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ECT is an Effective, but Ignored, Treatment of Psychosis
Max Fink, M.D.
From the Department of Psychiatry, State University of New York at Stony Brook, and
the Long Island Jewish-Hillside Medical Center, Glen Oaks, Long Island 11004.
Professor of Psychiatry and Neurology Emeritus, School of Medicine, SUNY at Stony
Brook; and Professor of Psychiatry, Albert Einstein College of Medicine.
From "Focus on Antipsychotics" edited by Dr. Ben Green, University
of Liverpool, UK.
Communities throughout the nation bear large numbers of the chronic mentally ill. They reside in state hospitals, prisons, shelters for the homeless, attend our clinics, and are the major participants in our revolving-door hospital admissions. For these patients, we prescribe one antipsychotic medicine after another, often in complex combinations with instructions that our patients follow poorly. Can more be done? Do we have more knowledge that we can apply? An answer lies in electroconvulsive therapy, a treatment that benefits these patients, but one that is often not available at the treatment venues that these patients attend. ECT has been given such a bad name that even clinicians who are skilled in its use, prefer less effective but less criticized options. Personal and public bias, lack of training among psychiatrists, and legislative and judicial limitations are additional hurdles. This essay summarizes our knowledge of ECT in the treatment of psychoses.
In the second quarter of the 20th Century, the principal treatments for patients with psychoses were insulin coma, leucotomy, and electroconvulsive therapy. The discovery of the antipsychotic effects of reserpine and chlorpromazine challenged their use.
For insulin coma, a random assignment comparison found chlorpromazine to be as effective, safer, and less expensive (Fink et al., 1958). Insulin coma units quickly closed.
For leucotomy, no direct comparison with antipsychotic drugs was made but the success rate of surgery was so low, the side effects so severe, and its acceptance so poor that the new drugs ended clinical interest. Psychosurgery remained in occasional use for experimental purposes.
For ECT, the comparisons with antipsychotic drugs found both treatments to be similarly effective (Fink, 1979; Fink and Sackeim, 1996; Abrams, 1997). The risks of the new drugs were not yet known, so the immediate ill effects of ECT in inducing fractures and cognitive deficits tipped the clinical balance in favor of the drugs. The ease of administration of the drugs and their assumed greater safety, and not a greater efficacy, encouraged their replacement of ECT.
While the new medicines minimized symptoms, few patients recovered fully. The patients came to depend on the medicines and their prolonged use brought on the risks of tardive dyskinesia, parkinsonism, and dystonia. Sudden deaths occurred and were not explained until the risk of the neuroleptic malignant syndrome was identified. It was the experience of pharmacotherapy-resistance, the failure of antipsychotic medicines to sustain a benefit, that drove a frustrating search for clinically more effective tactics. More potent drugs and diverse augmentation strategies made an impact, but the problem of pharmacotherapy-resistant psychosis persisted.
The marketing of clozapine, a drug with a history of toxicity that had led to its recall a decade earlier, is an example of the public willingness to use a medicine with some risk and limited efficacy. The initial reports showed clozapine to reduce psychosis rating scale scores by 30% in 30% of the patients (Kane et al., 1988). Despite its potential toxicity, this small benefit was sufficient to encourage the acceptance of its use. Clozapine was labeled an 'atypical neuroleptic' and international pharmaceutical companies spent untold millions to find drugs with similar pharmacologic profiles, leading to the marketing of risperidone, olanzapine, and quetiapine.
The same drive for a more effective and safer antipsychotic treatment led to re-examination of the experience with ECT in patients with schizophrenia. Professional attitudes to ECT for patients with schizophrenia were confused. Those physicians who had treated acutely ill schizophrenic patients recalled that ECT was effective, although the patients required many more treatments than did depressed or manic patients. An effective treatment course required from 15 to 25 ECT, spaced over two or more months. On the other hand, those physicians who treated the chronically ill, especially those warehoused in state facilities, had seen poorer results. Indeed, since more chronic patients than acutely ill were treated with ECT, the belief was widely held that ECT was ineffective in treating schizophrenia. In our review of 60 years of experience, we found ". . .it [ECT] to be an effective treatment for psychosis. ECT is particularly applicable in patients with first-break episodes, especially those marked by excitement, overactivity, delusions, or delirium; in the young to avoid the debilitating effects of chronic illness; and in syndromes characterized by catatonia, 'positive symptoms of psychosis', or schizoaffective features." (Fink and Sackeim, 1996). We argued ". . . for the use of ECT early in the course of treatment of acutely psychotic patients, especially in first-break psychotic patients with excitement, overactivity, delusions, or florid delirium, and in those who are young, to avoid the debilitating effects of chronic illness. If patients are treated effectively early in the course of their illness, we believe that the risks of chronicity of illness and deterioration in personality can be avoided." And we recommended: "There is need for prospective studies of ECT alone or ECT combined with neuroleptic drugs contrasted with neuroleptic drugs alone in patients with schizophrenia. Since the efficacy of combined medication and ECT is probably greater than ECT alone, combined therapy should be favored in prospective assessments."
Since almost all psychotic patients are treated with antipsychotic drugs today, the consideration of ECT comes mainly after the patients have failed multiple trials and complex combinations of medicines. Referral for ECT comes as the last recourse, usually when the patients are severely ill and hospital care is required. Professional concerns about the recurrence of psychosis and worsening of dyskinesia makes it common practice for prescribed medicines to be continued when ECT is added.
ECT augmentation. The successful augmentation of thiothixene by ECT in nine of nine resistant psychotic patients was reported by Friedel (1986). A similar success was found in a retrospective review in seven of eight schizophrenic patients when ECT was added to their antipsychotic medication (Gujavarty et al., 1987). In patients who had failed trials of loxapine alone when loxapine was augmented by ECT, the Brief Psychiatric Rating Scale (BPRS) scores decreased by more than 20% (Sajatovic and Meltzer, 1993). But the experience with clozapine and ECT provides compelling evidence of the efficacy of ECT augmentation (Fink, 1990).
The successful augmentation of clozapine by ECT was first recognized in 1991, when two reporters described their experience as "remarkable" (Klapheke, 1991a, b; Landy, 1991). Additional case examples quickly dotted the literature (Safferman and Munne, 1992; Dassa et al., 1993; Frankenburg et al., 1993; Green et al., 1994; Beale et al., 1994; Cardwell et al., 1995; Factor et al., 1995; Benatov et al., 1996; Lurie, 1996; Bhatia et al., 1998; Petrides et al., 1998; Sharif, 1998; Chanpattana et al., 1999; James and Gray, 1999; Kales et al., 1999; Chanpattana, 2000; Kupchik et al., 2000). Symptoms of delusional thinking, aggressivity, hallucinations, apathy, and withdrawal showed the most relief. For example, in a prospective study in progress, Petrides and Mendelowitz (2000) reported a greater than 40% reduction in BPRS psychosis scores in 7/12 patients who had failed multiple medication trials, including high doses of clozapine for extended durations. These pilot studies encouraged an NIMH-supported prospective controlled study in which clozapine-resistant psychotic patients are randomly assigned to continued clozapine or to ECT augmentation of continued clozapine, each for a minimum of eight weeks.
The interest in ECT augmentation of clozapine should not detract from the use of ECT with any antipsychotic medicine. Such synergy is well documented (Fink 1990, 1999; Klapheke, 1993).
ECT compared to drugs in psychoses other than schizophrenia. Psychoses are commonly first treated with antipsychotic drugs. But for psychotic depression and delirious mania, two well-defined psychoses, the efficacy of antipsychotic drugs alone is poor, and alternative treatments have a better prognosis. The concept of psychotic depression owes its recognition to the studies of Glassman and his associates who were monitoring imipramine treatment with weekly serum levels in hospitalized depressed patients (Glassman, Kantor and Shostak, 1975; Kantor and Glassman, 1977). Despite adequate imipramine serum levels, only three of 13 psychotic depressed patients (30%) improved compared to 14 of 21 non-psychotic depressed patients (66%). Nine of the 10 unimproved psychotic patients recovered with subsequent ECT. They concluded that the treatment of psychotic depressed patients with only a tricyclic antidepressant prolonged the suffering, increased the risk for suicide, and unnecessarily exposed them to toxicity.
This report was quickly verified. Italian investigators treated 437 depressed hospitalized patients with imipramine in doses of 200 to 350 mg/day for 25 days or longer (Avery and Lubrano, 1979). Of these, 247 patients (57%) recovered and were discharged. Each of the 190 unimproved patients was next treated with bilateral ECT, and of these, 156 (72%) recovered. Of the depressed patients who had not improved with imipramine, 43% were psychotic as well as depressed.
In summarizing the experience of the treatment of patients with psychotic depression, Kroessler (1985) reported that half the patients recovered when treated with antipsychotic drugs alone, and even fewer, approximately a third, improved with antidepressant drugs alone. With both antipsychotic and tricyclic antidepressant drugs together, two-thirds improved.
Delirious mania is a psychotic syndrome of the acute onset of excitement, grandiosity, emotional lability, delusions, and insomnia characteristic of mania, and disorientation and altered consciousness characteristic of delirium (Fink, 1999a, b). Drug toxicity, systemic illness, mania, and depression are common antecedents. Catatonia is a frequent accompaniment, and it is difficult to distinguish delirious mania from excited or malignant catatonia. Delirious mania is usually treated with antipsychotic drugs but such use is associated with neurotoxic risks. The effective and safe alternative is ECT, which is best given en bloc -- a series of two to four seizures on a daily basis.
In patients with psychotic depression and delirious mania, ECT exhibits effective antipsychotic actions when used alone, and is more effective than antipsychotic drugs.
Adverse events, contraindications, and interactions
The combination of antipsychotic drugs and ECT is remarkably safe (Klapheke, 1993; Nobler and Sackeim, 1993; Abrams 1997). Indeed, for some toxic effects of antipsychotic drugs as tardive dyskinesia, parkinsonism, and neuroleptic malignant syndrome, ECT is useful to reduce the severity of these motor syndromes.
There is little evidence that ECT worsens psychoses. Its benefits require large numbers of treatments so the cognitive effects become prominent. But if the psychosis resolves and treatments spaced further apart in time, the cognitive effects wane and the relief of psychosis becomes the dominant experience.
For the combined use of clozapine and ECT, adverse effects are remarkably few. In a single case, Beale et al. (1994) reported that the administration of caffeine to achieve a longer seizure with ECT in a patient receiving clozapine elicited a prolonged period of supraventricular tachycardia. Other than this experience, the literature is mute with regard to adverse effects of ECT augmented clozapine treatment.
Mode of Action
How are we to understand the synergism of antipsychotic drugs and ECT? Two aspects of physiology are relevant. Antipsychotic drugs lower seizure thresholds and incidental spontaneous seizures have been reported for many antipsychotic drugs (Klapheke, 1993). The induction of seizures is particularly well documented for chlorpromazine and clozapine. At high doses, clozapine elicits EEG seizure activity in both humans and in animals. This effect is occasionally seen clinically in the production of grand-mal seizures (Gunther et al., 1993; Haring et al., 1994; Malow et al., 1994; Jin, Potkin and Sandman, 1995; Risby et al., 1995; Denney and Stevens, 1995; Kales et al., 1995; Neufeld et al., 1996). An association between the degree of EEG slowing and serum clozapine levels is reported (Olesen et al., 1995; Freudenreich et al., 1997). These observations led Stevens (1995) to explain the beneficial effects of clozapine as due to increased excitability in subcortical brain areas, an idea that is consistent with concepts of the antagonism of seizures and psychosis (Meduna, 1985; Trimble, 1991).
The paradoxical association between the development of what is apparently an abnormal EEG with behavioral improvement in emotional disorders was highlighted in EEG studies of epileptic psychotic patients (Landolt, 1958). When epileptic patients were treated with anticonvulsant drugs and their seizures controlled, they exhibited psychotic symptoms although their EEG records were normalized. When the medications were reduced, allowing the return of seizures and EEG abnormalities, the clinical behavior improved. This association has been labeled 'forced normalization' or 'paradoxical normalization' (Wolf and Trimble, 1985; Pakalnis et al., 1987; Trimble 1991). (It was the apparent antagonism between epileptic seizures and the psychotic symptoms of dementia praecox that led Meduna to envision and develop convulsive therapy for the relief of dementia praecox [Meduna 1985]).
During convulsive therapy, the inter-seizure EEG is progressively filled with slow wave activity and seizure-like bursts (Roth 1952; Fink and Kahn, 1957; Fink, 1979; Sackeim, et al., 1996). The development and persistence of EEG slowing and burst activity is related to the clinical outcome. Patients who fail to develop high degrees of EEG slowing fail to improve clinically (Fink and Kahn, 1957), a finding recently confirmed by Sackeim et al. (1996).
Indeed, the development of an abnormal EEG (slowing of frequencies, development of burst activity) during clozapine therapy is associated with a better clinical outcome compared to the results when the EEG fails to change (Risby et al.,1995).
A second item of physiology that may explain how ECT augmentation works is the change in the blood-brain-barrier (BBB) that is induced by seizures. The BBB prevents many large molecules from crossing from the vascular to the CNS compartments. ECT, however, alters the BBB to allow such substances to cross into the CNS (Aird and Strait, 1945; Bolwig et al., 1977a, b). While the effect on the BBB of a single seizure is of short duration, repeated seizures allow the persistent transport of materials. Also, the penetration of substances varies widely in different brain regions (Cutler et al., 1968). As ECT compromises the BBB, greater amounts of clozapine penetrate to the brain without the limitations incurred by the effects on other body systems.
These two physiologic factors suggest an explanation. Both ECT and clozapine induce EEG seizure activity, a change that is operationally associated with a reduction in the signs of psychosis. The clinical efficacy of clozapine is dose-related, with higher doses having greater benefits. But high doses of clozapine are associated with systemic drowsiness, sialorrhea, or seizures, which limit the upper dosing levels. The changes in the BBB associated with ECT probably allow greater amounts of clozapine to pass to the brain without adverse systemic effects. The combination of increased seizure activity, impaired BBB with resulting higher brain concentrations of clozapine, encourages a more robust CNS effect of clozapine.
Treatment algorithms and ECT
Modern medical practice increasingly pleads for evidence-based treatment decisions. The decisions are codified in algorithms produced by assembled 'experts'. As there are few robust experimental studies of the efficacy of the new antipsychotic drugs, and none comparing their efficacy with that of ECT, the expert recommendations are based, almost exclusively and of necessity, on testimonials. Few experts treat many patients personally (most manage networks of treating doctors and nurses in data collecting networks) and fewer still have experience with ECT. They do not consider ECT in their algorithms, opining only that it is one of the alternative treatments occasionally used as a last resort.
This attitude is both inhumane and uneconomic (Fink, 1997b, 1999a). It is inhumane because it fails to recommend an effective treatment in a timely fashion, one that may ease suffering rapidly and safely. By such failure, patients with resolvable illnesses remain unwell and unproductive for themselves, their families, and society. It is uneconomic since the overall cost of a course of ECT is often less than repeated courses of medications especially when lost wages are factored in the estimates (Markowitz et al., 1996; Steffens et al., 1995).
A more reasonable guideline for the use of ECT in treating psychosis comes from the logic used to evaluate clozapine when it was known to be severely toxic. To assure that only treatment refractory patients were subjected to the possible toxicity of clozapine, the committees supporting such research argued that patients would have to fail two medication trials with antipsychotic drugs of two different classes, at adequate clinical dosages, each for a minimum of six weeks. Failure to improve with treatments of this rigorous standard justified exposure to the potentially toxic alternative (Kane et al., 1988). Since that model was successful in marketing clozapine, it seems reasonable to apply the same standard to the decision to use ECT in treating psychosis. Instead of waiting interminably before recommending ECT, psychotic patients should be referred for ECT augmentation after two antipsychotic medication trials have failed, or earlier in those patients who are suicidal, suffering from inanition, catatonia, or medically ill.
ConclusionThe efficacy of ECT in relieving psychosis is a clinical benefit that is infrequently recognized. When ECT was replaced by antipsychotic drugs, it was not that the drugs were more effective or even safer. The replacement was for their ease of use, widespread availability, and an antipathy to the use of ECT. In the four decades since the introduction of antipsychotic drugs, we have become inured to their side effects, tolerating tardive dyskinesia, neuroleptic malignant syndrome, parkinsonism, akathisia, unexplained deaths, and the development of apathy, withdrawal, and loss of motivation that characterizes the secondary effects of their prolonged use. At the same time, the risks of fracture, death, and cognitive decline that at one time characterized the side effects of ECT have been materially reduced. Indeed, there is no accepted contraindication to the use of ECT in treating the severe mentally ill.
The apathy of the profession results in ECT being ignored in the spate of treatment algorithms that are now being written. As these algorithms become codified in the management of the severe mentally ill, the benefits of ECT will become even more difficult to achieve. Our two-tier system of mental health care, in which the insured are able to obtain care in private and university psychiatric services (where ECT is available) while the indigent depend on state supported facilities (where it is not), further disadvantages the mentally ill poor and the minorities of all nations. Such failure consigns many hundreds, if not thousands, of patients to the prolonged misery of negative symptoms of schizophrenia, the loss of their most productive years, and their isolation from friends and family. The antipathy and apathy among psychiatrists and other mental health professionals toward an effective treatment is a sad commentary on the present education of psychiatrists and their co-workers. As our education is increasingly dominated by a pharmaceutical industry that ignores competing therapies, it becomes likely that few of the next generation of mental health workers will have experience with ECT. While the pre-eminence of the use of medications for psychotic patients is explained by their ease of use and efficacy, ECT augmentation of antipsychotic drugs compels greater attention to this combination for the relief of the burdens of pharmacotherapy-resistant psychosis.
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