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While electroconvulsive therapy (ECT) was initially considered a treatment for schizophrenia, it has become more commonly used in treatment-resistant depression (TRD) since the introduction of antipsychotics to treat schizophrenia.1,2 However, for patients with schizophrenia who are not responsive to these medications, ECT remains an essential treatment modality more than 80 years after it was first tested in a human patient.
“ECT was a mainstay of treatment in the late 1930’s and the 1940’s, prior to the development of neuroleptics,” explained Irving Reti, MBBS, MD, professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of the Brain Stimulation Program at Johns Hopkins. “Now the vast majority of patients with schizophrenia are treated with neuroleptics and only a small minority are treated with ECT, although this is somewhat different in the developing world.”
He estimates that 90% of the patients his team treats are individuals with TRD and says treating patients with schizophrenia is “not rare but not very common.”
“We have good evidence that clozapine-resistant schizophrenia can be helped by ECT and should be considered” for these patients, Dr Reti stated. One remaining question is whether continuation ECT helps patients sustain the improvements achieved with an acute course of ECT, and some data supports this benefit.3 He said it would also be helpful to explore whether unilateral ECT can show the same effectiveness as bilateral ECT while reducing the risk of side effects.
For additional discussion about the current role of ECT in schizophrenia treatment, we interviewed Amy Starr Aloysi, MD, MPH, associate professor of psychiatry and neurology at the Icahn School of Medicine at Mount Sinai in New York and director of the Mount Sinai Health System ECT Program; and Sohag N. Sanghani, MD, MPH, assistant professor in the department of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and director of Electroconvulsive Therapy (ECT) service at the Zucker Hillside Hospital in New York.
What is the current state of practice regarding ECT as a treatment for schizophrenia?
Dr Aloysi: ECT is known to be a helpful intervention for the management of schizophrenia, particularly with the positive symptoms. In fact, schizophrenia is the most common indication for ECT in many parts of the world. APA Guidelines recommend that ECT be considered when there is treatment-resistance. It is typically used as an adjunct to antipsychotics.4
Sanghani et al wrote an interesting review on the topic which was published in 2018 in Current Opinion in Psychiatry.5
ECT is known to be especially synergistic with clozapine. In current practice, ECT is typically used for those patients who have a partial or inadequate response to clozapine. (Approximately 30%-40% of patients remain symptomatic despite therapy with clozapine.)6 There may also be a role for ECT earlier on in the stabilization phase for severe acute psychosis in many patients.
Dr Sanghani: ECT is viewed as an effective and useful treatment in augmentation of antipsychotic response for patients with schizophrenia. It is not viewed as a substitute to medications. It is particularly helpful for clozapine-resistant schizophrenia as well as non-clozapine resistant schizophrenia. ECT is also occasionally used to target specific symptoms that respond quickly to ECT and may appear during the illness, such as catatonia, neuroleptic malignant syndrome, acute exacerbation of schizophrenia, suicidality, affective/depressive symptoms, or for patients unable to tolerate antipsychotic medications.
Schizophrenia is a chronic and nonepisodic illness and may require a larger number of ECT treatments compared with depression to see the response. Clinical research in schizophrenia is hindered by challenges in recruitment of subjects for long studies, controlling for potential confounding factors, funding, and lack of financial support from the pharmaceutical industry. Since it is unethical to conduct sham-ECT studies, double-blinding is not possible and hence randomized double-blind clinical trials are extremely difficult.
What are some of the most notable recent findings in this area?
Dr Aloysi: Several studies have documented the utility of ECT for schizophrenia. A 2015 study by Petrides et al demonstrated a 50% response rate in patients who did not respond to clozaril with an average number of 16 treatments (greater than typical in mood disorders).7 Other studies demonstrated a similar response rate of 54%-76%.6
ECT works more rapidly than antipsychotics and can help prevent patients with extreme psychotic agitation from harming themselves or others in inpatient settings. Therefore, in my opinion, ECT may have a role in acute psychosis in inpatient settings for patients with a high level of agitation, requiring frequent seclusions or restraints.
Bilateral electrode placement is the most studied in schizophrenia, however right unilateral (RUL) ECT has also been explored.8 Bilateral ECT is generally more effective than RUL ECT but is associated with slightly more cognitive side effects, although these are typically transient.
Maintenance ECT for schizophrenia can help augment response to antipsychotics. A 2018 study demonstrated that relapse rates were greater than 50% in the first year for patients with schizophrenia on risperidone vs a 15% relapse rate in those who continued on risperidone plus maintenance ECT over a year (monthly sessions after initial taper).9
Dr Sanghani: In the study by Petrides et al where ECT was used as augmentation of clozapine in clozapine-resistant schizophrenia, we overcame that challenge by blinding the interviewers.7 Given the possibility that patients may accidentally reveal their treatment, the interviews were recorded, and portions of the interviews were randomly deleted. Those tapes were then provided to blinded raters for rating.
The definition of response was 40% improvement, which is double the 20% improvement standard often used in antipsychotic studies. In this rigorous trial, about 50% patients responded (number needed to treat [NNT]=2), which is quite significant considering the severe nature of the participants’ illness and lack of other treatments with similar efficacy.
In a meta-analysis of ECT augmentation of clozapine in clozapine-resistant schizophrenia, the ECT augmentation was clearly superior at post-ECT assessment (NNT=3; 95% CI, 3-5) as well as at endpoint assessment (NNT=4; 95% CI, 3-8).10 A similar response rate was observed by Chanpattana et al when ECT was used in augmentation of flupenthixol.11 A meta-analysis of ECT augmentation of nonclozapine antipsychotics for treatment-resistant schizophrenia showed superior efficacy of ECT augmentation (NNT=6; 95% CI, 4–9).12
Current research seeks to identify ways to individualize the treatment and decrease cognitive side effects while maintaining efficacy.
What is the focus of debate13,14 about the usefulness (or lack thereof) regarding ECT, and what are your thoughts on the topic?
Dr Aloysi: It is clear that ECT can have antipsychotic effects, noted also in the finding that the presence of psychotic features is a predictor of response to ECT in depression.15 The role it plays in the treatment of acute and chronic schizophrenia – refractory or not – is still unclear, and more research is needed in this area.
There is a lack of awareness of the potential role for ECT in treatment-refractory schizophrenia.
Dr Sanghani: In the treatment of depression, the efficacy of ECT is very well-established and its place in the treatment algorithm is very well-defined. There is no debate among psychiatrists about ECT’s efficacy. People who debate ECT’s efficacy in depression are usually those who do not want to accept ECT as a form of treatment for any indication. Many of those individuals do not believe in psychiatric diagnosis or treatment as well.
The amount of research in the use of ECT in schizophrenia is not as large as in depression, however there is vast clinical experience worldwide over the span of more than 80 years. It would be fair to say that when it comes to treating clozapine-resistant schizophrenia, none of the other augmentation strategies have better evidence or better effect size.
There is cumulative evidence from clinical trials, open label studies, retrospective studies as well as meta-analysis of that data that support its usefulness in certain clinical scenarios. Recent reviews of literature and meta-analysis all point towards the role of ECT in treatment of schizophrenia and warrant further studies.2
This is the reason that most recent treatment guidelines for schizophrenia by different psychiatric societies, including the American Psychiatric Association and several others, include ECT as a treatment option.16
What are other key points that providers should know about ECT?
Dr Aloysi: There is a high degree of variability in the use of ECT and in the access to this intervention. In general, ECT is an underutilized and cost-effective treatment. Providers in academic medical centers may more readily have access to ECT and may be more likely to consider this for their patients.
Dr Sanghani: When considering ECT for an indication of schizophrenia, providers should discuss it with patients as an augmentation of antipsychotics and not as a substitute to antipsychotics.
Unlike depression, where remission is commonly achieved with ECT, in schizophrenia, clinically meaningful reduction in symptoms and not full remission is a more likely outcome. Hence, providers should offer it as a treatment to reduce the frequency and intensity of symptoms. There is a lot of inter-individual variation in the degree of response.
Involvement of family members in gauging the improvement is very critical. We have seen cases where, despite the continuation of psychotic symptoms, there is notable functional improvement which is meaningful to both patient and family.
Unlike depression, where the first sign of improvement is commonly seen between 4th and 6th ECT and maximum improvement by 8-12th ECT, patient and provider should plan for a longer acute course when used in schizophrenia, as the first sign of improvement may happen later in the course. One may need to go up to 20 ECT treatments before making a final determination of response vs nonresponse.
If a patient has clinically meaningful improvement, then maintenance ECT should be strongly considered. In the absence of a substitute treatment or maintenance ECT, the durability of the response is short in many cases.
What should be the focus of future research on this topic?
Dr Aloysi: Future research addressing the role of ECT for acute agitation in schizophrenia is indicated. In addition, the optimal treatment parameters still need to be explored, as well as the role of maintenance ECT in this disorder.
The mechanism of action of ECT in schizophrenia is important to explore, especially since ECT is known to increase CNS dopamine — which in theory could worsen psychosis, suggesting additional mechanisms to its efficacy.
Identification of predictors of response is also an important area.
Dr Sanghani: More research with adequate sample sizes is needed to replicate some of the previous studies that have shown effectiveness of ECT in treatment-resistant schizophrenia and various clinical subtypes. More research is also needed to optimize the treatment protocols, (ECT parameters, frequency of ECT, duration, etc.), as well as to measure long-term outcomes of treatment efficacy as well as cognitive side effects.
A group of researchers in France have recently announced the SURECT study, which is a prospective, assessor-blind multi-site study of two protocols of ECT in clozapine-resistant schizophrenia.17 More such studies would add to our understanding of this treatment.
Studies are needed to more accurately determine the effects of ECT on various brain regions and to identify biomarkers of response — eg, can hypoactivity or hyperactivity in certain parts of brain on function magnetic resonance imaging (fMRI) predict a good response to ECT augmentation? Could there be other biomarkers of response? Drs Argyelan and Malhotra from our group are conducting fMRI studies to address that question. More such studies are needed at different sites.18 Eventually, pooled data from multiple sites or sharing of actual data in consortiums will give us better answers.
Further research is needed to explore ways to reduce cognitive side effects. For example, recent electric field (EF) modeling studies suggest that the increase in hippocampus volume due to ECT is related to EF and is responsible for therapeutic efficacy as well as cognitive side effects. Determining the right amount of current to induce an electric field just enough to cause therapeutic neuroplasticity in the hippocampus without cognitive side effects would be one such approach and would lead to individualization of treatment parameters for each patient after a baseline MRI and EF modeling.19,20
Another approach is magnetic seizure therapy, in which magnetic fields are used instead of electricity to induce a more focal seizure.21
References
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3. Braga RJ, John M, Schooler NR, et al. Continuation electroconvulsive therapy for patients with clozapine-resistant schizophrenia: a pilot study. J ECT. 2019;35(3):156-160. doi:10.1097/YCT.0000000000000588
4. McClintock SM, Ranginwala N, Husain MM. Electroconvulsive therapy. In: KT Mueser and DV Jeste (eds.), Clinical handbook of schizophrenia. The Guilford Press. 2008;196–204
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10. Wang G, Zheng W, Li XB, et al. ECT augmentation of clozapine for clozapine-resistant schizophrenia: a meta-analysis of randomized controlled trials. J Psychiatr Res. 2018;105:23-32. doi:10.1016/j.jpsychires.2018.08.002
11. Chanpattana W, Chakrabhand ML, Sackeim HA, et al. Continuation ECT in treatment-resistant schizophrenia: a controlled study. J ECT. 1999 Sep;15(3):178-92. PMID: 10492856.
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13. Cummings MA, O’Day JA. Should electroconvulsive therapy (ECT) be banned for schizophrenia? CNS Spectr. 2021;1:1-3. doi:10.1017/S1092852921000109
14. Read J, Cunliffe S, Jauhar S, McLoughlin DM. Should we stop using electroconvulsive therapy? BMJ. 2019;364:k5233. doi:10.1136/bmj.k5233
15. van Diermen L, van den Ameele S, Kamperman AM, et al. Prediction of electroconvulsive therapy response and remission in major depression: meta-analysis. Br J Psychiatry. 2018;212(2):71-80. doi:10.1192/bjp.2017.28
16. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901
17. Moulier V, Krir MW, Dalmont M; SURECT Group, Guillin O, Rothärmel M. A prospective multicenter assessor-blinded randomized controlled study to compare the efficacy of short versus long protocols of electroconvulsive therapy as an augmentation strategy to clozapine in patients with ultra-resistant schizophrenia (SURECT study). Trials. 2021;22(1):284. doi:10.1186/s13063-021-05227-3
18. Argyelan M. Neural biomarkers of ECT response in schizophrenia. National Institutes of Health. Accessed January 23, 2022.
19. Argyelan M, Lencz T, Kang S, et al. ECT-induced cognitive side effects are associated with hippocampal enlargement. Transl Psychiatry. 2021;11(1):516. doi:10.1038/s41398-021-01641-y
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21. Jiang J, Zhang C, Li C, et al. Magnetic seizure therapy for treatment-resistant depression. Cochrane Database Syst Rev. 2021;6(6):CD013528. doi:10.1002/14651858.CD013528.pub2
