Summations
∙ The existing data suggest that combination of clozapine and electroconvulsive therapy is useful in managing patients who have treatment-resistant schizophrenia or who are refractory to clozapine alone.
∙ In terms of side-effects, there is a need to monitor patients carefully for side-effects like tachycardia, prolonged seizures and delirium.
Consideration
∙ Most evidence stems from case reports and case studies.
∙ Limited data are available with regard to the combined use of clozapine and electroconvulsive therapy.
Introduction
Clozapine is an atypical antipsychotic, which is usually reserved for patients with schizophrenia who have treatment resistance, because of its side-effect profile. Available evidence suggests that compared with other antipsychotics, clozapine has superior efficacy/effectiveness among patients with treatment-resistant schizophrenia (TRS) (Reference Kane, Honigfeld, Singer and Meltzer1,Reference Meltzer2). However, it is now increasingly becoming evident that significant proportions (40–70%) of TRS patients have suboptimal response to clozapine (Reference Kane, Honigfeld, Singer and Meltzer1,Reference Meltzer2). Owing to this, many patients with TRS do require augmentation of clozapine with other antipsychotics (Reference Sinclair and Adams3), other medications (Reference Sinclair and Adams3), transcranial magnetic stimulation (Reference Aleman, Sommer and Kahn4–Reference Shi, Yu, Cheung, Shum and Chan8) and transcranial direct-current stimulation (Reference Andrade9).
Electroconvulsive therapy (ECT) is possibly the oldest treatment modality in psychiatry, which has survived till today and is considered to be useful in patients with various severe mental disorders including schizophrenia. Many studies have shown that ECT is efficacious in patients with schizophrenia (Reference Braga and Petrides10). Over the years, in western countries, its use has been limited to patients with mood disorder, especially unipolar and bipolar depression. However, it is still used quite commonly in developing countries for the management of schizophrenia (Reference Chanpattana, Kunigiri, Kramer and Gangadhar11–Reference Chanpattana, Kramer, Kunigiri, Gangadhar, Kitphati and Andrade13). Studies that have evaluated the effectiveness of ECT in schizophrenia have used it in combination with various antipsychotic medications and suggest that it is very useful and safe in patients with treatment-refractory schizophrenia (Reference Braga and Petrides10).
As expected, due to existing evidence of the usefulness of ECT in patients refractory to antipsychotics including clozapine, many authors have evaluated the efficacy of the combined use of clozapine and ECT in patients with schizophrenia. Infact, the combined use of clozapine and ECT was proposed about 25 years ago (Reference Fink14) and was first reported a year later (Reference Klapheke15,Reference Klapheke16). However, initial reports caused an alarm about the epileptogenic potential of clozapine, as some patients experienced prolonged seizures with the combined use of clozapine and ECT (Reference Masiar and Johns17,Reference Bloch, Pollack and Mor18). However, later reports suggested that the risk for prolonged seizures with the combined used of clozapine and ECT is not seen universally. As a result, many authors have evaluated the efficacy of the combined use of clozapine and ECT.
Over the past two-and-half decades, reasonable amount of literature has accumulated, which suggests that this combination may be useful in a significant proportion of patients with schizophrenia who do not respond to clozapine alone or the two modalities individually. Many previous reviews have looked at the evidence for the combined use of clozapine and ECT (Reference Braga and Petrides10,Reference Kupchik, Spivak and Mester19–Reference Vayisoğlu and Yağcioğlu22). Some of these reviews have specifically focused on the available evidence among patients with schizophrenia (Reference Havaki-Kontaxaki, Ferentinos, Kontaxakis, Paplos and Soldatos20). These reviews have mostly focused on data published before 2005, and recent reviews (Reference Vayisoğlu and Yağcioğlu22) have not considered data published after 2005. In view of this, the present review aimed to systematically evaluate the available evidence for the combined use of clozapine and ECT in various psychiatric disorders.
Search strategies
For this review, an electronic search was carried out using PubMed, Google Scholar and Science Direct, EMBASE and SCOPUS to find all the relevant published studies in English language. The search terms that were used in various combinations were clozapine, ECT, combination, concurrent use, augmentation, schizophrenia, schizoaffective, bipolar disorder, mania, depression, treatment-resistance, clozapine-refractory and clozapine-resistance. All the search results were reviewed in order to identify studies reporting the use of a combination of clozapine and ECT. The full-text articles retrieved from the electronic search were further reviewed manually to locate additional references. Studies in which both clozapine and ECT were not used concurrently (i.e. there was no overlap of both the treatments) were excluded. The electronic searches also yielded reviews on this topic (Reference Braga and Petrides10,Reference Kupchik, Spivak and Mester19–Reference Vayisoğlu and Yağcioğlu22), and these were reviewed by the authors to find additional references. We were able to locate 40 reports (208 patients), which were reviewed for short-term effectiveness, long-term outcome and side-effects. Of these, occasional reports have described only the side-effect profile and have not explicitly commented on the outcome with regard to the effectiveness of the combined treatment (Reference Bloch, Pollack and Mor18,Reference Manjunatha, Ram Kumar, Vidyendaran, Muralidharan and John23,Reference Grubisha, Gopalan and Azzam24).
Type of available data
The majority of reports were in the form of case reports and case series, with only occasional studies including more than 10 patients receiving the combined treatment (Reference Frankenberg, Suppes and Mclean25–Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29).
Patient profile
The majority of data on the combined use of clozapine and ECT were available for patients diagnosed with schizophrenia. However, there were a little data for the use of combination in patients with schizoaffective disorder, bipolar disorder, current episode mania and patients with major depression. Occasional reports have used the combination for patients with psychosis in Parkinson’s disease (Reference Factor, Molho and Brown30). In terms of patient profile, the majority of studies have included adults (19–65 years), with occasional reports including patients aged 18 or less (Reference Bloch, Pollack and Mor18,Reference Flamarique, Castro-Fornieles and Garrido27) or those above 65 years of age (Reference Factor, Molho and Brown30–Reference Beale, Pritchett and Kellner32). In terms of gender profile, the majority of studies had higher number of male patients.
Short-term effectiveness
Reports that evaluated effectiveness in patients of schizophrenia have mostly included patients who are refractory to clozapine and were receiving clozapine for some time before being augmented with ECT (Reference Frankenberg, Suppes and Mclean25–Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28,Reference Cardwell and Nakai33). However, occasional reports have used the combination concurrently (Reference Flamarique, Castro-Fornieles and Garrido27,Reference Masoudzadeh and Khalilian34,Reference Koen, Van Den Berg and Niehaus35). Although some of the reports have used rating scales such as the Positive and Negative symptom scale (PANSS) and Brief Psychiatric Rating scale (BPRS) to evaluate the response of the combined treatment, many authors have not relied on the standardised rating scales and have reported the outcome on the basis of the subjective outcome (Reference Frankenberg, Suppes and Mclean25,Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28,Reference Kales, Tandon, Dequardo, Maixner, Jibson and Becks36–Reference Petrides, Fink, Abaza and Francis38). Some of the studies that have used the rating scales have used various cut-offs such as more than 20–40% reduction in the scores to consider the treatment response (Reference Kho, Blansjaar, De Vries, Babuskova, Zwinderman and Linszen26,Reference Flamarique, Castro-Fornieles and Garrido27,Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29), whereas other studies have just described the improvement in terms of reduction in the scores on the scale, without reporting the percentage of patients who responded to the treatment. One small case series (n=2) used the combined treatment in patients with psychosis in the presence of Parkinson’s disease and reported marked clinical improvement (Reference Factor, Molho and Brown30).
As shown in Table 1, there are 16 case reports/series providing information about 25 patients with schizophrenia or schizoaffective disorder (Reference Klapheke15,Reference Klapheke16). In most of these reports, ECT was considered after the use of clozapine, with some of the reports specifying that the patients were considered clozapine non-responsive before being considered for augmentation with ECT (Reference Kho, Blansjaar, De Vries, Babuskova, Zwinderman and Linszen26,Reference Flamarique, Castro-Fornieles and Garrido27,Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29,Reference Kales, Dequardo and Tandon31,Reference Kales, Tandon, Dequardo, Maixner, Jibson and Becks36,Reference Bannour, Bouhlel and Krir39–Reference James and Gray41). However, occasionally, some reports mentioned the use of clozapine following the use of ECT (Reference Bloch, Pollack and Mor18). The dose of clozapine used for these patients varied from 50 to 800 mg/day and the number of ECT sessions varied from 8 to 35, with use of continuation/maintenance ECT in some reports (Reference Bannour, Bouhlel and Krir39,Reference Vowels, Hitturlingappa and Bastiampillai42). In most of the reports, authors have suggested the use of bilateral ECT. In terms of response to the combined treatment, the evidence from case reports suggests that the combined treatment leads to reduction in psychopathology; however, in only occasional reports, standard rating scales have been used (Reference Kales, Dequardo and Tandon31,Reference Biedermann, Pfaffenberger, Baumgartner, Kemmler, Fleischhacker and Hofer40,Reference Benatov, Sirota and Megged43,Reference Husni, Haggarty and Peat44). Some case reports have included patients with schizophrenia with intellectual disability, (Reference Vowels, Hitturlingappa and Bastiampillai42) and in terms of specific symptoms some of the reports suggest improvement in violent (Reference Keller, Drexler and Lichtenberg45) and self-injurious behaviour (Reference Dean46).
Table 1 Case reports on use of clozapine and ECT in patients with schizophrenia and schizoaffective disorders
BPRS, Brief Psychiatric Rating scale; CGI, Clinical Global Impression scale; ECT, electroconvulsive therapy; F, female; GAF, Global Assessment of Functioning scale; M, male; PANSS, Positive and Negative symptom scale.
* These patients were diagnosed with schizoaffective disorder.
In terms of studies including five or more patients receiving combined clozapine and ECT treatment, we could identify 15 studies that included patients with schizophrenia or schizoaffective disorder, with sample sizes varying from 7 to 39 and with a total sample of 167 (See Table 2). Of these 15 studies, exact details were not available for two studies (Reference Fink14,Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29), as the author of one of these reports provided some information about the improvement in an editorial, (Reference Fink14) and in the second case the authors of the recently published study (Reference Petrides, Fink, Abaza and Francis38) mentioned about the improvement in a previous cohort of 15 patients, but they did not provide any reference for the same. Among these studies, some studies also included few patients with bipolar disorder and major depression (Reference Frankenberg, Suppes and Mclean25). All these reports have been either retrospective studies (Reference Frankenberg, Suppes and Mclean25,Reference Flamarique, Castro-Fornieles and Garrido27,Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28,Reference Cardwell and Nakai33) or open-label studies (Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29,Reference Masoudzadeh and Khalilian34–Reference Kales, Tandon, Dequardo, Maixner, Jibson and Becks36,Reference Klapheke47), except for that of Petrides et al. (Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29), which was a prospective randomised single-blind cross-over design study. Occasionally, studies have included a comparator group such as patients on clozapine alone (Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29,Reference Masoudzadeh and Khalilian34,Reference Koen, Van Den Berg and Niehaus35) and ECT alone (Reference Masoudzadeh and Khalilian34), non-clozapine group (Reference Flamarique, Castro-Fornieles and Garrido27,Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28). As with case reports, majority of these reports have included patients with TRS as well as clozapine-resistant. Most of these studies have used standard rating scales such as PANSS, BPRS and Clinical Global Impression (CGI) severity scale. As expected, in most of the studies, ECT was considered after using clozapine for variable period of time. However, in occasional studies, the use of clozapine followed the use of ECT in some of the patients (Reference Flamarique, Castro-Fornieles and Garrido27,Reference Cardwell and Nakai33) or both the treatments were started concurrently (Reference Masoudzadeh and Khalilian34,Reference Koen, Van Den Berg and Niehaus35,Reference James and Gray41). The dose of clozapine used varied from 200 to 800 mg/day and the number of ECT treatments varied from 8 to 18.
Table 2 Studies evaluating the effectiveness of clozapine and ECT in patients with schizophrenia and schizoaffective disorder
BL, Bilateral; BPRS, Brief Psychiatric Rating scale; CGI, Clinical Global Impression scale; CLZ, clozapine; CR, clozapine refractory; ECT, electroconvulsive therapy; F, female; M, male; NA, not available; PANSS, Positive and Negative symptom scale; TRS, treatment-resistant schizophrenia; UL, unilateral.
* These studies also included some of the patients with schizoaffective disorder.
In terms of the percentage of patients responding to the combined clozapine and ECT treatment, the range varied from 35.7% to 100%. However, it is important to note that this wide variation is possibly due to the difference in the criteria used to define ‘response’ across different studies using different scales. In terms of percentage reduction in symptoms across different scales, studies have reported a range varying from 26.9% to 71% reduction in the severity of symptoms. In studies where the authors have evaluated the response to different types of symptoms, evidence suggests that the combined treatment is beneficial in positive, negative and disorganised symptoms (Reference Flamarique, Castro-Fornieles and Garrido27).
When the combined treatment was compared with other strategies, evidence from one study suggested that the combined treatment led to higher reduction in negative symptoms in the combination and clozapine group compared with the ECT-only group (Reference Masoudzadeh and Khalilian34).
However, other studies have reported no difference in symptom reduction, when the combined treatment was compared with the clozapine-only group (Reference Koen, Van Den Berg and Niehaus35). Studies that have compared combination of clozapine and ECT with that of ECT and other psychotropics reported no difference in the response rate between the clozapine and non-clozapine groups (Reference Flamarique, Castro-Fornieles and Garrido27). In one study, which compared clozapine and non-clozapine groups, authors did not specifically report the response rate for the combined use of clozapine and ECT; however, in terms of comparison, they reported a lack of difference in improvement between the clozapine and ECT group and the non-clozapine and ECT group (Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28).
In terms of other outcome measures, studies suggest that the combined use of clozapine and ECT is associated with significantly lower duration of hospital stay and lower increase in the dose of clozapine in the combination group (Reference Koen, Van Den Berg and Niehaus35).
In terms of the effectiveness of the combined treatment of clozapine and ECT in mood disorders, data are limited to only 12 cases, of which eight cases are of bipolar disorder and four of unipolar depression (see Table 3). In general, these patients did not respond to the conventional treatments used in various combinations before being considered for clozapine. In a particular report, the patient did not respond to the treatment with clozapine alone or with ECT alone (Reference Chanpattana52). Overall, evidence suggests beneficial effect of the combined treatment. However, maintenance ECT was used in four out of the 10 patients.
Table 3 Case reports on the use of clozapine and ECT in patients with mood disorders
BL, bilateral; CLZ, clozapine; ECT, electroconvulsive therapy; F, female; GAF, Global Assessment of Functioning scale; M, male; NA, not available; UL, unilateral.
Long-term outcome
Compared with other aspects of the combined use of clozapine and ECT, reports have been inconsistent regarding the long-term outcome of the patients who received the combined treatment. Further, the reports that have mentioned about the long-term outcome have varied significantly in the duration of follow-up after last ECT, varying from 3 weeks to 24 months (See Table 4). From the available evidence, it can be concluded that some patients maintain sustained improvement after the last ECT.
Table 4 Studies reporting the long-term outcome of patients receiving clozapine and ECT
Mechanism of action
Fink (Reference Fink14) suggested that the positive treatment response with the combined use of clozapine and ECT could be due to the physiological changes that occur with two treatments. According to Fink, ECT leads to increase in the blood–brain barrier permeability and because of this, bigger molecules like clozapine are able to penetrate the brain better and are able to reach to more areas of the brain. Accordingly, ECT augments the effectiveness of clozapine. Another mechanism that could explain the augmentation of clozapine with ECT is the evidence in the form of an association between response to clozapine and the degree of electroencephalogram (EEG) slowing. Accordingly, when clozapine was augmented with ECT, it enhanced the EEG slowing and led to better response.
Side-effects
Since the beginning of the combined use of clozapine and ECT, reports have raised concerns about the side-effects like prolonged seizures (Reference Klapheke15) and tachycardia (Reference Klapheke15,Reference Masiar and Johns17,Reference Safferman and Munne54). However, over the years, the available data suggest that the incidence of prolonged seizures is not very high. Overall, existing literature showed prolongation of seizure/prolonged seizures only in four cases. There are occasional reports of delayed seizures (Reference Bloch, Pollack and Mor18) and development of grandmal epilepsy in patients while on clozapine (Reference Masiar and Johns17), which cannot in the real sense be considered related to the combined use of clozapine and ECT. As it is evident from Table 5, the common ECT-related side-effects seen with the combined use of clozapine and ECT include tachycardia and delirium or post ECT confusion. In terms of fatality, only one case report described fatal outcome in a patient 3 weeks after the last ECT, who developed supraventricular tachycardia (Reference Beale, Pritchett and Kellner32). Another report described development of Takotsubo cardiomyopathy few hours after the last ECT while on clozapine (Reference Grubisha, Gopalan and Azzam24). Some of the recent studies have specifically assessed cognitive functions of patients receiving the combined treatment and have actually reported no change (Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29,Reference Biedermann, Pfaffenberger, Baumgartner, Kemmler, Fleischhacker and Hofer40,Reference Kurian, Tharyan and Jacob57) or improvement in the same. Overall, from the available evidence, it can be concluded that the risk for prolonged seizure is possibly not very high. Studies that have compared the side-effects of clozapine alone with clozapine and ECT in combination also do not suggest that the combined use increases the risk of clozapine-related side-effects (Reference Masoudzadeh and Khalilian34).
Table 5 Side-effects associated with ECT in patients receiving combination of clozapine and ECT
Discussion
This review provides an update on the combined use of clozapine and ECT. Although some of the recent reviews have discussed the issue regarding the use of ECT in patients with schizophrenia (Reference Zervas, Theleritis and Soldatos58,Reference Trezise59), the present review provides further update on the available data for the combined use of clozapine and ECT. Further, in contrast with recent reviews (Reference Sinclair and Adams3,Reference Vayisoğlu and Yağcioğlu22), which have focused on data from clinical trials or observation studies only, the present review included all the existing data to the extent of case reports and covered additional data published recently regarding the combined use of clozapine and ECT (Reference Grubisha, Gopalan and Azzam24,Reference Kristensen, Hageman, Bauer, Jørgensen and Correll28,Reference Petrides, Malur, Braga, Bailine, Schooler and Malhotra29,Reference Bannour, Bouhlel and Krir39,Reference Vowels, Hitturlingappa and Bastiampillai42).
This review suggests that over the years data on the combined use of clozapine and ECT has expanded. When one looks at the literature, data has now expanded from the single case reports to small-sample retrospective studies and open-label trials. With the recent addition of a randomised single-blind cross-over trial, it can be said that the level of evidence has been further strengthened. Further, in contrast with earlier reports, most of the current reports have reported improvement in the form of reduction in psychopathology on standardised scales and some have reported the long-term outcomes of the patients treated by the combination.
Available evidence suggests that the combined use may be useful in patients with TRS and clozapine-refractory patients at least in the short-term. The recent randomised single-blind cross-over trial clearly shows that about half of the patients who initially did not respond to the clozapine trial responded to the clozapine and ECT combination. This study clearly shows the role of augmentation of clozapine with ECT. With regard to the long-term effectiveness, some of the data suggest that augmentation with a course of ECT with or without maintenance ECT leads to sustained improvement in some of the patients. In terms of the side-effects of the combined use of clozapine and ECT, available evidence suggests that incidence of worrisome side-effects is not very high (Reference Braga and Petrides10,Reference Kupchik, Spivak and Mester19–Reference Vayisoğlu and Yağcioğlu22,Reference Trezise59).
In routine clinical practice, it is quite often seen that patients with schizophrenia who do not respond to one or two adequate trials of antipsychotics are treated with polypharmacy. Studies across the globe suggest that about one-third or more patients receive polypharmacy before starting with clozapine treatment (Reference Taylor, Young and Paton60,Reference Howes, Vergunst, Gee, Mcguire, Kapur and Taylor61). Use of polypharmacy often leads to delay in starting with the clozapine treatment in patients who deserve the same. Some research suggests that this is probably due to the negative attitude towards and poor knowledge about clozapine among the psychiatrists (Reference Nielsen, Dahm, Lublin and Taylor62). However, evidence suggests that clozapine is possibly the most effective antipsychotic medication in patients with TRS (Reference Moore, Buchanan and Buckley63–Reference Warnez and Alessi-Severini65).
Accordingly, based on the available evidence, it can be said that patients with schizophrenia who have TRS should be adequately treated with clozapine as soon as possible so as to improve their outcome. In addition, if a patient does not respond to an adequate trial of clozapine, then clozapine must be augmented with ECT.
Data on use of the combination of clozapine and ECT in patients with bipolar and unipolar disorder are preliminary. However, this suggests that the combined use of clozapine and ECT may be a viable option in patients who do not respond to other treatments.
When one looks at the available literature, data are scarce in terms of evidence-based strategies to be used in treating patients with schizophrenia who do not respond to clozapine. The commonly used strategies include augmentation with other antipsychotic medication. The augmenting agents that have been evaluated include risperidone, aripiprazole, amisulpiride, sertindole, pimozide, ziprasidone, antidepressants, omega-3 fatty acids and lamotrigine (Reference Vayisoğlu and Yağcioğlu22). In a review of various double-blind placebo-controlled studies, open-label studies and case reports/case series evaluating the efficacy of these agents concluded than in general double-blind placebo-controlled trials show lack of superiority in treating patients with risperidone (two out of the three studies showing no additional benefit), aripiprazole, sertindole and placebo over placebo (Reference Vayisoğlu and Yağcioğlu22). Data from open-label studies provide some evidence to support the usefulness of some of these agents. However, some of these combinations are associated with higher rates of side-effects (Reference Vayisoğlu and Yağcioğlu22). When one compares the findings of augmentation of clozapine with ECT, the results appear to be more robust. Accordingly, it can be concluded that ECT should be held back for long in patients who show suboptimal response to clozapine.
However, it can be said that, although the evidence for the combined use of clozapine and ECT has expanded, there is still limited data on the combined use of clozapine and ECT. Further, the existing data are mostly in the form of case reports, case series and small studies. In many of these reports, the ratings of improvement are either not standardised and/or not blind. Most of the published literature is based on the positive treatment outcomes with only few studies reporting only the negative treatment outcomes and side-effects. Thus, it is quite possible that there is a bias towards publishing the positive response about the combination treatment. Accordingly, the non-response or negative response is not reported in the literature. The available evidence also suggests marked heterogeneity in the dose of clozapine used before starting ECT. Similarly, there is inconsistency in terms of issues related to the ECT technique and other ECT-related matters. Although some of the studies have reported the clozapine plasma levels, many studies do not provide information about the same. Accordingly, it can be mentioned that many cases considered as being ‘clozapine resistant’ may not actually be cases of ‘true clozapine resistance’, as these patients may not have been treated with clozapine at the desired plasma levels. Data on the cognitive outcome are also limited and marked by heterogeneity in the assessment of the same. Understandably, because of the small sample size, none of the studies have evaluated the correlates of the treatment response. In addition none of the studies have looked at other outcome measures like socio-occupational functioning and quality of life.
Therefore, there is further need to expand the literature. Future studies should follow a prospective study design in which patients are allocated to the combination of clozapine and ECT and other comparator groups such as clozapine alone, ECT alone, any other antipsychotic drug group or any other combination group. The raters and patients should be blind to the ratings of psychopathology, and long-term outcomes must be consistently evaluated. Besides psychopathology, studies also must evaluate other outcome measures like quality of life and socio-occupational functioning. Considering the fact that it may be possible to have a large sample at one centre, there is a need to have a multicentric study spread across different nations, using the same study design to evaluate the actual efficacy of the combined use of clozapine and ECT.
Acknowledgements
None. Authors’ Contributions: S.G., N.H. and N.K.: conception of idea; S.G. and N.H.: carrying out internet and manual searches; S.G., N.H. and N.K.: extraction of the data; S.G. and N.H.: writing the draft; S.G., N.H. and N.K.: final approval of the manuscript.
Financial Support
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
None.
