BRIEF REPORT
The (Lack of) Effect of Alprazolam on Eating Behavior in Anorexia Nervosa: A Preliminary Report Joanna E. Steinglass, M.D.1,2* Simona C. Kaplan, B.A.2 Ying Liu, M.S., M.Phil.1 Yuanjia Wang, Ph.D.1 B. Timothy Walsh, M.D.1,2
ABSTRACT Objective: Anxiety is a prominent symptom in anorexia nervosa (AN), and higher pre-meal anxiety has been associated with lower caloric intake. Yet, the causal relationship has not been assessed. We proposed that reducing anxiety with a short acting benzodiazepine would increase caloric intake among individuals with AN. Method: In a randomized, doubleblind, placebo controlled cross-over study, we administered alprazolam 0.75 mg to inpatients with AN (n 5 17) and assessed caloric intake in a laboratory test meal. Within-subject differences in caloric intake, anxiety, and fatigue were compared between alprazolam and placebo days.
Introduction Among patients with anorexia nervosa (AN), significantly reduced caloric intake persists even after intensive acute treatment,1, 2 and has been shown to relate to longer term outcome.3 One factor associated with food intake is eating-related anxiety: higher levels of pre-meal anxiety are related to lower caloric intake.4, 5 The relationship between anxiety and intake suggests that eating-related anxiety may be a useful treatment target.6 Yet the causal role of anxiety in food avoidance in AN has not been specifically investigated. The purpose of the current study was to examine whether anxiety contributes to the restrictive eating in AN by experimentally manipulating the level of anxiety. In this randomized, double-blind, placebo controlled cross-over study, we hypothesized that alprazolam, a short-acting benzodiazepine, compared with pla-
Accepted 20 July 0014 *Correspondence to: Joanna Steinglass, MD, 1051 Riverside Drive, Unit 98, New York, NY 10032. E-mail: [email protected] 1 Department of Psychiatry, Columbia University Medical Center, 622 West 168th Street New York, New York 2 Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive New York, New York. Published online 19 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22343 C 2014 Wiley Periodicals, Inc. V
International Journal of Eating Disorders 47:8 901–904 2014
Results: Caloric intake did not differ on alprazolam versus placebo (t15 5 1.72, p 5 .11). Alprazolam did not reduce anxiety, but was associated with increased fatigue. Discussion: This study was not able to evaluate the causal role of anxiety in meal intake among individuals with AN, as alprazolam did not alter anxiety symptoms. These data further suggest that the therapeutic role for short-acting benzoC 2014 diazepines in AN is likely limited. V Wiley Periodicals, Inc. Keywords: anorexia nervosa; benzodiazepine; anxiety; eating behavior; alprazolam (Int J Eat Disord 2014; 47:901–904)
cebo, would acutely reduce anxiety and would be associated with greater caloric intake in patients with AN.
Method Participants were 20 individuals with AN between the ages of 18 and 60 years. Eligible patients met DSM-57 criteria for AN, were medically stable, and were receiving inpatient treatment at the New York State Psychiatric Institute. Patients were excluded if they had comorbid diagnoses that might interfere with participation. Patients taking a stable dose of antidepressant medication were not excluded. To minimize effects of acute starvation and standardize weight, participation occurred when patients had achieved at least 80% ideal body weight,8 which corresponds to a body mass index (BMI) of 17.5 kg m22. This study was approved by the New York State Psychiatric Institute Institutional Review Board, and all participants provided written informed consent. This study was registered at ClinicalTrials.gov (NCT01411813). Psychological assessments were administered prior to the administration of study medication and immediately preceding the test meal. The Profile of Mood States (POMS)9 tension and fatigue subscales measured current states of anxiety and sedation, respectively. Anxiety was also measured using the Spielberger State-Trait Anxiety Inventory, State version (STAI-S).10
901
STEINGLASS ET AL. TABLE 1.
Eating behavior and psychological measures Mean 6 SD
Age (years) Duration of illness (years) Body mass index (kg m22)
25.6 6 7.8 11.1 6 8.0 18.0 6 0.6 Alprazolam (mean 6 SD)
Placebo (mean 6 SD)
W
p
Cohen’s d
229.53 6 311.83 15.65 6 8.61 51.76 6 11.34 12.94 6 5.64
205.82 6 284.50 16.12 6 10.18 52.88 6 13.07 10.06 6 7.14
52 40 39.5 10.5
.14 .74 .77 .02
0.08 20.05 20.09 0.45
Intake (Kcal) POMS tension STAI-S POMS fatigue
Medication Administration Alprazolam was selected as the study medication, based on previous work with women with pre-menstrual dysphoric disorder demonstrating increased intake with alprazolam.11 All participants received alprazolam 0.75 mg on one test day and placebo on the other. Order of medication administration was assigned randomly using a computer-generated algorithm in blocks of four. Medication administration was double-blinded. Pills were encapsulated to appear identical, and were dispensed by clinical staff blind to randomization assignment. Medication was administered 1.5 h prior to the test meal (at 10:30 am), following the procedures of Evans et al.,11 at the time of estimated peak plasma concentration.12 Test Meals The two test days occurred within 1 week of each other. Participants were provided a standardized breakfast consistent with their caloric prescription (800 kcal), and did not consume any food or liquid, other than water, prior to the laboratory meal 4 h later. 1
The test meal followed the procedures of Sysko et al. and consisted of 975 g of strawberry yogurt shake (1.04 kcal/g, 1014 kcal) in a covered, opaque, 83-fluid-ounce container with a straw. Participants were instructed to consume as much of the shake as they would like and were told that the meal would serve as their lunch for the day. Intake was measured by the change in weight (g) of the container before and after the meal (Acculab 7200 balance, readability 0.1 g). Statistical Analyses With 20 participants, we had 80% power to detect an effect of the magnitude found by Evans et al. (d > 0.94).The primary outcome measure was the withinsubject difference in caloric intake on alprazolam versus placebo. The secondary outcome was difference in anxiety. For each study day, change in symptoms with medication was calculated as premeal minus premedication scores. Prior to testing the primary hypotheses, we esti-
902
mated the carry-over effect from Day 1 to Day 2 (i.e., period effect), and conducted a paired Wilcoxon signedrank test to assess for the presence of a differential carryover effect between alprazolam and placebo at the significance level of 0.1.13 When no differential carry-over effect was present, outcomes from both days were combined for the remaining analyses. As the data were not normally distributed and the sample size was small, we used a nonparametric test (Wilcoxon rank test) to assess the effect of medication on intake, anxiety, and fatigue. We also performed a t test using within-subject difference scores as a sensitivity check. Lastly, we compared the mean change scores of anxiety and fatigue between alprazolam and placebo groups. Because of the possibility of a carry-over effect, the premedication baseline scores may differ between Day 1 and 2. Therefore, we only used day 1 data for these analyses.
Results Participants were twenty women with AN (11 binge-purge subtype; 9 restricting subtype). Three individuals (two binge purge, one restricting subtype) received a nutritional supplement (380 kcal) between breakfast and the first test meal; their data were excluded from analyses as their hunger level may have been altered. Two participants were on a stable dose of fluoxetine; five participants had comorbid anxiety disorder diagnoses. There was no significant carry-over effect of medication for caloric intake (W 5 47, p 5 .31), pre-meal POMS tension (W 5 22, p 5 .19), or STAI-S (W 5 27, p 5 .41), indicating that treatment assignment on Day 1 did not significantly impact scores on Day 2, allowing for combining data from both study days and conducting within-subject statistical analyses. Mean caloric intake and anxiety did not differ between alprazolam and placebo using Wilcoxon rank sum test (see Table 1), and results were International Journal of Eating Disorders 47:8 901–904 2014
ALPRAZOLAM AND EATING BEHAVIOR IN AN
FIGURE 1. Anxiety was not affected by medication administration, whereas sedation was. (A) Boxplot of change in anxiety with medication (premeal minus pre-medication) shows no differences by treatment group: profile of mood state (POMS) tension t15 5 0.45, p 5 .66; Spielberger anxiety inventory, State version (STAIS) t13.3 5 21.09, p 5 .30. (B) Boxplot of change in sedation with medication administration (pre-meal minus pre-medication) shows a marginally significant increase in sedation on alprazolam (t10.8 5 2.02, p 5 .07). As shown in Table 1, sedation differed signi˚cantly between study days.
confirmed by t test (caloric intake t15 5 1.72, p 5 .11; POMS t15 5 20.24, p 5 .81; STAIS t15 5 20.526, p 5 .61). There was no significant difference between alprazolam and placebo in the change in anxiety after medication administration on POMS tension (W 5 31.5, p 5 .70) or STAI-S (W 5 23, p 5 .22), (Fig. 1A). t tests confirmed these results, t15 5 0.45, p 5 .66, and t13.3 5 21.09, p 5 .30, respectively. Results did not differ between subtypes of AN. In further examination of medication effect, post hoc analyses of the POMS fatigue scale showed a significantly greater sedation with alprazolam (see Table 1). Change in fatigue after medication administration was marginally significant (W 5 54.5, p 5 .08), such that fatigue increased more with alprazolam than with placebo (Fig. 1B). A paired samples t test confirmed this trend, t10.8 5 2.02, p 5 .07.
International Journal of Eating Disorders 47:8 901–904 2014
Discussion This study aimed to acutely manipulate premeal anxiety with alprazolam, a short-acting anxiolytic, to examine whether pre-meal anxiety causally influences food intake. Contrary to our hypothesis, alprazolam affected neither intake nor anxiety. There were no significant differences in change in anxiety with medication administration, and mean anxiety was not significantly different on the alprazolam day versus placebo day. Thus, we were unable to achieve our initial aim of experimentally lowering anxiety and assessing the impact of that change on caloric intake. Given that alprazolam did not significantly affect anxiety scores in this sample, a finding inconsistent with previous research on benzodiazepines and anxiety in nonAN populations,12 the question arose as to whether 0.75 mg of medication was a sufficient dose. Our analyses indicated that alprazolam was associated with increases in sedation, suggesting that the 903
STEINGLASS ET AL.
chosen dose indeed had a detectable clinical effect consistent with the known properties of benzodiazepines. While there have been numerous trials showing no clinical utility for medication in AN,14 it was nevertheless surprising to find that alprazolam did not lead to acute anxiety reduction in our study, despite likely adequate bioavailability. One possible explanation is that the measures of anxiety we employed—while standard and widely employed— assess a component of anxiety that is less sensitive to benzodiazepines. It may be, for example, that alprazolam more strongly influences fear-like, or phobic, symptoms. If in our sample the anxiety scores relate more to obsessional or rule-based aspects of anxiety, perhaps this is less sensitive to treatment with alprazolam. Indeed, clonazepam has been shown to be of no benefit in obsessivecompulsive disorder.15 It is also possible that the severity and length of illness among this group of patients with AN are associated with an entrenched meal-related anxiety and/or with rules that are impervious to the effect of this medication. In summary, alprazolam was not associated with a significant change in caloric intake, and did not significantly impact pre-meal anxiety. The sample size was small and therefore the results must be considered as preliminary, and different test meals may have yielded different results. Furthermore, the study did not seek to evaluate dose-response. Nevertheless, the heightened fatigue following alprazolam administration suggests that the dose had an impact, but with significant variability among individuals. Alprazolam has been associated with increased intake in preclinical research,16 among healthy men,17 and among women with premenstrual dysphoric disorder.11 The lack of a significant effect in AN is therefore notable. We found one study in which a benzodiazepine was administered as the control condition,18 and no reports of placebo-controlled trials of benzodiazepines in AN, despite their use in clinical practice. Psychological treatments that specifically aim to decrease eating-related anxiety have yielded promising results.19, 20 In a randomized controlled trial, exposure and response prevention for AN that targeted eating-related anxiety was associated with better caloric intake than the comparison condition.20 Other meal-time interventions that target emotions have also successfully improved intake.21 Future research is needed to continue to examine the causal role of anxiety in restrictive intake
904
among individuals with AN, but the current results do not provide support for the potential utility of benzodiazepines.
References 1. Sysko R, Walsh BT, Schebendach J, Wilson GT. Eating behavior among women with anorexia nervosa. Am J Clin Nutr 2005;82:296–301. 2. Mayer LE, Schebendach J, Bodell LP, Shingleton RM, Walsh BT. Eating behavior in anorexia nervosa: Before and after treatment. Int J Eat Disord 2012; 45:290–293. 3. Schebendach JE, Mayer LE, Devlin MJ, Attia E, Contento IR, Wolf RL. Dietary energy density and diet variety as predictors of outcome in anorexia nervosa. Am J Clin Nutr 2008;87:810–816. 4. Steinglass JE, Sysko R, Mayer L, Berner LA, Schebendach J, Wang Y. Pre-meal anxiety and food intake in anorexia nervosa. Appetite 2010;55:214–218. 5. Lavender JM, De Young KP, Wonderlich SA, Crosby RD, Engel SG, Mitchell JE. Daily patterns of anxiety in anorexia nervosa: Associations with eating disorder behaviors in the natural environment. J Abnorm Psychol 2013;122(3): 672–683. 6. Steinglass JE, Sysko R, Glasofer D, Albano AM, Simpson HB, Walsh BT. Rationale for the application of exposure and response prevention to the treatment of anorexia nervosa. Int J Eat Disord 2011;44:134–141. 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington,VA: American Psychiatric Association, 2013. 8. MetropolitanLifeInsurance. New weight standards for men and women. Stat Bull 1959;40:1–4. 9. McNair PM, Lorr M, Droppelman LF. POMS Manual, 2nd ed. San Diego: Educational and Industrial Testing Service, 1981. 10. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs AG. Manual for the State-Trait Anxiety Inventory. Palo Alto: Consulting Psychologists Press, 1983. 11. Evans SM, Foltin RW, Fischman MW. Food “cravings” and the acute effects of alprazolam on food intake in women with premenstrual dysphoric disorder. Appetite 1999;32:331–349. 12. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 1993;24:453–471. 13. Grizzle JE. The two-period change-over design and its use in clinical trials. Biometrics 1965;21:467–480. 14. Crow SJ, Mitchell JE, Roerig JD, Steffen K. What potential role is there for medication treatment in anorexia nervosa? Int J Eat Disord 2009;42:1–8. 15. Hollander E, Kaplan A, Stahl SM. A double-blind, placebo-controlled trial of clonazepam in obsessive-compulsive disorder. World J Biol Psychiatry Off J World Feder Soc Biol Psychiatry 2003;4:30–34. 16. Cooper SJ. Benzodiazepines as appetite enhancing compounds. Appetite 1908;1:7–19. 17. Haney M, Comer SD, Fischman MW, Foltin RW. Alprazolam increases food intake in humans. Psychopharmacology (Berl) 1997;132:311–314. 18. Gross H, Ebert MH, Faden VB, Goldberg SC, Kaye WH, Caine ED. A doubleblind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. J Clin Psychopharmacol 1983;3:165–171. 19. Steinglass JE, Sysko R, Schebendach J, Strober M, Walsh BT. Fear Extinction in Anorexia Nervosa Using D-Cycloserine Paper presented at International Conference on Eating Disorders; June, 2006; Barcelona, Spain. 20. Steinglass JE, Albano AM, Simpson HB, Wang Y, Zou J, Attia E. Confronting fear using exposure and response prevention for anorexia nervosa: A randomized controlled pilot study. Int J Eat Disord 2014; 47:174–180. 21. Cardi V, Kan C, Roncero M, Harrison A, Lounes N, Tchanturia K. Mealtime support in anorexia nervosa: A within-subject comparison study of a novel vodcast intervention. Psychother Psychosom 2012;81:54–55.
International Journal of Eating Disorders 47:8 901–904 2014
The (Lack of) Effect of Alprazolam on Eating Behavior in Anorexia Nervosa: A Preliminary Report Joanna E. Steinglass, M.D.1,2* Simona C. Kaplan, B.A.2 Ying Liu, M.S., M.Phil.1 Yuanjia Wang, Ph.D.1 B. Timothy Walsh, M.D.1,2
ABSTRACT Objective: Anxiety is a prominent symptom in anorexia nervosa (AN), and higher pre-meal anxiety has been associated with lower caloric intake. Yet, the causal relationship has not been assessed. We proposed that reducing anxiety with a short acting benzodiazepine would increase caloric intake among individuals with AN. Method: In a randomized, doubleblind, placebo controlled cross-over study, we administered alprazolam 0.75 mg to inpatients with AN (n 5 17) and assessed caloric intake in a laboratory test meal. Within-subject differences in caloric intake, anxiety, and fatigue were compared between alprazolam and placebo days.
Introduction Among patients with anorexia nervosa (AN), significantly reduced caloric intake persists even after intensive acute treatment,1, 2 and has been shown to relate to longer term outcome.3 One factor associated with food intake is eating-related anxiety: higher levels of pre-meal anxiety are related to lower caloric intake.4, 5 The relationship between anxiety and intake suggests that eating-related anxiety may be a useful treatment target.6 Yet the causal role of anxiety in food avoidance in AN has not been specifically investigated. The purpose of the current study was to examine whether anxiety contributes to the restrictive eating in AN by experimentally manipulating the level of anxiety. In this randomized, double-blind, placebo controlled cross-over study, we hypothesized that alprazolam, a short-acting benzodiazepine, compared with pla-
Accepted 20 July 0014 *Correspondence to: Joanna Steinglass, MD, 1051 Riverside Drive, Unit 98, New York, NY 10032. E-mail: [email protected] 1 Department of Psychiatry, Columbia University Medical Center, 622 West 168th Street New York, New York 2 Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive New York, New York. Published online 19 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22343 C 2014 Wiley Periodicals, Inc. V
International Journal of Eating Disorders 47:8 901–904 2014
Results: Caloric intake did not differ on alprazolam versus placebo (t15 5 1.72, p 5 .11). Alprazolam did not reduce anxiety, but was associated with increased fatigue. Discussion: This study was not able to evaluate the causal role of anxiety in meal intake among individuals with AN, as alprazolam did not alter anxiety symptoms. These data further suggest that the therapeutic role for short-acting benzoC 2014 diazepines in AN is likely limited. V Wiley Periodicals, Inc. Keywords: anorexia nervosa; benzodiazepine; anxiety; eating behavior; alprazolam (Int J Eat Disord 2014; 47:901–904)
cebo, would acutely reduce anxiety and would be associated with greater caloric intake in patients with AN.
Method Participants were 20 individuals with AN between the ages of 18 and 60 years. Eligible patients met DSM-57 criteria for AN, were medically stable, and were receiving inpatient treatment at the New York State Psychiatric Institute. Patients were excluded if they had comorbid diagnoses that might interfere with participation. Patients taking a stable dose of antidepressant medication were not excluded. To minimize effects of acute starvation and standardize weight, participation occurred when patients had achieved at least 80% ideal body weight,8 which corresponds to a body mass index (BMI) of 17.5 kg m22. This study was approved by the New York State Psychiatric Institute Institutional Review Board, and all participants provided written informed consent. This study was registered at ClinicalTrials.gov (NCT01411813). Psychological assessments were administered prior to the administration of study medication and immediately preceding the test meal. The Profile of Mood States (POMS)9 tension and fatigue subscales measured current states of anxiety and sedation, respectively. Anxiety was also measured using the Spielberger State-Trait Anxiety Inventory, State version (STAI-S).10
901
STEINGLASS ET AL. TABLE 1.
Eating behavior and psychological measures Mean 6 SD
Age (years) Duration of illness (years) Body mass index (kg m22)
25.6 6 7.8 11.1 6 8.0 18.0 6 0.6 Alprazolam (mean 6 SD)
Placebo (mean 6 SD)
W
p
Cohen’s d
229.53 6 311.83 15.65 6 8.61 51.76 6 11.34 12.94 6 5.64
205.82 6 284.50 16.12 6 10.18 52.88 6 13.07 10.06 6 7.14
52 40 39.5 10.5
.14 .74 .77 .02
0.08 20.05 20.09 0.45
Intake (Kcal) POMS tension STAI-S POMS fatigue
Medication Administration Alprazolam was selected as the study medication, based on previous work with women with pre-menstrual dysphoric disorder demonstrating increased intake with alprazolam.11 All participants received alprazolam 0.75 mg on one test day and placebo on the other. Order of medication administration was assigned randomly using a computer-generated algorithm in blocks of four. Medication administration was double-blinded. Pills were encapsulated to appear identical, and were dispensed by clinical staff blind to randomization assignment. Medication was administered 1.5 h prior to the test meal (at 10:30 am), following the procedures of Evans et al.,11 at the time of estimated peak plasma concentration.12 Test Meals The two test days occurred within 1 week of each other. Participants were provided a standardized breakfast consistent with their caloric prescription (800 kcal), and did not consume any food or liquid, other than water, prior to the laboratory meal 4 h later. 1
The test meal followed the procedures of Sysko et al. and consisted of 975 g of strawberry yogurt shake (1.04 kcal/g, 1014 kcal) in a covered, opaque, 83-fluid-ounce container with a straw. Participants were instructed to consume as much of the shake as they would like and were told that the meal would serve as their lunch for the day. Intake was measured by the change in weight (g) of the container before and after the meal (Acculab 7200 balance, readability 0.1 g). Statistical Analyses With 20 participants, we had 80% power to detect an effect of the magnitude found by Evans et al. (d > 0.94).The primary outcome measure was the withinsubject difference in caloric intake on alprazolam versus placebo. The secondary outcome was difference in anxiety. For each study day, change in symptoms with medication was calculated as premeal minus premedication scores. Prior to testing the primary hypotheses, we esti-
902
mated the carry-over effect from Day 1 to Day 2 (i.e., period effect), and conducted a paired Wilcoxon signedrank test to assess for the presence of a differential carryover effect between alprazolam and placebo at the significance level of 0.1.13 When no differential carry-over effect was present, outcomes from both days were combined for the remaining analyses. As the data were not normally distributed and the sample size was small, we used a nonparametric test (Wilcoxon rank test) to assess the effect of medication on intake, anxiety, and fatigue. We also performed a t test using within-subject difference scores as a sensitivity check. Lastly, we compared the mean change scores of anxiety and fatigue between alprazolam and placebo groups. Because of the possibility of a carry-over effect, the premedication baseline scores may differ between Day 1 and 2. Therefore, we only used day 1 data for these analyses.
Results Participants were twenty women with AN (11 binge-purge subtype; 9 restricting subtype). Three individuals (two binge purge, one restricting subtype) received a nutritional supplement (380 kcal) between breakfast and the first test meal; their data were excluded from analyses as their hunger level may have been altered. Two participants were on a stable dose of fluoxetine; five participants had comorbid anxiety disorder diagnoses. There was no significant carry-over effect of medication for caloric intake (W 5 47, p 5 .31), pre-meal POMS tension (W 5 22, p 5 .19), or STAI-S (W 5 27, p 5 .41), indicating that treatment assignment on Day 1 did not significantly impact scores on Day 2, allowing for combining data from both study days and conducting within-subject statistical analyses. Mean caloric intake and anxiety did not differ between alprazolam and placebo using Wilcoxon rank sum test (see Table 1), and results were International Journal of Eating Disorders 47:8 901–904 2014
ALPRAZOLAM AND EATING BEHAVIOR IN AN
FIGURE 1. Anxiety was not affected by medication administration, whereas sedation was. (A) Boxplot of change in anxiety with medication (premeal minus pre-medication) shows no differences by treatment group: profile of mood state (POMS) tension t15 5 0.45, p 5 .66; Spielberger anxiety inventory, State version (STAIS) t13.3 5 21.09, p 5 .30. (B) Boxplot of change in sedation with medication administration (pre-meal minus pre-medication) shows a marginally significant increase in sedation on alprazolam (t10.8 5 2.02, p 5 .07). As shown in Table 1, sedation differed signi˚cantly between study days.
confirmed by t test (caloric intake t15 5 1.72, p 5 .11; POMS t15 5 20.24, p 5 .81; STAIS t15 5 20.526, p 5 .61). There was no significant difference between alprazolam and placebo in the change in anxiety after medication administration on POMS tension (W 5 31.5, p 5 .70) or STAI-S (W 5 23, p 5 .22), (Fig. 1A). t tests confirmed these results, t15 5 0.45, p 5 .66, and t13.3 5 21.09, p 5 .30, respectively. Results did not differ between subtypes of AN. In further examination of medication effect, post hoc analyses of the POMS fatigue scale showed a significantly greater sedation with alprazolam (see Table 1). Change in fatigue after medication administration was marginally significant (W 5 54.5, p 5 .08), such that fatigue increased more with alprazolam than with placebo (Fig. 1B). A paired samples t test confirmed this trend, t10.8 5 2.02, p 5 .07.
International Journal of Eating Disorders 47:8 901–904 2014
Discussion This study aimed to acutely manipulate premeal anxiety with alprazolam, a short-acting anxiolytic, to examine whether pre-meal anxiety causally influences food intake. Contrary to our hypothesis, alprazolam affected neither intake nor anxiety. There were no significant differences in change in anxiety with medication administration, and mean anxiety was not significantly different on the alprazolam day versus placebo day. Thus, we were unable to achieve our initial aim of experimentally lowering anxiety and assessing the impact of that change on caloric intake. Given that alprazolam did not significantly affect anxiety scores in this sample, a finding inconsistent with previous research on benzodiazepines and anxiety in nonAN populations,12 the question arose as to whether 0.75 mg of medication was a sufficient dose. Our analyses indicated that alprazolam was associated with increases in sedation, suggesting that the 903
STEINGLASS ET AL.
chosen dose indeed had a detectable clinical effect consistent with the known properties of benzodiazepines. While there have been numerous trials showing no clinical utility for medication in AN,14 it was nevertheless surprising to find that alprazolam did not lead to acute anxiety reduction in our study, despite likely adequate bioavailability. One possible explanation is that the measures of anxiety we employed—while standard and widely employed— assess a component of anxiety that is less sensitive to benzodiazepines. It may be, for example, that alprazolam more strongly influences fear-like, or phobic, symptoms. If in our sample the anxiety scores relate more to obsessional or rule-based aspects of anxiety, perhaps this is less sensitive to treatment with alprazolam. Indeed, clonazepam has been shown to be of no benefit in obsessivecompulsive disorder.15 It is also possible that the severity and length of illness among this group of patients with AN are associated with an entrenched meal-related anxiety and/or with rules that are impervious to the effect of this medication. In summary, alprazolam was not associated with a significant change in caloric intake, and did not significantly impact pre-meal anxiety. The sample size was small and therefore the results must be considered as preliminary, and different test meals may have yielded different results. Furthermore, the study did not seek to evaluate dose-response. Nevertheless, the heightened fatigue following alprazolam administration suggests that the dose had an impact, but with significant variability among individuals. Alprazolam has been associated with increased intake in preclinical research,16 among healthy men,17 and among women with premenstrual dysphoric disorder.11 The lack of a significant effect in AN is therefore notable. We found one study in which a benzodiazepine was administered as the control condition,18 and no reports of placebo-controlled trials of benzodiazepines in AN, despite their use in clinical practice. Psychological treatments that specifically aim to decrease eating-related anxiety have yielded promising results.19, 20 In a randomized controlled trial, exposure and response prevention for AN that targeted eating-related anxiety was associated with better caloric intake than the comparison condition.20 Other meal-time interventions that target emotions have also successfully improved intake.21 Future research is needed to continue to examine the causal role of anxiety in restrictive intake
904
among individuals with AN, but the current results do not provide support for the potential utility of benzodiazepines.
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International Journal of Eating Disorders 47:8 901–904 2014
