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Perplexities of treatment resistence in eating disorders
BMC Psychiatry 2013, 13 :292 doi:10.1186/1471-244X-13-292
Katherine A Halmi ([email protected])
ISSN 1471-244X
Article type Review
Submission date 22 April 2013
Acceptance date 12 September 2013
Publication date 7 November 2013
Article URL http://www.biomedcentral.com/1471-244X/13/292
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BMC Psychiatry
© 2013 Halmi This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Perplexities of treatment resistence in eating
disorders Katherine A Halmi 1*
* Corresponding author
Email: [email protected] 1 New York Presbyterian Hospital, Westchester Division, 21 Bloomingdale Rd,
Whites Plains, NY 10605, USA
Abstract
Background
Treatment resistance is an omnipresent frustration in eating di sorders. Attempts to identify
the features of this resistance and subsequently develop novel treatm ents have had modest
effects. This selective review examines treatment resistant features expressed in core eating
disorder psychopathology, comorbidities and biological features. Novel treatment s addressing
resistance are discussed.
Description
The core eating disorder psychopathology of anorexia nervosa becomes a coping mechanism
likely via vulnerable neurobiological features and conditioned learning to de al with life
events. Thus it is reinforcing and ego syntonic resulting in resistance to treatment. The
severity of core features such as preoccupations with body image , weight, eating and
exercising predicts greater resistance to treatment. Bulimia nervosa patients are less resistant
to treatment with treatment failure related to greater body image concerns, impulsivity,
depression, severe diet restriction and poor social adjustment. For those with binge eating
disorder overweight in childhood and high emotional eating predicts treatm ent resistance.
There is suggestive data that a diagnosis of an anxiety disorder and severe perfectionism may
confer treatment resistance in anorexia nervosa and substance use disorders or personality
disorders with impulse control problems may produce resistance to tr eatment in bulimia
nervosa. Traits such as perfectionism, cognitive inflexibility and negative affect with likely
genetic influences may also affect treatment resistance. Pharmacotherapy and novel therapies
have been developed to address treatment resistance. Atypical anti psychotic drugs have
shown some effect in treatment resistant anorexia nervosa and topiramate and high doses of
SSRIs are helpful for treatment of resistant binge eating disorder patients. There are
insufficient randomized controlled trials to evaluate the novel psychot herapies which are
primarily based on the core psychopathological features of the eating disorde rs.
Conclusion
Treatment resistance in eating disorders is usually predicted by the severity of the core eating
disorder psychopathology which develops from an interaction between environment al risk
factors with genetic traits and a vulnerable neurobiology. Future investigations of the
biological features and neurocircuitry of the core eating disorders psychopathology and
behaviors may provide information for more successful treatment interventions.
Keywords
Treatment resistance, Anorexia nervosa, Bulimia nervosa, Binge eating di sorder
Introduction
Treatment resistance is a common feature of eating disorders doc umented by poor response
rates in many treatment trials. Studies of predictors of respons e to treatment have shown
varying results depending on eating disorder diagnosis and definitions of response and
recovery [1]. A literature search from years 2000 to 2012 using the terms treatment
resistance, anorexia nervosa (AN), bulimia nervosa (BN), binge e ating disorder (BED), and
eating disorders yielded 38 papers from Pub Med and 26 papers from Psy ch Info. In the
overwhelming majority of these papers the term treatment re sistance was used
interchangeably with chronicity of illness or difficult to tre at. There were also multiple
definitions of treatment failure including no definition. The author decid ed not to present a
comprehensive review of “treatment resistance “but rather menti on those articles with salient
relevant features of the author’s interest in three areas; core eating disorder psychopathology,
comorbidity, and biological features. A variety of novel psychotherapie s addressing
“treatment resistance” in AN have been developed. All of these need further efficacy and
effectiveness trials and are referred to briefly as are som e pharmacotherapies for AN. A few
treatment studies with adequate sample sizes addressing “resi stant “patients with BN and
BED are presented along with the author’s suggestions. Review
Core eating disorder psychopathology
Treatment resistance is especially prominent in anorexia nervosa patients who often deny
their fear of gaining weight and the seriousness of their illness. Many female adolescents with
AN have stated openly they do not wish to develop into a mature female body and are fearful
of becoming independent of their family [1]. For many AN becomes a coping mechanism to
deal with adverse experiences. It provides an escape from aversive developmental (maturity)
issues and distressing life events often of an interpersonal nat ure. Changing their behavior is
an overwhelming and terrifying notion to the anorexia nervosa patient. Certain developm ental
features are common in anorexia nervosa. The majority of these pat ients have had a lack of
experience to foster personal independence [2]. This has produced a se nse of personal
ineffectiveness and poor self-esteem. Many of these patients al so have a social
ineffectiveness, which makes them feel ill at ease in dealing w ith their peers and with life
crises. They often have problems of developmental transitions from the prepubertal state
through puberty to a mature adult. Their immaturity and autonomy fears are expressed in the
form of refusing to separate from their parents. A plausible hypothe sis is that their
preoccupations with body image, weight, eating and exercising pr ovide a distraction for
dealing with distressing life events. In addition, the behavior of their illness gives them a
feeling of control and elevates their self-esteem. The mental changes occurring from severe
dieting and emaciation further augment treatment resistance. T hese symptoms of emotional
instability, irritability and loss of concentration make it more difficult for the patient to
engage in meaningful psychotherapy that results in behavior change. S everity of core eating
disorder psychopathology usually predicts greater resistance to tre atment in anorexia nervosa
patients [3].
Treatment resistance in bulimia nervosa should be able to be infer red from studies of
predictors of therapy response. Unfortunately, different studies have f ound different sets of
predictors both for treatment outcome and for attrition. Predictors ide ntified as statistically
significant in one study were not found significant in others. This ma y be due to several
factors including the type of therapy, the mode of delivery (i.e., individual or group format,
outpatient or inpatient treatment), and the characteristics of the population of bulimic subjects
studied. Many studies have had too few subjects to reliably identif y outcome predictors and
the definition of treatment success has varied from abstinence fr om binge eating and purging
to no longer meeting criterion of DSM-IV diagnostic criteria. P retreatment variables and the
methods of assessing treatment outcome have varied among the studies. The fact that bulimia
nervosa patients are less resistant to treatment than those wi th anorexia nervosa is
demonstrated by the fact there many more randomized controlled trials for treatment of
bulimia nervosa compared with anorexia nervosa, a condition in which few people are will ing
to enter the trials and when they do the dropout rate and lack of commi tment to treatment is
considerably greater. One study of 194 women with bulimia nervosa showe d those with the
treatment resistance (treatment failure) had greater concer ns about shape and had greater
impulsivity than those who responded to treatment. Non-responders to the imm ediate end of
treatment were also more likely to have current depression, a lowe r body mass index
indicating severe dietary restriction and poor social adjustment [4].
The problem of different studies showing contradictory results for predictors of treatment
resistance in BN is present as well as in BED. One study wi th a large sample of 144
individuals with binge eating disorder found a history of overweight dur ing childhood and
high emotional eating were predictors of treatment resistance [ 5]. In two recent studies
severity of body image disturbance and shape concerns were rel ated to treatment compliance
and resistance [6,7].
Psychiatric and psychological comorbidity
Studies presented in this section were chosen for large sample s ize or the mention of specific
traits or concepts. The most comprehensive psychiatric comorbidity st udy is from the U.S.
National Survey Replication [8]. In this study at least one life time comorbid psychiatric
DSM-IV disorder was present in 56.2% of anorexia nervosa participant s, 94.5% of those with
bulimia nervosa, 78.9% of those with binge eating disorder, 63.6% with sub thres hold binge
eating disorder, and 76.5% with any binge eating. Affective disorder s which are the most
prevalent of the comorbid psychiatric disorders associated with eat ing disorder were not
shown to influence the long term outcome response to treatment in bulim ia nervosa [9] or to
effect treatment acceptance or completion in anorexia nervosa [3]. The rates of anxiety
disorders were similar in 97 individuals with anorexia nervosa, 282 with bulimia nervosa and
293 with anorexia nervosa binge-purge subtype in a large genetic study [ 10]. Two-thirds of
the participants in this study reported one or more anxiety disorder s in their lifetime with the
most common diagnosis being obsessive-compulsive disorder, 41% and social phobi a, 20%.
In the majority of these patients the onset of anxiety disorders oc curred in childhood before
the emergence of their eating disorder. In this study those indivi duals who had a lifetime
diagnosis of an anxiety disorder and were currently ill with an eating disorder had more
symptoms of anxiety, harm avoidance, obsessionality and perfectionism suggesting that a
diagnosis of anxiety disorder and more severe symptoms of the trai ts mentioned may confer
treatment resistance. Substance use disorders (alcohol and or drug) oc cur in 40 to 50 percent
of disorders with binge eating. In these eating disorder subtypes substance use disorders are
associated with a high prevalence of major depression, anxiety disor ders, and cluster B
personality disorders [11]. The high degree of multiple comorbidities with substance use
disorders and eating disorders makes it difficult to determine t he effect that a substance use
disorder may have on treatment resistance. Personality disorders are also highly prevalent in
the eating disorder population. In one large comprehensive study [12] 69% of the patients had
a least one personality disorder and 31% of the bulimic subgroups had cl uster B impulsive
disorders of which the most prominent was borderline personality disorder present in 25%.
The prevalence of cluster C anxious personality disorders was pre sent in 30% of eating
disorder patients and did not vary according to eating disorder subtype. A review of bulimia
nervosa studies [13] concluded that personality disorders marked by prob lems with impulse
control were associated with a worse prognosis in these patients and thus suggesting an
association with treatment resistance.
There is some indication that personality traits may influence response to treatment and
treatment resistance. Perfectionism is a personality trait initially identified with anorexia
nervosa. In one study of 322 women with a history of anorexia nervosa gre ater perfectionism
was associated with lower body weight, greater prominence of e ating preoccupations and
rituals and a diminished motivation to change, the latter implying a greater resistance to
treatment [14]. There is an indication that temperament features may also affect
responsiveness to treatment in eating disorders. Diagnostic crossover from anorexia nervosa
to bulimia nervosa and visa versa in one large sample study was c onsistently associated with
low self-directiveness [15]. There is also a suggestion that the se verity of negative affect may
influence treatment responsiveness in binge eating disorder [16]. In a study of 74 individuals
with eating disorders including anorexia nervosa, bulimia nervosa and ea ting disorders not
otherwise specified, those patients with a combination of low self compassion and high fear
of self compassion at baseline had significantly poorer treatment responses [17]. In a
response to a stressful speech task, recovering anorectic patient s demonstrated greater
negative emotional responses compared with controls. The author suggested that the
persistence of a negative affect with distress following recove ry may place these patients at
risk for relapse and this may also influence anorectic patient’ s resistance to treatment [18].
Difficulties in cognitive flexibility are characteristics of patients with anorexia nervosa and
may account for treatment resistance in these patients [19]. Cogni tive remediation therapy
has been proposed as an adjunctive treatment for patients with anorex ia nervosa. On a scale
measuring existential well being anorexia nervosa participa nts were found to score
significantly lower than age matched controls [20]. The author’s sugges ted that anorexia is a
coping strategy that provides a sense of meaning and identity. Thi s however may cause more
existential anxiety since these individuals would have limited m echanisms for dealing with
this anxiety and make them resistant to treatment efforts.
In a treatment study of binge eating disorder those patients who responded to tr eatment with a
behavioral change had the following 6 attributes; 1) they strongly wanted and intended to
change for clear, personal reasons, 2) they faced a minimum of obstacles to change, 3) the
patient had the requisite skills and self-confidence to make the cha nge, 4) the patient felt
positive about the change and believed it would result in meaningful bene fits, 5) the patient
perceived the change as congruent with self image and social group norms, 6) the patient
received encouragement and support to change from valued persons [21].
Biological features
Considerable evidence for altered brain serotonin and dopamine function fr om brain imaging
is present for AN and BN. Although these alterations have not been shown to be directly
related to treatment resistance, there is evidence they are related to psychological and
behavioral features whose severity is associated with treatme nt resistance. For example,
serotonin transporter function has been related to extremes of impuls e control in BN [22]. A
positron emission tomography (PET) study found interactions between D2/D3 receptor and
serotonin transporter binding were related to harm avoidance. The lat ter is a measure of
inhibition and anxiety [23]. Another study showed increased serotonin 1A r eceptor binding in
recovered bulimics and this positively correlated to harm avoidance i n specific brain areas
[24]. A later study showed ill and recovered BN have altered serot onin transporter binding
which the authors suggest may influence responses to medication [25].
Psychometric studies have linked AN and BN to a cluster of moderately heritable personality
and temperamental traits, such as obsessionality, perfectionism, and harm avoidance [26] A
linkage analysis of an AN cohort containing extreme high ratings for drive-for-thinness and
obsessionality produced a significant linkage at 1q31.1 for those covaria tes. The allele
frequency differences in the GABA receptor SNP, GABRG 1 was found to be related to levels
of trait anxiety in anorexia and bulimia nervosa probands. High anxiety levels are
characteristic and present to a greater degree in persistent ly ill eating disorder probands
compared with those who have recovered. Thus, this GABA receptor aberra tion may be
related to treatment resistance [27]. In a study of behavioral prof iles of anorexia nervosa
probands and their parents, a class was identified of probands with mot her – daughter
symptom severity for eating disorder psychopathology and anxious/perfe ctionistic traits. It
could be hypothesized that these probands may have a genetic propensity for treatment
resistance [28].
Efforts at treating refractory patients
The literature on treating refractory patients consists mainly of suggestions based on
observations of patients. These studies are mostly uncontrolled and with small samples. Over
the past 20 years eating disorder hospital treatment has change d from long term treatment to
stabilization of acute episodes. For treatment resistant patient s this change has been
deleterious and not cost effective as shown in one study with readmis sions changing from 0%
to 27% of total admissions [29]. For anorexia nervosa patients contingenc ies attached to
behavioral goals could be changed or the intensity of treatment increased such as residential
treatment with a daily structure in careful monitoring to prevent readmissions. At times
involuntary hospitalization with enteral feeding may be necessar y. Pharmacotherapies that
have shown some effectiveness in treating resistant anorexia ne rvosa include haloperidol [30]
quetiapine and olanzapine [31,32] and Duloxetine [33]. Several novel psychotherapi es are
being developed for treating resistant anorexia nervosa include the following; 1) Cognitive
Behavioral Therapy Extended [34]: this focuses on addressing predi sposing and maintaining
factors of the eating disorder as well as involving caregiver s to support the patient with
matters regarding food, eating and psychological factors. Cognitive Remediation Therapy
was developed to treat an inflexible thinking style [35]. Modest res ults were obtained.
Another 10 session treatment package that primarily addresses emoti on processing
difficulties in the self and others and includes strategies to ma nage emotions and the practice
of emotion expression has also had modest results. This therapy is c alled Cognitive
Remediation and Emotional Skills Training (CREST) [36]. Maudsley Model for Treatment of
Adults with Anorexia Nervosa (MANTRA) is another form of therap y which addresses rigid
thinking styles with perfectionism and obsessive compulsive personal ity traits and the
avoidance of strong emotional responses to others. It includes motivati onal interviewing and
a CBT framework [37]. Community outreach partnership program (C OPP) has a goal of
improving quality of life and minimizing harm [38]. Specialist support ive clinical
management (SSCM) emphasizes support for changes that will improve quality of life as well
as physical well being. Its aim is to provide a therapeutic match to the chronic patient’s level
of ambivalence [39,40]. It does this by allowing flexibility in t he approach. Strober [41],
advocates a different paradigm in which management replaces tra ditional objectives of
therapy to support the patient in a palliative holding management of carefully measured
intensity. Small steps are taken to partially compensate or cushion the effects of the illness.
This is done by assuring the patient weight gain will not be a principle objection of the
management approach, encouraging the patient to maintain some type o f social activity and
involvement in hobbies, intellectual pursuits or activities that allow for feelings of pleasure. It also requires regular physical exams and exploring possibilities of improvement in nutrition.
In therapy with treatment resistant anorectics Vanderlinden [4 2], emphasizes the quality of
the therapeutic alliance and the timing of therapeutic strateg ies as well as focusing less on the
content of cognitions and more of the emotional involvement with cognitions. He also
emphasizes focusing on dysfunctional cognitions and messages within the family
communications and interactions.
In treating resistant bulimia nervosa patients sequential trea tment is often effective. In one
study [43], 20% of non responders to cognitive behavioral therapy responde d to fluoxetine or
interpersonal therapy at the same rate. Resistant bulimics ma y require a partial hospitalization
or inpatient program for a short period of stabilization. Additional or separate treatment for
comorbid diagnoses with bulimia may be indirectly helpful. Examples are alcoholics
anonymous for those with substance abuse or dialectal behavior therapy for those with
borderline personality disorders. Cue exposure was effectively used to treat resistant
adolescents with bulimia nervosa [44]. The authors emphasize that cue exposure prevented
the binge itself whereas exposure response therapy prevents post bi ngeing behaviors and the
latter has not been effective in treating resistant bulimics.
For binge eating disorder resistant patients a recommendation is suggested of high doses of
SSRIs or the drug topiramate starting at 25 mg daily and increased by 25 mg w eekly [45].
Conclusions
Trait – related multigenic and neurobiological vulnerability when m odulated by
environmental risk factors influence the development of eating disorders and may also
contribute to treatment resistance. These conditions once establis hed are sustained by
conditioned learning and state related pathophysiological changes [ 46]. Since none of the
efforts at treating resistant eating disorder patients have be en dramatically effective, future
investigations of neurobiological factors and neurocircuitry in eati ng disorder patients may
provide information for more successful treatment interventions.
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