Patricia Ares-Romero, MD, FASAM

Insight regarding proper timing to initiate electroconvulsive therapy to help manage depression.

 We’ve covered a lot of ground here today. I want to thank everyone for this rich and informative discussion. Before we conclude, I’d love to get final thoughts from each of you. Perhaps we can start with you, Angelos.

Angelos Halaris, MD, PhD, APA, ACNP, CINP:

 Thank you. This was a great idea and a great panel. It’s too bad we didn’t have 6 hours or longer to get more in depth about these very apt questions and issues you raised, Steve. I’d like to conclude by saying we need to help the public, including our patients and colleagues, raise their level of awareness of depressive illness in general, and the state of the art about what we can do. I’m not going to use the word pandemic because it has a different connotation, but it’s a very widespread problem worldwide.

Thanks to the [COVID-19] pandemic, the latest statistics as reported by the AMA [American Medical Association] a couple of days ago showed that of those who have been infected with COVID-19, about a third of them go on to develop clinical depression, anxiety, possibly substance abuse, suicidality, and even neurological sequelae. We have a serious situation here, and it behooves us to make the public and our colleagues—psychiatric and more so nonpsychiatric colleagues—aware that we have a real problem. There are a lot of things we can do. We’ve got to work as a team. We have to be cooperative and open-minded. Doing anything we can to help our patients be safe, get better, and have a life offers the best gratification of my entire career.

: That’s an important message, Angelos. Hopefully this discussion we’re having today that will be shared with our colleagues will go some distance toward accomplishing that. Thank you. Lisa, do you have final thoughts?

: Yes. Somewhat riffing off of what Angelos said, before the COVID-19 pandemic, the WHO [World Health Organization] said that in 2020, depression would be the leading cause of disability. That was before the pandemic ever happened. It’s 2021; no new data are out there, but each of us can hazard a guess as to where major depressive disorder lies. The overarching message for me is of love and patient-centered care. We’re living in times where there’s heightened sensitivity to everything. There’s a lot of talk in the community about who should be delivering care and what kind of care. But at the end of the day, each of us has made a commitment to mankind to help end suffering. If we keep that first, we’ll all make the world a better place.

: Those are beautiful sentiments, Lisa. Thank you. Patricia?

: I definitely agree with what my colleagues have said here on the panel. We really need to look at integrative care. Because depression is going to be so much more prominent in the next 5 to 10 years, we need to look and be able to identify patients who are suffering from depression and start treatment earlier. One of the biggest issues is that treatment is withheld and not started earlier. That’s why we’re seeing so many patients who later are resistant to medication as well. Refer early, educate yourself, and please don’t be scared of the new treatments we have: racemic ketamine, esketamine, and all the other things coming down the pike that we are very excited about. Don’t be afraid. Educate yourself. Know that there are other treatment options for your patients, and they deserve to be considered if they’re the right patient.

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Integrated Care and Treatment-Resistant Depression

 Let’s come back to TMS [transcranial magnetic stimulation] and ECT [electroconvulsive therapy], sticking first with first-line therapies with all the classes of medications and adverse effect profiles Patricia discussed. There are many examples of antidepressants that fall under each of those classes. Can any of you speak to what factors you consider when choosing a first-line antidepressant? What causes you then to potentially switch therapies either within a class or across classes?

Angelos Halaris, MD, PhD, APA, ACNP, CINP

: Yes, I’d be happy to start by saying what I’ve increasingly been doing. Since the era of pharmacogenomic testing, I’ve become a proponent. I’ve seen excellent results with treatment-resistant depression in particular. Where appropriate, I do it from the get-go before the trial and error and hit or miss approach. That guides me in choosing what medication would be congruent.

In the absence, reluctance, or inability to cover the cost of this testing, depending on the symptom profile, do I need more of an activating or sedating antidepressant? That gives me flexibility to pick and choose between something more serotonergic vs more of an SNRI [serotonin-norepinephrine reuptake inhibitor], like desvenlafaxine, which I like because it’s tolerated extremely well and does not lead to excessive sedation. If anything, it gives patients some energy and uplifts their mood. There’s even an antianxiety component, although it’s not very prominent. That’s the approach I take. I like MAOIs [monoamine oxidase inhibitors], especially the patch, selegiline, which is a great drug. I like it a lot. But for whatever reason, it’s not first line, for better or for worse.

 Sadly, as we talked about earlier, no matter what approach you take, there’s a high probability that patients will not adequately respond to treatment at some point, hence the high rates of treatment resistance. Lisa, in those cases, would you like to address when you think about potentially referring patients for ECT or TMS?

: Yes. This hits home for me. Just before I graduated, I used to teach ECT to the medical students at Yale [University School of Medicine]. The first thing you have to talk about is getting over the stigma of One Flew Over the Cuckoo’s Nest. Once you get that out there and you get Jack Nicholson out of the way, this is a great treatment. Where does it fit into the algorithm? That’s the question. If we’re speaking about things like catatonia and psychosis, it’s a different conversation than where ECT fits into the algorithm of treatment-resistant depression. With anybody who has treatment resistance with psychosis, this is automatically my go-to.

One of my good friends and training buddies in residency was like, “I’ll just tattoo ‘ECT me’ on the inside of my arm if this ever happens to me,” because of that rapid alleviation of the symptoms. Also, for pregnant women who are acutely suicidal, this is the go-to I would use. I’m now a little more conservative with my younger patients with regard to the cognitive [adverse] effects. I’m thinking about TMS or a form of ketamine when I’m thinking about other forms of depression outside of psychosis and women who are acutely suicidal in pregnancy. Those are usually the ones I think of first.

Electroconvulsive Therapy for Depression

Dr Patricia Ares-Romero highlights the traditional classes of antidepressant therapies available, reacts to common treatment-related adverse events, and describes when each type of therapy is most appropriate within a patient’s treatment course.

 Patricia, in your practice, if you’ve evaluated a patient whom you’ve diagnosed with depression, and you feel that a pharmacological option is appropriate, what are the traditional classes of antidepressants? What does their adverse-effect profile typically look like?

We have the SSRIs [selective serotonin reuptake inhibitors], which are the ones that most people go to first. Primary care physicians are usually the ones who go to them first. That’s usually the first-line treatment for most patients when they first come in if they have a major depression disorder, not treatment-resistant depression. They have a lot of adverse effects. There can be sedation. There can be issues with hypernatremia. I’ve seen patients experience that. The thing is that not all of them work the first time. We talked about that earlier in this conversation. We usually treat them with a first-line antidepressant. We also have SNRIs [serotonin-norepinephrine reuptake inhibitors] such as Effexor and Wellbutrin in our armamentarium. We usually treat them for 4 to 6 weeks. At adequate dose and treatment, it sometimes doesn’t work, so we switch to another class.

There are other things, such as tricyclics, which are the older ones and not used as much anymore, or the MAOIs [monoamine oxidase inhibitors], which most of the young physicians don’t use. They don’t have that specialty in using them, so they stay away from them, but they do work well for patients with depression. Then we have augmentation strategies. We augment with things such as lithium. There are also antipsychotic medications. Atypicals are also used for augmentation therapy.

There are these other things that we use. But usually when a patient comes to me with treatment-resistant depression, all these things have already been exhausted and used. This is when we turn to something like esketamine or ketamine or look at things like TMS [transcranial magnetic stimulation] or ECT [electroconvulsive therapy]. Because at this point, they’ve really struggled with this illness. They have all these other issues happening in their lives. Maybe they can’t get up to go to work, are having problems at home with their families, or can’t take their kids to school because they’re getting so depressed. That’s when it’s time to use something else, and we use these other modalities.

Traditional Classes of Antidepressant Therapies

The appropriateness for initiating psychotherapy, either alone or in combination with other therapies, as frontline treatment for depression.

 Let’s transition to discussing other treatment approaches for depression. Angelos, can you talk a little about first-line treatments? Do you tend to use psychotherapy as a first step in treatment? If so, do you use psychotherapy alone? Do you recommend it along with pharmacological treatment?

 Excellent question. First, it all depends on the initial evaluation, which I like to make as thorough as possible. It’s certainly not a 20- to 30-minute initial assessment. That’s a nonstarter. It’s 45 to 60 minutes, possibly with a follow-up to complete the initial evaluation if necessary. I really want to make sure I understand what the patient is going through. What life circumstances do they have to cope with? What are the stressors in the patient’s life? What’s their history? All these are factors are very important and will guide me as I choose the treatment approach.

For the most part, I consider medication a top priority, but not exclusively. I am a staunch proponent of combination treatment with a psychotherapeutic modality concomitantly in the same session. It may just be a matter of supportive and educational therapy, providing a listening ear, showing empathy and compassion for what the patient is going through, and giving them hope where hope is appropriate without misleading them and giving false promises. I want to see them frequently at the beginning, not, “Here’s a prescription. Nice knowing you. Come back in 3 to 6 months.” That’s malpractice in my view.

Very often, I choose intensive psychotherapy, depending on the situation and what the patient is also struggling with. I had the fortune of being trained in some kinds of intensive dynamic psychotherapy, and I still apply it as appropriate. If the patient is interested in embarking on it, that could be as often as once a week or once every other week. At the very least, a monthly supportive therapy for the first 4 to 6 months is my modus operandi.

Lisa Harding, MD: My approach is a little different. I have an MA [medical assistant] who’s an E-RYT [Experienced Registered Yoga Teacher] 500-hour teacher. Before the infusion or insufflation, my patients all undergo an introduction to mindfulness meditation, and they have a 10-minute body scan, exercise, and meditative process before they undergo their procedure. This came out of papers that talked about psychotherapy. There’s this psychedelic thing that happens with ketamine that we really can’t quantify or tap into. We’re talking about this really unconventional approach with this new treatment. It leaves a lot of questions unanswered and ready to be answered.

If you have a major depressive disorder, it’s your first episode, and it’s mild, psychotherapy might be the thing. I primarily treat people with treatment-resistant depression, so we’re usually starting an intervention modality. I give patients some grace in starting psychotherapy because I don’t want somebody with a MADRS [Montgomery–Åsberg Depression Rating Scale] of 32 who’s struggling and has been failed by these conventional medications to then engage in psychotherapy, which is sometimes really taxing. I show them some grace. Sometime midway through the treatment, they start psychotherapy.

Frontline Psychotherapy for Depression

Recommendations that can help clinicians navigate through the reimbursement process and best support patients who receive intranasal esketamine for treatment-resistant depression.

Treatment-Resistant Depression: Financial Support for Esketamine Therapy

Requirements that healthcare clinics must satisfy to become a certified treatment center permitted to administer intranasal esketamine to patients with treatment-resistant depression.

Incorporating Esketamine into Practice for Treatment-Resistant Depression

It sounds like all of you have a pretty thorough process for getting patients ready for treatment and do a wonderful job with it. I’m looking to any of you 3 if I need a doctor. You’re highlighting that there are some special logistical considerations in prescribing this therapy. Among them is actually procuring and prescribing intranasal esketamine. Patricia, would you like to start talking about the requirements health care settings have to satisfy in order to do so?

Yes. It varies between the setting. For instance, my outpatient clinic is part of a hospital setting, so we have an in-house pharmacy. For us, it’s a little easier, unless the patient’s insurance requires a specialty pharmacy. Otherwise, here’s what we do. When a patient is cleared, we go through the insurance. We make sure the patient understands their co-pay if they have a commercial insurer, because we want to make sure they are aware of what it’s going to cost. We’re telling them, “It’s a 3-month commitment, and every time you come in, this might be your co-pay.” We want to make sure we have that right up front. When we bring in a patient, one of our technicians walks with the patient to the pharmacy, which is right next door, and they sign for the medication. The patient never receives it. The technician brings it back to the treatment room so that we can provide the treatment. That’s one of the things. Other colleagues of mine have it shipped directly to their office from the specialty pharmacy.

 For us, it’s much easier. In regard to logistics, I often get asked, “Where do you put the patients? How much space do you need for it?” Between providers, everybody decides on something different. I had real estate in my clinic, so I was able to use individual rooms. Some of my colleagues will do the treatment in a room, but they don’t have enough rooms, so they’ll put 2 people in another room to rest. There are different models that can be used, but everyone would be able to do it in a private setting.

 I do this from a specialty pharmacy, like you mentioned, Patricia. Everybody starts on 56 mg. I’ve designed my clinics where every Monday and Thursday I do it, simply because of specialty pharmacies. I was originally treating on a Tuesday, but they need the lead time to deliver the drug. The crux is in doing your homework and finding the nearest specialty pharmacy that can deliver the drug to your office. After you have that, we have—per DEA [Drug Enforcement Administration] guidelines—a storage room, which is a drug room behind 2 locked doors. If the safe is less than 700 pounds, it has to bolted down. We have all those things in place.

Then we have a timeout process, by which the patient is given their card stating that it was delivered here and they’re given a card stating their co-pay. We have a timeout process between myself and Miami. We do patient name, date of birth, and everybody starts on 56 mg. Then I visit with the patient to determine the next dose, because we have to preorder it to have it delivered to the clinic for the next dose. That’s how we do it here.

 Terrific. Of course, to have it delivered to your office, you must be a certified Spravato treatment center. We mentioned that a bit earlier when we were talking about the REMS [Risk Evaluation and Mitigation Strategy] program. One of the requirements is to become a certified Spravato treatment center. Patricia, would you like to talk a little about what’s required to have that designation?

There’s paperwork to be completed. I was probably one of the first ones, so we needed to fill it out. Now, you can do it online on a portal. It’s things like who the provider is going to be, the DEA, your NPI [National Provider Identifier] number, and the actual location, a room number where you’re going to be administering the treatment. It’s a seamless process. You upload it, they verify everything, and then you’re able to be REMS-certified. The important thing is to make sure you certify the patient prior to treatment. That was one of the hiccups at the beginning. I was really excited to get a patient I knew started, and I brought him to the clinic and we did the treatment. I was told, “You were supposed to certify them first.” That was one of my hiccups. I wasn’t sure of the logistics. We now do it when they come in for the consultation. We get their consent and certify it then, and that gives us time to make sure we have medication. Then they come in for the next visit. It’s a really easy process.

Absolutely. There are guidelines for health care settings. You must be able to have visibility of the patient. You have to be able to monitor things like SpO2 [oxygen saturation] and their blood pressure at certain intervals. From the REMS form, all of us know we have to have a prior reading, one at 40 minutes after the dose is given, and one before the patient is discharged. Those things are what the REMS is ensuring the provider attests to having. I used to be an emergency department physician before I became a wonderful psychiatrist. One of the requirements is that at least 1 provider at the site of an outpatient setting is ACLS [advanced cardiac life support]-certified as a recommendation. In that same package insert, as well as from the FDA, there are guidelines for you to read through as a prescriber when you’re thinking about implementing this.

Angelos Halaris, MD, PhD, APA, ACNP, CINP: 

There’s one more thing that must be said. Because esketamine is a controlled substance, the sites that are going to be using and administering it must keep it in a locked safe. That’s commercially available; it’s not that expensive to buy, and it can be accessed either by a code or 2 locks. There are 2 individuals who each have a different key or their own code to open the safe and retrieve the vial and the applicator that’s going to be used for that patient at that particular time before locking it back up again.

These are all important logistical considerations when thinking about administering esketamine.

Getting Certified to Administer Esketamine for Treatment-Resistant Depression

Best practices that can be applied when working with patients and training staff on proper ways to administer intranasal esketamine therapy for treatment-resistant depression in a supervised medical setting.

As part of the REMS [Risk Evaluation and Mitigation Strategy], one of the requirements is that the medicine is administered in a REMS-certified center with supervised administration. Angelos, could you talk about the ease of self-administering nasal sprays for patients?

 Yes. It’s very easy. The patient has to be instructed, which you do the first time. They’re always under observation. We make sure their head is tilted at a 45-degree angle. They rest in a chair that can recline. We elevate their legs. We want to make sure they are really comfortable for 2 hours, or possibly longer if necessary. Then we show them how to do it. We practice first without the spray vial. There are practice vials available. We teach them how to do that before we get to the real medication. We tell them how to administer through the nostrils, changing the nostrils, how to make sure they don’t come in with a cold, runny nose, a cough, or anything that could interfere with the absorption of esketamine. That is all done from the get-go.

We ask them these questions upon arrival. If everything is clear, we remind them how to do it. They administer it themselves, but we watch them do it. We describe how they should sniff it a little and take 2 or 3 not-too-deep breaths through the nose, because if they breathe too heavily or too strongly, it goes right back down the throat. In fact, today, a patient told me, “Sometimes I take it in very vigorously and then I feel it in my throat.” That’s not good, because we lose some of it. That’s done under guidance and observation, but the administration is very easy. It’s like using a nasal spray for a common cold.

My 2 cents on that is similar to what Patricia was saying. The patients feel an autonomy. How often do they get to come to the doctor’s office and control how they get the medication? The company provides trainer devices. I have a different process. I have a process of consent, which is a different appointment than when they first come. In that consent process, the patient is allowed to go into the treatment room and sit in a chair that is similar to the one that they will sit in when they get their treatment. They play with the trainer device. Sometimes, it’s a very strange thing for the newer pharmacies to understand.

This is one of the drugs that’s self-administered, but under the supervision of a doctor. They’re allowed to reset the device and play with it as many times as they like. I also have a check-in and check-out process. It gives my patients confidence. We make sure they haven’t had anything to eat 4 hours before administration and nothing to drink 30 minutes before. We have them blow their nose before each device. Most of my patients resoundingly have asked me to tell the drug company to flavor it. It’s the same thing Angelos was saying. Patients will say, “This tastes like metal. Can’t they make it bubblegum?”

We talk through all of these things. I have a stock of lollipops in the room. They are for my patients who really can’t take it. They get a lollipop after the first insufflation. I’ve also found it really helpful to tell patients that it’s not like one of the conventional over-the-counter nasal sprays, because it does snap. Most patients have a tendency to pull back with something close to their face that snaps, so I’ve found it helpful to tell them there’s a back of the headrest that pulls up because the device snaps and they tend to pull back sometimes. It’s little nuances like that. My advice for providers is to take one of the trainers, go through the training video that’s on the website, do it yourself, and observe the things that you’re feeling in your body when you’re doing it. Give that same advice.

I love that, Lisa. I love that tip on the lollipop. For me, it’s a little hybrid. When a patient comes in for a consultation, if it’s not one of my patients, that’s usually when we let them do that. We show them the treatment rooms, we let them sit down and feel comfortable, we give them the treatments, we talk about the treatment, we get consent from them, and that’s when we send the paperwork for REMS.

The other thing I do from the beginning is try to make patients understand that it’s like a procedure. It’s like going to get a colonoscopy. You get all these instructions before you come in. You can’t drink, you can’t eat, you have to make sure that you do all these things, and you have somebody bring you. We did it that way, and the patients have been great. Make sure you take your hypertensive medication. I remember the first time I had a patient and we told him not to drink or eat. He showed up, but he hadn’t taken his hypertensive medication. Guess what? He couldn’t receive treatment that day because his blood pressure was all over the place. We make sure we do that. We make sure we tell the patient that if they take a benzodiazepine, they can’t take them that day. We want to make sure they do not take anything that’s sedative. Those are the types of things we do prior to their appointment. When they come in, our nurse makes sure we go through that checklist as well. But I adore the lollipop idea.

Yes, bubblegum flavor is a hit. It masks the flavor of anything.

Treatment-Resistant Depression: Administering Esketamine to Patients

The purpose and impact of the REMS program established to support the integration of intranasal esketamine into clinics that manage treatment-resistant depression.

Let us move on to discussing the practical considerations of delivering esketamine to patients and integrating this into patient care. Let us start with Angelos. Can you speak to the idea that intranasal esketamine has a risk evaluation and mitigation strategy [REMS]?

 Absolutely. As I mentioned a while ago, we have to make sure there are no conditions, such as aneurysmal disease, uncontrolled hypertension, substance abuse, or any other blood disease—not necessarily aneurysmal disease but hardening of the arteries, which could theoretically cause a rise in the blood pressure acutely with the possibility of having a bleed in the brain or elsewhere. That is the main thing. Other than that, it is a safe drug to use.

It has to be done on-site in the office, whether it is a private practice office, a clinic, or a hospital. It has to be done under 2-hour observation, longer if necessary in the opinion of the treating physician. The patient is not allowed to drive—certainly not after termination of the treatment. He or she must have somebody to take them home. We want to make sure there is somebody to pick the patient up. We stipulate that the escort shows up to pick up the patient, so we know that they are not going to drive themselves. Not that they want to fool us, but we never know. In fact, 1 patient today told me, “Doctor, I don’t have anybody to bring me next week. I’m OK to drive.” I said, “Absolutely not. Let us skip it if you do not have a driver. I don’t like it, but that’s the best thing to do.”

Addiction is a major issue. Benzodiazepines are allowed, but we need to exercise professional judgment. How much are they taking, and how long is the patient addicted? Is the patient asking for ever-increasing doses? Are there other drugs of abuse, including—I hate to say this—marijuana? I make a point that if they smoke marijuana, there is the potential, backed by research data, that THC [tetrahydrocannabinol]—especially if the content is high—could interfere with the metabolism of psychiatric drugs in general, including esketamine, thereby reducing the efficacy. I make a point of asking if they are ready to discontinue use. I make it clear that I have to rely on their commitment to refraining. That is not so much the case with nicotine, although I prefer that they don’t smoke, or at least reduce the frequency and number of cigarettes per day. That may or may not happen.

There’s nothing else that’s critical. The issue of a dissociative reaction is a possibility. There are occurrences of a true psychotic episode. In that case, we have to again exercise judgment. Either we keep the patient under observation longer, or we administer proper medication to help them return to increase their reality testing, so to speak. Of course, do not drive. Initially, the requirements were to not drive for 24 hours. Later on, the FDA relaxed that, and the company, Janssen Pharmaceuticals, modified the precautionary note to saying you may drive or operate machinery the following day after you’ve had a “restful night’s sleep.” I asked them to please define for us what a restful night’s sleep is. I didn’t get an answer. Nobody wanted to define a restful night’s sleep. I tell my patients, “For now, until further notice, I don’t want you to drive for 24 hours.”

You asked the question, “Why a REMS?” It is good for many reasons. I wish that a REMS existed for racemic ketamine. Patients and doctors enter contracts, whether verbally, or sometimes those of us who treat substance abuse have very arbitrary written contracts. This is a contract between you and your patient. This is a class 3 controlled substance. Ketamine is such a fantastic treatment. To protect it and it and not go the way of the opioid crisis, if we want to think of all the nefarious things that can happen, this is a great mitigating body that has been put in place to help us judiciously prescribe this.

For me, most patients have said, “Wow, this is really high tech.” They get a lot of confidence in knowing that the FDA is really overseeing this, that it is not some back-alley operation. Then they, too, understand their responsibility of the things that they are attesting to when they get enrolled in the REMS. We also have that ability where we do not see other prescribers, but if somebody tries to enroll the same patient at another site to try to get this medication, we can see that. If you think of it as an extension of a prescription monitoring program, it is a fantastic body that has been put in place to monitor how we are prescribing this drug.

I agree, Lisa. When I talked to my providers in the hospital at the beginning, everybody was concerned about prescribing and treating patients. I said, “This REMS is really put in place to protect us as well.” A patient cannot receive esketamine in another center if they are registered with you, so it really does protect us. The other thing is that they cannot understand why the patient cannot just get it at a pharmacy. Well, they cannot. We must receive it. It really does protect the patient, protect us, and—to Lisa’s point—protect the medication.

 It certainly sounds like all 3 of you really value the formalization of a REMS to ensure patient safety.

Angelos, to answer your question, “What is a restful night’s sleep?” I do not know how to define a restful night’s sleep, but I know it when I have had 1.

REMS Safety Program for Esketamine in Treatment-Resistant Depression

Practical experience regarding the timing and response to intranasal esketamine therapy for treatment-resistant depression.

All 3 of you have experience prescribing intranasal esketamine in a carefully screened population for an appropriate patient under careful medical conditions, so this question is for any of you. What is typical? How quickly do you tend to see improvements in depressive symptoms for these patients when they do respond?

In my experience, everybody has a response after the first treatment. The crux of the matter comes in the durability of that response. I have a big complaint about the psychiatric scales that we use. It’s half and half with how my patient is doing subjectively. I use a PHQ-9 [Patient Health Questionnaire-9] and MADRS [Montgomery-Asberg Depression Rating Scale]. Somebody can have a very low MADRS or PHQ-9 score that is indicative of remission and response, but if they’re still answering, “Yes, I’m having suicidal thoughts every day,” I don’t know if I count that as a win clinically.

For me, it’s half and half. My follow-ups are much closer if I’m treating suicidal ideation. Anecdotally and personally, that is the first symptom that tends to go if you’re looking at the MDSI [major depressive disorder with suicidal ideation] population. Within the first 24 hours, I definitely notice if it’s durable for that particular patient. Because we’re not doing this treatment in a vacuum, most patients strangely have their psychotherapy appointment right after either their infusion or nasal insufflation. I’m waiting on science to run the data on that clinical trial as to whether it’s more efficacious after they get ketamine.

Yes, that’s a great question. Patricia and Angelos, how about you? How quickly do you tend to see improvements?

 My experience is pretty much the same. Within the first 24 hours, we see some response. I’ve had patients where it’s taken 4 weeks for them to feel much better, so it goes both ways. They all respond—usually within the first 24 hours—which is really nice to see when the patient comes back for the second treatment and they’re feeling better. We also use the PHQ-9s and MADRS to make sure the insurance pays too.

 I don’t want to sound too negative about it. We do see a response after the first administration. I don’t want to be a devil’s advocate, but is that a true response or a placebo effect?

: I will interrupt you for 2 seconds. There’s no such thing as a placebo effect. There are the nonspecific, nonpharmacological effects that occur.

OK, I’ll grant you that, Lisa. Be that as it may, the initial response to the first administration response is a sense of relaxation and feeling lighter, even if it’s at least in part placebo because it’s a brand-new treatment and the expectations are high and, therefore, the person must feel better. The effects after the first—or even second—administration doesn’t last long, so the recommendation, if not mandate, of twice a week for the first 4 weeks is very appropriate.

In my experience, we start seeing more stable response improvements after 2 to 3 weeks on average and then the patient goes home. Let’s say the administration was given on a Thursday and they come back on a Monday or Tuesday the following week. The effects usually last longer and longer into the intervening weekend and eventually become more stable and more pervasive. That’s when we can say, “OK, now I can afford to have you come once a week, and down the road, once every other week.” That’s the approach I’ve taken. For the most part, it has proven to be the right approach.

Absolutely. Having been on clinical trials myself, we all know that the data in the clinical trial is a result of you seeing maybe 2 or 3 doctors. There are all these people fussing about you. It’s somewhat replicated in esketamine and racemic ketamine administrations. You’re coming in, being attended to, and being monitored. I agree with you. This definitely needs to continue to be studied. How do we enhance all of our long-term treatments? Is it that we bring somebody with sertraline in and put them in a fancy room and also administer it under those conditions? Would our adherence and our outcomes be better? Maybe.

Yes, Lisa. You mentioned the nonspecific effects of treatment. Certainly, intranasal esketamine is a high-touch treatment and perhaps an advantage if we’re trying to leverage any aspect of mechanism that might help our patients feel better and feel better sooner. To echo what Angelos said—I’ll chime in with my own experience with both IV [intravenous] ketamine and intranasal esketamine—it’s very gratifying to see these very rapid responses that can be almost immediate. Certainly, that immediate response may not be fully consistent or durable. It does seem that the accumulation of treatments over a period of time has an additive effect and helps to extend that durability of response. I recognize that when I say “seems to be,” it would be better to actually measure those outcomes so we have something to validate it. It sounds like all of you are measuring outcomes, which I applaud you for. As you