Troncales y multiplexión

Electroconvulsive therapy (ECT) has been available to patients for over seventy years and is frequently recognised as the most efficacious treatment for severe depression (The UK ECT Review Group, 2003). ECT has achieved remission rates of 75% to 80% in a variety of studies and meta-analyses (Petrides et al. 2001; The UK ECT Review Group, 2003; Husain et al. 2004). The UK ECT Review Group meta-analysis included studies where patients were administered the TCAs imipramine and amitriptyline, the MAOI phenelzine, the SSRI paroxetine, lithium, or a combination of these drugs. The effect of drug treatment and ECT on depression was measured by the Hamilton Depression Rating Scale (HDRS). Pharmacotherapy was found to be significantly less effective at reducing HDRS scores compared to ECT treatment. An average difference of 5.2 points on the HDRS was calculated (The UK ECT Review Group, 2003). ECT treatment effect was superior to sham ECT as well as placebo treatment (Kho et al. 2003; Pagnin et al. 2004).

1.2.3.1 History of ECT and clinical effectiveness

Seizure induction has been used for centuries to treat mental illness; during the 16th

century Paracelsus, a Swiss alchemist, chemically induced seizures to “cure lunacy” (Prudic, 2005). However, it was the scientific investigations initiated by Ladislaus von Meduna that led to the development of ECT. In 1934, Meduna induced epileptic seizures in an effort to compensate for the loss of glial cells seen in schizophrenic patients. He successfully induced seizures by administering camphor and later metrazol. Chemical convulsive therapy induced unpleasant sensations in conscious patients during the preictal stage of treatment. As a result, electrically induced seizures replaced chemical seizure induction in the treatment of mental disorders (Abrams, 1997a).

ECT has been used therapeutically since the 1930’s. Ugo Cerletti, with others, had studied the induction of epileptic seizures in dogs by electrical currents. Further work was conducted, under Cerletti’s direction in the Clinic for Mental and Nervous Diseases in Rome, which led to the development of a safe and reliable method for seizure induction in dogs and pigs. In 1938, the method was refined for use on human patients. The first patient was successfully treated that year and “electroshock” became a new therapy for the treatment of psychopathologies (Accornero, 1988). Shortly after, the use of ECT spread to the United States. By the 1950’s it was extensively used to treat a broad range of symptoms and had become a mainstay for the treatment of psychiatric disorders (Abrams, 1997a). The introduction of effective pharmacotherapy for depression during the early 1950s led to a decline in ECT use before a small resurgence in popularity in the 1980’s

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(Thompson et al. 1994). Abrams estimated that between 1 and 2 million patients worldwide receives ECT each year (Abrams, 1997a). Approximately 100,000 patients receive ECT in the U.S. annually (National Institute of Mental Health, 2008).

It is not yet understood how controlled seizure induction normalise a dysfunctional brain when spontaneous seizures are damaging and even dangerous to the brain and person (Fink, 2009). The mechanisms of ECT remain to be fully elucidated.

1.2.3.2 Side-effects of ECT

ECT is a medically safe and effective treatment for depression. It is mainly used to treat cases of severe depression, usually after multiple drug treatments have been administered but failed. It is recommended for treatment of cases of drug resistant depression (Task Force Report of the American Psychiatric Association, 2001). One reason why ECT is not administered earlier in the course of the illness is due to the range of side- effects associated with treatment. The side-effects range from physical to cognitive deficits and memory loss. Immediately after treatment, patients may experience disorientation, headache or backache. Nausea and vomiting, often a result of the anaesthetic wearing off, may also be experienced. However, these side-effects are short lived and easily treated (Fink, 2009).

Memory loss, whether short term or longer, is reported by patients to be one of the main reasons to seek other forms of treatment before agreeing to ECT as a form of therapy. Cognitive side-effects have been reported by patients since ECT was first introduced (Prudic et al. 2000). In reality, many of the cognitive side-effects of ECT are short-lived and do not have a significant long-term impact on patients. A meta-analysis of eighty-four studies, looking at twenty-four different cognitive variables found that cognitive deficits did not persist among the variables after fifteen days. For the first three days following ECT, there was evidence of significant cognitive impairment. Medium to large deficits were seen in executive functioning in this period. After fifteen days, most variables examined improved to, or beyond, baseline levels (Semkovska and McLoughlin, 2010). Depressed patients had lower performance scores in memory tests conducted before ECT than non-depressed controls. After ECT, the scores were again lower in depressed patients suggesting retrograde amnesia. However, at a three-month follow-up, depressed patient scores had returned to pre-treatment levels. Anterograde memory showed no significant deterioration following ECT. Overall, memory deficits induced by ECT were temporary (Meeter et al. 2011).

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Seizure induction is required for ECT to have an antidepressant effect. Treatments with lower, subconvulsive doses of electrical stimulation were not sufficient to induce an antidepressant response in patients (Ulett et al. 1956). In rodents, subconvulsive seizure induction did not induce sprouting of mossy fibres, the axons of dentate gyrus granule cells, while electroconvulsive stimulation (ECS) did (Lamont et al. 2001). However, a more recent study has manipulated a subconvulsive electrical stimulation protocol and may have reduced ECS-associated cognitive side-effects while still having an antidepressant effect (Gersner et al. 2009).

The mortality rate associated with ECT is low. Patients treated with ECT in a psychiatric hospital were less likely to die of natural causes than their fellow in-patients (Munk-Olsen et al. 2007). In Texas, there were two to ten deaths per 100,000 sessions of ECT over a five-year period (1993-1998). The mortality rate associated with anaesthesia use was two per 100,000, based on 48,852 sessions of ECT (Shiwach et al. 2001). In the U.S. death by lightning is six times more likely than by ECT (Abram, 1997b).

The public perception of ECT as a frightening and damaging treatment arises from its inaccurate representation in the media and a history of poor treatment practice (Payne and Prudic, 2009). Despite the side-effects associated with this treatment, ECT is an effective treatment for severe depression and may be the most suitable therapeutic option available for patients with treatment resistant depression.

1.2.3.3 Modifications to ECT to improve side effect profile

ECT has been refined in an effort to reduce the associated side-effects. Treatment parameters that have been modified include pulse waveform, electrode placement and stimulus pulse width.

ECT was traditionally delivered in sine-wave form (Figure 1-1(A)) which was replaced by brief pulse delivery (Figure 1-1 (B)) when it was determined that brief pulse ECT induced fewer side-effects (Weiner et al. 1986). Sine wave ECT delivered almost seven times the current (coulombs per second) of brief pulse ECT. Brief pulse ECT has a typical pulse width of 0.5ms – 1.5 ms while a sine wave had a phase period of 8.33ms (Sackeim et al. 2008). The excess inefficient energy of sine wave ECT may explain its poor side effect profile even compared to brief pulse ECT.

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Figure 1-1 Treatment parameters for ECT

(A) Sine wave bidirectional pulse form (B) Brief pulse and ultra brief pulse ECT. Brief pulses range from approximately 0.5ms-1.5ms in width; ultra brief pulses are normally up to 0.3ms wide. (C) Bilateral and unilateral electrode placement, from (Lisanby, 2007).

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Another modification to the ECT administration protocol is to deliver ECT unilaterally instead of bilaterally (Figure 1-1(C)). Bilateral ECT is administered via electrodes placed fronto-temporally on both sides of the head. Unilateral ECT is administered via electrodes placed on the non-dominant hemisphere. One electrode is placed temporally and one is placed ipsilateral to the vertex of the head on the same hemisphere (Fink, 2009). Unilateral ECT must be delivered at a higher intensity than bilateral ECT to be an effective antidepressant treatment (Sackeim et al. 2000; Kellner at al. 2010). Typically, unilateral ECT is delivered at 6 times seizure threshold while bilateral ECT is delivered at 1.5 times seizure threshold (Sienaert et al. 2009, 2010). Seizure threshold is determined by repeatedly administering incremental subconvulsive stimulation until the smallest electrical dose required to induce a tonic-clonic seizure of a minimum acceptable duration is obtained (Abrams, 1997a).

However, unilateral ECT does not appear to be as effective an antidepressant treatment as bilateral ECT (Sackeim et al. 1993; Rosa et al. 2006). Unilateral ECT may result in fewer cognitive side-effects than bilateral ECT. Deficits in memory for events and details, impersonal memories, are more apparent in bilateral than unilateral ECT (Lisanby et al. 2000). However, some authors report little difference in the memory deficits induced by unilateral or bilateral ECT (Kellner et al. 2010).

Few preclinical studies have been conducted to examine the effect of unilateral or bilateral ECS on the rodent brain, with a single study looking at the effects of electrode placement on dopamine release (McGarvey et al. 1993) in which bilateral ECS was found to induce greater dopamine release than unilateral ECS. No studies comparing the antidepressant efficacy of bilateral compared to unilateral ECS have been conducted to date.

Another mechanism to improve the side-effect profile of ECT is the suggestion that delivering the charge in ultra brief instead of brief pulse form may reduce the cognitive side-effects while maintaining therapeutic efficacy (Figure 1-1 (B)). An ultra brief pulse is typically no more than 0.3ms wide while brief pulse ECT is normally delivered in 0.5ms- 1.5ms wide pulses (Niemantsverdriet et al. 2011; Roepke et al. 2011). Ultra brief pulse ECT treatment produced less anterograde and retrograde amnesia. Ultra brief pulse unilateral ECT memory deficits were significantly less severe than those deficits induced by brief pulse and ultra brief pulse bilateral ECT (Sackeim et al. 2008). Ultra brief pulse unilateral ECT appeared to result in fewer cognitive side-effects especially in relation to retrograde autobiographical memory and visual and verbal information retention than did standard unilateral ECT (Loo et al. 2008).

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While some clinical studies have proposed that ultra brief pulse ECT is as efficient as brief pulse ECT (Sackeim et al. 2008; Niemantsverdriet et al. 2011) others suggest that this treatment results in a slower, less effective clinical response (Loo et al. 2008; McCormick et al. 2009).

The side-effects of ECT can be disturbing for patients and coupled with the stigma attached to the treatment may prevent its use in clinically appropriate situations. Investigating the parameters of ECT has lead to an improvement in the side-effect profile. However, further study is required to minimise the negative effects associated with this treatment while maintaining its therapeutic efficacy.