Ketamine for Treatment-Resistant Depression: New Studies on Safety and Cognitive Impact

What’s happening – Two recent studies examined the role of ketamine in helping people with treatment-resistant depression (TRD). In the first study, Araújo de Freitas et al examined the neurocognitive aspects of ketamine and esketamine for treating TRD. Patients (n=54) were infused with either ketamine or esketamine and cognition was assessed at three points: baseline, 24 hours after infusion and 7 days later. The team found that both ketamine and esketamine improved some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed and several measures related to episodic verbal memory. The authors noted concerns from previous research that showed ketamine may lead to cognitive impairment in high doses, as well as impairment in antidepressant doses, but wrote that most studies have shown cognitive improvement. Treatment with both drugs was found to be cognitively safe when used at low levels for depression in this study, and the authors consider it “imperative” that the safety of long-term use be further researched in the future.

More on ketamine and esketamine and cognition in our Psy-Q below.

The second study investigated the assumption that ketamine could exacerbate psychotic symptoms in people with TRD and psychosis, a supposition that often excludes these patients from clinical trials. Veraart et al conducted a systematic review of 9 pilot studies (n=41) and found that this assumption was not supported by the data. Short-term ketamine use was found to be safe and effective for this patient population with no psychotic exacerbation observed. The authors wrote that in some cases, psychotic symptoms improved or disappeared after administration of ketamine or esketamine for TRD.

Why it’s complicated – A limitation to using ketamine for TRD is that the time to relapse can be relatively short (median 2-4 weeks), wrote McMullen et al in a systematic review designed to explore strategies to prolong ketamine’s effects. The team reviewed 22 studies and found that no modality was able to sufficiently prolong the acute efficacy of ketamine in TRD, but that several modalities showed potential.

Reports & Perspectives

  • Maintaining the initial treatment gains of ketamine infusions for TRD is “a major unmet need,” wrote George I Papakostas, MD, in the Journal of Clinical Psychiatry.
  • ABC News recently covered the increasing awareness and use of ketamine to treat depression and mentioned the access issues for patients whose insurance typically does not cover its use.
  • In a study published in Psychiatric Research, Rosenblat et al evaluated the impact of COVID-19 restrictions on the effectiveness of ketamine infusions for patients with TRD and found that its effectiveness was comparable when compared to a group of patients who had received infusions prior to the pandemic.
  • @JD_Rosenblat (Joshua Rosenblat, MD, MSc, FRCPC, and lead author of the COVID-19 study above) tweeted about a paper that he co-authored about ketamine’s side effects, “See our practical paper on Prevention and Management of Common Adverse Effects of #Ketamine and #Esketamine in Patients with #Mood Disorders”
  • @KetamineClinics (Ketamine Clinics Los Angeles) linked to a Fox News segment on ketamine, tweeting, “Two of our wonderful patients were featured with Ketamine Clinics Los Angeles on @FOXLA news in a segment featuring Ketamine Infusion Therapy for the treatment of Mood Disorders.”
  • @amp6 (Anna Mehler Paperny, a Reuters reporter and author of a memoir about mental illness, Hello I Want to Die Please Fix Me) tweeted about her article in The Globe and Mail, “I wrote about ketamine; our flawed, evolving understanding of depression; and chasing wellness when your brain doesn’t remember what ‘well’ means.”

In Practice

Psy-Q Challenge

Are ketamine and esketamine cognitively safe in subanesthetic doses to manage TRD? Lucas Araújo de Freitas MD, PhD, and Lucas Quarantini MD, PhD, answer.

Get the Answer

Aduhelm’s Future: Controversy over FDA Approval of Alzheimer’s Drug Continues

What’s happening – Since the FDA’s controversial approval of aducanumab (Aduhelm, Biogen) in early June 2021, uncertainty and debates about the drug’s future are still going strong. Here’s a quick overview:

Revised prescribing instructions for aducanumab

  • FDA’s approval of aducanumab was initially for all individuals diagnosed with Alzheimer’s disease but on July 8, the agency updated its prescribing guidelines to only include those individuals with mild cognitive impairment or mild dementia. This change is in line with the population that participated in Biogen’s clinical trials of the drug.

Investigations into aducanumab’s approval

  • On June 24, Senators Elizabeth Warren (D-MA) and Bill Cassidy, MD, (R-LA) called for a hearing to examine “the vexing new questions and challenges” that aducanumab’s approval raises for Medicare.
  • On June 25, the House Committees on Oversight and Reform and on Energy and Commerce announced an investigation into aducanumab’s approval process. They asked the FDA for more detailed documentation about pricing and business strategies for the drug on July 12, citing concern for its “atypical approval process.” The July 12 letter also cited a STAT News report about an alleged secret campaign called Project Onyx in which Biogen tried to persuade the FDA to approve the drug.
  • On July 9, FDA acting chief Janet Woodcock, MD, asked the Office of Inspector General (OIG) to conduct an independent review of the agency’s decision to approve aducanumab and of the interactions between FDA and Biogen representatives.
  • The OIG said last week that it will investigate the FDA’s accelerated approval pathway and its use in the approval of aducanumab, but that it “will not assess the scientific appropriateness of the FDA’s approval of any of the drugs under review.” The OIG’s review may come in multiple reports and is expected to be completed in fiscal year 2023, which begins on Oct. 1, 2022.

How will patients get Aduhelm?

  • This week, the VA said it will not include Aduhelm on its national formulary, citing lack of evidence of efficacy and a risk of severe side effects. Biogen told Reuters that there is a pathway for VA patients to get the drug under certain circumstances.
  • Last month, the Cleveland Clinic and Mount Sinai’s Health System in New York City decided not to administer Aduhelm to patients, although doctors are able to prescribe it for patients to receive elsewhere.
  • Time asks whether Aduhelm “will make a difference” if clinics won’t provide it and insurers won’t cover aducanumab, and STAT News discusses the Aduhelm limbo that patients face while waiting for hospitals and insurers to decide what to do about the drug.

Opposing viewpoints on aducanumab

  • JAMA Internal Medicine published several viewpoint articles about the issue last month. One article from FDA representatives explained why Aduhelm was a good fit for the accelerated approval pathway, while another calls for reforms for this approval pathway, and another article discusses the problems facing Medicare.
  • Two weeks ago, NEJM published three editorials about Aduhelm. One was a similar article from FDA members defending the use of the accelerated approval pathway; another was a perspective from seven current or former FDA members of the Peripheral and Central Nervous System Advisory Committee that advised the agency not to approve Aduhelm, including the three members who resigned in protest after the approval, that explains why they believe the “FDA’s decision is at odds with the evidence” and the drug should not have been approved; while a third editorial discussed what clinicians should know when prescribing aducanumab.
  • @akesselheim (Aaron Kesselheim, one of the three FDA advisory panel members who resigned after Aduhelm’s approval) tweeted about the FDA’s revised prescribing information issued on July 8, “This is a welcome step and addresses one of many problems with this drug approval, but the FDA/Biogen should be doing much more now to help patients by actively combatting misperceptions about this drug.”
  • @reshmagar (Dr. Reshma Ramachandran, MD, MPP, who previously shared her views with Psycom Pro) addressed the FDA’s JAMA article in a heated thread on Twitter, “So many issues with this piece in @JAMAInternalMed from @US_FDA officials (Dunn, Stein, & Cavazzoni) attempting to justify their poor choice in approving #aducanumab – don’t bother reading it unless you want your blood to boil. I’ll summarize instead
  • @jasonkarlawish (Jason Karlawish, MD, professor of medicine at UPenn) tweeted, “In this @PhillyInquirer essay ‘We can’t drug our way out of despair over Alzheimer’s’ I explain why @US_FDA approval of @biogen #aduhelm angers some caregivers & persons living with #Alzheimers. This is the latest event in a century long, maddening story…”
  • @Penn_Memory (The Penn Memory Center at Penn Medicine) quoted Dr. Jason Karlawish in a recent podcast with Dr. Kesselheim, “The belief that approval of Aduhelm (aducanumab) will lead to greater innovation in Alzheimer’s research is ‘a business argument…not a scientific argument…not a public health argument. And I reject it,’ said @jasonkarlawish on @GeriPalBlog.”

In Practice

How to talk to patients and caregivers about aducanumab

Zuranolone for Postpartum Depression: Phase 3 Results Show Reduction in PPD Symptoms

What’s happening – Zuranolone (Sage Therapeutics, Biogen), an investigational once-daily oral medication for postpartum depression (PPD), performed better than placebo at reducing PPD symptoms in a double-blind, randomized, Phase 3 clinical trial of 151 women with PPD who took it for 2 weeks. The study used the 17-item Hamilton Rating Scale for Depression (HAMD-17) to assess treatment response. The authors observed reductions in depressive symptoms by Day 3, and these were sustained through Day 45.

Zuranolone has a similar mechanism of action to Sage’s brexanolone (Zulresso), which is an injectable neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator that is administered over a period of 60 hours. Brexanolone received FDA approval in March 2019 and is the first drug to be specifically approved for PPD. Because patients must be monitored during the 60-hour infusion period in a clinical setting, and the drug costs $34,000 without insurance, its access is limited. Zuranolone could be taken orally at home, and although the price is yet unknown, the hope is that, if approved, it will be more accessible to women who need it.

Zuranolone is also being studied for the treatment of major depressive disorder (MDD), for which it received breakthrough therapy designation from the FDA in 2018.

Why it’s complicated – The COVID-19 pandemic has increased feelings of depression, anxiety, loneliness, and post-traumatic stress in pregnant and postpartum women, according to a worldwide survey of 6,894 women conducted by Harvard researchers. The authors noted that the levels of distress reported in the study were higher than what was found in this population pre-pandemic and highlighted the need for specialized outreach.

Reports & Perspectives

  • PPD does not only affect women—roughly 10% of new fathers experience depression after a child’s birth, and up to 25% during the 3- to 6-month postpartum period, writes Kim Hooper in a New York Times piece about her husband’s struggle with post-partum depression.
  • Read Time’s coverage of the recent zuranolone trial data.
  • NPR reported on the difficulties faced by women in California who want brexanolone for PPD but have trouble navigating their insurer’s hurdles.
  • A study on state paid family leave policies found that the plans improved mental health among new parents. Findings were mixed for the effects on children’s mental health.
  • @JClinPsychiatry (Journal of Clinical Psychiatry) tweeted: “In the West, #postpartum #depression & #psychosis have been linked to later mental disorders in both mothers & children, but does this hold true for #Asian populations? This analysis of data from a #Taiwan insurance database investigated that question.”
  • @thecrimson (The Harvard Crimson) tweeted, “Pregnant and postpartum women around the world reported high levels of loneliness, post-traumatic stress, and anxiety or depression during the Covid-19 pandemic in a Harvard School of Public Health study”
  • @NPR tweeted, “Becoming a mother is a huge life transition. The feeling of being on an emotional rollercoaster, not recognizing your body in the mirror, thinking that you’ve lost yourself — it’s all part of the process, and it’s called matrescence.” Within that article is a link to their prior report on PPD.

In Practice

Last Updated: Aug 26, 2021