In this Special Report, let's re-evalute depression.
SPECIAL REPORT: TREATMENT-RESISTANT DEPRESSION
The goal of this Special Report is to help you manage treatment-resistant depression (TRD) as best as possible while minimizing harm. This requires first recognizing the kind of depression with which your patient presents to ensure the treatment strategy is the most appropriate.
As none of the historical terms (eg, neurotic, psychotic, melancholic) or DSM terms (eg, dysthymia, major depression, mixed features) are distinct biological entities, let us turn to etiology for a better understanding and a refined diagnosis. In my experience, there are 5 kinds of common clinical depression, worth differentiating in that they call for varying treatments (Table). This list is not exhaustive, but the 5 types probably account for most of the depressions seen in clinical practice. Importantly, each type responds best with different approaches.
Halting or decreasing stress is obviously the most direct treatment, but often that is not feasible. Psychosocial stressors can be directly addressed with several forms of psychotherapy. For millennia, the principles of cognitive behavior therapy (CBT) have helped individuals manage situations they cannot change. Aaron T. Beck, MD, a founder of CBT, quoted the Roman emperor Marcus Aurelius: “If thou are pained by any external thing, it is not the thing that disturbs thee, but thine own judgment about it. And it is in thy power to wipe out this judgment now.”1
Likewise, interpersonal therapy (IPT) could also directly address the source of the problem. But IPT is much less widely available than CBT, especially because a basic version of CBT can be procured via apps that have shown to be nearly as effective as individual CBT from a live therapist, and equally effective if provided with some telephone and text support.2,3
Do antidepressants help in chronic psychosocial stress? For many individuals, the answer is yes. However, concern has been raised that the main benefit of antidepressants in this context is an emotional blunting.4 This sounds like the effects of CBT, but CBT does not blunt other emotional responses, as has been described for antidepressants in 20% to 94% of patients,5 and in asymptomatic volunteers.6
Teicher et al7 noted that childhood trauma is associated with “a cascade of molecular and neurobiological transformations that distinguish patients with maltreatment histories from their nonmaltreated counterparts.” They cited results from the international Study to Predict Optimized Treatment for Depression (NCT00693849), which found that antidepressants led to remission in 84% of patients with no abuse history versus only 16% of those with such a history.8
Childhood trauma is also associated with a worse outcome in psychotherapy trials.9 However, a recent trial compared cognitive processing therapy (CPT) with a posttraumatic stress disorder (PTSD)-focused variation of dialectical behavior therapy (DBT-PTSD).10 Symptomatic remission, including depression symptoms, was achieved in 58% of the DBT-PTSD participants and 41% of the CPT participants. At minimum, these data suggest that psychotherapy is an important treatment modality to consider for patients with a history of childhood trauma.
Medical Conditions and Treatments
Depression secondary to a medical condition or treatment may be addressed by resolving the medical issue or switching the medical treatment. However, that too may not be easy or completely feasible.
There are some new developments in this area. The advent of neuroactive steroids for postpartum depression is an exciting advance; and yet, as always, any new treatment carries unknown risks that only reveal themselves with years of use.
In addition to (or instead of) antidepressants, a modality like behavioral activation therapy (BAT) might be worth considering. For example, the Medical University of South Carolina Hollings Cancer Center is studying an app-based version of BAT11 that has shown evidence of efficacy in depression.12
Patients with TRD have high rates of bipolarity.13 In one specialty clinic, for instance, 80% of patients referred with TRD had enough bipolarity to warrant switching to a mood stabilizer–based regimen.14 Failure to recognize subtle bipolarity can lead to multiple trials of antidepressants. For example, in one psychiatric consultation program where undetected bipolarity was common, patients received an average of 2.7 antidepressants before referral.15,16
Antidepressants can induce manic episodes and mixed states, although this is relatively uncommon.17 Thus, antidepressant monotherapy is not recommended in mixed states.17-19 Mood stabilizers are the principal option. When patients are taking a mood stabilizer as well as an antidepressant and are still having mixed state symptoms, clinicians can consider tapering the antidepressant. In one case series, this was associated with a reduction in suicidality as well as anxiety.20
Although awaiting replication, a study (NCT02519543) from Calkin et al21 (recipient of the 2023 Best Paper award from the American Society of Clinical Psychopharmacology22) suggested that metformin may have an antidepressant effect in select patients with treatment- resistant bipolar depression. Among participants whose insulin resistance reverted to normal on metformin, 80% met response criteria on the Montgomery-Asberg Depression Rating Scale versus 40% of those who did not convert.
Other Presentations of MDD
The usual list of antidepressant alternatives may be considered (eg, a different psychotherapy; lithium or thyroid augmentation; and light therapy, even in nonseasonal depression), along with some exciting new options.23 New treatments also have potential applicability in the other kinds of depression. For example, the putative mechanism of psilocybin in depression—Default Mode Network modulation24—makes it worth considering for patients with trauma histories as well as major depression.
The adage, “When your treatment is not working, question your diagnosis” is still an important one when faced with potential TRD. Are there some treatments that might better target the depression? In reframing the type of depression, we can also reframe what constitutes an “antidepressant,” and choose the safest, most effective treatment for each patient. Although they can be tremendously helpful—indeed, lifesaving—antidepressants carry substantial risks, sometimes with only moderate potential for benefit relative to placebo.25
With all of this in mind, TRD remains a challenge. The authors contributing to this Special Report will share their perspectives and strategies to further support you and your patients.
Dr Phelps is research editor at the Psychopharmacology Institute; emeritus faculty at Samaritan Mental Health in Corvallis, Oregon; and founder of PsychEducation.org. He is the bipolar disorder section editor for Psychiatric Times® and the author of A Spectrum Approach to Mood Disorders for clinicians and Bipolar, Not So Much for patients and their families.
1. Robertson D, Codd RT III. Stoic philosophy as a cognitive-behavioral therapy. The Behavior Therapist. 2019;42(2):42-50.
2. Carlbring P, Andersson G, Cuijpers P, et al. Internet-based vs. face-to-face cognitive behavior therapy for psychiatric and somatic disorders: an updated systematic review and meta-analysis. Cogn Behav Ther. 2018;47(1):1-18.
3. Cuijpers P, Noma H, Karyotaki E, et al. Individual, group, telephone, self-help and internet-based cognitive behavior therapy for adult depression; a network meta-analysis of delivery methods. JAMA Psychiatry. 2019;76(7):700-707.
4. Goodwin GM, Price J, De Bodinat C, Laredo J. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord. 2017;221:31-35.
5. Masdrakis VG, Markianos M, Baldwin DS. Apathy associated with antidepressant drugs: a systematic review. Acta Neuropsychiatr. 2023:35(4):189-204.
6. Langley C, Armand S, Luo Q, et al. Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study. Neuropsychopharmacology. 2023;48(4):664-670.
7. Teicher MH, Gordon JB, Nemeroff CB. Recognizing the importance of childhood maltreatment as a critical factor in psychiatric diagnoses, treatment, research, prevention, and education. Mol Psychiatry. 2022;27(3):1331-1338.
8. Williams LM, Debattista C, Duchemin AM, et al. Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression. Transl Psychiatry. 2016;6(5):e799.
9. Karatzias T, Murphy P, Cloitre M, et al. Psychological interventions for ICD-11 complex PTSD symptoms: systematic review and meta-analysis. Psychol Med. 2019;49(11):1761-1775.
10. Bohus M, Kleindienst N, Hahn C, et al. Dialectical behavior therapy for posttraumatic stress disorder (DBT-PTSD) compared with cognitive processing therapy (CPT) in complex presentations of PTSD in women survivors of childhood abuse: a randomized clinical trial. JAMA Psychiatry. 2020;77(12):1235-1245.
11. Telehealth interventions and remote methods. Hollings Cancer Center. Accessed September 15, 2023. https://hollingscancercenter.musc.edu/research/labs/team-impact/studies/telehealth
12. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827.
13. Correa R, Akiskal H, Gilmer W, et al. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord. 2010;127(1-3):10-18.
14. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2-3):251-257.
15. Phelps J, Bale J, Squires K 3rd, Pipitone O. Bipolarity in a collaborative care model variation: detection, prevalence, and outcomes. Psychiatr Serv. 2020;71(11):1098-1103.
16. Phelps JR, James J 3rd. Psychiatric consultation in the collaborative care model: the “bipolar sieve” effect. Med Hypotheses. 2017;105:10-16.
17. Swann AC, Lafer B, Perugi G, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170(1):31-42.
18. Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22(2):203-219.
19. Yatham LN, Chakrabarty T, Bond DJ, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations. Bipolar Disord. 2021;23(8):767-788.
20. Phelps J, Manipod V. Treating anxiety by discontinuing antidepressants: a case series. Med Hypotheses. 2012;79(3):338-341.
21. Calkin CV, Chengappa KNR, Cairns K, et al. Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial. J Clin Psychiatry. 2022;83(2):21m14022.
22. American Society of Clinical Psychopharmacology. Paul Wender best paper in the Journal of Clinical Psychiatry. Accessed September 15, 2023. https://ascpp.org/paul-wender-best-paper-in-the-journal-of-clinical-psychiatry-award/
23. Reis DJ, Hoffberg AS, Stearns-Yoder KA, Bahraini NH. Bright light therapy for mental and behavioral illness: a systematic umbrella review. Chronobiol Int. 2023;40(2):204-214.
24. Gattuso JJ, Perkins D, Ruffell S, et al. Default mode network modulation by psychedelics: a systematic review. Int J Neuropsychopharmacol. 2023;26(3):155-188.
25. Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open. 2019;9(6):e024886.