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Use of Nutritional Supplements to Increase the Efficacy of Fluoxetine in the Treatment of Nicole C. Barbarich,1 Claire W. McConaha,1 Katherine A. Halmi,2 Kelly Gendall,1 Suzanne R. Sunday,2 Jill Gaskill,1 Maria La Via,1 Guido K. Frank,1 Sarah Brooks,1 Katherine H. Plotnicov,1 and Walter H. Kaye1* 1 Department of Psychiatry, University of Pittsburgh Medical School, Anorexia and Bulimia Nervosa Research Module, Pittsburgh, Pennsylvania 2 New York Presbyterian Hospital, Weill Medical College of Cornell University - Westchester Division, White Plains, New York Abstract: Objective: Selective serotonin reuptake inhibitor (SSRI) medication does not appear tobe effective in ill, malnourished anorexia nervosa (AN) patients. However, it may be effective inpreventing relapse after weight restoration. The purpose of this study was to determine whethernutritional supplements could potentiate the effects of fluoxetine in underweight AN subjects.
Method: Twenty-six subjects with AN participated in a trial of fluoxetine. In a double-blind,placebo-controlled manner, subjects received either nutritional supplements or a nutritionalplacebo. The nutritional supplement included tryptophan (the precursor of serotonin), vitamins,minerals, and essential fatty acids believed to influence serotonin pathway function. Results:There was no significant difference in weight gain between subjects treated with fluoxetine plusnutritional supplements versus fluoxetine plus a nutritional placebo. Moreover, there were nosignificant differences between groups on mean changes in anxiety or obsessive and compulsivesymptoms. Discussion: The results of this study suggest that supplement strategies are not asubstitute for adequate nutrition and are ineffective in increasing the efficacy of fluoxetine inunderweight AN subjects. # 2003 by Wiley Periodicals, Inc. Int J Eat Disord 35: 10–15, 2004.
Key words: nutritional supplements; fluoxetine; anorexia nervosa Anorexia nervosa (AN) is a disorder of unknown etiology characterized by restricted eating, a relentless pursuit of thinness, and obsessive fears of becoming fat. The onset ofAN is typically in early adolescence, with approximately 90% of subjetcs being female *Correspondence to: Walter H. Kaye, M.D., University of Pittsburgh Medical Center, Anorexia and Bulimia Nervosa Research Module, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, 600 Iroquois Building,Pittsburgh, PA 15213. E-mail: kayewh@msx.upmc.edu Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/eat.10235 Fluoxetine and Nutritional Supplements in AN (American Psychiatric Association, 1994). AN is often characterized by a chronic andrelapsing course (Herzog, Nussbaum, & Marmor, 1996) and it has the highest death rateof any psychiatric disorder (Sullivan, 1995). Moreover, the hospital utilization rate for ANis higher than any other psychiatric disorder, aside from schizophrenia and other organicmental disorders (McKenzie & Joyce, 1992).
Pharmacologic and psychological treatments have been of limited efficacy in the treat- ment of underweight, malnourished AN individuals (Attia, Haiman, Walsh, & Flater, 1998;Ferguson, La Via, Crossan, & Kaye, 1999; Peterson & Mitchell, 1999; Strober, Pataki,Freeman, & DeAntonio, 1999). In contrast, a recent study (Kaye et al., 2001) showed thatwhen the selective serotonin reuptake inhibitor (SSRI), fluoxetine, was given after weightrestoration, it significantly reduced the rate of relapse in AN. Specifically, in a double-blind,placebo-controlled trial of fluoxetine in 35 patients with restrictor-type AN, fluoxetineimproved outcome and reduced relapse after weight restoration when patients were fol-lowed for 1 year as outpatients. Fluoxetine administration was associated with a significantreduction in core eating disorder symptoms, depression, anxiety, obsessions, and compul-sions. Fluoxetine, however, appears to be ineffective in malnourished patients with AN(Attia et al., 1998; Ferguson et al., 1999). The efficacy of fluoxetine in preventing relapse inweight-restored individuals with AN suggests that nutritional factors may play a role in theefficacy of SSRIs.
One potential reason for the effectiveness of fluoxetine during the recovered state may be the drug’s actions on serotonin (5-HT), a neurotransmitter system found to be dysregulatedin individuals with AN. When assessed after long-term recovery, individuals with AN haveincreased levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the cere-brospinal fluid (CSF; Kaye, Gwirtsman, George, & Ebert, 1991). In addition, recent studiesusing 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-HToutput. It has been suggested that fluoxetine may be efficacious during the recovered statein AN by modulating an intrinsic defect of serotonergic activity in these individuals.
Fluoxetine and other SSRIs depend on neuronal release of 5-HT for their action (Tollefson, 1995). If the release of 5-HT from presynaptic neuronal sites was compromisedsubstantially and net synaptic 5-HT concentration was negligible, a clinically meaningfulresponse to an SSRI might not occur. During the acute phase of illness, individuals with ANhave reduced 5-HIAA in the CSF (Kaye, Ebert, Raleigh, & Lake, 1984), suggesting reducedsynaptic 5-HT. This may be due to a reduced supply or availability of tryptophan, anessential amino acid precursor of 5-HT that must be obtained through the diet. Dependingon dietary intake and the relative proportions of carbohydrates and proteins, meal con-sumption may enhance brain 5-HT release (Fernstrom & Wurtman, 1971). A restricted dietin animals and healthy humans significantly lowers plasma tryptophan, decreases brain5-HT synthesis, down-regulates the density of 5-HT transporters, and produces a compen-satory supersensitivity of postsynaptic receptors in response to reduced 5-HT turnover(Goodwin, Fairburn, & Cowen, 1987; Huether, Zhou, & Ruther, 1997). Dieting reducestryptophan availability, thereby limiting potential serotonergic production (Anderson,Parry-Billings, Newsholme, Fairburn, & Cowen, 1990). Low basal (Kumai, Tamai, Fujii,Nakagawa, & Aoki, 1988) and post ingestive (Alderdice, Dinsmore, Buchanan, & Adams,1985) insulin concentrations in AN may further contribute to the reduced availability oftryptophan for 5-HT synthesis.
Impaired 5-HT functional activity may also be a consequence of an inadequate avail- ability of a number of other nutrients that are essential to normal 5-HT synthesis andfunction. Zinc is a mineral that influences membrane stability to the extent that zinc deficiency increases membrane fluidity, causing loss of receptor function (McClain,Stuart, Kasarskis, & Humphries, 1993). Vitamin B6 is a cofactor required in the reactionthat converts tryptophan to 5-HT (Sharma & Dakshinamurti, 1994). Vitamin B12 andfolate are also required for the formation of tetrahydrobiopterin, a hydroxylase cofactorin 5-HT synthesis (Coppen et al., 1989). Dietary deficiency and lowered biochemicalactivity of these B vitamins in some individuals with AN (Mira, Stewart, & Abraham,1989; Nunez, Moreiras, & Carbajal, 1995; Rock & Curran-Celentano, 1994; Rock &Vasantharajan, 1995) may compromise the ability of SSRIs to facilitate serotonergicfunction.
In theory, the consumption of nutritional supplements containing tryptophan and essential fatty acids might increase levels of available tryptophan and facilitate 5-HTsynthesis in the brain. The purpose of this study was to determine if the use of thesesupplements would increase the efficacy of fluoxetine in underweight AN subjects.
Twenty-six individuals with AN were enrolled in a 6-month trial of fluoxetine. Parti- cipants were recruited from the eating disorders programs at Western Psychiatric Insti-tute and Clinic (Pittsburgh, PA) and New York Hospital, Cornell Medical Center (NewYork, NY). All subjects provided written informed consent before the start of the studyand the study had the approval of the site’s institutional review board. Ten subjects wererestricting-type AN, 6 subjects were restricting and purging only-type AN, and 10subjects were binge eating/purging-type AN.
Subjects enrolled in the study were started on a dose of 20–40 mg of fluoxetine.
Individual doses were titrated throughout the study to balance unwanted side effectswith beneficial effects on mood. The dose of fluoxetine at the end of the study rangedfrom 20 mg to 60 mg. Subjects were weighed at weekly intervals for the first 8 weeks, at2-week intervals for 6 weeks, and at 4-week intervals for 12 weeks.
Psychological assessments were completed at baseline and at 3 and 6 months. The following assessment battery was used: the Frost Multidimensional Perfectionism Scale(Frost, Marten, Lahart, & Rosenblate, 1990), the Speilberger State-Trait Anxiety Inventory(STAI-Y; Spielberger, Gorsuch & Lushene, 1970), and the Yale-Brown Obsessive Com-pulsive Scale (Goodman et al., 1989).
Using a randomized, double-blind design, subjects were assigned to one of two supplement groups (Table 1). The active group consumed daily dietary supplementsconsisting of 2.3 g of tryptophan (Ajinomoto, Paramus, NJ), taken in a divided dose in themorning and evening, and one multivitamin/mineral capsule per day in the morning.
This regimen provided 100% of the recommended dietary allowance for vitamins andminerals. In addition, subjects in the active group were given four fish oil capsules(Martek Biosciences, Columbia, MD) per day in the morning, which provided 600 mgof docosahexanoic acid and 180 mg of arachadonic acid daily. The placebo groupreceived an equivalent number of inactive capsules containing starch and high oleicsunflower oil taken in the morning and evening.
Fluoxetine and Nutritional Supplements in AN Table 1. Distribution of eating disorder diagnoses Note: RAN ¼ restricting and purging only-type anorexia nervosa; BAN ¼ binge eating/purging-type anorexia nervosa.
Independent sample t tests were used to assess differences in overall changes in weight and mood between the active and placebo groups.
Subjects with AN were 23.0 Æ 6.3 years old and had a mean age of onset of 16.1 Æ 4.6 years. Of the initial 26 subjects, 15 subjects were assigned randomly to the active group and11 subjects were assigned to the placebo group. Nine subjects completed the full 26 weeksof the study (completion group), 13 subjects completed 5–18 weeks of the study (mid-drop-out group), and 4 subjects dropped out within 4 weeks of entering the study (early drop-out group; see Table 1 for a distribution of diagnoses within groups). Of the 17 subjectswho dropped out of the study at or before 18 weeks, 58.8% of subjects were in the placebogroup. Of the 9 subjects who completed 26 weeks of the study, 77.8% of subjects were inthe active group. Given the substantial rate of drop-out, an analysis of group differences(completion vs. drop-out groups) was performed on demographic variables (Table 2). Startage of laxative abuse was the only variable that showed a significant group difference.
Therefore, all 9 subjects who completed the full 26 weeks (the completion group) wereincluded in the analyses of weight gain and changes in mood.
Mean weight gain per week was not significantly different between the active group and the placebo group (0.27 Æ 0.3 kg per week vs. 0.10 Æ 0.1 kg per week), t (7) ¼ 1.58, p ¼ ns.
Table 2. Comparison of group variables (M Æ SD) aDrop-out group includes both early drop-outs and mid-drop-outs.
*p < .01.
Overall, there were no significant differences between the active group and the placebo groupon baseline scores on the STAI-Y (43.5 Æ 17.6 vs. 54.5 Æ 3.5), t (4) ¼ À0.83, p ¼ ns, or the Yale-Brown Obsessive Compulsive Scale (11.8 Æ 14.2 vs. 12.0 Æ 11.3), t (6) ¼ À0.02, p ¼ ns. Whenassessed at end point, there were no significant differences between the active group and theplacebo group on mean changes in anxiety (À7.8 Æ 23.8 vs. À10.5 Æ 0.7), t (4) ¼ 0.15, p ¼ ns, orobsessive and compulsive symptoms (À9.2 Æ 12.9 vs. À6.5 Æ 3.5), t (6) ¼ À0.27, p ¼ ns.
The use of nutritional supplements containing tryptophan and essential fatty acids did not increase the efficacy of fluoxetine in individuals with AN who were underweight.
The potential reason why nutritional supplementation was ineffective in these indivi-duals remains uncertain. It may be that a combination of long-term malnutrition anddecreased serotonergic activity altered the potential effectiveness of nutritional supple-mentation. Caloric content and insulin secretion interact through a dynamic process withcontinuous changes throughout the day. Therefore, modest nutritional supplementationmay not be sufficient to offset the physiologic changes in these systems caused bymalnutrition.
The limitations of this study included a small sample size, two different sites, and a significant drop-out rate before the full 26 weeks. In summary, this study suggests thatsupplement strategies are not a substitute for adequate nutrition and are ineffective inincreasing the efficacy of fluoxetine in underweight AN individuals.
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