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Greetings from Boston, Massachusetts. This is Oliver Freudenreich, or Dr. F, presenting for the Psychopharmacology Institute.
Today, I address clozapine augmentation with electroconvulsive therapy (ECT). Although seemingly a niche subject, it is pertinent for practitioners treating individuals with treatment-resistant schizophrenia and prescribing clozapine, as this clinical dilemma will arise. What actions do you undertake when patients exhibit no response to clozapine?
Here is a guarded secret I share with my trainees regarding clozapine: A substantial fraction of individuals initiated on clozapine for treatment resistance will not experience significant improvement. I inform patients and their families during clozapine discussions that the probability of a positive response is approximately 50/50. Consequently, you might face the challenge of managing patients who, despite intensive efforts, including clozapine administration, fail to improve substantially. What is the subsequent strategy?
The article chosen for this Quick Take is courtesy of colleagues from Zagreb, Croatia. They engaged patients with treatment-resistant schizophrenia, assigning them to receive either clozapine alone or clozapine augmented with ECT over 8 weeks. Assignment to the treatment groups depended on whether the patient exhibited mere treatment resistance or both treatment resistance and clozapine resistance, based on the Treatment Response and Resistance in Psychosis Working Group Criteria. Interestingly, this was not a random assignment; instead, historical data and the nature of patients’ treatment resistance influenced their group placement. The basic treatment-resistant group underwent clozapine therapy (it remains ambiguous at which point they entered the trial), whereas the augmentation group, identified by their nonresponse to clozapine, had ECT implemented—administered bilaterally 3 times weekly for the first month, then biweekly for the subsequent month.
Assessments at the commencement and conclusion of the 8 weeks involved standard psychopathology scales for psychosis or schizophrenia trials—namely, the Clinical Global Impressions Scale (CGI) and the Positive and Negative Syndrome Scale (PANSS)—conducted by evaluators unaware of the patients’ group designation. The study ultimately comprised a relatively large sample: 30 clozapine participants and 36 participants receiving clozapine plus ECT completed the trial.
My key takeaways from the study are twofold. Firstly, the authors successfully demonstrated the existence of distinct populations within treatment-resistant schizophrenia, as evidenced by differing baseline characteristics. The ultra–treatment-resistant group was generally younger, presented lower PANSS scores, and had undergone more hospitalizations or episodes. Secondly, the administration of ECT to clozapine-resistant patients proved beneficial, with total PANSS scores reducing nearly 30%, from 87 to 68—a clinically meaningful decrease. These findings align with CGI scores, which diminished from 5.7 (markedly ill) to 3.2 (mildly ill)—changes that clinicians will find significant.
However, I perceive that the study design restricts further conclusions, as it lacked randomization and the groups were intentionally diverse. Thus, comparing treatment responses, which the authors attempted through various statistical techniques, seems less insightful than examining the ECT group independently, as I have outlined.
Clinically, procuring ECT may present obstacles, perhaps being unfeasible in certain settings, and it carries inherent risks. A crucial clinical decision emerges if a patient responds positively to ECT: What is the next step post-ECT? Many individuals eventually regress after ECT cessation. I have overseen several patients who received maintenance ECT for years, indicating its viability. Conducting serial evaluations, akin to CGI or PANSS, during the initial treatment phase, like in this study, could assist in determining whether the continued effort and risks of ECT are justified after the initial 2 months. It is pertinent to note that even minor enhancements in severely ill patients can yield substantial clinical differences. Despite persistent psychotic symptoms, for instance, a marked reduction in violent behavior significantly impacts management strategies in more regulated environments, like group homes or chronic wards.
I would like to address an often overlooked aspect: Are we genuinely augmenting clozapine, or are we observing an ECT response? Conversely, it seems illogical to augment a nonresponse. Many professionals might not realize that ECT serves as a potent treatment for psychosis. Before antipsychotics’ inception, its routine usage was testament to its efficacy. The contemporary landscape sees ECT primarily utilized for depression and catatonia.
Today’s clinical bottom line is that ECT stands as an effective remedy, extending beyond depression to include treatment-resistant psychosis. I advocate earnest consideration of ECT, especially for patients with schizophrenia who continue to suffer despite a comprehensive clozapine trial. It remains one of the more substantiated clozapine augmentation methodologies.
Thank you for listening to this Quick Take.
Abstract
Clozapine in Treatment-Resistant Schizophrenia and Its Augmentation With Electroconvulsive Therapy in Ultra-Treatment-Resistant Schizophrenia
Vjekoslav Peitl, Antonia Puljić, Mislav Škrobo, Sergej Nadalin, Lidija Fumić Dunkić, Dalibor Karlović
Clozapine is considered the gold standard for patients with treatment-resistant schizophrenia (TRS) who have previously tried other antipsychotics at adequate doses (two or more, with at least one being atypical). However, despite optimal treatment, a subgroup of TRS patients with what is known as ultra-treatment-resistant schizophrenia (UTRS) fails to respond to clozapine, which occurs in 40-70% of cases. The most common approach to manage UTRS involves augmenting clozapine with pharmacological or non-pharmacological interventions, with a growing body of evidence that supports the use of electroconvulsive therapy (ECT) as an augmenter. This prospective non-randomized 8-week study, which followed the TRIPP Working Group guidelines and is one of few that separate TRS from UTRS, aimed to evaluate the effectiveness of clozapine in TRS patients and the efficacy of ECT augmentation of clozapine in UTRS patients. Patients with TRS were assigned to receive clozapine alone (clozapine group), whereas UTRS patients received bilateral ECT in addition to their current medication regimen (ECT plus clozapine group). The severity of symptoms was evaluated using the Clinical Global Impression Scale (CGI) and Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of the 8-week trial. Both treatment approaches resulted in improved CGI and PANSS scores. The results suggest that both clozapine and ECT are effective treatment options for patients with TRS and UTRS, respectively, and that adherence to guidelines should provide a better frame for future clinical studies.
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Reference
Peitl, V., Puljić, A., Škrobo, M., Nadalin, S., Fumić Dunkić, L., & Karlović, D. (2023). Clozapine in treatment-resistant schizophrenia and its augmentation with electroconvulsive therapy in ultra-treatment-resistant schizophrenia. Biomedicines, 11(4), 1072.
