Electroconvulsive Therapy and Schizophrenia. H. A. Sackeim Schizophrenia, Chapter 27. 2003. Dr. Yaron Gilat
History • Hippocrates was the first to observe that malaria-induced convulsions in insane patients was able to bring a reduction in their symptoms. • 1927 – Manfred Sakel introduces the insulin-induced coma and convulsions to treat schizophrenia. • 1935 – Meduna first deliberatly induced seizures with the aim of treating schizophrenia, using IM camphor. • 1938 - Cerletti & Bini introduced electricity as a method of seizure induction, again with the intent of treating schizophrenia. • 1940’s & 1950’s – ECT widely adopted and extended to other disorders. • In subsequent years, the introduction of effective pharmacological treatments, led to a sharp drop in ECT utilization. • In recent years interest and use of ECT had increased.
Stigma ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Lack of Consensus • Unlike its use in MDD, the indications for the use of ECT and its efficacy in schizophrenia are less clear. • Some authorities have dismissed or warned against the use of ECT in schizophrenia. • Others are disputed. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
The American Psychiatric Association (APA) Task force on ECT (1990): • ECT is an effective treatment for “psychotic schizophrenic exacerbations”, particularly in the context of catatonia, when affective symptomatology is prominent, or when there is a history of favorable response to ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
The Canadian Psychiatric Association: • Pharmacological agents are typically more effective. Thus … • ECT should be reserved for schizophrenic patients who had failed at least one adequate pharmacological trail. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
The (APA) Task force on ECT (2001): • Recommended the treatment for psychotic schizophrenic exacerbations when: • Episode duration is short. • Catatonic symptomatology is prominent. • A history of favorable response to ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Unfortunately… • “Despite more than 5 decades of widespread clinical use, the administration of ECT to those with schizophrenia lacks a strong research base” (Tharyan 2000). • Among expert groups and national psychiatric associations, there is a lack of consensus regarding the role of ECT in schizophrenia. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Issues for discussion. • Is ECT useful in the treatment of schizophrenia? • If so, for what types of schiz. or for what symptoms? • At what point should ECT be considered? • Should it be administered after neuroleptics have failed, or in combination with medications to enhance efficacy or to reduce neuroleptic dosage? • Are there risks in providing ECT to schiz.? • How should ECT be administered? • How many treatments should be given? • How long do the beneficial & adverse effects last? • Is there a place for maintenance ECT?
Efficacy • Studies of sham vs. real ECT in schizophrenia. • Studies comparing ECT with neuroleptics or other therapies. • Studies comparing combined ECT and medication treatment with medication alone or ECT alone. • ECT and neuroleptic medication in medication-resistant schizophrenic patients. • Atypical antipsychotics and ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies of sham vs. real ECT in schizophrenia. • 1950’s and 1960’s studies failed to demonstrate a therapeutic advantage for ECT vs. general anaesthesia alone. • Recent studies (1980’s) found clinically significant therapeutic advantages for real ECT. • The source of this discrepancy is unknown. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies of sham vs. real ECT in schizophrenia – cont... Possibly; • In recent studies patients have been maintained on neuroleptic medications; there is reason to believe that the combination of ECT and neuroleptics is more effective than either form of monotherapy. • In recent studies the advantage of real ECT only pertained to the period of time during and immediately following ECT. Within months, symptomatic differences were not evident. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies comparing ECT with neuroleptics or other therapies. • The literature is methodologically limited. • It appears that generally short-term outcome was equivalent or superior with antipsychotic medication relative to ECT. • Little indication about the clinical or treatment history features that might distinguish schiz. who preferentially respond to antipsychotic medications or ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies comparing ECT with neuroleptics or other therapies – cont... • A seemingly consistent, though unexpected, theme was the suggestion that patients who were administered ECT had superior long-term outcome compared with medication groups. • The possibility that ECT may have beneficial long-term effects merits attention. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies comparing combined ECT and medication treatment with medication alone or ECT alone. • The literature is also methodologically limited. • ECT alone vs. ECT combined with antipsychotic medication; suggestions that the combination was more effective. • Antipsychotic medication monotherapy vs. ECT combined with antipsychotic medication; evidence that the combination was more effective. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Studies comparing combined ECT and medication treatment with medication alone or ECT alone – cont... • In some cases, a superior outcome was obtained despite an apparent lower average neuroleptic dose in the combination condition. • Few studies followed patients beyond the acute treatment; therefore, the relative persistence of any advantage for combination treatment is unknown. • Smith et al. (1967); reduced rate of relapse at 6 m and 1 y, in patients treated acutely with neuroleptics and ECT relative to neuroleptics alone. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
ECT and neuroleptic medication in medication-resistant schizophrenic patients. • No double-blind random assignment study contrasting the efficacy of ECT and neuroleptics and continued neuroleptics alone. • All the information on this issue comes largely from large case series or impressionistic observations. • There are indications that some, if not many,medication-resistant schiz. may benefit substantially by the addition of ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
ECT and neuroleptic medication in medication-resistant schizophrenic patients – cont... • “…our own experience […] has suggested that the combination may result in dramatic improvement in only a small minority of patients, and is without substantial benefit in most cases.” • The [short] duration of the current episode (as opposed to the duration of the illness) may be a potent predictor of response to ECT in medication-resistant schizophrenia. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Atypical antipsychotics and ECT. • The published literature is relatively merge. • “…rigorous investigation of the combination of ECT and clozapine is needed”. • Kupchik et al. (2000); the most extensive case review ; combined ECT/clozapine treatment is effective and safe in treatment-resistant schiz. • “…there has yet to be documentation of the safety or efficacy of ECT when combined with other newer atypical antipsychotics…”. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Prediction of outcome. • Demographic & clinical predictors. • Symptoms responsive to ECT. • Special populations; - Catatonia. - Lethal catatonia. - Schizoaffective disorder. - Neuroleptic Malignant Syndrome (NMS). ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Demographic & clinical predictors • Early studies often lacked standardized diagnostic criteria and often used assessment techniques of questionable reliability. • Unfortunately, very few recent studies have examined predictors of ECT response in sciz. Those who have, found…; ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Symptoms responsive to ECT • In recent years little research has examined the symptoms of schiz. that show most benefit from the use of ECT on positive and negative symptoms. • Various studies resulted in various findings; - delusions of control & of reference, delusional mood, thought interference and auditory hallucinations were particularly responsive. - symptoms of hostility and ideas of persecution improved under CPZ & ECT vs. medication alone. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Symptoms responsive to ECT – cont… • Chanpattana & Sackeim (2002);253 neuroleptic-resistant patients treated with ECT & flupenthixol. - marked improvement in specific positive symptoms (hostility, thought disturbance and activation). - intermediate effect on affective symptoms. - no effect or worsening of specific negative symptoms. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Symptoms responsive to ECT – cont… Note: • Despite the pronounced efficacy of ECT in MDD, affective symptoms are not especially responsive in patients with schizophrenia. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Special populations Catatonia • Contradictory studies. • “In our experience ECT results in rapid and often dramatic improvement in specific catatonic features, such as mutism and motility disturbance. […] Catatonia may accompany or be a residual symptom of NMS, and there is evidence that ECT is rapidly effective in treating these catatonic manifestations”. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Special populations – cont… Lethal catatonia • A life-threatening condition, characterized by stupor or excitement, hyperthermia, clouded consciousness and autonomic dysregulation. • Mann et al. (1986); ~ 90% schizophrenia. ~ 60% death, most m/p d/t pulmonary embolism. • Neuroleptics – limited efficacy. • ECT, particularly prior to a comatose stage, is particularly effective and favored as the treatment of choice. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Special populations – cont… ? Schizoaffective disorder • APA Task Force on ECT (1990) suggested this form of treatment is particularly valuable when schiz. patients present with prominent affective symptoms. • Recent studies did not show affective symptoms to have a strong predictive value for final outcome. • Reports exist which suggest that medication-resistant patients, characterized by marked psychotic and affective symptoms and by confusion, respond rapidly to ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Special populations – cont… Neuroleptic malignant syndrome (NMS) • An iatrogenic form lethal catatonia induced by exposure to neuroleptics. • Several reviews have documented that ECT is an effective treatment for NMS. • Given the marked haemodynamic alterations associated with ECT, in the NMS patient it is advisable to first use medication strategies to stabilize autonomic function, before starting ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique. • Work on refining ECT technique has concentrated almost exclusively on MDD. • Issues for discussion; - Electrode placement. - Stimulus intensity. - Treatment duration & frequency. - Continuation/ maintenance ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Electrode placement • Whether electrodes are placed on one or both sides of the head can have marked effects on cognitive consequences. • Bifrontotemporal placement produces more extensive, severe and persistent amnestic effects than unilateral placements. • Lt. hemisphere placement (vs. Rt.) is associated with longer delay in return of orientation and greater verbal amnestic deficits. • Rt. Hemisphere placement (vs. Lt.) typically results in greater amnestic non-verbal deficits. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Electrode placement – cont… • Lt. unilateral ECT is rarely used. • In mood disorders an ongoing debate is nearing resolution as at high stimulus intensity, Rt. unilateral ECT appears to match to efficacy of bilateral ECT, but retains important cognitive advantages. • Only 4 studies regarding unilateral vs. bilateral ECT have been conducted in schizophrenia. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Electrode placement – cont… • Each of these 4 trails failed to detect differences in efficacy. • Therefore, at best, there are weak indications that Rt. unilateral ECT may be equivalent in efficacy when treating schizophrenia. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Stimulus intensity • In MDD there is evidence that higher electrical dosage above seizure threshold results in more rapid response. • Only one study examined this in schizophrenia; - 3 groups; just above seizure threshold, twice the threshold and four times the threshold. - the 1st group required more ECT treatments and more days to meet remitter criteria. As with MDD, higher stimulus intensity accelerates response in schizophrenia.
Treatment technique – cont... Treatment duration & frequency • Early views maintained that schiz. require more closely spaced treatments and longer courses than patients with other conditions and that negative symptoms may require even more treatments. • Empirical evidence bearing on these views is scant. • Recent trails of ECT in schiz. have used small numbers of treatments (6 – 12), with positive results. • It is quite possible that beliefs regarding long ECT courses to achieve response or to prevent relapse are without merit.
Treatment technique – cont... Treatment duration & frequency – cont… • “…Clinicians should be guided by manifestations of clinical improvement and side-effects when determining whether to continue with ECT. Prescribing a fixed number of treatments is not appropriate”. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Continuation/ maintenance ECT • Mostly early studies (1940’s – 1960’s). • Those early reports seemingly found maintenance ECT successful in controlling symptoms in schiz. • Without question, difficulties in convincing and in compliance limit the use of this strategy in schiz. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Treatment technique – cont... Continuation/ maintenance ECT – cont… • Chanpattana et al. (1999); - 45 schiz. who remitted under ECT & flupenthixol. - 1st group; continuation ECT alone – 93% relapse over 6 m period. - 2nd group; continuation flupenthixol alone – 93% relapse over 6 m period. - 3rd group; continuation flupenthixol & ECT – 40% relapse over 6 m period. combination continuation with ECT and an antipsychotic may be more effective than either modality alone.
Side-effects. • Morbidity & mortality. • Cognition. • Neuropathological effects. • Movement disorders. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Side-effects – cont… • Mortality - 1:10,000 (as with general anaesthesia for minor surgery). • Major source of mortality & morbidity is cardiovascular complications. • The risk of serious complications is increased in the elderly, in those with pre-existing medical conditions (particularly cardiac) and in those receiving concurrent medications for medical conditions. • Cardiovascular collapse & respiratory depression may occur when Reserpine is combined with ECT.
Side-effects – cont… Cognition • Most studies failed to demonstrate any cognitive decline after ECT treatments. • Some even demonstrated improvements. • Two criticized studies did show a decline in cognitive tests in male schiz. who received 50 or more ECT treatments. • “Overall, this is little reason to suspect that ECT results in more severe neuropsychological effects in schiz. patients than in other populations”.
Side-effects – cont… Neuropathological effects • Modern ECT, involving generalized seizures that last approximately 1 minute, under conditions of general anaesthesia, muscle relaxation and continuous oxygenation does not provide the conditions necessary for neuronal death. • Numerous studies of MRI, CSF and plasma markers of brain damage reported negative findings following courses of ECT. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Side-effects – cont… Movement disorders • Acute extrapyramidal syndromes (EPS), mainly neuroleptic-induced parkinsonism (NIP) as well as tardive dyskinesia (TD) are major drawbacks of traditional neuroleptic treatment. • While EPS is considered reversible, prospective studies suggested that NIP predicts the subsequent development of TD. • NIP and akathisia may also persist following the discontinuation of neuroleptics.
Side-effects – cont… Movement disorders – cont… • ECT has antiparkinsonian properties and is known to improve clinical symptoms in idiopathic Parkinson's disease in the short term. • ECT also has ameliorative effects on NIP. • On the basis of incidental findings, several reports introduced the notion that ECT might protect against NIP and by this also against TD. • Several papers also reported a meaningful and sustained remission of TD following ECT.
Side-effects – cont… Movement disorders – cont… • No controlled prospective investigation was performed, thus no firm conclusion can be offered. • If ,in fact, ECT does offer long term protection against the iatrogenic effects of later exposure to neuroleptics, this will contradict the general impression that the behavioral and physiological effects of ECT are typically transient. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Conclusions ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Conclusions #1 • Little doubt exists that ECT is efficacious in the treatment of schizophrenia; at least in patients with acute exacerbations & short episode duration. • Even in those, short term benefits of ECT equal or fall below the benefits of traditional antipsychotic monotherapy. • In contrast, evidence suggests that combination treatment of ECT + neuroleptic is superior, in the short-term outcome, to either therapy alone. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Conclusions #2 • The anti-parkinsonian effects of ECT may aid in limiting extrapyramidal side-effects and in offering greater flexibility in neuroleptic dosing. • Although the evidential basis is less substantial, it appears that ECT exerts additive or synergistic effects with atypical antipsychotics. • There is a surprising suggestion that ECT may exert long-term benefits (functioning, relapse). ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Conclusions #3 • Schizophrenic patients treated with ECT earlier in their history may be less likely or have delayed manifestations of NIP and TD. • At this point, there is little information to guide the clinician which schizophrenic patient will benefit most from ECT. • Substantial response is often observed after 8-10 treatments, contrasting the long-held view that protracted courses are required. ECT & SCHIZOPHRENIA. Yaron Gilat. 22/11/2004
Conclusions #4 • “…in a small minority, ECT is associated with dramatic effects and can produce the first symptomatic remission to be observed in years… It is our view that, regardless of chronicity, shcizophrenic patients who have exhausted pharmacological alternatives deserve a course of ECT”.