A retrospective study of SSRI treatment in adolescent anorexia nervosa: insufficient evidence for efficacy

Abstract

Although selective-serotonin-reuptake-inhibitors (SSRI) have been of limited efficacy in the treatment of eating disorder psychopathology and comorbid symptoms of malnourished patients with anorexia nervosa (AN), there is recent data suggesting that SSRI may play a role in preventing relapse among weight-restored patients. Though some previous studies included patients in late adolescence, the vast majority of investigated subjects have been adults. The aim of our retrospective study was to assess the effects of SSRI treatment in partially weight-restored children and adolescents with AN.

Thirty two females with AN (mean 14.5 ± 1.4 years) were investigated three times during inpatient treatment and at 3- and 6-month follow-up for BMI, eating disorder psychopathology, depressive symptomology, and obsessive-compulsive symptomology. Medication history during inpatient and outpatient treatment was reconstructed at the 6-month follow-up. Nineteen patients received SSRI treatment, while 13 subjects were non-medicated. In comparison to the non-SSRI group, the SSRI group had similar BMI and obsessive-compulsive scores, but higher levels of core eating disorder psychopathology and depressive symptoms at the start of medication.

Rates of re-admissions were similar in both groups (SSRI group: 36%, non-SSRI group: 31%, Φ: p = 0.72). Repeated measures ANOVA revealed no significant group with time interactions for BMI-SDS (p = 0.84), core eating disorder symptoms (ANIS, p = 0.79), depression (DIKJ, p = 0.75), and obsessive-compulsive (CY-BOCS, p = 0.40) scores indicating minimal or no effects of SSRI medication on the course of these variables.

In conclusion, our results challenge the efficacy of SSRI medication in the treatment of eating disorder psychopathology as well as depressive and obsessive-compulsive comorbidity in adolescent AN. Clinicians should be chary in prescribing SSRI in adolescent AN unless randomized controlled trials have proofed the benefit of these drugs.

Introduction

In anorexia nervosa (AN), inpatient therapies are efficient in weight rehabilitation, but rates of relapses are nevertheless high, especially within the first 6 months after discharge (Strober et al., 1997a; Herpertz-Dahlmann et al., 2001). Although pharmacologic treatments with different agents including selective-serotonin-reuptake-inhibitors (SSRI) have been of limited efficacy in acutely ill malnourished patients (Mitchell et al., 2003; Ferguson et al., 1999), there is recent data suggesting that SSRI may play a role in preventing relapse in weight-restored patients (Kaye et al., 2001).

One potential reason for the effectiveness of SSRI during the recovered state may be the drug’s actions on serotonin (5-HT), a neurotransmitter system found to be dysregulated in individuals with AN. When assessed after long-term recovery, individuals with AN have increased levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the cerebrospinal fluid (Kaye et al., 1991a, Kaye et al., 1991b). In addition, recent studies using positron emission tomography have found decreased activity at the 5-HT2A receptor (Frank et al., 2002), indicating a compensatory response of the brain to increased 5-HT output. It has been suggested that SSRI may be efficacious during the recovered state of AN by modulating an intrinsic defect of serotonergic activity in these individuals.

Furthermore, some studies, though not all have shown SSRI to be helpful in depressive illness (for a review see Ryan et al., 2003; Kastelic et al., 2000). SSRI have proven effective for the treatment of obsessive-compulsive disorders in childhood and adolescence (Geller et al., 2003) as well as for binge eating behaviour in bulimia nervosa (Kotler et al., 2003; Fluoxetine BN Study Group, 1992). Like AN, these disorders have been linked to a dysregulation in the serotonergic system. Depressive and obsessive-compulsive symptoms are frequently comorbid with AN during the acute stage and often persist after recovery of the eating disorder (Herpertz-Dahlmann et al., 2001). Therefore, some researchers believe that these disorders share with AN a dysfunction of the serotonergic system (Kaye et al., 1998).

The literature concerning SSRI drug trials in AN will be reviewed here. Attia et al. (1998) performed a 7-week double-blind, randomized, placebo-controlled trial of fluoxetine in 47 adult anorectic patients (age 26 ± 7.4 years, BMI 15 ± 4.2 kg/m²). Fluoxetine treatment added no benefit over the established therapies in any parameter, including weight gain, depression, and obsessive symptoms within 7 weeks. Santonastaso et al. (2001) and Fassino et al. (2002) confirmed a lack of weight gain, but in both studies a reduction of comorbid symptoms was reported. According to Santonastaso and colleagues, administration of sertraline improved depression, interoceptive awareness, and perfectionism but not BMI in a 14-week open controlled trial of 11 medicated AN patients when compared to 11 non-medicated controls (age 19.3 ± 4.7 years, BMI 16.1 ± 1 kg/m²). In a 3-months randomized, controlled study of citalopram treatment, Fassino and colleagues investigated 26 medicated AN patients (age 24 5.3 years, BMI 16.2 ± 0.8 kg/m²) and 26 controls (waiting list condition, age 25 ± 8.6 years, BMI 15.6 ± 1.4 kg/m²). There were no significant differences in weight gain between both groups, but in the citalopram group, but a decrease in depression, obsessive-compulsive symptoms, and trait-anger scores. Nevertheless, these results have to be interpreted with caution since 30% of the patients in both study groups dropped out of the trial.

The observation periods of the above mentioned studies were short, and SSRIs were administered to malnourished patients. In a retrospective chart review of 24 adult patients with AN treated with an SSRI and 16 non-medicated AN subjects, Ferguson and colleagues (1999) showed that SSRI medication had no effect on eating disorder symptoms in malnourished underweight anorectics. The authors suggested that SSRIs were not effective in these patients because of low synaptic 5-HT concentration leading to inefficient inhibition of 5-HT re-uptake. They postulated that a clinically meaningful SSRI response was more likely to occur after partial weight recovery and a subsequent higher 5-HT concentration. The same working group (Kaye et al., 1991a, Kaye et al., 1991b) accomplished an open trial of fluoxetine treatment in 31 AN subjects after partial weight restoration (age 20 ± 7 years, mean average body weight 89 ± 6%). At the time of the follow-up (11 ± 6 months on fluoxetine), 29 of the 31 patients had maintained their body weight at or above 85% of average body weight. The authors hypothesized that fluoxetine treatment may help patients to maintain a healthy body weight as outpatients by reducing obsessionality, depression, and anxiety. Kaye and colleagues substantiated their findings with a 1-year double-blind placebo-controlled adjunctive administration of fluoxetine after inpatient treatment with at least partial weight recovery in 35 subjects with restrictive AN (age 23 ± 9 years, BMI 15 ± 4.2 kg/m²) who were treated in an outpatient psychotherapeutical setting (Kaye et al., 2001). They found a positive effect of fluoxetine on BMI development; a reduction in core eating disorder symptoms, obsessive thoughts, and depressed mood; and a reduced relapse rate for patients remaining on fluoxetine treatment for a year. Nevertheless, these results were biased by a high drop-out rate in the fluoxetine (37%) and the placebo group (84%).

In contrast to the results of Kaye et al., 1991a, Kaye et al., 2001, Kaye et al., 1991b, Strober et al. (1997b) found that adjunctive fluoxetine medication does not have a significant effect on BMI, anxiety, and depression scores in a 2-year naturalistic follow-up study of 33 women with restrictive AN who had received medication during and after successful inpatient treatment when compared to 33 historic controls without medication (mean age 17.6 years, BMI 18.6 ± 1.3 kg/m²). In the study of Santonastaso et al. (2001), BMI was also followed-up after 64 weeks. Consistent with the results of Strober et al. (1997b), no significant differences between medicated and non-medicated subjects were found.

In sum, drug trials of SSRI treatment in AN have revealed a mixed set of findings and many questions remain. For example, it has yet to be determined whether certain symptoms are especially responsive to SSRI-medication: core eating disorder symptoms, depression, or obsessionality. Moreover, there is very little data concerning the use of SSRI in children and adolescents with AN. Although some previous studies included patients in late adolescence, the vast majority of subjects have been adults. The effects of psychopharmacological agents in children and adolescents may differ considerably from those observed in adults. Therefore, the clinical application of medications with children based on research findings with adults is problematic. Despite this, the use of SSRIs in children and adolescents with AN has increased during the last years (Zito et al., 2003). In this context, it is of obvious interest to assess both the efficacy of SSRIs in the treatment of core eating disorder psychopathology and of comorbidity in children and adolescents with AN.

This report is the first to describe the response to adjunctive SSRI treatment in terms of BMI development and change of eating disorder psychopathology and depressive and obsessive-compulsive symptoms in children and adolescents with AN in comparison to a non-medicated control group during inpatient treatment and at a 6-month follow-up.