Translate this page into:
Treatment Resistant Schizophrenia and Graded Modified Electro Convulsive Therapy
*Corresponding author: Dr. Mona Srivastava, MD, Professor, Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. mona.srivastava1@bhu.ac.in
-
Received: ,
Accepted: ,
How to cite this article: Chauhan M, Mishra D, Srivastava M . Treatment Resistant Schizophrenia and Graded Modified Electro Convulsive Therapy. Acad Bull Ment Health. 2025;3:112-16. doi: 10.25259/ABMH_6_2025
Abstract
Objectives:
Schizophrenia, a debilitating psychiatric disorder, often presents with chronic and treatment- resistant symptoms. While anti-psychotic medications remain the mainstay of treatment, a subset of patients remains refractory. Reasons for treatment resistance are multiple, ranging from neurobiological anatomical to genetic, socio-familial, and personal factors, lifestyle, and pharmacodynamic factors.
Material and Methods:
A judicious mix of medication and graded modified electroconvulsive therapy (ECT) is mostly helpful and helps in mitigating symptoms. Here we will describe 10 cases of treatment-resistant schizophrenia, which responded to a specific tailored approach. Medication and ECT were helpful in offering a reduction of symptoms.
Results:
All 10 cases were followed for 6 months, and it was seen that the patients who had received ECT during admission and who were on maintenance ECT showed a significant decrease in the positive and negative syndrome scale (PANSS) score and improvement in their day-to-day functioning.
Conclusion:
A tailored-designed patient-specific protocol is desirable and effective.
Keywords
Clozapine
Electro-convulsive therapy (ECT)
KANE'S criteria
PANSS
Resistant Schizophrenia
INTRODUCTION
Treatment-Resistant Schizophrenia (TRS) is marked by the severity of existing symptoms, multiple relapses, hospitalizations, a deteriorating quality of life (QOL), and socio-occupational functioning.[1–3] The result is an increase in the burden of care in terms of economic and familial involvement and healthcare infrastructure.[4-9] Pharmacologically, the atypical antipsychotic clozapine has been the favored agent for TRS. Literature suggests that 40-70% of the patients do not respond to clozapine monotherapy.[6,7] Thus, alternative and cheaper options are a need for this subgroup. This subgroup of patients is the most severely affected.[8] Further clinical guidelines and operational definitions have been elaborated in recent consensus efforts.[10,11]
Objective
This study aims to present a case series of 10 patients diagnosed with chronic schizophrenia from a tertiary care center, evaluating the causes and factors behind the resistance and the role of maintenance modified electro convulsive therapy (mECT).
MATERIAL AND METHODS
A prospective analysis was conducted on a cohort of 10 patients diagnosed with chronic schizophrenia, of which five underwent maintenance ECT, anti-psychotics, and long-acting depots over 6 months at our tertiary care center. Three more were put on anti-psychotics and long-acting depots. mECT was refused by attendants due to social stigma. Two patients were administered clozapine and first-generation anti-psychotics (as mECT was refused by family members and a depot was not affordable due to financial constraints). Clinical outcomes, including symptom severity, functional status, and adverse effects, were systematically evaluated using standardized assessment tools (positive and negative syndrome scale [PANSS]).[12]
Inclusion criteria
Chronic treatment-resistant cases of schizophrenia (diagnosis by international classification of diseases (ICD)-10 and treatment resistance by modified KANE’S criteria)
Age: 18-65 years of age
The duration of treatment has been at least 2 years.
Exclusion criteria
Presence of mood disorders, schizo-affective disorder, primary delusional disorder, or other psychotic disorder not meeting criteria for schizophrenia
Medical, neurological conditions like epilepsy, Parkinson's disease, dementia
Pregnancy or breastfeeding females
Persistent non-adherence to previous treatment regimens
RESULT
Ten cases fulfilling the criteria for chronic resistant schizophrenia and assessment of clozapine resistance were also studied. The nature of symptoms was variable, including delusions of persecution, delusions of infidelity, and commanding hallucinations. This was interrupted by affective symptoms where the patient would be excited and develop familiarity [Table 1].[13]
| Adequate clozapine treatment | |
|---|---|
| Dose | 200-500 mg/dL |
| Blood levels | >350 ng/mL |
| Treatment duration | 2-3 months |
| Treatment adherence | >80% of optimized doses for treatment duration |
| Non response | <20% reduction in symptoms and lesser response in the level of functioning. |
Summary of the role of dopamine and clozapine in schizophrenia treatment. Data adapted from Howes et al. (2017) and Kane & Correll (2016).
They had sought treatment from various psychiatrists without full remission of symptoms.
Patients 1 to 5 received mECT sessions and were put on maintenance mECT. They showed a significant reduction in the PANSS score from about 25-45% [Table 2].[14]
| No. | Age and gender | Occupation | Marital status | Symptoms | Duration of symptom | Treatment received | PANSS |
|---|---|---|---|---|---|---|---|
| 1 | 29/ f | Engineer | Unmarried | Hearing of voices Delusion of persecution Irrelevant talk Muttering to self Decreased sleep Poor compliance to medications |
9 yrs | Tab Clozapine 600 mg OD Syp Valproate 10 mL BD Tab Lithium 400 mg BD Tab Lurasidone 40 mg BD Long acting depots Inj olanzapine (300 mg) every 15 days Inj flupentixol (40 mg) every week Inj paloperidone 75 mg every month ECT sessions : 8 in IPD maintenance ECT every 15 days for 3 months then once monthly |
At admission 74 At 3 month 56 At 6 month 42 |
| 2 | 45/f | Housewife | Married | Delusion of persecution Staring gaze Gesturing in air Muttering to self Decreased sleep |
11 yrs | Tab Clozapine 150 mg OD Tab Blonanserin 4mg BD Tab Lithium 300 mg BD Tab THP 2 mg BD ECT sessions : 6 in IPD Maintenance ECT Every 3 months |
At admission 66 At 3 month 48 At 6 month 34 |
| 3 | 28/f | Stays at home | Unmarried | Delusion of persecution Delusion of pregnancy Hearing of voices Muttering to self Aggressive, abusive towards family members |
6 yrs | Tab cariprazine 1.5 mg 1-x-2 Tab lurasidone 40 mg 1-x-1 Tab lithium 400 mg BD Tab oxcarabazepine 300 mg BD Tab THP (2 mg)1-1-x 6 mECT session f/b Maintenance ECT session every 1 month |
At admission 78 At 3 month 64 At 6 month 50 |
| 4 | 55/F | Housewife | Married | Delusion of persecution Aggressive abusive Muttering to self |
Tb clozapine 200mg BD Tb valproate (500) BD Tb olanzapine 20 mg HS Tb THP 4mg 1 OD Was given 6 ECT session and was put on maintenance ECT every month |
at admission 78 At 3 month 70 At 6 month 56 |
|
| 5 | 25/f | Student | Unmarried | Delusion of control Repeated sexual images Increased talk Over expenditure Muttering to self |
4 yrs | Tab clozapine 200 mg BD Tab divalproate (500) BD Tab lithium (400) BD Inj olanzapine 210 mg I/M Every 2 weeks Tab THP 2mg 1—1—x Tab fluoxetine 40 mg OD Patient had 3 ECTt session while admitted 6 months ago and was taken on maintenance mECT every 1 month |
At admission 72 At 3 month 84 (after clozapine Was removed Due to side effects At 6 months 44 |
| 6 | 46/M | Doctor | Married | Delusion of persecution Hearing of voices Muttering to self Fearfulness Poor personal care |
14 yrs | Tb clozapine(100) 1--x--2 Tb lithium(400) BD Tb lurasidone(40) 1 OD Inj paliperidone 150 mg depot f/b 100 mg and 75 mg monthly |
At 1 month 84 At 3 month 78 At 6 month 64 |
| 7 | 62/F | Homemaker | Married | Hearing of voices Decreased social interaction Easy irritability |
10 yr | Tab clozapine 200 mg HS Tab THP 2mg 2 OD Inj paloperidone 75 mg monthly |
At first day of Contact 64 At 3 month 53 At 6 month 48 |
| 8 | 48/f | Housewife | Married | Delusion of infidelity Aggressive, abusive towards husband Poor compliance to med Decreased appetite |
5 yrs. | Tab clozapine 200 mg BD Tab bupropion 150 mg BD Tab lithium 300 mg BD Tab THP 2 mg 1-1-x Tab propranolol 40 mg 1/2OD Injpaloperidone 75 mg every once month |
At admission 58 At 3 month 52 At 6 month 44 |
| 9 | 39 /M | Self employed |
Married | Hearing of voices Dec social interaction Inappropriate smile Dec sleep |
10 yrs | Tab clozapine 200 mg 1-x-2 Tab lithium 400 mg BD Tab haloperidol 5 mg OD Tab pacitane 4 mg OD |
At the first day of Contact 64 At 3 month 58 At 6 month 55 |
| 10 | 32/M | Unemployed | Unmarried | Multiple bouts of laughter Dec social interaction Gesturing in air Cognitive decline |
5 yr | Tab clozapine 250 mg OD Tab haloperidol 1.5mg BD Tab lithium 400 mg 1 HS Tab fluoxetine 20 mg OD |
At day of first contact 76 At 3 month 72 At 6 month 68 |
OD: Once daily, BD: Twice daily, THP: Trihexyphenidyl (an anticholinergic drug used in extrapyramidal symptoms), PANSS: Positive and negative syndrome scale, ECT: Electro convulsive therapy, IPD: Inpatient department, MECTP: Modified electro convulsive therapy protocol, HS: At bedtime
Patients 6, 7, and 8 receiving long-acting injectable (LAI) paloperidone, along with clozapine, also showed a 20-30% reduction in the PANSS score, as compared to patients 9 and 10, whose reductions were less than 15%.
Patient (1) was treated by various doctors but was unresponsive. This patient was administered 600 mg clozapine augmented with two mood stabilizers, valproate and lithium. After eight ECT sessions, the patient showed nearly 70% improvement on symptoms and a 43.24% reduction of the PANSS score. She was then put on maintenance ECT regularly, at 15 days, then at one month; her PANSS score was 40 and below.
Augmentation with first- and second-generation antipsychotics
Addition of first-generation antipsychotics with clozapine in patients 9 and 10 showed insignificant improvement in the PANSS score.
Similarly, in patients 1, 2, 3, 4, and 5, adding second-generation antipsychotics did not show much improvement in PANSS when assessed retrospectively. Subjective variation of patients due to recall bias can be considered.
Augmentation with mood stabilizers
Combining valproate and lithium in two of the patients helped in controlling the affective symptoms and increased libido and aggression in two of the females, while the patient only on lithium or valproate showed less improvement in overall functioning.
DISCUSSION
Determinants of schizophrenia are becoming resistant. Out of the 10 cases studied, who were taken in outpatient department (OPD) through convenience sampling, seven were females and three were males.
Females were more resistant to treatment as compared to males, with a larger number of females reported as chronic schziophrenia patients in our OPD, which is not in accordance with the usual data of females having a better prognosis
More chronic stressors, stigma in various regions, and lack of compliance due to dependency on family members can have led to the development of more chronicity in these females.
All 10 cases were followed for a period of 6 months, and it was seen that the patient who had received ECT during admission and who were on maintenance ECT showed a significant decrease in PANSS score and improvement in their day-today functioning [Table 3].
| Patient | Percentage reduction in PANSS |
|---|---|
| 1 | 43.24% |
| 2 | 48.4% |
| 3 | 35.89% |
| 4 | 28.2% |
| 5 | 38.8% |
| 6 | 23.8% |
| 7 | 25% |
| 8 | 24.13% |
| 9 | 14.06% |
| 10 | 11.08% |
PANSS: Positive and negative syndrome scale
Patients who received maintenance ECT every month, as compared to every three months, showed better control of symptoms and reduction in the PANSS score, both 1 month/3 month graded mECT patients were better as compared to patients plainly on clozapine.
Augmentation with mood stabilizers showed better improvement in controlling affective symptoms and aggression compared to clozapine alone.
Keeping the patients on once a fortnight injectable like LAI olanzapine paloperidone showed symptoms controlled at a baseline level and was effective in patients who had poor compliance with medications. The newer depot of paliperidone was tried in patients and proved to be effective in improving compliance. For chronic schizophrenic patients not showing any improvement in clozapine maintenance, ECT has proven to be the most effective way.
Preparing a module for maintenance ECT/graded ECT
For maintenance therapy, mECT may be administered every month or every three months, depending on the patient’s clinical condition and response to the treatment.
Treatment schedules can be individualized after assessing the patient’s symptoms, side effects, and overall progress before determining the appropriate frequency of mECT.
Education involving misconceptions about mECT should be given to patients so that more people with resistance can benefit from it.
Limitations
The sample size was small (n=10), studies involving larger populations need to be done
In these patients, economically viable versions like haloperidol deconate were not tried for the potential development of EPS. The probability of the safe 1st generation depot was likely to be lesser; hence, second-generation depots were tried.
Limited follow-up period
Ethical issues, including the potential risks of mECT (like cognitive side effects) in vulnerable populations, may be harder to address comprehensively in a small case series.
CONCLUSION
An individualized treatment plan combining graded mECT with suitable medications demonstrated effectiveness in managing treatment-resistant schizophrenia. Monthly maintenance ECT led to greater improvement in symptoms and PANSS scores. These findings underscore the value of personalized strategies in improving outcomes for this challenging patient group.
Authors’ contributions:
MC: Collected and curated the clinical data; MS: Provided the cases, supervised the clinical management, and guided the study design; DM: Drafted, structured, and edited the manuscript; all authors reviewed and approved the final version.
Ethical approval:
The research/study approved by the Institutional Ethics Committee at Banaras Hindu University, Institute of Medical Sciences, Ref:IMS/IEC/2025/7996, dated 25th June 2020.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI
Financial support and sponsorship: Nil.
References
- Dopamine Synthesis Capacity in Patients with Treatment-resistant Schizophrenia. Am J Psychiatry. 2012;169:1203-10.
- [CrossRef] [PubMed] [Google Scholar]
- Treatment-Resistant Schizophrenia: Current Insights on the Pharmacogenomics of Antipsychotics. Pharmgenomics Pers Med. 2016;9:117-29.
- [CrossRef] [PubMed] [Google Scholar]
- Schizophrenia: An Integrated Sociodevelopmental-cognitive Model. Lancet. 2014;383:1677-8.
- [CrossRef] [PubMed] [Google Scholar]
- The Dopamine Hypothesis of Schizophrenia: Version III-The Final Common Pathway. Schizophrenia Bulletin. 2009;35:549-62.
- [CrossRef] [PubMed] [Google Scholar]
- Childhood Trauma, Psychosis and Schizophrenia: A Literature Review with Theoretical and Clinical Implications. Acta Psychiatr Scand. 2005;112:330-50.
- [CrossRef] [PubMed] [Google Scholar]
- Treatment-resistant Schizophrenia: Evidence-based Strategies. Mens Sana Monogr. 2012;10:20-32.
- [CrossRef] [PubMed] [Google Scholar]
- Half a Century of Antipsychotics and Still a Central Role for Dopamine D2 Receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:1081-90.
- [CrossRef] [PubMed] [Google Scholar]
- Expressed Emotion and Psychiatric Relapse: A Meta-analysis. Arch Gen Psychiatry. 1998;55:547-52.
- [CrossRef] [PubMed] [Google Scholar]
- Treatment-resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry. 2017;174:216-29.
- [CrossRef] [PubMed] [Google Scholar]
- Treatment of Patients with Schizophrenia. American Psychiatric Association. 2010;1:104-13.
- [Google Scholar]
- The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophrenia bulletin. 1987;13:261-76.
- [CrossRef] [PubMed] [Google Scholar]
- The Role of Clozapine in Treatment-resistant Schizophrenia. JAMA Psychiatry. 2016;73:187-8.
- [CrossRef] [PubMed] [Google Scholar]
- The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia. Biol Psychiatry. 2017;81:9-20.
- [CrossRef] [PubMed] [Google Scholar]