|Year : 2014 | Volume
| Issue : 1 | Page : 18-22
Clozapine response and pre-treatment EEG-is there some kind of relationship
Amresh Shrivastava1, Megan Johnston2, Nilesh Shah3, Larry Stitt4, Shivanshu Shrivastava3, Avinash De Sousa3
1 Department of Psychiatry, Elgin Early Intervention Program for Psychosis, The University of Western Ontario, Ontario, Canada; Mental Health Resource Foundation, Mumbai, Maharashtra, India
2 Department of Psychology, University of Toronto, Toronto, Ontario, Canada
3 Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India
4 Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
|Date of Web Publication||18-Nov-2014|
Avinash De Sousa
Carmel, 18, St. Francis Road, Off S. V. Road, Santacruz West, Mumbai - 400 054, Maharashtra, India
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Clozapine has been used widely in the management of treatment-resistant schizophrenia. The present study aims at determining whether pre-treatment electroencephalography (EEG) abnormalities would serve as a marker for response to clozapine treatment. Subjects and Methods: This was a cross-sectional study done in a tertiary care center in Mumbai where patients diagnosed with schizophrenia using DSM-IV criteria and resistant schizophrenia using Kane criteria were assessed using EEG prior to starting clozapine treatment. They were rated for symptomatic improvement using the Positive and Negative Syndrome Scale (PANSS) along with Clinical Global Improvement for Severity (CGI-S). The results were statistically analysed and presented. Results: 55 out of the 80 patients in the study showed baseline EEG abnormalities. The mean duration of illness in the patients were 2.65 years. Slow wave and background EEG abnormalities were common in pre-treatment EEG. 36.4% patients in the study showed clinical response. Patients with negative symptoms and baseline EEG abnormalities showed better response. Conclusions: The study was circumscribed and had many limitations due to a small sample size. The relation between pre-treatment EEG abnormalities and clozapine response could not be statistically correlated and it could not be ascertained to be a marker for response to clozapine therapy.
Keywords: Clozapine, electroencephalography, electroencephalography abnormalities, schizophrenia, treatment resistant schizophrenia
|How to cite this article:|
Shrivastava A, Johnston M, Shah N, Stitt L, Shrivastava S, Sousa AD. Clozapine response and pre-treatment EEG-is there some kind of relationship. Ind Psychiatry J 2014;23:18-22
Clozapine is benzodiazepine derivative, with receptor blocking activity at dopamine receptors (D1, D2 and D4) as well as serotonin (5-HT1A and 5HT2) receptors.  Clozapine is considered a gold standard in treatment of schizophrenia, particularly for those who do not show adequate response to antipsychotic therapy.  Despite this, about 40-50% of patients treated with clozapine do not show good response, as such, its potential remains neglected.  Clozapine usage is limited since many patients who may benefit from clozapine still do not receive it because of the numerous side effects that can be life threatening at times, such as angranulocytosis, myocarditis and seizures.  There is a need to develop a reliable method to determine whether the patient will or will not respond to clozapine, as this will greatly help clinicians to decide on clozapine therapy. Similarly, a method which can identify chances of potential side effects in a patient who could be treated with clozapine will be another indicator to assert clozapine use.  Studies have been continually looking for clinical and biological factors which could predict or even indicate candidates for good response to clozapine.  Several predictors of response have been proposed; however, none of these have been met with success. 
A number of studies have reported electroencephalographic (EEG) abnormality due to clozapine, and its incidence report ranges from 16% to 75%. ,,, Numerous other studies have reported that patients who had prior EEG abnormalities responded poorly to clozapine. Patients exhibiting side effects of seizure also showed EEG abnormality and poor response to treatment. These clinical observations led to the hypothesis that patients who develop EEG abnormality during the course of clozapine therapy will have less favourable outcome.  This was widely researched but the results remain inconclusive. Within the general population, electroencephalogram (EEG) abnormalities are reportedly common, likewise they are seen in both acute and chronic, as well as treatment resistant and drug naïve first episode schizophrenia patients as well.  EEG changes also appear due to several other factors, such as psychotropic medication, particularly atypical antipsychotics, neurological comorbidity, and substance abuse, alongside numerous other factors, which are not uncommonly seen in the schizophrenia population.  Due to these confounding variables, studies have attempted to correlate both, pre-treatment and post treatment EEG abnormality with clozapine response  ; yet the results so far have not been conclusive. Since these observations remain inconclusive there may be some merit to re-examine if EEG changes can predict response to clozapine. It therefore, cannot be said if post clozapine therapy EEG changes are actually due to clozapine, or may simply be present in the pre-treatment stage. It is likely that these abnormalities are already present, and carried forward, thus being seen in the post clozapine phase. If that is the case, outcome due to clozapine amongst those who did not have EEG changes before starting clozapine, may be a better indicator for response to clozapine therapy.  The present study examines response to clozapine amongst patients having EEG abnormality prior to beginning clozapine treatment.
| Subjects and Methods|| |
This cross-sectional, prospective, cohort study was carried out in a non-governmental psychiatric hospital, in Mumbai, India. Ethics permission was obtained from the Local Independent Ethics Committee of Mumbai. Patients were recruited from an inpatient and outpatient routine clinical setting and were diagnosed as having schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Participants ranged in age from 18 to 45 years and were classified as treatment resistant as per Kane's criteria.  Participants were excluded on the basis of the following criteria: Previous trials of clozapine, having any significant medical illness, head trauma, alcoholism or substance abuse, obesity, diabetes, hypertension, neurological disorder, seizure disorder, hematological conditions, cardiac abnormality, or pregnancy. Clinical assessment and a conventional 12-channel EEG recording, which are commonly used in psychiatry, were done at baseline and 12 weeks. Baseline hemogram and biochemical investigations were also done.
The decision to start clozapine treatment was made purely on the basis of clinical need of the patient. The clinic nurse or physician explained the details of clozapine therapy to the patients and relatives. After taking consent to be treated with clozapine, treatment began. Patients were given a wash out period of 2 days after gradually stopping the older antipsychotic, benzodiazepines were used for any symptoms occurring between these 2 days, clozapine was started 25 mg per day with gradual increases weekly.
Conventional 12-channel resting stage EEG was recorded for 30 minutes, with 3 minutes of photic stimulation. Abundance of slow wave and presence of epileptogenic abnormality in EEG was considered abnormal, as decided by visual impression. EEG interpretation and analysis was completed by an experienced EEG technician. Psychopathology was measured by Positive and Negative Symptom Scales (PANSS)  and the Clinical Global Impression Scale (CGIS).  Outcome criterion was measured as a clinical response of less than or equal to 2 on the CGIS, or a 30% or more reduction on the total PANSS score. In addition, negative and positive symptom scores of less than 14, from base to endpoint, were indicative of clinical response. Data were statistically analyzed by comparing patients with and without EEG changes before starting clozapine and outcome at 12 weeks.
| Results|| |
Total 80 patients completed the 12-week treatment with clozapine; 25 participants did not present with baseline EEG abnormality, whereas 55 patients did exhibit abnormal baseline EEG. Patient clinical and demographic characteristics are given in [Table 1]. The majority of participants were males (82.5% male, 17.5% female), with a mean age of 33 years and a duration of illness of 2.65 years. There was no significant difference in the patients' samples between those who had pre-clozapine EEG abnormality and those who did not; therefore, the two groups are comparable across all aspects, regardless of baseline abnormalities.
Fifty-five patients had abnormal EEG at baseline, which increased at the end of the 12-week treatment. Most of the abnormality was seen in slow wave background activity. In all, 36.4% of patients showed response to clozapine based upon CGIS and a 30% reduction in PANSS. Composite EEG abnormality at the baseline did not correlate with any of the outcome criteria at the 12-week endpoint, excluding negative symptoms that showed a positive correlation; however, it missed statistical significance (40% at baseline vs. 20% at endpoint, P = 0.060). Patients with negative symptoms and EEG abnormalities at baseline showed better outcome. In conclusion, there was no statistically significant correlation between the presence of EEG abnormality and outcome of clozapine treatment after 12 weeks [Table 2].
| Discussion|| |
EEG abnormality is seen in various aspects of schizophrenia, particularly first episode psychosis or following exposure to typical and atypical antipsychotics.  EEG abnormality may also appear due to previous head injury, postnatal complication, subclinical seizures and several other factors, including EEG abnormality that did not normalize due to antipsychotic treatment.  The use of antipsychotic drugs, specifically clozapine produces mainly slow wave epileptiform abnormalities. , At the very least, EEG abnormality seen in pre-clozapine treatment may be due to a combination of abnormalities seen in schizophrenia, as well as prior antipsychotic usage before clozapine therapy. EEG abnormality due to clozapine is well described. , A number of studies have shown increases in abnormal EEG after clozapine treatment, ranging from 16% to 75% of patients.  Researchers examined EEG changes in 323 hospitalized patients and reports that EEG abnormality risk varied widely among specific antipsychotics. In particular, risk was high in clozapine and olanzapine, moderate with risperidone and typical neuroleptics, and low with quetiapine. In addition, comorbid hypertension, bipolarity, and older age - but not dose or clinical responses-are associated with risk.  The present study shows that some patients may have an abnormal EEG at baseline, the most common of which was the abundance of slow wave, alpha wave and the occasional epileptogenic activity. The patients with first episode psychosis attending the hospital were treated, and those who developed treatment resistance were screened for clozapine therapy. It is not possible to comment if the pre-clozapine EEG abnormalities existed since the time when antipsychotics were prescribed for the first time. Abnormalities were seen in slow wave and epileptogenic activity. We measured slow wave, sharp wave, and background theta activity and developed a composite abnormality for comparative purposes.
Our study has attempted to examine if the presence of EEG abnormality before starting clozapine can differentiate between those who show good response at the end of 12 weeks, and those who did not show good outcome as per defined criteria. We found that pre-treatment EEG abnormality did not correlate with clozapine response at 12 weeks. There are very few reports about the negative association of baseline EEG and clinical response. It is a sparsely studied area, particularly with conventional EEG. Although independently all EEG parameters show worsening, none of these have been found to be significant in predicting response to clozapine on clinical parameters. Although many studies have shown a positive association in this regard ,, , others have observed negative results. Another study from a cohort of 15 patients reported that EEG abnormalities occurred more frequently (64%) in schizophrenic patients who receive clozapine, yet the EEG changes do not necessarily predict the occurrence of convulsions.  On the other hand, one study showed the possibility of predicting response by pre-treatment EEG.  The correlation of outcome and baseline EEG still remains equivocal; similarly, correlation of EEG changes after treatment with clozapine also remains inconclusive. There is some evidence to suggest a favorable clinical response in specific groups of patients predicted by EEG abnormalities before clozapine treatment. In another study, pre-treatment intra-hemispheric asymmetry on EEG predicted short-term response to clozapine treatment in schizophrenia.  A number of authors have investigated the factors associated with response to clozapine, but findings are contradictory. Reviewing the evidence, some suggested that as of yet, there are no predictors of response to clozapine, rather, there are only markers of response. 
The mechanism of action of clozapine-induced seizures, as well as for EEG abnormality is unknown. EEG abnormality occur independent of clinical seizure, and there is no information on follow-up of patients who had EEG abnormality to examine if in future they develop seizures. Thus, it is not clear if these EEG changes are sub-threshold for seizures, though acetylcholine, nicotinic, gamma-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA) and 5-HT 2A have been implicated. Experimental studies do suggest the possibility of kindling. ,,
| Conclusions|| |
Electrophysiological changes in schizophrenia itself is complex, and it is so far not clear why there are EEG abnormalities, specifically how such abnormalities reduce the outcome in schizophrenia. Our study has limitations to make a strong case because of the use of conventional EEG, visual analysis of EEG, lack of strict research design, small sample size and poor methodology and measurements. Based on the findings, it can be concluded that pre-treatment EEG abnormality does not show any correlation with any of the outcome parameters, after 12 weeks of clozapine treatment. It is disappointing, but future studies with good methodology and design will be very helpful in this complex area of routine clinical practice.
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[Table 1], [Table 2]