This 16-week randomized double-blind placebo-controlled trial by Attia et al. «Attia E, Steinglass JE, Walsh BT, ym. Olanzapine V...»1 compared olanzapine with placebo for outpatients with anorexia nervosa. The study was conducted at total of five sites in US and Canada from December 2010 to December 2016.
Recruitment of participants (N=152, 96% women, ages 18-65 years, BMI ≥14.0 and ≤18.5, mean 16.7) occurred primarily through clinical referrals and local media. Diagnosis of anorexia nervosa was made according to DSM-IV criteria (with the exception of the requirement for amenorrhea), assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, and confirmed by clinician interview. Participants were required to have taken no antipsychotic medication or other medication known to affect weight during the previous 4 weeks. Participants could be on a stable dosage of other psychotropic medications and could be engaged in outpatient psychotherapy if they had not consistently gained weight (>3lb) over the 4 weeks prior to study participation. Participants could not be in intensive outpatient treatments such as partial hospital or day programs. Co-occurring psychiatric diagnoses included mood disorder (current: 32.9%, past: 36.8%), prior alcohol abuse (7.2%) or dependence (11.8%), prior substance abuse (5.3%) or dependence (7.2%), anxiety disorder (current: 40.1%; past: 18.4%), and prior eating disorder other than anorexia nervosa (9.2%). The mean number of comorbid diagnoses was 2.1 (SD=1.4). Psychotropic medication use included antidepressants (N=45, 29.6%), sedative-hypnotics (N=23, 15.1%), or other psychotropic medications (N=19, 12.5%).
Treatment with study medication was terminated if the participant met study exclusion criteria (e.g., if BMI fell below 14.0), if the participant's weight decreased at four consecutive visits or fell below 90% of study baseline weight, or if the participant voluntarily withdrew. Individuals were also excluded from the study if they had 1) a medical problem that required urgent attention 2) a psychiatric problem that required immediate attention; 3) a current diagnosis of substance abuse or dependence, schizophrenia, schizophreniform disorder, or bipolar illness; 4) a neurological problem, history of a seizure disorder, or dementia; or 4) an allergy to olanzapine or a documented failure to respond to or inability to tolerate olanzapine at 10 mg/day.
Olanzapine (2.5 mg) and matching placebo pills were provided by Eli Lilly. Medication was dispensed in a double-blind fashion after the baseline assessments. Participants met with a study psychiatrist weekly for 16 weeks. Medication was initiated at 2.5 mg/day for 2 weeks, then increased to 5 mg/day for 2 weeks. At week 4, the dosage was increased to the maximum of 10 mg/day. The titration was halted or the dosage decreased if the participant reported significant adverse effects.
Randomization lists were generated by a computer program using a random number generator seeded by time of day. Randomization assignments were kept by the pharmacy at each site. All clinical staff, study coordinators and statisticians remained blind to medication assignment during the study.
Height and weight were measured at baseline, and weight, the primary physical outcome measure, was measured at each weekly assessment. Overall illness severity and change were assessed by a study psychiatrist weekly using the 7-point Clinical Global Impressions (CGI) severity scale and Improvement scale. These were anchored to assessments of weight, eating behavior, and mood. The primary psychological outcome measure was obsessionality, assessed with the Yale-Brown Obsessive Compulsive Scale interview (YBOCS). Symptoms of eating disorder severity, depression, and anxiety were examined using the following assessments, collected at baseline and 8 and 16 weeks after randomization: the Eating Disorder Examination (EDE), the Center for Epidemiologic Studies Depression Scale (CES-D), and the Zung Anxiety Inventory.
In the intent-to-treat analysis including all available data from all 152 randomized patients, olanzapine was associated with a significantly greater rate of weight gain (BMI increase of 0.259 per month [SE=0.051]) than placebo (BMI increase of 0.095 per month [SE=0.053]; p=0.026). There was no significant interaction between treatment group and either anorexia nervosa subtype (restricting versus binge-purge) or treatment site on rate of change of BMI. There was no significant difference between treatment groups in rate of change in YBOCS total score or YBOCS subscale scores.
Individuals in the olanzapine group had a threefold greater likelihood of being rated much or very much improved at week 16, although this difference did not reach statistical significance (OR = 3.2, 95% CI = 0.83 - 11.78, p=0.094); there was no significant difference between the treatment groups in likelihood of a reduction in CGI severity score. There was no significant difference between the groups in rate of change in the EDE subscale scores for weight concerns, restraint, or eating concerns, in CES-D score, or in Zung Anxiety Inventory score. There was a significantly greater rate of increase on the EDE shape concerns subscale in the olanzapine group compared with the placebo group (p=0.01); there was no significant association between the increase in EDE shape concerns and rate of increase in BMI (p=0.15).
At study termination, there were no significant differences in the frequency of abnormal results between the olanzapine and placebo groups on blood tests to assess metabolic abnormalities (serum cholesterol, triglycerides, HDL, LDL, the ratio of cholesterol to HDL, hemoglobin A1C, ALAT, ASAT). At study termination, a significantly smaller fraction of the patients in the olanzapine group were rated as having moderate or severe symptoms of trouble concentrating (14.5% compared with 32.7%; p=0.02), difficulty sitting still (6.5% compared with 18.2%; p=0.05), trouble falling asleep (9.7% compared with 30.9%; p=0.004), and trouble staying asleep (14.5% compared with 40.0%, p=0.002). There were also lower frequencies of complaints of headache (4.8% compared with 14.5%, p=0.07), tremors or shakiness (0% compared with 5.5%; p=0.06), and nervousness (14.5% compared with 27.3%; p=0.09) in the olanzapine group, although these differences did not reach statistical significance. Three patients in the olanzapine group, compared with none in the placebo group, were withdrawn because of suicidal ideation (N=2) or suicide attempt (N=1).
The authors concluded that results of both the intent-to-treat and per-protocol analyses indicated that in an outpatient setting, olanzapine offered modest benefit in weight gain, with patients in the olanzapine group gaining approximately 0.165 BMI points more per month than those in the placebo group, equivalent to approximately 0.454 kg more per month for a woman of average height (165 cm). In other words, patients on olanzapine gained 0.259 BMI points per month on average, equivalent to 0.681 kg per month. There was also a tendency for patients in the olanzapine group to be more likely to be rated by their clinician as much or very much improved over time.
The study by Spettigue et al. «Spettigue et al. Evaluation of the Efficacy and Sa...»2 was a non-randomized open-label trial. Participants were adolescents ages 11 to 17 years. Inclusion criteria were 1) Fulfilling the diagnostic criteria for AN (restrictive or binge-eating/purging subtype) or Eating disorder not otherwise specified (EDNOS), according to DSM-IV, and weighing 85% or less of his or her treatment goal weight; all patients would now meet DSM-5 criteria for anorexia nervosa; and 2) Receiving medical and psychological treatment in the eating disorder program at the children's hospital in Canada.
Exclusion criteria were 1) Currently receiving treatment with any other antipsychotic medication, mood stabilizer, or stimulant; 2) Known diagnosis of diabetes, impaired glucose tolerance, hyperlipidemia, hepatic dysfunction, substance dependence, narrow angle glaucoma, paralytic ileus, pancreatitis, or any other medical illness that would be considered to significantly impact treatment or recovery from the eating disorder; 3) Inability to comply with trial requirements including lack of comprehension of English.
4) Pregnant or breast-feeding; 5) Known allergy or known sensitivity to products in olanzapine. 6) Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrolment. 7) Liver function tests (ASAT/ALAT) > 2× normal.
8) Electrocardiogram: QTc > 450 msec or arrhythmia other than sinus bradycardia; conduction abnormalities prolonged QTc or other. 9) LDL-C > 4.9 mmol/L; 10) Total cholesterol/HDL ratio > 6; 11) Random glucose > 11 mmol/L (or Fasting glucose ≥ 6.1 mmol/L); 12) Neutrophil count < 0.5 x 109/L.
The mean age of participants was 15.48 years (SD = 1.45), 29 (90.6%) were females. 28 (87.5%) met criteria for DSM-IV-TR anorexia nervosa restrictive subtype or eating disorder not otherwise specified (EDNOS) restrictive subtype, and 4 (12.5%) had a diagnosis of anorexia nervosa binge-eating/ purging subtype. Majority of participants (n = 27; 84.4%) were inpatients at the time of recruitment, and 5 (15.6%) were outpatients.
Participants who chose at any point to take olanzapine belonged to the medication group, and those who opted not to take olanzapine were assigned to the comparison group.
Participants in the comparison group were eligible to switch into the medication group up until the end of week 8 in the study. This accommodation allowed participants who were not willing to start olanzapine at the beginning of treatment, to change their minds and request treatment with olanzapine. Comparison group participants who started olanzapine after treatment initiation were not included in the comparison cohort and instead were assigned to a third group: the switch group.
All participants received standard care from the eating disorder team, and all were offered adjunctive treatment with the medication olanzapine. The generic product, Teva-olanzapine (Teva Canada Limited) was used. Olanzapine doses replicated the eating disorder program's standard clinical practice with respect to dose administered and dosage adjustments being based on individual need and tolerability as determined by the treating clinician, rather than on an ‘a priori' dosing.
The eating disorder program was guided by the principles of Maudsley family-based treatment (FBT). Each patient was assigned a therapist who offers a combination of FBT plus individual therapy. The multidisciplinary team offered medical care, nutritional rehabilitation, and psychotherapy. The study was conducted between 2010 and 2014 by a specialized eating disorder team located in a children's hospital in Canada (Children's Hospital of Eastern Ontario, Ottawa).
Primary outcomes were rate of change in weight (kg) across the 12 weeks of the trial (weight gain) and rate of change of percentage of treatment goal weight. Weight was assessed weekly for the first 4 weeks of the study and biweekly thereafter. Secondary outcomes were psychological measures: self-reported depression, anxiety and eating disorder symptoms were assessed at baseline and weeks 4, 8, and 12 using the reliable and valid Children's Depression Inventory (CDI), the Multidimensional Anxiety Scale for Children (MASC), the Eating Disorder Inventory-3 (EDI-3) for eating disorder cognitions, and the Eating Disorder Examination Questionnaire-Adolescent (EDEQ) for eating disorder symptoms and behaviors.
Medical and safety monitoring included electrocardiogram (ECG), hematology and biochemistry results, patient-reported side effects, and clinician-assessed extrapyramidal symptoms.
Patient-reported side effects were assessed using an adverse event checklist (AEC) developed by the investigators. The AEC asked participants to rate the following symptoms as absent or present: dizziness, somnolence, agitation, restlessness, headache, dry mouth, constipation, and stiff muscles. Participants were encouraged to specify any other symptoms in a blank space provided on the AEC. Study physicians followed up on any endorsed symptoms. Extrapyramidal symptoms were assessed by a physician using the Extrapyramidal Symptom Rating Scale (ESRS). The ESRS assesses four medication-induced movement disorders: Parkinsonism, akathisia, dystonia, and tardive dyskinesia.
Of 239 patients assessed, 65 (27%) met study inclusion criteria. 38 participants enrolled in the trial and 32 were retained for analyses; 6 participants were excluded. 14 participants accepted olanzapine at the time of study entry and were assigned to the medication group; 18 chose not to take olanzapine at study entry and were assigned to the comparison group. Of the 18 comparison group participants, 8 changed their minds and requested olanzapine as part of their treatment (switch group), leaving 10 participants in the comparison group.
Mean weekly weight gain for the comparison group was 0.66 kg/week over 12 weeks, and the mean weekly weight gain for the medication group was 1.09 kg/week over 12 weeks.
Both the medication and comparison groups experienced significant gains in weight across time (p < 0.001), with medication group participants gaining more weight per week (12.2 kg over 10 weeks) than those in the comparison group (who gained 7.6 kg over ten weeks) (p = 0.03).
Both the medication and comparison groups experienced significant gains in percentage of treatment goal weight across time (p < 0.001), with medication group participants approaching their goal weight at a faster rate than those in the comparison group (p = 0.02).
The rate of weight gain before and after starting olanzapine among the switch group participants was also examined: 2 participants who switched within five weeks and the 1 participant who switched at week eight were included. 5 participants who switched within 2 weeks were not examined due to lack of time points. For the 3 participants examined, mean rate of weight gain before starting olanzapine was 1.01 kg/week, and mean rate of weight gain after starting olanzapine was 1.42 kg/week.
All participants experienced a significant decrease in depression (p = 0.002) and anxiety (p = 0.039) throughout the 12-week study period. The two groups did not differ in rate of change of depression scores (p = 0.36) or anxiety scores (p =0.49). Similarly, participants experienced a significant decrease in self-reported eating disorder behaviors (p=0.004), but no differences between groups were seen (p=0.90). Drive for thinness decreased from baseline to week 12 (p =0.009), but no differences between groups were found (p = 0.19). Body dissatisfaction did not change significantly throughout the study (p =0.14), and did not differ between groups (p=0.34).
There were no serious adverse effects reported throughout the study timeframe. Serum fasting glucose, HbA1C, total cholesterol, HDL, LDL, triglycerides, ALAT, ASAT, creatine kinase, amylase, prolactin, and complete blood counts with differentials were checked at baseline, and weeks 2, 4, 8, and 12. The majority of participants, including those in the comparison group, (n = 19/32; 59.4% of participants from both groups) experienced a biochemistry result outside the reference range at some point throughout the study.
Participants in the medication/switch group experienced a higher frequency of abnormal values deemed clinically significant by a study physician when compared to the comparison group. None of the differences reached statistical significance, but all adverse effects occurred in the medication/switch group. Of medication/switch group participants 8/22 (27%) experienced elevated ALAT levels while taking olanzapine; 3/22 (14%) of the same participants experienced a concurrent elevated ASAT value. Of participants, 7/22 (32%), all in the medication group, experienced an asymptomatic elevated serum prolactin result while taking olanzapine. Of participants, 5/22 (23%) in the medication/switch group experienced an elevated total cholesterol value (3 of whom also experienced an elevated LDL value (3/22 = 13.6%), and 4 of whom also experienced elevated HDL values (4/22 = 18%). One participant in the medication/switch group (1/22 = 4.6%) had an elevated triglyceride value.
Self-reported side effects that were examined included: dizziness, somnolence, agitation, restlessness, headache, dry mouth, constipation, and stiff muscles. Subjectively, patients on olanzapine tended to experience less agitation (13.0% versus 33.3%), headache (21.7% versus 33.3%), and constipation (30.4% versus 33.3%) than the comparison group. However, they reported more dizziness (30.4% versus 22.2%), muscle stiffness (39.1% versus 22.2%), somnolence (34.8% versus 33.3%), and dry mouth (26.1% versus 22.2%). Subjective restlessness was approximately equal between the groups (21.7% in medication group and 22.2% in comparison group). Physician monitored extrapyramidal symptoms resulted in the following clinical global impression of severity ratings: parkinsonism and dyskinesia absent, akathisia mild for two patients, dystonia mild for one patient. One participant in each group experienced prolonged QTc, defined as QTc > 460 ms: 470 ms for the comparison group participant, and 462 ms for the medication group participant.
Participants in the medication group were on olanzapine for a mean of 55 days (SD = 21, range 16 - 86 days). Starting doses ranged from 1.25 mg/day to 5 mg/day, and dose increase increments ranged from 1.25 mg/day to 2.5 mg/day. Treatment doses ranged from 2.5 mg to 15 mg daily. Nine (40.9%) discontinued olanzapine treatment at their physician's recommendation because they had reached their treatment goal weight; seven (31.8%) because the treating physician recommended stopping the medication because of an adverse effect, most commonly elevated liver function tests and elevated cholesterol values; and one (4.5%) participant discontinued olanzapine on her own as she felt it was not helping her. Five participants (22.7%) remained on olanzapine for the length of the study.
The meta-analysis of randomized-controlled trials (N=7 studies in total) by Dold et al. «Dold M, Aigner M, Klabunde M, ym. Second-Generatio...»3 assessed second-generation antipsychotic drugs in anorexia nervosa. This review includes only results concerning olanzapine (N= 4 studies; «Brambilla F, Garcia CS, Fassino S, ym. Olanzapine ...»4, «Bissada H, Tasca GA, Barber AM, ym. Olanzapine in ...»5, «Attia E, Kaplan AS, Walsh BT, ym. Olanzapine versu...»6, «Kafantaris V, Leigh E, Hertz S, ym. A placebo-cont...»7).
Initial literature search yielded 698 citations and finally, six citations on four trials were incorporated. Altogether, seven RCTs with a total of 201 participants were included, of whom 95 were randomly assigned to treatment with an SGA and 106 to placebo or no treatment.
All published and unpublished RCTs that compared second-generation antipsychotic drugs with placebo or no treatment in the pharmacological management of anorexia nervosa were included. No limitations in terms of trial duration, age of the participants, gender, comorbidities, and the subtypes of anorexia nervosa were applied. In those studies indicating the subtype of anorexia nervosa 64.2% suffered from the restricting subtype and the remaining ones from the binge-purging subtype. Four trials examined an antipsychotic medication with olanzapine (n = 112), two with quetiapine (n = 48), and one with risperidone (n = 41); all olanzapine trials were double-blinded. The mean age of patients was 24.1 ± 6.3 years and under 18 years of age in two trials, of which another included olanzapine. 98.5% of all participants were female. The mean (±SD) BMI at baseline was 16.3 ± 0.5 kg/m2.
In all olanzapine studies, participants attended an eating disorder program containing standardized psychotherapeutic and/ or psychosocial interventions. All but one olanzapine trials were sponsored and/or supported by pharmaceutical companies. Overall attrition was moderate (10-25%) in three olanzapine trials and high (>25%) in one olanzapine trial. All four RCTs appeared to be free of other potential sources of bias.
The primary outcome was body weight gain measured by mean change in body mass index (BMI) from study baseline to endpoint. Secondary outcomes were overall change of anorectic symptoms assessed by mean changes in the total scores of the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) and the Eating Disorders Inventory (EDI). Further secondary outcomes were the number of dropouts due to any reason (all-cause discontinuation), due to inefficacy, and due to adverse effects.
Primary outcome, mean BMI change: Olanzapine (n = 94; Hedges's g = 0.26, 95% CI: –0.13 to 0.65; p = 0.2), was not significantly different from placebo or no treatment.
Secondary outcome, overall change of anorectic symptoms: For the mean YBC-EDS total score changes, no significant between-group differences in comparison to the control group (placebo / no treatment) for olanzapine was detected. The same was true regarding the mean change in EDI total score. Likewise, for olanzapine, there were no significant between-group differences in terms of the number of participants leaving the study early due to any reason, due to inefficacy of treatment, or due to adverse effects. Sensitivity analysis did not alter the effect sizes regarding statistically significant between-group differences, and there was no evidence of publication bias using funnel plot.