ECT for treatment-resistant depression

Introduction

Electroconvulsive therapy (ECT) is the oldest biologic treatment in psychiatry still in use and continues to play a crucial role in the management of treatment-resistant depression (TRD). ECT has been shown to be significantly more effective than pharmacotherapy in the management of TRD, with many studies citing remission rates of 50%–60% compared to 10%–40% with further medication adjustments ( ; ; ). Rates of remission are even higher, nearing 80%–90%, in depression with certain features such as catatonia or psychosis ( ).

Beyond immediate symptom reduction, ECT has also been shown to reduce the rate of psychiatric hospitalizations, long-term risk of suicide, and all-cause mortality in the TRD population ( ; ; ). In addition, a study using a cost-effectiveness model projected that ECT decreases the time an individual experiences uncontrolled depression from 50% of life years to 33%–37% over a 4-year period. This study also found ECT to be a cost-effective option after two failed antidepressant trials, making it a reasonable strategy earlier in treatment resistance due to its excellent health-economic advantages ( ).

Despite the known benefits of ECT, the rate of utilization in the TRD population remains low. In a 2017 analysis, only 1.5% of psychiatric inpatients with a severe affective disorder received ECT while hospitalized ( ). In a review of a large insurance claims database of individuals with depression, fewer than 1% ever received ECT ( ). The reasons for the under use of ECT are likely multifactorial including stigma, concerns over adverse side effects, and lack of access. Despite often negative public opinion of ECT, studies have consistently demonstrated its safety and efficacy, even in special populations including children, pregnant women, and geriatric patients. Furthermore, the practice of ECT has evolved since its inception with several advances reducing side effect burden while maintaining efficacy.

ECT basics

ECT involves passing a carefully controlled electrical stimulus through the scalp to induce a generalized seizure. The stimulus is delivered by two electrodes creating an electrical current which causes rapid discharge of nerve impulses and subsequent seizure activity. Two common electrode placements are used. Right unilateral (RUL) involves one electrode placed at the vertex of the head and the other electrode on the right temple ( Fig. 19.1 ). Both electrodes are set on the temples for the bitemporal (BT) placement ( Fig. 19.2 ). RUL ECT is generally associated with less cognitive side effects, while BT ECT appears to have a faster speed of response ( ). The seizure is self-limited and usually lasts between 20 and 60 s. ECT is done under general anesthesia including the use of muscle relaxants such as succinylcholine that prevents any physical convulsion from occurring. Seizure duration and morphology is monitored by electroencephalography (EEG). An acute ECT course is typically 9–15 treatments occurring 2–3 times per week with significant variability depending on symptom response and underlying diagnoses. Response is typically not seen until treatments 6–8 but can also vary widely. Once a patient reaches remission or a response plateau, he or she may be transitioned to a taper or maintenance ECT if relapse risk is considered high for an individual.

History and development

In the early 1900s, there was increasing interest in the use of “physical therapies” for the treatment of neuropsychiatric illness after malarial fever was shown to successfully treat neurosyphilis ( ). This interest spread to psychiatric disease where physicians explored strategies to directly treat the brain rather than relying on psychotherapy only. This prompted the development of convulsive therapies by Dr. Ladislas von Meduna in 1934 in Budapest, Hungary. Dr. Meduna hypothesized that there was an “antagonism” between epilepsy and schizophrenia and therefore started to use convulsive therapy to treat psychosis ( ). He initially used camphor and then later pentylenetetrazole to chemically induce convulsions with noticeable reduction in psychotic symptoms ( ). As a result of his success, convulsive treatment units sprang up all over Europe and the United States ( ).

Chemically induced convulsive therapy was quickly taken over by ECT after Dr. Ugo Cerletti showed greater success and consistency inducing convulsions by applying electricity directly to the brain ( ). Since ECT showed good efficacy in reducing psychotic symptoms in schizophrenia patients, its use quickly spread to the treatment of other affective disorders including depression ( ). Due to positive results, ECT became the standard treatment for individuals hospitalized with depression by the 1950s ( ).

As ECT became more widely used, a number of important advances were made. “Modified ECT” was developed where general anesthetics and then muscle relaxants were used (initially curare in 1940 and then succinylcholine in 1952) to sedate patients and minimize complications of physical seizures ( ). Unilateral ECT use began in 1949 to reduce cognitive side effects since it avoids directly stimulating the dominant hemisphere in the majority of individuals therefore reducing the impact on verbal memory ( ). Brief pulse ECT use began shortly thereafter ( ). Brief pulse ECT is a pulsatile wave-form and is more efficient in stimulating neurons and inducing seizures than sinusoidal stimulation of older machines which is associated with more prominent memory side effects. Brief pulse devices are the standard of care in modern ECT practice.

Despite its efficacy and widespread use, ECT almost vanished from psychiatric practice in the 1960s. The rapid shift in reduced ECT use arose from a change in public opinion about the treatment due to the rise of the antipsychiatry movement ( ). Much of the public’s outrage regarding ECT came from the impact of Ken Kesey’s book “One Flew Over the Cuckoo’s Nest” which was published in 1962 and later turned into a widely popular film in 1975 ( ).

ECT use remained lower until the 1980s when a gradual resurgence began. One of the biggest turning points was the summary of the NIH Consensus Conference on Electroconvulsive Therapy published in JAMA in October of 1985 that noted, “Not a single controlled study has shown another form of treatment to be superior to ECT in the short-term management of severe depression.” Since then, ECT has been accepted in psychiatry as the gold standard for treatment of refractory mood disorders and its use throughout the United States has been slowly increasing ( ).

Mechanisms of action

The mechanisms of action of ECT are not fully understood and there is no unifying theory on how ECT exerts its powerful antidepressant effects. However, over the years a number of theories have been investigated. These have included ECT’s effects on monoamines, seizure threshold/anticonvulsant action, the neuroendocrine system, and molecular pathways associated with neurogenesis such as increased brain-derived neurotrophic factor (BDNF). Other recent functional and structural neuroimaging studies have also produced interesting findings.

The monoamine neurotransmitter system has long been a focus of neurobiology studies in ECT, and many studies have sought to discover changes in norepinephrine, serotonin, and dopamine metabolites in bodily fluids including cerebrospinal fluid, urine, or blood as a result of treatment ( ). As an example of this work, showed that the CSF monoamine metabolites of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were both significantly elevated following ECT.

During a course of ECT, it is well known that seizure thresholds often rise and seizure durations shorten. This led to the anticonvulsant theory of ECT and the search for biologic correlates such as changes in gamma-aminobutyric acid (GABA) in animal models and ictal and postictal EEG findings which appear to indicate brain inhibitory processes are in play ( ). Despite the prevalent anticonvulsant effects of ECT, there is no consistent data to suggest a clear association between clinical outcomes in depression and increases in seizure threshold ( ; ).

ECT induces an array of acute neuroendocrine effects including release of adrenocorticotropic hormone, prolactin, and cortisol. Hypothalamic-pituitary-adrenal (HPA) dysregulation became a primary focus as a possible marker for melancholic or psychotic depression. Past studies show that dexamethasone suppression test (DST) abnormalities are corrected with ECT, but are not strongly connected to depression improvement ( ; ).

Modern concepts in ECT mechanisms have also focused on neuroplasticity and neurogenesis. Brain-derived neurotrophic factor (BDNF), a widely distributed nervous system neurotrophic protein, has roles in neurotransmitter modulation, neural genesis, and neuronal plasticity. Animal and human ECT studies have been conducted for over 20 years investigating BDNF and its effects. In animal models, it has been shown that neurogenesis, synaptogenesis, and glial proliferation in the hippocampus occur with electroconvulsive seizures (ECS) ( ). In humans, a metaanalysis of nine ECT studies in depression found that BDNF serum levels were increased after ECT. These findings suggest that BDNF may be a potential biomarker of response in patients receiving ECT for depression.

Since it is not possible to readily examine the microscopic, molecular, or neuroplastic changes ECT has on the human brain, tools such as high-resolution magnetic resonance imaging (MRI) or functional MRI have helped bridge the knowledge gap by exploring possible structural and connectivity changes. In recent years, structural studies have focused on areas of the medial temporal lobe such as the hippocampus and amygdala which generally show volume increases with ECT. However, pooled data from the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) have not correlated these changes to positive ECT outcomes ( ). However, found that ECT response may be associated to structural changes in other areas in cortical, striatal, and lateral prefrontal areas also implicated in depression. Functional connectivity techniques and analyses are complex. In depression, there is a “hyperconnectivity” concept where mood networks exhibit increased resting state connectivity. This hyperconnectivity may be a biomarker for depression and may also be reduced with treatments. An early small study significantly showed such a reduction in frontal connectivity after ECT ( ). Other recent studies have examined hippocampal connectivity in ECT showing varied changes associated with ECT response ( ; ). Despite the complexities of ECT’s neurophysiologic effects, advancements continue to be made on many fronts to foster our understanding of how ECT may work, but from past and recent research, ECT appears to likely have a multitude of potential mechanisms.

Clinical studies

General Efficacy Profile : ECT is not only one of the oldest biologic treatment in psychiatry, but it is also the most effective treatment for severe mood disorders, treatment refractory schizophrenia, catatonia, and neuroleptic malignant syndrome (NMS). Due to the speed of response with ECT which is typically 2–4 weeks compared to 4–6 weeks at the earliest with medications, ECT is the treatment of choice when rapid improvement is needed due to life threatening psychiatric symptoms ( ). ECT has also been deemed a safe treatment as reflected by the recent Federal Drug Administration’s (FDA) reclassification ECT devices from Class III to the lower risk category Class II ( ).

Details of ECT’s effectiveness in treating unipolar and bipolar depression will be discussed at length below, but ECT has shown similar, if not higher, response rates, in treating mania, catatonia, and psychosis. ECT is an important treatment strategy listed in the national and international guidelines for the treatment of mania, especially in life threatening or treatment refractory cases ( ; ). ECT has similarly demonstrated effectiveness at rapidly reducing catatonic symptoms regardless of underlying etiology and is the treatment of choice in patients whose catatonia does not fully respond to benzodiazepines ( ; ; ). While ECT is less commonly used in the United States for schizophrenia and schizoaffective disorders, it has been shown to be effective at reducing psychotic symptoms that do not respond to antipsychotics ( ). Recent studies suggest synergistic, antipsychotic effects when ECT is combined with Clozaril, producing 50% response rates in patients who did not respond to clozapine alone ( ).

General Efficacy in Treatment-Resistant Depression: Clinical studies have consistently shown the efficacy of ECT in TRD. While few true recent randomized control trials exist due to excellent efficacy of ECT in older trials and the inherent ethical issues of administering general anesthesia with sham ECT, data from several large observational studies for the treatment of depression highlight extremely positive results. One such large study led by the Columbia University Consortium was published in 2001. The goal of the study was to examine relapse rates among ECT remitters maintained on different psychotropic medication regimens versus placebo following an acute treatment course. Two hundred and ninety participants with severe depression completed an acute bilateral or right unilateral ECT course. At the end of the treatment course, 55% of subjects had reached remission defined as a 60% reduction in Hamilton Depression (HAM-D) scale scores as well as a total HAM-D of less than or equal to 10 ( ).

Another large ECT study conducted by the Consortium for Research on ECT (CORE) assessed acute depression outcomes in a first phase followed by a second phase of continued medications vs continued ECT. During the first phase, the study included 253 participants with an HAMD score of ≥ 21. The participants received bitemporal ECT three times weekly with repeated HAMD ratings. By the end of the study, remission (defined by achieving HAMD scores less than or equal to 10 on 2 consecutive assessments) was achieved in 75% of the subjects. Of note, remission was achieved relatively early in the treatment course by 34% of subjects before their 6th treatment, and 65% reached remission at or before their 10th ECT ( ).

In recent decades, ECT studies have centered around determining the efficacy and side effect profiles of various electrode placements. Many studies comparing right unilateral (RUL) vs bitemporal (BT) generally show that RUL is associated with less anterograde and retrograde amnesia compared to BT placement ( ; ; ; ; ; ). However, in order to maintain similar efficacy to BT ECT, the electrical dose delivered for RUL ECT needs to be significantly above an individual’s seizure threshold. BT ECT is very effective at doses approximately two times above seizure threshold while RUL ECT is most effective at five to six times above seizure threshold. This was elucidated by comparing the efficacy of RUL ECT at three dosage levels above threshold (1.5 times threshold- low-dosage RUL , 2.5 times threshold- moderate-dosage RUL , and 6 times threshold- high dosage RUL ) versus BT ECT at 1.5 times threshold. Ultimately, high dose RUL and BT ECT were found to have similar remission rates (65%), but the remission rates for low and moderate dosage RUL ECT were only 30% and 35%, respectively. Of note, the study did find that BT ECT resulted in greater acute cognitive side effects than any dosage of unilateral ECT and that retrograde memory difficulties persisted even 2 months after ECT with BT ECT.

One of the other important ECT advancements has been modifications to stimulus parameters, specifically pulse width. The electrical stimulus delivered during an ECT treatment is composed of brief rectangular square-wave pulses which historically ranged from 0.5 to 2 ms in width. As the optimal pulse width to induce neuronal depolarization is estimated to be 0.1–0.2 ms, the use of narrower pulse widths was proposed as a more efficient way of inducing a seizure. Since less electricity is delivered to the neuron when depolarized, it was hypothesized that a smaller pulse width would cause less neuronal irritation and therefore fewer cognitive side effects ( ). There has now been a shift from brief pulse (0.5–2.0 ms) to ultrabrief pulse ECT (< 0.5 ms) especially with RUL ECT. While studies comparing the effectiveness of the two vary, ultrabrief pulse ECT has been shown to have fewer cognitive side effects in several domains ( ).

Direct comparison to other treatments