ترکیب راهنمایی بالینی اولانزاپین/فلوکستین در کودکان و نوجوانان با دو قطبی I افسردگی:کارآزمایی دو سو کور، دارونما -کنترل شده تصادفی

Objective To assess the efficacy and safety of olanzapine/fluoxetine combination (OFC) for the acute treatment of bipolar depression in children and adolescents. Method Patients 10 to 17 years of age with bipolar I disorder (BP-I), depressed episode, baseline Children’s Depression Rating Scale–Revised (CDRS-R) total score ≥40, Young Mania Rating Scale (YMRS) total score ≤15, and YMRS-item 1 ≤2 were randomized to OFC (6/25–12/50 mg/day olanzapine/fluoxetine; n = 170) or placebo (n = 85) for up to 8 weeks of double-blind treatment. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated-measures methodology. Results Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients (−28.4 versus −23.4, p = .003; effect size = .46), with between-group differences statistically significant at week 1 (p = .02) and all subsequent visits (all p < .01). Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient’s endpoint was significantly greater for OFC- than for placebo-treated patients (4.4 kg versus 0.5 kg, p < .001). Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval (QTc) were also common or very common but generally not clinically significant. Conclusion In this study, OFC was superior to placebo, and has been approved by the US Food and Drug Administration (FDA) for the acute treatment of bipolar I depression in patients 10 to 17 years of age. Benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia. Clinical trial registration information—A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://clinicaltrials.gov; NCT00844857.

Treatment of the depressive phase of bipolar disorder (BD) in children and adolescents remains a significant unmet medical need. Relative to those diagnosed in adulthood, patients diagnosed with BD during childhood or adolescence have significantly reduced quality of life1 and greater risk of poorer psychiatric, psychosocial, and health-related outcomes,2 including greater risk of suicidal behavior.3 and 4 Inadequate or delayed symptom control in these young patients may have serious impacts on social, emotional, and educational development that can leave this already-vulnerable population even further impaired and disadvantaged. Consequently, rapid and reliable intervention is critical. Unfortunately, the pharmacological treatment of bipolar depression poses a major therapeutic challenge. Unopposed antidepressant therapy may potentially precipitate manic symptoms,5 and although there are multiple medications effective for the treatment of mania, treatment of the depressive phase of the illness remains understudied in both children and adults, and many frequently used treatments, such as lithium, valproate, and lamotrigine, have limited or no evidence to support their use for the acute treatment of bipolar depression.6 At present, only 3 medications are approved for the acute treatment of bipolar depression in adults in the United States by the US Food and Drug Administration (FDA): quetiapine, lurasidone, and olanzapine/fluoxetine combination (OFC). With regard to testing these medications in children and adolescents, 2 randomized, double-blind studies of quetiapine were conducted in patients 10 to 17 years of age diagnosed with bipolar depression, but both studies failed to demonstrate a significant benefit of quetiapine versus placebo in that population.7 and 8 Pediatric trials of lurasidone are still pending. OFC is a fixed-dose combination capsule, available in generic preparation, which contains the second-generation antipsychotic (SGA) olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Olanzapine and fluoxetine can also be separately co-administered to achieve the same approximate proportions as the fixed-combination OFC capsule.9 and 10 Olanzapine is an effective mood stabilizer11, 12 and 13 that appears to enhance the antidepressant action of fluoxetine,14 and 15 as demonstrated in adult studies of treatment-resistant depression, which showed OFC to be superior to fluoxetine alone.16, 17 and 18 OFC has also demonstrated rapid and robust improvement of depressive symptoms in adults with bipolar I depression19 and 20 without increasing risk of switch to mania, and was superior to placebo,19 olanzapine monotherapy,19 and lamotrigine21 during acute treatment. Although OFC has not previously been studied in patients <18 years of age, its components have been evaluated separately for other indications for which they are now FDA approved. Fluoxetine has been shown to be efficacious for the treatment of major depressive disorder (MDD) in patients 8 to 18 years of age 22 and 23 and for obsessive-compulsive disorder in patients 7 to 17 years of age,24 and is generally very well tolerated, with a safety profile similar to that observed in adults.25 Olanzapine has been shown to be efficacious for the treatment of schizophrenia and manic or mixed episodes associated with BD in adolescents 13 to 17 years of age.26 and 27 The most frequent adverse events observed with olanzapine in adolescents included weight gain and somnolence,26 and 27 with adolescent patients likely to gain more weight, experience increased somnolence/sedation, and have greater increases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, prolactin, and hepatic aminotransferase levels than those observed in adults treated with olanzapine.10 As a result, US labeling for olanzapine warns that clinicians may wish to consider prescribing other medications first in adolescents.10 Although OFC in children and adolescents would be expected to carry a metabolic risk similar to that of olanzapine monotherapy, the previous lack of an approved medication for the treatment of pediatric bipolar depression supported the need to assess OFC as a possible acute treatment option despite this risk. The objective of the present study was to assess the efficacy and safety of OFC versus placebo for the treatment of depressive episodes associated with bipolar I disorder (BP-I) in children and adolescents. This study was conducted at the request of the FDA as part of the Pediatric Research Equity Act.

A total of 255 patients (170 OFC, 85 placebo) comprised the mITT population (Figure 1). Of these, 176 (69.0%) completed the study, with no statistically significant differences between treatment groups regarding study completion or reasons for discontinuation. However, discontinuation due to an AE was more than twice as high for the OFC group (14.1%) as for the placebo group (5.9%; p = .060). The most frequent AE leading to discontinuation for OFC-treated patients was weight gain (n = 5, 2.9%). Full-size image (45 K) Figure 1. Patient disposition. Note: ITT = intent-to-treat; mITT = modified intent-to-treat; OFC = olanzapine/fluoxetine combination. Figure options There were no statistically significant differences between groups in baseline demographics or illness characteristics (Table 1). Patients were 51% male, 71% white, 13% black, 9% mixed race, and 6% American Indian, with 24% of all patients describing their ethnicity as Hispanic. Mean age was 14.7 years. Mean symptom scores at baseline were indicative of an acutely ill patient population with moderately severe depression and an absence of mania in the current episode. Patients were predominantly outpatients; 12 were inpatients at any time during the double-blind period. Previous psychotropic medications had been taken by 61% of patients in the past year, with the most common being risperidone (14%), quetiapine (12%), aripiprazole (9%), and valproic acid (9%). Table 1. Baseline Patient Characteristics Variable OFC (n = 170) Placebo (n = 85) Total (N = 255) Age (y), mean (SD) 14.6 (2.3) 15.0 (2.1) 14.7 (2.3) 10–12 years of age, n (%) 29 (17.1) 10 (11.8) 39 (15.3) 13–17 years of age, n (%) 141 (82.9) 75 (88.2) 216 (84.7) Sex, male, n (%) 84 (49.4) 46 (54.1) 130 (51.0) Race, white, n (%) 119 (70.0) 61 (71.8) 180 (70.6) Ethnicity, Hispanic, n (%) 38 (22.4) 23 (27.1) 61 (23.9) No. of previous episodes mania, median 1 2 1 No. of previous episodes depression, median 2 2 2 CDRS-R total score, mean (SD) 54.6 (10.0) 53.7 (8.1) 54.3 (9.4) YMRS total score, mean (SD) 6.1 (3.8) 6.2 (3.9) 6.1 (3.8) CGI-BP overall severity, mean (SD) 4.4 (0.7) 4.3 (0.7) 4.4 (0.7) Current comorbid ADHD diagnosis, n (%) 45 (26.5) 17 (20.0) 62 (24.3) Note: ADHD = attention-deficit/hyperactivity disorder; CDRS-R = Children’s Depression Rating Scale–Revised; CGI-BP = Clinical Global Impressions Scale–Bipolar Version; OFC = olanzapine/fluoxetine combination; YMRS =Young Mania Rating Scale. Table options Mean doses of olanzapine and fluoxetine during the study were 7.7 mg/day (SD = 2.1) and 37.6 mg/day (SD = 8.4), respectively. The most common dose during the study was 12/50 mg, which was the target dose of the forced titration and the highest dose allowed; it was the modal dose for 39% of OFC-treated patients. Concomitant benzodiazepine use occurred more frequently in placebo-treated patients (14.1%) than OFC-treated patients (4.7%; p = .013). Three patients used a concomitant anticholinergic (1.2% in each group).