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Anorexia Nervosa and Psychosis

Pauline S. Powers, MD, Heather Simpson, MS3,
and Terrance McCormick, BS

Dr. Powers is professor of psychiatry, Ms. Simpson is a fourth-year medical student, and Mr. McCormick is a clinical research data and financial specialist, all in the Department of Psychiatry and Behavioral Medicine at the University of South Florida in Tampa.

Disclosure: Dr. Powers receives grant and/or research support from AstraZeneca and Eli Lilly. Ms. Simpson and Mr. McCormick report no affiliations with or financial interests in any commercial organization that might pose a conflict of interest.

Please direct all correspondence to: Pauline S. Powers, MD, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 E Fletcher Ave, Tampa, FL 33613; Tel: 813-974-2926; Fax: 813-974-2882; E-mail: [email protected].

Abstract

This article summarizes findings supporting the theory that some patients with anorexia nervosa (AN) have psychotic features. The results of a study in which the Positive and Negative Syndrome Scale for schizophrenia was administered to patients with AN is described. The similarities and differences between AN patients and historical schizophrenic patient controls are discussed. It is proposed that the next revision of the Diagnostic and Statistical Manual of Mental Disorders include a severity modifier for AN indicating that some patients may have psychotic features. Studies utilizing antipsychotic medications for patients with AN are outlined and a practical guide for the use of these medications is presented. The need for randomized placebo-controlled double-blind studies is emphasized.

Introduction

Anorexia nervosa (AN) is a serious life-threatening illness that typically begins in adolescence. Lifetime prevalence has been estimated at 0.3% to 0.7% in females and 0.1% to 0.2% in males.^1,2 Premature mortality rates among untreated patients range between 10% and 18% after 20 years.^3,4 Although 90% to 95% of patients are female, there is some evidence that this ratio may be changing and that more males are being affected.² Treatment is complex, lengthy, expensive, and difficult to access. The etiology of AN is unknown, although one popular theory has suggested that vulnerable adolescents in dysfunctional families living in a culture obsessed with thinness are at risk for developing AN.⁵ More recently, it has been demonstrated that there is a significant genetic vulnerability for AN.⁶ Other recent studies have implicated neurotransmitters (particularly serotonin) in the etiology and psychopathogenesis of the disorder.^7,8

Studies of the etiology of AN have been hampered by problems with the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).⁹ Some required criteria may actually be epiphenomena rather than core characteristics of the illness. For example, not all patients are fearful of becoming fat,¹⁰ some patients do not have a body image disturbance,¹¹ and amenorrhea is not always present in patients who meet all the other criteria for AN.¹² Also, some features of the illness that were part of the earliest descriptions are not included in the current diagnostic criteria; for example, denial of illness and lack of insight may actually be core symptoms of AN.

In this article, the concept that some patients with AN may have a psychotic illness is presented. Theoretical and experimental evidence supporting this idea will be presented. Research in which the Positive and Negative Syndrome Scale (PANSS) was administered to patients with AN is presented and the results are compared to patients with schizophrenia. The results of several preliminary treatment studies utilizing typical or atypical antipsychotics is then described. The authors propose a change in the current diagnostic criteria to include a severity modifier for patients with psychotic features. Finally, the benefits and risks of antipsychotic medication in the management of AN patients are described and recommendations for their uses provided.

Is Anorexia Nervosa a Psychotic Disorder?

During the last 30 years, several authors have theorized that AN might be a psychotic disorder.^13-15 Certain key features of AN could be related to psychosis. For example, patients with the disorder typically believe they are overweight or normal weight even when they are dramatically and obviously underweight. Logic, reassurance, and threats are typically ineffective in convincing the patient that she is underweight or that being underweight poses any physiological danger.

In 1873, Lesegue described AN as¹⁶:

An inexhaustible optimism, against which supplications and menaces alike are of no avail: “I do not suffer and must then be well…” So often have I heard this phrase repeated by patients that now it has come to represent for me a symptom—almost a sign. The whole disease is summed in this intellectual perversion.

Dorland’s Illustrated Medical Dictionary¹⁷ likewise defines a delusion as follows:

A false belief which cannot be corrected by reason… It cannot be corrected by argument or persuasion or even by the evidence of the patient’s own senses.

Thus, it could be concluded that many patients are delusional about their physical condition.

In addition, misperceptions are common, and frequently connected with delusional ideation about size and shape. These misperceptions have been called a body image disturbance or body dissatisfaction. Using a variety of instruments¹⁸ many studies have demonstrated that patients perceive themselves as larger than they are in reality. The changes that occur with weight gain or weight loss are counterintuitive. For example, it has been noted that during the development of AN, dissatisfaction (and accuracy of perceptions) with size and shape typically worsen, but during weight gain this dissatisfaction often decreases. If fear of weight gain actually underlies body image disturbances, the changes with weight loss and weight gain would be expected to lie in the opposite direction.

Other abnormalities of perception have also been seen in patients with AN. For example, several patients have complained that they hear an “anorexic voice”; although some of these patients describe this as an internal conflict, others experience the voice as external. Some female patients describe a male voice telling them not to eat. These misperceptions meet the criteria for an auditory hallucination.

Many AN patients have subtle neuropsychological abnormalities similar to those seen in patients with schizophrenia, including impaired verbal learning, attention deficits, and abnormalities in executive functioning.^19,20 These abnormalities do not all resolve with weight gain²¹ and do not appear to be related to depression.²² It has recently been suggested that abnormalities in cognition may precede onset of eating abnormalities in AN.²³ Enlarged cerebral ventricles with decreases in both white and gray matter are often seen in patients with AN^24,25; deficits in gray matter are also seen in some patients with schizophrenia and enlarged ventricles are seen in patients with psychotic depression.²⁶

Another frequent finding in AN is an elevated cortisol level.²⁷ Although the etiology of this finding is not known, elevations in cortisol might be correlated with psychotic symptoms or cognitive defects, as has been suggested in other patients who have hypercortisolemia.^28,29

A complicating factor is the semi-starvation that occurs in patients with AN. Multiple physiological abnormalities might account for some of the cognitive and perceptual symptoms and brain abnormalities seen in patients with AN. Also, some patients may have both AN and schizophrenia.³⁰ One study³¹ found that male veterans with AN were at high risk for comorbid schizophrenia or other psychotic disorders. Also, in some patients AN may be a prodrome to the later development of schizophrenia. Another possibility may be that some AN patients have symptoms that are analogous to patients with severe affective disorders who develop psychotic symptoms consistent with their mood. The psychosis that these AN patients develop might be consistent with their weight, food, and shape concerns.

Neurotransmitters and AN

In the search for the etiology of AN, several neurotransmitters have been implicated. Serotonin has been the best studied and current evidence suggests that serotonin dysregulation is present when patients are underweight and may persist even after weight restoration.³² The efficacy of the antidepressants, particularly the serotonin reuptake inhibitors (SRIs), in the management of AN has been studied in several small trials. In general, the SRIs have been found to be ineffective when patients are underweight,³³ but may be helpful in preventing relapse in weight recovered patients.³⁴

Abnormalities in dopamine may also contribute to the development of AN. Dopamine (D) has been postulated to be involved in the regulation of eating behavior, particularly in the hedonic factors which underlie motivation for eating. Animal studies have found that increased activity of dopaminergic receptors reduces food intake and duration of food intake.³⁵ Apomorphine-induced anorectic behaviors in animals are antagonized by D₁ and D₂ receptor blockers such as sulpiride and pimozide, both of which are antipsychotics.³⁶ Persistent alterations of D in weight-restored restricting-type anorexics have also been demonstrated.³⁷

Several symptoms seen in AN might be related to dopamine. For example, the increased hyperactivity frequently seen in AN patients might be associated with increased dopamine neurotransmission. Wang and colleagues³⁸ have shown that individuals with obesity have decreased D₂ receptor activity. Kaye³⁹ has suggested that D₂ receptor activity may be inversely related to weight, with AN on one end and obesity on the other end of the spectrum. As a class, the antipsychotic medications reduce levels of D, particularly D₂.⁴⁰ Thus, antipsychotic medications might be useful in the treatment of patients with AN.

In addition to effects on the D system, the second-generation atypical antipsychotics also have effects on the serotonin system. The atypical antipsychotics which modulate dopamine and have varying levels of effects on the serotonin system may be even more promising treatments for patients with AN than the typical antipsychotics.

Evidence from the Positive and Negative Syndrome Scale

The Positive and Negative Syndrome Scale (PANSS) was developed by Kay and colleagues^41-43 to assess the positive and negative symptoms of schizophrenia. It is a clinician-administered instrument requiring a detailed interview with the patient lasting 30–45 minutes supplemented by collateral information obtained from the family or others involved with the patient.⁴⁴ Semi-structured interviews have been developed for the interview with the patient.⁴⁵ A questionnaire has also been developed to obtain information from a family member or care provider.⁴⁶ The PANSS is administered by a mental health professional skilled in interviewing patients with schizophrenia and trained and certified in the use of the PANSS and its rating system. There are 33 items on the PANSS that are scored on several scales: the Positive Scale, Negative Scale, Composite Index, General Psychopathology Scale, and Supplemental Aggression Risk Profile. Additional scores for clusters of symptoms include the Anergia, Thought Disturbance, Activation, Paranoid/Belligerence, and Depression Scales. Each of the 33 items on the test is rated on a 7-point scale ranging from 1 (absent) to 7 (extreme). The method for determining the rating for each item is clearly specified using well-defined anchors. The PANSS has been used extensively in pharmaceutical trials of antipsychotics and scores on this instrument are frequently the criteria which determine whether or not an antipsychotic medication is judged to be effective in reducing symptoms of psychosis.

To determine if patients with AN have symptoms of psychosis, the PANSS was administered to 39 patients by certified raters during the screening period for two medication trials approved by the University of South Florida Institutional Review Board.⁴⁷ The patients met DSM-IV-TR⁹ criteria for AN; 45% had the restricting type of AN and 55% had the binge-purge type of AN. All but three of the patients were female; mean age was 26 (range was 14–56 years of age) and mean body mass index (weight in kg divided by height in m squared) was 16.⁴⁷ The Structured Clinical Interview for DSM-IV Axis-I Disorders⁴⁸ was also administered to confirm the clinical diagnosis of AN and to exclude patients who met criteria for either schizophrenia or schizoaffective disorder.

Scores from these 39 AN patients were compared to validated reference scores from 240 patients with schizophrenia (using the PANSS manual⁴⁴). The mean score for the PANSS General Psychopathology Scale for the AN patients was 33 (Standard Deviation [SD]=6.1) and 39.6 (SD=9.3) for the schizophrenic patients, with the range of possible scores from 7–112. As shown in Figure 1, although some patients with schizophrenia scored higher than any of the patients with AN, there was significant overlap in scores between the AN patients and the schizophrenic patients. As shown in Figure 2, the mean PANSS Positive Scale score for the AN group was 12.3 (SD=3.6) and 19.9 for the schizophrenic group (SD=6.2), with a range of possible scores from 7–49. Although nearly 30% of AN patients had no symptoms on this scale, >70% had some symptoms and a few patients had many positive symptoms. During the interview with the patients, several complained of hearing an “anorexic voice” telling them not to eat, some were conceptually disorganized, and some were convinced they were “fat” despite evidence to the contrary. Among the 39 patients, 28 had mild but definite evidence of at least one delusion (eg, several patients were afraid that if food touched their plate they would gain weight even if they did not eat). Similarly, 27 patients had at least mild but definite suspiciousness; a typical example was the belief that care providers or family members were secretly adding calories to food that was served.

As shown in Figure 3, the pattern was similar for the PANSS Negative Scale; although some patients with schizophrenia scored higher than any of the patients with AN, there was significant overlap in scores. Patients frequently had blunted affect or were emotionally withdrawn. As shown in Figure 4, the pattern was slightly different for the PANSS Depression Scale, with patients with AN scoring higher than patients with schizophrenia on this scale.

Thus, many patients with AN have scores on key scales of the PANSS that are similar, although not identical, to scores seen in patients with schizophrenia. It may be that some patients with AN, but not all, have psychotic features to their illness.

Preliminary Treatment Studies Utilizing Antipsychotics

Typical Antipsychotic Medications

Three early European studies of typical antipsychotics for the treatment of AN evaluated sulpiride⁴⁹ and pimozide^50,51; neither were found to be particularly effective in promoting weight gain. More recently, a single-blind study⁵² compared the effectiveness of amisulpride, fluoxetine, and clomipramine in restricting AN patients. It found that the 12 patients treated with amisulpride had a more significant increase in mean weight than patients treated with the other two drugs. Amisulpride is not approved for any indication by the Food and Drug Administration and is not available in the United States.

Another typical antipsychotic, haloperidol, has been studied as an adjunctive treatment in 13 restricting AN outpatients who had not responded to conventional treatment.⁵³ These patients were described as treatment resistant, defined as having persistent and resistant anorectic symptoms despite multiple standard therapies. Haloperidol in low doses in an open-label study resulted in significant weight gain, as well as improvements on the Eating Disorder Inventory⁵⁴ scale measuring symptoms of AN.

Atypical Antipsychotic Medication

Several case reports found that olanzapine, one of the early atypical or second-generation antipsychotics, was beneficial for some treatment-resistant AN patients and that there were improvements in both weight and insight into illness.^55-57 Powers and colleagues⁴⁷ reported in an open-label study that 18 patients who received 10 mg of olanzapine over a 10-week period gained a mean of 5 lbs. Fourteen patients completed the study: ten patients gained a mean of 8.75 lbs and three of these patients gained to ideal body weight. The remaining four patients who completed the study lost a mean of 2.25 lbs. The PANSS was administered to patients in this study and there were significant declines in the total PANSS scores among patients who gained weight but not among those who lost weight. In another study,⁵⁸ 18 patients were retrospectively questioned about their response to olanzapine; they reported decreases in anxiety, difficulty eating, and core eating disorder symptoms after taking olanzapine. It is possible that the improvements noted were all related to weight gain, but this seems unlikely since the actual gain was modest (mean=5 lbs).

An interim report⁵⁹ on an ongoing clinical trial with quetiapine for patients with AN suggests that weight gain is modest with this antipsychotic, but that there are improvements in scores on the PANSS, as well as improvements in several core symptoms measured by the Eating Disorder Inventory.⁵⁴

Risperidone has been reported to be effective in a case report⁶⁰ but no clinical trials have been reported. As of this writing, there have been no reports of treatment of AN with the other FDA-approved atypical antipsychotics (ie, clozapine, ziprasidone, or aripiprazole).

Although the results of the studies of certain atypical antipsychotics, especially olanzapine, are promising, thus far no multisite, randomized, double-blind, placebo-controlled studies have been performed. The only randomized controlled trial (which was not placebo controlled) was the study of 12 patients with amisulpride⁵²; this medication is not available in the US.

Treatment Recommendations: Risk/Benefit Ratio

Despite the absence of appropriate controlled trials, the antipsychotic medications, particularly olanzapine, are being widely used for patients with AN. Although certain other treatments are considered standard (eg, behavioral weight gain programs) and some are recommended in various treatment guidelines and algorithms,^61,62 none meet the criteria for evidence-based medicine.⁶³ Given the lack of needed studies, the severity of the illness, and the need for treatment now, it is likely that the use of possibly effective treatments will increase. Therefore, the risk-to-benefit ratio of using various antipsychotic medications, given the current state of knowledge, will be summarized.

Although one open-label clinical trial found that haloperidol was helpful,⁵³ the risk of extrapyramidal side effects should be carefully considered. Underweight AN patients are debilitated and may be more likely to develop extrapyramidal symptoms. If utilized, there should be careful monitoring for Parkinsonian symptoms, dystonia, dyskinesia, and akathisia with the various movement scales.^64-66

Of the atypical antipsychotics, olanzapine has been the best studied,^47,55-57 but no controlled study has been done. Also, no studies have yet been undertaken delineating the timing for use of olanzapine. Since olanzapine (and some of the other atypical antipsychotics, including risperidone and quetiapine) are associated with weight gain, it may be that these medications should only be used during the weight gain phase of treatment, not the weight maintenance phase. In any case, weight should be carefully monitored to prevent gain above ideal body weight.

Quetiapine has been studied in a clinical trial and the interim report⁵⁹ suggested that the drug may be helpful in reducing certain core symptoms of AN, but appears to be less effective in promoting needed weight gain.

Clozapine, the first atypical antipsychotic approved for use in schizophrenia, has not been studied for AN. However, it would be an unlikely choice because of the risk of seizures and agranulocytosis, both of which might be more likely in patients with AN. Although the risk of extrapyramidal symptoms and akathisia is lower with the atypical antipsychotics, risk is still present and may be more likely with risperidone, particularly in doses >4–6 mg. The only information available about risperidone in the treatment of AN is from a single case report.⁶⁰

The remaining two atypical antipsychotics currently approved by the FDA for schizophrenia are ziprasidone and aripiprazole. Both of these medications are less likely to be associated with weight gain and thus may be less likely to be helpful during the weight gain phase of AN, but neither has been studied. With ziprasidone, the risk of QT prolongation and the potentially lethal torsades de pointes could be greater in patients with AN, since many have hypokalemia and some patients have QT prolongation.

Proposal for a Severity Modifier in Revised Criteria for Anorexia Nervosa

The current diagnostic criteria in the DSM-IV-TR include two subtypes of AN but do not include criteria for determining severity. It is proposed that in future revised diagnostic criteria one level of severity for AN might include “anorexia nervosa with psychotic features.” Just as some patients with depression have mood-congruent psychotic features, it appears that some patients with AN have psychotic symptoms congruent with the core symptoms of AN. In some patients, these psychotic features include the delusional belief that they are fat and auditory hallucinations described as an “anorexic voice.” The Table lists a possible method of classifying severity of AN, including a modifier for psychotic features. Although many underweight AN patients have definite psychotic symptoms, a feature differentiating them from patients with schizophrenia is that these symptoms are related to the eating and body image problems, whereas the psychotic symptoms in schizophrenia are not related to any particular theme.

Conclusion

This article hypothesizes that some patients with AN may have psychotic symptoms and provides preliminary evidence supporting this hypothesis. Although it is clear that not all patients with AN have psychotic symptoms, it may be that some patients have delusions and/or hallucinations consistent with weight, food, and shape themes characteristic of AN. The use of antipsychotics in the management of AN has become widespread but the scientific basis for use of these medications is meager. The few available open-label studies are summarized and the need for randomized placebo-controlled trials is emphasized. A practical guide for the use of the antipsychotics including the need for a careful risk/benefit evaluation is provided. PP

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