#479 Managing Treatment-Resistant Depression featuring Dr. Jessi Gold

April 14, 2025 | By Zoya Surani

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Transcript available via YouTube

Lead the way in depression management! We’re joined by Dr. Jessi Gold, a psychiatrist and mental health advocate, who provides essential pearls on ways to recognize the multifaceted nature of depression and similarly presenting medical conditions. We also discuss the complexities of treatment options including various medication options and therapies, and how to choose between these treatments.

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Show Segments

• Intro
• Case 1 from Kashlak
• Medical conditions that can mimic depression
• Diagnosis of depression
• How to explain depression to family
• Initial treatment options for depression
• Case 2 from Kashlak
• Suicide risk assessment
• Trialing, augmenting, and tapering of medications
• Pharmacogenetic testing
• Alternate treatment options: TMS, ECT, ketamine, psilocybin, cannabis
• Outro

Disclosures

Dr. Gold reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Treatment-Resistant Depression Pearls

1. Before diagnosing depression, always rule out other medical causes (e.g., hypothyroidism, obstructive sleep apnea, anemia, vitamin deficiencies) through thorough patient history and medical workup.
2. Every patient presenting with depressive symptoms should undergo a thorough suicide risk assessment. This should include direct questioning as well as gathering information from family or loved ones.
3. SSRIs remain the most commonly prescribed and effective first-line treatment for depression, especially when combined with therapy.
4. Understand the side effect profiles of antidepressants to guide medication selection. 
5. When switching or discontinuing antidepressant medications, taper them slowly to reduce withdrawal symptoms.
6. Consider referral to a psychiatrist when the patient’s depression management becomes too challenging and they are not improving in their symptoms.
7. If a patient has failed two full trials of antidepressant medications (adequate dose and duration), they are considered to have treatment-resistant depression. 
8. If a patient has a partial response to an antidepressant, consider adding an adjunct medication (e.g., bupropion, aripiprazole) rather than switching medications entirely.
9. For treatment-resistant depression, consider advanced therapies like TMS, which stimulates brain regions involved in mood regulation or ECT for severe cases with psychosis or suicidality. 
10. Newer therapies, including ketamine and psilocybin, are also becoming more readily available. Tailoring these treatments based on individual patient needs and careful monitoring is essential for optimal management.

Treatment-Resistant Depression 

Mimickers of Depression

Depression, or Major Depressive Disorder, is a diagnosis of exclusion, so it is important to rule out medical causes first. If a patient is presenting with low mood and they do not have a previous diagnosis of depression, Dr. Gold recommends gathering a thorough history and doing a full workup on the patient. Recommended workup is similar to workup for patients with fatigue, including: BMP (to check for electrolyte imbalances), thyroid panel (to evaluate for hypothyroidism), CBC and iron/ferritin (to check for anemia/low iron), vitamin B12 and vitamin D (to rule out vitamin deficiencies). A sleep study can also be done (to evaluate for OSA).

Hypothyroidism

If a patient is presenting with low mood, low energy, or fatigue, it is always a good idea to check thyroid functioning. Hypothyroidism, even if patients are on medications like levothyroxine, can still present with depression-like symptoms if it is not being treated effectively. 

Obstructive Sleep Apnea

Daytime somnolence, headaches, and fatigue are symptoms shared by OSA and depression. A thorough history from the patient and partner/family, as well as a sleep study can help aid in a diagnosis of OSA. 

Premenstrual Dysphoric Disorder

Timing of depressive symptoms in relation to hormonal cycle is very important to understand to distinguish between diagnosis of premenstrual syndrome, PMDD, and depression. This is important because this helps guide the treatment plan from OCPs to SSRIs (Jespersen et al., 2024).

Vitamin Deficiencies

Many vitamin deficiencies can be a source of fatigue in a patient, but Vitamin D and B12 are more common and are easily correctable if low. 

Anemia

Low threshold to check CBC and ferritin in patients with low mood/energy. Ferritin can still be low in a patient with a normal hemoglobin, so it is important to check to determine if patient has an iron deficiency.

Seasonal Affective Disorder (SAD)

Timing of depressive episodes is also important in order to understand whether there is a seasonal/weather component to the symptoms. The most prevalent form of SAD is experienced during the winter months. While antidepressants are also indicated for SAD, other treatment interventions (i.e. bright light therapy) would also be indicated. 

Life Events

It is important to gather information about recent changes in the patient’s history. Did they recently move and lose their support system? Did they recently lose a job? Are they coming off of nights, and adjusting to days? Are they in a hard rotation or project at work?  Asking these questions can better identify what support may be most beneficial to helping them during a transition period. 

Diagnosing Depression

Most individuals who die by suicide saw their primary care provider more recently than any other healthcare provider, so screening by PCPs is essential (Ahmedani et al., 2014). Dr. Gold shares that the PHQ2 and PHQ9 are good screening tools providers can use for a quick assessment, and routine screening of recommendation is recommended by the USPSTF (US Preventive Services Task Force, 2023). 

A diagnosis of depression includes having 5+ symptoms of depressed mood or anhedonia, changes in sleep, interest, guilt, energy, concentration, appetite, psychomotor retardation or agitation, and thoughts, plans, or behaviors related to suicide. These symptoms must be present over the same two-week period and impact the individual’s day to day life.

How to Explain Depression to Others

A diagnosis of depression can be associated with very varied levels of receptiveness. Dr. Gold explains that it is important to hear what individuals are hearing about a diagnosis of depression from their household, loved ones, and peers. She shares that understanding the questions and concerns can help you provide better guidance than assuming what their pushback may be related to. 

Ultimately, depression is a real illness that has a basis in biology. It is a treatable illness as well, just like how some individuals have high blood pressure and need to take medications. It is not a weakness to accept help or to start medication. 

Dr. Gold also shared that she reminds her college-aged patients that they are equipped to make informed decisions about their bodies, regardless of what others may believe about depression management. These can be hard conversations, but they are important ones to have. 

Initial Treatment Options

For individuals who are requiring treatment for depression, it is important to see if they have tried any medications previously. Additionally, if family members have had success with any treatment methods, that can also help guide management.

Dr. Gold shares that SSRIs are the most common place to start with treatment, and are especially beneficial in patients receptive to attending therapy as they work very well together. If someone is unwilling to start medications, it is important to have a conversation about their whys first. Ultimately, it is the patient’s decision and if they prefer therapy first, shared-decision making can be used to decide the timeline the patient will try therapy alone before trying out alternate options. 

It is also important to remember that every treatment method takes time. Getting a therapist takes time. Medications like SSRIs take time, with many studies showing that most medications take 6-8 weeks to become effective (Chu & Wadhwa, 2023). If the waitlist for therapy is months long, the patient might be receptive to trialing an antidepressant in the interim. 

The STAR*D trial was the largest antidepressant study conducted, comparing the acute and long-term treatment for individuals, providing guidance that SSRIs are effective in individuals as first line for treatment (Rush et al., 2006). Dr. Gold shares that it is also important to consider side effect profiles and other medical conditions co-occurring with patients. For example, if a patient also has PMDD, sertraline might be a good option. Chronic pain? Try an SNRI, like duloxetine. Fatigue, overeating, and atypical depression? Bupropion. Trouble sleeping, but comfortable with possible weight gain? Mirtazapine. It is also important to understand the availability of treatment options and associated costs. 

In general, it is recommended to start at a low dose to assess adverse effects/tolerability of medication for the patient. If the patient is tolerating the lowest dose, providers can increase after 1 week. 

Adverse Effects of Medications

Side effect profiles for each antidepressant medication differ and are important to review with patients. 

Some antidepressants, particularly SSRIs, can be dangerous to individuals with bipolar disorder as they can precipitate mania (Ciray et al., 2021). In individuals presenting with depression, it is very important to rule out mania by asking questions like if they have ever felt invincible, on top of the world, had different uncharacteristic behaviors, or risky behaviors. Family history of bipolar disorder is also important to ask about. 

Anticipatory guidance should be provided to patients about the possible chance of having undiagnosed bipolar and it is necessary to share the signs to look out for that would necessitate the patient seeking care and stopping their medication. 

Additionally, SSRIs do have a black box warning for increased risk of suicidality in children and young adults aged 18-24 (Edinhoff et al., 2021). It is important to counsel patients on this and come up with a safety plan. It is important to note that while some studies have found an increased risk of suicide attempts with these medications initially, there is a no difference in completed suicide rates (Li et al., 2022).

Encourage patients to reach out to you about how trying medication goes for them. Dr. Gold recommends asking patients to be as open as possible for the medication trial, as she wants to receive their message and update to understand what is going on. Dr. Williams sets a calendar notification for the  two-week mark of patients trying new medications to do a phone call check-in to hear how patients are doing on the medication. This can also help the patient feel validated and not overburdened by needing to check in if it might be challenging to do so for them.  

Discontinuing Medications

Dr. Gold shares that the six-month mark on medications is a good time to check in with a patient presenting with a first episode of depression to see how the medication has been going and if they have been at a stable dose for a while. If the patient desires discontinuing medications, it is possible to begin to taper the medication if it seems appropriate (Lee et al., 2023). 

Treatment-Resistant Depression

Dr. Gold recommends referring a patient to a psychiatrist whenever their management becomes complicated or challenging, and especially if they have failed 1-2 trials of medications for depression. If an individual fails two or more complete trials of antidepressant medications, they are now considered to have treatment-resistant depression (Gaynes et al., 2020). Complete trials refers to trials of medication that are adequate in dose and duration.

An estimated 2.8 million individuals in the United States have treatment-resistant depression (Zhdanava et al., 2021). Navigating the treatment plan for these individuals can be challenging and time-consuming, so it is helpful to recruit a psychiatrist for help.

Suicide Risk Assessment

It is important to do a suicide risk assessment for all patients presenting with signs and symptoms of depression. Dr. Gold emphasizes the importance of understanding how safe an individual is, whether from asking the patient directly or talking to family members to get a better idea. This also helps determine what the appropriate plan can be for sending the patient home if they are not an imminent danger to themselves or others that would necessitate hospitalization. 

Medication Trials

Are the patient’s failed trials truly failed trials? Dr. Gold discusses how for most medications to have had a full trial, patients should have been on a high dose of the medication for >4-6 weeks. If they stopped the medication for side effects, then that might not be a “true fail” and it is possible the medication can still be effective in them. It is also important to understand if for any of the medications they previously tried, they experienced a partial response, as this might help guide future trials of medications. For example, as citalopram and escitalopram and venlafaxine and desvenlafaxine are chemically similar to each other, it is possible to try the other medication if there was a partial response. Alternatively, if one was associated with very bad side effects, trying the other would not be recommended. Family history of successful medication use for depression can also help guide medication decisions. 

Augmentation of Medication

If a patient is receiving a partial response from a medication, it is appropriate to add in an adjunct medication to enhance the initial medication’s effects. Dr. Gold shares that there are various options for adjuncts, but the two she most commonly uses are bupropion and aripiprazole. Adding an adjunct can be especially helpful to avoid having to taper down and up medications when trying to switch antidepressants.

Tapering of Medications

Different medications have different mechanisms of action, so just because SSRIs may not work in your patient, SNRIs can since they act on varied neurotransmitters. Switching from medications can cause withdrawal side effects, which can differ in severity across each medication. Dr. Gold finds that venlafaxine and paroxetine are associated with worse withdrawals (i.e., flu-like symptoms, “brain zaps”) and talks to patients about the possibility upfront.

It is important to properly taper medications to mitigate withdrawal symptoms in a patient (Horowitz and Taylor, 2019). When tapering medications, you can either taper off of one and start another, or do what is called a cross-taper, and go down on the initial medication while increasing the new medication, which Dr. Gold prefers. One approach Dr. Gold uses is to go down on the initial medication every 2 weeks, and before tapering down, checking with the patient to ensure they are feeling okay and not having worsening withdrawal symptoms. If a patient is not feeling well after having tapered down, wait until the patient does improve until going down on the medication further. 

Dr. Gold describes an example plan for a cross taper between sertraline and venlafaxine as below. It is important to remember the strength of medications to properly determine the equivalent amount when tapering. Every person is also different, so while this is an ideal schedule, some patients can take a lot longer to come off of a medication.

Pharmacogenomic Testing

Dr. Gold shares that the primary issue with pharmacogenetic testing she faces is that it is typically not covered by insurance, so it can be an expensive out-of-pocket cost. Additionally, the testing shows correlations, not causations, so having a genetic marker may suggest that an individual might be less likely to metabolize a certain medication, but it is not guaranteed. 

The testing can be helpful in patients hesitant to start medications, or nervous about which medication to start with. This is because it might be reassuring to hear that the physician picked the starting medication based on what was in the “green zone” from the testing. Always provide the caveat that this testing is not perfect, and it is possible none of the medications in the green zone will be tolerated so then they will need to try medications in the yellow and red zones. Some testing results will also recommend the more expensive medications, so it is important to use shared-decision making and appropriate counseling with patients about these differences in recommendations. 

Transcranial Magnetic Stimulation (TMS)

TMS is a new and emerging therapy  (Wang et al., 2023). Most insurance plans cover TMS only for treatment-resistant depression, meaning after having failed two full trials of medications. For TMS, individuals go in every day for short sessions (15 minutes to an hour) for a few weeks. A protocol for this method is available from Nolan Williams team at Stanford (Cole et al., 2020).  Dr. Gold shares that some of the benefits for TMS vs electroconvulsive therapy include TMS not being associated with retrograde amnesia and not requiring general anesthesia, while the side effects include scalp irritation, headaches, and in rare cases, seizures. 

Electroconvulsive Therapy (ECT)

In very severe cases of depression (e.g., severe suicidality, depression with psychotic features, catatonia), inpatient ECT is a very effective and quick treatment option (Subramanian et al., 2022). ECT is associated with remission in a majority of patients and is essential in the care of treatment-resistant depression (Hsieh, 2023). 

Ketamine

A newer therapy option. Intranasal ketamine is an approved treatment for treatment-resistant depression, but it can be costly and patients must be observed while taking the medication (An et al., 2021). Observation is required as the medication can cause dissociation in patients. Ketamine has been shown to be especially helpful in individuals with acute suicidality (Maguire et al., 2021). 

Psilocybin

Also a newer therapy option. Psilocybin, or one of the ingredients in  “shrooms”, is an experimental treatment method for treatment-resistant depression. When done safely, it involves the patient having a small dose of psilocybin during a session with a therapist. It is difficult to determine whether the psilocybin or therapy may be more effective as the psilocybin is only provided under a controlled environment (Borissova and Rucker, 2024). Dr. Gold notes that some patients try to do this on their own with street drugs—and that could be dangerous.

Cannabis

Cannabis is not beneficial in patients with depression as cannabis can cause similar symptoms, including low concentration, motivation, and energy (Langlois et al., 2021). In these situations, Dr. Gold describes it is sometimes helpful to act as a negotiator to find ways to decrease the patient’s usage of cannabis or to determine a timeline for when it would be appropriate to discuss their cannabis usage. 

Long-term Plan

Antidepressants, TMS or ECT maintenance are options for long-term management of treatment-resistant depression. For treatment resistant patients, it is unlikely they will be able to not be in treatment at all to manage their symptoms.  It is important to remind patients to not stop medications/treatment when they are feeling better, as it is important to safely taper off treatment methods. For individuals with treatment-resistant depression, they will need close observation of symptoms if they are discontinued from their treatment anyway. 

Links

1. How Do You Feel? Dr. Jessi Gold
2. American Psychological Association
3. National Alliance on Mental Illness
4. American Foundation for Suicide Prevention

Goal

Listeners will develop a framework to approach the evaluation and management of individuals with depression and treatment-resistant depression.

Learning objectives

After listening to this episode listeners will…  

1. Learn to recognize depression and provide tips for self-directed management of depression.
2. Navigate pharmacological and non-pharmacological treatments of major depressive disorder.
3. Develop an approach for managing treatment-resistant depression with more recently researched therapies (ketamine, ECT, psilocybin).

Citation

Surani, Z., Gold J., Williams PN, Watto MF. “#479 Treatment-Resistant Depression”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date 7 April, 2025.