Does ketamine restore lost synapses? It may, but that doesn't explain its rapid clinical effects

Bravado SPRAVATO™ (esketamine)
© Janssen Pharmaceuticals, Inc. 2019.

Ketamine is the miracle drug that cures depression:

“Recent studies report what is arguably the most important discovery in half a century: the therapeutic agent ketamine that produces rapid (within hours) antidepressant actions in treatment-resistant depressed patients (4, 5). Notably, the rapid antidepressant actions of ketamine are associated with fast induction of synaptogenesis in rodents and reversal of the atrophy caused by chronic stress (6, 7).”

– Duman & Aghajanian (2012). Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science 338: 68-72.

Beware the risks of ketamine:

“While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

– Sanacora et al. (2017). A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74: 399-405.

Ketamine, dark and light:

Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”?

For years, I've been utterly fascinated by these separate strands of research that rarely (if ever) intersect. Why is that? Because there's no such thing as “one receptor, one behavior.” And because like most scientific endeavors, neuro-pharmacology/psychiatry research is highly specialized, with experts in one microfield ignoring the literature produced by another...

– The Neurocritic (2015). On the Long Way Down: The Neurophenomenology of Ketamine

Confused?? You're not alone.


FDA Approval

The animal tranquilizer and club drug ketamine — now known as a “miraculous” cure for treatment resistant depression — has been approved by the FDA in a nasal spray formulation. No more messy IV infusions at shady clinics.

Here's a key Twitter thread that marks the occasion:

The pricing for esketamine is unconscionable. It’s just one stereoisomer of ketamine, which btw works fine. https://t.co/iwIdEAzky3

— Drug Monkey (@drugmonkeyblog) March 6, 2019

How does it work?

A new paper in Science (Moda-Sava et al., 2019) touts the importance of spine formation and synaptogenesis — basically, the remodeling of synapses in microcircuits  — in prefrontal cortex, a region important for the top-down control of behavior. Specifically, ketamine and its downstream actions are involved in the creation of new spines on dendrites, and in the formation of new synapses. But it turns out this is NOT linked to the rapid improvement in 'depressive' symptoms observed in a mouse model.

Moda-Sava et al. (2019)

So I think we're still in the dark about why some humans can show immediate (albeit short-lived) relief from their unrelenting depression symptoms after ketamine infusion. Moda-Sava et al. say:

Ketamine’s acute effects on depression-related behavior and circuit function occur rapidly and precede the onset of spine formation, which in turn suggests that spine remodeling may be an activity-dependent adaptation to changes in circuit function (83, 88) and is consistent with theoretical models implicating synaptic homeostasis mechanisms in depression and the stress response (89, 90). Although not required for inducing ketamine’s effects acutely, these newly formed spines are critical for sustaining the antidepressant effect over time.

But the problem is, depressed humans require constant treatment with ketamine to maintain any semblance of an effective clinical response, because the beneficial effect is fleeting. If we accept the possibility that ketamine acts through the mTOR signalling pathway, in the long run detrimental effects on the brain (and non-brain systems) may occur (e.g., bladder damage, various cancers, psychosis, etc).

But let's stay isolated in our silos, with our heads in the sand.

Thanks to @o_ceifero for alerting me to this study.

Further Reading

Ketamine for Depression: Yay or Neigh?

Warning about Ketamine in the American Journal of Psychiatry

Chronic Ketamine for Depression: An Unethical Case Study?

still more on ketamine for depression

Update on Ketamine in Palliative Care Settings

Ketamine - Magic Antidepressant, or Expensive Illusion? - by Neuroskeptic

Fighting Depression with Special K - by Scicurious

On the Long Way Down: The Neurophenomenology of Ketamine


Reference

Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364(6436). pii: eaat8078.