Early onset of schizophrenia spectrum disorders (SSDs), with onset of psychotic symptoms before age 18, is a severe form of the disorder that presents with more social disability and poor outcome.1,2 In general, the pharmacological treatment, as in adult onset schizophrenia, consists of antipsychotics. However, adolescents seem more susceptible to adverse effects.3,4
Clozapine is an antipsychotic used in treatment-resistant cases of SSD, and it has been reported to be the most efficacious pharmacological treatment for these patients.5,6 It has been suggested that it may have an important role in early treatment of first-episode patients who do not respond to other antipsychotics.7 Hospitalization rate has been used in some observational studies as an outcome measure to evaluate the effectiveness of antipsychotics in adults,8–12 and some studies have shown reduced rehospitalization in adult patients with SSDs treated with clozapine.11,13,14 Studies have also suggested that clozapine can improve catatonic symptoms.15–17
In adolescents, clozapine has been shown to be superior to other second-generation antipsychotics (SGAs) for treating psychotic disorders.18–20 It has also been associated with a decrease in violent behavior in this population.20 Moreover, a decrease in the number of hospitalizations and a greater ability to live in less restricted environments have been described when childhood-onset schizophrenia was treated with clozapine.21
Regarding safety, clozapine may cause adverse effects similar to other antipsychotics. These include hypersalivation, sedation, incontinence, akathisia, cardiac adverse effects such as QT prolongation, orthostatic hypotension, weight gain with metabolic changes, tachycardia, and, in rare cases, endocarditis.22 Other potential adverse effects include electroencephalographic (EEG) changes,23 myoclonus, and seizures.24 However, treatment with clozapine is also associated with a higher risk than other antipsychotics of agranulocytosis, and, as a result, weekly monitoring of white blood cell count is mandatory during the first 18 weeks of treatment.22,25–28 These factors complicate the use of the drug and have made it a second-line treatment for SSDs in both adolescents and adults.22
Electroconvulsive therapy (ECT) is an effective treatment for resistant schizophrenia in adults.29 There are also several reports showing that ECT is a safe and effective treatment for some adolescents with SSDs.30–39 Following the recommendations of the Academy of Child and Adolescent Psychiatry,33 before an adolescent is considered for ECT, he/she must meet 3 criteria:
- Diagnosis: Severe, persistent major depression or mania with or without psychotic features, schizoaffective disorder, or, less often, schizophrenia. Electroconvulsive therapy may also be used to treat catatonia and neuroleptic malignant syndrome.
- Severity of symptoms: The patient’s symptoms must be severe, persistent, and significantly disabling. They may include life-threatening symptoms such as the refusal to eat or drink, severe suicidality, uncontrollable mania, and florid psychosis.
- Lack of treatment response: Failure to respond to at least 2 adequate trials of appropriate psychopharmacological agents accompanied by other appropriate treatment modalities. Both duration and dose determine the adequacy of medication trials. It may be necessary to conduct these trials in a hospital setting. Electroconvulsive therapy may be considered earlier in cases in which (a) adequate medication trials are not possible because of the patient’s inability to tolerate psychopharmacological treatment, (b) the adolescent is grossly incapacitated and thus cannot take medication, or (c) waiting for a response to a psychopharmacological treatment may endanger the life of the adolescent.
Potential adverse effects of ECT include impairment of memory and new learning, tardive seizures, prolonged seizures, and risks associated with general anesthesia.33,40 However, the incidence of these adverse effects is very low. In adolescents, few patients have presented these adverse effects, and all of them fully recovered.40,41 Regarding long-term cognitive effects, some studies performed with adult samples showed slight cognitive impairments.42 However, in 2 studies with adolescents treated with ECT, no cognitive impairment was found.43,44 Other minor effects are headache, nausea, vomiting, muscle aches, confusion, and agitation. No fatality has ever been reported associated with ECT in adolescents.45
Combining ECT with clozapine was first proposed in 1990.46 This combination has been used in resistant cases and was found to be promising in preliminary studies of adults with a diagnosis of SSD.47,48 Two studies have reviewed this combination in adults, the first one examining resistant cases and the second one focused on patients with SSDs. These showed an improvement in 67% and 72% of their respective samples.49,50
Another study with adult patients has suggested that there might be clinical benefits of combining ECT treatment with antipsychotic medication, especially SGA, including clozapine.51 Moreover, the combination of clozapine and ECT has been reported to be superior to either treatment alone.29,52
The combination of ECT and clozapine and maintenance clozapine treatment has also been suggested to prolong clinical improvements derived from ECT.53–55 Clozapine therapy by itself is unlikely to provide a rapid response when needed, whereas ECT tends to create a rapid but short-lived response.55 A report of 2 cases of catatonia treated with ECT showed that clozapine was also effective for preventing patients from relapse during a 2-year follow up.56
Safety is an important issue when combining ECT and clozapine, although few published cases have reported adverse effects, and almost all of these have involved adults. Lowering of seizure threshold (ST), grand mal seizures, and cardiac arrhythmias has been described in the literature.57–60 Sinus tachycardia and elevated blood pressure were reported in other cases.61–63 The incidence of these adverse effects is unknown; however, most of the published cases suggest that ECT and clozapine may be safely combined.49,50,52,64–69
Although clozapine is believed to lower ST and prolong seizure duration during ECT,57 variables such as age (younger subjects showing longer seizures), stimulation energy, depth narcosis (lighter anesthesia prolonging seizure durations), and previous ECT treatments have also played an important role. 45,70–73 Anesthetic agents have also been reported to influence seizure duration. Patients treated with propofol receive a higher electrical charge, and seizure duration is decreased with no significant difference in the clinical outcome.74
There are no published cases in the literature specifically assessing the safety and effectiveness of combining clozapine and ECT in adolescents. However, 2 published cases concern catatonic adolescents using ECT and clozapine together,75,76 and at least 2 other adolescent patients with SSD in a series of cases also used this combined treatment.30 In none of these cases were any relevant adverse effects found. Still, there is very little information in the literature regarding the safety and effectiveness of combining clozapine and ECT in adolescents, despite the severity of early onset of SSD1,2 and the need to find the most rapid and efficacious treatment.
The aim of this study was to evaluate the safety and effectiveness of combining ECT and clozapine in a sample of adolescents with SSDs and compare this to the combination of ECT with other antipsychotics and benzodiazepines. We hypothesized that the treatment groups would show no relevant differences regarding adverse effects but that different ECT parameters would be found between them. Moreover, we hypothesized that the combination of clozapine and ECT would be equally effective after the acute ECT course, and that patients treated with clozapine for 1 year after ECT would have a lower rate of rehospitalization.
MATERIALS AND METHODS
Data regarding 28 adolescents aged 13 to 18 years and with diagnoses of SSDs (schizophrenia, n = 21; or schizoaffective, n = 7, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were retrospectively studied. The ethics committee of our center approved this retrospective study. Twelve of the adolescents had been treated with ECT and clozapine (clozapine group) and 16 with ECT and other antipsychotics (n = 14) or benzodiazepines alone (n = 2) (nonclozapine group). The reasons for changing treatment from other antipsychotics to clozapine in the clozapine group were the following: 8 patients, lack of response; 1 patient, intolerance to other antipsychotics; and 3 patients, who presented with catatonia while treated with other antipsychotics, which were changed to clozapine at the same time as ECT was begun. Two patients in the clozapine group and 3 in the nonclozapine group were treated with mood stabilizers.
The patients received ECT 2 or 3 times per week with a constant-current, brief-pulse device. All treatment stimuli were delivered with bifrontotemporal electrode placement administered using a MECTA-SR2 and a SPECTRUM 5000Q ECT devices (MECTA Corp, Lake Oswego, OR). Seizure threshold was titrated at the first session, starting with a stimulus dose that took into account electrode placement, age, and sex.77 In the following sessions, stimulus dose was 1.5 times or 2.5 times the initial seizure threshold.
Electroencephalographic and motor seizure manifestations were monitored to ensure that an adequate ictal response occurred, to detect prolonged seizure activity, and to regulate stimulus dosage. Stimulus parameters (frequency, stimulus train duration, pulse width, and current) were modified when needed if duration of seizure was not adequate. Succinylcholine (30–120 mg), atropine (0–1 mg), and sodium thiopental (75–450 mg) or propofol (120–170 mg) were used for anesthesia. Acute ECT was continued until the patients either remitted or had shown no further improvement over the course of 3 consecutive treatment sessions. Some patients received continuation ECT treatment after the acute ECT course). They initially received weekly continuation ECT treatment for the first month, followed by treatments every other week during the second month, and monthly afterwards for 4 months.78
Assessment of Safety
All patients were monitored after ECT for vital signs including heart and respiratory rates, pulse oximetry, and electrocardiographic activity in the recovery room until vital signs were stabilized as part of the ECT protocol. When patients were stabilized, they were moved to the inpatient unit, where they remained in observation, and vital signs were also monitored at least 3 times per day.
Other Adverse Effects
They were assessed after ECT using a systematic protocol. This consists of a list of the most frequent adverse effects that have been reported after a session of ECT (headache, myalgias, nausea, vomiting, agitation, restlessness, and orientation). A specialized nurse asks patients if any of these adverse effects are present and registers them systematically.
White blood cell counts were performed to monitor for agranulocytosis following international monitoring guidelines for patients taking clozapine.25,27
Assessment of Effectiveness
All subjects were assessed with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) before and after acute ECT treatment. These were administered by the same psychiatrist (IB).
Positive and Negative Syndrome Scale
This is a 30-item rating scale that aims to assess the symptom severity of subjects with psychosis. It is subdivided into 3 subscales—positive, negative, and general psychopathology—and a total score.79,80 Each subscale and the total score are all evaluated from 1 to 7 according to the severity of the symptoms.
Clinical Global Impression—Improvement Scale
This is a clinical scale scored from 1 to 7, which assesses the severity of symptoms. A better level is indicated by lower scores.81
Rate of Rehospitalization
Taking previous literature into account8–12, the rate of rehospitalization after acute ECT course during 1-year follow-up was included in the assessment. Information about 21 patients regarding antipsychotic treatment and rate of rehospitalization was obtained from our own medical records. Seven patients were treated in other centers after acute ECT course, and their families were contacted by telephone to gather this information. Two patients could not be contacted by telephone and were therefore excluded from the rehospitalization analysis.
The Kolmogorov-Smirnov with the Levene test was applied to test the normality of the sample distribution and the equality of variances.
Two different statistical analyses were performed. The first one compared sociodemographic, clinical variables, and rate and number of rehospitalizations of subjects between the clozapine group (n = 12) and the nonclozapine group (n = 16) using the χ2 test or t test as appropriate. The percentage of responders was defined as those showing a 20% reduction of PANSS total scores compared to baseline.82
The second analysis was conducted with the total number of sessions (n = 388) to compare ECT parameters and adverse effects across groups using t tests and χ2 test as appropriate.
SPSS15.0 software package was used to perform the analyses.
Subjects of the Sample
All patients were hospitalized in our center, Hospital Clinic i Universitari of Barcelona, between 2003 and 2010 and underwent at least 1 acute ECT course. The total number of ECT sessions was 388 for the whole sample. Of 256 patients with SSDs who were hospitalized during that period, 28 subjects were treated with ECT. Thirteen of these patients were included in a previous report of ECT in SSDs in adolescents.30 The center’s ECT committee approved the indication for each patient following the American Academy of Child and Adolescent Psychiatry (AACAP) recommendation criteria for ECT.33 Written informed consent for ECT was provided by legal guardians. Most patients were referred to ECT owing to resistance to treatment and/or intolerance to medication adverse effects (n = 22); other patients presented with catatonia (n = 5) or neuroleptic malignant syndrome (n = 1). Resistance to treatment was defined as lack of response to at least 2 adequate trials of antipsychotic medication (equivalent dosages of ≥500 mg of chlorpromazine and at least ≥4 weeks of treatment for each antipsychotic).83,84 Pharmacological treatments of the sample previous to ECT are shown in Table 1.
Comparison of Clozapine Group and Nonclozapine Group in Demographic and Clinical Characteristics of Subjects
No statistically significant differences were found between the clozapine and nonclozapine groups in sex, family history, diagnosis, reason for referral to ECT, number of previous treatments, number of hospitalizations in the previous year, and PANSS and CGI scores at baseline (Table 2). Fourteen patients in the nonclozapine group were receiving other antipsychotics (risperidone, amisulpride, haloperidol, olanzapine, quetiapine, paliperidone, and aripiprazole) with 3 patients also receiving mood stabilizers (oxcarbazepine, lithium, valproic acid). Two patients were receiving only benzodiazepines (diazepam and lorazepam).
In the clozapine group, 2 patients were taking mood stabilizers (lithium and valproic acid). There were no differences between groups regarding treatment with benzodiazepines (clozapine, n = 4; and nonclozapine, n = 2; χ2 = 1.29; P = 0.35) and mood stabilizers (clozapine, n = 2; and nonclozapine, n = 3; χ2 = 0.20; P = 1.0). The patients treated with clozapine had a mean ± SD dose of 316 ± 178 mg/d (range, 25–600 mg) during ECT treatment. Six patients had started clozapine before ECT treatment, and also 6 patients started titrating clozapine at the same time as ECT was being administered. The mean ± SD dose of clozapine in those 6 patients in the last ECT session was 254.17 ± 138.22 mg/d. However, the mean ± SD dose of all patients in the last ECT session was 335.42 ± 160.41 mg/d.
Comparison of the Clozapine Group and the Nonclozapine Group in ECT parameters
The nonclozapine group had a mean ± SD number of sessions of 14.19 ± 4.91, and the clozapine group had 13 ± 3.95. There were no statistically significant differences in the mean number of ECT sessions between the groups (t = 0.68, P = 0.49).
There was 1 patient in the nonclozapine group treated with propofol as anesthetic agent. We compared the ECT parameters of this patient (20 sessions) with patients treated with thiopental (362 sessions), and all parameters were significantly different (pulse width [thiopental], 1.38 ± 0.18 milliseconds [ms], vs pulse width [propofol], 1.99 ± 0.44 ms; t = −44; P = 0.000; frequency [thiopental], 68.75 ± 10.25 Hz, vs frequency [propofol], 87.00 ± 4.70 Hz, t = −15; P = 0.000; duration [thiopental], 0.97 ± 0.22 seconds vs duration [propofol], 2.00 ± 0.39 seconds; t = −11; P = 0.000; current [thiopental], 0.72 ± 0.09 A vs current propofol, 0.80 ± 0.00 A, t = −16.60; P = 0.000; charge [thiopental], 138.18 ± 58.17 milicoulombs (mC) vs charge [propofol], 559.69 ± 136.97 mC; t = −13.69; P = 0.000). Regarding mean EEG seizure duration, there were also differences (thiopental, 44.08 ± 16.22 seconds, vs propofol, 32.50 ± 12.40 seconds; t = 3.99; P = 0.001).
We removed this patient from the sample to compare ECT parameters between groups and have a more homogeneous sample. Significant differences were found between groups in the current used, but the mean charge to induce seizure and other ECT parameters were similar. Regarding mean EEG seizure duration, no significant differences were found between the clozapine and nonclozapine groups. Electroconvulsive therapy parameters are shown in Table 3.
Comparison of Adverse Effects in Clozapine Group and Nonclozapine Group
Looking at all the ECT sessions (n = 388), mean blood pressure and cardiac frequency (CF) were higher in the clozapine group’s pre-ECT session and post-ECT session. However, the degree of change in CF and blood pressure during ECT sessions was similar in both groups (Table 3).
Other adverse effects identified after each session (n = 388) are presented in Table 4. Overall, 7.5% of the ECT sessions of our sample resulted in headache, 1.8% restlessness and agitation and 0.8% myalgia. The nonclozapine group had significantly greater restlessness and agitation, but no differences were found in other adverse effects.
Although 4 patients (14.28%) from the sample presented with tachycardia during hospitalization, (CF >100 beats per minute) and 3 (10.71%) of them belonged to the clozapine group, no significant differences were found between the groups (χ2 = 1.96; P = 0.28).
Agranulocytosis or neutropenia did not occur in any of the subjects in the clozapine group.
Comparison of Clozapine Group and Nonclozapine Group in Effectiveness
When we compared PANSS and CGI scores of both groups after acute ECT course, no differences were identified. The percentage of responders in both groups was similar: 66.7% in the clozapine group and 68.8% in the nonclozapine group (Table 2).
Data regarding the rate of rehospitalization during 1 year of follow-up were obtained for 26 patients (2 patients from the clozapine group could not be contacted). Fourteen patients were treated with clozapine for the whole year, four of them having started treatment with clozapine after acute ECT. Twelve patients were treated with other antipsychotics and one of them with benzodiazepines.
When we compared the rate of rehospitalization during 1-year follow-up, the patients in the clozapine group showed a lower rate of rehospitalization than the patients in the nonclozapine group (χ2 = 7.98; P = 0.009). Of the patients in the nonclozapine group, 58.3% (n = 7) were rehospitalized during follow-up, whereas only 7.1% of the clozapine group (n = 1) was rehospitalized. Moreover, total number of rehospitalizations was significantly higher in the nonclozapine group (0.83 times vs 0.07 times; t = 2.72; P = 0.018).
Some patients were also receiving continuation ECT, but there were no differences between groups in the number of patients receiving continuation ECT (number of patients in the clozapine group, 9; number of patients in the nonclozapine group, 9; χ2 = 1.07; P = 0.43) and in the number of ECT sessions (mean ± SD sessions in clozapine group, 8.44 ± 11.23; mean ± SD sessions in the nonclozapine group, 5.25 ± 4.02; t = −1.05; P = 0.307). However, 2 patients in the nonclozapine group who were rehospitalized received a new index course of ECT.
One patient in the nonclozapine group who received continuation ECT had a tonic seizure after the 17th session, and the EEG showed epileptiform activity. Valproate was initiated, and the EEG was found to be normal when it was repeated. Another patient who needed a new index course of ECT had a tardive seizure with epileptiform activity in the EEG. Both patients stopped treatment with ECT and have remained seizure-free ever since.
The main finding of this retrospective study, comparing patients treated with a combination of ECT and clozapine to a group treated with ECT with other antipsychotics or benzodiazepines, was that both combinations were equally safe in adolescents with SSDs. Electroconvulsive therapy parameters were similar across groups, but for current that was slightly lower in the patients treated with clozapine. Both treatments were equally effective after acute ECT course, but patients treated with clozapine had a lower rate of rehospitalization at 1-year follow-up.
Regarding ECT course, the mean number of sessions was similar in the clozapine and nonclozapine groups and slightly higher than what has been reported in the adult literature in which a combination of clozapine and ECT has been used.49,50 Regarding EEG duration, there were no significant differences between the groups. This is similar to what was reported in a sample of adults that showed a nonsignificant increase of 2.4 seconds in EEG duration while on clozapine and undergoing ECT.69 However, another adult study, Gazdag et al57 found differences in seizure duration depending on which antipsychotic the patients were taking at the time ECT was being conducted. The authors concluded that clozapine seemed epileptogenic, like olanzapine and zuclopenthixol. In our sample, none of the subjects presented with prolonged seizures.
Except for the current used, ECT parameters were similar in the clozapine and nonclozapine groups, after removing the 1 patient treated with propofol as anesthetic agent. Mean charge was also similar in both groups and lower than what has been reported in adult patients with combined treatment of ECT and clozapine (charge in an adult sample was 220 mC).67 This finding was expected as age has been reported to decrease ST, and less energy is needed to induce a seizure.57,70
The MECTA-SR2 and the SPECTRUM 5000Q ECT devices allow the psychiatrist to modify stimulus parameters (current, duration, frequency, and pulse width) if the duration of seizure is not adequate. Current can be modified every 0.10 A (eg, from 0.70 to 0.80 A). Current was higher in the patients in the nonclozapine group compared to the patients in the clozapine group (0.70 vs 0.73 A). However, it could be argued that this difference was not relevant. These data are consistent with what was found by Bundy et al,70 who concluded that the anticonvulsive properties of narcotic agents have a much greater influence than concomitant psychotropic medication on seizure adequacy.
When adverse effects were examined, mean CF and blood pressure increase during ECT sessions were similar in both groups. However, mean CF in the clozapine group was higher than in the nonclozapine group before and after ECT, which could relate to a higher frequency of tachycardia in patients treated with clozapine.22,85
As has been observed in previous studies,33,45 some adverse effects during ECT sessions in our sample were headache, myalgia, restlessness, and agitation. Moreover, restlessness and agitation were significantly higher in the nonclozapine group. However, to our knowledge, ours is the first study assessing adverse effects in adolescent samples of patients with SSDs treated with ECT and clozapine.
None of the subjects presented with cardiac arrhythmias or tardive seizures during acute ECT course. However, 2 patients presented tardive seizures during continuation ECT treatment. Considering that age and number of previous ECT treatments may influence the ST, stimulation energy may need to be decreased or readjusted when continuation ECT treatment is needed in this population.45,70–73
Four patients (14.28%) presented with tachycardia during hospitalization, 3 (10.71%) of them belonging to the clozapine group; although the difference between the groups was not statistically significant. These data are lower than what was reported in 1 study reviewing published cases of patients with SSDs treated with a combination of clozapine and ECT in adults,49 and consistent with another review of resistant cases in adults treated with the same combination.50
White blood cell count tests of the clozapine group showed none of the subjects presenting with agranulocytosis during ECT treatment. These findings regarding safety are comparable to what has been described in the literature of adult patients with SSDs.49,50,52,64–69
When we compared effectiveness in both groups before ECT and after ECT, similar response rates were found (clozapine group, 66.7%; nonclozapine group, 68.8%), with response being defined as a 20% reduction of PANNS total score at end point. Doses of clozapine were lower than in other studies (512 and 385 mg/d vs 316 mg/d).49,50 However, because 6 patients from the clozapine group began titrating clozapine at the same time as ECT was administered, we could not conclude that, among our sample, the combination was more effective at short term, as clozapine could take up to 3 or 6 months before complete response.55 Improvements in the PANSS scale were found on the positive and general subscales in both groups. Negative symptoms, as measured by the PANSS negative subscale, did not improve with a acute ECT course in either of the groups. This is similar to what has been reported previously in the literature regarding negative symptoms.30,86
The response rate in the clozapine group was similar to that found in the literature with adults. Improvements of 72% were found in a review of all cases published from January 1980 to July 2005 (n = 22) of patients with resistance to clozapine with SSDs treated with the combination of ECT and clozapine.46
A review of 36 adult patients resistant to other antipsychotics and treated with both ECT and clozapine showed 67% improvement,47 although the diagnoses of the sample were heterogeneous. Moreover, a study comparing clozapine, ECT, and a combination of both in a sample of adult patients with schizophrenia showed greater response in the latter group, with a reduction of 71% in mean PANSS score,52 which is higher than in our sample. Nevertheless, that study was conducted with a smaller sample. There are no published studies in adolescents with SSDs regarding the combination of ECT and clozapine.
The rate of rehospitalizations during 1 year follow-up was lower in the clozapine group (7.1%) compared to the nonclozapine group (58.3%). These findings are supported by some studies that have reported reduced rehospitalization for adult patients with schizophrenia on clozapine.8,11,13,14,87 Some studies in adults have suggested that clozapine may perpetuate the clinical response obtained by ECT.53–55 However, 2 studies found no differences between clozapine and risperidone regarding rehospitalization.8,10
Among the limitations of our study, we should point out that it is a retrospective study of clinical practice. This has shortcomings because it is not done in a blind fashion or randomized. Another possible limitation is that patients were heterogeneous regarding the reason why they were referred to ECT. The study also included a small sample, but that could be explained in part by the fact that ECT and clozapine are generally second-line treatments for SSDs. Finally, it should be noted that rehospitalization rate is not a very specific measure of outcome.
The study also has certain strengths. First, it included a homogeneous sample of adolescents with a diagnosis of schizophrenia or schizoaffective disorder, and all diagnoses were made by the same psychiatrist. Additionally, to our knowledge, this is the only study assessing the safety and effectiveness of a combination of ECT and clozapine in a sample of adolescents with SSDs.
Our data suggest that a combination of clozapine and ECT is safe and effective for either catatonic or antipsychotic-resistant adolescents with SSDs, and reduces the rate of rehospitalization during 1-year follow-up. More research is needed in this area, considering the severity of SSDs in adolescents and the need for data regarding effective treatments for resistant cases.
AUTHOR DISCLOSURE INFORMATION
Itziar Flamarique, Juan Miguel Garrido, Elena de la Serna, Alexandre Pons, and Inmaculada Baeza affirm that they have no conflicts of interest.
Professor Miguel Bernardo received consulting fees from Bristol-Myers Squibb-Otsuka, Wyeth, and Janssen-Cilag.
Dr Josefina Castro-Fornieles has had the following relationships which may represent a conflict of interest: consultant, Eli Lilly and Pfizer; and travel support, Eli Lilly.
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