Electroconvulsive Therapy

Between 1917 and 1937, four methods for producing physiological shock were discovered, tested, and used in psychiatric practice for treating psychosis: fever, insulin-induced coma, medication-induced convulsions, and electrically induced convulsions (electroconvulsive therapy). In the Western world, only electroconvulsive therapy remains as a standard and effective treatment for psychiatric conditions (APA, 1998). First, malaria-induced fever was used to treat neurosyphillitic paresis. Later, insulin-induced coma was used to treat schizophrenia. Also, von Meduna noticed a "biological antagonism" between epilepsy and schizophrenia. The theory postulated that individuals with epilepsy were not likely to develop schizophrenia. This concept was later disproved. To treat schizophrenia/psychosis, von Meduna experimented with different drugs until he was able to obtain reliable convulsions with intravenous injection of pentamethylenetetrazol (or METRAZOL, a circulatory and respiratory stimulant) (von Meduna, 1937; Fink, 1984b). The seizures ensued quickly and violently. They caused spine fractures in a great number of patients. Later Bennett combined METRAZOL with curare and scopolamine to paralyze and sedate the patients (Bennett, 1994). In 1937, Cerletti and Bini applied transcranial electroconvulsive shock therapy to induce seizures safely and reliably (Bini, 1995). It was received with great enthusiasm given the remarkable therapeutic effects (in patients who now would most likely be classified as psychotically depressed) and the technical ease of administration compared to insulin or METRAZOL shock. Since then, ECT became the method of choice for convulsive therapy.

Over 60 years of experience have significantly improved this technique with the use of muscle relaxants, anesthesia with short-acting agents following preoxygenation of the brain, use of electroencephalography (EEG) seizure monitoring, and studies on optimal electrical stimulation parameters. The death rate, due primarily to cardiac arrhythmia, decreased from 0.1 percent in the 1950 to less than 2 for 100,000 ECT treatments (Abrams, 1997; Shiwach et al., 2002). One of the primary concerns with ECT remains the cognitive side effects (Sackeim, 2002). Patients do experience a variable degree of postictal confusion and retrograde amnesia with the procedure. These have been linked to electrode placement, intensity and waveform of stimulus, frequency of treatments, and underlying medical conditions (Sackeim et al., 1993). Although cognitive impairment is generally confined to information learned in the weeks surrounding ECT treatment itself, cognitive impairment has sometimes been reported several months after treatment. The capacity to learn and retain new information may be affected over these several months. There is no objective evidence that ECT has any long-term effect on the autobiographical memory (Lisanby et al., 2002). Structural brain magnetic resonance imaging (MRI) studies before and after ECT have also failed to show abnormalities attributed to the treatments (Devanand et al., 1994), nor changes in the hippocampal N-acetylaspartate signals (an indirect measure of neuronal integrity) (Ende et al., 2002).

Unlike the other contemporary somatic interventions, the Food and Drug Administration (FDA) never approved ECT for clinical use since such regulations came into effect much later. The current indications, possible adverse effects, and recommendations for treatment procedures have been summarized in a task force report published by the American Psychiatric Association Committee on ECT (1990). ECT has a proven efficacy in a variety of neuropsychiatry conditions such as in depression (including psychotic depression), mania, schizophrenia and neuroleptic malignant syndrome.

The primary use for ECT is in treating depression when pharmacotherapy has failed or has not been tolerated. It has response rates reported in the range of 80 to 90 percent as a first-line treatment, and in the range of 50 to 60 percent for patients who have not responded to 1 or more trials of treatment with antidepressant drugs (Sackeim et al., 2002b). Right unilateral (UL) ECT has traditionally been thought to be less efficacious than bilateral (BL) ECT but with less cognitive side effects. In the last decade, however, high-intensity UL ECT [with 6 times (Sackeim et al., 2000) or 8 to 12 times (McCall et al., 2002) the initial seizure threshold] have proven to equal BL ECT with less cognitive side effects.

The FDA-approved devices in the United States are limited to 576 milliCoulombs (mC), which limits the clinical application of suprathreshold intensities. Higher intensities lead to higher rates of cognitive impairment. Researchers at Columbia University are investigating changing the electrical pulse being given with ECT. Namely, they are stimulating with ultrabrief waveforms, a closer pulse to brain physiology, which may help decrease cognitive side effects (Sackeim et al., 2002c).

Although an effective treatment for getting a person out of an acute depressive episode, Sackeim et al. (2002a) have demonstrated that most depressed subjects who respond to ECT will require some sort of maintenance therapy. Even with adequate pharmacotherapy, 39 percent of patients will relapse within 6 months. The use of intermittent ECT for continuation (C-ECT) or maintenance treatment may also be considered. Retrospective reports show noticeable functional and socioeconomic benefits with C-ECT. Prospective controlled studies are underway.

A limiting factor to clinical response with ECT, which now holds for most antide-pressant therapies (including TMS and VNS), is a history of treatment resistance or the number of prior treatment failures (Sackeim et al., 1992). Comorbid personality disorders are associated with a limited response as is outpatient ECT treatment.

In addition to depression, ECT has also been applied successfully in mania (Mil-stein et al., 1987) and schizophrenia (Tharyan et al., 2002). The concomitant use of neuroleptics has been found beneficial in some cases. Some are investigating whether ECT plays a neuroprotective role and leads to better prognosis if applied early in the course of illness, but this is currently unclear.

Electroconvulsive therapy has also been administered to treat psychiatric sequelae of a number of neurological disorders including depression secondary to a cerebral vascular accident, Parkinson disease, epilepsy and status epilepticus, multiple sclerosis, Huntington disease, tardive dyskinesia, and a few others (McDonald et al., 2002). Of these other disorders, the American Psychiatric Association has approved ECT only for Parkinson's disease and epilepsy although the clinical effects may not be long lived.

The ECT mechanisms of action have not been fully worked out (see Chapter 8). It was initially believed that a seizure with adequate quality and duration (a minimum of 25 sec) would reach into the diencephalic brain structures and stimulate the hypothalamic-pituitary-adrenal (HPA) axis (Abrams et al., 1976). This in turn would release neuropeptides such as adreno-cortico-trophic hormone (ACTH), thyrotropin releasing hormone (TRH), prolactin, vasopressin, and oxytocin (Nemeroff et al., 1991; Nakajima et al., 1989; Mathe et al., 1991). Contrary to this theory, parietal lead placement does not treat depression despite a surge in prolactin and oxytocin. Another old theory is that postictal delirium correlates with efficacy. This theory has also been abandoned.

It is now apparent that site of origination of the seizure is important in ECT treatment. Temporo-parietal lead placement, for example, does not treat depression (Bailine et al., 2001). Targeting a functional mood-regulating network (in the case of antidepressant effect) appears crucial to the efficacy of the procedure. Bilateral (BL) and right unilateral (UL) frontal placements are now the norm. More recently, informed by imaging work implicating the lateral and medial prefrontal cortex in mood regulation, researchers have applied the electrodes medially (approximately on the forehead above each eye) in a procedure labeled bifrontal ECT (BF). BF ECT has shown equal efficacy to BL ECT (both given at 1.5 times the seizure threshold), with BF having a slight cognitive/memory advantage as the electric current may spare the temporal lobes where the hippocampus is located (Bailine et al., 2002).

Some researchers have pointed out that the seizure itself is important in ECT's antidepressant effect (Krystal, 1998) since a failure to induce one is nontherapeutic. However, as will be developed below, data from TMS and VNS may argue against this principle. One working theory of the importance of seizures in ECT's antidepressant effect focuses on the dynamic interplay between the ictal and postictal phases. The placement of electrodes for inducing of a seizure, the ictal duration, intensity

(high-voltage spikes and waves), and coherence in ictal-EEG between right and left hemisphere are all important factors in ECT's efficacy (Fink et al., 1982; McCall et al., 1995). So are the stimulated compensatory mechanisms for stopping the seizure. A greater suppression of the postictal EEG has been shown to be a key factor. Fink and colleagues demonstrated a relationship between frontal delta activity and response to treatment (Fink, 1984a). Neuroimaging studies have also shed light on this dynamic interplay (Rosenberg et al., 1988; Nobler et al., 1999). Studies have shown an increase in cerebral blood flow (CBF) up to 300 percent of baseline values and in cerebral metabolic rate (CMR) up to 200 percent during the ictal period. In contrast, these measures decrease postictally (Nobler et al., 2001). In imaging studies, it has been found that the degree of prefrontal deactivation following ECT correlated with improvement. Even when imaged 2 months following ECT, the inverse correlation between frontal region low CBF and clinical improvement remains. This may appear counterintuitive as Nobler et al. (1999) showed that in a depressed untreated cohort, the CBF in anterior and deeper limbic regions is relatively lower than it is in healthy matched controls. This finding has now been replicated in many studies. The role of this shutdown effect in regulating mood remains to be determined.

Another theory by which ECT has been proposed to work is the anticonvulsant hypothesis (Post et al., 1986). It posits that enhanced transmission of inhibitory neurotransmitters [gamma-aminobutyric acid (GABA) and endogenous opioids] constitutes the essential elements of ECT's therapeutic effect in mood disorders. However, how the anticonvulsant properties of ECT relate to the mechanisms of action of antidepressant drugs is still unknown.

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