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#403 Hotcakes: Ketamine, Kratom, Nonhormone therapy for menopause, Metformin for long COVID, and New Breast Cancer Screening Recs

July 10, 2023 | By



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Join us as we review recent practice-changing articles on ketamine vs ECT for refractory depression, nonhormone treatment (fezolinetant) for menopause, metformin for long COVID, new breast cancer screening draft recommendations, and a primer on kratom. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).

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Show Segments

  • Intro, disclaimer
  • Ketamine vs ECT for refractory depression, 
  • Nonhormone treatment (fezolinetant) for menopause, 
  • Metformin for long COVID, 
  • New breast cancer screening draft recommendations, 
  • A primer on kratom
  • Outro

Hotcake #1 Ketamine for Depression (Rahul)

Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ect for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315-2325.

What was the research question? Is ketamine non-inferior to electroconvulsive therapy (ECT) for moderate-to-severe treatment-resistant depression?

Why is this study important? 1 in 3 patients with depression have a suboptimal treatment response. ECT is an effective option for these patients, but has downsides: it requires general anesthesia, produces transient cognitive and memory impairment, and some stigma remains. Ketamine is increasingly being used for treatment-resistant depression, but prior studies have not confirmed its efficacy. 

How was the study done? This was a randomized, unblinded, pragmatic non-inferiority trial: patients were randomized to receive ECT (3 times per week for 3 weeks) or IV ketamine (2 times per week for 3 weeks). The primary outcome was a 50% or greater reduction from baseline level in the QIDS-SR-16 (a SIGECAPS symptom inventory) at 3 weeks. Patients who had a response to either treatment were followed for 6 months for assessment of secondary outcomes. 

Who were the patients? 400 patients with moderate-to-severe depression without psychosis were randomized. Patients were in their mid 40s, roughly equal men and women, essentially all non-hispanic white, and 90% were outpatients. The average duration of depression was over 20 years, with a median of 5 previous episodes. The majority had a family history of depression, and 1 in 3 had attempted suicide. Many had concomitant anxiety; comorbid substance use disorders were uncommon.  

Top-line results: At 3 weeks, 55% of patients getting ketamine had a clinical response, compared with 41% of patients getting ECT. The non-inferiority margin was -10%, and the absolute difference was +14% (+3.9 – +24.2), confirming noninferiority. Both groups had a similar improvement in quality of life at 6 months. Musculoskeletal pain and weakness were more common with ECT, and dissociative symptoms were more common with ketamine. 

Learning points & limitations: There are at least two sources of bias towards ketamine performing better in this study. The first is differential loss to follow-up: 16% of people assigned to ECT didn’t do it, vs only 3% of those assigned to ketamine (this is also a type of post-randomization selection bias). The second is that ECT was unilateral: this is less effective than bilateral ECT, but aims to minimize adverse effects. Unanswered questions from this trial about the durability of response and the consequences of long-term ketamine use (40% of patients at 6 months were still using ketamine) remain.

Bottom line/Hotcakes rating: 4/5

Further reading:

Hotcake #2 Non-hormonal therapy for VMS (Watto)

Lederman S, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023 Apr 1;401(10382):1091-1102. doi: 10.1016/S0140-6736(23)00085-5. Epub 2023 Mar 13. PMID: 36924778. 

What was the research question? Does fezolinetant, a neurokinin 3 receptor antagonist, reduce the frequency and severity of vasomotor symptoms of menopause and lead to meaningful improvement in quality of life?

Why is this study important? Many women have comorbidities that preclude the use of hormonal therapy. Fezolinetant is a non-hormonal first-in-class NK3 antagonist to treat vasomotor symptoms.

How was the study done? This was a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. The trial included 97 sites in the USA and Europe. Participants were assigned 1:1:1 to once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg.

Who were the patients? Women 40–65 years old without any major comorbid conditions (cancer, kidney, liver disease, even hypertension) with an average of seven or more moderate-to-severe hot flashes per day.  

Top-line results: This was a positive trial. Fezolinetant 30 mg and 45 mg once daily were efficacious and well-tolerated versus placebo. Co-primary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. Participants had an average of 10-11 hot flashes per day at baseline in all treatment groups. At week 12, this dropped to less than 5 hot flashes per day in both treatment groups compared with 7 per day in the placebo group. Severity of hot flashes was also reduced. They did not observe an improvement in patient reported sleep disturbance.

Learning points & limitations: This was a positive trial. Looking for sources of chance or bias that could explain this, one concern is that it was funded by Astellas Pharma (4 authors were employees). The consort diagram also shows that this was a somewhat highly selected population, with only 25% of screened patients ultimately enrolled. There is also evidence of regression to the mean in severity of menopause symptoms, which illustrates the importance of having a placebo group. A strong placebo effect has also been observed in prior studies of menopause therapies, which could explain the improvement in the placebo group.  

Bottom line/Hotcakes rating 3.5/5

Further reading:

  • Nonhormone therapy position statement of NAMS 2023 (PMID: 37252752): Includes a level 1 recommendation in favor of using fezolinetant.
  • SKYLIGHT-2 (Johnson, 2023): Identical trial to SKYLIGHT-1.
  • SKYLIGHT-4 (Neal-Perry, 2023): No increase in endometrial hyperplasia or malignancy. Liver test abnormalities more than three times upper limit were more common with fezolinetant than placebo, but absolute numbers were small. 

Hotcake #3 Metformin for Long COVID (Paul)

Bramante CT et al.  2023.  Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.  The Lancet Infectious Diseases June 8; S1473-3099(23)0029902. doi: 10.1016/S1473-3099(23)00299-2.

What was the research question? Does treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV2 infection reduce the risk of long COVID among outpatients?

Why is this study important? The CDC reports that 19% of patients who have had COVID are still experiencing symptoms. Long COVID disproportionally affects racial and ethnic minority populations.

How was the study done? This was a secondary analysis of a previously published investigator-initiated, randomized, quadruple-blind, placebo-controlled study. In this study, the primary outcome was cumulative incidence of long COVID, assessed via monthly follow-up with patients for 300 days. In the original study, participants were randomized in a 2 x 3 factorial design; in this study, outcomes were compared among patients who received metformin and placebo (for 14 days each)

Who were the patients? Overweight or obese adults aged 30-85 years who had COVID-19 symptoms for less than 7 days with a positive test within 3 days of enrollment were included. Patients with prior COVID, prior exposure to study drugs, and who received treatment for COVID-19 with one of the FDA-authorized medications (including remdesivir and nirmatrelvir/r) were excluded. Pregnant and lactating women were not excluded.

Top-line results: Outpatient treatment of acute COVID with metformin reduced long COVID incidence by 41% at 300 days (absolute risk reduction: 4.1%).  

Learning points & limitations: This was a positive study. Although ascertainment of the outcome relied on self-report of a poorly defined entity, this study was generally well-designed and there are not many sources of chance or bias that seem like they could explain these results. However, a major limitation in our ability to apply these results is that this study population is very difficult to identify: many people receive treatment for COVID with remdesivir or nirmatrelvir/r, and with >95% of people having some form of immunity from vaccination and infection, whether the same magnitude of benefit seen in this study exists today is unclear. Notably, the NIH treatment guidelines still do not recommend the use of metformin, but it remains to be seen how these data will affect the guidelines.

Bottom line/Hotcakes rating: 4/5 (Paul says, “compelling, but not sure I’d change management just yet.”) 

Further Reading:

Hot take #1 Breast Cancer Screening Age (Watto)

USPSTF Draft Recommendation Breast Cancer Screening 2023

Summary: Due to an increase in breast cancer in younger women and poorer breast cancer outcomes in Black women, the USPSTF task force is changing from a grade “C” to a “B” for screening women in their 40s. The task force continues to give “I” statements for screening women aged 75 years or older and supplemental screening for women with dense breasts.

Bottom line: The standard breast cancer screening age will be decreased from 50 to 40 years old every other year (per the draft recommendation). We still don’t know how to best handle additional screening for women with dense breasts and continued screening for women over 75 years old. It should be noted that the American College of Radiology and Society for Breast Imaging issued a joint statement encouraging annual screening for average-risk women above 40 years old (B rating) and to continue screening as long as the woman remains in good health and has a reasonable life expectancy. 

Hot take #2 Kratom (Paul)

Swogger MT, et al. Understanding Kratom Use: A Guide for Healthcare Providers. Front Pharmacol. 2022 Mar 2;13:801855. doi: 10.3389/fphar.2022.801855. PMID: 35308216; PMCID: PMC8924421. 

Summary: Kratom comes from the leaves of a tree indigenous to Southeast Asia, where it has been used for centuries as a medication to treat things like hypertension, cough, and fever. It has been traditionally used at low doses as a stimulant to increase productivity, and was popular among field laborers. It also has analgesic properties. It remains widespread in its native lands, where leaves are chewed or brewed into a tea. 

Kratom contains dozens of alkaloids, including mitragynine and 7-hydroxymitragynine, which are primarily responsible for its psychoactive properties. Both substances have partial affinity for the mu opioid receptors, which is what is thought to be why there are analgesic effects. It does not activate the beta arrestin pathway that results in respiratory depression or sedation, and appears to also work as a COX-2 pathway inhibitor, have alpha-2 agonism, and serotonergic and dopaminergic antagonism as well!

Kratom use has spread to the West (estimated 10-16 million US adults have used), where it is sold at head shops and gas stations in concentrated form as powders and capsules. It is not recognized as a dietary supplement by the FDA, and is currently not regulated by the DEA, although it is listed as a “substance of concern.”

Used primarily for management of pain, mood, and increased attention, there are case reports of Kratom being used to mitigate opioid withdrawal. Increasing use has led to increased reports of dependence, withdrawal syndromes, and increased Poison Control calls. Case reports describing adverse effects include seizures, transient paralysis, liver injury, and even cardiopulmonary arrest. It is hard to assess mortality data. The dependence and withdrawal appears to be milder than with opioids, and there are case reports of treating Kratom use disorder with buprenorphine.

Bottom line: There isn’t enough known to make a lot of recommendations at this time, but keep your eyes peeled as use increases and consider assessing for Kratom use in patients with other substance use.  


Links are included in the show notes above.


Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

  1. Discuss the use of ketamine for refractory major depression
  2. Determine the utility of metformin to prevent long COVID
  3. Discuss the safety and efficacy of fezolinetant for vasomotor symptoms of menopause


The Curbsiders report no relevant financial disclosures. 


Ganatra R, Williams PN, Watto MF. “#403 Hotcakes: Ketamine, Kratom, Nonhormone therapy for menopause, Metformin for long COVID, and New Breast Cancer Screening Recs”. The Curbsiders Internal Medicine Podcast. Final publishing date, July 10,


  1. July 14, 2023, 8:48pm Phillip Madonia writes:

    Your podcasts and transcripts are concise and on point. You are a treasure!

  2. July 15, 2023, 1:11am Rahul Ganatra writes:

    Thanks for listening and for your kind words!

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Episode Credits

Written and Hosted by: Rahul Ganatra MD, MPH; Paul Williams, MD, FACP, Matthew Watto MD, FACP

Cover Art: Matthew Watto MD, FACP

Reviewer: Rahul Ganatra MD, MPH

Technical Production: Pod Paste

Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP

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The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit and search for this episode to claim credit.

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