Patients with major depressive disorder (MDD) often experience an inadequate response to antidepressant therapy. NPs play a vital role in educating patients about treatment response, including setting appropriate expectations for treatment and explaining the next steps should a patient not respond adequately. This peer exchange will teach you the skills to navigate this complex but common situation, including how to communicate about treatment response in MDD and how to navigate patients’ reactions should they experience a less-than-optimal response to medication.
JH: Hello, I’m Johnathon Hickman, and I’m a psychiatric-mental health nurse practitioner in New Hampshire.
KS: I’m Kate Sullivan, and I’m a psychiatric-mental health nurse practitioner at a Neuropsychology Practice in Knoxville, TN. Today, John and I are going to be discussing something that you have probably already encountered in your patient care—and if not, you very likely will; that being, when patients do not respond adequately to antidepressant treatment for major depressive disorder, or MDD. Specifically, we are going to talk about how you can help patients navigate this tricky situation.
JH: Inadequate response to antidepressant treatment for MDD is fairly common and it can leave patients feeling pretty pessimistic about their treatment plan and their chances for recovery.1-3 Although you might not be able to control whether or not a patient responds to an antidepressant, you can control what you tell them about this phenomenon and how you help them cope with their reactions to it.
KS: These are not trivial skills. The information you share with patients about partial response and nonresponse to treatment, and the ways in which you communicate with them, can go a long way toward helping patients feel confident and empowered. That can be critically important when you’ve hit a bump in the road to recovery.
Let’s get started.
What is Inadequate Treatment Response in MDD?
KS: I think it’s vital that we help our patients understand inadequate treatment response and how common it is. This “normalizes” the situation and helps patients understand that they are not alone on this journey. Treatment remission is also relatively common in MDD. The Sequenced Treatment Alternatives to Relieve Depression study, or STAR*D, evaluated effectiveness of antidepressant therapy in 2,876 patients with MDD through 4 levels of treatment. The response rate to initial antidepressant monotherapy was 47%, with an initial remission rate of 33%.4 Remission rates following a second line of treatment were 31%.4 Response and remission rates to antidepressant treatment decrease with each additional treatment step, with remission more likely to occur during steps 1 or 2 of treatment than during steps 3 or 4.4
John, given that there is no universal definition of inadequate treatment response for MDD,5 how do you usually go about determining whether a patient is experiencing this?
JH: I follow the recommendations of clinical practice guidelines, particularly those outlined by the American Psychiatric Association (APA).6 The APA notes that if a patient does not exhibit at least moderate improvement after 4 to 8 weeks of antidepressant therapy, it’s time to start looking into possible factors that could be preventing the patient from experiencing a therapeutic benefit.6 These factors may include such things as: Does the patient have the right diagnosis? Are they on an appropriate dose of the medication? Are there any intolerable side effects present? Are there any medication compliance issues? Are there other medical comorbidities complicating treatment response?5 And, overall, does the treatment plan need to be changed?
How about you, Kate, how do you assess antidepressant treatment response?
KS: I rely on clinical guidelines as well, but I also find that treatment monitoring and evaluation tools such as the 9-Item Patient Health Questionnaire, also known as the PHQ-9, the Hamilton Depression Rating Scale, and the Beck Depression Inventory are useful for tracking treatment response in a quantifiable way. The APA also recommends using standardized rating measures for assessing remission.6
It’s pretty easy to use standardized psychiatric rating scales in this way. Most validated measures will have cutoff scores that indicate whether a person’s symptoms are improving, which gives you an idea of whether the antidepressant is working. This is particularly important because remission is the goal of MDD treatment.
JH: Right. For example, the Hamilton Depression Rating Scale7 defines clinical remission as a score of 0 to 7, whereas the widely used PHQ-98,9 considers any score less than 5 to be indicative of remission.
KS: Additionally, some assessment tools can be used to measure whether an antidepressant is working. Specifically, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (the MGH ATRQ) is a validated measure that can be used to assess the adequacy of an antidepressant dose and trial duration, as well as the extent to which the antidepressant is improving the patient’s depressive symptoms.10
Assessing treatment response is a cornerstone of quality care. In cases of MDD, partial response and treatment nonresponse make patients more vulnerable to relapse and result in poor treatment outcomes, reduced functioning, and prolonged suffering.
Understanding Patients’ Reactions to Inadequate Treatment Response in MDD
KS: Let’s transition a bit and talk about inadequate treatment response from the patient’s perspective.
Understandably, patients can feel upset when their antidepressant does not work as intended.3 They often need to try multiple medications before finding one that works for them, and this process can be stressful and tiresome. It’s important to remind your patients to not give up just because a treatment has failed to provide them with adequate benefit.
JH: I agree. We need to be persistent in helping our patients find the right treatment for them, because when patients with MDD do not respond to their antidepressant, practical—and potentially serious—consequences can occur. Research has shown that inadequate treatment response in MDD can be associated with many negative outcomes, such as lower work productivity; an increased risk of unemployment, difficulties in social functioning, increased utilization of emergency department, increased rates of hospitalization, and sadly even suicide.2,3
Acknowledging and addressing the broad range of struggles that patients may experience because of inadequate treatment response is part of providing comprehensive, patient-centered, high-quality care. It also shows empathy, and it can help you establish and maintain a rapport with your patients.
KS: This reminds me about a survey published a few years ago. The survey was administered to just over 2,000 individuals across 6 countries, including the United States, and it reported some interesting—although maybe not surprising—findings regarding how patients feel about experiencing inadequate response to antidepressants.3 Specifically, the survey showed that among patients experiencing inadequate treatment response, approximately 30% felt frustrated; 27% felt hopeless; 27% felt apprehensive, nervous, anxious, or scared; another 27% felt resigned; and 25% felt dissatisfied with their medication.3 Of the patients who reported feeling dissatisfied with their medicine, one-third said they felt like they wanted to quit taking their medicine altogether, and nearly 15% said they do not take their medication regularly because of their frustration with it.3
Finally, about 19% of patients in the survey said they felt frustrated with their healthcare provider.3 This underscores that inadequate treatment response not only impacts your patients directly, but it can also impact their relationship with you.
JH: I think another valuable takeaway from this survey is that it demonstrates the importance of regularly monitoring patients for treatment response with timely follow-up appointments. You can evaluate their response through standardized psychiatric rating scales, like the ones we mentioned before, as well as clinical probes, which are conversational questions based on diagnostic criteria that can help you assess the patient’s symptoms more thoroughly. Information on scales for MDD and guidance on how to use them in clinical practice can be found under the Clinical Tools section of the NP Psych Navigator website. Regardless of whichever methods you use to monitor response to treatment, it’s critical that you do so regularly and in a timely manner so that if the treatment plan needs to be altered, that can be done so quickly and appropriately.
Helping Patients Navigate Their Reactions to Inadequate Treatment Response in MDD
JH: That survey is eye-opening, even if, like you said, it’s not necessarily surprising. It shows the importance of attempting to understand how complex this situation is for our patients and how it is impacting their daily lives.
KS: This is why education is so critical to helping patients understand that inadequate treatment response in MDD is not a rare phenomenon and that it certainly does not mean there is no hope for recovery.
Patients seem to feel somewhat reassured when I let them know that many people with MDD may have to try multiple meds before finding one that works for them. I also make sure to provide education about inadequate treatment response before starting their first antidepressant. In other words, I do not wait for inadequate treatment response to occur before I talk with them about it. I think being proactive is an important part of setting realistic expectations.
JH: I agree; that makes sense.
KS: I also make sure we discuss “next steps,” should their symptoms not respond to their current medication, which I believe can prevent patients from feeling completely helpless or hopeless.
JH: I assume you do that because it paints a realistic picture of what might happen, and that also equips them with a plan, which ultimately can protect them against a sense of hopelessness about their depression.
KS: That’s exactly right.
JH: I think there’s a lot of power in the words we choose, and using language that conveys empathy is key to making patients feel understood, supported, and empowered.
KS: That’s an excellent point. What kinds of statements do you think patients find most helpful?
JH: Well Kate, I’m a realist. So I acknowledge the reality of the situation with my patients. This way I don’t come across as minimizing or as “sugar-coating” things, which can ultimately undermine the therapeutic relationship. At the same time, I want to inject positivity into my words. For example, I might say something like, “I know this is very frustrating, and we will work together to figure out the best treatment for you.” Or I might say something like, “I can imagine how upsetting this might be for you. Please remember that you’re not alone. I’ve seen this before and I’m still here to help you figure things out.”
KS: That makes a lot of sense.
JH: As we mentioned earlier, I also think we need to choose words that normalize partial response and nonresponse to treatment. This way patients can feel comfortable talking about it, and they are less likely to internalize any shame or guilt they may be experiencing. This is not their fault.
To do that, I might say something like, “Sometimes people may find that their first few antidepressant trials do not fully work for them. If that’s the case for you, just know you’re not alone and we still have plenty of good options.”
KS: I like that approach and will often say something similar, such as, “It’s not unusual to need to try multiple meds before you find the one that works best for you. This doesn’t mean that there’s something wrong with you or that you will never get better.”
JH: I think that however you choose to phrase it, the important thing is to be a model for your patients by expressing realistic optimism. If you fake the optimism, patients always see through this. Also, if you’re pessimistic about their chances for recovery, that erodes their sense of hope and self-efficacy. How can we expect patients to have a positive outlook if we, as experienced healthcare providers, don’t have a positive outlook ourselves?
KS: I completely agree, especially about the need to be realistic. As we were discussing earlier, the landmark STAR*D trial showed us that the response and remission rates to antidepressant treatment decrease substantially with additional treatment steps—hence the importance of optimizing treatment early.9 This means that frequent screening, assessing, monitoring, and following up with patients to ensure they are responding well to medicine is crucial. In performing these steps, you are also reducing the chances that the patient will have to cycle through multiple antidepressants. Obtaining an optimal treatment response as early as possible should be the goal of all healthcare providers working with patients with MDD.
JH: Let’s end this discussion by briefly addressing treatment options in patients who experience an inadequate response to initial MDD therapy. There are really 2 strategies we want to highlight here.
KS: First, consider adding a referral for psychosocial treatment, such as cognitive-behavioral therapy, or CBT. The combination of antidepressant therapy and CBT has been shown to help reduce symptoms of depression even more so than antidepressant therapy alone, so this is definitely something to think about if an antidepressant is not sufficiently relieving a patient’s symptoms.5 CBT and other psychosocial treatments can help patients learn and reinforce coping skills related to the stressors of living with depression—including the stressor of treatment nonresponse.
However, referral to psychosocial treatment is not always enough. Sometimes, I have to look at augmenting antidepressants with additional pharmacotherapy as well.
JH: Exactly. In those instances, another strategy I will consider is the augmentation of their antidepressant with an atypical antipsychotic. The APA clinical practice guidelines support this approach for patients who have not responded to more than 2 trials of antidepressants.6 Moreover, atypical antipsychotics have been studied systematically and with a large number of randomized controlled trials. In fact, the Food and Drug Administration has approved 4 atypical antipsychotics as safe and effective as an add-on treatment for MDD.1
Even though augmentation with an atypical antipsychotic might not be the right strategy for every patient with MDD, it is certainly worth considering as an option as it is a supported intervention by both the APA and the FDA. You can consult the APA clinical practice guidelines for more information about when and how to use antipsychotics as add-on therapy for patients who do not respond adequately to antidepressants.6
KS: Hopefully you found this to be an informative discussion that will help you better understand how to work with patients in navigating the common challenge of partial response and nonresponse to antidepressants. I want to thank my colleague, John, for helping to lead this conversation, and we both want to thank you for tuning in.
JH: Thanks for joining us!
Jonathan Hickman, MSN
Mr Hickman graduated with his MSN from the University of Florida in 2012. Since that time, he has been functioning as a Psychiatric-Mental Health Nurse Practitioner in New Hampshire in a variety of capacities. He has been serving patients at a private practice, community mental health center, advocated for both New Hampshire and Massachusetts residents by educating insurance companies on the use of psychiatric medications, partnered with University of New Hampshire as an Expert Clinical Observer to help train future Psychiatric-Mental Health Nurse Practitioners, as well as speaking nationally for several pharmaceutical companies. He loves educating both providers and patients alike, and continually learning from their individual experiences, as well.
Kate Sullivan, MSN, APN
Ms Sullivan is an American Nurses Credentialing Center board-certified adult psychiatric nurse practitioner who provides psychiatric evaluation and medication management services for adults 16 years old and over. Kate has been a psychiatric nurse practitioner for 12 years, and has worked in private practice, specializing in complex trauma, forensics, end of life issues, and LGBTQIA and neurodivergent populations. She currently works at a respected Neuropsychology Practice, Knoxville Behavioral & Mental Health Services, where she is the sole prescriber. Kate serves on the Crisis Stabilization Team for the Knoxville Police Department and is a regular teacher in their Police Academy on the subject of posttraumatic stress disorder. She had a major research paper on bipolar disorder published in 2020 and is a revered speaker, across the state and nationally, on a diverse array of subjects. She continues to be highly sought after as a thought leader in her field by a multitude of private firms, first responder departments, medical and other research groups.
Thase ME. Adjunctive therapy with second-generation antipsychotics: the new standard for treatment-resistant depression? Focus. 2016;14(2):180-183.
- Caldiroli A, Capuzzi E, Tagliabue I, et al. Augmentative pharmacological strategies in treatment-resistant major depression: a comprehensive review. Int J Mol Sci. 2021;22(23):13070.
- Mago R, Fagiolini A, Weiller E, Weiss C. Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder. BMC Psychiatry. 2018;18(1):1-9.
- Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60(11):1439-1445.
- Haddad PM, Talbot PS, Anderson IM, McAllister-Williams RH. Managing inadequate antidepressant response in depressive illness. British Med Bull. 2015;115(1):183-201.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010.
- Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
- Kroenke K. Enhancing the clinical utility of depression screening. Can Med Assoc J. 2012;184(3).
- Sussman N. Translating science into service: lessons learned from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Prim Care Companion J Clin Psychiatry. 2007;9:331–337.
- Freeman MP, Pooley J, Flynn MJ, et al. Guarding the gate: remote structured assessments to enhance enrollment precision in depression trials. J Clin Psychopharm. 2017;37(2):176-181.
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