Psychiatric Annals

PSYCHOPHARMACOTHERAPY OF SPECIAL PATIENT POPULATIONS 

The Psychopharmacotherapy of Eating Disorders

Anne M Leach, MD

Abstract

Anorexia nervosa (AN) and bulimia nervosa (BN), although subject to tremendous media attention, are not common disorders, with a combined prevalence of about 4%.1 In over 90% of the cases, those with eating disorders are female, with illness onset typically at or after puberty. These illnesses are far more prevalent in industrialized societies, where physical attractiveness is defined by slenderness. Eating disorders are associated with significant impairment of functioning as well as significant morbidity and mortality, prompting a need for effective treatments. While psychotherapy, particularly cognitive and cognitive-behavioral therapies, has been the cornerstone of treatment for both disorders, our focus will be on recent advances in the pharmacologic treatment of AN and BN.

ANOREXIA NERVOSA

AN has been recognized for over a century. The four major DSM-IV criteria are well accepted and essentially identical to those found in DSM-III-R, as can be seen in Table 1. The critical change between these two nosologies is subtyping based on the presence or absence of hinging or purging. This feature acknowledges recent research demonstrating significant clinical differences between anorectic restrictors, who lose weight through dieting, fasting, or excessive exercise, and anorectic bulimics, who regularly engage in binge eating and/or purging.

Few controlled studies of pharmacologic interventions in AN have been published, and most of these have not shown much promise for any given medication. The following is a critical review of this literature.

Antidepressants

There are several reasons to anticipate that antidepressants may be effective in the treatment of AN. Malnutrition has been shown to produce a syndrome that is virtually indistinguishable from depression, with anhedonia, weight loss, motor retardation, anergia, and decreased ability to think or concentrate. In addition, the high comorbidity between AN and mood disturbances, and the preponderance of mood disorders in first-degree relatives of those with AN have led some clinicians to consider and treat AN as a depressive variant.

Clomipramine. Clomipramine was the earliest studied antidepressant in AN, in part because of its efficacy in the treatment of obsessive-compulsive disorder. Specifically, clinicians thought it might be useful in AN because of the obsessive quality of anorectics' preoccupation with food. Lacey and Crisp randomized 13 anorectic patients to receive clomipramine or placebo, but found no benefit with the active drug.2 This group was followed for several years, with no statistical difference in weight gain or adjustment noted. Unfortunately, the clomipramine dose (i.e., 50 mg/day) was far less than that typically used to treat depressive and obsessive-compulsive symptoms and plasma levels were not monitored.

Amitriptyline. Amitriptyline is the best studied antidepressant for AN. Halmi and colleagues found that patients treated with doses averaging 160 mg/day reached weight goals almost 13 days quicker and had a greater decrease in depressive symptoms compared to those treated with placebo.3 Biederman's group randomly assigned 43 patients to placebo or amitriptyline in doses averaging 115 mg/day for 5 weeks, but found no advantage to using this drug and no relationship between serum levels and weight gain or psychiatric symptomatology.4

Monoamine Oxidase Inhibitors. We know of no controlled studies using MAOIs in AN. An open-label study conducted by Kennedy et al, however, was not promising in that anorectics treated with isocarboxazid demonstrated less restrictive eating behaviors, but did not gain weight.5 The authors warn of the increased risk of tyramine-induced hypertensive crises in this population known for its impulsive eating behaviors. With the eventual introduction of the safer selective and reversible inhibitors of monoamine oxidase A (RIMAs), these agents should be further explored to clarify their role in the treatment of AN.

Selective Serotonin Reuptake Inhibitors. Recent research has focused on the selective serotonin reuptake inhibitors…

Anorexia nervosa (AN) and bulimia nervosa (BN), although subject to tremendous media attention, are not common disorders, with a combined prevalence of about 4%.1 In over 90% of the cases, those with eating disorders are female, with illness onset typically at or after puberty. These illnesses are far more prevalent in industrialized societies, where physical attractiveness is defined by slenderness. Eating disorders are associated with significant impairment of functioning as well as significant morbidity and mortality, prompting a need for effective treatments. While psychotherapy, particularly cognitive and cognitive-behavioral therapies, has been the cornerstone of treatment for both disorders, our focus will be on recent advances in the pharmacologic treatment of AN and BN.

ANOREXIA NERVOSA

AN has been recognized for over a century. The four major DSM-IV criteria are well accepted and essentially identical to those found in DSM-III-R, as can be seen in Table 1. The critical change between these two nosologies is subtyping based on the presence or absence of hinging or purging. This feature acknowledges recent research demonstrating significant clinical differences between anorectic restrictors, who lose weight through dieting, fasting, or excessive exercise, and anorectic bulimics, who regularly engage in binge eating and/or purging.

Few controlled studies of pharmacologic interventions in AN have been published, and most of these have not shown much promise for any given medication. The following is a critical review of this literature.

Antidepressants

There are several reasons to anticipate that antidepressants may be effective in the treatment of AN. Malnutrition has been shown to produce a syndrome that is virtually indistinguishable from depression, with anhedonia, weight loss, motor retardation, anergia, and decreased ability to think or concentrate. In addition, the high comorbidity between AN and mood disturbances, and the preponderance of mood disorders in first-degree relatives of those with AN have led some clinicians to consider and treat AN as a depressive variant.

Clomipramine. Clomipramine was the earliest studied antidepressant in AN, in part because of its efficacy in the treatment of obsessive-compulsive disorder. Specifically, clinicians thought it might be useful in AN because of the obsessive quality of anorectics' preoccupation with food. Lacey and Crisp randomized 13 anorectic patients to receive clomipramine or placebo, but found no benefit with the active drug.2 This group was followed for several years, with no statistical difference in weight gain or adjustment noted. Unfortunately, the clomipramine dose (i.e., 50 mg/day) was far less than that typically used to treat depressive and obsessive-compulsive symptoms and plasma levels were not monitored.

Amitriptyline. Amitriptyline is the best studied antidepressant for AN. Halmi and colleagues found that patients treated with doses averaging 160 mg/day reached weight goals almost 13 days quicker and had a greater decrease in depressive symptoms compared to those treated with placebo.3 Biederman's group randomly assigned 43 patients to placebo or amitriptyline in doses averaging 115 mg/day for 5 weeks, but found no advantage to using this drug and no relationship between serum levels and weight gain or psychiatric symptomatology.4

Monoamine Oxidase Inhibitors. We know of no controlled studies using MAOIs in AN. An open-label study conducted by Kennedy et al, however, was not promising in that anorectics treated with isocarboxazid demonstrated less restrictive eating behaviors, but did not gain weight.5 The authors warn of the increased risk of tyramine-induced hypertensive crises in this population known for its impulsive eating behaviors. With the eventual introduction of the safer selective and reversible inhibitors of monoamine oxidase A (RIMAs), these agents should be further explored to clarify their role in the treatment of AN.

Selective Serotonin Reuptake Inhibitors. Recent research has focused on the selective serotonin reuptake inhibitors (SSRIs) for several reasons:

* Serotonin has been shown to be important in regulating feeding behaviors in animals.

* Anorectics have demonstrated disturbances of serotonergic activity.

* Serotonergic agents have proven efficacy with obsessive-compulsive symptoms.

Gwirtsman and colleagues reported on six patients with chronic, refractory AN who were treated openly with fluoxetine.6 All patients had diminished depressive symptoms and associated weight gain. Kaye's group treated 31 anorectics with fluoxetine for an average of 11 months, with 29 patients able to maintain themselves at or above 85% average body weight.7 Response was also categorized based on improvement in eating behaviors, mood, and obsessional symptoms, judged as good in 10, partial in 17, and poor in 4 anorectic patients. It is of note that restrictor anorectics fared significantly better than bulimic anorectics, because the authors had previously demonstrated that the restrictor subgroup has increased serotonin turnover compared to their bulimic counterparts.

Conclusion. It is important to keep in mind that antidepressants should be used with caution in this medically compromised population. Malnourished AN patients may be less responsive to antidepressants than the general population and are definitely more susceptible to their side effects. In particular, heterocyclicinduced side effects such as hypotension and arrhythmias may be fatal.

Antipsychotics

Since their introduction, antipsychotics have been used in the treatment of AN. The apparent role of dopamine in feeding and satiety involves increased receptor activity, producing symptoms similar to those found in AN. Thus, it seems reasonable to use dopamineblocking agents to alter these behaviors. It also seems appropriate to use the sedative side effects of these drugs to decrease anxiety associated with eating.

Chlorpromazine. Chlorpromazine has been widely used in this context despite the lack of controlled studies demonstrating its efficacy. Two small crossover studies examined the efficacy of other antipsychotics in AN. In one, 4 to 6 mg/day of pimozide was found to be marginally better than placebo, with patients demonstrating a small nonsignificant improvement in weight and in some attitudes toward eating.8 In the other study, 400 to 600 mg/day of sulpiride were no more effective than placebo in terms of weight gain or characteristic anorectic behaviors or attitudes.9 The role of novel antipsychotics, such as risperidone, has yet to be explored.

Table

TABLE 1DSM-IV Diagnostic Criteria for 307.1 Anorexia Nervosa

TABLE 1

DSM-IV Diagnostic Criteria for 307.1 Anorexia Nervosa

Similar to the caution that must be exercised with heterocyclic antidepressants, antipsychotics must be used carefully and sparingly in this physiologically impaired population. In particular, low-potency agents (most notably, chlorpromazine) may cause extreme hypotension and hypothermia in patients with AN.

Other Drug Interventions

Many other medications have been tried in AN with varying degrees of success. Some authors recommend the use of anxiolytics early in the refeeding process to decrease the concern over loss of control and weight gain without the hypotension and hypothermia that frequently accompany antipsychotic use. In a small, short-term, doubleblind, placebo-controlled study of lithium, Gross and colleagues found that this mood stabilizer enhanced weight gain in AN. Unfortunately, its use is severely restricted by the electrolyte imbalances that result from frequent vomiting, fluid restriction, and laxative abuse.10 Anecdotal literature suggests that electroconvulsive therapy (ECT) may be effective in some patients with AN. Ferguson reviewed this literature and discussed three anorectics treated with ECT, two of whom demonstrated some improvement in weight gain and related behavioral symptoms.11

Table

TABLE 2DSM-IV Diagnostic Criteria for 307.51 Bulimia Nervosa

TABLE 2

DSM-IV Diagnostic Criteria for 307.51 Bulimia Nervosa

The serotonin antagonist cyproheptadine has been used to stimulate appetite in underweight, medically ill populations. In the only controlled study done to date, cyproheptadine in doses of 12 to 32 mg/day was found to have a small but significant advantage over placebo, with more rapid weight gain and diminution of depressive symptoms. Interestingly, cyproheptadine was most useful in anorectic restrictors, while anorectic bulimics did worse on the medication.

Agents that increase gastric emptying have been used in the treatment of AN, because delayed gastric emptying is common in anorectics and the resultant gastric retention further discourages eating. For example, metoclopramide and domperidone can accelerate the rate of gastric emptying. In a small, double-blind trial, a similar agent, cisapride, not only increased the speed of gastric emptying in AN, but promoted weight gain as well.12

Zinc supplementation has also been reported to increase weight gain in open trials of anorectic patients. In a double-blind, randomized trial involving 35 anorectic females who received either 100 mg zinc gluconate or placebo, the rate of body mass index increase in the zinc-supplemented group was twice that of the placebo group.13

Although we noted earlier that antipsychotics have been used in the treatment of AN, Johanson and Knorr surprisingly reported benefit with 0.6 to 3.0 g of L-dopa in nine AN patients treated for 2 to 4 weeks.14 Five of these patients gained more than 3 kg, two gained up to 1 kg, and one lost 1 kg during the study.

Finally, the theory that AN may be an addiction to dieting mediated by endogenous opioids has spawned case reports of the use of opiate antagonists in this disorder. Both naloxone and naltrexone have shown some promise, but this approach needs to be explored in double-blind, placebo-controlled studies.15,16

Conclusion

The role of pharmacotherapy in AN remains unclear. A meta-analysis of eating disorder programs suggests that medication programs alone fail to produce consistent weight gain in AN.17 Better results appear possible if medication, when appropriate, is integrated into a comprehensive treatment program. Typically, those programs include nutritional counseling, behavior modification techniques, and individual, group, and family therapy. Thus, structured, multidimensional approaches seem to be most effective with this population.

BULIMIA NERVOSA

Binge eating has been documented for centuries, but the first description of BN as a distinct syndrome was in 1979.18 The DSM-III, published in 1980, was the first edition to include BN as a separate diagnostic category rather than a variant of AN. As Table 2 demonstrates, there are no major changes in DSM-IV criteria; however, new subtyping allows the clinician to distinguish between individuals who purge and those who use nonpurging behaviors. More significantly, the addition of a fifth criterion specifies that the disorder not occur exclusively during episodes of AN, preventing patients from receiving both AN and BN diagnoses.

While attempts to treat AN pharmacologically have generally been disappointing, the role of medication in the treatment of BN is more promising. Thus, there have been more positive studies published, many of which used larger sample sizes and were well controlled.

Antidepressants

Pope and colleagues published the first double-blind, placebo-controlled trial demonstrating the efficacy of antidepressants in BN.19 They found 200 mg/day of imipramine significantly superior to placebo in decreasing the frequency of binges, the intensity of binges, and the preoccupation with food. These results were replicated several years later by Agras' group.20 Most recently, Mitchell et al randomly assigned patients to 12 weeks of imipramine only, placebo only, imipramine plus group psychotherapy, or placebo plus group psychotherapy.21 Although more complicated than a straightforward medication versus placebo trial, the results suggested that the three active treatment cells were more efficacious than placebo in reducing bulimic behaviors and improving mood. Some BN subsets may not be as responsive to active treatment; however, Rothschild's group recently demonstrated that imipramine was no more effective than placebo in treating bulimia in atypical depressives.22

Desipramine. Desipramine has been found superior to placebo in the treatment of BN by Hughes and coworkers, who demonstrated that serum levels were positively correlated with improvement of bulimic behaviors.23 Similar results were also obtained in a crossover design study by Barlow and colleagues.24

More recent work has examined the long-term effects of desipramine on BN outcome. After confirming the superiority of desipramine over placebo for short-term treatment in 78 bulimics, Walsh and colleagues followed 29 desipramine responders maintained on active drug for 16 weeks and found no further improvement during this time.25 Nine of these patients then underwent a 24-week double-blind, placebo-controlled discontinuation phase. Four of the five desipramine-treated bulimics completed the study without relapse, while 2 of the 4 placebotreated patients relapsed, only one completed the study, and another dropped out after 13 weeks. While the sample size is too small to draw any definitive conclusions, this study suggests that it may be useful to treat bulimics with desipramine for more than 6 months.

In another study, Agras' group followed patients who were randomly assigned to 16 or 24 weeks of desipramine treatment for 1 year.26 The group treated for 24 weeks maintained significantly higher rates of improvement and recovery, again suggesting that those with BN be treated with antidepressants for a minimum of 6 months.

Amitriptyline. Mitchell and Groat reported one of the few well-controlled studies of antidepressants, unfortunately finding active drug therapy only marginally effective in the treatment of BN.27 This may have been due in part to the relatively low amitriptyline doses used (maximum 150 mg/day), resulting in average blood levels of only 103 ng/mL.

MAOIs. The overlap between atypical depression and BN, particularly the hyperphagia common to both disorders, has led investigators to try monoamine oxidase inhibitors (MAOIs) in the treatment of BN. Isocarboxazid and phenelzine have both been found superior to placebo in controlled, double-blind studies of patients with BN.28'29 In a study of atypically depressed bulimics, phenelzine was found to be significantly more effective than either placebo or imipramine in treating both the depressive and the bulimic symptoms.22 It is of note that 11 of 18 patients receiving isocarboxazid and 24 of 27 patients receiving phenelzine in the above studies discontinued treatment due to side effects. More recently, the selective MAOI brofaromine was found to be superior to placebo in decreasing the frequency of vomiting in BN, but not in decreasing the frequency of bulging, changing bulimic attitudes, or decreasing self-reports of depression or anxiety.30

Some clinicians justifiably question the safety of prescribing medications requiring dietary restrictions to a population whose symptoms include lack of control over food intake. As noted earlier in the discussion on AN, selective and reversible inhibitors of monoamine oxidase A may prove to be safer, and thus more useful.

Other Antidepressants. Two later generation antidepressants, bupropion and trazodone, have proven efficacy in BN, as demonstrated in well-controlled trials.31»32 Unfortunately, four of the patients treated with bupropion experienced grand mal seizures in this study, leading to this medication being contraindicated in patients with eating disorders. While mianserin is the only antidepressant other than amitriptyline not found to have an advantage over placebo in the treatment of BN, the 60 mg/day dose used was significantly less than the usual antidepressant dose of 150 mg/day.33 Nomifensine, no longer available due to unacceptable adverse effects, was shown to be efficacious in the treatment of BN in two uncontrolled studies. Subsequently, a small, double-blind, placebocontrolled, crossover design study replicated these earlier findings.34-36

SSRIs. Perhaps the most promising results have come from the use of selective serotonin reuptake inhibitors (SSRIs) in BN. The first controlled study using fluoxetine was small, but showed a definite treatment advantage over placebo. 3 7 Subsequently, a large multicenter study confirmed this finding. 38 Almost 400 outpatients were randomly assigned to 20 or 60 mg/day of fluoxetine or placebo for 8 weeks. Fluoxetine at the higher dose was superior to placebo and to 20 mg of fluoxetine in decreasing both vomiting and bulging. Fluoxetine at 20 mg/day significantly decreased vomiting but not binging compared to placebo. Both doses of fluoxetine were well tolerated by study participants. These findings conflict, however, with those of a double-blind trial of 60 mg/day of fluoxetine versus placebo in 40 patients. 39 In this study, both groups demonstrated improvement, with no significant difference between them. The authors posit the existence of a "ceiling effect" due to the intensive inpatient care and behavioral therapy. In essence, the effect of these factors is so great that they limit the ability to demonstrate any improvement gained by the addition of medication.

While there is little research using other SSRIs in BN, results from an open-label trial of fluvoxamine in 20 patients and a single case report of a patient treated with sertraline are encouraging.40,41

Other Drug Interventions

Although anticonvulsants have been used to treat BN, there has been little success. Nineteen subjects were treated for 12 weeks in a doubleblind crossover study of unspecified doses of Phenytoin and placebo.42 While the mean number of binges on phenytoin decreased slightly, it was not significantly different from placebo. There are several problems with this study, however, including the fact that 7 of the 19 patients had subtherapeutic phenytoin levels (including two patients whose levels indicated gross noncompliance), and that the study explicitly targeted binge eaters rather than bulimics. Carbamazepine was administered to six patients in a double-blind crossover study, but the only patient who demonstrated marked improvement had a history consistent with bipolar disorder.43

A small controlled study of Uthium in the treatment of BN was no more promising, with patients on active drug showing no more improvement than those on placebo.44 The relatively low plasma levels (0.62 mEq/L) achieved may have been a factor in this outcome.

Paralleling the AN story, animal studies implicating endogenous opioids in the regulation of stress-induced eating prompted a controlled trial of the opioid antagonist naltrexone. It failed to elicit a significant reduction in bulimic behaviors, however.45

Other than antidepressants, the most encouraging research to date is in the area of serotonergic agonists, with fenfluramine the best studied of these agents. Thus, two small trials found fenfluramine to have antibulimic potential, but a later study did not replicate these findings.46"48 In one study, 43 patients were treated for 8 weeks with 45 mg/day fenfluramine or placebo. Because abnormal eating behaviors improved in both groups, fenfluramine did not offer a significant advantage over placebo. The authors refer to the earlier hypothesized "ceiling effect" to explain this finding, as all patients received cognitive-behavioral therapy in addition to medication.

The role of medication in the treatment of BN seems better established than its role in the treatment of AN. The American Psychiatric Association Practice Guideline for Eating Disorders suggests that antidepressants may be useful in BN independent of the presence of depression.17 They may be particularly helpful, however, in patients with depression, anxiety, obsessions, and in those who have failed psychosocial therapies.

CONCLUSION

Eating disorders are well-recognized psychiatric illnesses associated with significant morbidity and mortality. Attempts to treat AN with medications have proved disappointing; thus, psychotherapy using cognitive and behavioral interventions remains central to the effective treatment of AN. Bulimia nervosa has been more responsive to pharmacotherapy. In particular, antidepressants appear to play an important role in the treatment of BN. Clearly, when used, medications should never be the sole treatment of any eating disorder, but in selected patients they may play an integral part of a comprehensive treatment strategy.17 It is also important to note that eating disorders are frequently accompanied by other comorbid Axis I illnesses requiring pharmacotherapy, particularly mood and anxiety disorders.

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30. Kennedy SH, Goldbloom DS, Ralevski E, et al. Is there a role for selective monoamine oxidase inhibitor therapy in bulimia nervosa? A placebo-controlled trial of brofaromine. J Clin Psychopharmacol. 1993; 13:415-422.

31. Home RL, Ferguson JM, Pope HG, et al. Treatment of bulimia with bupropion: a multi-center controlled trial. J Clin Psychiatry. 1988; 49:262-266.

32. Pope HG, Keck PE, McElroy S, et al. A placebo-controlled study of trazodone in bulimia nervosa. J Clin Psychopharmacol. 1989; 9:254-259.

33. Sabine E, Yonace A, Farrington AJ, et al. Bulimia nervosa: a placebo-controlled, double-blind, therapeutic trial of mianserin. Br J Clin Pharmacol. 1983; 15: 195S-202S.

34. Nassr DG. Successful treatment of bulimia with nomifensine. Am J Psychiatry. 1986; 143:373-374.

35. Pope HG, Herridge PL, Hudson JI, et al. Treatment of bulimia with nomifensine. Am J Psychiatry. 1986; 143:371-372.

36. Price WA, Babai MR. Antidepressant drug therapy for bulimia: current status revisited. J Clin Psychiatry. 1987; 48:385.

37. Freeman CP, Munro JK. Drug and group treatments for bulimia/bulimia nervosa. J Psychosom Res. 1988; 32:647-660.

38. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoretine in the treatment of bulimia nervosa: a multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry. 1992; 49:139-147.

39. Fichter MM, Leibl K, Rief W, et al. Fluoxetine versus placebo: a double-blind study with bulimic inpatients undergoing intensive psychotherapy. Pharmacopsychiatry. 1991; 24:1-7.

40. Aguso-Gutierrez JL, Palazo'n M, Ayusa-Mateos JL. Open trial of fluvoxamine in the treatment of bulimia nervosa. Int J Eat Disord. 1994; 15:245-249.

41. Roberts JM, Lydiard RB. Sertraline in the treatment of bulimia nervosa. Am J Psychiatry. 1993; 150:1753.

42. Wermuth BM, Davis KL, Hollister LE, Stunkard AJ. Phenytoin treatment of the binge-eating syndrome. Am J Psychiatry. 1977; 134:1249-1253.

43. Kaplan AS, Garfinkel PE, Darby PL, Garner DM. Carbamazepine in the treatment of bulimia. Am J Psychiatry. 1983; 140:1225-1226.

44. Hsu LKG, Clement L, Santhouse R, Ju ESY. Treatment of bulimia nervosa with lithium carbonate: a controlled study. J Nerv Ment Dis. 1991; 179:351-355.

45. Mitchell JE, Christenson G, Jennings J, et al. A placebocontrolled, double-blind cross-over study of naltrexone hydrochloride in outpatients with normal weight bulimia. J Clin Psychopharmacol. 1989; 9:94-97.

46. Robinson PH, Checkley SA, Russell GFM. Suppression of eating by fenfluramine in patients with bulimia nervosa. Br J Psychiatry. 1985; 146:169-176.

47. Russell GFM, Checkley SA, Feldman J, et al. A controlled trial of d-fenfluramine in bulimia nervosa. Clin Neuropharmacol. 1988; 11:S146-S159.

48. Fahy TA, Eisler I, Russell GFM. A placebo-controlled trial of d-fenfluramine in bulimia nervosa. Br J Psychiatry. 1993; 162:597-603.

TABLE 1

DSM-IV Diagnostic Criteria for 307.1 Anorexia Nervosa

TABLE 2

DSM-IV Diagnostic Criteria for 307.51 Bulimia Nervosa

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