Thomas R. Verny is a clinical psychiatrist, academic, award-winning author, poet and public speaker. He is the author of eight books, including the global bestseller The Secret Life of the Unborn Child and The Embodied Mind: Understanding the Mysteries of Cellular Memory, Consciousness and Our Bodies.
Major depressive disorder affects more than 280 million people worldwide and represents a leading cause of disability. [1] Owing to the advance of a wide range of psychiatric drugs and psychotherapies, about 60 to 70 per cent of patients improve.
The remaining 30 per cent of patients do not respond to several trials of drugs and psychotherapy. Their illnesses drag on like long COVID. They are said to suffer from treatment-resistant depressions [2] and treatment-resistant schizophrenias. [3] It is to treat these refractory diseases that psychiatrists, neurosurgeons and other professionals have come to explore alternative avenues of treatment.
Presently, their therapeutic choices consist of anesthetics like ketamine, psychedelics such as psilocybin or various forms of electrical brain stimulation. So, let’s take a deep dive, as my grandchildren would say, into this variety of treatments.
Ketamine was introduced as an anesthetic in the 1970s both in Canada and the U.S. Since then, driven by research into ketamine’s effectiveness for treatment-resistant depression and other mental-health conditions, ketamine clinics have been rapidly expanding across both countries.
KATA, Canada’s Ketamine Clinic and Provider Directory, lists ketamine clinics that are safe, ethical and employ trained mental-health professionals. [4] A similar directory in the U.S. is ASKP3, the American Society of Ketamine for Physicians, Psychotherapists & Practitioners. [5]
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Ketamine may be administered intravenously, intranasally (esketamine) or orally. Multiple recent randomized controlled trials and observational studies confirmed rapid antidepressant and anti-suicidal effects (hours to days) of all forms of ketamine while adverse events were mild and transient. [6,7] In one study from the University Health Network, Toronto, depression and suicidality scores were significantly decreased after an acute course of ketamine infusions, with improvements persisting while patients continued to receive maintenance infusions over several weeks and months. The authors opined that these results provide preliminary support for the long-term clinical utility of maintenance ketamine infusions. [8]
A potential paradigm shift for treating a wide variety of mental disorders is the revival of interest in psilocybin in psychopharmacological research. [9]
Psilocybin holds promise for psychiatry but its successful translation from research to clinical practice demands more robust evidence on efficacy, safety and methodological rigour. Other factors, such as legal and ethical issues, need to be successfully addressed to facilitate psilocybin’s implementation in health care systems. [10]
Notably, a recent systematic review of 16 clinical trials investigating psychedelics such as psilocybin, LSD, ibogaine and ayahuasca to treat addictions showed promise in reducing alcohol and tobacco dependence, with psilocybin being particularly effective in decreasing cravings and promoting long-term abstinence. [11]
In 1955, when I started my postgraduate studies in psychiatry, one of my first placements was at the Ontario Hospital in Toronto, now the Centre for Addiction and Mental Health. The most intractable depressed or schizophrenic patients received electroconvulsive therapy (ECT).
Though much improved, ECT, first introduced in 1939 in Italy, is still widely used. Today, it is considered as one of the most effective therapies for treatment-resistant depression, with many studies reporting high response/remission rates in 60 to 80 per cent of severely depressed patients. Large studies have also demonstrated that ECT reduces suicidal ideation and is associated with lower suicide/mortality. [12,13]
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In each ECT treatment, the patient is given a muscle relaxant and a general anesthetic. When they fall asleep, two metal discs (electrodes) are fastened to their temples. Then a small electric current is passed between the electrodes and through part of the brain that causes a controlled therapeutic seizure usually lasting 20 to 90 seconds. [14]
Effectiveness varies by technique. Right unilateral ultrabrief pulse ECT produces lower remission rates, while conventional bilateral ECT produces higher remission rates. [15] Contemporary studies of patients with treatment-resistant depression are showing somewhat lower response rates to ECT compared with earlier studies. [16]
Unfortunately, absent maintenance medication or maintenance ECT, relapse rates in some centres are up to 50 per cent in the first year. [17] Also, a good number of patients complain of minor side effects such as headache, nausea and muscle stiffness. More troubling is persistence of confusion, loss of autobiographical memory and short-term reduction in new learning. [12]
Improved ECT techniques and clear guidelines for the use of ECT have reduced the risk and severity of memory side effects. ECT continues to have lower patient acceptance owing to negative perceptions and concern over adverse cognitive effects. As with all therapeutic interventions, whether they be pharmaceutical, electronic or surgical, the patient should be advised beforehand of the risks and benefits.
Now let us switch our attention to electrical brain stimulation (EBS), which, like ECT, entails the application of electrical current directly to the brain by fastening electrodes to the head. The most prominent of these non-invasive methods are transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial magnetic stimulation (TMS) and repetitive transcranial magnetic stimulation (rTMS).
Repetitive transcranial magnetic stimulation, which is also referred to as magnetic seizure therapy (MST), is an approved treatment for adults with depression in many parts of the world. Recently, I spoke to Dr. Daniel Blumberger, the scientific director of the Temerty Centre for Therapeutic Brain Intervention at CAMH. He confirmed that he and his team have so far treated 200 patients with depression, mostly in the outpatient department. In the population studied they found a significant reduction in depressive symptoms with MST with fewer cognitive side effects than those following ECT. Their research contributed to the therapy’s increasing global adoption.
It uses a highly focused magnetic coil placed on the scalp to trigger a short, controlled seizure while the patient is under general anesthesia. The therapy aims to produce antidepressant effects comparable to ECT but with greater precision and fewer cognitive adverse effects, as its stronger, targeted magnetic pulses are directed at a part of the brain called the dorsolateral prefrontal cortex, commonly implicated in depression. [18]
It does not require an anesthetic and can be administered in a doctor’s office or clinic setting. The treatment lasts about three to eight minutes. It has limited side effects and generally leads to rapid symptom relief. [19] Patients can return to their regular activities immediately after treatment. [20]
An alternative method is transcranial direct current stimulation (tDCS), which has also demonstrated antidepressant efficacy. As with all EBSs, it presents adherence and logistical challenges. To remedy this situation, home-based tDCS, requiring only a flexible cap or band with electrodes worn over the forehead, has been introduced. Evidence suggests that tDCS can be safely administered under remote medical supervision in the home. So, that may be another option where these devices are available. [21,22]
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The above-mentioned methods are all non-invasive. In contrast, the following are invasive in the sense that they require surgical instruments that enter or penetrate the body, often by cutting the skin, bones and neural tissues. Invasive methods involve direct cortical stimulation (DCS), deep brain stimulation (DBS) and microstimulation.
DBS requires burr holes to be drilled through the cranium. Then, tiny tubes are inserted through which one-millimetre electrodes are passed. These are connected to a very small stimulating device placed under the person’s collarbone, like a heart pacemaker.
When successful, DBS may interrupt irregular brain signals that cause depression. The procedure, like every other surgical intervention, carries certain risks: infection, bleed, hardware problems plus possible neuropsychiatric effects.
A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression from China identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB) and nucleus accumbens (NAcc). I apologize for this tsunami of medical jargon, but their relevance will become apparent. The overall effect was positive, irrespective of the targeted area. [23]
Stanley Caroff, an emeritus professor of psychiatry at the University of Pennsylvania Perelman School of Medicine, highlighted that there is no consensus on which brain regions are optimal for stimulation. He is of the opinion that, “Given the safety concerns, the evidence is insufficient to recommend DBS as a depression treatment, in light of the many other approved options available.” [24]
All this came to my mind when I read in a recent issue of The Globe and Mail Anna Mehler Paperny’s account of her DBS treatment at Toronto’s Sunnybrook Health Sciences Centre. She describes in vivid detail a battery of assessments, scans and follow-ups, two surgeries, the first one when a metal frame was drilled into the skin and muscle of her head and neck to help neurosurgeons navigate the insertion of the electrodes into her brain. This was followed by a second operation five days after the first under a general anesthetic when her electrodes were connected to a generator under her clavicle. Then she developed a nasty infection which necessitated a visit to the emergency department with the customary wait of 19 hours and four hours on the ward before she was treated in the OR. There were many months of appointments with her doctors to adjust the electrical stimulation. And of course, she had to take time off from work.
While the treatments were covered by research grants and OHIP, there were still transportation and other expenses. In conclusion, she says, “I am still taking ketamine. Some days I feel a new foundation of resilience; some days it remains inaccessible.” [25]
You would have to be a person feeling seriously hopeless and at the same time possess an almost heroic strength of character to continue along a path this arduous. And no guarantees of the results.
If I were faced with a choice between invasive and non-invasive electrotherapeutics, I would ask myself, do the benefits justify the risks?
And one more piece of advice. When looking for a treatment of what ails you, keep in mind that we are all different and that what worked for a friend of yours may not work for you, and vice versa.
References
- Herrman, Helen, Vikram Patel, Toshiaki A. Furukawa et al. “Time for united action on depression: a Lancet–World Psychiatric Association Commission.” The Lancet 399, no. 10328 (2022): 957-1022.
- McIntyre, R. S., Alsuwaidan, M., Goldberg, J. F., … & Maj, M. (2023). Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World psychiatry, 22(3), 394-412.
- Pandey, A., & Kalita, K. N. (2022). Treatment-resistant schizophrenia: How far have we traveled? Frontiers in Psychiatry, 13, 994425.
- KATA katacanada.org/ketamine-clinic-provider-directory/
- The American Society of Ketamine for Physicians, Psychotherapists & Practitioners. askp.org/
- Medeiros, G. C., Demo, I., Zarate Jr, C. A., & Gould, T. D. (2024). Personalized use of ketamine and esketamine for treatment-resistant depression. Translational psychiatry, 14(1), 481.
- Glue, P., Loo, C., Fam, J.,., Young, A. H., & Surman, P. (2024). Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nature medicine, 30(7), 2004-2009.
- Haikazian, S., McIntyre, R. S., Orsini, D. K., … & Rosenblat, J. D. (2025). Real world effectiveness of maintenance ketamine infusions for treatment-resistant depression in major depressive disorder and bipolar disorder. Psychiatry Research, 116691.
- Kittur, M. E., Jones, B. D., Blumberger, D. M., Rosenblat, J. D., & Husain, M. I. (2025). Mapping psilocybin therapy: A systematic review of therapeutic frameworks, adaptations, and standardization across contemporary clinical trials. Journal of Affective Disorders, 119952.
- Scala, M., Fabbri, C, Amerio, A., … & Serretti, A. (2024). The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges. CNS spectrums, 1-15.
- Hogea, L., Tabugan, D. C., Nussbaum, L., Cojocaru, A., … & Anghel, T. (2025). The therapeutic potential of psychedelics in treating substance use disorders: A review of clinical trials. Medicina, 61(2), 278.
- Porter, R. J., Baune, B. T., Boyce, P., … & Malhi, G. S. (2020). Cognitive side-effects of electroconvulsive therapy: what are they, how to monitor them and what to tell patients. BJPsych open, 6(3), e40.
- Odermatt, J., Sarlon, J., Schneider, E., … & Brühl, A. B. (2025). Electroconvulsive therapy reduces suicidality and all-cause mortality in refractory depression: A systematic review and meta-analysis of neurostimulation studies. Neuroscience Applied, 4, 105520.
- CAMH, Electroconvulsive therapy (ECT)
- Jelovac, A., & McLoughlin, D. M. (2025). Ultrabrief pulse electroconvulsive therapy for depression: a systematic review and meta-analysis. Molecular Psychiatry, 1-10.
- Haq, Aazaz U., Adam F. Sitzmann, Mona L. Goldman, Daniel F. Maixner, and Brian J. Mickey. “Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors.” J Clin Psychiatry 76, no. 10 (2015): 1374-1384.
- Ruiz, A., Haseeb, A., Baumgartner, W., Lueng, E., Scaini, G., & De Quevedo, J. L. (2025). New insights into the mechanisms of electroconvulsive therapy in treatment-resistant depression. Frontiers in psychiatry, 16, 1614076.
- Lisanby SH, Schlaepfer TE, Fisch HU, Sackeim HA. Magnetic seizure therapy of major depression. Arch Gen Psychiatry. 2001;58(3):303-305.
- George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stimulation: applications in neuropsychiatry. Arch Gen Psychiatry. 1999;56(4):300-311.
- Deng ZD, Lisanby SH, Peterchev AV. (2011). Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study. J Neural Eng. 8(1):016007
- Woodham, R. D., Selvaraj, S., Ghazi-Noori, A. R., … & Fu, C. H. (2025). Home-based transcranial direct current stimulation treatment for major depressive disorder: a fully remote phase 2 randomized sham-controlled trial. Nature medicine, 31(1), 87-95.
- Borrione, Lucas, Beatriz A., Natasha KS Moran et al. “Home-use transcranial direct current stimulation for the treatment of a major depressive episode: a randomized clinical trial.” Jama psychiatry 81, no. 4 (2024): 329-337.
- Zhou, C., Zhang, H., Chen, J., … & Xie, P. (2018). A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 82, 224-232.
- Zagorski, N. (2020). Experts Debate What’s Next for DBS for Depression. Psychiatric News. Vol 55, no. 6.
- Paperny, Anna M (2025). Holes in my head. Wires in my brain. The Globe and Mail.
