With ECT‚ the response rate for treatment-refractory patients is sobering‚ and the treatment is not without risks and adverse effects.
Electroconvulsive therapy (ECT) has been practiced since 1938 and is one of the best-studied treatment modalities. Because of its long history‚ it has been the comparator for a number of subsequent therapies‚ including pharmacological and other somatic interventions. Even with ECT‚ however‚ the response rate for treatment-refractory patients is sobering‚ and the treatment is not without risks and adverse effects.1 Still‚ it can be effective when other interventions have failed.
Treatment-refractory major depression is the primary indication for ECT‚ although ECT may have particular utility in psychotic depression‚ catatonia‚ and suicidality as well.2 The American Psychiatric Association (APA) guidelines also list an indication for schizophrenia.3
The Case Vignette illustrates a fairly typical case for ECT referral‚ and the patient is a reasonable candidate.
John‚ 55 years old‚ is referred for ECT evaluation. He has a long history of recurrent major depression (including in childhood)‚ with onset of the current episode 6 months earlier. He presents with depressed mood‚ anxiety‚ middle insomnia‚ social isolation‚ marked fatigue‚ significant anhedonia‚ and profound loss of interest and motivation. His concentration‚ attention‚ and short-term memory are also negatively affected. His appetite is normal and his weight is stable. He denies suicidal ideation and past suicide attempts but acknowledges thinking that his life is pointless. He denies psychotic or manic symptoms. He is having problems at work and there is significant marital discord at home.
John first sought treatment in his early 30s. He has taken a number of antidepressants of different classes‚ some of which worked partially‚ until they lost their effectiveness or he had unacceptable adverse effects. He desperately wants symptom relief‚ as soon as possible‚ but is very concerned about cognitive adverse effects of ECT.
To suppress the electrically induced tonic-clonic motor seizure activity‚ and thus minimize musculoskeletal complications‚ paralytic agents are administered. Because conscious paralysis would be very distressful‚ patients receive general anesthesia. ECT entails a series of treatments‚ typically 6 to 12‚ to achieve response or remission. Cognitive adverse effects are the major concern‚ especially for patients and their families.4‚5 Even with full remission‚ relapse rates remain high‚ particularly for the nonpsychotic medication–resistant population.1 Generally‚ once symptom remission is achieved‚ ECT is frequently discontinued. However‚ some patients get continuation (to prevent relapse) or maintenance (recurrence prophylaxis) ECT.3‚6‚7
When to refer
The decision to pursue ECT is based on a number of factors‚ including “ diagnosis‚ type and severity of symptoms‚ treatment history‚ consideration of the anticipated risks and benefits of ECT and alternative treatment options‚ and patient preference.”3 The principal diagnostic indication is unipolar or bipolar depression. “ Policies and procedures should be developed to ensure proper informed consent‚ including when‚ how‚ and from whom consent is to be obtained and the nature and scope of information to be provided. . . . Informed consent should be obtained from the patient except when the patient lacks capacity to consent.”3
There is evidence to suggest that a significant number of patients referred for ECT have not had adequate medication trials.6‚8‚9 The response rate for patients who are not medication-resistant is higher‚ up to 90% in one multisite study (log-linear analysis x2 = 6.82‚ df = 1‚ P = .009)‚ with site differences in the rates of patients classified as medication-resistant‚ patient age‚ Hamilton depression scores‚ and total number of ECT sessions.
The global rating of reliability did not differ among patients who were classified as medication-resistant and having inadequate pharmacotherapy before ECT.8 The FDA efficacy review estimated the overall treatment effect to be 78%.10 For treatment-refractory patients‚ the ECT response rate may be about 50% to 60%.8‚9
Personality disorders comorbid with major depression are common‚ with poorer outcomes with psychotherapy or pharmacotherapy. Patients with these comorbid conditions are likely to be referred for ECT. One study examined 139 patients with a primary diagnosis of unipolar major depression and scores of at least 20 on the 24-item Hamilton Depression Rating Scale; personality disorders were assessed with a structured interview. Outcomes were compared in patients with no personality disorder‚ patients with borderline personality disorder‚ and patients with personality disorders other than borderline personality disorder. Only 22% of patients with borderline personality disorder met criteria for remission‚ compared with 56% of patients with personality disorders other than borderline personality disorder and 70% of patients with no personality disorder.
Findings from the study indicate that the diagnosis of borderline personality disorder is a predictor of poor response to ECT (x2 = 11.63‚ df = 1‚ P = .001) and has potentially significant implications for the selection of candidates for ECT.11 Still‚ the APA guidelines do not suggest a prohibition of ECT in patients with comorbid borderline personality disorder. There is a similar stance for patients with comorbid dysthymia‚ because ECT is rarely used for dysthymia alone.3
ECT can be rapidly effective in mania and catatonia‚ and it can be an early consideration for depressions with psychotic features. Although antipsychotics continue to be the first-line intervention‚ ECT can be considered in patients with medication-resistant schizophrenia. However‚ the probability of significant improvement may be low. There are special considerations for children and adolescents (additional evaluation from a child and adolescent psychiatrist is recommended) and for pregnant women (procedural considerations and additional monitoring are needed).3
Unfortunately‚ some practitioners see ECT as a treatment of last resort‚ whatever the presenting diagnosis. This kind of thinking on the part of referring psychiatrists and patients is discouraged. There are relative contraindications for ECT‚ but few absolute ones. Many patients present with comorbid psychiatric disorders for which ECT is not indicated. There are comorbid medical conditions that also affect the risk to benefit ratio.
Electrically induced seizures can be associated with transient cardiovascular changes (asytole‚ bradycardia‚ tachycardia‚ hypertension‚ increased myocardial oxygen demand)‚ increased intracranial pressure‚ increased intraocular pressure‚ release of catecholamines‚ and other effects that can exacerbate preexisting conditions. These conditions require optimization of their management and/or procedural changes to minimize morbidity and mortality.
Precautions must be taken in patients with unstable or severe cardiovascular conditions (eg‚ recent myocardial infarction‚ unstable angina‚ congestive heart failure‚ uncontrolled hypertension)‚ aneurysm‚ increased intracranial pressure‚ recent cerebral infarction‚ or pulmonary conditions (eg‚ chronic obstructive pulmonary disease‚ asthma‚ pneumonia)‚ and in patients who fall into the American Society of Anesthesiologists rating level 4 or 5.3
The mortality rate has fallen over the decades of ECT practice.12 The number of deaths resulting from ECT is estimated to be 1 per 10‚000 patients‚ or 1 per 80‚000 treatments.3 The Veterans Affairs (VA) National Center for Patient Safety database estimate is less than 1 death per 73‚400 treatments (or less than 1 per 14‚000 patients). No associated deaths were reported in any VA hospital between 1999 and 2010.13 In California from 1984 to 1994 and in Texas from 1993 to 1998‚ there were less than 2 deaths per 100‚000 treatments.14‚15
The mainstays for the reduction of adverse effects include electrode placement‚ stimulus energy‚ waveform‚ and frequency of treatment (Figure 1).16
The two best-studied placements are right unilateral (RUL) and bilateral (BL‚ also known as bitemporal and bifrontotemporal) placements. RUL ECT has fewer cognitive adverse effects than BL ECT; however‚ unless it is administered well above seizure threshold‚ RUL ECT is less effective (double-blind randomized trial‚ P = .054).17 Suprathreshold RUL ECT can approach the efficacy of BL ECT. In one study‚ the response rates of both were 65%.9 In another study‚ in which patients were randomized to titrated moderate suprathreshold or fixed high-dose RUL ECT‚ the response rates were 39% and 67%‚ respectively (x2 = 5.6‚ P = .02).18
ECT practitioners must often choose between maximizing effectiveness and minimizing adverse effects. This prompts some practitioners to use BL placement‚ frequently at high stimulus energy‚ almost exclusively. Others start with RUL and switch to BL placement if there is a lack of response‚ generally after 4 to 6 treatments.19 The APA guidelines suggest reassessing the indication for continued ECT and making a change in implementation after 6 to 10 treatments if the patient has slow or minimal clinical improvement. These changes could include switching electrode placement from RUL to BL‚ increasing stimulus energy‚ and augmentation strategies.3
Semkovska and colleagues20 performed a meta-analysis (with an effort to control for publication bias) of 39 studies (1415 patients) to clarify the advantages of RUL relative to BL‚ stimulus intensity‚ and time interval between final assessment and cognitive assessment. They found that cognitive differences associated with electrode placement and stimulus intensity were limited to the first 3 days after unilateral treatment: effect sizes ranged from –1.10 to –0.21 (95% confidence interval [CI]‚ –1.53 to –0.67‚ –0.40 to 0.01‚ respectively).
Within this time frame‚ there were fewer cognitive disturbances compared with BL placement and more compared with higher stimulus intensity. After this subacute period‚ there were no significant differences between RUL and BL and no remaining significant relationship between stimulus intensity and cognitive performance after RUL ECT. The time interval after final treatment was predictive of continuous improvement in anterograde episodic memory‚ autobiographical memory‚ and executive functioning.
Left unilateral ECT is considered an alternative when RUL is contraindicated‚ typically when there is a skull defect. It is also a consideration for left-handed patients‚ in an effort to avoid stimulation of language centers. However‚ the lateralization of language centers for an estimated 70% of this group of patients is similar to that for right-handed patients; 15% have bilateral representation; and only 15% are right dominant for language. Handedness may also be an unreliable predictor. While most practitioners use RUL placement regardless of handedness‚ an alternative strategy is to switch laterality over the initial sessions to gauge which is associated with fewer cognitive adverse effects.3‚21
Bifrontal ECT has been investigated as a way to maximize response without increasing cognitive adverse effects (by avoiding stimulation over the temporal region) and directing treatment toward circuits in the frontal cortex that may play an important role in depression.22 As described by Abrams‚23‚24 bifrontal placement was initially sidelined because benefits were intermediate; the electrodes were too close together and there were skin burns secondary to shunting. Interest was renewed in the 1990s with a number of published clinical trials and apparent widespread use.21
One study showed bifrontal ECT had the best antidepressant (P < .01) and cognitive (P < .05) outcomes and required the fewest treatments‚ compared with BL and RUL ECT. However‚ the differential cognitive effects were not evident 3 months after the last ECT.25‚26
Bailine and colleagues27 randomized 48 patients to either BL or bifrontal ECT (stimulus titration at first treatment‚ subsequent treatments 1.5 times seizure threshold). All 24 patients in the bifrontal group and 23 of the 24 patients in the BL group met remission criteria (Hamilton Depression scale less than 10‚ first Hamilton Depression scale less than 3‚ or Clinical Global Impression improvement score less than 3) by the 12th treatment. The BL group had a significant decrease in the mini-mental state score that was considered to be clinically significant‚ albeit small (P = .03).
The researchers attributed efficacy and improved cognitive performance to avoidance of stimulation over the temporal areas while retaining bilateral stimulation. They also speculated that bifrontal placement may have the advantage of fewer dental complications‚ since the masseter muscles may receive less direct stimulation.
In a double-blind controlled trial‚ Eschweiler and colleagues28 randomized 92 patients to either 6 RUL (2.5 times seizure threshold) or 6 BL (1.5 times seizure threshold) sessions. While there was no difference in the response rate and only a minor cognitive difference between the two groups‚ only 12 of the 46 patients (26%) in each group responded (odds ratio tested by Fisher’s exact test and used to calculate 95% CI; CI‚ 18-36; odds ratio‚ 0.35 to 2.8). The reasons for this low response rate were unclear‚ although this may have been a function of selection bias of a particularly treatment-resistant population late in the course of their illness.
Kellner and colleagues29 report the results of a large‚ double-blind‚ controlled trial of 230 patients who were randomized to bifrontal placement at 1.5 times seizure threshold‚ BL at 1.5 times seizure threshold‚ or RUL at 6 times seizure threshold. Antidepressant outcomes were comparable‚ with remission rates of 55% for RUL (95% CI‚ 43-66)‚ 61% for bifrontal (95% CI‚ 50-71)‚ and 64% for BL (95% CI‚ 53-75). BL placement resulted in a faster reduction of symptoms‚ but there were few cognitive differences among the 3 treatment arms. The researchers note that BL placement could be used preferentially in urgent clinical situations. RUL placement can be effective at high stimulus intensity and could be the initial choice if there is concern about retrograde amnesia. Bifrontal placement did not have a cognitive advantage‚ nor was RUL consistently better than BL placement on cognitive measures.
One potential advantage of bifrontal ECT is a lower risk of bradycardia and asystole compared with BL and standard pulse width RUL ECT. Bifrontal ECT could be considered for patients with arrhythmia. Ultrabrief pulse width RUL ECT is associated with less bradycardia (P = .004) and asystole (P = .001) than standard pulse width RUL ECT‚ although the data were collected in the context of clinical service‚ via printed ECGs‚ and were not systematically controlled.30
Left anterior‚ right temporal (LART‚ or left frontal‚ right temporal) placement seeks to decrease cognitive adverse effects by minimizing the impact on the temporal/hippocampal areas. This placement is less well studied‚ although in small open and double-blind pilot trials‚ LART had comparable efficacy and fewer cognitive adverse effects.31-33 It is not known how widely this modality is used. Some practitioners use it as an intermediate step between RUL and BL ECT.
It is well established that the stimulus energy must be above seizure threshold (suprathreshold) to maximize treatment efficacy. Seizure threshold-the minimum amount of energy to elicit a generalized seizure-is highly variable‚ up to 40-fold in some estimates. Men‚ the elderly‚ and BL placement tend to have a higher seizure threshold. Seizure threshold is also inconstant because ECT has an anticonvulsant effect that raises seizure threshold (paired t‚ P < .001).34 Treatment protocols vary from titration procedures to fixed-dose strategies because there are different schools of thought about how much above seizure threshold a stimulus should be.
Some practitioners‚ during the first treatment session‚ determine seizure threshold by delivering increasingly larger stimuli until a generalized seizure of adequate length (at least 15 seconds as measured by motor activity or electroencephalogram) is obtained. There are a number of methodologies by which this stimulus titration is done. Electrode placement‚ sex‚ age‚ dosages of anesthetics‚ and concomitant medications can be used to predict seizure threshold.3 However‚ seizure threshold typically increases over the series. Proxies such as seizure length‚ seizure quality‚ and clinical response are signs that stimulation is no longer suprathreshold and stimulus intensity should be increased.
Seizure threshold increases with age; thus‚ a method that sets the stimulus energy based on the patient’s age can be used.35 Because this might cause patients to be stimulated at higher intensity than necessary‚ some practitioners use the “ half age” method.28 The APA guidelines recommend that unilateral treatments be moderately to markedly suprathreshold (2.5 to 6 times seizure threshold) and that BL treatments be moderately suprathreshold (1.5 to 2.5 times seizure threshold) because the efficacy of BL placement is less sensitive to suprathreshold dosing than is unilateral placement.3
There have been calls for higher-output machines in the United States to achieve the dosages required for effective unilateral ECT.36 However‚ whatever the placement‚ higher-energy stimulation is associated with increased cognitive adverse effects. Manipulation of pulse width may allow for more efficiency in inducing seizures‚ with fewer cognitive adverse effects.
The first ECT apparatus used sine waves‚ which were inefficient in inducing seizures and were associated with significant cognitive adverse effects.5‚37 Brief pulse has fewer cognitive adverse effects‚ without a reduction in efficacy. As a result‚ the APA guidelines state that the continued use of sine wave stimulation is not justified.3 However‚ the ideal pulse width continues to be studied.
The chronaxie‚ or optimal width for neuronal polarization‚ is estimated to be 0.1 to 0.2 millisecond.38‚39 Until recently‚ most devices had a pulse width range of 0.5 to 2 milliseconds. Ultrabrief pulse width of less than 0.5 millisecond had been considered earlier in ECT history but was not pursued because of concerns about efficacy. Now there is resurgent interest.
Using a double-masked study‚ Sackeim and colleagues40 sought to determine whether ultrabrief pulse and RUL placement would minimize cognitive adverse effects but not at the expense of efficacy. Patients were randomized to RUL ECT at 6 times seizure threshold or BL ECT at 2.5 times seizure threshold‚ using brief pulse (1.5 milliseconds) or ultrabrief pulse (0.3 millisecond). The remission rate was 73% for ultrabrief pulse RUL ECT‚ 65% for standard brief pulse BL ECT‚ 59% for standard brief pulse RUL ECT‚ and 35% for ultrabrief pulse BL ECT (all P < .05 after covariate adjustment). The ultrabrief pulse RUL group had less severe cognitive adverse effects (P < .001).
The researchers concluded that ultrabrief stimulus markedly reduces cognitive adverse effects (acute‚ short-term‚ and long-term)‚ and efficacy can be preserved with markedly suprathreshold RUL ECT-efficacy comparable to high-dose BL ECT. There was speculation that the efficacy of BL ECT may have been improved if stimulus intensity had been greater than 2.5 times the initial seizure threshold‚ although cognitive adverse effects may have also increased.
Niemantsverdriet and colleagues41 compared 0.25-millisecond ultrabrief pulse with 0.5-millisecond brief pulse in BL ECT. In their study‚ where response was defined as 50% or greater decrease in Hamilton depression score and remission as a score of less than 7‚ 73.6% of ultrabrief pulse recipients were responders (42.1% remitters) and 75.6% of brief pulse recipients were responders (45.6% remitters); no significant difference was found between the two groups (P = .947). The researchers attributed different outcomes to study design (retrospective vs prospective)‚ patient population (unipolar depression only vs both bipolar and unipolar depression‚ their sample perhaps more severely depressed)‚ prior history of ECT (their sample was ECT-naive)‚ and the differences in the comparator pulse widths (0.25 and 0.5 millisecond vs 0.3 and 1.5 milliseconds).
Sienaert and colleagues42 compared ultrabrief (0.3 millisecond) bifrontal ECT at 1.5 times seizure threshold with RUL ECT at 6 times seizure threshold. Of the 64 patients‚ 78% were responders (n = 50)‚ and 65% (n = 42) were remitters. There was no significant difference in response and remission between the two groups. Not only was there no deterioration in neuropsychological measures (attention‚ executive function/working memory‚ anterograde episodic memory‚ episodic autobiographical memory‚ and subjective memory)‚ but patients assessed their memory as improved and there were no significant differences between groups.
The authors caution that ultrabrief ECT may require more sessions (and therefore may produce more cognitive adverse effects)‚ that perceived memory improvement may be a function of improved depression‚ and that only 72.8% of their sample completed the post-ECT battery of neuropsychological tests.
Loo and colleagues43 compared ultrabrief pulse (0.3 millisecond) at 6 times seizure threshold with brief pulse (1.0 millisecond) at 5 times seizure threshold in RUL placement in a study limited by its naturalistic‚ nonrandomized design. The remission rate was lower than that found in the Sackeim40 study‚ but the difference was not significant. If those patients who completed treatment with RUL ECT only (not switched to BL placement) are considered‚ the response/remission rates were 97%/61% for the ultrabrief pulse RUL group and 79%/57% for the brief pulse RUL group.
Patients who received ultrabrief pulse width did require more ECT treatments. However‚ their cognitive measures were superior‚ especially on retention (P < .05) and autobiographical memory (P < .01).
Quante and colleagues44 compared 3 stimulus intensities (4‚ 7‚ and 10 times seizure threshold) of ultrabrief pulse width (0.3 millisecond) in RUL ECT in a randomized‚ double-blind‚ pilot study limited by its small number of subjects and lack of acute reorientation data. There was no significant difference in the response rate: all 3 groups had a significant response to 9 treatments (P < .005)‚ although the higher stimulus intensity groups had significant impairment in verbal memory (x2 = 6398‚ df = 2‚ P = .041).
There is evidence to suggest that patients who respond to ultrabrief RUL ECT are not clinically different from other ECT responders.45 Ultrabrief pulse may be a way to increase the effectiveness of RUL ECT by allowing for suprathreshold stimulation without increasing cognitive adverse effects. It may also allow for lower stimulus intensity in BL ECT‚ which would decrease cognitive adverse effects while maintaining efficacy.
Frequency of treatments
Cognitive adverse effects tend to accumulate as a function of the frequency and total number of treatments. Index ECT is done acutely for symptom reduction‚ with the goal of response or remission. In the United States‚ index ECT is typically done 3 times a week‚ usually for 6 to 12 treatments. Some patients have dramatic response to the first treatment and significant improvement after a few treatments‚ while others require more than 12 treatments to achieve maximum response. Index treatments can be done on an inpatient or outpatient basis.
In the United Kingdom and other countries‚ ECT is done twice a week. Lerer and colleagues46 found that twice-weekly ECT was just as effective‚ with fewer cognitive adverse effects (P = .05)‚ although the total number of treatments was higher.
Charlson and associates47 performed a comprehensive review and meta-analysis of the existing literature to examine the efficacy of 2- and 3-times-a-week treatment schedules. Their findings showed similar efficacy between the two schedules. With the twice-a-week regimen‚ the duration of each treatment was longer but the number of actual treatments was lower. Data were insufficient for a pooled analysis of cognitive data‚ but findings suggest that twice-weekly ECT was associated with fewer cognitive adverse effects.
Continuation ECT is done weekly to monthly as prophylaxis against relapse‚ which can occur as quickly as 1 week after the last index treatment. In a multisite‚ randomized‚ parallel‚ 6-month trial‚ Kellner and colleagues6 compared continuation ECT with pharmacotherapy in patients who achieved remission after ECT. In the continuation ECT group‚ 37.1% of the patients relapsed and 46.1% of the patients maintained symptom remission. In the continuation pharmacotherapy group (nortriptyline plus lithium-a combination shown to be effective in relapse prevention after successful ECT1)‚ 31.6% of the patients relapsed and 46.3% of the patients maintained symptom remission. They were statistically equivalent.
In addition‚ more than half of the patients relapsed or dropped out of the study. Better initial interventions and strategies to prevent relapse are needed. Maintenance ECT can be used long-term to prevent new episodes‚ much as one would continue effective pharmacotherapy.
COGNITIVE ADVERSE EFFECTS
As a procedure administered under general anesthesia and secondary to cognitive adverse effects‚ written informed consent is the standard of care for ECT. A prominent safety concern about ECT is its cognitive adverse effects‚ which can include acute/short-term as well as long-term cognitive adverse effects.10‚16 According to an FDA review‚10 patients can experience postictal confusion that typically quickly resolves‚ and there has been no evidence of persistent disorientation. Anterograde memory disturbances typically resolve within 2 weeks. Global cognitive functioning is unchanged or improved within 3 to 6 months compared with baseline-the latter perhaps a function of improved depression.
Retrograde amnesia‚ both autobiographical and impersonal‚ is a particular concern. The ability to retrieve historical or factual information seems to return to baseline within 6 months‚ but evidence is inconclusive about personal memory. Autobiographical memory is harder to measure and verify and can be influenced by depression and comorbid preexisting cognitive disorders. The reports of loss of autobiographical information are sobering.10‚16 It is a potential adverse effect that patients and their families seem to fear most.
Retrograde amnesia with ECT appears to be more problematic than anterograde amnesia. ECT produces deficits in both autobiographical and impersonal memory‚ but both improve after an ECT course. However‚ some patients are left with residual deficits. Retrograde amnesia is worse with BL ECT and sine wave stimuli; the extent of retrograde deficits does not significantly correlate with clinical improvement; and measurement is complicated by self-report‚ which correlates better with therapeutic outcome than more objective measures.48
A seminal study by Lisanby and associates4 attempted to tease apart the differential effects on autobiographical and impersonal memory. For the cognitive assessments‚ patients with major depression were randomized to RUL or BL ECT (each at either low or high stimulus energy). The researchers created the Personal and Impersonal Memory Test (PIMT) to elicit memories of events 4 years before assessment and to rate each personal event for its salience. The PIMT was administered to affected individuals and controls at baseline‚ during the week after ECT‚ and at 2-month follow-up.
The authors noted that it had been thought that ECT had its most negative impact on autobiographical memory. In contrast‚ they found that deficits were greatest and most persistent for impersonal memory (knowledge about the world and public events)‚ recent events compared with distant ones‚ and less salient events. As expected‚ BL ECT produced more profound deficits‚ especially for impersonal events (P < .001).
Sackeim and colleagues5 also found that BL ECT caused more severe and persisting retrograde amnesia 6 months after acute treatment.
OTHER ADVERSE EFFECTS
Common adverse effects can include headache (including precipitation of migraine headaches)‚ musculoskeletal discomfort (including jaw pain and exacerbation of temporomandibular joint problems)‚ and nausea. There is a risk of injury to teeth and tongue laceration if they are not adequately protected by a bite block. Cardiovascular adverse effects include bradycardia‚ tachycardia‚ and hypertension. Infrequent but serious complications include postictal agitation or emergence delirium‚ takotsubo cardiomyopathy (catecholamine release causes myocardial stunning and a reversible cardiomyopathy)‚ prolonged seizures‚ and status epilepticus.49 Rarer still is rupture of the bladder.50‚51
The choice of anesthetic agent (eg‚ methohexital‚ propofol‚ ketamine‚ etomidate‚ remifentanil) can have a differential impact on adverse effects such as nausea and cardiovascular events without necessarily reducing efficacy.52-55 The choice of anesthetic can also influence seizure threshold and seizure length‚ which becomes an issue when it is difficult to induce an adequate seizure in patients with high seizure thresholds. If stimulus energy can be lowered‚ cognitive adverse effects may be minimized.
The FDA review10 estimated an ECT response rate of 78% but found its impact limited to the acute phase of less than 4 weeks. Efforts made to improve ECT outcomes include increasing seizure length with hyperventilation‚ intravenous caffeine‚ and switching anesthetic agents.56‚57 However‚ seizure length may not correlate with clinical outcome.
The choice of anesthetic agent may have differential effects on cognition. These effects may be a function of impact on seizure threshold‚ because lowering seizure threshold allows for less stimulus energy to induce a seizure‚ less energy to stay above seizure threshold‚ and perhaps fewer treatments as a result of this improved efficiency. Some patients get switched to BL placement‚ which is associated with more cognitive adverse effects‚ primarily because of an issue with seizure threshold and seizure length. This is an important consideration if high-dose (either titrated or fixed-dose) RUL ECT can approach the clinical efficacy of BL ECT.9‚18
Ketamine has garnered interest as an anesthetic agent‚ an antidepressant in its own right‚ and a cognitive enhancer with improved short-term memory after ECT.58 Although more research is needed‚ combining ECT with antidepressants may improve outcomes in some patients.
Sackeim and colleagues59 undertook a prospective‚ triple-masked‚ placebo-controlled study of patients who were randomized to nortriptyline‚ venlafaxine‚ or placebo during high-dose RUL or moderate-dose BL ECT. The patients who received concomitant nortriptyline and venlafaxine had improved remission rates without an increase in adverse effects (analysis of covariance [ANCOVA] on post-ECT Hamilton Depression scores‚ intent-to-treat F2308 = 3.44; P = .03 and completers F2242 = 2.88; P = .06; log-linear analyses on remission rates‚ intent-to-treat P = .04 and completers P = .02).
Nortriptyline improved remission rates by about 15% and had a slight cognitive advantage (except for measures of retrograde amnesia‚ all other measured cognitive adverse effects were reduced with nortriptyline). Venlafaxine also improved ECT outcomes‚ although less so than nortriptyline‚ with a range of no impact to modestly negative impact on cognition.
The combination of ECT and psychotherapy is also worthy of further investigation because patients frequently have comorbidities that are not amenable to ECT.60 The data for pharmacological attempts to reduce cognitive adverse effects are limited and inconsistent‚ although they are promising for the cholinesterase inhibitors.61 With the use of cholinesterase inhibitors‚ initial concerns about drug-drug interaction with succinylcholine that could prolong paralysis; precipitate bradycardia‚ cardiac arrhythmias‚ and asystole; or prolong seizures have not been widely reported.62 The study of neuroprotective agents in ECT is intricate because the mechanisms for ECT-mediated cognitive adverse effects are poorly understood; clinical trials are methodologically challenging; and a wide range of tools are needed to assess short- and long-term‚ subjective and objective‚ and anterograde and retrograde (autobiographical and impersonal) cognitive deficits.61
Manipulating stimulus intensity (by lowering seizure threshold)‚ electrode placement (avoiding temporal areas)‚ waveform (ultrabrief pulse width)‚ and frequency of ECT (consider twice a week if there are cognitive adverse effects) and adding concomitant antidepressants may allow improved response as well as decreased adverse effects. However‚ because ECT is frequently used because of past treatment failure‚ when conservative implementation fails‚ providers reasonably become more assertive in all of those parameters. This can increase cognitive adverse effects.
We know ECT is not always effective. The APA guidelines indicate that patients can be considered nonresponders after at least 10 treatments if optimization efforts are not successful.3 Until there are consistently better alternatives for severe depression‚ ECT remains a safe and effective intervention. In the interim‚ we will await the findings of the FDA on the classification of ECT devices. Practitioners should use ECT judiciously and take care to minimize adverse effects as much as possible (Figure 2).
The following are some suggestions for reducing adverse effects of ECT and improving patient outcomes:
• Patients and referring mental health professionals should be educated about the likelihood of response‚ remission‚ and adverse effects: ECT is not globally effective; medication-resistant patients can be resistant to ECT as well
• Prospective patients and their families should be well informed of potential adverse effects‚ including cognitive ones that can persist well beyond index treatment: written informed consent is the standard of care
• Care should be taken‚ after ECT has started‚ to ensure that patients understand changes in the regimen‚ because they may have already experienced adverse cognitive effects
• Cognitive batteries used in research protocols‚ while sensitive‚ are not easily generalized to clinical practice: user- (and resource-) friendly methods of ongoing cognitive assessment would be a boon to patients‚ families‚ and ECT practitioners
• If a patient has responded‚ relapse prevention should be assertive‚ regardless of the method that is chosen
[Editor's note: This article was originally published in the February 2012 issue of Psychiatric Times as a CME. Now expired as a CME activity, it is published here for educational purposes only]
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