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Navigating Challenging to Treat Forms of Depression

Depression does not discriminate. It is a disease that takes hold of your life and turns it upside down. Particularly for those patients with challenging to treat depression, it can feel like there is no end in sight. As a practicing psychiatrist for more than 20 years, I have worked with patients of all different backgrounds to help lessen the impact of depression on their lives.

One of the most important things to know about depression is that no two cases are the same. Every person has a different story, diagnosis and treatment experience. It can be hard to understand what’s happening, know how to best advocate for yourself and know how to support loved ones who are diagnosed. 

If you or a loved one are struggling with depression, read on to learn more about the types of depression, treatment options and how to advocate for the best possible outcome. 

What is Major Depressive Disorder?

Depression (major depressive disorder) is a common and serious medical illness that negatively affects how you feel, the way you think and how you act. Fortunately, it is also treatable. Depression causes feelings of sadness and/or a loss of interest in activities you once enjoyed. It can lead to a variety of emotional and physical problems and can decrease your ability to function at work and at home.

What is challenging to treat depression? 

Challenging to treat forms of depression are even more complex. Two forms of MDD that are more challenging to treat include:

  • Treatment-Resistant Depression (TRD) is typically defined as MDD in patients who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode.
  • Major Depressive Disorder (MDD) With Suicidal Thoughts or Actions is when a person experiences a sudden worsening of depressive symptoms, which can cause them to consider or act on thoughts of self-harm or suicide. 
    • While people who live with suicidal ideation are sometimes diagnosed with MDD, not all patients living with MDD have suicidal thoughts or actions.

Struggling with your depressive symptoms? You’re not alone.

Suicidal thoughts or actions can be common, which is why it is important if you are struggling to be open about your thoughts and not be afraid to discuss them with your care team or support system. There is a false belief that talking about suicide increases the chances of dying by suicide, when in fact, proactively having these tough conversations can help you or someone you love to feel less alone. 

New callout box should read: If you or someone you know is struggling emotionally or has concerns about their mental health, please call or text the 988 Suicide & Crisis Lifeline at 988.

What treatment options are there for depression? 

There are a variety of treatment options for people living with TRD and MDD with suicidal thoughts or actions. I personally feel that psychotherapy (talk therapy) is a key component of any treatment plan for those living with depression. Talk therapy is focused on exploring relationships between a person’s thoughts, feelings and behaviors, which can help identify underlying issues or situations that may be adding to depressive feelings. Talk therapy also can help patients deal with life changes such as emotional trauma and interpersonal relationships. 

Although depression is a disease of the brain, things happen in our lives that are out of our control and may feel triggering in the moment or at a later time. Talk therapy can help people process these stressors and identify destructive or triggering behaviors. For some people, talk therapy is best combined with medication in order to fully treat depression. 

Speaking with my patients allows me to check in and see how they are progressing, talk about recent events or triggers, and understand how they feel their medication is impacting their life. It gives me a holistic look at what may or may not be working for the individual so we can discuss adjustments that may be needed.

Here are some of the most common treatment options for challenging forms of depression, often used in combination with psychotherapy: 

  • Oral antidepressants treat depression by increasing certain chemicals in the brain such as serotonin, norepinephrine, and/or dopamine or by blocking the reabsorption of those neurotransmitters in the brain known to regulate mood and relieve depression. These medications are typically taken in a pill form.
  • Electroconvulsive Therapy (ECT) is a procedure where a person is placed under general anesthesia and small electric currents are routed through the brain in a controlled way to trigger a brief seizure, which then affects neurons and chemicals in the brain. It can take a series of ECT treatments for patients to feel relief of severe depression.
  • Transcranial Magnetic Stimulation (TMS) is a noninvasive procedure where a large electromagnetic coil is placed against a person’s scalp. During a TMS session, a magnetic field is created to stimulate neurons in the brain through short pulses that are targeted to certain areas of the brain that are believed to control mood and thus improve depressive symptoms.  Several sessions are typically needed over a series of weeks. 
  • SPRAVATO® (esketamine) CII nasal spray is a treatment I have been using for my patients with challenging to treat depression. It was approved by the FDA in 2019 to treat TRD in adults, and in 2020 to treat depressive symptoms in adults with MDD with suicidal thoughts or actions. In both cases, SPRAVATO® is administered in combination with an oral antidepressant under the supervision of a healthcare professional in a certified SPRAVATO® treatment center. Although the way SPRAVATO® works is not completely understood, it is believed to take a different approach and act on a different neurotransmitter, called glutamate, which regulates communication between nerve cells in the brain.

It is not known if SPRAVATO® is safe and effective for use in preventing suicide or in reducing suicidal thoughts or actions. Use of SPRAVATO® does not rule out the need for hospitalization if clinically necessary for a given patient, even if the patient shows initial improvement. As with any medication, there are potential side effects that are important to understand before beginning treatment, the most serious of which include sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation), breathing problems (respiratory depression and respiratory arrest), the risk of abuse and misuse, and increased risk of suicidal thoughts or actions. (Please see Important Safety Information including BOXED WARNINGS and a list of side effects below. Click here). SPRAVATO® is not the right fit for everyone, but if you are considering this treatment or are interested in learning more, please connect with your doctor and check out the SPRAVATO® treatment center locator tool.

How can I advocate for myself with my care team?

One of the most important factors to finding the right treatment plan is having an open and trusting relationship with your care team. Finding a safe, reliable space and educational resources is critical. I work to empower my patients to ask questions and take an active role in their care. If a treatment plan isn’t working for you, it doesn’t mean you did anything wrong or that there aren’t other options. I never want someone to feel like they have to accept depressive symptoms as the status quo. I firmly believe that if your doctor isn’t willing to have a dialogue, discuss options and answer questions, then it’s time to find a new one. 

How can I help a loved one living with depression?

Caring for someone with TRD or MDD with suicidal ideation can be difficult. Your loved one’s depressive symptoms can make it difficult for them to find the motivation to care for themselves and perform everyday tasks like eating, brushing their teeth or going to the store. Some of the most helpful ways to support a loved one include:

      • Legitimizing their feelings and experiences to help establish trust
      • Meeting them where they are each day. If they don’t want to talk, let them know it’s okay
      • Avoiding dismissive comments such as how someone has “everything going for them” or wishing they could “just snap out of it.” These sentiments can minimize their experience and aren’t supportive

If you are having trouble communicating with or relating to what your loved one is experiencing, ask how you can support them or connect with their doctor to determine the best approach. 

Caregivers not only need to educate themselves on their loved one’s depression to support them, but they need to also make sure they are finding ways to feel supported themselves. The National Alliance on Mental Illness (NAMI) has great family support groups that can provide caregivers, family members and loved ones a safe setting to share their experiences, challenges and successes, as well as gain hope from one another. 

Please know you and your loved ones are not alone. If you or someone you know is struggling emotionally or has concerns about their mental health, there are ways to get help. Please reach out to one of the hotlines below:

      • Call or text the 988 Suicide & Crisis Lifeline: 988
      • Call the National Alliance on Mental Illness HelpLine at 1-800-950-NAMI (6264)
      • Call the Substance Abuse and Mental Health Services Administration at 1-800-626-HELP (4357)
      • Text HOME to 741741 for free, 24/7 crisis support in the U.S.

For additional resources on challenging to treat forms of depression please visit the following sites:

Dr. Ares-Romero was compensated by Janssen for her time to write and develop this article.


What is SPRAVATO® (esketamine) CIII nasal spray?

SPRAVATO® is a prescription medicine, used along with an antidepressant taken by mouth to treat:

      • Adults with treatment-resistant depression (TRD)
      • Depressive symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions

SPRAVATO® is not for use as a medicine to prevent or relieve pain (anesthetic). It is not known if SPRAVATO® is safe or effective as an anesthetic medicine.

It is not known if SPRAVATO® is safe and effective for use in preventing suicide or in reducing suicidal thoughts or actions. SPRAVATO® is not for use in place of hospitalization if your healthcare provider determines that hospitalization is needed, even if improvement is experienced after the first dose of SPRAVATO®.

It is not known if SPRAVATO® is safe and effective in children.


What is the most important information I should know about SPRAVATO®?
SPRAVATO® can cause serious side effects, including:

  • Sedation and dissociation. SPRAVATO® may cause sleepiness (sedation), fainting,  dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your  thoughts, feelings, space and time (dissociation).
    • Tell your healthcare provider right away if you feel like you cannot stay awake or if  you feel like you are going to pass out.
    • Your healthcare provider must monitor you for serious side effects for at least 2  hours after taking SPRAVATO®. Your healthcare provider will decide when you are  ready to leave the healthcare setting.
  • Respiratory depression was observed with the use of SPRAVATO®; additionally, there were rare reports of respiratory arrest.
    • Your healthcare provider must monitor you for serious side effects for at least 2 hours (including pulse oximetry) after taking SPRAVATO®. Your healthcare provider will decide when you are ready to leave the healthcare setting.
  • Abuse and misuse. There is a risk for abuse and physical and psychological dependence  with SPRAVATO® treatment. Your healthcare provider should check you for signs of  abuse and dependence before and during treatment with SPRAVATO®.
    • Tell your healthcare provider if you have ever abused or been dependent on alcohol,  prescription medicines, or street drugs.
    • Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.
  • SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS). Because of the risks for sedation, dissociation, respiratory depression, and abuse and misuse, SPRAVATO® is only available through a  restricted program called the SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS)  Program. SPRAVATO® can only be administered at healthcare settings certified in the  SPRAVATO® REMS Program. Patients treated in outpatient healthcare settings (e.g.,  medical offices and clinics) must be enrolled in the program.
  • Increased risk of suicidal thoughts and actions. Antidepressant medicines may increase  suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. SPRAVATO® is not for use in children. 
    • Depression and other serious mental illnesses are the most important causes of  suicidal thoughts and actions. Some people may have a higher risk of having  suicidal thoughts or actions. These include people who have (or have a family  history of) depression or a history of suicidal thoughts or actions.
  • How can I watch for and try to prevent suicidal thoughts and actions in myself or a  family member?
    • Pay close attention to any changes, especially sudden changes, in mood, behavior,  thoughts, or feelings, or if you develop suicidal thoughts or actions.
    • Tell your healthcare provider right away if you have any new or sudden changes  in mood, behavior, thoughts, or feelings.
    • Keep all follow-up visits with your healthcare provider as scheduled. Call your  healthcare provider between visits as needed, especially if you have concerns  about symptoms.
  • Tell your healthcare provider right away if you or your family member have any of the  following symptoms, especially if they are new, worse, or worry you:
    • suicide attempts
    • thoughts about suicide or dying
    • worsening depression
    • other unusual changes in behavior or mood

Do not take SPRAVATO® if you:

  • have blood vessel (aneurysmal vascular) disease (including in the brain, chest, abdominal  aorta, arms and legs
  • have an abnormal connection between your veins and arteries (arteriovenous  malformation)
  • have a history of bleeding in the brain
  • are allergic to esketamine, ketamine, or any of the other ingredients in SPRAVATO®.

If you are not sure if you have any of the above conditions, talk to your healthcare provider before taking SPRAVATO®.   

Before you take SPRAVATO®, tell your healthcare provider about all of your medical  conditions, including if you: 

  • have heart or brain problems, including:
    • high blood pressure (hypertension)
    • slow or fast heartbeats that cause shortness of breath, chest pain, lightheadedness,  or fainting
    • history of heart attack
    • history of stroke
    • heart valve disease or heart failure
    • history of brain injury or any condition where there is increased pressure in the brain
  • have liver problems
  • have ever had a condition called “psychosis” (see, feel, or hear things that are not there, or  believe in things that are not true).
  • are pregnant or plan to become pregnant. SPRAVATO® may harm your baby. You should not  take SPRAVATO® if you are pregnant.
    • Tell your healthcare provider right away if you become pregnant during treatment  with SPRAVATO®.
    • If you are able to become pregnant, talk to your healthcare provider about methods  to prevent pregnancy during treatment with SPRAVATO®.
    • There is a pregnancy registry for women who are exposed to SPRAVATO® during  pregnancy. The purpose of the registry is to collect information about the health of  women exposed to SPRAVATO® and their baby. If you become pregnant during  treatment with SPRAVATO®, talk to your healthcare provider about registering with  the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at
  • are breastfeeding or plan to breastfeed. You should not breastfeed during treatment with SPRAVATO®.

Tell your healthcare provider about all the medicines that you take, including prescription and  over-the-counter medicines, vitamins and herbal supplements. Taking SPRAVATO® with certain  medicine may cause side effects. 

Especially tell your healthcare provider if you take central nervous system (CNS) depressants,  psychostimulants, or monoamine oxidase inhibitors (MAOIs) medicine. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. 

How will I take SPRAVATO®

  • You will take SPRAVATO® nasal spray yourself, under the supervision of a healthcare  provider in a healthcare setting. Your healthcare provider will show you how to use the  SPRAVATO® nasal spray device.
  • Your healthcare provider will tell you how much SPRAVATO® you will take and when you  will take it.
  • Follow your SPRAVATO® treatment schedule exactly as your healthcare provider tells you  to.
  • During and after each use of the SPRAVATO® nasal spray device, you will be checked by a  healthcare provider who will decide when you are ready to leave the healthcare setting.
  • You will need to plan for a caregiver or family member to drive you home after taking  SPRAVATO®.
  • If you miss a SPRAVATO® treatment, your healthcare provider may change your dose and  treatment schedule.
  • Some people taking SPRAVATO® get nausea and vomiting. You should not eat for at least 2  hours before taking SPRAVATO® and not drink liquids at least 30 minutes before taking  SPRAVATO®.
  • If you take a nasal corticosteroid or nasal decongestant medicine take these medicines at  least 1 hour before taking SPRAVATO®.

What should I avoid while taking SPRAVATO®

Do not drive, operate machinery, or do anything where you need to be completely alert after  taking SPRAVATO®. Do not take part in these activities until the next day following a restful  sleep. See “What is the most important information I should know about SPRAVATO®?” 

What are the possible side effects of SPRAVATO®

SPRAVATO® may cause serious side effects including: 

See “What is the most important information I should know about SPRAVATO®?” 

Increased blood pressure.  SPRAVATO® can cause a temporary increase in your blood  pressure that may last for about 4 hours after taking a dose. Your healthcare provider will  check your blood pressure before taking SPRAVATO® and for at least 2 hours after you take SPRAVATO®. Tell your healthcare provider right away if you get chest pain, shortness of  breath, sudden severe headache, change in vision, or seizures after taking SPRAVATO®.

Problems with thinking clearly. Tell your healthcare provider if you have problems thinking or remembering. 

Bladder problems. Tell your healthcare provider if you develop trouble urinating, such as a frequent or urgent need to urinate, pain when urinating, or urinating frequently at night.  

The most common side effects of SPRAVATO® when used along with an antidepressant taken  by mouth include: 

  • feeling disconnected from yourself, your thoughts, feelings and things  around you 
  • dizziness
  • nausea
  • feeling sleepy
  • spinning sensation
  • decreased feeling of sensitivity (numbness)
  • feeling anxious
  • lack of energy
  • increased blood pressure
  • vomiting
  • feeling drunk
  • feeling very happy or excited

If these common side effects occur, they usually happen right after taking SPRAVATO® and go  away the same day. 

These are not all the possible side effects of SPRAVATO®.  

Call your doctor for medical advice about side effects. You may report side effects to FDA at  1-800-FDA-1088. 

Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO® and discuss any questions you may have with your healthcare provider.


For more information about SPRAVATO®, please visit

This information is intended for the use of patients and caregivers in the United States and its territories only. Laws, regulatory requirements and medical practices for pharmaceutical products vary from country to country. The Prescribing Information included here may not be appropriate for use outside the United States and its territories.


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