A revolution is occurring in our thinking about the neurochemistry and treatment of depression. Spectacular therapeutic results with ketamine imply that neurotransmission with glutamic acid is involved (see the older post below for the background) In addition gamma amino butyric acid (GABA) may also be a player. That’s why a recent review [ Neuron vol. 102 pp. 75 – 94 ’19 ] is worth a careful reading.
Like all new fields, early results are particularly confusing. In particular the statement was made that in addition to NMDA receptor blockers (such as ketamine) positive allosteric modifiers (PAMs) of the NMDAR also are therapeutic in depression (the latter in animal models only, a phase III trial in depression having failed).
So I wrote the lead author ”
Great review, but how do you reconcile the rapid antidepressant action of the NMDAR blocker ketamine and friends and an NMDAR PAM (positive allosteric modifier)”
I got the following back —
We have data indicating that ketamine blocks NMDA receptors on GABA neurons resulting in disinhibition and increased synaptic activity of principle neurons, whereas the PAM (rapastinel) acts directly on NMDA receptors on principle neurons to produce a similar downstream effect
It didn’t make sense that drugs having opposite effects on the same therapeutic target (the NMDAR) would have the same therapeutic effect.
So I wrote
If I understand you correctly, this implies that the subunit composition of the NMDARs at the two sites (GABA interneurons and principal neurons) is different.
I got the following back, which is positively Talmudic in its logical intricacy.
If this is correct, a lot of neuropharmacology on drug effects will require rethinking. What does the readership think?
Stock tip — update
The FDA approved esketamine (Spravato) last week (see copy of original post at the end). I had recommended buying Johnson and Johnson if the FDA approved it. I think it’s a good long term buy, but there is no rush for the following reason — Esketamine is not a drug you can get a prescription for and take on you own. Because of the psychiatric side effects it must be administered in a SPRAVATO REMS.
Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO™ is available only through a restricted program called the SPRAVATO™ REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.
Important requirements of the SPRAVATO™ REMS include the following:
- Healthcare settings must be certified in the program and ensure that SPRAVATO™ is:
- Only dispensed in healthcare settings and administered to patients who are enrolled in the program.
- Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO™.
- Pharmacies must be certified in the REMS and must only dispense SPRAVATO™ to healthcare settings that are certified in the program.
So you can’t go to some shady practitioner who’ll say you have treatment resistant depression and get some (e.g. the pill pushers for opiates, ‘medical’ marihuana etc. etc.)
So there aren’t going to be hordes of users right away, although the stuff I’ve read implies that there will be eventually.
If you have a subscription to Cell have a look at vol. 101 pp. 774 – 778 ’19 by the guys at Yale who did some of the original work. If not content yourself with this.
They are refreshingly honest.
“Was the Discovery of Ketamine’s Antidepressant Serendipitous?Of course. However, its discovery emerged from the testing of a novel mechanistic hypothesis related to the pathophysiology of depression.”
Stock tip
The past performance of stock recommendations is no guarantee that it will continue — which is fortunate as my first tip (ONTX) was a disaster. I knew it was a 10 to one shot but with a 100 to 1 payoff. People play the lottery with worse odds. Anyway ONTX had a rationale — for the gory details see — https://luysii.wordpress.com/2016/06/01/in-a-gambling-mood/
For those brave souls who followed this recommendation (including yours truly) here’s another.
On 4 March 2019 if the FDA approves esketamine for depression, buy Johnson and Johnson. Why? Some people think that no drug for depression works that well, as big Pharma in the past only was reporting positive studies. The following is from Nature 21 February 2019.
Depression drug A form of the hallucinogenic party drug ketamine has cleared one of the final hurdles towards clinical use as an antidepressant. During a 12 February meeting at the US Food and Drug Administration (FDA) in Silver Spring, Maryland,an independent advisory panel voted 14 to 2 in favour of recommending a compound known as esketamine for use in treating depression.
What’s so hot about esketamine? First its mechanism of action is completely different than the SSRIs, Monoamine oxidase inhibitors, or tricyclic antidepressants.
As you likely know, antidepressants usually take a few weeks to work at least in endogenous depression. My clinical experience as a neurologist is slightly different, as I only used it for patients with disease I couldn’t help (end stage MS etc. etc.) where the only normal response to the situation was depression. They often helped patients within a week.
I was staggered when I read the following paper back in the day. But there was no followup essentially.
Patients Eighteen subjects with DSM-IV major depression (treatment resistant).
Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.
Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.
Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
Read this again: showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week.
This is absolutely unheard of. Yet the paper essentially disappeared.
What is esketamine? It’s related to ketamine (a veterinary anesthetic and drug of abuse) in exactly the same way that a glove for your left hand is related to a right handed glove. The two drugs are optical isomers of each other.
What’s so important about the mirror image? It means that esketamine may well act rather differently than ketamine (the fact that ketamine worked is against this). The classic example is thalidomide, one optical isomer of which causes horrible malformations (phocomelia) while the other is a sedative used in the treatment of multiple myeloma and leprosy.
If toxic side effects can be avoided, the market is enormous. It is estimated that 25% of women and 10% of men will have a major depression at some point in their lives.
Initially, Esketamine ( SPRAVATOTM) will likely be limited to treatment resistant depression. But depressed people will find a way to get it and their docs will find a way to give it. Who wants to wait three weeks. Just think of the extremely sketchy ‘medical indications’ for marihuana.
Chemiotics II 