Role of Fluoxetine in Anorexia Nervosa

BACKGROUND

Anorexia nervosa is a serious psychiatric disorder associated with the development of unusual eating behavior. Anorexia nervosa is characterized by a distorted body image, a relentless pursuit of thinness, and an obsessive fear of becoming fat. ¹ Recognized for >100 years, anorexia nervosa generally affects females from 12 to 18 years of age and has a mortality rate of 5–22%. ²

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ² (DSM-IV) criteria for anorexia nervosa are defined as a subject exhibiting the following: <85% of ideal body weight (IBW), an intense fear of gaining weight despite being underweight, denial of the seriousness of the current low body weight, and amenorrhea in postmenarcheal women (the absence of ≥3 consecutive menstrual cycles). The most common causes of death in this population are cardiac arrest (caused by electrolyte imbalance) and suicide.^3,4 It should also be noted that, following successful weight restoration, there is a high rate of relapse, making these patients particularly challenging to treat. ⁵

Drugs that have been studied for the treatment of anorexia nervosa include tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and clomipramine; selective serotonin-reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, and citalopram; chlorpromazine; cyproheptadine; and lithium. Antidepressants are the only therapy that has shown efficacy over placebo. Among antidepressants, SSRIs are now considered as a first-line pharmacologic therapy because they are well tolerated and have a better safety profile than TCAs. ⁶ Due to limited data available, it is difficult to conclude that one SSRI is more efficacious than another. However, among SSRIs, fluoxetine has been most extensively studied in the treatment of anorexia nervosa.

The American Psychiatric Association Practice Guidelines for Anorexia Nervosa ⁷ recommends the use of antidepressants to prevent relapses in weight-restored patients or to treat associated features of anorexia nervosa such as depression, obsessive–compulsive symptoms, or inadequate response to psychosocial therapy. The guidelines also recommend SSRIs as the preferred class of agents among antidepressants for their safety profile. However, because of fluoxetine's long half-life (2–3 d for the parent drug and 4–16 d for its metabolite, norfluoxetine), dosing adjustment should be considered in patients with severely impaired renal function and/or impaired hepatic function to prevent any sequelae from prolonging the drug's half-life in long-term therapy. Also, the potential for significant drug interactions should be monitored when fluoxetine is combined with other medications that are metabolized by the liver, such as CYP2C9, 2C19, 2D6, 3A3/4 enzyme inhibitors, or 1A2 at a high dose.

Patients with anorexia nervosa also frequently present with symptoms of obsessive–compulsive disorder and show central nervous system (CNS) disturbances in serotonergic activity even after recovery and long-term weight restoration. ⁸ The presence of obsessive–compulsive disorder symptoms and CNS disturbances in this population supports the use of SSRIs in the treatment of anorexia nervosa. One case report ⁹ describes a 42-year-old woman who had anorexia nervosa for 27 years. In the course of her treatment, monoamine oxidase inhibitors (MAOIs), TCAs, bupropion, and lithium were found to have intolerable adverse effects or were ineffective. However, her symptoms improved and her weight was restored with the use of fluoxetine.

Is fluoxetine at all superior to other SSRIs in treating anorexia nervosa? Because few studies are conducted using SSRIs (especially those other than fluoxetine) in the treatment of patients with anorexia nervosa, it is still too early to conclude that one SSRI is better than another.

Literature Review

Presented here are studies in which paroxetine, sertraline, and citalopram were used in the treatment of anorexia nervosa. One case ¹⁰ involved a 34-year-old woman who had (and for 20 years was repeatedly hospitalized for) anorexia nervosa, obsessive–compulsive disorder, and schizotypal personality disorder. This patient was put on a treatment regimen of paroxetine 40 mg/d, and the dosage was titrated up to 60 mg/d after 1 week in combination with pimozide 2 mg/d for 9 months. The patient showed great improvement in weight gain and achieved resolution of the psychopathologic problems as well as the schizotypal symptoms.

Santonastaso et al. ¹¹ studied 11 restricting types of anorexia nervosa patients treated with sertraline and observed 11 patients in a control group. Upon assessing these 2 groups as outpatients after 14 and 64 weeks by structured interview and self-reported questionnaires, both groups showed significant improvement in body weight; improvement of depression and obsessive–compulsive symptoms was seen in the sertraline group.

Fassino et al. ¹² studied 26 patients taking citalopram 10 mg/d and compared results with those of 26 patients in a control group. Citalopram was titrated up to 20 mg/d after 6 days and was maintained for at least 12 weeks. The citalopram group showed improvement in depression and obsessive–compulsive symptoms, but failed to show superior effect in weight gain. Both the citalopram group (p = 0.003) and the control group (p = 0.007) showed significant improvement in weight gain, which may indicate the importance of supportive care in these populations and not necessarily a beneficial effect from medication.

An open trial conducted by Gwirtsman et al. ¹³ supports the superior effect of fluoxetine over other antidepressants for patients with anorexia nervosa. In one study, 6 patients (5 women) were undergoing treatment for anorexia nervosa. Duration of illness ranged from 2 to 18 years, with an age range of 20–39 years and a weight range of 34.5–55.9 kg. The addition of fluoxetine to the treatment protocol for this group resulted in a significant mean weight gain of 8.6 kg (range 2.7–14.5) over a mean time of 7.6 months as well as improvement in symptoms of depression and obsessive–compulsive disorder. All 6 patients were previously unresponsive to TCAs, trazodone, and/or MAOIs and had histories of multiple recurrence of the disorder. Out of 6 patients, 5 showed improvement in weight gain and exhibited reduced obsessive–compulsive symptoms with the use of fluoxetine.

An open-label, pilot study design conducted by Kaye et al. ¹⁴ studied 34 patients (33 women) with anorexia nervosa, ranging in age from 13 to 27 years. Subjects had participated in either the outpatient or inpatient eating disorder treatment program at the Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center. These subjects met the DSM-IV criteria for anorexia nervosa. Fluoxetine was initiated as an adjunct to psychotherapy and as supportive therapy after weight was restored to 95% of IBW or during weight restoration (71–91% of IBW). Three of 34 patients dropped out of the study within a 3-month period. At 1 year after treatment with fluoxetine, 29 of 31 patients had maintained their weight at ≥85% IBW. Although the power of this study is limited by the small sample size, 10 out of the 31 patients (given a mean dosage of 26 mg/d for a mean duration of 10 mo) had no relapses after weight was restored. Additionally, 27 of 31 patients (87%) maintained their weight at ≥85% IBW and/or had reduced symptoms of obsessive–compulsive disorder and depression. Fluoxetine improved symptoms and reduced relapses in patients whose weights were restored.

The same investigator ¹⁵ conducted a double-blind, placebo-controlled study with 35 patients with both the restricting and restricting–purging types of anorexia nervosa who were admitted to the inpatient eating disorders treatment program at the Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center. All patients were women and met the DSM-IV criteria for anorexia nervosa. All were provided with intensive cognitive behavior and dietary therapy. Once weight was restored to ≥90% of average body weight, the patients were randomly assigned to receive fluoxetine (age 23 ± 9 y; mean ± SD) or placebo (22 ± 6 y) 2–4 weeks prior to discharge. They were then observed as outpatients for 1 year. Fluoxetine treatment was initiated at a dosage of 20 mg/d and was adjusted over 52 weeks. In the fluoxetine therapy group, 10 of 16 patients (78%) remained on fluoxetine therapy for 1 year, resulting in significant weight gain and reduction of relapse. In the placebo group, only 3 of 19 patients (27%) remained on placebo for 1 year. While survival analysis showed significant differences (p = 0.002) between patients taking fluoxetine compared with those taking placebo, the power of this study is limited by the small sample size.

A double-blind, placebo-controlled trial conducted by Attia et al. ¹⁶ at the New York State Psychiatric Institute studied 31 female inpatients with anorexia nervosa over 7 weeks. Ages ranged from 16 to 45 years. These patients had had anorexia for 8 ± 5.8 years. Once weight was restored to ≥65% of IBW (mean 72% IBW), patients were randomly given treatment with placebo (16 patients) or fluoxetine (15 patients, 20 mg/d, increased to 60 mg/d over 1 wk). Three of the patients in the fluoxetine group required dosage adjustment due to adverse effects (insomnia, agitation, blurry vision). Although both the fluoxetine and the placebo groups showed statistically significant improvements (p < 0.05; paired t-test) on all measured criteria (weight gain, depression, obsessive–compulsive symptoms), the fluoxetine group showed no significant improvement over the placebo group. It is important to realize that all of the patients were provided with intensive psychotherapy and supportive care during the trial period, which may have contributed to the significant improvements of symptoms in both groups. Additionally, the power of the study is limited by the small sample size and the short duration of the trial period (mean 36 d), which may be an insufficient time period to detect the efficacy of fluoxetine. It also demonstrated that fluoxetine may not be beneficial in patients who are severely underweight. ¹⁶

Summary

The inpatient setting and very short clinical trial period in the study conducted by Attia et al. ¹⁶ may have contributed to the short-term improvement of symptoms, but did not allow sufficient time to observe any beneficial effects of fluoxetine. It may also explain inefficacy of fluoxetine in treating severely underweight patients with anorexia nervosa. The other studies support the efficacy of fluoxetine through reduced symptoms of depression and obsessive–compulsive disorder once weight was restored.^13–15 However, due to limited data and experience with the use of fluoxetine in patients with anorexia nervosa, further studies with larger sample sizes are needed to prove the superior effects of fluoxetine and other SSRIs in the treatment of this disorder.

Although psychotherapy, behavioral therapy, and nutritional therapy still remain as the mainstays of treatment, SSRIs should be considered once weight is restored to prevent relapse or to treat the psychopathologic core of anorexia nervosa (depression and obsessive–compulsive traits).