Chapter 2: 2.1. - Indications for Use of ECT

Convulsive therapy has been in continuous use for more than 60 years. The clinical literature establishing its efficacy in specific disorders is amongst the most substantial for any medical treatment (Weiner and Coffey 1988; Mukherjee et al. 1994; Krueger and Sackeim 1995; Sackeim et al. 1995; Abrams 1997a). Like other medical treatments, various sources of evidence support the efficacy of ECT in specific conditions. The indications for ECT have been defined by randomized controlled trials comparing ECT to sham interventions or treatment alternatives and similar trials comparing modifications of ECT technique. The indications for ECT have also been supported by reports of uncontrolled clinical series, case studies, and surveys of expert opinion.

The decision to recommend the use of ECT derives from a risk/benefit analysis for the specific patient. This analysis considers the diagnosis of the patient and the severity of the presenting illness, the patient's treatment history, the anticipated speed of action and efficacy of ECT, the medical risks and anticipated adverse side effects, and the likely speed of action, efficacy, and safety of alternative treatments.

2.2. Referral for ECT

2.2.1. Primary use. There is considerable variability among practitioners in the frequency with which ECT is used a first-line or primary treatment or is only considered for secondary use after patients have not responded to other interventions. ECT is a major treatment in psychiatry, with well defined indications. It should not be reserved for use only as a "last resort." Such practice may deprive patients of an effective treatment, delay response and prolong suffering, and may possibly contribute to treatment resistance. In major depression, the chronicity of the index episode is one of the few consistent predictors of clinical outcome with ECT or pharmacotherapy (Hobson 1953; Hamilton and White 1960; Kukopulos et al. 1977; Dunn and Quinlan 1978; Magni et al. 1988; Black et al. 1989b, 1993; Kindler et al. 1991; Prudic et al. 1996). Patients with longer duration of current illness have a reduced probability of responding to antidepressant treatments. The possibility has been raised that exposure to ineffective treatment or to a longer duration of episode actively contributes to treatment resistance (Fava and Davidson 1996; Flint and Rifat 1996).

The likely speed and efficacy of ECT are factors that influence its use as a primary intervention. Particularly in major depression and acute mania, substantial clinical improvement often occurs soon after the start of ECT. It is common for patients to manifest appreciable improvement after one or two treatments (Segman et al. 1995; Nobler et al. 1997). In addition, the time to achieve maximal response is often more rapid than that with psychotropic medications (Sackeim et al. 1995). Besides speed of action, the likelihood of obtaining significant clinical improvement is often more certain with ECT than with other treatment alternatives. Therefore, when a rapid or a higher probability of response is needed, as when patients are severely medically ill, or at risk to harm themselves or others, primary use of ECT should be considered.

Other considerations for the first-line use of ECT involve the patient's medical status, treatment history, and treatment preference. Due to the patient's medical status, in some situations, ECT may be safer than alternative treatments (Sackeim 1993, 1998; Weiner et al. in press). This circumstance most commonly arises among the infirm elderly and during pregnancy (see Sections 6.2 and 6.3). Positive response to ECT in the past, particularly in the context medication resistance or intolerance, leads to early consideration of ECT. At times, patients will prefer to receive ECT over alternative treatments, but commonly the opposite will be the case. Patient preferences should be discussed and given weight prior to making treatment recommendations.

Some practitioners also base a decision for primary use of ECT upon other factors, including the nature and severity of symptomatology. Severe major depression with psychotic features, manic delirium, or catatonia are conditions for which there is a clear consensus favoring early reliance on ECT (Weiner and Coffey 1988).

2.2.2. Secondary use. The most common use of ECT is in patients who have not responded to other treatments. During the course of pharmacotherapy, lack of clinical response, intolerance of side effects, deterioration in the psychiatric condition, the appearance of suicidality or inanition are reasons to consider the use of ECT.

The definition of medication resistance and its implications with respect to a referral for ECT have been the subject of considerable discussion (Quitkin et al. 1984; Kroessler 1985; Keller et al. 1986; Prudic et al. 1990; Sackeim et al. 1990a, 1990b; Rush and Thase 1995; Prudic et al. 1996). At present there are no accepted standards by which to define medication resistance. In practice, when assessing the adequacy of pharmacological treatment, psychiatrists rely upon factors such as the type of medication used, dosage, blood levels, duration of treatment, compliance with the medication regimen, adverse effects, nature and degree of therapeutic response, and type and severity of clinical symptomatology (Prudic et al. 1996). For example, patients with psychotic depression should not be viewed as pharmacological nonresponders unless a trial of an antipsychotic medication has been attempted in combination with an antidepressant medication (Spiker et al. 1985; Nelson et al. 1986; Chan et al. 1987). Regardless of diagnosis, patients who have not responded to psychotherapy alone should not be considered treatment resistant in the context of referral for ECT.

In general, failure of patients with major depression to respond to one or more antidepressant medications trials does not preclude a favorable response to ECT (Avery and Lubrano 1979; Paul et al. 1981; Magni et al. 1988; Prudic et al. 1996). Indeed, compared to other treatment alternatives, the probability of response to ECT among patients with medication-resistant depression may be favorable. This is not to say, however, that medication resistance does not predict clinical outcome of ECT. Patients who have not responded to one or more adequate antidepressant medication trials have a lower probability of responding to ECT compared to patients treated with ECT without having received an adequate medication trial during the index episode (Prudic et al. 1990, 1996; Shapira et al. 1996). In addition, medication-resistant patients may require particularly intensive ECT treatment to achieve symptomatic improvement. Consequently, the bulk of patients who fail to benefit from ECT are likely to also be patients who have received, and not benefited from, adequate pharmacotherapy. The relationship between medication resistance and ECT outcome may be stronger for tricyclic antidepressants (TCAs) than for selective serotonin reuptake inhibitors (SSRIs) (Prudic et al. 1996).

2.3. Major Diagnostic Indications

2.3.1. Efficacy in major depression. The efficacy of ECT in depressive mood disorders is documented by an impressive body of research, beginning with the open trials of the 1940s (Kalinowsky and Hoch 1946, 1961; Sargant and Slater 1954); the comparative ECT/pharmacotherapy trials of the 1960s (Greenblatt et al. 1964; Medical Research Council 1965); the comparisons of ECT and sham-ECT, both in the 1950s and in the more recent British studies (Freeman et al. 1978; Lambourn and Gill 1978; Johnstone et al. 1980; West 1981; Brandon et al. 1984; Gregory, et al. 1985; see Sackeim 1989 for a review); and the recent studies contrasting variations in ECT technique (Weiner et al. 1986a, 1986b; Sackeim et al. 1987a; Scott et al. 1992; Letemendia et al. 1991; Sackeim et al. 1993).

While ECT was first introduced as a treatment for schizophrenia, it was quickly found to be especially effective in patients with mood disorders, both in the treatment of depressive and manic states. In the 1940's and 1950's, ECT was a mainstay in the treatment of mood disorders, with response rates between 80-90% commonly reported (Kalinowsky and Hoch 1946; Sargant and Slater 1954). The results of these early, largely impressionistic studies have been summarized by the American Psychiatric Association (1978), Fink (1979), Kiloh et al. (1988), Mukherjee et al. (1994) and Abrams (1997a).

Post (1972) suggested that prior to the introduction of ECT, elderly patients with depression often manifested a chronic course or died of intercurrent medical illnesses in psychiatric institutions. A number of studies have contrasted the clinical outcome of depressed patients who received inadequate or no biological treatment to that of patients who received ECT. While none of this work used prospective, random assignment designs, the findings have been uniform. ECT resulted in decreased chronicity and morbidity, and decreased rates of mortality (Avery and Winokur 1976; Babigian and Guttmacher 1984; Wesner and Winokur 1989; Philibert et al. 1995). In much of this work, the advantages of ECT were particularly pronounced in elderly patients. For example, in a recent retrospective comparison of elderly depressed patients treated with ECT or pharmacotherapy, Philibert et al. (1995) found that at long-term follow-up rates of mortality and significant depressive symptomatology were higher in the pharmacotherapy group.

With the introduction of the TCAs and monoamine oxidase inhibitors (MAOIs), random assignment trials were conducted in depressed patients in which ECT was used as the "gold-standard" by which to establish the efficacy of the medications. Three of these studies involved random assignment and blind ratings, and each found a significant therapeutic advantage for ECT over TCAs and placebo (Greenblatt et al. 1964; Medical Research Council 1965; Gangadhar et al. 1982). Other studies also reported ECT to be as or more effective than TCA (Bruce et al. 1960; Kristiansen 1961; Norris and Clancy 1961: Robin and Harris 1962; Stanley and Fleming 1962; Fahy et al. 1963 ); Hutchinson and Smedberg 1963; Wilson et al. 1963; McDonald et al. 1966; Davidson et al. 1978) or MAOIs (King 1959; Kilo et al. 1960; Stanley and Fleming 1962): Hutchinson and Smedberg 1963; Davidson et al. 1978). Janicak et al. (1985), in a meta-analysis of this work, reported that the average response rate to ECT was 20% higher when compared to TCAs and 45% higher than MAOIs.

It should be noted that standards for adequate pharmacological treatment have changed over the decades (Quitkin 1985; Sackeim et al. 1990a), and that, by current criteria, few of these early comparative trials used aggressive pharmacotherapy in terms of dosage and/or duration (Rifkin 1988). In addition, these studies usually focused on depressed patients who were receiving their first biological treatment during the index episode. More recently, in a small study, Dinan and Barry (1989) randomized patients who did not respond to monotherapy with a TCA to treatment with ECT or the combination of a TCA and lithium carbonate. The ECT and the pharmacotherapy groups had equivalent efficacy, but the TCA/lithium, combination may have had an advantage in terms of speed of response.

No studies have compared the efficacy of ECT with newer antidepressant medications, including the SSRIs or medications such as bupropion, mirtazapine, nefazadone, or venlafaxine. However, no trial has ever found an antidepressant medication regimen to be more effective than ECT. Among patients who are receiving ECT as a first-line treatment, or who have received inadequate pharmacotherapy during the index episode due to intolerance, response rates continue to be reported in the range of 90% (Prudic et al. 1990, 1996). Among patients who have not responded to one or more adequate antidepressant trials, the response rate is still substantial, in the range of 50-60%.

The time to achieve full symptomatic improvement with antidepressant medications is typically estimated as 4 to 6 weeks (Quitkin et al. 1984, 1996). This delay until response may be longer in older patients (Salzman et al. 1995). In contrast, the average ECT course for major depression consists of 8-9 treatments (Sackeim et al. 1993; Prudic et al. 1996). Thus, when ECT is administered at a schedule of three treatments per week, full symptomatic improvement usually occurs more rapidly than with pharmacological treatment (Sackeim et al. 1995; Nobler et al. 1997).

ECT is a highly structured treatment, involving a complex, repeatedly administered procedure that is accompanied by high expectations of therapeutic success. Such conditions may augment placebo effects. Given this concern, a set of double-blind, random assignment trials were conducted in England during the late 1970's and 1980's that contrasted 'real' ECT with 'sham' ECT - the repeated administration of anesthesia alone. With one exception (Lambourn and Gill 1978), real ECT was found consistently to be more efficacious than sham treatment (Freeman et al. 1978; Johnstone et al. 1980; West 1981; Brandon et al. 1984; Gregory et al. 1985; see Sackeim 1989 for a review). The exceptional study (Lambourn and Gill 1978) used a form of real ECT, involving low stimulus intensity and right unilateral electrode placement, that is now known to be ineffective (Sackeim et al. 1987a, 1993). Overall, the real vs. sham ECT studies demonstrated that the passage of an electrical stimulus and/or the elicitation of a generalized seizure were necessary for ECT to exert antidepressant effects. Following the randomized acute treatment period, the patients who participated in these studies were free to receive other forms of acute or continuation treatment, including ECT. Consequently, information regarding the duration of symptomatic improvement with real versus sham treatment could not be obtained in this research.

Finally, there have been a host of studies in the treatment of major depression that have contrasted variations in ECT technique, manipulating factors such as stimulus waveform, electrode placement, and stimulus dosage. An important practical observation that emerged was that the efficacy of ECT is equivalent regardless of the use of sine wave or brief pulse stimulation, but that sine wave stimulation results in more severe cognitive impairments (Carney et. al. 1976; Weiner et al. 1986a; Scott et al. 1992). More critical in establishing the efficacy of ECT was the demonstration that the clinical outcome with ECT is dependent on electrode placement and the stimulus dosage (Sackeim et al. 1987a. 1993). These factors can dramatically impact on the efficacy of the treatment, with response rates varying from 17% to 70%. This work went beyond sham-controlled studies, since the forms of ECT that differed markedly in efficacy all involved electrical stimulation and the production of a generalized seizure. Thus, technical factors in ECT administration can strongly influence efficacy.

Prediction of response. ECT is an effective antidepressant in all subtypes of major depressive disorder. Nonetheless, there have been many attempts to determine whether particular subgroups of depressed patients or particular clinical features of depressive illness have prognostic value with respect to ECT's therapeutic effects.

In the 1950's and 1960's, a series of studies showed impressive power to predict clinical outcome in depressed patients on the basis of pre-ECT symptomatology and history (Hobson 1953; Hamilton and White 1960; Rose 1963; Carney et al. 1965; Mendels 1967; see Nobler & Sackeim 1996 and Abrams 1997a for reviews). This work is now largely of historical interest (Hamilton 1986). While the early research emphasized the importance of vegetative or melancholic features as prognostic of positive ECT outcome, recent studies restricted to patients with major depression suggest that subtyping as endogenous or melancholic has little predictive value (Abrams et al. 1973; Coryell and Zimmerman 1984; Zimmerman et al. 1985, 1986; Prudic et al. 1989; Abrams and Vedak 1991; Black et al. 1986; Sackeim and Rush 1996). It is likely that the early positive associations were due to the inclusion of patients with "neurotic depression" or dysthymia in the sampling. Similarly, the distinction between unipolar and bipolar depressive illness has generally been found to be unrelated to therapeutic outcome (Abrams and Taylor 1974; Perris and d'Elia 1966; Black et al. 1986, 1993; Zorumski et al. 1986; Aronson et al. 1988).

In recent research a few clinical features have been related to ECT therapeutic outcome. The majority of studies that have examined the distinction between psychotic and nonpsychotic depression found superior response rates among the psychotic subtype (Hobson 1953: Mendels 1965a, 1965b: Hamilton and White 1960; Mandel et al. 1977; Avery and Lubrano 1979: Clinical Research Centre 1984; Kroessler 1985; Lykouras et al. 1986; Pande et al. 1990; Buchan et al. 1992; see also Parker et al. 1992: Sobin et al. 1996). This is of particular note given the established inferior response rate in psychotic or delusional depression to monotherapy with an antidepressant or antipsychotic medication (Spiker et al. 1985; Chan et al. 1987; Parker et al. 1992). To be effective, a pharmacological trial in psychotic depression should involve combination treatment with an antidepressant and an antipsychotic medication (Nelson et al. 1986; Parker et al. 1992; Rothschild et al. 1993; Wolfersdorf et al. 1995). However, relatively few patients referred for ECT with psychotic depression are administered such combination treatment in sufficient dosage and duration to be considered adequate (Mulsant et al. 1997). Multiple factors may be contributory. Many patients cannot tolerate the dosage of antipsychotic medications generally viewed as necessary for an adequate medication trial in this subtype (Spiker et al. 1985 Nelson et al. 1986). Patients with psychotic depression commonly have severe symptomatology, and are at increased risk for suicide (Roose et al. 1983). The rapid onset and high probability of improvement with ECT makes this treatment of particular value for these patients.

Several studies have also noted that, as with pharmacological treatment, patients with long duration of current episode are less likely to respond to ECT (Hobson 195 Hamilton and White 1960; Kukopulos et al. 1977; Dunn and Quinlan 1978; Magni et al. 1988; Black et al. 1989b. 1993; Kindler et al. 1991; Prudic et al. 1996). As already discussed, the treatment history of patients may provide a useful predictor of ECT outcome, with patients who have failed one or more adequate medication trials showing a substantial, but diminished, rate of ECT response (Prudic et al. 1990, 1996). In the majority of relevant studies patient age has been associated with ECT outcome (Gold and Chiarello 1944; Roberts 1959a, 1959b; Greenblatt et al. 1962; Nystrom 1964; Mendels 1965a, 1965b; Folstein et al. 1973; Stromgren 1973; Coryell and Zimmerman 1984: Black et al. 1993). Older patients are more likely to show marked benefit compared to younger patients (see Sackeim 1993, 1998 for reviews). Gender, race and socioeconomic status do not predict ECT outcome.

The presence of catatonia or catatonic symptoms may be a particularly favorable prognostic sign. Catatonia occurs in patients with severe affective disorders (Abrams and Taylor 1976; Taylor and Abrams 1977), and is now recognized in the DSM-IV as a specifier of a major depressive or manic episode (APA 1994). Catatonia may also present as a consequence of some severe medical illnesses (Breakey and Kala 1977; O'Toole and Dyck 1977; Hafeiz 1987), as well as among patients with schizophrenia. The clinical literature suggests that regardless of diagnosis, ECT is effective in treating catatonic symptoms, including the more malignant form of "lethal catatonia" (Mann et al. 1986, 1990; Geretsegger and Rochawanski 1987; Rohland et al. 1993; Bush et al. 1996).

Major depression which occurs in individuals with preexisting psychiatric or medical disorders is termed "secondary depression." Uncontrolled studies suggest that patients with secondary depression respond less well to somatic treatments, including ECT, than those with primary depressions (Bibb and Guze 1972; Coryell et al. 1985; Zorumski et al. 1986; Black et al. 1988, 1993). Patients with major depression and a co-morbid personality disorder may have a reduced probability of ECT response (Zimmerman et al. 1986; Black et al. 1988). However, there is sufficient variability in outcome with ECT that each case of secondary depression must be considered on its own merits. For example, patients with post-stroke depression (Murray et al. 1986; House 1987; Allman and Hawton 1987; deQuardo and Tandon 1988, Gustafson et al. 1995) are believed to have a relatively good prognosis with ECT. Patients with major depression superimposed on a personality disorder (e.g. Borderline Personality Disorder) should not be denied ECT out of hand.

Dysthymia as the sole clinical diagnosis has been rarely treated with ECT. However, a history of dysthymia preceding a major depressive episode is common and does not appear to have predictive value with regard to ECT outcome. Indeed, recent evidence suggests that the degree of residual svmptomatology following ECT is equivalent in patients with major depression superimposed on a dysthymic baseline, i.e., "double depression", and in patients with major depression without a history of dysthymia (Prudic et al. 1993).

Patient features, such as psychosis, medication resistance, and episode duration, only have statistical associations with ECT outcome. This information may be considered in the overall risk/benefit analysis of ECT. For example, a patient with a nonpsychotic, chronic major depression, who has failed to respond to multiple robust medication trials may be less likely to respond to ECT than other patients. Nonetheless, the probability of response with alternative treatments may be still lower, and the use of ECT justified.

2.3.2. Mania. Mania is a syndrome that, when fully expressed, is potentially life-threatening due to exhaustion, excitement, and violence. The early case literature first suggested that ECT is rapidly effective in mania (Smith et al. 1943; Impastato and Almansi 1943; Kino and Thorpe 1946). A series of retrospective studies comprised either naturalistic case series or comparisons of outcome with ECT to that with lithium carbonate or chlorpromazine (McCabe 1976; McCabe and Norris 1977; Thomas and Reddy 1982; Black et al. 1986; Alexander et al. 1988), Stromgren 1988; Mukherjee and Debsikdar 1992). This literature supported the efficacy of ECT in acute mania, and suggested equivalent or superior antimanic properties relative to lithium and chlorpromazine (see Mukherjee et al. 1994 for a review). There have been three prospective comparative studies of clinical outcome of ECT in acute mania. One study primarily compared ECT with lithium treatment (Small et al. 1988), another study compared ECT with combined treatment with lithium and haloperidol (Mukherjee et al. 1988. 1994), and in patients receiving neuroleptic treatment, one study compared real and sham ECT (Sikdar et al. 1994). While each of the prospective studies had small samples, the findings supported the conclusion that ECT was efficacious in acute mania, and likely resulted in superior short-term outcome than the comparison pharmacological conditions. In a review of the English language literature, Mukherjee et al. (1994) reported that ECT was associated with remission or marked clinical improvement in 80% of 589 patients with acute mania.

However, since the availability of lithium and anticonvulsant and antipsychotic medications, ECT has generally been reserved for patients with acute mania who do not respond to adequate pharmacological treatment. There is evidence from the retrospective and prospective studies that a substantial number of medication-resistant patients with mania benefit from ECT (McCabe 1976; Black et al. 1986; Mukherjee et al. 1988). For example, one of the prospective studies required that patients had failed an adequate trial of lithium and/or an antipsychotic medication prior to randomization to ECT or intensive pharmacotherapy. Clinical outcome was superior with ECT compared to combined treatment with lithium and haloperidol (Mukherjee et al. 1989). Nonetheless, the evidence suggests that, as with major depression, medication resistance predicts poorer response to ECT in acute mania (Mukherjee et al. 1994). While the majority of medication-resistant patients with acute mania respond to ECT, the response rate is lower than among patients in whom ECT is used as a first-line treatment.

The rare syndrome of manic delirium represents a primary indication for the use of ECT, as it is rapidly effective with a high margin of safety (Constant 1972; Heshe and Roeder 1975; Kramp and Bolwig 1981). In addition, manic patients who cycle rapidly may be particularly unresponsive to medications, and ECT may represent an effective alternative treatment (Berman and Wolpert 1987; Mosolov and Moshchevitin 1990; Vanelle et al. 1994).

Other than medication resistance, there have been few attempts to examine clinical features predictive of ECT response in acute mania. One study suggested that symptoms of anger, irritability and suspiciousness were associated with poorer ECT outcome. Overall severity of mania and degree of depression (mixed state) at preECT baseline were not related to ECT response (Schnur et al. 1992). In this respect, there may be some overlap between the clinical features predictive of response to ECT and lithium in acute mania (Goodwin and Jamison 1990).

2.3.3. Schizophrenia. Convulsive therapy was introduced as a treatment for schizophrenia (Fink 1979). Early in its use, it became evident that efficacy of ECT was superior in mood disorders than in schizophrenia. The introduction of effective antipsychotic medications markedly reduced the utilization of ECT in patients with schizophrenia. However, ECT remains an important treatment modality, particularly for patients with schizophrenia who do not respond to pharmacological treatment (Fink and Sackeim 1996). In the United States, schizophrenia and related conditions (schizophreniform and schizoaffective disorders) constitute the second most common diagnostic indication for ECT (Thompson and Blaine 1987; Thompson et al. 1994).

The earliest reports on the efficacy of ECT in patients with schizophrenia largely comprised uncontrolled case series (Guttmann et al. 1939; Ross and Malzberg 1939; Zeifert 1941; Kalinowsky 1943; Kalinowsky and Worthing 1943; Danziger and Kindwall 1946; Kino and Thorpe 1946; Kennedy and Anchel 1948; Miller et al. 1953), historical comparisons (Ellison and Hamilton 1949; Gottlieb and Huston 1951; Currier et al. 1952; Bond 1954) and comparisons of ECT with milieu therapy or psychotherapy (Goldfarb and Kieve 1945; McKinnon 1948; Palmer et al. 1951; Wolff 1955; Rachlin et al. 1956). These early reports lacked operational criteria for diagnosis and it is likely that the samples included mood-disorder patients, given the overinclusiveness of the diagnosis of schizophrenia in that era (Kendell 1971; Pope and Lipinski, 1978). Often, patient samples and outcome criteria were poorly characterized. Nonetheless, the early reports were enthusiastic regarding the efficacy of ECT, noting that a large proportion of patients with schizophrenia, typically on the order of 75%, showed remission or marked improvement (see Salzman, 1980; Small, 1985; Krueger and Sackeim 1995 for reviews). In this early work, it was also noted that ECT was considerably less effective in schizophrenic patients with insidious onset and long duration of illness (Cheney and Drewry, 1938: Ross and Malzberg 1939; Zeifert 1941; Chafetz 1943; Kalinowsky 1943; Lowinger and Huddleson 1945; Danziger and Kindwall 1946; Shoor and Adams 1950; Herzberg 1954). It was also suggested that schizophrenic patients commonly required particularly long courses of ECT to achieve full benefit (Kalinowsky, 1943; Baker et al. 1960a).

Seven trials have used a 'real vs. sham ECT' design to examine efficacy in patients with schizophrenia (Miller et al. 1953; Ulett et al. 1954, 1956; Brill et al. 1957, 1959a, 1959b, 1959c; Heath et al. 1964; Taylor and Fleminger 1980; Brandon et al. 1985; Abraham and Kulhara 1987; see Krueger and Sackeim 1995 for a review). The studies prior to 1980 failed to demonstrate a therapeutic advantage of real ECT relative to sham treatment (Miller et al. 1953; Brill et al. 1959a, 1959b, 1959c; Health et al. 1964). In contrast, the three more recent studies all found a substantial advantage for real ECT in short-term therapeutic outcome (Taylor and Fleminger 1980; Brandon et al. 1985; Abraham and Kulhara 1987). The factors that likely account for this discrepancy are the chronicity of the patients studied and the use of concomitant antipsychotic medication (Krueger and Sackeim 1995). The early studies focused mainly on patients with a chronic, unremitting course, while patients with acute exacerbations were more common in recent studies. All of the recent studies involved use of antipsychotic medications in both the real ECT and sham groups. As discussed below, there is evidence that the combination of ECT and antipsychotic medication is more effective in schizophrenia than either treatment alone.

The utility of monotherapy with ECT or antipsychotic medication was compared in a variety of retrospective (DeWet 1957; Borowitz 1959; Ayres 1960; Rohde and Sargant 1961) and prospective (Baker et al. 1958, 1960b; Langsley et al. 1959; King 1960; Ray 1962; Childers 1964; May and Tuma 1965, May 1968; May et al. 1976,1981; Bagadia et al. 1970; Murrillo and Exner 1973a, 1973b; Exner and Murrillo 1973, 1977; Bagadia et al. 1983) studies of patients with schizophrenia. In general, short-term clinical outcome in schizophrenia with antipsychotic medication was found to be equivalent or superior to that of ECT, although there were exceptions.

(Murrillo and Exner 1973a). However, a consistent theme in this literature was the suggestion that patients with schizophrenia who had received ECT had superior long-term outcome compared with medication groups (Baker et al. 1958; Ayres 1960; May et al. 1976, 1981; Exner and Murrillo 1977). This research was conducted in an era when the importance of continuation and maintenance treatment was not appreciated and none of the studies controlled the treatment received following resolution of the schizophrenic episode. Nonetheless, the possibility that ECT may have long-term beneficial effects in schizophrenia merits attention.

A variety of prospective studies have compared the efficacy of combination treatment using ECT and antipsychotic medication with monotherapy with ECT or antipsychotic medication (Ray 1962; Childers 1964; Smith et al. 1967; Janakiramaiah et al. 1982; Small et al. 1982; Ungvari and Petho 1982; Abraham and Kulhara 1987; Das et al. 1991). Relatively few of these studies involved random assignment and blind outcome assessment. Nonetheless, in each of the three studies in which ECT alone was compared with ECT combined with an antipsychotic, medication there was evidence that the combination was more effective (Ray 1962; Childers 1964; Small et al. 1982). With the exception of Janakiramaiah et al (1982), all studies that compared the combination treatment with antipsychotic medication monotherapy found the combination treatment to be more effective (Ray 1962; Childers, 1964: Smith et al. 1967; Small et al. 1982: Ungvari and Petho 1982; Abraham and Kulhara 1987; Das et al. 1991). This pattern held despite the dosage of the antipsychotic medication often being lower when combined with ECT. The few findings on the persistence of benefit suggested that there was a reduced rate of relapse in patients who had received the combination of ECT and antipsychotic medication as acute phase treatment. A new study has also found that combination ECT and antipsychotic medication is more effective as a continuation therapy than either treatment alone in patients with medication-resistant schizophrenia who respond to the combination treatment in the acute phase (Chanpattana et al. in press). These results support the recommendation that in the treatment of patients with schizophrenia and possibly other psychotic conditions the combination of ECT and antipsychotic medication may be preferable to the use of ECT alone.

In current practice ECT is rarely used as a first-line treatment for patients with schizophrenia. Most commonly, ECT is considered in patients with schizophrenia only after unsuccessful treatment with antipsychotic medication. Thus, the key clinical issue concerns the efficacy of ECT in medication-resistant schizophrenic patients.

There has yet to be a prospective, blinded study in which patients with medication-resistant schizophrenia are randomized to continued treatment with antipsychotic medication or to ECT (either alone or in combination with antipsychotic medication). Information on this issue comes from naturalistic case series (Childers and Therrien 1961; Rahman 1968; Lewis 1982; Friedel 1986; Gujavarty et al, 1987; Konig and Glatter-Gotz 1990; Milstein et al. 1990; Sajatovi and Meltzer 1993; Chanpattana et al. in press). This work suggests that a substantial number of patients with medication-resistant schizophrenia benefit when treated with combination ECT and antipsychotic medication. The safe and effective use of ECT has been reported when it has been administered in combination with traditional antipsychotic medications (Friedel 1986; Gujavarty et al. 1987; Sajatovi and Meltzer 1993) or those with atypical properties, particularly clozapine (Masiar and Johns 1991; Klapheke 1991a. 1993; Landy 1991; Safferman and Munne 1992; Frankenburg et al. 1992; Cardwell and Nakai, 1995; Farah et al. 1995; Benatov et al. 1996). While some practitioners have been concerned that clozapine may increase the likelihood of prolonged or tardive seizures when combined with ECT (Bloch et al. 1996), such adverse events appear to be rare.

Prediction of response. Since the earliest research, the clinical feature most strongly associated with the therapeutic outcome of ECT in patients with schizophrenia has been the duration of illness. Patients with acute onset of symptoms (i.e., psychotic exacerbations) and shorter illness duration are more likely to benefit from ECT than patients with persistent, unremitting symptomatology (Cheney & Drewry 1938; Ross and Malzberg 1939; Zeifert 1941; Kalinowsky 1943; Lowinger and Huddelson 1945; Danziger and Kindwall 1946; Herzberg 1954; Landmark et al. 1987; Dodwell and Goldberg 1989). Less consistently, preoccupation with delusions and hallucinations (Landmark et al. 1987), fewer schizoid and paranoid premorbid personality traits (Wittman 1941; Dodwell and Goldberg 1989), and the presence of catatonic symptoms (Kalinowsky and Worthing 19431; Hamilton and Wall 1948; Ellison and Hamilton 1949; Wells, 1973; Pataki et al. 1992) have been linked to positive therapeutic effects. In general, the features that have been associated with the clinical outcome of ECT in patients with schizophrenia overlap substantially with features that predict outcome with pharmacotherapy (Leff and Wing 1971; World Health Organization 1979; Watt et al. 1983). While patients with unremitting, chronic schizophrenia are the least likely to respond, it has also been argued that such patients should not be denied a trial of ECT (Fink and Sackeim 1996). The probability of significant improvement with ECT may be low in such patients, but alternative therapeutic options may be even more limited, and a small minority of patients with chronic schizophrenia may show dramatic improvement following ECT.

ECT may also be considered in the treatment of patients with schizoaffective or schizophreniform disorder (Tsuang, et al. 1979; Pope et al. 1980; Ries et al. 1981; Black et al. 1987c). The presence of perplexity or confusion in patients with schizoaffective disorder may be predictive of positive clinical outcome (Perris 1974; Dempsy et al. 1975; Dodwell and Goldberg 1989). Many practitioners believe that the manifestation of affective symptoms in patients with schizophrenia is predictive of positive clinical outcome. However, the evidence supporting this view is inconsistent (Folstein et al. 1973; Wells 1973, Dodwell and Goldberg 1989).

2.4. Other Diagnostic Indications

ECT has been used successfully in some other conditions, although this utilization has been rare in recent years (American Psychiatric Association 1978, 1990, Thompson et al. 1994). Much of this usage has been reported as case material, and typically reflects the administration of ECT only after other treatment options have been exhausted or when the patient presents with life-threatening symptomatology. Because of the absence of controlled studies, which would, in any event, be difficult to carry out given the low utilization rates, any such referrals for ECT should be well substantiated in the clinical record. The use of psychiatric or medical consultation by individuals experienced in the management of the specific condition may be a useful component of the evaluation process.

2.4.1. Psychiatric disorders. Besides the major diagnostic indications discussed above, the evidence for the efficacy of ECT in the treatment of other psychiatric disorders is limited. As noted earlier, major diagnostic indications for ECT may coexist with other conditions, and practitioners should not be dissuaded by the presence of secondary diagnoses from recommending, ECT when it is otherwise indicated, e.g., a major depressive episode in a patient with a pre-existing anxiety disorder. However, there is no evidence of beneficial effects in patients with Axis II disorders or most other Axis I disorders who do not also have one of the major diagnostic indications for ECT. Although there are case reports of favorable outcome in some selective conditions, evidence for efficacy is limited. For example, some patients with medication-resistant obsessive compulsive disorder may show improvement with ECT (Gruber 1971; Dubois 1984; Mellman and Gorman 1984; Janike et al. 1987; Khanna et al. 1988; Maletzky et al. 1994). However, there have been no controlled studies in this disorder, and the longevity of the beneficial effect is uncertain.

2.4.2. Mental disorders due to medical conditions. Severe affective and psychotic conditions secondary to medical and neurological disorders, as well as certain types of deliria, may be responsive to ECT. The use of ECT in such conditions is rare and should be reserved for patients who are resistant or intolerant to more standard medical treatments, or who require an urgent response. Prior to ECT, attention should be given to the evaluation of the underlying etiology of the medical disorder. It is largely of historical interest that ECT has been reported to be of benefit in conditions such as alcoholic delirium (Dudley and Williams 1972; Kramp and Bolwig 1981), toxic delirium secondary to phencyclidine (PCP) (Rosen et al. 1984; Dinwiddie et al. 1988), and in mental syndromes due to enteric fevers (Breakey and Kala 1977; O'Toole and Dyck 1977; Hafeiz 1987), head injury (Kant et al. 1995), and other causes (Stromgren 1997). ECT has been effective in mental syndromes secondary to lupus erythematosus (Guze 1967; Allen and Pitts 1978; Douglas and Schwartz 1982; Mac and Pardo 1983). Catatonia may-be secondary to a variety of medical conditions and is usually responsive to ECT (Fricchione et al. 1990; Rummans and Bassingthwaighte 1991; Bush et al. 1996).

When evaluating potential secondary mental syndromes, it is important to recognize that cognitive impairment may be a manifestation of major depressive disorder. Indeed, many patients with major depression have cognitive deficits (Sackeim and Steif 1988). There is a subgroup of patients with severe cognitive impairment that resolves with treatment of the major depression. This condition has been termed "pseudodementia" (Caine, 1981). Occasionally, the cognitive impairment may be sufficiently severe to mask the presence of affective symptoms. When such patients have been treated with ECT, recovery has often been dramatic (Allen 1982; McAllister and Price 1982: Grunhaus et al. 1983: Burke et al. 1985: Bulbena and Berrios 1986; O'Shea et al. 1987; Fink 1989). It should be noted, however, that the presence of pre-existing neurological impairment or disorder increases the risks for ECT-induced delirium and for more severe and persistent amnestic effects (Figiel et al. 1990; Krystal and Coffey, 1997). Furthermore, among patients with major depression without known neurological disease, the extent of preECT cognitive impairment also appears to predict the severity of amnesia at follow-up. Thus, while patients with baseline impairment thought to be secondary to the depressive episode may show improved global cognitive function at follow-up, they may also be subject to greater retrograde amnesia (Sobin et al. 1995).

2.4.3. Medical disorders. The physiological effects associated with ECT may result in therapeutic benefit in certain medical disorders, independent of antidepressant, antimanic, and antipsychotic actions. Since effective alternative treatments are usually available for these medical disorders. ECT should be reserved for use on a secondary basis.

There is now considerable experience in the use of ECT in patient's with Parkinson's disease (see Rasmussen and Abrams 1991; Kellner et al. 1994 for reviews). Independent of effects on psychiatric symptoms, ECT commonly results in general improvement in motor function (Lebensohn and Jenkins 1975; Dysken et al. 1976; Ananth et al. 1979; Atre-Vaidya and Jampala 1988; Roth et al. 1988; Stem 1991; Jeanneau, 1993; Pridmore and Pollard 1996). Patients with the "on-off" phenomenon, in particular, may show considerable improvement (Balldin et al. 1980 198 1; Ward et al. 1980; Andersen et al. 1987). However, the beneficial effects of ECT on the motor symptoms of Parkinson's disease are highly variable in duration. Particularly in patients who are resistant or intolerant to standard pharmacotherapy, there is preliminary evidence that continuation or maintenance ECT may be helpful in prolonging the therapeutic effects (Pridmore and Pollard 1996).

Neuroleptic malignant syndrome (NMS) is a medical condition that has been repeatedly shown to improve following ECT (Pearlman 1986; Hermle and Oepen 1986; Pope et al. 1986-1 Kellam 1987; Addonizio and Susman 1987; Casey 1987; Hermesh et al. 1987; Weiner and Coffey 1987; Davis et al. 1991). ECT is usually considered in such patients after autonomic stability has been achieved, and should not be used without discontinuation of neuroleptic medications. Since the presentation of NMS restricts the pharmacological options for treatment of the psychiatric condition, ECT may have the advantage of being effective for both the manifestations of NMS and the psychiatric disorder.

ECT has marked anticonvulsant properties (Sackeim et al. 1983; Post et al. 1986) and its use as an anticonvulsant in patients with seizure disorders has been reported since the 1940s (Kalinowsky and Kennedy 1943; Caplan 1945, 1946; Sackeim et al. 1983; Schnur et al. 1989). ECT may be of value in patients with intractable epilepsy or status epilepticus unresponsive to pharmacological treatment (Dubovsky 1986; Hsiao et al. 1987; Griesener et al. 1997; Krystal and Coffey 1997).

RECOMMENDATIONS

2.1. General Statement

Referrals for ECT are based upon a combination of factors, including, the patient's diagnosis, type and severity of symptoms, treatment history, consideration of the anticipated risks and benefits of ECT and alternative treatment options, and patient preference. There are no diagnoses which should automatically lead to treatment with ECT. In most cases ECT is used following treatment failure on psychotropic medications (see Section 2.2.2), although specific criteria exist for the use of ECT as a first-line treatment (see Section 2.2.1).

2.2. When Should a Referral for ECT Be Made?

2.2.1. Primary Use of ECT

Situations where ECT may be used prior to a trial of psychotropic medication include, but are not limited to, any of the following:

a) need for rapid, definitive response due to the severity of a psychiatric or medical condition

b) the risks of other treatments outweigh the risks of ECT

c) history of poor medication response or good ECT response in one or more previous episodes of illness

d) patient preference

2.2.2. Secondary Use of ECT

In other situations, a trial of an alternative therapy should be considered prior to referral for ECT. Subsequent referral for ECT should be based on at least one of the following:

a) treatment resistance (taking into account issues such as choice of medication, dosage and duration of trial, and compliance)

b) intolerance or adverse effects with pharmacotherapy which are deemed less likely or less severe with ECT

c) deterioration of the patient's psychiatric or medical condition creating a need for a rapid, definitive response

2.3. Major Diagnostic Indications

Diagnoses for which either compelling data support the efficacy of ECT or a strong consensus exists in the field supporting such use:

2.3.1. Major Depression

a) ECT is an effective treatment for all subtypes of unipolar major depression, including major depression single episode (296.2x) and major depression, recurrent (296.3x) (American Psychiatric Association 1994).

b) ECT is an effective treatment for all subtypes of bipolar major depression, including bipolar disorder; depressed (296.5x); bipolar disorder mixed (296.6x); and bipolar disorder not otherwise specified (296.70).

2.3.2. Mania

ECT is an effective treatment for all subtypes of mania, including bipolar disorder, mania (296.4x); bipolar disorder, mixed (296.6x), and bipolar disorder, not otherwise specified (296.70).

2.3.3. Schizophrenia and Related Disorders

a) ECT is an effective treatment for psychotic exacerbations in patients with schizophrenia in any of the following situations:

1) when duration of illness from initial onset is short

2) when psychotic symptoms in the present episode have an abrupt or recent onset

3) catatonia (295.2x) or

4) when there is a history of a favorable response to ECT

b) ECT is effective in related psychotic disorders, notably schizophreniform disorder (295.40) and schizoaffective disorder (295.70). ECT may also be useful in patients with psychotic disorders not otherwise specified (298-90) when the clinical features are similar to those of other major diagnostic indications.

2.4. Other Diagnostic Indications

There are other diagnoses for which the efficacy data for ECT are only suggestive or where only- a partial consensus exists in the field supporting its use. In such cases, ECT should be recommended only after standard treatment alternatives have been considered as a primary intervention. The existence of such disorders, however, should not deter the use of ECT for treatment of patients who also have a concurrent major diagnostic indication.

2.4.1. Psychiatric Disorders

Although ECT has sometimes been of assistance in the treatment of psychiatric disorders other than those described above (Major Diagnostic Indications, Section 2.3), such use is not adequately substantiated and should be carefully justified in the clinical record on a case-by-case basis.

2.4.2. Psychiatric Disorders Due to Medical Conditions

ECT may be effective in the management of severe secondary affective and psychotic conditions displaying symptomatology similar to primary psychiatric diagnoses, including catatonic states.

There is some evidence that ECT may be effective in treating deliria of various etiologies, including toxic and metabolic.

2.4.3. Medical Disorders

The neurobiological effects of ECT may be of benefit in a small number of medical disorders.

Such conditions include:

a) Parkinson's disease (particularly with the "on-off ' phenomenon b) neuroleptic malignant syndrome

c) intractable seizure disorder

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