Latest Advancements: Treating Challenging-to-Treat Depression (podcast transcript)

Podcast Intro: Welcome to PsychPearls podcast by Psychiatric Times with thoughtful insights into the world of psychiatry, these podcasts provide expert insights, commentaries, clinical pearls, and more on the topics and trends in psychiatry and mental health that are important to you and your practice.

Patricia Cabrera Jaramillo, MD: Hello and welcome to this PsychPearls podcast by Psychiatric Times. I'm Dr. Patricia Cabrera, Group Medical Director for Mood at Johnson & Johnson. Joining me here is Dr. Michael Asbach, Associate Director of Interventional Psychiatry at DENT Neurologic Institute, and in this episode we'll be talking about the latest innovations in clinical depression. This podcast episode is sponsored by Johnson & Johnson. Dr. Michael Asbach has been compensated by Johnson & Johnson for this time to participate in this podcast.

By many measures, mental health is currently one of the greatest unmet needs in healthcare, if not the greatest. At Johnson & Johnson, our neuroscience team is working towards a world where mental illness is understood, identified, and treated in a timely manner by 2030. This is a topic that I'm very passionate about, and I'm pleased to be joined by Dr. Michael Asbach to help me shed light on this important issue and how the treatment landscape for depression is evolving. Dr. Asbach, thanks for joining.

Michael Asbach, DMSc, PA-C: Well, thank you for having me. And just a little bit about myself. I am a Psych PA, as you said. I'm the Associate Director of Interventional Psychiatry up in Buffalo, New York at DENT Neurologic Institute, and I've been treating depression for 12 years now, my entire career. And I'm really excited for today's conversation. I think it's a great opportunity for you and I to talk about, unfortunately, a patient population that has really suffered, and I'm excited to have more options available to this group.

Patricia Cabrera, M.D.: Great, great. Welcome again. So recent studies have reinforced what we all see - a big jump in depression rates in the years since the COVID-19 pandemic. What I find striking is that even as prevalence increases, many people still don't really understand the different forms of depression, particularly those who are struggling with more severe or challenging-to-treat forms.

Michael Asbach, DMSc, PA-C: I think that's right. I think we still think of depression, even as a clinician, I think sometimes we often misconstrue depression as just sadness, and we don't always realize how debilitating depression can be, especially in the more severe forms.

Major depression is one of the most common mental illnesses in America. We estimate that there's maybe 21 million in the U.S. that have had at least one major depressive episode, but if we break it down a little bit further, data from the CDC estimates that nearly 1 in 5 adults report having been diagnosed with depression in their lifetime. At a rate of 20%, that means that people we're interacting with on a daily basis are people that have struggled with this. Coworkers, friends, family, loved ones. Depression is a serious illness, and it can negatively affect how you feel, the way you act. It's a serious illness and it can really impact every aspect of our life. But fortunately, it's also treatable.

Depression causes feelings of sadness or loss of interest and activities that you previously enjoyed, but it can also lead to a variety of emotional and physical problems that can decrease functioning both at work and at home. And this is in large part why depression is the leading cause of disability, both in the U.S. and worldwide.

Patricia Cabrera, M.D.: Yes, you're absolutely right. Depression is often defined as one type of illness. But in fact, an estimated one third of U.S. adults living with major depressive disorder do not respond to two different antidepressants of adequate dose and duration, is what's often defined as treatment-resistant depression or TRD. This creates a significant ongoing burden emotionally, functionally, and economically. It is also important to know that some people also have a severe form of major depressive disorder, where a person experiences a sudden worsening of depressive symptoms, which can cause them to consider or act on thoughts of self-harm or suicide.

According to the CDC, after declining in 2019 and 2020, suicide rates increased approximately 5% in the United States in 2021. And it's also important to know; however, that not all people living with major depressive disorder have suicidal thoughts or actions. Michael, as you know, advancements in treatment options available for major depressive disorder or TRD have been limited or not widely available. Patients have continued trying treatments that don't work, have had inadequate response, which can be extremely frustrating and exhausting, and cause a significant negative impact on their lives. However, there are available options out there that can work for some patients.

Michael Asbach, DMSc, PA-C: Yeah, I think that's right, and I'd love to go through those with you, Patty, because some people that are listening to this may not be familiar with all the available options. So, what I'd like to do is maybe we can split this into two different conversations. First, we'll talk about the options for treatment-resistant depression that have been historically available, and then we'll pivot and talk about the things that we now have. These innovations that are coming and currently here. Advancements in treatment options for TRD have been evolving, but so many times patients end up cycling through multiple treatments before they find something that works. You said earlier that up to 30% of patients with depression end up meeting that criteria as treatment resistant, meaning two or more med failures. And this can really have a significant impact on their lives. We talked earlier that depression is functionally debilitating.

It has an impact on every aspect of their life. And these patients that have more severe, more challenging forms of depression, they continue to suffer. And even as we're cycling through these different medication options, trying to find something that works, this can often lead to months, if not years of suffering as we're trying to find a solution. Historically, for patients that don't respond to treatment, we have a couple different options.

Oral antidepressants would be the one that always comes front of mind, and these work by increasing serotonin, norepinephrine, and/or dopamine, or by blocking the reabsorption of these neurotransmitters in the brain in areas we know to regulate mood and relieve depression. We also can use antipsychotics. Antipsychotics can reduce or eliminate symptoms of psychosis such as delusions or hallucinations by affecting the brain chemical that we know as dopamine. While all antipsychotics play a vital role in treating schizophrenia or schizoaffective disorder, second generation antipsychotics, so the newer class, can also be used to treat acute mania, bipolar disorder, or treatment-resistant depression. Traditionally, when we use an antipsychotic for depression, we're adding that on to an antidepressant. So, if someone's on an antidepressant and may be demonstrating a partial improvement, we augment with that antipsychotic in an effort to bring them closer to remission.

Another option that we've had available to us for depression is transcranial magnetic stimulation. And this is a procedure that involves placing an electromagnetic coil against the person's scalp to stimulate neurons in the brain through short pulses that are targeted to certain areas that are believed to control mood. And in this way, we can improve depression.

Another option is electroconvulsive therapy. And this is where we take small electrical currents that route through the brain in a controlled way to trigger a brief seizure. This can affect the neurons and then in turn affect the chemicals, thus improving depression. With all of these treatments though, one of the major limitations with them is that none of them move terribly fast. And as we said earlier, depression is debilitating.

People are suffering not only emotionally but functionally as well when they have depression. And even when these treatments work, it can take weeks, sometimes even months for patients to feel any relief from their depression. And for those who are treatment resistant, many times they may struggle to find something that works and manage their symptoms. And a lot of times medication alone just may not be enough.

Psychotherapy, in my opinion, is a key component of any treatment plan. So, as we talked about these different interventions, I would always encourage patients to also incorporate psychotherapy as well. Research shows that combination of medication and psychotherapy is going to be the most superior in terms of achieving results.

Patricia Cabrera, M.D.: Thank you, Michael. It's also very exciting to see the advancement in the psychopharmacology field as novel mechanisms-of-action and molecules are currently being studied. One advancement in the treatment of challenging-to-treat depression in recent years is SPRAVATO®.

Approved by the US Food and Drug Administration in 2019, SPRAVATO®, esketamine CIII nasal spray, is used in combination with an oral antidepressant to treat adults with treatment-resistant depression, or TRD. In 2020, the FDA-approved a second indication to treat depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions, also taken in conjunction with an oral antidepressant. SPRAVATO® contains esketamine, a schedule 3 controlled substance, C3, and may be subject to abuse and diversion. Although a derivative of ketamine, SPRAVATO® is not for use as a medicine to prevent or relieve pain or anesthetic. And as you might remember, we spoke previously about the increase in suicide rates in the U.S. So, I want to make clear, that it is also not known if SPRAVATO® is safe and effective for the use of preventing suicide or reducing suicidal thoughts or actions and should not be used in place of hospitalization. SPRAVATO® is different because it acts on the glutamate pathway. The medication has a proven safety and efficacy profile and is well studied.

Johnson & Johnson has worked closely with the FDA to develop an infrastructure by ensuring its patients' safety and mitigates the risk of abuse by requiring patients to receive SPRAVATO® under medical supervision. This includes a Risk Evaluation and Mitigation Strategy, or REMS, program for patients to self-administer the nasal spray under the supervision of a medical professional at a treatment center and remain there for at least two hours post-administration to track any adverse events. SPRAVATO® can cause sleepiness, sedation, fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space, and time, which we call dissociation, and breathing problems, respiratory depression, and respiratory arrest. Please stay tuned for important safety information during and after this episode.

SPRAVATO® represents a different way to treat patients. I would like to ask you, how has it changed your approach to treating patients?

Michael Asbach, DMSc, PA-C: I think it's changed a lot of things, and I think you already hit on it just in the way that you worded that, Patty, that it allows a different way for us to treat patients. We take a lot of students at our clinic, and I always like to tell them that with depression, if you think about it, there's over 10,000 different symptom combinations that still meet the criteria of major depressive disorder. My gut tells me that if something can present in 10,000 different ways, that probably means that it's a rather complex illness with a lot of different pathology and it's going to be quite heterogeneous. It's logical to me then that our treatment is also going to have to be diverse and different for each patient.

Historically, we've been limited in what options we've had, and we've often tried to maybe fit a square peg in a round hole because we didn't have as many treatment options available. So, I think the biggest change for me is that now we have more options. And that's a really exciting thing because it allows us to maybe approach our patients in a more personalized manner as we're trying to help them feel better. The other thing I think that is really key with this is that having rapid acting treatments is a really important thing.

We want to think about depression as an urgent or a patient emergency. The patient is having an immense amount of disability, amount of functional difficulty secondary to their depression. Maybe they're not in work, maybe they're having relational strain because of their depressive illness. And the faster that we can get that patient feeling better, the quicker we can restore them to their normal life.

The primary antidepressant activity of SPRAVATO® is not believed to directly involve the inhibition of serotonin or norepinephrine reuptake. SPRAVATO® is an NMDA receptor antagonist, and an NMDA receptor is an ionotropic glutamate receptor. Now of course, mechanism of action is hypothesized, but as we said earlier, this is different. It allows us to offer different approaches for patients that may need different things. When I approach all these conversations with my patients that have depression, I'm always trying to figure out what type of depression they have and make sure that I can work with them to identify the best treatment plan that will fit their unique lifestyle or needs.

It's important that when we talk to patients and we're deciding the next steps in terms of treatment, that we share research with them and also ensure that these conversations are collaborative. I'm a big believer in shared decision making. We want the patient to feel empowered. We want the patient to have the agency to be part of their decision making, not only in what their treatment goals are, deciding what's important to them, what are the things about their depression or about their recovery that they need to prioritize, but then also agency in carrying out that treatment plan. I think it's incredibly important. A big part of that is the patient and the provider need to be open and honest with each other to try and figure out what the best path is forward.

In our clinic, we've done an internal analysis, and we found that the average SPRAVATO® patient, by the time they make it to our clinic, has tried and failed five different antidepressants. As we know, the definition of treatment-resistant depression is only two antidepressant failures of adequate dose and duration. And yet, by the time they're referred to our clinic, they've tried and failed five treatments. This means months, if not years, of medication failure of non-response where they're continuing to have debilitating symptoms of depression. And this can be hard. This can make it very difficult for the patient to have hope. To have a willingness to engage in yet another treatment option. In fact, I just saw a patient recently. She came into our clinic for a consultation for SPRAVATO®. And in my consultations, I always like to ask my patients, when is the last time that you felt you were free of depression, where you had no symptoms of depression. And she couldn't give an answer. She indicated that her entire adult life, over 20 years, she has struggled with depression. She doesn't even know what normal feels like because depression has been a defining feature of her life, for decades. Thankfully, this individual is now in our SPRAVATO® program, and she's doing well. And we're working together to define what a depression free life can look like.

Patricia Cabrera, M.D.: Thank you for sharing. And that's so wonderful to hear that through shared decision making, your patient who was struggling for so long, is finally able to find a treatment plan that has been working to manage her depressive symptoms. Of course, as with any medication, SPRAVATO® has risks and benefits with it. It also has a box warning for sedation, disassociation, respiratory depression, potential for abuse and misuse, and increased risk for suicidal thoughts and behaviors. So, it is important to look at each patient individually to determine if SPRAVATO® could be the right fit for them. Now, there has been increasing interest in the role that psychedelic substances might play in the treatment of several psychiatric disorders, including depression. Michael, could you share what you know about the use of psychedelic drugs to treat mental health conditions?

Michael Asbach, DMSc, PA-C: It’s such a fascinating topic, and I think it’s one that we’re going to be hearing about and talking about in psychiatry more and more in the next few years. I think my stance, if I were to summarize my view on psychedelics, I would define it as cautious optimism, and caution, I think, is really the key here. I always am inherently a little bit nervous when we have a cultural moment where podcasters, social media influencers, where everyone is jumping on the band wagon and getting excited. And I think there’s a lot of reason to be excited for psychedelics, but at the same time, it’s very important in medicine that we also are aware of where the evidence lies and make sure that we are always as clinicians following the evidence.

Just to give some context, I think since the pandemic, mental health conditions have continued to worsen and certainly depression being part of that, we’ve seen a steady rise in rates of depression since the start of the pandemic. And I think this is in part growing or fueling interest in these alternative treatment approaches.

In 2022, the American Psychiatric Association issued a position statement that did recognize the value of clinical investigation for psychedelics, but within that position statement, they also stressed that there's currently inadequate scientific evidence to endorse the use of psychedelics to treat any psychiatric disorder or mental illness. So, in my clinic, when I have conversations with my patients, I actually like to refer them to that 2022 position statement, because it's a nice reminder that there can be a lot of excitement for preclinical trials or even observational trials, but that does not necessarily mean that randomized control trials are going to lead to the same outcome. So, excitement and optimism is totally worthwhile, but we have to continue to follow the evidence and that APA statement is a great reminder even when I'm talking to patients.

In June of 2023, the FDA published draft guidance highlighting fundamental considerations for designing clinical trials for psychedelic drugs and using these to treat medical conditions including psychiatric or substance use disorders. So that's another big step in the right direction. And this has the potential to really be an innovative practice or an innovative treatment for mental health, but the benefits and the harms of this therapy still need to be determined. We need to make sure that we're not getting out over our skis or getting ahead of the evidence. It's important to remember that psychedelic treatment for mental health disorders should be determined by scientific evidence and clinical studies to evaluate safety and effectiveness of these drugs by the FDA. Not every psychiatric clinician may provide rapid acting interventional treatments, but the emergence of these treatments will require clinicians to incorporate and change their care and delivery.

So I think for clinicians that are listening to this, whether it's SPRAVATO®, whether it's other interventional services, or even psychedelics in the near future, it's really important that you're staying up to date on all the available evidence, because things are moving quite fast, and it's imperative that you're aware of where the latest developments are, but also where the limitations of evidence are as related to psychedelics.

While some are turning to these alternate psychedelic treatments, it's important to also remember that SPRAVATO®, or esketamine, is the only treatment option derived from ketamine approved by the FDA in conjunction with an oral antidepressant, or adults with treatment-resistant depression, and depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions.

So, to tie it back to where I started, cautious optimism is certainly warranted. I think it's exciting. I'm so thrilled that we're continuing to have innovation and development in the field after many decades of just having the same classes of antidepressants that were quite limited. We talked earlier, Patty, on how they fall short sometimes. So, it's exciting, but at the same time, we have to be very cautious and not get caught up in all the excitement and get beyond the available evidence.

Patricia Cabrera, M.D.: Thank you, Michael. I also wanted to clarify that SPRAVATO® and ketamine each have a different chemical composition. While SPRAVATO® has FDA-approved indications, administration, study data, and safety measures for the treatment of challenging-to-treat forms of depression, ketamine does not for psychiatric use.

Michael, can you share a bit about ketamine and how it is different from SPRAVATO®?

Michael Asbach, DMSc, PA-C: I think I have this conversation nearly every day with patients that are referred to our clinic. So, it really is important that as clinicians we understand the differences between the two because our patients will ask. In terms of chemical composition, ketamine is a mixture of two enantiomers or compounds with opposite shapes, R-ketamine and esketamine. We typically refer to ketamine as racemic, meaning that there's a mixture of both of the enantiomers. SPRAVATO® is different because it only contains esketamine, which has a higher affinity for the NMDA receptor and therefore it allows lower dosing with less fluid volume making intranasal dosing possible.

Ketamine is not approved by the FDA for treatment of any mental illness or psychiatric disorder. Ketamine is FDA-approved as an intravenous or intramuscular injection solution for the induction or maintenance of general anesthesia for diagnostic or surgical procedures. Any such use of ketamine to treat severe depression is considered off-label use, meaning that there's no standardized approach to the administration, dosing, frequency, or treatment of such patients, and any off-label use or treatment for a non-FDA approved indication may put the patient at risk for serious adverse events.This is important to understand, as ketamine clinics are becoming more abundant, and given the mental health crisis in the US, people with challenging- to -treat depression must get the help that they need. It's critical, but it's equally important that, as you said, we ensure close collaboration between a patient and their healthcare team. To make sure that they receive a proven, safe, and effective treatment option.

So once again, shared decision making, but also as a clinician, really understanding the available evidence and where the empirical evidence lies for all of these treatments that we've discussed today.

Patricia Cabrera, M.D.: I couldn't agree more. With no standard approach for administration, dosing frequency, or treatment duration, there is a potential for dosing errors. Safety risks associated with off label ketamine use. In contrast, SPRAVATO® has a unique nasal spray administration. The nasal spray device is also pre-filled at a fixed dose and has been rigorously tested to ensure the right dose of medication is delivered to patients at each use.

At Johnson & Johnson, the safety of the people who take our medicines is top priority, which is why rigorous safety and post administration measures have been in place since 2019 since the approval of SPRAVATO® by the FDA. This infrastructure, the SPRAVATO® REMS program, is required by the FDA to ensure patient safety and help patients and healthcare providers treating them to feel more confident in the ability to manage known side effects associated with this medicine. SPRAVATO® has proven short- and long-term results for people with treatment-resistant depression. The FDA has not determined if ketamine is safe and effective for such use.

Most recently, the FDA issued a patient and consumer safety alert warning patients and healthcare providers about the potential risk associated with compounded ketamine products for the treatment of psychiatric disorder. The agency also noted that it was not aware of evidence to suggest that it is safer, more effective, or works faster than medications that are FDA approved.

Now, more than ever, there's an urgent need for continued advancement in mental health. We look forward to collaborating with industry partners to help foster innovation and provide a space for critical discussions and key learnings.

At Johnson & Johnson we're inspired to accelerate hope and healing for patients with serious depression, which is why we're committed to continued investment and research to identify new pathways in which innovative treatments may offer solutions to patients most severely impacted by mental illness.

Michael Asbach, DMSc, PA-C: Absolutely, Patty. And I think in closing, I'd maybe break my message into two different parts.

Speaking to patients, my hope is that as you work to try and manage your treatment-resistant depression, know that this is a serious condition and that your struggles are seen. We know that this is very tough. We know it's hard. And I would encourage you that if you're struggling with depression, not to give up. There are options out there and there are things available that can provide a rapid acting effect. So, continue to work with your healthcare team to find those solutions and try those next options.

For fellow clinicians, it's our duty ethically, professionally to remain up to date with the rapidly changing clinical landscape in mental health and make sure that we're educating ourselves on these changes of how care is delivered. Because ultimately our education, staying abreast to these latest updates will allow us to optimize the care for our patients and make sure that we're providing the best quality, compassionate care that we can. We must do our part to address the needs of our patients, and this means educating and helping our patients as well, as they navigate the treatment landscape to ensure that they receive safe, effective, and timely treatment for a very challenging-to-treat condition of depression.

Patricia Cabrera, M.D.: Michael, thank you for joining this discussion about innovation in the rapidly evolving spectrum of depression. And to our listeners, thank you for listening to this episode of the Psychiatric Times PsychPearls podcast, courtesy of Johnson & Johnson. This podcast was approved under cp-437057 version one. Please stay tuned for important safety information about SPRAVATO®.

Indications and Important Safety Information

Indications:

SPRAVATO® (esketamine) CIII Nasal Spray is indicated, in conjunction with an oral antidepressant, for the treatment of:

• Treatment-resistant depression (TRD) in adults.
• Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

Limitations of Use:

• The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO® does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO®.
• SPRAVATO® is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO® as an anesthetic agent have not been established.

Important Safety Information

CONTRAINDICATIONS

SPRAVATO® is contraindicated in patients with:

• Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
• History of intracerebral hemorrhage.
• Hypersensitivity to esketamine, ketamine, or any of the excipients.

WARNINGS AND PRECAUTIONS

Sedation: SPRAVATO® may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. In clinical trials, 48% to 61% of SPRAVATO®-treated patients developed sedation and 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness.

Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants (e.g., benzodiazepines, opioids, alcohol).

Dissociation: The most common psychological effects of SPRAVATO® were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO®-treated patients developed dissociative or perceptual changes). Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.

Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

Respiratory Depression: In postmarketing experience, respiratory depression was observed with the use of SPRAVATO®. In addition, there were rare reports of respiratory arrest.

Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

Abuse and Misuse: SPRAVATO® contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient’s risk for abuse or misuse prior to prescribing and monitor all patients for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence.

SPRAVATO® 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, respiratory depression, 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 and administered in healthcare settings.
  • Patients treated in outpatient settings (e.g., medical offices and clinics) must be 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.

Further information, including a list of certified pharmacies, is available at www.SPRAVATOrems.com/ or 1-855-382-6022.

Suicidal Thoughts and Behaviors in Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included adult and pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. SPRAVATO® is not approved in pediatric (<18 years of age) patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO® and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Increase in Blood Pressure: SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO® administration and last approximately 4 hours.

Approximately 8% to 19% of SPRAVATO®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risk.

Assess BP prior to administration of SPRAVATO®. In patients whose BP is elevated prior to SPRAVATO® administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO® therapy should take into account the balance of benefit and risk in individual patients.

BP should be monitored for at least 2 hours after SPRAVATO® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.

Closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) or monoamine oxidase inhibitors (MAOIs).

In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.

Cognitive Impairment

Short-Term Cognitive Impairment: In a study in healthy volunteers, a single dose of SPRAVATO® caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO®-treated subjects required a greater effort to complete the cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO® and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.

Long-Term Cognitive Impairment: Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. No adverse effects of SPRAVATO® nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO® have not been evaluated beyond one year.

Impaired Ability to Drive and Operate Machinery: Before SPRAVATO® administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO®.

Ulcerative or Interstitial Cystitis: Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO® nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO®-treated patients than in placebo-treated patients. No cases of esketamine-related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year.

Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO® and refer to an appropriate healthcare provider as clinically warranted.

PREGNANCY, EMBRYO-FETAL TOXICITY, AND LACTATION

SPRAVATO® is not recommended during pregnancy. SPRAVATO® may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO® in utero. Advise women of reproductive potential to consider pregnancy planning and prevention.

There are risks to the mother associated with untreated depression in pregnancy. If a woman becomes pregnant while being treated with SPRAVATO®, treatment with SPRAVATO® should be discontinued and the patient should be counseled about the potential risk to the fetus.

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

SPRAVATO® is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO®.

SELECT USE IN SPECIFIC POPULATIONS

Geriatric Use: No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age. At the end of a 4-week, randomized, double-blind study, there was no statistically significant difference between groups on the primary efficacy endpoint.

Hepatic Impairment: SPRAVATO®-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.

SPRAVATO® has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.

ADVERSE REACTIONS

The most common adverse reactions with SPRAVATO® plus oral antidepressant (incidence ≥5% and at least twice that of placebo nasal spray plus oral antidepressant) were:

TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.

Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO®.

cp-170362v5

End of Transcript

cp-447827v1