Collaborative Approach to Treatment-Resistant Depression Management: A Q&A With Michael Asbach, DMSc, PA-C

Click here to read the transcript.

Major depressive disorder (MDD) can cause a variety of emotional and physical challenges for patients. In addition to impacting their ability to function at work and at home, a person often experiences a sudden worsening of depressive symptoms, which may cause them to consider or act on thoughts of self-harm or suicide. However, not all people living with MDD have suicidal thoughts or behavior.¹

In this interview, Associate Director of Interventional Psychiatry at DENT Neurologic Institute, Michael Asbach, DMSc, PA-C, discusses the impact of severe clinical depression and the recent treatment innovations available for adult patients.

Psychiatric Times®: In your work, you are often called on to help treat patients struggling with MDD. Can you give an overview of the prevalence of this condition in the US?

Michael Asbach, DMSc, PA-C: National data from the CDC estimates, as of 2020, nearly 1 in 5 people report having been diagnosed with depression in their lifetime.² Depression is often perceived as one type of illness, but it is heterogeneous.³

MDD is a horrible and debilitating illness, regardless of age or stage of life. We know depression occurs most frequently in women aged 25 to 44.⁴ And although I have patients suffering from depression across the life-span, a lot of my patients in their 20s and 30s have tried many different medications over the years without relief. I worry about the functional impact of depression in my young adult patients who are at a pivotal time in their lives. Depressive illness may impair a formative time of life when young adults are finding partners, buying houses, starting families, and establishing their careers.

For my depressed patients, I think a lot about loneliness and isolation. We know that loneliness can substantially contribute to mental health struggles. Isolation is also a core feature of major depressive disorder and the lack of social connection coupled with depression can lead to a vicious cycle. As a person’s depression becomes more severe, individuals often become more isolated and diminished ability to fully function at work can develop. A lack of strong psychosocial support may cause some patients to fall through the cracks, risking further functional decompensation due to reduced access to medical care.

Certain communities are more affected by mental health disorders than others. For example, LGBTQ+ adults are three times more likely to experience a mental health disorder than heterosexual individuals.⁵ And patients in the LGBTQ+ community may have barriers to treatment, whether that be a lack of access to safe, compassionate, and empathetic care, or fear of stigma or discrimination.

It is imperative that we encourage people struggling to find a treatment that works for them to seek help and have these conversations with their healthcare team. More and more, we are seeing that there are tailored resources available for these groups, but they just don’t know where to find them.

We also talk about how depression is one of the leading causes of disability, but we don’t necessarily think about what that means or what that looks like. An estimated one-third of U.S. adults living with MDD do not respond adequately to two different antidepressants during the same depressive episode, often defined as treatment-resistant depression or TRD.⁶

Psychiatric Times®: Often, symptoms of depression are not adequately resolved with treatment. What sorts of challenges do your patients with treatment-resistant depression (TRD) face on a daily basis?

Michael Asbach, DMSc, PA-C: As depression takes hold, it is associated with functional impairment, which makes it that much harder to dig out of the episode. We know that exercise, diet, sleep, medication, and support from loved ones are all things that can effectively modulate depression. Those lifestyle interventions are very difficult for patients if they are struggling to complete the basic tasks of daily living.

I have a patient I just saw recently who is struggling with TRD. We’ve tried many treatment options, none of which have provided significant relief. Recently, he was hospitalized briefly for a suicide attempt and lost his job as a result of the illness. Now he’s at home, his family is at work or at school while he’s at home, so the isolation has worsened. He lost touch with his friends because he just doesn’t feel well enough to attend card night or a hockey game. Depression, for him, is more than the symptoms. He describes it as a dark shadow that’s cast over every aspect of his life.

I think his experience really demonstrates what a profound impact depression can have on someone’s life and emphasizes the importance of identifying a therapeutic approach that can help resolve symptoms.

Psychiatric Times®: How do you work with your patients to identify the right TRD treatment plan, and what are the current treatment options available?

Michael Asbach, DMSc, PA-C: As clinicians, we need to make sure that we are providing safe, empathetic care in an environment where the patient feels they can be vulnerable, where the patient feels that they can pursue treatment, and where the patient feels comfortable to express what they need.

Education and empowerment allow the patient to take an active part in their care while also encouraging the patient to be aggressive in their treatment plan. Often depression leads to this feeling of hopelessness where patients feel that they don’t have agency in their own life. Shared decision-making restores a sense of agency and hope that the patient’s TRD is a treatable condition.

One of the best things that we can do as clinicians is work with patients and use shared decision making to determine what is best for them individually, since every person is different. A critical part of shared decision-making involves educating patients on various treatment options, risks, benefits, logistical challenges, or concerns. The second part is aggressive treatment planning. By the time patients have reached that moniker of TRD, by definition, that means that they’ve had at least several months or even years cycling through many treatments without relief, and as mentioned earlier, lots of lost hope and despair.

I think it can be frustrating for patients when they are receiving therapeutic options essentially targeting the same 3 monoamines in different combinations over and over again but expecting different results. It’s important to encourage patients not only to try something new, but also educate them that we can be aggressive and decisive with our treatment of depression.

The way I like to explain it to patients is that depression is complicated. There are over 10,000 different symptom combinations that can occur, so we need more than just three chemicals for our therapeutic approach – especially for those living with TRD. In addition to antipsychotics, there are other alternative treatment options we can augment oral antidepressant treatments with, including transcranial magnetic stimulation, electroconvulsive therapy, and SPRAVATO® (esketamine) CIII nasal spray, each with their own benefits and risks.⁷

Psychiatric Times®: What makes SPRAVATO® unique, and what makes it a good fit for patients who have struggled with other treatments?

Michael Asbach, DMSc, PA-C: SPRAVATO®, in conjunction with an oral antidepressant, can be an excellent option for adult patients with TRD or depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior.

Every single time a patient comes to my office at this stage, they have tried lots of serotonin modulators. They’ve probably tried something that modulates norepinephrine and dopamine, but we don’t typically have patients coming in with mechanisms or trials outside of those 3 monoamines. SPRAVATO® was the first new mechanism-of-action approved by the FDA in 30 years targeting TRD and offers us an opportunity to try a different approach because it acts on the glutamate pathway by blocking the NMDA receptor. The exact mechanism is unknown, and there is not a guarantee that everyone’s going to respond; however, for patients with TRD, we should move on to different approaches and different therapeutic targets, in hopes of providing different results and better outcomes.

SPRAVATO® contains esketamine, a Schedule III controlled substance (CIII). To help ensure patient safety, SPRAVATO® is only available through a restricted distribution program called the SPRAVATO® Risk Evaluation & Mitigation Strategy (REMS). Patients self-administer the nasal spray at a REMS-certified treatment center under the direct supervision of their healthcare provider and are monitored for at least two hours afterwards to track any serious adverse events, such as sedation, dissociation, respiratory depression, abuse and misuse.⁸ (Please see additional Important Safety Information including BOXED WARNINGS and a list of side effects below. Click here.)

As with any medication, there are risks and benefits. Which is why it’s important to discuss the potentially serious side effects of SPRAVATO® with your patients, when determining if it could be a good fit for them.

Psychiatric Times®: How has SPRAVATO® helped your patients manage their symptoms of challenging-to-treat depression in the short- and long-term? Any insights you can share from your patients’ recent experience?

Michael Asbach, DMSc, PA-C: I have a patient who started 4 weeks ago in our SPRAVATO® clinic. She lives with treatment-resistant depression and has struggled to manage her symptoms for decades without any relief. But now, every single time we’ve done treatment, her husband comes bounding into the room and excitedly gives us the report of how her depressive symptoms have continued to steadily improve since the last appointment.

The other example that I would look at is a longer-term patient who started with us in 2019. When she started with us, she was in her mid-30s, had already tried more than 10 medications without relief, and was struggling to function on a daily basis. Now, she has been coming in every two weeks for the past five years to receive treatment. For the first time in a long time, her depressive symptoms are under control, and she’s been able to build positive momentum and focus her attention on getting a job and working towards her professional goals. She’s been doing wonderfully and over the years has been consistent with her SPRAVATO® treatment. Incorporating SPRAVATO® into her treatment plan helped her build a platform to work off of that allowed her to make lasting, durable changes in her life.

For TRD, there is longer-term safety and efficacy data for up to 6 years.⁹ We know that depression is a relapsing-remitting condition. If we have someone that has TRD and they stop treatment, the likelihood that they will experience another depressive episode is fairly high. With that being said, every single patient is different. We always want to make sure that we are empowering the patient through shared decision making to achieve their treatment goals.

In our clinic, we have patients on SPRAVATO® as a maintenance therapy along with an oral antidepressant. We also have patients who have reduced the frequency of their treatment to every other week where they’re able to have less frequent treatment and still maintain results.

Psychiatric Times®: Any closing thoughts you’d like to share?

Michael Asbach, DMSc, PA-C: Improvement in clinician's diagnostic assessment of patients and advancements in treatment options should enable TRD patients’ serious but often treatable condition to be recognized earlier, so they don’t have to continue cycling through countless treatments. Providers should continue to employ shared decision-making with their patients to help them achieve the best outcomes. I think as clinicians, the biggest thing that we need to do is stay up to date on treatment innovation and increase our expectation for how quickly we can safely achieve results.

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

References:

¹ American Psychiatric Association. What is depression? Accessed March 1, 2024. https://www.psychiatry.org/patients-families/depression/what-is-depression

² Centers for Disease Control and Prevention. National, state-level, and county-level prevalence estimates of adults aged ≥18 years self-reporting a lifetime diagnosis of depression — United States, 2020. Accessed March 1, 2024. https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm

³ Lynch CJ, Gunning FM, Liston C. Causes and consequences of diagnostic heterogeneity in depression: paths to discovering novel biological depression subtypes. Biol Psychiatry. 2020;88(1):83-94. doi: 10.1016/j.biopsych.2020.01.012. Epub 2020 Jan 28. PMID: 32171465.

⁴ Mental Health America. Depression in women. Accessed March 1, 2024. https://www.mhanational.org/depression-women#3

⁵ Anxiety & Depression Association of America. LGBTQ+ community. Accessed March 1, 2024. https://adaa.org/find-help/by-demographics/lgbtq

⁶ Agency for Healthcare Research and Quality. Definition of treatment-resistant depression in the Medicare population. Accessed March 1, 2024. https://www.ncbi.nlm.nih.gov/books/NBK526366/pdf/Bookshelf_NBK526366.pdf

⁷ National Alliance on Mental Illness. Types of medication. Accessed March 1, 2024. https://www.nami.org/About-Mental-Illness/Treatments/Mental-Health-Medications/Types-of-Medication

⁸ SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

⁹ Zaki N et al. Long-term safety and maintenance of response with esketamine nasal spray in treatment-resistant depression: final results of the SUSTAIN-3 Study. Poster presented at: Psych Congress; September 6-10, 2023; Nashville, TN.

cp-445610v1