Fluoxetine in the Management of Major Depressive Disorder in Children and Adolescents: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background

Fluoxetine is a serotonin-specific reuptake inhibitor antidepressant and is the only approved pharmacological treatment for major depressive disorder (MDD) in children and adolescent.

Methods

We searched the published randomized controlled-trials to review fluoxetine efficacy and tolerability using the databases PubMed, EudraCT, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials for fluoxetine role in managing MDD in children and adolescents. A meta-analysis was conducted using the identified 7 clinical trials to assess efficacy using the outcomes: Children's Depression Rating Scale–Revised (CDRS-R), Clinical Global Impressions–Severity of Illness (CGI-S) and Clinical Global Impressions–Improvement (CGI-I) response rate. The risk of discontinuation due to adverse effects and common side effects were examined.

Results

The mean difference in change from baseline for CDRS-R was −2.72 (95% confidence interval [CI], −3.96, −1.48) favoring fluoxetine treatment (P < .001). Similarly, mean difference for CGI-S was −0.21 (95% CI, −0.36, −0.06). The risk ratio (RR) of discontinuing due to adverse events was 0.98 (95% CI, 0.54, 1.83), with RR for headache side effects 1.34 (95% CI, 1.03, 1.74) and rash 2.6 (95% CI, 1.32, 5.14).

Conclusion

Fluoxetine demonstrates significant improvements in symptom intensity control in young patients suffering from MDD and is considered well tolerated with similar rates of trials discontinuation; however, fluoxetine was associated with a higher risk of headache and rash side effects. These findings will guide psychiatrists and pharmacists in their clinical role for supporting the care of young mental health patients.

Introduction

Depression is characterized by low mood and loss of pleasure ¹ with symptoms including reduced concentration, feeling of guilt, negative thoughts, and disturbed sleep. ² According to The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition; DSM-5), ³ individuals must be experiencing 5 or more symptoms (depressed mood, diminished interest or pleasure, significant weight loss, slowing down of thought, and a reduction of physical movement, fatigue, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and recurrent suicidal ideation) during 2-week period with at least either depressed mood or loss of interest/pleasure as a core symptom. ⁴

Worldwide, over 260 million suffer from depressive disorders—a main cause of disability—leading to difficulties in social functioning and suicide. ⁵ In children and adolescents, depression increased incidence of alcohol consumption, drug use, and self-harm. ⁶ Alcohol abuse has been shown to decrease serotonin levels leading to deteriorating of the depressive symptoms and increased suicide incidence. ⁷ For a diagnosis of depression to be made, the patient must have experienced symptoms for most of the day for 2 weeks, ¹ while International Statistical Classification of Diseases (ICD-10) classifies depression into 3 main categories: mild, moderate, and severe. Depression in adults is diagnosed using psychiatric scales such as Beck Depression Inventory (BDI), while clinician-rated scale such as Children's Depression Rating Scale–Revised (CDRS-R) are used for children/adolescents. ⁸

A variety of antidepressants have shown efficacy in depression management in adults, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). ⁹ In contrast, few studies have been conducted in young people, where it is recommended that pharmacological therapy is initiated once psychological treatment is in use. SSRIs are the first-line pharmacological therapy in young people and currently, fluoxetine is the only licensed antidepressant for adolescents in the United Kingdom. ¹ On the other hand, there are some concerns regarding association of SSRI with suicide incidence in children and adolescents.^10–12

SSRIs inhibit the neurotransmitter 5-hydroxytryptamine (serotonin) reuptake into serotoninergic neurones, leading to increased serotonin level in the synapse. Compared with TCAs, SSRIs cause less anticholinergic side effects and are safer in overdose. ⁹ SSRIs are also indicated for the management of comorbid anxiety and obsessive-compulsive disorder (OCD). ⁹ Fluoxetine is relatively long-acting with a half-life of 1 to 3 days, which could increase further to 4 to 6 days following chronic administration ¹³ and is extensively sequestered in tissues. ¹⁴ Fluoxetine is mainly metabolized via the CYP2D6 pathway in the liver to the active metabolite norfluoxetine (half-life ∼9 days). ¹³ The aim of the systematic meta-analysis is to update knowledge regarding fluoxetine efficacy and safety compared with placebo in children and adolescents diagnosed with MDD.

Methods

Search Strategy

The focused research question is, “Will fluoxetine compared with placebo lower the severity of depression and alter adverse effects' incidence in children and adolescents with MDD?”

The study population included children and adolescent patients taking part in randomized controlled trials (RCTs) assigned to either fluoxetine or placebo for the management of MDD. A literature search was performed for RCTs investigating the efficacy and/or safety of fluoxetine compared with placebo. The search terms “fluoxetine, placebo, major depressive disorders” were used in PubMed, ScienceDirect, EudraCT, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials up to September 2019 with filters applied such as “clinical trials” and “child/adolescents.” No restrictions on study size, year of study, or duration were set. Titles were screened for relevance, duplicates removed, then abstracts screened before the remaining relevant full texts were examined to find those meeting the inclusion criteria (Figure 1).

Figure 1.

Prisma flow chart for literature search results of fluoxetine versus placebo in major depressive disorder for children and adolescents.

Efficacy and Tolerability Outcomes

The primary efficacy outcomes of included RCT were measured using self-report or clinician-rated scales, where generally, clinician-rated scales are more reliable. One of the most commonly used scales was CDRS-R, a clinician-rated scale used to measure the severity of depression, ¹⁵ which contains 17 items in total, 14 of which were rated from 1 to 7 with the remaining 3 rated from 1 to 5 with a total score can range from 17 to 113. ⁸ Clinical Global Impressions–Severity of Illness Score (CGI-S), a clinician-rated scale, was also used for depressive symptoms severity. ¹⁶ The primary tolerability and safety outcomes for fluoxetine were discontinuation due to adverse effects and side effects.

Statistical Analysis

Review Manager 5.3 (RevMan) along with the Cochrane Collaboration tool for assessing the risk of bias ¹⁷ , ¹⁸ was used to assess the levels of selection, performance, detection, attrition, and reporting bias in each of the chosen RCTs. “Characteristics of study” tables were completed in RevMan for each of the individual studies and a summary table was created. ¹⁸

The inverse variance method with fixed effects model was used to calculate the mean differences (MDs) for continuous outcomes. The Mantel-Haenszel method with random effects model used to calculate the risk ratio (RR) for dichotomous outcomes (risk of discontinuation due to adverse effects and side effects) ¹⁹ using RevMan, 95% confidence intervals was determined. The value of P < .05 was regarded as statistically significant. ¹⁸ Variations can occur between trials as they will differ in aspects such as participants, interventions, and outcomes; ²⁰ thus, a test for heterogeneity was carried out using chi-squared test and I ² value.

Results

Search Results and Included Studies

Figure 1 shows the selection process of included RCTs. PubMed, EudraCT, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials were searched for “Fluoxetine” giving 2441 records in total. After removing duplicates and screening titles and abstracts, 24 studies were included in full text screening, while 7 RCTs met the inclusion criteria.^21–27 Table 1 shows the characteristics of the included published randomized controlled trials that investigated the tolerability, safety, or efficacy of fluoxetine in patients suffering from MDD; a total of 1259 patients were included in the studies analyzed within this review. All RCTs were double-blinded and placebo-controlled with treatment duration range 6 to 10 weeks. Studies were undertaken in regions including United States, Russia with similar prevalence and incidence rates to the United Kingdom. ²⁸ Trials containing serious comorbidities, including diagnosis of other The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition; DSM-IV) defined disorders such as bipolar disorder, psychotic depression, or substance abuse disorder, were excluded.

Table 1.

Randomized Controlled Trials Included in the Meta-Analysis.

Study	Design	Duration, wk	Dose range, mg/d	Population
Atkinson 21	Double-blinded, placebo control	10	Placebo	103
			Flu 20-40	117
B1Y-MC-HCCJ 22	Double-blinded, placebo control	6	Placebo	21
			Flu 20-60	19
Emslie 23	Double-blinded, placebo control	8	Placebo	48
			Flu 20	48
Emslie 24	Double-blinded, placebo control	8	Placebo	109
			Flu 20	110
Emslie 25	Double-blinded, placebo control	10	Placebo	117
			Flu 20	122
March 26	Double-blinded, placebo control	6	Placebo	109
			Flu 20	112
Weihs 27	Double-blinded, placebo control	8	Placebo	112
			Flu 20	112

Note. Flu = Fluoxetine.

Figure 2 shows the risk of bias with the sequence generation, allocation concealment, and blinding mostly with “unclear” risk due to insufficient information. The patients in all the studies were randomly assigned and there was certain level of blinding for both participants and personnel. The domains relating to the completeness of data and reporting of outcomes were “low” risk of bias, while other risks were high due to the high extent of trials funding/support by pharmaceutical companies (Figure 2).

Figure 2.

Risk of bias summary and methodological quality graph: review authors' judgments about each risk of bias item for each included study and each methodological quality item presented as percentages across all included studies.

Efficacy of Fluoxetine in Children and Adolescents Major Depressive Disorders

The mean change from baseline in CDRS-R was −2.72 (95% confidence interval [CI], −3.96, −1.48) favoring fluoxetine treatment (P < .001), with a total of 601 fluoxetine patients and 592 placebo patients included in the analysis (Figure 3a). The forest plot shows the MD for all the studies individually favor fluoxetine with some degree of heterogeneity between the studies (χ ²  = 16.52, I ²  = 70%). The MD for CGI-S was −0.21 with 95% CI, −0.36 to −0.06 (Figure 3b) favoring fluoxetine. Atkinson show data not consistent with the other trials regarding CGI-S, with high heterogeneity between the studies (χ ²  = 17.81, I ²  = 78%). CGI response rate was higher in fluoxetine compared with placebo, with an RR = 1.46 (1.27–1.67) (Figure 3c) and moderate heterogeneity between trials (χ ²  = 4.36, I ²  = 31%).

Figure 3.

Efficacy outcomes measures for fluoxetine versus placebo in the management of major depressive disorder for children and adolescents.

Note. (a) Outcome: CDRS-R total score changes, (b) CGI-S total score changes, (c) CGI-I response rate, (d) CDRS-R subscale—mood total score changes, (e) CDRS-R subscale—somatic total score changes, and (f) CDRS-R subscale—behavior total score changes. CDRS-R = Children's Depression Rating Scale–Revised; CGI-S = Clinical Global Impressions–Severity; CGI-I = Clinical Global Impression scale–Improvement.

Only 2 RCTs ²³ , ²⁴ measured the effect of fluoxetine on CDRS mood, somatic, and behavior subscales (Figures 3d-3f) with the overall result showed a positive effect for fluoxetine on all 3 subscales with MD from baseline −2.65 (95% CI, −3.77, −1.52), −2.48 (95% CI, −3.61, −1.34), and −1.77 (95% CI, −2.6, −0.94), respectively, with low to moderate heterogeneity among the studies.

Tolerability and Safety of Fluoxetine in Children and Adolescents Major Depressive Disorders

The overall RR for trial discontinuation due to adverse effects is 0.99 (0.54–1.83), P = .98, showing no major differences between fluoxetine and placebo groups (Figure 4a), with some variation among the studies with some favoring fluoxetine, and others favoring placebo (I ²  = 12%). There was no significant statistical difference in the total incidence of side effects between fluoxetine and placebo (P = .52) (Figure 4b). Fluoxetine was associated with some mild side effects including headache RR = 1.34 (1.03-1.74), P = .03 and rash RR = 2.60 (1.32–5.14), P = .006 (Figure 4). For the other side effects such as suicidal ideation, dizziness, sedation, nausea, and vomiting, no significant statistical differences were detected between fluoxetine and placebo.

Figure 4.

Tolerability and safety profile of fluoxetine compared with placebo: (a) outcome: trial withdrawal due to adverse event, (b) outcome: total incidence of side effects, (c) outcome: side effect—headache, and (d) outcome: side effect—rash.

Discussion and Conclusion

This systematic review/meta-analysis investigated the efficacy and safety of fluoxetine for the management of MDD in children and adolescents using the available clinical trials. Fluoxetine improved CDRS-R total psychiatric scale used for measuring symptom severity in young patients with depression. Fluoxetine also showed significant improvements in CGI-S and CGI-I response rate. This meta-analysis update knowledge regarding the role of fluoxetine as it is currently, the only antidepressant licensed for use in children and adolescents. These results are consistent with a previous meta-analysis that showed fluoxetine and escitalopram the only treatments with possible efficacy as antidepressants in children and adolescents. ²⁹ These results (Figure 3) confirmed the efficacy of fluoxetine as highlighted in other meta-analyses covering several antidepressants and showing a moderate beneficial role of fluoxetine in MDD. ³⁰ , ³¹ Another meta-analysis casted doubt on the role of fluoxetine in MDD in children and adolescents ³² ; however, new data included from recent trials are included in this article supports fluoxetine efficacy. Risk of discontinuing was similar in fluoxetine compared with placebo with equal risk of total side effects in the fluoxetine treatment compared with placebo.

These results confirm that there were insignificant changes in treatment emergent suicidal thoughts with fluoxetine, in agreement with previous research. ²⁹ Generally, these findings focused on fluoxetine as antidepressant in the management of MDD supported and updated other researchers' work ³³ that showed efficacy consistent with these findings even in adults. ³⁴ Furthermore, these findings showed fluoxetine efficacy as a pharmacological treatment of MDD in children and adolescents ³⁵ while including a recent large-scale clinical trial. ²⁷ Results (Figure 4) also show that fluoxetine was associated with mild side effects such as headache (RR = 1.34) and Rash (RR = 2.6). This review shows that fluoxetine is well tolerated and significantly improves MDD in children and adolescents. The results need to be interpreted with caution as the treatment length ranged from just 6 to 10 weeks, with not enough evidence for long-term treatment effects, while several doses of fluoxetine were used with different efficacy and side effects profile. Therefore, it is recommended that further research using different doses with long-term treatment is conducted for a more comprehensive understanding of the role of fluoxetine in the management of MDD.