- Email: [email protected]
ECT rekindles pharmacological response in schizophrenia
European Psychiatry 24 (2009) 521–525
Original article
ECT rekindles pharmacological response in schizophrenia H. Hustig 1, R. Onilov 2,* Central Northern Adelaide Health Service, Royal Adelaide Hospital, Adelaide, Australia Received 13 November 2008; received in revised form 14 April 2009; accepted 15 April 2009 Available online 24 June 2009
Abstract Objective: The aim of our naturalistic-observational study was to determine the efficacy and utility of electroconvulsive therapy (ECT) in clinical population of individuals with schizophrenia where pharmacological response was suboptimal. Methods: The cohort comprised 27 patients suffering from schizophrenia with refractoriness to antipsychotic agents and with severe, disabling symptoms. They only interventional assessing tool was clinical global impression (CGI-S) performed at the baseline and at the end of the treatment. Results: The administration of ECT resulted in overall clinical improvement reflected in CGI scales and descriptions in clinical notes. On 12 months follow-up period, 10 patients (37.1%) maintained improvement and were able to continue with pharmacological therapy only, suggesting its rekindling effect, especially with Clozapine. Conversely, 17 patients (62.9%) deteriorated and required an additional course of ECT to maintain improvement. In some cases, maintenance ECT treatment was required. The group who engaged in self-harming behaviour at baseline demonstrated they were more likely to relapse into psychosis at the end of the first course of ECT, their self-harming behaviour abated, especially when maintenance ECT was undertaken. Conclusions: Although limited by lack of control group, small sample size, heterogeneous symptom profiles and various concurrent neuroleptic agents, the ECT proved as valuable and safe augmentative procedure when unsatisfactory response to pharmacological interventions had been demonstrated prior to interventions. This effect was evident despite the chronicity of the illness. # 2009 Elsevier Masson SAS. All rights reserved. Keywords: ECT; Schizophrenia; Pharmacological responsiveness
1. Introduction 1.1. Brief historical review Despite a controversial history, electroconvulsive therapy (ECT) represents an efficient and safe treatment procedure. Ugo Cerletti in association with Lucio Bini and L.B. Kalinowski first used ECT in April 1938 in human subject diagnosed with schizophrenia with significant improvement. ECT received a worldwide acclaim in 1939 with expansion of its use in affective disorders due to the promotional input of Kalinowski. In 1960s–1970s, the use of ECT decreased significantly due to neuroleptic era and stigma associated with ECT and use in schizophrenia was reduced to
* Corresponding author. 5/21 Giles St, Toorak Gardens, SA 5065, Australia. Tel.: +61 8 83311324, +61 439578617 (mob). E-mail address: [email protected] (R. Onilov). 1 Rehabilitation Services, Glenside Campus, CNAHS, Adelaide, Australia. 2 Emergency Department, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia.
the catatonic subtype. Over the last 20 years, it regained its faded popularity in treatment of affective disorders of patients who are treatment-resistant to pharmacological agents [12,14,16]. In schizophrenia, it appears that efficacy rates in of ECT being given in combination with antipsychotics varies significantly but could be estimated ranging between 50–70%. Kupchik et al. [10] assessed 36 patients who were treated with combination of ECT-Clozapine because of refractoriness to antipsychotic agents and ECT alone. According to authors, 67% of the patients showed satisfactory clinical improvement suggesting that such a combination may be a therapeutic option. In their study, Petrides and Mendelowitz [13] reported a greater than 40% reduction in BPRS psychosis scores in seven of 12 patients (58.3%) who had failed multiple medication trials, including high doses of Clozapine for extended durations. Konig and Glatter-Gotz [9] used ECT in 13 patients diagnosed with schizophrenia who showed resistance to neuroleptics. The average number of ECT treatments ranged
0924-9338/$ – see front matter # 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.04.005
522
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525
between six and 20. According to their results, nine patients achieved stable remission. The reduction of aggressive behaviours (non-responsive pharmacotherapy) is often used as an indication for ECT. Hirose et al. [5] conducted an open trial involving 10 male individuals examining the efficacy of ECT in combination with Risperidone in schizophrenic patients with prominent aggressive behaviour. The aggressive behaviour in five of the six patients, experiencing positive symptoms, was abolished in 12 days. The remaining four patients, mostly presenting with negative features, improved in 10 days. Nine patients showed no signs of exacerbation for a period of 6 months. A similar study by Tang et al. [17] involved 15 patients with treatment-resistant schizophrenia who were given eight to 20 ECT sessions and their previous antipsychotics were maintained. Patients demonstrated that assessment after each ECT treatment made a noticeable improvement in the GAS and clinical global impression (CGI). Final assessment performed at 2 months after first session revealed improvement in the BPRS and SANS scores and improved in social functioning. 1.2. Mechanisms of actions Due to complex impact on brain functionality, there are multiple theories associated with the mechanisms of action of the ECT. It appears rather difficult to isolate the most likely one applicable to symptom reduction in schizophrenia. Recent neuromodulating effects of ECT have shown a link between application of the electroconvulsive seizure and enhanced proliferation of the endothelial cells in the paraventricular nucleus, supraoptic nucleus and ventromedial nucleus of the hypothalamus which are thought to be associated in pathophysiology of affective disorders [7]. There is growing evidence of impact of ECT on brain-derived neurotropic factor with subsequent influence on neuroproliferation and serotonin and noradrenaline neurotransmitter systems. However, dopamine pathways dominate the understanding of the pathophysiology of schizophrenia. According to some studies, the rise of the serum prolactin level as a response to ECT was accompanied by a slight but significant decrease of the serum dopamine-beta-hydroxylase activity. A significant negative correlation was found between baseline serum dopamine-beta-hydroxylase activity and prolactin response. These data indicate a correlation between serum dopaminebeta-hydroxylase activity and central dopaminergic function. Prolactin response to ECT is supposed to be the result of the dopaminergic action of ECT [1]. Evidences of enhanced dopamine synthesis, turnover and dopamine mediated behaviour [4,11,15] are postulated mechanism of ECT effectiveness in schizophrenia. 2. Materials and methods Initially, the observation study was performed at the Clinical Psychiatric Hospital, Chisinau, Republic of Moldova and subsequently at the Glenside Campus Mental Health Service, Adelaide, Australia.
During this 3-year naturalistic study, 27 treatment-refractory patients with chronic, unremitting schizophrenia received a variable number of ECT treatments as adjunctive component for augmentation of neuroleptic therapy. The data collection for this study was based on evaluation of clinical records of these patients. The only intervention consisted of completion by treating clinicians of CGI-S at baseline and at the end of therapy. The sub-classification of patients suffering from schizophrenia refractory to neuroleptic therapy, according to ICD-10, is as follows: 19 patients were diagnosed with paranoid type, three patients with catatonic type and five patients were assessed as suffering from undifferentiated type. The criteria for treatment refractoriness were the lack of response after at least two 6-week trials of neuroleptics and the CGI score of four or more. The main indications for ECT were symptom severity combined with an intolerance of Clozapine and associated side effects, refractoriness to antipsychotics, including to Clozapine, refusal to accept Clozapine and finally unsatisfactory clinical improvement after commencement of Clozapine. All subjects were males with age ranging from 18 to 37 years (mean 30.16) with length of illness from 1.5 to 19 years (mean 10.40). Predominant clinical presentations were consistent with paranoid, paranoid-hallucinatory and catatonic-paranoid syndromes associated with self-harming and/or violent behaviour. In all cases, ECT had been given in bitemporal placement. The treatment was given twice or thrice weekly. For anaesthetic purposes, Propofol was used in all cases, whereas muscle relaxation was induced by Suxamethonium. After each ECT session, patients were evaluated in order to determine the need for further treatment and to exclude any adverse event. 3. Results No one from the cohort experienced any major adverse reactions from ECT treatment. There was transient post-ictal confusion in few patients which resolved subsequently with no reported sequelae. The occurrence of confusion was effectively combated by increasing the intervals between treatments from thrice to twice weekly. Number of ECT treatments applied ranged from eight to 14 (mean 11.68) (Table 1). According to the follow-up over the period of 12 months after applied ECT, 10 (37.1%) out of 27 patients maintained clinical improvement; they showed an improvement of at least two points on the CGI at the end of therapy. Of the remaining, 17 (62.9%) relapsed within 12 months, six patients improved by one point and eleven patients improved by two points on the CGI at the end of the first course of ECT. A second trial of ECT was undertaken with eight of the 17 continuing on maintenance ECT. Five out of the 17 who relapsed within 12 months were at a high risk for self-harm or actually self-inflicted bodily damage; these five stopped this behaviour following a second course of ECT or with maintenance ECT despite a partial recurrence of psychotic symptoms. The rationale for maintenance treatment has been determined by benefits after first and second treatments, improved
Table 1 n
Age
Duration of illness (years)
18
2
2 3 4
19 21 21
3 2 3
5 6 7 8
22 23 23 25
5 5 4 6
9 10
25 25
4 8
11 12
26 27
7 8
13
28
8
14 15
29 28
9 6
16 17
28 31
10 11
18 19 20
32 32 35
13 14 17
21
35
16
22 23 24 25 26 27
36 36 36 37 37 37
16 18 16 17 18 19
Medication prior to electroconvulsive therapy
CGI prior to electroconvulsive therapy
CGI post-electroconvulsive therapy
Number of electroconvulsive therapy sessions
Duration of clinical improvement (12 months follow-up)
Repetitive set of electroconvulsive therapy (within 12 months follow-up)
Maintenance electroconvulsive therapy (within 12 months follow-up)
Paranoid Aggressive behaviour Paranoid Paranoid Undifferentiated Self-harm Paranoid Paranoid Catatonic Paranoid Self-harm Paranoid Undifferentiated Self-harm Catatonic Paranoid Self-harm Paranoid Aggressive behaviour Paranoid Undifferentiated Self-harm Catatonic Paranoid
Haloperidol
6
4
12
12 months
No
No
Sulpiride Chlorpromazine, Sulpiride Thioridazine
7 6 6
5 4 5
12 10 8
1.5 months 6.5 months 2 months
Yes Yes Yes
No No Yes
Haloperidol Trifluoperazine Risperidone Chlorpromazine Haloperidol Sulpiride Olanzapine
7 5 7 6
5 4 4 4
12 14 9 14
12 months 2 months 12 months 3 weeks
No Yes No Yes
No No No Yes
5 7
4 5
12 12
2.5 months 3 months
Yes Yes
Yes Yes
Haloperidol Chlorpromazine Trifluoperazine Clozapine
6 7
4 5
9 12
12 months 5 weeks
No Yes
No Yes
6
4
16
12 months
No
No
Triflouperazine Zuclopenthixol decanoate Olanzapine Haloperidol Haloperidol Thioridazine Olanzapine Haloperidol Clozapine
6 7
4 5
10 12
7 months 2 months
Yes Yes
No Yes
7 5
4 4
8 11
12 months 3 months
No Yes
No No
6 6 6
4 5 4
12 10 16
5 weeks 4 months 12 months
Yes Yes No
Yes No No
Fluphenazine
6
4
12
12 months
No
No
Haloperidol Pimozide Trifluoperazine Haloperidol Haloperidol Risperidone
6 6 7 6 6 6
4 4 5 5 4 5
11 14 12 12 12 10
12 months 8 months 1 month 2.5 months 12 months 2 months
No Yes Yes Yes No Yes
No No Yes No No No
Undifferentiated Paranoid Paranoid Aggressive behaviour Paranoid Aggressive behaviour Paranoid Undifferentiated Paranoid Paranoid Paranoid Paranoid
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525
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Clinical syndrome
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524
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525
functioning and recurrence of symptoms after completion of the course. The usual pattern of administering ECT for maintenance purposes consisted of initially of one session weekly for 1 month then frequency was reduced to one ECT treatment fortnightly over next few months. From phenomenological point of view, all three patients with catatonic symptomatology improved and symptoms were absent over the 12 months of follow-up. Dividing the cohort on age and duration of illness, two distinct groups were identified. First group comprised 16 individuals of age group from 18 to 28 years with illness history less than 10 years and a second group constituted 11 patients aged from 31 to 37 years with illness duration from 10 to 19 years. The rate of relapse was similar in both groups, namely 62.5% in younger group versus 63.6% in the older group; however, the need for maintenance ECT rate was higher in younger group – 37.5% in comparison to the older group with –18.1%. Of note is the response of the two patients in whom treatment with Clozapine had been unsatisfactory prior to ECT. Following ECT their remission was maintained with Clozapine. 4. Discussion A significant proportion, up to a quarter [2], of patients suffering of schizophrenia show resistance to psychopharmacological intervention and this necessitates the need for alternative therapies. The outcome of our review supports the suggestion that administration of ECT is effective adjunctive component in cases of refractoriness to antipsychotic agents. There was a noticeable improvement in their overall CGI. During the treatment, there were no adverse clinical reactions as a result of combination of neuroleptics and ECT. However, there was a high rate of relapse, 62.9% patients relapsed shortly after cessation of electroconvulsive treatment. This required either administration of another course of ECT and/or subsequent maintenance ECT which induced a resolution of disturbing symptoms for a period of 12 months. The patients with catatonic component showed full and sustainable recovery confirming once again high response rate of this syndrome to ECT. Although relapses occurred despite treatment, the frequency, severity and duration of relapses were diminished by ECT. The patients initially presenting with high self-harm at baseline responded with significant abolition of self-harming behaviour and/or suicidal tendencies. It appears that ECT is an effective and valuable therapeutic option in patients with inadequate response to antipsychotics, even those who show poor response to Clozapine or Clozapine is contraindicated because of life-threatening side effects. This outcome replicates other available studies and case reports of the use of ECT in treatment refractory patients. ECT may provide a useful first step in management of people who refuses to accept Clozapine or refuse to undergo haematological monitoring. In these cases, ECT could be given to obtain rapid control over their symptoms and aggression. With the establishment of partial insight, Clozapine could be initiated. Although the numbers were small, Clozapine therapy
per se perpetuates clinical benefits derived from ECT and this is consistent with other core reports [3,6]. Our finding for the need for a second course of maintenance ECT supports the work of Kho et al. [8]. In an open label study of ECT as adjunctive options in 11 schizophrenic patients resistant to Clozapine, eight patients achieved a remission but five relapsed. Three out of five patients who relapsed remained stable with a second ECT course and Clozapine. Despite half a century of practice, little systematic evidence about use of ECT in chronic schizophrenia has been published. Further investigation of usage of ECT as adjunctive agent to antipsychotics in clinical cases proved to be treatment-resistant is required. Limitations of this paper include the naturalistic nature of this study and lack of independent raters of outcome. Whilst logistically more difficult to undertake there is clearly a need for the following: randomization and blinding of studies to provide higher reliability and validity of outcomes; testing of comparative efficacy with different electrode placement, namely bitemporal, unilateral and bifrontal applications; evaluation of optimal number of ECT sessions after achieving clinical response because there is no agreement yet concerning the length of treatment with divergent opinions suggesting 20 sessions or more while others supporting the amount of treatments used in treatment of depression, commonly up to 12; length and frequency of maintenance treatment in the prevention of relapse; longitudinal evaluation of remission stability in those who do not receive maintenance therapy, with clearer guidance regarding the efficacy of discrete courses of ECT on longitudinal outcomes. Acknowledgements None. References [1] Arato M, Bagdy G. Neuroendocrine study of the mechanisms of action of electroconvulsive therapy. Neuropsychobiology 1982;8:162–8. [2] Brenner HD, Dencker SJ, Goldstein MJ, et al. Defining treatment refractoriness in schizophrenia’’. Schizophr Bull 1990;16:551–61. [3] Green A, Zalma A, Berman I, et al. Clozapine following ECT: two-step treatment. J Clin Psychiatry 1994;55:388–90. [4] Green AR, Deakin JWF. Deletion of brain noradrenaline prevents electroconvulsive shock induced enhancement of 5-hydroxytryptamine and dopamine mediated behaviour. Nature 1980;285:232–3. [5] Hirose, Shigehiro, Ashby Charles Jr R, Mills, Mark JJD. Effectiveness of ECT Combined with Risperidone Against Aggression in Schizophrenia. J ECT 2001;17:22–6. [6] James DV, Gray NS. Elective combined electroconvulsive and clozapine therapy. Int Clin Psychopharmacol 1999;14:69–72. [7] Janson L, Hellsten J, Tingström A. Region Specific Hypothalamic Neuronal Activation and Endothelial Cell Proliferation in Response to Electroconvulsive Seizures. Biol Psychiatry 2006;60:874–81.
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525 [8] Kho KH, Blansjaar BA, de Vries S, et al. Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia. Eur Arch Psychiatry Clin Neurosci 2004;254:372–9. [9] Konig P, Glatter-Gotz U. Combined electroconvulsive and neuroleptic therapy in schizophrenia refractory to neuroleptics. Schizophr Res 1990; 3:351–4. [10] Kupchik M, Spivak B, Mester R, et al. Combined electroconvulsiveclozapine therapy. Clin Neuropharmacol 2000;23:14–6. [11] Modigh K. Long term effects of electroconvulsive shock therapy on synthesis, turnover and uptake of brain monoamines. Psychopharmacology 1976;49:179–85. [12] Oprea N, Nacu A, Revenco M. Psihiatrie. Chisinau, Editura Stiinta; 1994.
525
[13] Petrides G, Mendelowitz A. Preliminary findings in ECT augmentation of clozapine in clozapine-resistant psychotic patients. Personal communication, September 2000. [14] Predescu V. Psihiatria, vol.1, Editura Medicala˘, Bucures¸ti; 1984. [15] Smith SE, Acton L, Sharp T. Enhancement of dopamine-mediated behaviour by the NMDA antagonists MK-801 and CPP: similarities with repeated electroconvulsive shock. Psychopharmacology 2004; 85–94. [16] Snejnevski G. Îndrumar în Psihiatrie. Moscova, Medicina; 1985. [17] Tang, Wai Kwong, Ungvari, Gabor S. Efficacy of Electroconvulsive therapy combined with antipsychotic medication in treatment-resistant schizophrenia: A prospective, open trial. J ECT 2002;18:90–4.
Original article
ECT rekindles pharmacological response in schizophrenia H. Hustig 1, R. Onilov 2,* Central Northern Adelaide Health Service, Royal Adelaide Hospital, Adelaide, Australia Received 13 November 2008; received in revised form 14 April 2009; accepted 15 April 2009 Available online 24 June 2009
Abstract Objective: The aim of our naturalistic-observational study was to determine the efficacy and utility of electroconvulsive therapy (ECT) in clinical population of individuals with schizophrenia where pharmacological response was suboptimal. Methods: The cohort comprised 27 patients suffering from schizophrenia with refractoriness to antipsychotic agents and with severe, disabling symptoms. They only interventional assessing tool was clinical global impression (CGI-S) performed at the baseline and at the end of the treatment. Results: The administration of ECT resulted in overall clinical improvement reflected in CGI scales and descriptions in clinical notes. On 12 months follow-up period, 10 patients (37.1%) maintained improvement and were able to continue with pharmacological therapy only, suggesting its rekindling effect, especially with Clozapine. Conversely, 17 patients (62.9%) deteriorated and required an additional course of ECT to maintain improvement. In some cases, maintenance ECT treatment was required. The group who engaged in self-harming behaviour at baseline demonstrated they were more likely to relapse into psychosis at the end of the first course of ECT, their self-harming behaviour abated, especially when maintenance ECT was undertaken. Conclusions: Although limited by lack of control group, small sample size, heterogeneous symptom profiles and various concurrent neuroleptic agents, the ECT proved as valuable and safe augmentative procedure when unsatisfactory response to pharmacological interventions had been demonstrated prior to interventions. This effect was evident despite the chronicity of the illness. # 2009 Elsevier Masson SAS. All rights reserved. Keywords: ECT; Schizophrenia; Pharmacological responsiveness
1. Introduction 1.1. Brief historical review Despite a controversial history, electroconvulsive therapy (ECT) represents an efficient and safe treatment procedure. Ugo Cerletti in association with Lucio Bini and L.B. Kalinowski first used ECT in April 1938 in human subject diagnosed with schizophrenia with significant improvement. ECT received a worldwide acclaim in 1939 with expansion of its use in affective disorders due to the promotional input of Kalinowski. In 1960s–1970s, the use of ECT decreased significantly due to neuroleptic era and stigma associated with ECT and use in schizophrenia was reduced to
* Corresponding author. 5/21 Giles St, Toorak Gardens, SA 5065, Australia. Tel.: +61 8 83311324, +61 439578617 (mob). E-mail address: [email protected] (R. Onilov). 1 Rehabilitation Services, Glenside Campus, CNAHS, Adelaide, Australia. 2 Emergency Department, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia.
the catatonic subtype. Over the last 20 years, it regained its faded popularity in treatment of affective disorders of patients who are treatment-resistant to pharmacological agents [12,14,16]. In schizophrenia, it appears that efficacy rates in of ECT being given in combination with antipsychotics varies significantly but could be estimated ranging between 50–70%. Kupchik et al. [10] assessed 36 patients who were treated with combination of ECT-Clozapine because of refractoriness to antipsychotic agents and ECT alone. According to authors, 67% of the patients showed satisfactory clinical improvement suggesting that such a combination may be a therapeutic option. In their study, Petrides and Mendelowitz [13] reported a greater than 40% reduction in BPRS psychosis scores in seven of 12 patients (58.3%) who had failed multiple medication trials, including high doses of Clozapine for extended durations. Konig and Glatter-Gotz [9] used ECT in 13 patients diagnosed with schizophrenia who showed resistance to neuroleptics. The average number of ECT treatments ranged
0924-9338/$ – see front matter # 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.04.005
522
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525
between six and 20. According to their results, nine patients achieved stable remission. The reduction of aggressive behaviours (non-responsive pharmacotherapy) is often used as an indication for ECT. Hirose et al. [5] conducted an open trial involving 10 male individuals examining the efficacy of ECT in combination with Risperidone in schizophrenic patients with prominent aggressive behaviour. The aggressive behaviour in five of the six patients, experiencing positive symptoms, was abolished in 12 days. The remaining four patients, mostly presenting with negative features, improved in 10 days. Nine patients showed no signs of exacerbation for a period of 6 months. A similar study by Tang et al. [17] involved 15 patients with treatment-resistant schizophrenia who were given eight to 20 ECT sessions and their previous antipsychotics were maintained. Patients demonstrated that assessment after each ECT treatment made a noticeable improvement in the GAS and clinical global impression (CGI). Final assessment performed at 2 months after first session revealed improvement in the BPRS and SANS scores and improved in social functioning. 1.2. Mechanisms of actions Due to complex impact on brain functionality, there are multiple theories associated with the mechanisms of action of the ECT. It appears rather difficult to isolate the most likely one applicable to symptom reduction in schizophrenia. Recent neuromodulating effects of ECT have shown a link between application of the electroconvulsive seizure and enhanced proliferation of the endothelial cells in the paraventricular nucleus, supraoptic nucleus and ventromedial nucleus of the hypothalamus which are thought to be associated in pathophysiology of affective disorders [7]. There is growing evidence of impact of ECT on brain-derived neurotropic factor with subsequent influence on neuroproliferation and serotonin and noradrenaline neurotransmitter systems. However, dopamine pathways dominate the understanding of the pathophysiology of schizophrenia. According to some studies, the rise of the serum prolactin level as a response to ECT was accompanied by a slight but significant decrease of the serum dopamine-beta-hydroxylase activity. A significant negative correlation was found between baseline serum dopamine-beta-hydroxylase activity and prolactin response. These data indicate a correlation between serum dopaminebeta-hydroxylase activity and central dopaminergic function. Prolactin response to ECT is supposed to be the result of the dopaminergic action of ECT [1]. Evidences of enhanced dopamine synthesis, turnover and dopamine mediated behaviour [4,11,15] are postulated mechanism of ECT effectiveness in schizophrenia. 2. Materials and methods Initially, the observation study was performed at the Clinical Psychiatric Hospital, Chisinau, Republic of Moldova and subsequently at the Glenside Campus Mental Health Service, Adelaide, Australia.
During this 3-year naturalistic study, 27 treatment-refractory patients with chronic, unremitting schizophrenia received a variable number of ECT treatments as adjunctive component for augmentation of neuroleptic therapy. The data collection for this study was based on evaluation of clinical records of these patients. The only intervention consisted of completion by treating clinicians of CGI-S at baseline and at the end of therapy. The sub-classification of patients suffering from schizophrenia refractory to neuroleptic therapy, according to ICD-10, is as follows: 19 patients were diagnosed with paranoid type, three patients with catatonic type and five patients were assessed as suffering from undifferentiated type. The criteria for treatment refractoriness were the lack of response after at least two 6-week trials of neuroleptics and the CGI score of four or more. The main indications for ECT were symptom severity combined with an intolerance of Clozapine and associated side effects, refractoriness to antipsychotics, including to Clozapine, refusal to accept Clozapine and finally unsatisfactory clinical improvement after commencement of Clozapine. All subjects were males with age ranging from 18 to 37 years (mean 30.16) with length of illness from 1.5 to 19 years (mean 10.40). Predominant clinical presentations were consistent with paranoid, paranoid-hallucinatory and catatonic-paranoid syndromes associated with self-harming and/or violent behaviour. In all cases, ECT had been given in bitemporal placement. The treatment was given twice or thrice weekly. For anaesthetic purposes, Propofol was used in all cases, whereas muscle relaxation was induced by Suxamethonium. After each ECT session, patients were evaluated in order to determine the need for further treatment and to exclude any adverse event. 3. Results No one from the cohort experienced any major adverse reactions from ECT treatment. There was transient post-ictal confusion in few patients which resolved subsequently with no reported sequelae. The occurrence of confusion was effectively combated by increasing the intervals between treatments from thrice to twice weekly. Number of ECT treatments applied ranged from eight to 14 (mean 11.68) (Table 1). According to the follow-up over the period of 12 months after applied ECT, 10 (37.1%) out of 27 patients maintained clinical improvement; they showed an improvement of at least two points on the CGI at the end of therapy. Of the remaining, 17 (62.9%) relapsed within 12 months, six patients improved by one point and eleven patients improved by two points on the CGI at the end of the first course of ECT. A second trial of ECT was undertaken with eight of the 17 continuing on maintenance ECT. Five out of the 17 who relapsed within 12 months were at a high risk for self-harm or actually self-inflicted bodily damage; these five stopped this behaviour following a second course of ECT or with maintenance ECT despite a partial recurrence of psychotic symptoms. The rationale for maintenance treatment has been determined by benefits after first and second treatments, improved
Table 1 n
Age
Duration of illness (years)
18
2
2 3 4
19 21 21
3 2 3
5 6 7 8
22 23 23 25
5 5 4 6
9 10
25 25
4 8
11 12
26 27
7 8
13
28
8
14 15
29 28
9 6
16 17
28 31
10 11
18 19 20
32 32 35
13 14 17
21
35
16
22 23 24 25 26 27
36 36 36 37 37 37
16 18 16 17 18 19
Medication prior to electroconvulsive therapy
CGI prior to electroconvulsive therapy
CGI post-electroconvulsive therapy
Number of electroconvulsive therapy sessions
Duration of clinical improvement (12 months follow-up)
Repetitive set of electroconvulsive therapy (within 12 months follow-up)
Maintenance electroconvulsive therapy (within 12 months follow-up)
Paranoid Aggressive behaviour Paranoid Paranoid Undifferentiated Self-harm Paranoid Paranoid Catatonic Paranoid Self-harm Paranoid Undifferentiated Self-harm Catatonic Paranoid Self-harm Paranoid Aggressive behaviour Paranoid Undifferentiated Self-harm Catatonic Paranoid
Haloperidol
6
4
12
12 months
No
No
Sulpiride Chlorpromazine, Sulpiride Thioridazine
7 6 6
5 4 5
12 10 8
1.5 months 6.5 months 2 months
Yes Yes Yes
No No Yes
Haloperidol Trifluoperazine Risperidone Chlorpromazine Haloperidol Sulpiride Olanzapine
7 5 7 6
5 4 4 4
12 14 9 14
12 months 2 months 12 months 3 weeks
No Yes No Yes
No No No Yes
5 7
4 5
12 12
2.5 months 3 months
Yes Yes
Yes Yes
Haloperidol Chlorpromazine Trifluoperazine Clozapine
6 7
4 5
9 12
12 months 5 weeks
No Yes
No Yes
6
4
16
12 months
No
No
Triflouperazine Zuclopenthixol decanoate Olanzapine Haloperidol Haloperidol Thioridazine Olanzapine Haloperidol Clozapine
6 7
4 5
10 12
7 months 2 months
Yes Yes
No Yes
7 5
4 4
8 11
12 months 3 months
No Yes
No No
6 6 6
4 5 4
12 10 16
5 weeks 4 months 12 months
Yes Yes No
Yes No No
Fluphenazine
6
4
12
12 months
No
No
Haloperidol Pimozide Trifluoperazine Haloperidol Haloperidol Risperidone
6 6 7 6 6 6
4 4 5 5 4 5
11 14 12 12 12 10
12 months 8 months 1 month 2.5 months 12 months 2 months
No Yes Yes Yes No Yes
No No Yes No No No
Undifferentiated Paranoid Paranoid Aggressive behaviour Paranoid Aggressive behaviour Paranoid Undifferentiated Paranoid Paranoid Paranoid Paranoid
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525
1
Clinical syndrome
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functioning and recurrence of symptoms after completion of the course. The usual pattern of administering ECT for maintenance purposes consisted of initially of one session weekly for 1 month then frequency was reduced to one ECT treatment fortnightly over next few months. From phenomenological point of view, all three patients with catatonic symptomatology improved and symptoms were absent over the 12 months of follow-up. Dividing the cohort on age and duration of illness, two distinct groups were identified. First group comprised 16 individuals of age group from 18 to 28 years with illness history less than 10 years and a second group constituted 11 patients aged from 31 to 37 years with illness duration from 10 to 19 years. The rate of relapse was similar in both groups, namely 62.5% in younger group versus 63.6% in the older group; however, the need for maintenance ECT rate was higher in younger group – 37.5% in comparison to the older group with –18.1%. Of note is the response of the two patients in whom treatment with Clozapine had been unsatisfactory prior to ECT. Following ECT their remission was maintained with Clozapine. 4. Discussion A significant proportion, up to a quarter [2], of patients suffering of schizophrenia show resistance to psychopharmacological intervention and this necessitates the need for alternative therapies. The outcome of our review supports the suggestion that administration of ECT is effective adjunctive component in cases of refractoriness to antipsychotic agents. There was a noticeable improvement in their overall CGI. During the treatment, there were no adverse clinical reactions as a result of combination of neuroleptics and ECT. However, there was a high rate of relapse, 62.9% patients relapsed shortly after cessation of electroconvulsive treatment. This required either administration of another course of ECT and/or subsequent maintenance ECT which induced a resolution of disturbing symptoms for a period of 12 months. The patients with catatonic component showed full and sustainable recovery confirming once again high response rate of this syndrome to ECT. Although relapses occurred despite treatment, the frequency, severity and duration of relapses were diminished by ECT. The patients initially presenting with high self-harm at baseline responded with significant abolition of self-harming behaviour and/or suicidal tendencies. It appears that ECT is an effective and valuable therapeutic option in patients with inadequate response to antipsychotics, even those who show poor response to Clozapine or Clozapine is contraindicated because of life-threatening side effects. This outcome replicates other available studies and case reports of the use of ECT in treatment refractory patients. ECT may provide a useful first step in management of people who refuses to accept Clozapine or refuse to undergo haematological monitoring. In these cases, ECT could be given to obtain rapid control over their symptoms and aggression. With the establishment of partial insight, Clozapine could be initiated. Although the numbers were small, Clozapine therapy
per se perpetuates clinical benefits derived from ECT and this is consistent with other core reports [3,6]. Our finding for the need for a second course of maintenance ECT supports the work of Kho et al. [8]. In an open label study of ECT as adjunctive options in 11 schizophrenic patients resistant to Clozapine, eight patients achieved a remission but five relapsed. Three out of five patients who relapsed remained stable with a second ECT course and Clozapine. Despite half a century of practice, little systematic evidence about use of ECT in chronic schizophrenia has been published. Further investigation of usage of ECT as adjunctive agent to antipsychotics in clinical cases proved to be treatment-resistant is required. Limitations of this paper include the naturalistic nature of this study and lack of independent raters of outcome. Whilst logistically more difficult to undertake there is clearly a need for the following: randomization and blinding of studies to provide higher reliability and validity of outcomes; testing of comparative efficacy with different electrode placement, namely bitemporal, unilateral and bifrontal applications; evaluation of optimal number of ECT sessions after achieving clinical response because there is no agreement yet concerning the length of treatment with divergent opinions suggesting 20 sessions or more while others supporting the amount of treatments used in treatment of depression, commonly up to 12; length and frequency of maintenance treatment in the prevention of relapse; longitudinal evaluation of remission stability in those who do not receive maintenance therapy, with clearer guidance regarding the efficacy of discrete courses of ECT on longitudinal outcomes. Acknowledgements None. References [1] Arato M, Bagdy G. Neuroendocrine study of the mechanisms of action of electroconvulsive therapy. Neuropsychobiology 1982;8:162–8. [2] Brenner HD, Dencker SJ, Goldstein MJ, et al. Defining treatment refractoriness in schizophrenia’’. Schizophr Bull 1990;16:551–61. [3] Green A, Zalma A, Berman I, et al. Clozapine following ECT: two-step treatment. J Clin Psychiatry 1994;55:388–90. [4] Green AR, Deakin JWF. Deletion of brain noradrenaline prevents electroconvulsive shock induced enhancement of 5-hydroxytryptamine and dopamine mediated behaviour. Nature 1980;285:232–3. [5] Hirose, Shigehiro, Ashby Charles Jr R, Mills, Mark JJD. Effectiveness of ECT Combined with Risperidone Against Aggression in Schizophrenia. J ECT 2001;17:22–6. [6] James DV, Gray NS. Elective combined electroconvulsive and clozapine therapy. Int Clin Psychopharmacol 1999;14:69–72. [7] Janson L, Hellsten J, Tingström A. Region Specific Hypothalamic Neuronal Activation and Endothelial Cell Proliferation in Response to Electroconvulsive Seizures. Biol Psychiatry 2006;60:874–81.
H. Hustig, R. Onilov / European Psychiatry 24 (2009) 521–525 [8] Kho KH, Blansjaar BA, de Vries S, et al. Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia. Eur Arch Psychiatry Clin Neurosci 2004;254:372–9. [9] Konig P, Glatter-Gotz U. Combined electroconvulsive and neuroleptic therapy in schizophrenia refractory to neuroleptics. Schizophr Res 1990; 3:351–4. [10] Kupchik M, Spivak B, Mester R, et al. Combined electroconvulsiveclozapine therapy. Clin Neuropharmacol 2000;23:14–6. [11] Modigh K. Long term effects of electroconvulsive shock therapy on synthesis, turnover and uptake of brain monoamines. Psychopharmacology 1976;49:179–85. [12] Oprea N, Nacu A, Revenco M. Psihiatrie. Chisinau, Editura Stiinta; 1994.
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