Treatment Resistant Depression and it’s impact on life: looking toward more contemporary options in 2022

Intractable depression now has multiple options and hope for its resolution – read on

Intractable depression is something that occurs in 20-30 percent of patients with major depression. It is called treatment resistant depression or TRD according to Zhadanava M, Oilon, D,Ghelerter I, et al. (2021). There are more medications than ever and a range of programs for treatment resistant depression that some may not have heard about. For that reason this review will be useful.

As the name implies, treatment resistant depression is highly refractory to the typical treatments that generally include psychopharmacology and psychotherapy. I have had the clinical opportunity to meet with men and women in psychotherapy who are diagnosed with major depression but for some of them, nothing has helped. They have had multiple trials on numerous medications and psychotherapy with little to no relief of symptoms. Some describe a worsening of symptoms after beginning treatment and some claim this to be signs of an allergic reaction to the medication. The British Journal of General Practice has published a list of the first line antidepressants in 2019, Kendrick,Taylor, and Johnson. The meta analysis is conducted in 2019 revealed 21 medication’s that showed efficacy and tolerability in patients with it it may be depression. They found agomelatine, (Valdoxan), amitriptyline – a tricyclic antidepressant but is prescribed for various nerve, arthritis, and muscle pain, escitalopram (Lexapro) – may treat generalized anxiety as well as depression, mirtazapine (Remeron), used for poor sleep hygiene, failure to thrive, and major depression, paroxetine, (Paxil), venlafaxine, (Effexor) may help with GAD and panic anxiety, and vortioxetine (Trintellix) more effective than others.

These patients are intractable in their sadness and become resolute that nothing will help them. Most have been talkative, intellectually curious, but deeply sad in my presence. They are often hopeless that they may never feel a few moments of joy each day, no matter what they do. Many feel embarrassed for being so overwhelmed with life and barely hold on from week to week. Others take life with little hope that things will ever change and, for them, suicide is always on the drawing board. These few patients sometimes need a more structured living arrangement, usually a hospital.  Many patients with intractable depression live life with their final exit all cued up and ready to roll. Some plan to move west to states like Oregon that has physician assisted suicide – saved for when they can no longer live with themselves. For these people, I work with them to find a greater purpose upon which to focus and measure success – often one day at a time. In addition to psychotherapy it is important to get these folks moving with rigorous exercise and activities to find greater purpose. Some patients decide to return to school, work or start attending church again. This programs not only enhance dopamine transport but they also result in social interpersonal contact, something many are missing as they grow older.

There are now new and controversial treatments for treatment resistant depression that are being reported in the psychiatric literature bringing hope to families everywhere. Treatment like transcranial magnetic stimulation, ketamine treatment, stellate ganglion block, deep brain stimulation (requires a surgical procedure to set a deep brain stimuator in the area of the brain that subserves the aura of well-being, and even psilocybin, a powerful psychedelic. Family members sometimes ask why can’t we do something less invasive? The transcranial magnestic procedure is non invasive and uses strong magnetic fields to stimulate neurons within the brain in the area that underlies mood regulation. Treatment requires 15-30 sessions. Readers may have heard little about these treatments, but for families who have watched their loved ones languish, they offer a modest hope that life for their loved ones now has options and promise. These are the cases that you worry about at the end of the day. These are the cases that may not buy what you are selling when it comes to a therapeutic modality or trial of medication that they have already tried and failed. The handoff to one of theses specialty options including ECT – electroconvulsive therapy needs to be a careful one and deep brain stimulation requires sensitivity and cautious optimism about the likelihood of success. A little halo affect can go a long way in getting a good first impression, and a good start to a new treatment modality. A careful history about what medications have been tried and failed is important to document including the length of time they took the drug.

Still newer is the return of hypnotic and synthetic therapy. Scientists are using psilocybin to bring patients through their depression in one of two treatments. Reader may understand that psilocybin are the main ingredients in LSD. There is a growing literature on the use of psilocybin to improve depression resistant cases. Those participating in psychedelic studies often say the experience was among the most meaningful of their lives, on a par with the birth of a child or death of a parent. Many report feeling a sense of connectedness with the universe. “This psilocybin journey was the single most transformative experience of my life,” Mr.Fernandez wrote in a medium post in 2018 reported in a recent NY Times opinion piece by Dana Smith, Ph.D (taken 7-16-2022).

I saw the 60 minutes story on SGB a year or two ago as a possible treatment for refractory PTSD. Many patients now matter how many medications the the and even combined with hours of individual psychotherapy still have reactive symptoms of the condition. SGB stands for Stellate Ganglion Block. Ganglion simply means a bundle of nerve fibers. We have numerous ganglia in our bodies. The Stellate ganglion is different and offers a potentially serendipitous treatment option for posttraumatic stress disorder (PTSD) that heretofore has been refractory to conventional psychiatric therapy. It may hold promise for co-occurring depression as well. It involves a neurochemical blockade of the stellate ganglion. The use of a small amount of anesthesia provides a risk free blockade of the autonomic nervous system overflow that contributes to the toxic levels stress hormones like adrenaline and cortisol that directly add to feelings of anxiety and hyperarousal among people with PTSD. This elevated arousal puts them on high alert night and day. This is not sustainable. 

Here in Massachusetts, the MGH has a Stereotactic Functional Neurosurgery Program that among other things does SGB for medically intractable Obsessive-compulsive disorder and Major depression under a current protocol at MGH. Surgical options are not considered until when medical options are no longer effective or side effects may be severe (Functional Neurosurgery Program, Massachusetts General Hospital website, taken August 22, 2022. DBS has been utilized for Parkinson’s disorder for many years. For people who suffer with major depression many are hopeless and believe the world may be better without them in it. These alternative treatments like: ECT, TMS, Ketamine, stellate ganglion block, and DBS afford greater options at some personal cost. While they are intensive and in some cases invasive there is a trade off in terms of quality of life. The tipping point in my view, when people are isolated, hopeless, and their depression becomes a barrier to functional living, like failure to thrive, the cost of not taking a broad approach to treatment is too great. Human suffering can sometimes be so silent that no one takes notice. The treatment resistant are sometimes elderly and often alone. It is these people that I worry about in my practice as a clinician here in Massachusetts.


Zhadanava M, Oilon, D,Ghelerter I, et al. (2021). The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. Journal of Clinical Psychiatry; 82(2):20m13699

Kendrick, T, Taylor D, Johnson, C. (2019). Which first-line antidepressant? British Journal of General Practice; 69 (680): 114-115.

Smith, Dana (2022) Taking the Magic Out of Magic Mushrooms, Opinion, NY Times, July 16, 2022

Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponté KL, Guss J, Bossis AP, Grigsby J, Fischer S, Ross S. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol.Feb;34(2):155-166. doi: 10.1177/0269881119897615. Epub 2020 Jan 9. PMID: 31916890.

MGH (2022) Stereotactic Functional Neurosurgery Program, Website taken 8-22-2022.