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 I want to shift gears for a second and ask about getting this cost covered and stuff like that with your patients. Can you provide your perspective on the cost associated with the administration of intranasal esketamine and how you navigate payer reimbursement?

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

 That’s a very good question. The news is still a little unclear. We’ve had a lot of problems getting insurance companies to fund it. They require a lot of justification and paperwork. However, the company Janssen [Pharmaceuticals] provides assistance through CarePath. I don’t know how independent CarePath is from Janssen, but it doesn’t matter. We’ve used CarePath, and we continue to use them. That’s the first issue we do. Once we obtain the insurance information with patients’ written consent, their data are passed on to CarePath. They’re amazingly efficient in getting an answer to us within 36 to 48 hours about their evaluation. It saves our staff tons of time.

 Absolutely. We use them as well, and because of their work, sometimes we’ve gotten a co-pay as little as $10 for some of our patients.

 I agree. Yes, $10 co-pay. Sometimes it’s been $20. That’s amazing. But jumping through hoops with insurance companies is still an issue.

 Yes. The other thing that some insurance companies require is evidence by means of rating scales and scores that the treatment is effective, because they’re not going to continue to pay thousands of dollars if the treatment is ineffective. I understand that. What I routinely do is either a MADRS [Montgomery-Asberg Depression Rating Scale] scale at the start, or I prefer the 17-item Hamilton Rating Scale for Depression.

 Oh my goodness. Where have you been all these years?

 I love it. Yes, that’s the 1 I use as well. How often do you do it? I do it at the beginning and then at treatment 8 to prove maintenance going forward.

 Yes, I do it at the beginning, then no later than 4 weeks later after the completion of the first month of treatment, and then no less than monthly intervals thereafter. Once they’re in the maintenance phase and come back for treatment twice a month—I haven’t gone down to once a month yet, but I’m thinking about 3-week intervals down the road—I do it monthly thereafter just to make sure we’re staying on track. It’s a long journey to get there. These are patients who have suffered for decades if not for life.

 It’s so interesting that you say that. Can I tell you why? I’m smiling because we practice in a really similar way. I’m also hoping to get to once a month just like you. But it’s because you and I are different in that we see a lot of treatment-resistant patients. For us, we’re like that last line of defense. It’s really nice to find a colleague who has good clinical practice.

 We need to hold these kinds of discussions a little more frequently.

 We really do. I wish we could keep talking, but in wrapping up, I have a question. What advice do you have for other clinicians who are thinking about considering this as a therapeutic option for their patients?

 My advice is that it works as long as you do it right for the right patient in the right constellation. I know we’re short of time, but I want to get back to a question you raised a few minutes ago regarding the dissociation and sedation. They both occur. So far, every patient has had a different dissociative reaction. The sedation is more or less pretty consistent with everybody, but the dissociative reaction is highly individual. It can be fascinating, with visions. I could write a book about those. I have found the dissociative reactions can be vehicles to do interpretation of their life right on site. As they come out of the dissociative reaction, they’re comfortable and calmer. That’s a wonderful setting to intervene psychotherapeutically.

 Thank you so much. I agree with that. It’s so strange. Because when you mentioned rating scales, I also smiled because I don’t think we have a rating scale yet to measure a dissociative effect. They’re individual. Sometimes I find it dependent on the time of year with how those patterns go. I’ve had patients tell me everything from they were seeing machines to they were floating outside themselves.

Thank you very much for your time. I hope we can do this again.

 Absolutely. This was worth our time, Lisa. Very nice to meet you and compare notes. Let’s keep it going.

 Yes, let’s do this again. Thank you so much, everyone. Thank you all for watching this 

 presentation. This has been an excellent discussion, and we hope you found the information to be valuable to your clinical practice.

 Thank you. We really appreciate it. This is a major service to our colleagues and patients.

This transcript has been edited for clarity.

Lisa Harding, MD, and Angelos Halaris, MD, PhD, APA, ACNP, CINP, give advice to any clinicians considering the use of intranasal esketamine for treatment resistant depression.

Advising Clinicians on Using Intranasal Esketamine

 Angelos, what kind of training did your pharmacist or the doctor that’s running it in the setting have to undergo? What do you think they needed to understand about being set up to do this? Like you, I’ve done this in a university setting as well as in a private practice. One of the questions I want to help demystify for a psychiatrist is, “Can I do this by myself? Do I need to have an anesthetist with me?” Could you touch on your own comfort level in doing this yourself as a psychiatrist?

 Very much so. I’m very comfortable doing it, not by myself. We need to have 1 clinician, preferably an RN [registered nurse] or APRN [advanced practice registered nurse], who keeps a close eye on the patient for the entire 2 hours, ideally inside the room or in an adjacent room where the nurse or medical assistant can keep an eye on the patients throughout the entire 2-hour observation period. Other than that, if there’s a pharmacy embedded within the institution, the pharmacy needs to become REMS [Risk Evaluation and Mitigation Strategy] certified. That’s not a terrible training, but there are certain requirements mandated by the FDA that need to be met in order to be certified as a pharmacist or as a pharmacy.

In the case of a practice site that doesn’t employ a pharmacist or doesn’t have their own pharmacy, there are certified pharmacies that are available. That works very smoothly in terms of ordering the medication ahead of time with refills like any other medication. These refills obviously need to be updated as necessary. Insurance companies have to go through the process of approving a refill. It’s no different from any other medication.

 Excellent. Thank you so much for demystifying that.

 It’s not that cumbersome. It sounds scarier than it really is.

 Tell me a little about how you enroll your patients with the REMS setting. Given the COVID-19 pandemic, we’ve utilized a lot of the REMS enrollment online. We’ve used the email system, in which we send it to the patient and that reduces the number of times that they have to come in the office. What have you been doing with your patients in terms of enrolling them in the REMS? Because the sticking point is that the patient has to be enrolled in the REMS before the first treatment. We really like to talk about that with the referring for providers who refer to us.

 Yes. My approach is to see the patient, ideally in the office or via video telehealth. I want to see the patient, if not on site in the office, then at least in the video. It’s a limited face-to-face contact, but better than just telephone. Then I go through the assessment we discussed earlier. If I deem the patient is a suitable candidate, then we proceed to obtain the registration of the patient. It’s that simple. It has to be submitted to the REMS office before any treatment can be started.

Drs Harding and Halaris review the requirements health care settings must follow in order to procure, prescribe, and dispense intranasal esketamine as treatment resistant depression therapy.

Health Care Requirements to be Aware of for Intranasal Esketamine

 I have a question about you being a certified REMS [Risk Evaluation and Mitigation Strategy] treatment center. What was involved in becoming a REMS treatment center?

 It’s not as awesome or as scary as it may sound. First, you need to have a physician who’s REMS certified. That’s a process that requires training and exposure. In my case, because I was involved early on during phase 3 clinical trials, I pretty much automatically became certified and have maintained my certification. I take it with me when I go to bed every night, so to speak. That has allowed me to help establish REMS-certified treatment centers, both at a university medical center and in a private practice setting.

The process is fairly simple. It takes an application. The company Janssen [Pharmaceuticals] is very helpful in assisting prospective sites, whether a medical center or a private practice setting, achieve REMS certification. Certain conditions needed to be met: the equipment—there’s no equipment other than a suitable chair for the patient to rest comfortably; monitoring vital signs; and installing a safe, because the medication needs to be under double lock with limited access with a code for the REMS-certified provider, which applies to the physician as well as a nurse usually, or an APN [advanced practice nurse].

 I’m curious to ask you what your conversation is about misuse and abuse. I have patients who have treatment-resistant depression who are a couple of years out from substance abuse. I don’t preclude those patients in my private practice, but it’s a very different conversation in terms of the other treatments. “Are you in AE? Are you in NE? Are you going to groups? What does that look like? For me, it’s an extension of the conversation that I already have with patients whom I prescribe any schedule 3 substance to. What about you?

 There are lots of issues. We need more time. Let me go back to the contraindications. Blood pressure is a major issue, and I want to be on record reinforcing the need for stable blood pressure. Sometimes patients come in on blood medication. I’ve had 1 patient who was on 3 blood pressure medications and upon initial evaluation, her blood pressure was all over the place. I can reinforce and stress efficiently they need to have adequate stable control of hypertension if hypertension is an issue. And allow 2 weeks after adjustment of medications to make sure that blood pressure remains stable, because blood pressure elevation does happen almost invariably. Generally, if blood pressure is stable, we’re looking at 20 to 30 mmHg in systolic blood pressure. That’s relatively short-lived. We start seeing it at about 20 minutes postadministration, and by 60 to 90 minutes, it’s almost close to baseline. That’s 1 issue that’s very important.

 We have similar data as well. My anecdotal experience in our office is we usually find between 60 and 90 minutes is when things start to “normalize.”

Two psychiatrists discuss the importance of intranasal esketamine having a Risk Evaluation and Mitigation Strategy (REMS) and how that impacts treatment for treatment resistant depression.

Intransal Esketamine and REMS

 You mentioned before that you were on the clinical trials for intranasal esketamine. I wanted to talk about the TRANSFORM trial. As you know, the objective of TRANSFORM is that the STAR*D clinical trial showed that a third of our patients don’t respond adequately. This trial is a phase 3 double-blind active control multicenter study that was basically comparing the primary efficacy end point from baseline up to 28 days of patients who were flexibly dosed with esketamine plus a newly initiated antidepressant or the newly initiated antidepressant plus a placebo nasal spray. I wanted to ask you specifically if you had any comments on the efficacy or the safety that came out of this trial.

 Good question. There are many published reports about intranasal esketamine. Most of them were pertaining to the phase 3 clinical trials, including a geriatric study that’s part of the TRANSFORM-3 clinical trial. Frankly, the results are mixed, as presented in the literature. I have at least 2 comments to make about that. Initially, ketamine in general and by extension intranasal esketamine were presented for whatever reasons as panaceas; that they would be the miracle drug that works after a single administration. Those are false hopes. But yes, there’s response.

 I agree with you, Angelos. Because the very definition of MDD [major depressive disorder] is that it’s a chronic illness. I tell my patients that just like diabetes, where you’re on insulin for life, literature has taught us over the years that major depressive disorders are chronic illness. It’s really interesting that you highlighted the point that the 2 patients whom you’ll be treating today are in the maintenance phase. This is not a cure, so thank you so much for highlighting that.

 The other issue is that 4 weeks is inadequate. Most of these trials were 4 weeks long, twice a week for the first weeks. This is how the FDA approved it, suggesting for the marketed product twice a week for the first 4 weeks, then once a week for weeks 5 to 8, and then thereafter at the discretion of the physician. I understand. I try to abide by it. But once a product becomes widely available, invariably, we gather different data and impressions based on actual experience. I may call it real-life experience rather than the laboratory-based during a clinical trial, if you allow me the expression. I’m not being critical about it. I understand clinical trials. I’ve done them throughout my entire career. That’s what a clinical trial is supposed to be. But allow for the experience of the practitioners once the product is on the market.

Based on my experience and that of some of my colleagues, esketamine needs longer exposure. In some cases, in my practice, I’ve gone beyond 4 weeks of twice-a-week treatments until I was satisfied that I was getting a sustained good response. Then I gradually reduced the frequency.

 I agree with you 100%. My comment isn’t pejorative on clinical trials either, but we get these cookie-cutter patients who don’t represent the patients who walk into my office every day. Also, remember that in a clinical trial setting, patients are being attended to twice a week for 4 weeks by a great clinical team. You get a psychiatrist and a psychotherapist. They’re called. They have unscheduled visits. It’s true not only for the intranasal esketamine. For most drugs postmarketing, you’ll find that that efficacy drops because it becomes more like real-world data.

Dr Halaris, in your screenings of these patients, who are the patients you find would most benefit from this esketamine therapy? Are there any contraindications to esketamine?

 Once the work-up has been completed, as I outlined earlier, and we’ve ruled out patients as far as ancillary conditions, laboratories, pharmacogenomic testing that I described earlier, then the patient as of then must be on an oral antidepressant concomitantly. I prefer to start the antidepressant, whether it’s new or replacing an older one, based on the pharmacogenomic testing. I’d like to see how the patient does and adjust the dose to the point where we get some response. Obviously, it’s not going to be remission, because if we have remission, that obviates the need to give intranasal esketamine. That doesn’t happen. But we get some response so that the concomitant presence of the oral antidepressant is justified.

 Same here. We do pretty much the same thing in practice. When we talk about the patients who we think would benefit from it and the patients who are referred to us, if any provider is struggling and they’re on their third or fourth antidepressant, we ask them to do exactly as you’ve outlined. Let’s look at this patient in the 360-degree wheel. Let’s get all the testing. Let’s rule out any medical causes. As we know, people with any cardiovascular or intracerebral, intra-abdominal, aneurysmal vascular disease, histories of hemorrhages, and things like that are the contraindications. For us specifically, we talk to the patients and their caregivers about the risk of sedation dissociation and the need for the patients to be in a REMS [Risk Evaluation and Mitigation Strategy]–certified setting. We tell the patient that’s the reason why the patients are assessed in terms of blood pressure before we even initiate the treatment. And we’re having a conversation.

Drs Harding and Halaris evaluate the phase 3 TRANSFORM trial that studied intranasal esketamine as a therapy option for treatment resistant depression.

Phase 3 TRANSFORM Trial

 I’ll ask a question that you touched on a little earlier to get into the drugs that target the glutamatergic system. What do you think about them in fitting into this algorithm of treatment-resistant depression [TRD]?

 In my practice, after I’ve determined that we’re dealing with a true TRD, not a presumptive TRD—I know I sound like a broken record—

 I’m with you on that broken record. I’m the other half of it.

 I consider 2 options in my algorithm of choices: either TMS [transcranial magnetic stimulation], which is also very time consuming, given that the average number of sessions is about 35. It’s a minimum 3 days a week on site in the office, preferably 5 days a week. That amounts to roughly 7 or 8 weeks back to back. It also requires maintenance. The response is generally quite good. Even after the first few treatments, we can get a response, but I’ve also witnessed the loss of efficacy after termination of the initial acute treatment phase of about 35 sessions.

 I agree with you. I do this clinically as well, and it’s a travesty that we can’t figure out what maintenance looks like. It’s really good to hear a colleague express this as well, and that I’m not on an island by myself with these same outcomes.

 Next to TMS, I consider intranasal esketamine. I’ve used it before approval by the FDA in 2019 in phase 3 clinical trials and subsequently after it was approved at our institution. I still do it. As a matter of fact, I had a maintenance patient just an hour ago, and another is coming back for maintenance intranasal esketamine right after we’re done with this discussion. It’s a very interesting approach, not so much the classic neurotransmitters or serotonin-norepinephrine-dopamine, but at the NMDA receptor blockade that involves predominantly, but not exclusively, glutamatergic transmission.

 Absolutely. What are your thoughts on the intravenous ketamine that is used off-label? We’ve been using that off-label since before intranasal esketamine came on the market.

 Yes. I haven’t used the intravenous ketamine for the reasons you mentioned. It’s not FDA approved. It’s very costly. It is not really regulated, as intranasal esketamine is by the REMS [Risk Evaluation and Mitigation Strategy] program.

Two experts examine the impact of targeting the glutamatergic system as therapy for treatment resistant depression.

Targeting the Glutamatergic System for Treatment Resistant Depression

 What are your thoughts on treating this patient with intranasal esketamine? How quickly do you think the patient would have had a response?

 Excellent question. I’d like to first ensure that everything else has been done prior to considering intranasal esketamine and rule out other conditions. Everything we talked about a few minutes ago is important, including the thorough work-up and psychiatric history. Assuming all these things have been done, then I believe we’re dealing with a case of true TRD [treatment-resistant depression] and not presumptive TRD. I make a distinction between these 2. In my book, true TRD is the 1 that has ruled out all potential contributory factors, including the pharmacogenomic testing. If all these criteria have been met and we have a patient with true TRD, then I’d consider intranasal esketamine.

 I want to touch on the other therapies in terms of your thinking of where other modalities fall in treatment-resistant depression. What do you consider the frontline therapy? Would you refer a patient like this for another brain stimulation therapy, such as ECT [electroconvulsive therapy]?

 Yes. ECT used to be almost a mainstay back in the old days. When I was training in psychiatry, it wasn’t quite daily routine, but it was used very frequently at almost all centers. That’s not the case now. In fact, if we want somebody to receive ECT, we have to search for a place where it can be done. It’s very effective, but the effect doesn’t last forever, and the issue of maintenance ECT is acknowledged. The potential for some kind of cognitive impairment is still an issue.

 Yes, I agree with you. And because this is a patient with chronic kidney disease whom you’re subjecting to generalized anesthesia—we treat these patients, and I don‘t know whether she has reached the stage where she’s on dialysis, because the scenario didn’t get into it—in thinking through where the therapies lie, I thought intranasal esketamine was a really good choice for this patient. My view of the question that I posed to you regarding where in the algorithm I put my treatments, we’ve moved away from plugging the patient into the algorithm, and we’re instead having the patient’s symptoms guide where we are. There’s no cookie-cutter patient who fits into a scenario; we’re looking at it. You raise a good point. If this patient is 42 years old, we don’t know what her job is. With the risk vs benefit for the cognitive impairment that could occur with a treatment like ECT, would they be a consideration?

Lisa Harding, MD, and Angelos Halaris, MD, PhD, APA, ACNP, CINP, discuss their thoughts on starting treatment with intransal esketamine and what to expect.

Case 2: Starting a Patient on Intranasal Esketamine

 We’re going to answer some of these questions as well as we move on to the second case scenario. This is a patient who’s been diagnosed with treatment-resistant depression and has been prescribed intranasal esketamine. This patient is a 42-year-old woman with long-standing MDD [major depressive disorder] and chronic anxiety who was diagnosed in her 20s. She’s now referred with complaints of anxiety, hedonia, and boredom. The patient has tried several treatments over the course of her illness, such as quetiapine, citalopram, paroxetine, and lithium, without complete relief of symptoms. Blood levels were checked regularly and found to be within therapeutic range. She has since developed chronic kidney disease. The patient has a BMI [body mass index] of 30 and severe scoliosis. She was subsequently started on intranasal esketamine.

Angelos, my overall impression of this patient is pretty similar to the first one. When she presented with anxiety, hedonia, and boredom, were those symptoms the beginning of the chronic kidney failure that was found later on? With what frequency were her laboratory tests being drawn? It’s really interesting that this patient was on quetiapine as well. In thinking through where that fit into her treatment regimen, what line of treatment was that? What symptoms was that helping with? In terms of the paroxetine, how much of her symptoms did it even help with? By the blood draws, we know they’re referring to the lithium. The intranasal esketamine was a really good choice in this patient given that if we look at the second-generation augmentation with antipsychotics in a patient who already has a BMI of 30 and looking at the possible auctions of metabolic syndrome vs trying a medication that doesn’t have those effects. What are your thoughts?

 My thoughts are similar to what I shared with you in regard to the first case. But this case is also complicated in its own right because of the concomitant serious medical condition, kidney disease, which could lead to kidney failure and even death. The question is how much of that is in reaction to the physical debilitation. How extensive is the medical problem? Is it being addressed successfully? Is this patient receiving any supportive therapy to help her accept and live with the debilitation from the physical point of view?

I’d like to add another thought that applies to the first case as well. With respect to the selection of a pharmacotherapeutic agent, there are tests on the market that we refer to summarily as pharmacogenomic testing. There are a handful of products marketed, most of them are approved by the FDA, and these tests allow the prescribing provider to ascertain whether the pharmacogenomic profile of the patient will allow us to select a medication that’s congruent. For example, some patients have a pharmacogenomic profile with a variant of the serotonin transporter gene that indicates an SSRI [selective serotonin reuptake inhibitors] wouldn’t be the best choice. Additionally, the test results of such testing allow the provider to determine how to dose the medication. Some people are rapid metabolizers, in which case a higher dose may be OK to achieve response. The reverse can also be true. We could have slow metabolizers with a specific cytochrome P450 enzyme, in which case even conventional doses could lead to adverse effects and lack of tolerability. These are important pieces of information that we can now obtain with a simple test that’s generally covered by insurance with affordable co-pay and can turn people’s lives around.

 Science has given us many advantages. But my aspirational hope is that litmus tests will come. It’s amazing to know whether they’re fast metabolizers or slow metabolizers, because we know that attrition occurs. When patients get lost to follow-up, they stop medications because of the adverse effects. That is an amazing tool. But stretching beyond that, how do we measure response? We don’t have that litmus test yet to say. Even though they can metabolize the drug, are they going to respond to it?

Two psychiatrists review the case of 42-year-old female patient with a treatment resistant depression diagnosis that was prescribed intranasal esketamine.

Case 2: Prescribing Intranasal Esketamine

 This brings up a good point when we look at the biopsychosocial model of how we approach our patients. With presentations where the patient was also involved in psychotherapy, was it the right kind of psychotherapy? I find that that also plays an important part in a patient’s overall wellness. Are they getting CBT [cognitive behavioral therapy] when they should be getting DBT [dialectical behavior therapy]? It’s important to look at the patient as a whole.

When we think about the prevalence of treatment-resistant depression, we go back to thinking about our landmark STAR*D clinical trial. The takeaway point from that clinical trial was that a third of our patients won’t respond to our treatment regimens. When we look at this patient, he definitely meets the qualification for treatment-resistant depression having answered your questions and mine. Was this a full work-up in terms of a good diagnostic psychiatric interview? Were the medical causes ruled out? Given that, by the time he would’ve tried and not responded to 2 antidepressants, for an adequate dose and duration, that is the consensus definition that we have right now for treatment-resistant depression.

 Absolutely correct. I couldn’t agree with you more. Taking a thorough psychiatric history and developmental history for any age group, especially someone as young as this 26-year-old man, assessing childhood trauma, mistreatment, abuse, parenting, and family relations are all critical factors that predispose an individual to chronic relapsing nonremitting depression that must be addressed. The best way to address these issues is through psychotherapy. That also depends on what the individual’s psychiatric, family, and developmental history is like. Certainly, psychoanalytic and psychodynamic therapy shouldn’t be excluded. It takes longer and is a major investment, but in my experience, it works and pays off. DBT and CBT could be also considered, and should sometimes be considered in combination. Most definitely, supportive therapy should be done in conjunction with pharmacotherapy. I’m a very strong believer in combined pharmacotherapy with psychotherapy.

Drs Harding and Halaris provide an overview of treatment resistant depression, including prevalence and determining a diagnosis.

Case 1: An Overview of Treatment Resistant Depression

Psychiatric Times® Case-Based Psych Perspectives

 titled “Managing Patients With Treatment-Resistant Depression.” I’m Dr Lisa Harding, a board-certified psychiatrist and a clinical instructor of psychiatry at the Yale School of Medicine in New Haven, Connecticut. Joining me is the esteemed Dr Angelos Halaris, a board-certified psychiatrist and a professor of psychiatry at Loyola University Chicago’s Stritch School of Medicine in Maywood, Illinois. The goal of our discussion is to share insights in diagnosing treatment-resistant depression [TRD] and reasons for inadequate treatment response with antidepressant therapy, as well as to provide a brief overview of available treatment options and to offer recommendations on how treat patients with this disorder. Welcome, Dr Halaris.

 Thank you so much for inviting me. I’m honored by your invitation and glad to be here.

 It’s nice to see you again. We’ll start by reviewing a couple of case scenarios. The first case presentation, No. 1, is a patient newly diagnosed with treatment-resistant depression. A 26-year-old man with a history of major depressive disorder for over 7 years presents with complaints of trouble sleeping as well as feeling unhappy, worried, and fatigued. He gradually developed sleeping difficulty as well as low mood and loss of interest. He tried multiple treatments, including escitalopram, fluoxetine, venlafaxine, and bupropion. However, his symptoms weren’t fully relieved. He was subsequently diagnosed with treatment-resistant depression. The patient reports having an average childhood, being an average student, and having good relationships with coworkers and no problems at work. He was always involved in psychotherapy, and denied any drug or alcohol use.

My overall impression of this case is this is a young patient who’s supposed to be living the life actuation part of his life, and he has now tried and failed more than 2 antidepressants. One of the things coming to mind was, is he stopping these antidepressants because of adverse effects, as I see in my clinical practice? What was the adequate dose of the adequate trial in terms of these medications that he was prescribed? Dr Halaris, what are your overall impressions of the case?

 Much like what you just said, Lisa, as presented, this brief case scenario leaves many more unanswered questions, some of which you already touched upon. I’d like to reinforce your own questions and add a few of mine as well. First and foremost, what kind of work-up was done prior to diagnosing the patient and then treating him with the list of mainly SSRIs [selective serotonin reuptake inhibitors] and SNRIs [serotonin and norepinephrine reuptake inhibitors]? By that, I mean where other factors that are known to contribute to depression, and especially TRD, had they been carefully assessed by means of a thorough psychiatric diagnostic evaluation and the pretty much established blood work that we know is essential, such as ruling out endocrinopathies, assessing HPA [hypothalamic-pituitary-adrenal] function, looking at diabetes, inflammatory conditions, any chronic medical illnesses that invariably lead to chronic inflammation, including neuroinflammation. Because if there’s an inflammatory focus elsewhere in the body, these pro-inflammatory substances known as cytokines invariably make their way into the brain parenchyma and stimulate microglia and astrocytes to also become inflamed. So we have a relocation of the peripheral inflammation into the brain leading to neuroinflammation. These are all factors that I’d like to see addressed.

Other issues are obviously vitamin deficiencies, notably vitamin D, especially during the winter months. But this also happens in summer months in susceptible individuals. I’m amazed at the frequency of vitamin D deficiency, including in young people. Unless we make a point to check these issues routinely at the initial evaluation, some of the symptoms of vitamin D deficiency resemble symptoms of depressive disorder with anxiety, low energy, low motivation, sense of desperation, attention-focusing issues and so on. The good news is that it’s fixable by administering the right supplementation of vitamin D.

Lisa Harding, MD, and Angelos Halaris, MD, PhD, APA, ACNP, CINP, review a case of a 26-year-old male patient who was recently diagnosed with treatment resistant depression

Case 1: Newly Diagnosed Treatment Resistant Depression

More good news regarding treatment choices in major depressive disorder (MDD) and postpartum depression (PPD), as the 2 companies working on zuranolone announced that they will submit a New Drug Application (NDA) to the US Food and Drug Administration (FDA).

Following discussions with the FDA, including a pre-NDA meeting this fall, Biogen Inc. and Sage Therapeutics Inc. decided to initially seek FDA approval of zuranolone in the treatment of MDD in late 2022, with plans to file for PPD in the first half of 2023. The initial submission package for MDD will include data from ongoing pharmacology and clinical studies, plus data from the LANDSCAPE and NEST clinical trial program studies, both of which include several studies examining the effectiveness of zuranolone in several thousand patients in various dosing, treatment paradigms, and clinical endpoints. Data from PPD 301-SKYLARK, a NEST program ongoing placebo-controlled study of zuranolone in patients with PPD, will be added to the separate filing for PPD. 

“We are pleased to share what we believe is an efficient filing pathway for zuranolone, with the goal of bringing a new treatment option to the millions of people who suffer from depression worldwide,” said Alfred Sandrock Jr, MD, PhD, Head of Research and Development at Biogen, in a press release.

Zuranolone is a once-daily, 2-week, investigational oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM) in development for the treatment of MDD and PPD that is designed to potentially serve as a rapid-acting sustainable treatment option. The drug received the Breakthrough Therapy Designation from the FDA in February 2018.

Recently, Sage shared results from their SHORELINE study, which found the agent to be safe and effective in the sample of patients with MDD.

 In that trial, investigators found that almost half of all participants who positively responded to the initial 14-day course of zuranolone 30 mg did not require additional treatment to maintain wellness through a year of follow-up.

“In the clinical development programs, zuranolone has shown remarkably consistent, rapid, and sustained reductions in depressive symptoms, including anxiety and sleep loss, in addition to a well-tolerated safety profile,” said Barry Greene, Chief Executive Officer at Sage Therapeutics, in a press release. “We believe we have a solid filing package with four adequate and well controlled trials now in hand and, if approved, zuranolone will fill a real unmet need and be welcomed by people living with depression.” 

1. Sage Therapeutics and Biogen announce plans to submit a New Drug Application (NDA) for zuranolone to the U.S. Food and Drug Administration in the second half of 2022 with rolling submission expected to start in early 2022. News Release. Sage Therapeutics. October 19, 2021. Accessed October 19, 2021. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-plans-submit-new-drug 

2. Sage Therapeutics receives FDA Breakthrough Therapy Designation for SAGE-217 for the treatment of major depressive disorder. News Release. Sage Therapeutics. February 7, 2018. Accessed October 19, 2021. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-receives-fda-breakthrough-therapy-designation

3. Kuntz L. Anticipated phase 3 interim results for Sage’s depression treatment, zuranolone. Psychiatric Times. October 14, 2021. Accessed October 19, 2021. 

https://www.psychiatrictimes.com/view/anticipated-phase-3-interim-results-for-sage-s-depression-treatment-zuranalone

New Drug Application to be submitted for MDD in late 2022, with separate filing for PPD planned for early 2023. 

Depression