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3 Overlooked Causes of Treatment-Resistant Depression

3. Circadian rhythm.

Key points

  • The term "treatment-resistant depression" only takes into account failed pharmacological interventions.
  • Mental health is biopsychosocial, so treatment resistance should encourage other interventions, like therapy.
  • Personality issues, buried trauma, and circadian rhythm defects could be culprits in stubborn depression.
Gerd Altman/Pixabay
Source: Gerd Altman/Pixabay

Treatment-resistant (refractory) depression has been a fertile topic for several decades (e.g., Freyhan, 1978; Nierenberg & Amsterdam, 1990; Voineskos, 2020). Unfortunately, as noted by Voineskos, treatment-resistant depression is generally defined as patients having failed two antidepressant trials. The condition apparently takes little into account outside biological intervention.

Knowing that mental illness tends to be a bio-psycho-social equation (i.e., Tripathi et al., 2019), it’s surprising that the idea of treatment resistance primarily considers a pharmacological standpoint. Some researchers have begun investigating the efficacy of psychotherapy in conjunction with pharmacology for treatment-resistant depression cases. For example, Van Bronswijk et al. (2019), did a comparison of 22 studies of pharmacology and psychotherapy versus only pharmacology intervention in difficult-to-treat cases. They found that the former was more efficacious, and opined that psychotherapy should be included in treatment-resistant depression guidelines.

Further, if someone has been told their depression is resistant, it’s worth examining what’s been looked at. Depression is often a downstream effect of a bigger issue, and providers, both prescriber and therapist, could only be focusing on reducing depression symptoms. If the activating issue is not addressed, it makes sense that little improvement would occur. It’s like trying to quell the pain of a large splinter by constantly trying new painkillers instead of removing the splinter.

As readers can imagine, being told debilitating depression is resistant implies it is “untreatable.” This may cultivate a matter of iatrogenic illness, with demoralization and hopelessness compounding the original diagnosis.

The following are three other areas to consider if someone’s depression is ostensibly treatment-resistant:

Personality Pathology

People with personality disorders frequently have co-occurring depression. In 1996, Thase wrote, "The role of personality disorders in the management of chronic, treatment-refractory depressive states is one of the least studied, yet more interesting topics in the treatment of mood disorder." Considering the chronic fallout from significantly maladaptive interpersonal styles of personality-disordered people, this isn’t surprising. However, still, comparatively little has been researched in this department.

This depression/personality relationship is easily illustrated by avoidant personality disorder (AVPD). Those with AVPD have a pervasive pattern of negative self-evaluation in comparison to others that drives social inhibitions. In effect, they feel they just don’t measure up, and that nobody would ever really want to associate with them, so why bother trying just to be scrutinized? They lack confidence and motivation, assuming they’ll just fail or become subject to scrutiny, and thus tend not to achieve what they’d like. An AVPD patient I knew, recognizing this pattern in themselves, once said, “I’m just a dreamer.”

It’s easy to see how this kind of lens on life would drive someone to be depressed. A provider could, understandably, assume that the inhibitions and lack of confidence are due to the depression, and thus pointedly work on reducing depression symptoms. Unfortunately, depression is downstream of the AVPD and, without pointed work on the personality complications, direct depression work will likely only provide tenuous stability at best. In fact, Banyard et al. (2021) did a meta-analysis and noted that “…patients meeting diagnostic criteria for a [personality disorder] tended to improve less than patients without a [personality disorder] after CBT for depression.”

Providers concerned about treatment-resistant depression would do well to consider if personality is playing a role. Depression is not uncommon as a symptom in Diagnostic and Statistical Manual (DSM) personality disorders, particularly borderline, histrionic, avoidant, and dependent personality disorders (DSM-5). Other personality styles not included in the DSM, including depressive, passive-aggressive, and self-defeating personalities (i.e., Millon, 2011) also are often depressed.


The effects of trauma are vast, and it’s no surprise that depression is highly correlated with trauma and PTSD (e.g., Shalev et al., 1998; Afzali et al., 2017). Add to this that not everyone traumatized reports it (i.e., Centers for Disease Control, 2023), so it isn't far-fetched to surmise it also won't necessarily be broached in therapy. Similarly, not all people admitting to trauma in therapy are willing to engage in working on it. Considering the aforementioned, we can see how a fertile bed is maintained for depression to chronically blossom.

For providers who have an intuition that trauma is at hand, but has not been revealed, wondering aloud if there is a buried conflict the person has not yet shared could be helpful. For example, "Alex, we've been wrestling with depression for many months. You've been faithful to the antidepressant regimen, and you've put in a lot of work in our therapy sessions, yet something seems to be anchoring you to a persistent bad mood. I can't help but wonder if something is in your depths that perhaps you feel you've sufficiently dealt with, or maybe even buried, that is tugging on your emotions behind the scenes."

Providers who have stubbornly-depressed patients with known, but unaddressed, trauma, may wish to carefully explore entering trauma work. It can help to begin by educating the patient on the correlation between depression and trauma, and resolution may prove to be a "two-fer." Resolving the trauma can lift the depressive cloud.

Gerd Altman/Pixabay
Source: Gerd Altman/Pixabay

Circadian Rhythm

In 2009, researchers Kalman & Kalman released a study called "Depression as Chronobiological Illness," illustrating the complicated relationship between our synchronicity with natural rhythms and depression. Since then, the link between circadian rhythm and mood has been a burgeoning topic in depression research (e.g., Robillard et al., 2018; Walker et al., 2020; Crouse et al., 2021). Some researchers, such as Boehler et al. (2021), doing animal studies, discovered bio-genetic complications within the suprachiasmatic nucleus, a part of the brain that sets circadian rhythm (Ma & Morrison, 2022), as contributors to depression, and could soon provide further insight into human experience.

A basic hypothesis is that disruption in circadian rhythm leads to significant sleep disturbance and/or other hormonal imbalances, the downstream effect being a mood disorder (e.g., Vadnie & McClung, 2017; Lamont et al., 2022).

Anyone who has been sleep-deprived knows that moodiness, trouble concentrating, and fatigue can happen after one night of insomnia. Now imagine if one's circadian rhythm becomes the equivalent of a slipped timing belt in a car. Like the car, they're going to be chronically running poorly. The constant moodiness, trouble concentrating, and fatigue on top of the sleep deprivation can easily engender disinterest in previously enjoyed activities, isolation, and perhaps even suicidality if one feels chronically rundown. It's a picture of depression, but rooted in sleep or chronobiological pathology.

Providers working with individuals who have had little response to antidepressants and/or psychotherapy despite good effort may also consider referring the patient to a sleep specialist. This is especially true if the person has a history of working third shift or perhaps constantly crossing time zones, like pilots, and an irregular sleep pattern was ingrained into their lives at any point.

Disclaimer: The material provided in this post is for informational purposes only and is not intended to diagnose, treat, or prevent any illness in readers or people they know. The information should not replace personalized care or intervention from an individual’s provider or formal supervision if you’re a practitioner or student.

To find a therapist near you, visit the Psychology Today Therapy Directory.

Facebook/LinkedIn image: EGHStock/Shutterstock


Afzali, M.H., Sunderland, M., Teesson, M., Carragher, N., Mills, K. & Slade, T. (2017). A network approach to the comorbidity between posttraumatic stress disorder and major depressive disorder: The role of overlapping symptoms. Journal of Affective Disorders, 208, 490-496.

American Psychiatric Association, (2022). Diagnostic and statistical manual of mental disorders (5th ed, text revision.)

Boehler, N.A., Fung, S.W., Hegazi. S., Cheng. A.H., & Cheng, H.-YM. (2021). Sox2 ablation in the suprachiasmatic nucleus perturbs anxiety and depressive-like behaviors. Neurology International, 13(4), 541-554.

Crouse, J.J., Carpenter, J.S., Song, Y.J.C., Hockey, S.J., Naismith, S.L., Grunstein, R.R., Scott, E.M., Merikangas, K.R. Scott, J. & Hickie, I.B. (2021). Circadian rhythm sleep–wake disturbances and depression in young people: Implications for prevention and early intervention. The Lancet Psychiatry, 8(9), 813-823.

Freyhan, F.A., (1978). Treatment-resistant or untreatable? Comprehensive Psychiatry, 19(2), 97-101.

Kalman, S. & Kalman, J. (2009). Depression as chronobiological illness. Neuropsychopharmacologia Hungarica, 11(2), 69-81.

Lamont, E.W., Legault-Coutu, D., Cermakian, N., & Boivin, D.B. (2007). The role of circadian clock genes in mental disorders. Dialogues in Clinical Neuroscience, 9(3), 333-342.

Ma, M.A. & Morrison, E.H. [Updated 2022 Jul 25]. Neuroanatomy, nucleus suprachiasmatic. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:

Millon, T. (2011). Disorders of personality: Introducing a DSM/ICD spectrum from normal to abnormal (3rd ed). Wiley.

Nierenberg, A.A. & Amsterdam, J.D. (1990). Treatment-resistant depression: Definition and treatment approaches. The Journal of Clinical Psychiatry, 51, 39-50.

Robillard, R., Carpenter, J.S., Rogers, N.L., Fares, S., Grierson, A.B., et al. (2018). Circadian rhythms and psychiatric profiles in young adults with unipolar depressive disorders. Translational Psychiatry, 8(213).

Shalev, A.Y., Freedman, S., Peri, T., Brandes, D., Sahar, T., Orr, S.P., & Pitman, R.K. (1998). Prospective study of posttraumatic stress disorder and depression following trauma. The American Journal of Psychiatry, 155(5), 630-637.

Thase, M.E. (1996). The role of axis II comorbidity in the management of patients with treatment-resistant depression. Psychiatric Clinics of North America, 19(2), 287-309.

Tripathi A., Das, A., & Kar, S.K. (2019). Biopsychosocial model in contemporary psychiatry: Current validity and future prospects. Indian Journal of Psychological Medicine, 41(6), 582-585.

Vadnie, C.A. & McClung, C.A. (2017). Circadian rhythms in regulation of brain processes and role in psychiatric disorders. Neural Plasticity, 2017.

Van Bronswijk, S., Moopen, N., Beijers, L., Ruhe, H., & Peeters, F. (2019). Effectiveness of psychotherapy for treatment-resistant depression: A meta-analysis and meta-regression. Psychological Medicine, 49(3), 366-379. doi:10.1017/S003329171800199X

Voineskos D., Daskalakis Z.J., & Blumberger, D.M. (2020). Management of treatment-resistant Depression: Challenges and strategies. Neuropsychiatric Disorder Treatment, 21(16), 221-234.

Walker, W.H., Walton, J.C., DeVries, A.C. & Nelson, R.J. (2020). Circadian rhythm disruption and mental health. Translational Psychiatry, 10(28).

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