed to be interviewed regarding his experience with at-home oral ketamine prescribed through an online provider. Mr Ryan has suffered from dysthymia and mild anxiety without much relief from medication or counseling. He has used psychedelics including LSD, 

, and mescaline for spiritual growth and as a mind-expanding practice. He denies any history of recreational drug use. He reached out to 1 of the telehealth companies offering at-home ketamine after reading an article about the potential benefits of this therapy.

He paid an upfront fee for a package, which included an initial online meeting, follow-up, and exit assessment with a nurse practitioner (NP), 2 sessions with a ketamine “guide,” 6 doses of oral ketamine, and a kit that included a blood pressure cuff, eye mask, educational resources, journal, pen, and audio program to listen to during dosing.

The initial assessment was conducted virtually over 30 minutes in which he was asked about his symptoms, drug experiences, height, weight, medical history, and expectation of treatment. He had to show his blood pressure reading from his cuff. He was not asked to share his health care providers’ names, to sign releases for his HCPs, or to provide any blood work.

He was then sent 450 mg of oral dissolvable ketamine to his home. On the day of dosing, he had a virtual session with his guide during which he was told what to expect during dosing and how to take the medication, given therapeutic readings, and instructed to set an intention for the experience. He had to show his blood pressure readings and have someone else in the home with him before dosing. The guide was not online during the entire session but was available if needed. Mr Ryan was instructed to check in 1 hour after dosing.

Mr Ryan experienced a moderately high level of dissociation with no significant adverse effects. He found it to be pleasant and therapeutic. He had a follow-up visit with the prescribing nurse practitioner a few days later and was then sent all 5 remaining treatments at 750 mg per dose. He met virtually with the guide for the second session. During the last 4 sessions, he was not required to show any more blood pressure readings or to meet with the guide or the NP. He had unlimited access to the guide via texting if he desired.

After his sixth treatment, Mr Ryan had a virtual exit visit with the NP and was offered another 6 doses without a guide for a lower fee. He could pay extra for the guide as well as for an audio program for depression, anxiety, or self-esteem. Although his experience was positive overall, he did have some concerns about the level of monitoring. He would prefer an in-person, more closely supervised experience if it was affordable and available in a warm, therapeutic setting rather than a sterile, medical office environment.

At-home ketamine treatment initiated by an online provider presents many legal, clinical, and ethical challenges to HCPs and potential risks to patients. Some legal questions are whether online prescribing of ketamine, a Schedule III medication, meets criteria for the looser rules of prescribing a CS without an in-person examination, particularly if ketamine is being used for a mind-expanding, emotionally cathartic purpose. The current law states that the prescription must be for a legitimate medical purpose by a practitioner in their usual course of their professional role.

 Whether this meets that definition could be an area of debate. Additionally, by continuing their psychiatric medications and other treatment while they are receiving at-home ketamine, is a clinician giving consent to this treatment? Is a clinician liable if there are complications or drug interactions with a medication they are prescribing during at-home ketamine administration?

Issues of safety evoke clinical questions as to who should be prescribing concomitant psychiatric medicines during ketamine use. There may be medical and/or psychiatric changes related to ketamine dosing that could require alterations in the medication regimen. Although most side effects of ketamine are mild and transient, there are potentially serious safety concerns including elevations in blood pressure, anxiety, severe dissociation, 

 Long-term risks of therapeutic ketamine dosing remain unknown.

Although there are no specific guidelines for off-label ketamine administration, there are standards of care that often include a dosing range based on weight, a medical screening that typically includes baseline blood work, and, in many cases, drug screens and an EKG, along with coordination of care with the patient’s HCPs. Most clinicians dosing ketamine will follow blood pressure, pulse, and, in some cases, pulse oximetry and cardiac monitoring by a trained health care professional during each treatment. Esketamine shares many of the same risks as racemic ketamine and was approved with the restriction that it could only be administered under a Risk Evaluation and Mitigation Strategy (REMS) program.

 REMS is for certain medications with serious safety concerns to help ensure the benefits outweigh the risks. There is required registration and training for the patients, HCPs, and pharmacists. There is a 2-hour minimum observation by a medical professional and blood pressure monitoring in office with a prescriber onsite.

With the self-administration and availability of multiple dosing with at-home ketamine, there is an opportunity for intentional or unintentional overadherence and overdosing. There is a risk with combining at-home ketamine with alcohol or drugs of abuse including opiates, amphetamines, or benzodiazepines, or with legitimately prescribed medications that could have serious and life-threatening interactions.

This also raises questions as to whether oral ketamine is even efficacious in the treatment of any psychiatric condition. Ketamine been most studied with intravenous administration starting at doses of 0.5 mg/kg. There are only 2 randomized control studies looking at antidepressant efficacy of oral ketamine in which much lower doses were used than those given by many online prescribers.

 Most other studies are small case reports and series.

Oral ketamine has low and varied bioavailability (

), leading to questions such as what is the safe and effective dose to prescribe?

 Additionally, ketamine is a drug of abuse with street value. Online practitioners sending multiple doses at once puts the patients at risk of overdose, abuse, and diversion.

We made the decision to notify Mr Brad that we did not agree with his decision to undergo at-home ketamine. Our concern was whether this was an appropriate treatment for him and what we perceived was inadequate at-home monitoring. Furthermore, we were not comfortable with the concomitant use of benzodiazepines and high-dose stimulants. We suggested that if he was going to continue this treatment against our recommendation, he taper off both of those medications. We informed him that we felt it was unsafe for us to continue managing his psychiatric medications while he was self-administering ketamine at home.

This case illustrates an important issue that clinicians will likely soon confront (if they are not encountering it already). Although at-home ketamine is a reality for now, it is conceivable that similar issues may arise with other off-label or unproven therapies, including the much-hyped psychedelic medicines, becoming available to our patients. Access to these therapies, even when illegal, is becoming easier, and government agencies, medical regulatory bodies, and clinicians need to be prepared to manage these situations as they arise.

is a psychiatrist at PsychAtlanta/PsychAtlanta Research Center and on the faculty in the Department of Psychiatry at the Medical College of Georgia. Dr Banov reports disclosures as a speaker for AbbVie, Supernus, Janssen, Intracellular Therapies, and Teva. 

is an MD candidate at the Louisiana State University Health Sciences Center.

Acknowledgment: Thanks to Marla Fleming, APRN, for her assistance in this article.

1. Wilkinson ST, Toprak M, Turner MS, et al. 

A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders.

2. Sanacora G, Frye MA, McDonald W, et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. 

A consensus statement on the use of ketamine in the treatment of mood disorders.

3. Berman RM, Cappiello A, Anand A, et al. 

Antidepressant effects of ketamine in depressed patients.

4. Murrough JW, Iosifescu DV, Chang LC, et al. 

Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

6. Thielking M. Ketamine gives hope to patients with severe depression. But some clinics stray from the science and hype its benefits. STAT. September 24, 2018. Accessed August 16, 2022. 

https://www.statnews.com/2018/09/24/ketamine-clinics-severe-depression-treatment

7. Ketamine: science-backed, safe, and effective. Mindbloom. Accessed August 16, 2022. 

8. How it works. My Ketamine Home. Accessed August 16, 2022. 

9. Treatment protocol. Smith Ketamine Services. Accessed August 16, 2022. 

https://smithfamilymd.com/treatment-protocol/

Implementation of the Ryan Haight Online Pharmacy Consumer Protection Act of 2008.

11. DEA information on telemedicine. Substance Abuse and Mental Health Services Administration. 2020. Accessed August 16, 2022. 

https://www.samhsa.gov/sites/default/files/programs_campaigns/medication_assisted/dea-information-telemedicine.pdf

12. State telehealth policies for online prescribing. Center for Connected Health Policy. 2022. Accessed August 16, 2022. 

https://www.cchpca.org/topic/online-prescribing/

13. Jercich K. More than 70 orgs urge DEA: revise telehealth controlled-substance rules. Healthcare IT News. March 7, 2022. Accessed August 16, 2022. 

https://www.healthcareitnews.com/news/more-70-orgs-urge-dea-revise-telehealth-controlled-substance-rules

14. aan het Rot M, Collins KA, Murrough JW, et al. 

Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.

15. A long-term, safety and efficacy study of intranasal esketamine in treatment-resistant depression (SUSTAIN-2). ClinicalTrials.gov. Updated May 6, 2020. Accessed August 16, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02497287

16. Rosenblat JD, Carvalho AF, Li M, et al. 

Oral ketamine for depression: a systematic review.

17. Al Shirawi MI, Kennedy SH, Ho KT, et al. 

Oral ketamine in treatment-resistant depression: a clinical effectiveness case series.

18. Schoevers RA, Chaves TV, Balukova SM, et al. 

Oral ketamine for the treatment of pain and treatment-resistant depression.

Association of craving and depressive symptoms in ketamine-dependent patients undergoing withdrawal treatment.

At-home ketamine treatment initiated by an online provider presents many legal, clinical, and ethical challenges...

The Online, At-Home Ketamine Experience: A Clinician’s Dilemma

 covered a wide variety of psychiatric issues and industry updates, from assessment and management of older age bipolar disorder to the relationship between antidepressants and emotional numbing. Here are some highlights from the week.

Assessment of Individuals With Older Age Bipolar Disorder

The DSM-5 describes bipolar disorder (BD) as a condition that is characterized by recurrent and/or cyclical episodes of mania or hypomania and depression. In the DSM-5, there are 2 subtypes of BD: bipolar I disorder (BD-I) and bipolar II disorder (BD-II). A diagnosis of BD-I is established if an individual experiences at least 1 manic episode with additional major depressive and/or hypomanic episodes. Individuals are diagnosed with BD-II if they experience at least 1 hypomanic episode and at least 1 major depressive episode without any manic episodes. Although BD is not as common among older adults as it is among younger adults, available evidence indicates that the total number of older adults with BD is expected to increase significantly over the next few decades. It has been observed that between 1980 and 1998, the relative frequency of late-onset bipolar disorder increased from 1% to 11%. 

Antidepressants Do Not Work by Numbing Emotions

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that antidepressants are “not much better than a sugar pill.” It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression. 

Considering National and Personal Character in Russia’s Invasion of Ukraine

I caught a brief interchange of the September 27th “Late Show” when Stephen Colbert was interviewing the well-known foreign war correspondent Clarissa Ward. She seemed to be concluding that Russia has an unusual propensity to tolerate suffering, so that a long war would not be all that psychologically difficult for the country as a whole.

Her comment reminded me of how long Russia was able to hold out, starvation common by the end, to the siege of Leningrad by the German Nazis in World War II. They ultimately shifted the whole tide of the war. 

The Strength and Value of Organized Psychiatry

Is organized medicine really on the decline? As more nursing and other allied organizations are growing and becoming more politically active, what is happening to membership in physician organizations? Given the increasing stressors of the COVID-19 pandemic, gun violence, physician wellbeing, rising health care costs, the scope of practice issues, and government intrusion on medical decision making, this is a time when physicians, the field, and our patients need help more than ever. Is there still strength in numbers? 

. And be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

From older age bipolar disorder to the relationship between antidepressants and emotional numbing, here are highlights from the week in Psychiatric Times.

The Week in Review: September 26-30

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that 

 are “not much better than a sugar pill.”

 It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression.

Perhaps if we had a better understanding of antidepressants’ mechanisms of action—and how these mechanisms interact with this drug-responsive subgroup—we would be better able to predict which patients are likely to do well on antidepressants. Unfortunately, the matter is further complicated by the marked heterogeneity of 

 (MDD), which almost certainly contains several biological subtypes.

Critics of antidepressant treatment sometimes argue that antidepressants work—to the extent that critics acknowledge they work—by “numbing” or “blunting” emotions. Thus, Moncrieff has hypothesized that “Antidepressant-induced emotional numbness may directly reduce the intensity of people’s feelings of depression.”

 Similarly, Moncrieff and Horowitz have argued that

“…antidepressants appear to have a generalized emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it…[but] if antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

A recent review provided a much more nuanced picture, concluding that

“Emotional blunting has been reported by many patients diagnosed with MDD, but its neuropsychological basis remains indefinite. Most patients specifically attribute this symptom to their antidepressant medication; however, some psychologists believe that emotional blunting is also a residual symptom of depression due to incomplete treatment.”

In this article, we examine 3 independent studies of antidepressant treatment in major depression and its effects on emotional numbing or blunting. The key difference between 2 of these studies and much of the critical writing about antidepressants is their use of the 

Oxford Questionnaire on the Emotional Side-effects of Antidepressants

 (OQESA or OQuESA)—arguably the “gold standard” of assessment in this area.

 (This scale is now called the Oxford Depression Questionnaire, or ODQ.)

We shall see that none of the studies support the claim that antidepressants act to reduce depression through a process of emotional blunting or “numbing.” This is not to deny the clinical importance of assessing emotional blunting in the course of antidepressant treatment, nor is it to discount in any way the patient’s felt experience during treatment.

A Randomized-Controlled Study from France

Corruble and colleagues carried out a randomized, controlled, double-blind study comparing agomelatine (25-50 mg/d, n=164) and the SSRI, escitalopram (10-20 mg/d, n=160).

 Agomelatine is an atypical antidepressant that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. It is not approved for use in the United States. [

https://www.psychiatryadvisor.com/home/depression-advisor/unique-attributes-of-agomelatine-might-renew-interest/]

The trial involved 12 weeks of active treatment, then a 12-week double-blind extension. The effects of these drugs on emotional experiences were compared in patients who completed the OQESA (agomelatine: n= 25; escitalopram: n= 20). Agomelatine and escitalopram similarly improved depressive symptoms, but emotional blunting was reported by 60% of patients taking escitalopram, versus 28% of those taking agomelatine.

At baseline before antidepressant treatment, the emotional experiences probed were extremely common and the same in both treatment groups. Of 20 OQESA items, 8 were more common in the escitalopram group and 12 in the agomelatine group. The occurrence of blunting items was associated with the depressed state measured by the Hamilton Depression Scale (HAMD) and Clinical Global Impression (CGI). Emotional blunting was significantly less prominent after 2 weeks, 12 weeks, and 24 weeks of treatment. At 24 weeks, emotional blunting was endorsed more frequently in the escitalopram group than in the agomelatine group, despite similar depression ratings in the 2 groups.

The authors concluded that “emotional blunting is prominent among patients with MDD at baseline” and hypothesized that emotional blunting “…behaves overall like a correlate of depressive symptoms.”

“The simplest explanation for our present findings is that emotional blunting is a symptom of depression not measured in conventional scales, which is incompletely treated with SSRIs as compared with agomelatine.” 

In short, the study findings provide no support for the claim that antidepressants act by a generalized emotion-numbing effect.

Two More Studies Reach Similar Conclusions

In a 16-week study of 98 patients diagnosed with MDD, Aşçibaşi et al analyzed the effects of antidepressant treatment (SSRI, n = 41; SNRI, n=40, other, n=13) on Montgomery-Åsberg Depression Rating Scale (MADRS) and OQESA scores.

 The OQESA scale was used at the 8- and 16-week visits. In brief, the study found that 

as the rate of remitted patients is increased, OQESA scores get decreased; 

and furthermore, the OQESA score of the remitted group was statistically low when compared with that of the nonremitted group at the 8- and 16-week visits. OQESA and MADRS scores were significantly correlated in all assessments. The authors opined that “…during the treatment of depression, depression-related emotional blunting symptoms and antidepressant-related emotional adverse effects may coexist”; however, “…as the severity of [the] depressive syndrome decreases, the severity of emotional adverse effects due to the antidepressants also decreases.”

These findings are not consistent with the claim that 

 reduce depressive symptoms via an emotion-numbing effect.

Finally, Peters et al analyzed data from adult outpatients with acute MDD who participated in 3 8-week randomized controlled trials.

 Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383), and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the “inability to feel” item from the MADRS. The study found that emotional responsiveness 

, on average, in all treatment groups, and that fewer than 6% of participants experienced more emotional blunting after antidepressant treatment. The authors acknowledged that this was a short-term study that cannot speak to the long-term effects of antidepressant treatment. Nonetheless, they concluded that, “The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response.” Rather—and consistent with the previous 2 studies—the authors hypothesized that “In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.”

Some Important Caveats and Study Limitations

 highlight the methodological advantages and limitations of the research discussed in this article. The Peters et al study has the highest-quality evidence, using completed controlled clinical trials, with a substantial number of research participants in each arm, including the placebo group.

 The study also uses the most neutral screen for emotional blunting, in that there is no suggestion of what might be the cause.

 both use the OQESA/ODQ, which was designed to measure more than emotional blunting and has a separate section to determine if the patient endorses emotional blunting to be caused by antidepressant treatment. The wording of the questions—and the fact that no other possible etiology for emotional blunting is suggested in the remainder of the questionnaire—is a potential source of bias. In this case, the participants are forced to choose antidepressants as an etiology. In effect, this is a “leading question,” and research participants may be able to guess that antidepressant induced emotional blunting is a focus of the research.

 In contrast, MADRS Item 8 captures emotional blunting but does not suggest a specific cause.

Emotional numbing or blunting is a fairly common complaint among patients taking serotonergic antidepressants and appears less common with noradrenergic/dopaminergic agents like 

 It is important to inform and educate patients about this problem and to inquire about it periodically, since emotional blunting is both distressing and associated with poor adherence to antidepressant treatment.

 However, it should not be assumed that the patient’s antidepressant is necessarily 

 of the patient’s complaint, since emotional blunting or numbing is frequently reported at baseline (prior to treatment).

Indeed, the studies reviewed here show that antidepressants did 

 significantly decrease emotional responsiveness, and that treatment response was 

 mediated by emotional blunting. More likely, emotional numbing, in most cases, is a residuum of the original depression.

How, then, do antidepressants work? Their precise mechanism of action is not fully understood, although recent studies point to the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which is now regarded as “… a key player in antidepressant action.”

 Antidepressants may also have anti-inflammatory effects—potentially important, since major depression is associated with elevated biomarkers of inflammation.

 During the past 4 years, 2 antidepressants modulating the glutamate system have been approved by the US Food and Drug Administration (FDA) for the treatment of major depression.

As patients improve with antidepressant treatment, emotional numbing decreases.

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