By Anastasia Alenova
Major depressive disorder (MDD), commonly known as depression, affects over 264 million people worldwide, with one third of patients suffering from a treatment resistant form of the disorder. When medication and psychotherapy are ineffective, electroconvulsive therapy (ECT) is often recommended, leading to an improvement in over 50% of patients (McDonald et al., 2019). Typically used in severe cases, such as patients with suicidal tendencies requiring rapid treatment, ECT is a very effective therapy for depression.
ECT involves administering a brief electrical stimulation to the brain while the patient is under anaesthesia. This electrical stimulus consists of a series of 100 – 1000 bidirectional pulses between two electrodes placed on the patient’s head. Each pulse lasts 0.3 – 1.5 milliseconds (ms) and is separated by periods of electrical silence lasting 6 – 16 ms (Swartz, 2014). The effects of the consecutive pulses aggregate to trigger a seizure. At the neuronal level, ECT disrupts the cell membrane and the functioning of the ion transport channels, leading to increased ion leakage across the membrane. Cations, and especially sodium ions normally kept at a low concentration intracellularly, begin to accumulate inside the cell. As additional pulses arrive, the internal voltage rises to the neuronal firing threshold. These neurons are known as seizure foci, and, in a wave-like manner, trigger adjacent neurons to fire, eventually leading to a seizure (Swartz, 2014).
Despite the seemingly unconventional methodology, these controlled seizures have demonstrated therapeutic benefits at the macroscopic, as well as chemical, level.
Anti-depressant free patients with treatment refractory depression had a decrease of depressive symptoms after successful ECT. According to ECT animal models, this therapy increases neuroplasticity in certain limbic structures involved in the pathophysiology of depression (Tendolkar et al., 2013). Depression is associated with hippocampal atrophy and decreased amygdala volume, but the volume of both structures is increased after ECT. Studies in adult rats by Singh et al. (2017) revealed that ECT normalises the volume in both aforementioned structures by upregulating adult neurogenesis and increasing microglia and oligodendrocyte precursor cell proliferation in both the hippocampus and amygdala. Enhanced gliogenesis has also been reported in humans post ECT treatment, along with synaptogenesis, angiogenesis, dendritogenesis, and mossy fibre sprouting in the hippocampus (Singh et al., 2017).
Enhanced neuroplasticity also leads to improved connectivity at the hippocampus. ECT regulates certain networks that are impaired during depression, such as networks associated with attention regulation and mood and emotion processing. Particularly, this therapy decreases hyperconnectivity in networks responsible for depressive rumination.
These improvements are enhanced by altered regional cerebral blood flow (rCBF). After ECT treatment, rCBF was increased in the amygdala, parahippocampal gyri and limbic structures of depressive patients. This increased blood flow was accompanied by neuro-chemical release which helped induce angiogenesis and neurogenesis. On a microscopic level, the neurochemical release triggered by ECT changed the chemical and hormonal balance in depressive patients. Exposure to a seizure, such as one caused by ECT, causes the brain to release neurochemicals including transcription factors, hormones, neurotrophic factors and neurotransmitters.
The ECT-caused increase in neuroplasticity is also due to an increase in neurotrophic factors, which have a role in growth and development of brain structures. Depressed patients have low levels of brain-derived neurotrophic factors (BNDF), responsible for neural growth proliferation, repair and survival. BNDF levels, and other factors such as glial cell-line derived neurotrophic factor, were normalised after ECT, with an enhanced expression in the hippocampus. ECT also prevents cell death by inhibiting pro-apoptotic signalling, via inactivation of pro-apoptotic factors such as Bad, or downregulation of c-Myc, a proto-oncogene involved in neural apoptosis (Singh et al., 2017).
Furthermore, ECT acts on stress hormone levels, which are often disturbed in patients with mood disorders. In depression, dopamine receptor binding is reduced in the hippocampus; ECT treatment counteracts this by increasing binding. On the other hand, the hypo-pituitary-adrenal axis is hyperactive in depressed patients, causing elevated cortisol levels, which in turn negatively impact neurogenesis and gliogenesis. ECT has been found to reduce cortisol levels back to normal in those patients, enhancing neuroplasticity.
Moreover, animal experiments have shown that the expression of certain genes, which encode for neuropeptides and transcription factors, is altered during ECT. For example, the expression of the growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) gene is increased post ECT, which leads to dendritic proliferation in nascent neurons of the hippocampal dentate gyrus (Singh et al., 2017). These collective effects contribute to enhanced neuroplasticity and decrease of depressive symptoms.
ECT acts on multiple levels of the brain and can be very effective in treating depression. It is unfortunately not a cure, with patients required to continue maintenance treatment such as medication or ongoing ECT treatment to prevent a relapse (McDonald et al., 2019).
Albeit unusual, ECT is safe and reliable. Any cognitive impairments associated with this treatment is often resolved in the first three days. After 15 days of ECT, an improvement beyond baseline can be observed in processing speed, attention and working memory, spatial problem solving and many more cognitive areas, counteracting the range of cognitive deficits present in depression (Semkovska et al., 2010).
However, this therapy is not without its limitations. The knowledge on neurobiological effects of ECT remains, for the most part, restrained to animal models – and many findings conducted on human patients are inconsistent, meaning firm inferences cannot be drawn. Moving forward, better homogeneity in research methodology and population studies, as well as the presence of a control group, may achieve more accurate results. One fact remains constant, whilst the therapy has had success, no single mechanism can explain the therapeutic effect of ECT in patients suffering from depression.
References:
McDonald, W. & Fochtmann, L. (2019) What is Electroconvulsive therapy (ECT)? [online] American Psychiatric Association. Available at: https://www.psychiatry.org/patients-families/ect [Accessed 23 Sep. 2020]
Swartz, C. (2014) A Mechanism of Seizure Induction by Electricity and its Clinical Implications. The Journal of ECT. 30 (2), 94-97. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24810777. Available from: doi: 10.1097/YCT.0000000000000139.
Tendolkar, I., van Beek, M., van Oostrom, I., Mulder, M., Janzing, J., Voshaar, R. O. & van Eijndhoven, P. (2013) Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: A longitudinal pilot study. Psychiatry Research. Neuroimaging. 214 (3), 197-203. Available from: https://www.clinicalkey.es/playcontent/1-s2.0-S0925492713002606. Available from: doi: 10.1016/j.pscychresns.2013.09.004.
Singh, A. & Kar, S. K. (2017) How Electroconvulsive Therapy Works?: Understanding the Neurobiological Mechanisms. Clinical Psychopharmacology and Neuroscience : The Official Scientific Journal of the Korean College of Neuropsychopharmacology. 15 (3), 210-221. Available from: https://search.datacite.org/works/10.9758/cpn.2017.15.3.210. Available from: doi: 10.9758/cpn.2017.15.3.210.
Semkovska, M. & McLoughlin, D. M. (2010) Objective Cognitive Performance Associated with Electroconvulsive Therapy for Depression: A Systematic Review and Meta-Analysis. Biological Psychiatry (1969). 68 (6), 568-577. Available from: https://search.datacite.org/works/10.1016/j.biopsych.2010.06.009. Available from: doi: 10.1016/j.biopsych.2010.06.009.
Imperial Bioscience Review 