The TEOSS study methods have been described in detail in prior publications.3,5
In this report we focus on the 44-week, double-blind extension phase that followed the 8-week, double-blind acute trial. The primary results of the acute study have been described previously.3
During maintenance, youths continued to receive the same antipsychotic drug that they were administered during the acute phase. Treatment response and side effects were assessed every 4 weeks. Patients could be seen more frequently if clinically indicated.
All study procedures were reviewed and approved by the institutional review boards at each of the 4 study sites. Participant safety was also monitored by the National Institute of Mental Health (NIMH) Data and Safety Monitoring Board. All participants and their guardians provided written informed assent and consent, respectively.
For the sake of clarity, interventions prior to receiving therapy in the acute study will be denoted as occurring at the baseline time point. Weeks 8–52 specifically refer to time points in this maintenance study. In other words, week eight is the start of the maintenance study.
Youths, ages 8 to 19 years, who met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder were enrolled in the acute 8-week trial. Diagnostic methods, inclusion/exclusion criteria, and baseline characteristics of the sample are described elsewhere.2, 3, 5
After acute treatment, participants who: 1) were adequately tolerating their initially assigned treatment; and 2) had an adequate response to treatment (defined by a 20% reduction in baseline Positive and Negative Syndrome Scale (PANSS)6
score plus a Clinical Global Impression-Improvement (CGI-I)7
score of 1 or 2, indicative of being “very much improved” or “much improved”) were eligible to continue on maintenance therapy. In addition, seven patients who did not meet the acute phase responder criteria but who had improved sufficiently were allowed to continue into maintenance therapy because it was felt to be in the best clinical interest of the patients.
Subjects were treated with flexible doses of molindone (10–140 mg/day), olanzapine (2.5–20 mg/day), or risperidone (0.5–6 mg/day). Dose increases were based on clinical need. All youths who were assigned to treatment with molindone also received 0.5 mg twice daily of benztropine in order to reduce the risk of extrapyramidal symptoms (EPS). All other patients received matching placebo. Flexible dosing within these dose ranges was continued during the maintenance phase.
Adjunctive psychotropics permitted included: benztropine or trihexyphenidyl (for EPS); propranolol (for akathisia); lorazepam or clonazepam (for agitation and insomnia); fluoxetine, sertraline, or citalopram (serotonin selective reuptake inhibitors, “SSRIs,” for depression), and valproate or lithium (“mood stabilizers” for manic symptoms). Diphenydramine could be prescribed for upper respiratory symptoms or insomnia. It is classified as a “psychotropic” for this manuscript due to the fact that diphenhydramie can also reduce EPS (although it was not used primarily for that purpose in this trial). Trazodone could be prescribed for insomnia. These adjunctive agents could be discontinued if they were no longer clinically indicated.
Efficacy Measures and Outcomes
The PANSS (a 30-item, clinician-rated scale used for the comprehensive assessment of psychotic symptoms), the Brief Psychiatric Rating Scale for Children (BPRS-C)8
(an assessment for the severity of 18 common psychiatric and behavioral problems with subscales for positive and negative symptoms, depression, and mania), and the Clinical Global Impression-Severity (CGI-S)7
(measurement of illness severity) were administered at all study visits. The Child and Adolescent Functional Assessment Scale (CAFAS)9
was administered at baseline and weeks 8, 24 and 52/end of study (EOS).
Adverse Event and Safety Monitoring
In addition to open-ended inquiry about the presence of adverse events, the Monitoring of Side Effects Scale (MOSES)10
was also used to ascertain adverse events. Events of moderate severity or higher which were not judged to be related to the underlying psychopathology were recorded as adverse events. EPS were monitored using the Neurological Rating Scale (NRS),11
the Barnes Akathisia Scale (BAS),12
and the Abnormal Involuntary Movement Scale (AIMS).7
Vital signs, height, weight, and body mass index (BMI),13
were also assessed. With the exception of the AIMS (obtained at baseline and weeks 8, 24, 36, and 52/end of study), other measures were obtained at each visit.
Between February 2002 and December 2005, subjects who gained more than 25% of their pre-treatment body weight were reviewed by the investigators in order to determine whether study withdrawal was appropriate. In December 2005, all subjects who had gained more than 7% of their body weight were reviewed in order to determine whether the apparent benefits experienced by the participants justified the associated risks. If a participant’s BMI was ≥ 30 kg/m2 and the participant had gained more than 30% of their body weight since their pre-treatment assessment, treatment discontinuation was required regardless of symptom response. Electrocardiograms (ECGs) were obtained at baseline and weeks 8, 24, 36, 52/ end of study. ECGs were read by a pediatric specialist in order to monitor for possible QTc prolongation.
Routine fasting blood and urine chemistries were obtained at baseline and weeks 8, 24, 36, and 52/end of study. Prolactin and thyroid-stimulating hormone (TSH) were measured at baseline, week 8, and week 52/end of study. Prolactin was also measured at weeks 24 and 36. Also, urine toxicology screens and pregnancy tests were collected at weeks 8 and 52/end of study. If a female subject was receiving adjunctive valproate or lithium, additional pregnancy tests were done at weeks 24 and 36.
Continuous variables were analyzed via F-tests in a one-way analysis of variance (ANOVA) with last observation carried forward change from baseline as outcome. To investigate possible violations of distributional assumptions due to small treatment group sizes, a nonparametric Kruskal-Wallis (three groups) or Wilcoxon test (2 groups) was also performed as a sensitivity analysis for each continuous outcome. Total scores for patients with missing items in their PANSS or CAFAS evaluations were weighted to reflect the number of items completed. Data for glucose, cholesterol, triglycerides, HDL, and LDL were included only if the patient was fasting at the time of laboratory data collection.
Categorical outcomes, including proportions of patients taking concomitant medications or experiencing adverse events, were compared across treatment groups using exact chi-square tests. Concomitant medications were categorized post-hoc by the lead investigator using the text descriptions given in the database. Adverse events were categorized using their assigned MOSES category, except those with MOSES category “Other”, for which a new adverse event category was created post-hoc by the lead investigator. To assess the presence of tardive dyskinesia, patient records were reviewed post-hoc by the investigators for any patient having 1) two or more items on the AIMS with scores 2 or higher, 2) one or more items on the AIMS with score 3 or higher, or 3) a score on any of the neurological scales of the MOSES of 3 or higher.
Time to discontinuation was estimated via Kaplan Meier survival curves and compared among treatment groups using a log-rank test. Time to discontinuation for each patient was computed by subtracting the dates of the baseline and termination study visits.
Due to the exploratory and descriptive purposes of this paper, no adjustments for multiple comparisons were made. All analyses were conducted using SAS software (Cary, NC) version 9.