12:32 PM

476 - Cholinesterase Inhibitors, Ketamine and Depression, Don’t “Dis” Grief

Take 3 – Practical Practice Pointers©

From the Literature

1) Cholinesterase Inhibitors for Dementia and All-cause Mortality


Cholinesterase inhibitors (donepezil, galantamine and others, “CEIs”) have been the sole available pharmacologic therapies for dementia for years. Interest in their routine use is tempered by the findings of only small, short-term benefits in cognitive ability and functional status from these medications. The authors of a new systematic review reflected that CEIs also have cardiovascular effects and asked the question – do CEIs impact long-term overall mortality and cardiovascular mortality in patients with dementia?

The authors used a comprehensive search to include both randomized controlled trials (RCTs) and non-randomized controlled studies with a lower risk of bias (e.g., cohort studies, but not case-control studies). Studies involving the use of CEIs for any type of dementia and lasting at least 24 weeks were included. The review was conducted using the PRISMA review checklist and rigorous quality standards for systematic reviews.

The review found 12 RCTs (N = 7272) and 12 non-randomized controlled studies (N=71,881) that contained data for all-cause mortality. The age of the subjects ranged from 69 to 85, and the baseline mini mental status exam scores (available for 15 of the 24 studies) ranged from 21.8 to 6.5. The RCTs were generally of low risk of bias but were shorter (mean 9 months). The non-randomized studies were longer (mean 36 months), most were at moderate risk of bias, and only one was a prospective study.

The unadjusted death rates from 15 RCTs showed a decreased risk of all-cause mortality (RR 0.74, 95% CI 0.66 to 0.84). When adjusted death rates from the multivariable analysis of 11 cohort studies and 1 RCT were pooled, there was a similar decreased risk (RR 0.77, 95% CI 0.70 to 0.84). The estimated number need to treat for a year to avoid one additional death was 29 (95% CI 22–42). Cardiovascular mortality was also significantly reduced (after analysis of the 5 studies with this outcome), from 5.1 per 100 person-years in control patients to 3.4 per 100 person-years in CEI patients.

There was no heterogeneity in the RCTs, but significant heterogeneity in the non-randomized studies – which the review authors explain by differences in settings and populations in these studies. The results were robust to several careful sensitivity analyses, including one that showed that adding the non-randomized studies to the RCTs reduced the effect size, which the authors interpreted as a confirmatory sign, since the typical result of bias in studies is to overestimate the effect. A funnel plot was asymmetric, revealing some possibility of publication bias, but a trial sequential analysis (used to evaluate the strength of association across a body of evidence) showed that future studies were very unlikely to change this association.

The authors propose several hypotheses to explain the improvement in all-cause mortality, but the true explanation remains uncertain.

John’s Comments:

This evidence brings up a difficult management issue. Reviews to date on the effects of CEIs on cognitive function and quality of life have shown only limited benefit, so we must integrate the possibility of prolonging life with these medications with their inability to improve its quality substantially, as well as their known adverse effects (nausea, dizziness, bradycardia, syncope, etc.). These medications should be prescribed after thoughtful conversations with patients and family members (when possible).


·         Truong C, Recto C, Lafont C, Canoui-Poitrine F, Belmin JB, Lafuente-Lafuente C. Effect of Cholinesterase Inhibitors on Mortality in Patients With Dementia: A Systematic Review of Randomized and Nonrandomized Trials. Neurology. Published online September 12, 2022. Link

From the Pharm and a Question From a Colleague

2)  The Uses of IV Ketamine



“I’m recently had a patient ask about IV ketamine infusions for depression.  Is this legit?” 


Intravenous ketamine is a relatively new option in patients with treatment resistant depression (TRD).  Ketamine’s mechanism of action as an NMDA receptor antagonist is thought to have an antidepressant effect through the downstream enhancement of glutamatergic neurotransmission.  When first studied in 2000, ketamine was shown to have therapeutic reductions in depression scores compared to placebo.  However, ketamine is not indicated by the FDA for TRD—thus, infusions are rarely covered by insurance and may be too expensive for most patients when paid for out-of-pocket. However, more affordable alternatives may be available to patients with TRD.

Both peer-reviewed guidelines and meta-analyses support the short-term efficacy of ketamine in TRD. The 2021 Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines recommend ketamine as a third-line treatment for depression in adults after failing eight-week trials of two or more first-line antidepressants from different classes with one or more adjunctive agents. Additionally, a 2016 meta-analysis of 9 double-blinded randomized control trials by Han et al. supported intravenous ketamine’s efficacy in reducing depression scores at 24 hours, 72 hours, and 7 days post-treatment timepoints. However, less evidence exists to support long-term efficacy.

The adverse effects associated with intravenous ketamine normally take place during and shortly following infusion. Up to 80% of patients experience dissociation and hallucinations during infusion, but these symptoms usually resolve within one hour. Additionally, patients often experience vestibular symptoms—such as dizziness (43%), nausea/vomiting (34%), and headache (32%)—and sympathomimetic symptoms like hypertension and tachycardia (9%) during infusion. The CANMAT guidelines recommend close monitoring for at least one hour following infusion and for patients to be discharged once their vital signs and mental state have returned to baseline. Long term safety studies have not been conducted specifically for ketamine infusions in depression but are thought to be related to long-term risks associated with chronic ketamine misuse, such as cognitive dysfunction and “ketamine bladder.”

Nevertheless, ketamine infusions are expensive and are often paid for out-of-pocket. Despite the body of evidence supporting ketamine in TRD, it still lacks an FDA indication for use in depression. Due to its off-label status, insurers will rarely provide coverage for ketamine infusions. As a result, patients who receive intravenous ketamine for TRD must cover the full cost of both the infusion and fees for administration and peri-infusion observation.  A single ketamine infusion at the Carilion Clinic Interventional Psychiatry Clinic is $250. For many patients with TRD, intravenous ketamine is likely too expensive and not a feasible option for chronic treatment.

There are potential treatment alternatives available for patients who cannot afford ketamine infusions.  Esketamine (Spravato)—the S-enantiomer of ketamine—is a nasal spray with an FDA indication for TRD that may be covered by private insurers with a prior authorization or through patient payment assistance programs from the manufacturer.  However, esketamine must still be administered by a healthcare professional and patients must be monitored after administration.  Another treatment option for patients is Mindbloom, a telemedicine subscription that offers at-home oral ketamine treatment with concomitant cognitive behavioral therapy sessions. However, Mindbloom is still costly—a 6-session Mindbloom course costs $1158— and less evidence exists to support oral ketamine’s efficacy in depression treatment compared to intravenous administration.

Mark’s Comments:

My thanks to Gabriel Prieur, PharmD resident, for taking the lead on this Pointer. It is important for we who practice primary care medicine to be aware of these new options and to be equipped to answer initial questions that may be asked about them. 


·         Conley AA, Norwood AEQ, Hatvany TC, Griffith JD, Barber KE. Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis. Psychopharmacology. 2021;238(7):1737-1752.  Link

·         Han Y, Chen J, Zou D, et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat. 2016;12:2859-2867.  Link

·         Mindbloom.com. Pricing.  Published 2021. Accessed November 28, 2022. Link

·         Swainson J, McGirr A, Blier P, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force recommendations for the use of racemic ketamine in adults with major depressive disorder. Can J Psychiatry. 2021;66(2):113-125.  Link

From PeerRxMed ( www.PeerRxMed.org )

3)  We are “Grief-Worthy,” So Don’t “Dis” Your Grief, and Theirs


"Grief is not a disorder, a disease or a sign of weakness. It is an emotional, physical and spiritual necessity, the price you pay for love. The only cure for grief is to grieve."  Rabbi Earl Grollman, author and an internationally recognized bereavement counselor

I used to think I was “bad at grieving.”  Often, what I was feeling on the inside as a result of loss never seemed to quite make it to the “outside,” and when it did, what was expressed didn’t really capture what I was feeling.  Even more often, I preempted what was trying to be expressed by deeming it unworthy of expression.  In doing so, I now understand I was experiencing a common phenomenon for healthcare professionals called self-disenfranchised grief – when we deny, minimize, or trivialize our own grief.

Where did I learn this behavior?  There are many factors that contribute to the grieving experience, including an individual’s personality, their past experiences with grief, other factors in their life, the specific circumstances involved, as well as the values and norms of their family and culture of origin and those of their present culture/s.  In the “culture of medicine” and certainly in medical training, too often the practice of disenfranchised grief is reinforced and even encouraged.   

Disenfranchised grief occurs when the emotional reaction to a loss not openly accepted as appropriate or justified and can therefore go unacknowledged or unsupported.  It can be reinforced by words and phrases such as “unprofessional,” “too emotionally involved,” or “just get over it.”  Not feeling welcome or comfortable to outwardly express the emotions that come with a loss exacts an emotional toll that can be isolating and long-lasting.  It can also be turned on oneself, causing denial or suppression of grief not only in professional circumstances, but in the entirety of life.  

Where does this commonly show up for we clinicians?  Our medical practice brings us to the “intersection of life,” where loss is commonplace.  Those we care for daily bring their loss to us, from chronic disease and disability in themselves and others to the loss of a job, a loved one, a relationship, material possessions, a pet, or a dream.  We often feel the need to “protect” ourselves from the emotional toll associated with all this loss, and can project that onto others as well.  Soon, we can become “hardened” to it or find unhealthy outlets to “escape” from it, and in the process, lose our compassion, our humanity, our “soul” … and often, our health. 

It is therefore essential for we who work in healthcare to find a better way and to advocate for, create, and promote cultures that support healthy grieving for ourselves, our colleagues, our care teams, and the patients and families we serve.  That process starts by acknowledging, rather than disenfranchising, the grief we experience and honoring how we experience it.  While there is no one way to grieve, we grieve “badly” when we suppress, rather than finding constructive ways to express, the emotions we are experiencing around loss.   The good news is that you are surrounded by others who are on a similar journey.  Reach out and check in with them often and allow them to do the same with you.  Next week, in the final installment of this series on professional grief, I’ll provide an example as to how this outreach might look.  In the meantime, remember we are never alone on this professional journey unless we choose to be – and no one should care, or grieve, alone.


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org