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Join L. Joseph Parker, a research physician, as we explore the intricacies of depression treatment. We’ll delve into the prevailing theories about serotonin, the delayed effects of SSRIs and SNRIs, and the emerging neuroplastic theory of depression. Discover how ketamine offers rapid relief and its potential synergy with traditional antidepressants. We’ll also discuss the risks and benefits of these treatments and the importance of investing in further research to address this critical issue.

L. Joseph Parker is a research physician.

He discusses the KevinMD article, “Can ketamine and SSRIs offer a complete depression treatment?”

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast, and get CME for this episode by clicking on the CME link in the show notes. We welcome back Joseph Parker. He is a research physician. Today’s KevinMD article is titled “Can ketamine and SSRIs offer a complete depression treatment?” Joseph, welcome back to the show.

L. Joseph Parker: Thank you very much.

Kevin Pho: So you’ve been on the show multiple times. Go to KevinMD.com/podcast, click the search icon in the upper right-hand corner, and search for Joseph’s name to hear his story. But today we’re going to talk about ketamine, SSRIs and their place in depression treatment. So tell us, how did your interest and your article come together?

L. Joseph Parker: Ketamine was recognized as having some antidepressant properties pretty early on. Of course, it’s been used as an anesthetic for a long time, and then we started using it in emergency rooms for acute pain, and now it’s used for chronic pain, and I’ll have a note on that later. But the S-enantiomer, the left-handed molecule, was approved for the treatment of depression as a nasal spray, and the VA had really started using that extensively. Now, it’s pretty expensive. The little spray bottle that you get has two sprays in it, and that’s $784 right now, and you need to do that repeatedly. You’re going to need about 12 of those. So it’s not a cheap therapy, but it seems to be very effective, and one thing that’s very unique about it is that it works very quickly.

Now, one of the problems with just about every other antidepressant that we try to use, the SSRIs or SNRIs, is that they take maybe six to eight weeks before the patient starts feeling better. And sometimes, when you’ve got low motivation and low mood, the motivation comes up before the mood does. There were some studies that seemed to indicate there could be a higher risk of suicidal ideation and suicidal actions, especially in younger patients. I think it’s especially in younger patients because impulse control is always an issue in younger patients, especially young men. The frontal lobe doesn’t myelinate in men until we’re about 25 years old, if that, and so it’s probably an impulse control issue. You start someone on an antidepressant and you’ve got to wait six to eight weeks for it to take effect.

But quite often people don’t come to a doctor for depression until they’re having some pretty serious thoughts, and that was another thing they found when they followed up on these studies. It wasn’t necessarily that the antidepressant was predisposing someone to harming themselves. It was that by the time they go to the doctor they’re almost there, and then for those next few weeks, when they’re not really getting better and their mood’s not improving, they’re still at risk of harming themselves. A very extensive study done in one of the Scandinavian countries showed that the rate of suicide was lower with treatment than without treatment for people at the same stage. So when they were coming to their doctors saying this is serious, it was still better to treat than not to treat. The SSRI was not influencing them.

So correlation does not prove causation. If you prescribe someone a pain medicine and they die within the next six months, if you’re treating cancer, that’s not uncommon, and it’s not because you prescribed them a pain medicine. The same thing goes for antidepressants. If you prescribe someone an antidepressant and they do something, it doesn’t mean that the antidepressant caused it. We do know that the six-to-eight-week window can be dangerous for patients.

The unique thing about ketamine is that it works within a few hours. It works almost instantly. Ketamine is only approved for the treatment of depression in that left enantiomer form, esketamine, as a nasal spray, and it’s only for the treatment of treatment-resistant depression. They just added a new criterion to it: major depressive disorder with thoughts of or actions of suicide. But can they afford it? That’s the hardest thing. No matter how wonderful a medication is, if someone’s insurance won’t cover it, or if you have to get a prior authorization, there goes your six-week window.

So ketamine is available in much cheaper forms, and a lot of doctors are starting to use it in that form off-label. Whereas esketamine is the left-hand molecule, the racemic mixture, regular ketamine, is very cheap. It’s been around a long time, and compounding pharmacies can prepare it in tablet form, a powdered pill form or capsule, and they’ll actually make nasal sprays out of it. In these medications the left enantiomer is still there, so you’re still going to get the good effects, and this could dramatically reduce rates of self-harm during that window before the SSRIs kick in.

Now, the SSRIs are still important, because while ketamine has a rapid, immediate response, it tends to taper, whereas the SSRIs have a very slow response, but they tend to go up, right? So you can use the two together: Start them at the same time, maybe do a treatment with ketamine while you start the SSRI, evaluate, and do a second treatment if you need to. The ketamine doesn’t have to be dosed daily. You can do it in the office. Some doctors have done it with intramuscular injections, and some do it through IV infusions.

Kevin Pho: So I was going to ask about that, in terms of the off-label use. I’ve seen these ketamine clinics pop up, and there are some ketamine-trained psychiatrists who oversee some of these clinics. So contrast these clinics and their role in terms of giving patients ketamine.

L. Joseph Parker: I think there’s about to be a huge crackdown on ketamine use. I see signs that there is political pressure by the manufacturers of esketamine to protect their market share, and so you see articles coming out saying that these aren’t FDA-approved for this purpose, that this is off-label use. Now, this is a controlled medication, and while the Supreme Court has said doctors can prescribe medications off-label, a controlled medication is subject to the control of the DEA, and the DEA can prosecute a doctor for using something off-label by saying it was not for a legitimate reason. So if you use it and you go to court and you say, “I used the ketamine for chronic pain,” or “I used the ketamine for depression,” they will ask, “Did you use the type that is approved for that?” And you’ll have to say, “No, I used a different type.” Well, the jury is not going to understand the racemic mixtures and the enantiomers, and while your attorney should do their best to educate them, that’s going to be a little tough. Esketamine is the only one that’s approved for this purpose. I think if a patient comes in and says they’re having thoughts of hurting themselves, then that’s an excellent therapy.

Using it as these clinics are, it does appear to help, from all the studies I’ve read. It does appear to help chronic pain, especially central sensitization, where the second- and third-order neurons are firing too fast and the pain just continues despite there being no first-order neuron stimulation. So someone has lost a leg or an arm, and that person has this terrible phantom limb pain. That pain is not being generated by the arm or leg being injured continuously. It’s being generated by a reverberating circuit that has set up in that pain reporting system. What ketamine does is immediately cause spines to project on dendrites and increase synaptic plasticity, so you can make new connections. You can unlearn old habits, you can learn new things. It reopens that window, and that can help reset people who have a bad circuit.

Now, it’s also used recreationally, because it makes people feel drunk and dissociated, and some people like to explore these different feelings. I don’t recommend, of course, the recreational use of any psychoactive substance. If you like the way your mind is working, it’s a bad idea to put in something that can change how those connections work. We all know that LSD can cause flashbacks 10 years later. High doses of ketamine, unless you have a medical reason to reset circuits, are not a good idea at all.

But the fact is that someone uses it wrongfully somewhere, and it’s not an addictive substance. It does not activate the nucleus accumbens, it does not release dopamine, it does not boost endorphins. You don’t get tolerance. Actually, it becomes more effective the longer you use it, which is pretty interesting, so you can sometimes step down the dose. So it’s a different medication, but the fact that anyone will abuse it will allow people to throw a fit about it, sort of like they do with cannabis. I don’t recommend the recreational use of cannabis to my patients, or to anybody, but it’s less dangerous than alcohol by a long way, and not even close to nicotine. Nicotine kills 600,000 people a year. So if someone’s going to do something, that’s probably one of the milder things they can do, though it’s still not good for you. But neither are cheeseburgers or doughnuts. So for these doctors using ketamine off-label, I expect we’ll probably see some prosecutions coming up pretty quickly.

Kevin Pho: So if I’m a primary care physician and I have a patient in front of me who I think may be a candidate for ketamine, with depression not responding to SSRIs and some component of suicidality, you mentioned there are different forms available. There’s the nasal spray, I could refer to a psychiatrist or an IV ketamine clinic, or to a compounding pharmacy for perhaps an oral version. So what kind of recommendations do you have? Where can I turn in terms of taking that next step?

L. Joseph Parker: Fight hard to get samples of the esketamine. Most people who come to you with depression are not yet having suicidal ideation and suicidal thoughts. If someone is, that allows you to use that medication in an FDA-approved manner. So I would fight to get samples and coupons and everything you can get, because of the amazing way it works. It might only take one dose to help reduce that person’s suicidal thoughts and ideation, and that’s been well proven in several studies, so that can be a lifesaving treatment. I would reserve it for those who are having suicidal thoughts and ideation. If someone is treatment-resistant, I would let a psychiatrist make that determination to use it for that purpose.

But if you’re a primary care doctor and someone comes to you and says, “Hey, I’m very depressed, I’m having suicidal thoughts,” and you refer them to a psychiatrist, it’ll be six months before they get in. So you need to do something. If there’s something you can do that could help them, you need to do it, and esketamine is probably the best way to do that right now. So coupons, whatever you can do to have that medication on hand, right, so that they can get it immediately.

Kevin Pho: What are some of the risks and side effects of ketamine today?

L. Joseph Parker: Of course it causes lethargy, and patients will have almost a paranoid, hallucinogenic phase, where they think some things are trying to hurt them and they start to panic a little bit. Quite often it’s given with Versed or some other benzodiazepine to dampen that down a little bit, and that appears effective. It can increase blood pressure and cause a little nausea and numbness, so you’ve got to tell them to expect all this. Don’t let them drive that day. It should wear off after six to eight hours. I would do a treatment in the morning and not let them drive all day, and then they can drive the next day. You can get a little vertigo, and in extreme cases you can have vomiting.

Now, a lot depends on the dose, and the antidepressant dose is very low compared to the anesthetic dose, and all these side effects are really related to anesthetic doses. For someone my size, for anesthesia, you’re going to use 0.5 to 1.5 milligrams per kilogram. I weigh 100 kilograms, so you’re looking at 50 to 100 milligrams. For esketamine, you’re using a tiny little dose. It’s called Spravato, and it’s 28 milligrams per dose. So that’s nothing. That’s about 5 percent of a dose for someone my size for anesthesia. Using that tiny dose, most people don’t have any side effects at all, except they feel weird. They just feel a little dissociated.

Kevin Pho: Now, we’ve been talking about ketamine in the context of acute episodes of depression associated with suicidality. Is there a role for ketamine in the chronic management of depression, in conjunction with SSRIs?

L. Joseph Parker: I think there is a good role for it in the treatment of chronic pain. Chronic pain causes an increase in stress hormones, even something as simple as cortisol, and cortisol inhibits neurogenesis. Now, ketamine acts on the glutamate receptor. It’s an antagonist to the NMDA receptors that work through glutamate, and it has immediate actions, like the protrusions on the dendrites and the synaptogenesis. Down the road, it also encourages neurogenesis, so the hippocampus starts producing more neurons, and you’re able to think your way out of a problem. Depression is kind of when we just see no way out of our problem, and it appears that neurogenesis is a big part of being able to see and imagine that we have a way out.

The SSRIs increase neurogenesis down the road, and we now think that has more of an effect on depression than the serotonin effects do, because serotonin levels go up immediately, but the person’s mood doesn’t change for six to eight weeks. So I do think chronic pain causes chronic depression, and by treating pain with this medication you treat the depression. You give the person hope, you help them feel better, they’ll be more active, they won’t be despondent. We have an epidemic of pain patients committing suicide in this country right now. It is extremely hard to get treated for chronic pain. As doctors are no longer prescribing opioids, they’re scrambling for something to use to treat chronic pain, and many of them are turning to ketamine, and it is effective.

Kevin Pho: We’re talking to L. Joseph Parker. He’s a research physician. Today’s KevinMD article is “Can ketamine and SSRIs offer a complete depression treatment?” Joseph, let’s end with some take-home messages that you want to leave with the KevinMD audience.

L. Joseph Parker: I would say that I would leave the off-label use of ketamine to specialists. If I were a primary care physician, I would try to get samples and coupons for esketamine. I would have that on hand for use with suicidal ideation in the setting of depression, and I would use it for that only.

Kevin Pho: Joseph, thank you so much for sharing your perspective and insight, and thanks again for coming back on the show.

L. Joseph Parker: Thank you.