Low-Dose Olanzapine Monotherapy in Girls with Anorexia Nervosa,Restricting Subtype: Focus on Hyperactivity

Abstract

Objective:

The aim of this study was to evaluate the efficacy of olanzapine in girls with anorexia nervosa, restricting subtype (ANr).

Methods:

Thirteen patients (mean age 13.7 ± 2.3 years, age range 9.6–16.3 years) enrolled in a multimodal treatment for ANr were evaluated with standardized measures at baseline and after 1 and 6 months after starting low-dose olanzapine monotherapy (mean dose 4.13 mg/day).

Results:

A significant improvement was evident on weight (body mass index, BMI), global functioning (Children's Global Assessment Scale, CGAS), eating attitudes (Eating Attitudes Test-26, EAT-26), anxious-depressive symptoms (Child Behavior Checklist, CBCL) and hyperactivity (Structured Inventory for Anorexic and Bulimic Syndromes, SIAB). At the end of the 6-month follow up, 7 patients were responders according to an improvement of at least 50% in the EAT-26 results. The only measure that improved significantly in responders, but not in nonresponders, was hyperactivity (SIAB). Clinical improvement, in terms of both body mass index (BMI) recovery and global functioning, paralleled the improvement of hyperactivity, was evident at the end of the first month of treatment, and further increased in the following 5 months, with minimal side effects.

Conclusions:

Low-dose olanzapine monotherapy may be useful as adjunctive treatment of youths with ANr. It is suggested that efficacy may be mediated by a decrease of hyperactivity.

Introduction

E ssential features of anorexia nervosa (AN) are the refusal to maintain a minimally normal body weight, an intense fear of gaining weight, and disturbance in experiencing body weight and shape (American Psychiatric Association 1994). In postmenarcheal females, amenorrhea (the absence of at least three consecutive menstrual cycles) is an associated feature. Two different subtypes of the disorders are specified, the restricting type (ANr), in which weight loss is accomplished exclusively through massive reduction of food intake and excessive exercise (hyperactivity), and the binge-eating/purging type, in which binge eating is usually associated with purging through self-induced vomiting or misuse of laxatives and diuretics or enemas (American Psychiatric Association 1994). Convergent evidence confirms that these two subtypes are distinct forms, with specific associated clinical and personologic features, and probably with different biological underpinnings (impulse dyscontrol in binge-eating/purging type vs. perfectionism in restricted subtype) (Kaye and Walsh, 2002).

From the first description of AN (Gull 1888), hyperactivity was considered one of the main symptoms of AN; however, this manifestation was later regarded as a secondary psychopathological manifestation, not included in the main or associated features. Only recently has hyperactivity in AN has become the object of systematic studies (Davis et al. 1994; Hebebrand et al. 2003; Holtkamp et al. 2003; Hillebrand et al. 2005). It is still debated whether hyperactivity is a secondary symptom aimed at consuming calories and losing weight, or if it has a primary and specific role in the clinical picture and outcome of AN (Davis et al. 1994; Davis et al. 1997). Several studies (Epling and Pierce 1988) support the notion that dieting and exercise are “sister activities,” that is, mutually reinforcing and self-perpetuating behaviors. The mutual activation of neurobiologic reward systems is consistent with the observations that hyperactivity is agreeable and rewarding (Gull 1888). Even though, according to this view, hyperactivity may be considered a possible target for the treatment of AN, data on hyperactivity in young adolescents with ANr are still lacking.

Within the context of a multidisciplinary approach, pharmacologic treatment can play an important role in the management of adolescent AN (Kaye and Walsh 2002). Atypical antipsychotics, particularly olanzapine (Barbarich et al. 2004; Dennis et al. 2006; Brambilla et al. 2007; Dunican and Del Dotto 2007; Bissada et al. 2008), have proved to be effective in the management of adolescents with severe AN, even though the main target of this action is still unclear. It has been suggested that olanzapine may improve mood and anxiety, and/or delusional ideation about body image, and/or body weight, food, and calories intake (Davis et al. 2003; Malina et al. 2003; Bissada et al. 2008). Recently an open-label study (Hillebrand et al. 2005) supported the notion that olanzapine may work through its role in reducing physical activity. This study showed that olanzapine treatment reduces development of activity-based anorexia (ABA) in rats and also diminishes activity levels of hyperactive AN patients, but it does not affect body weight.

In our study we have assessed efficacy of olanzapine treatment in a small sample of girls with AN. Compared with other studies, we selected a sample of girls with a narrow age range (9.6–16.3 years). All of the patients presented ANr, and hyperactivity was a major focus of assessment.

Method

Sample

This was a prospective study based on 13 children and adolescents (mean age 13.7 ± 2.3 years, age range 9.6–16.3 years), referred to our Service for Eating Disorders by other hospitals, community-based child psychiatrists, pediatricians, or family members, and enrolled in a multimodal treatment. Inclusion criteria were a diagnosis of ANr according to historical information, symptoms ratings according to the Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM-IV) (American Psychiatric Association 1994), and a structured clinical interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL) (Kaufman et al. 1997). Structured interview diagnoses (AN and co-morbidities) were considered positive only if DSM-IV criteria were met unequivocally, including number of symptoms, duration, and impairment. Exclusion criteria were a diagnosis of mental retardation and/or pervasive developmental disorder and/or schizophrenia and/or other medical diseases. Other demographic and clinical characteristics of the sample are shown in Table 1.

Table 1.

General and Clinical Characteristics of the Sample

Mean age ± SD; age range (years)	13.7 ± 2.3; 9.6–16.3
Mean BMI ± SD; BMI range	13.7 ± 1.5; 10–15.4
Mean age at onset ± SD; age range of onset (years)	12.5 ± 1.9; 9–15
Δt (months) onset − T0 ± SD (range)	15.5 ± 10.3 (2–31)
Co-morbidity axis I (n, %)
Depressive disorder	5 (38.5)
Depressive disorder + anxiety disorder	6 (46.2)
No co-morbidity axis I	2 (15.4)

Abbreviations: SD = Standard deviation; BMI = body mass index.

All patients and their families participated in the study voluntarily after informed consent was obtained for assessment and treatment procedures, including a prospective follow up. The study was approved by the Ethical Committee of our Hospital.

Measures

The K-SADS-PL was administered individually to the children and adolescents participating in the study by trained child psychiatrists during the diagnostic procedure. Additional measures at the beginning of the study and after 6 months were: (1) Height and weight measurements (converted to body mass index [BMI], that is kg/m²); (2) Clinical Global Impressions– Severity (CGI-S) score (Guy 1976), a single item recorded at the baseline that rates the severity of global symptomatology on a scale from 1 (“normal”) to 7 (“extremely ill”); (3) Children's Global Assessment Scale (CGAS) (Shaffer 1983), which describes the severity of functional impairment on a scale from 0 (severe impairment) to 100 (superior functioning), with scores above 70 indicating a normal functioning; (4) Child Behavior Checklist (CBCL) (Achenbach 1991), a scale completed by parents that rates social competences and behavioral features of persons aged between 4 and 18, with scores above 63 indicating a pathological functioning (Total score and Internalizing and Externalizing scores were considered in this study); (5) Eating Attitude Test (EAT-26) (Garner and Garfinkel 1979; Garner et al. 1982; Mintz and O'Halloran 2000), which assesses symptoms and anxiety typical of the eating disorder through 26 items and gives a total score (pathological if it is above 20) and three other scores relating to Oral Control, Dieting, and Bulimic symptoms; (6) Eating Disorder Inventory (EDI-2) (Garner 1991), a self-report instrument with 91 items concerning eating disorder that explores 11 subscales clinically important for eating disorders; (7) Structured Inventory for Anorexic and Bulimic Syndromes–Expert form (SIAB-EX) (Fichter et al. 1998), a semistructured interview with 62 items, one of them defining the excessive exercise, rated on a 5-point scale with probes and prespecified anchors, that assesses planned and spontaneous physical activity within the last 3 months (see Table 2). All of these measures were obtained at baseline and at the end of the 6-month follow up. Additionally, we also obtained BMI, SIAB, and CGAS scoring after 1 month of drug therapy.

Table 2.

Structured Inventory for Anorexic and Bulimic Syndromes-Expert form (SIAB-EX) (Fichter et al. 1998): Definition of the Five Levels of Hyperactivity

• Level 1 No excessive physical activity.

• Level 2 Slight and/or rare excessive physical activity: The person rarely excercises (for example, on weekends or in the evenings) to burn calories or to reduce weight, but can just as well turn to other activities, if they are interesting or appear more important.

• Level 3 Marked and/or occasional excessive physical activity: The person excercises sometimes (up to twice weekly) or with marked vigor, the person may report discomfort when prevented from physical activity, and distraction is possible but is associated with some discomfort.

• Level 4 Strong and/or frequent excessive physical activity: The person objectively excercises very much (every day for >1 hour or three to four times a week for 2 hours or more), and also experiences discomfort when prevented from physical activity.

• Level 5 Very strong excessive physical activity: Excessive physical activity occurs more than once a day or for longer periods (>1.5 hours/day), and the physical activity occurs irrespective of physical weakness and pain.

To identify the effect of olanzapine on symptoms of ANr, and to disentangle it from a general effect of the medication on mood and/or behavior, a specific measure of the eating disorder, the EAT-26, was considered as the primary measure of clinical response. Patients were considered responders when they improved their EAT-26 Total score at least 50%.

Treatment

A week after the beginning of a multimodal treatment, including psychotherapy, psychoeducation, assisted feeding, and prolonged control of somatic conditions, all of the participants began olanzapine monotherapy at a starting dose of 1.25–2.5 mg/day. Eight patients remained at this dosage, while the other 5 patients received a mean dose of 4 ± 3.40 mg/day (range 3.75–12.5 mg/day). Side effects (increase of liver enzymes) occurred in 2 patients and receded after decreasing olanzapine dosage. The final mean dosage in the whole sample was 4.1 ± 2.9 mg/day.

Statistical analysis

Chi-squared analyses were used on categorical variables, and unpaired t-tests were used on continuous variables. The paired t-test was used to measure improvement, whereas the independent samples t-test was used to compare responders and nonresponders. Owing to the multiple comparisons and the number of patients, our results are prone both to Type I and Type II statistical errors. However, given the exploratory nature of this study, we set significance at the 0.05 level, two-tailed, without using a post hoc Bonferroni correction.

Results

To examine efficacy of pharmacotherapy, pre- and posttreatment scores of BMI, CGAS, CGI-S, EAT-26, EDI-2, and SIAB were considered (Table 3). At the 6-month follow up, both BMI score and global measures of functioning (CGAS) and clinical severity (CGI-S) improved significantly (p < 0.001). Both the CBCL Total Score (p = 0.044) and Internalizing Scale (p = 0.034) improved significantly. Even though the improvement was less evident, compared to CGI-S, the two scores switched from the pathological to the nonclinical domain. The EAT-26 total scores markedly improved (p = 0.014), including Dieting (p = 0.047), Bulimic (p = 0.018), and Oral Control (p = 0.014). The EDI-2 showed significant improvement only in two areas, Interoceptive Awareness (p = 0.012) and Impulsivity (p = 0.008). The measure of hyperactivity (according to SIAB-EX) also resulted in significant improvement (p = 0.005).

Table 3.

Comparisons of Measures Between Baseline and 6-Month End Point

	Baseline Mean (SD)	6-month Mean (SD)	t (df )	P
BMI	13.7 (1.5)	16.3 (1.4)	−4.7 (24)	<0.001^*
CGAS	44.2 (7.6)	56.5 (7.5)	−4.2 (24)	<0.001^*
CGI-S	6 (0.6)	4.7 (0.8)	4.6 (24)	<0.001^*
CBCL total	63.4 (7.1)	58.0 (5.6)	2.1 (24)	0.044^*
CBCL internalizing	67.4 (9.5)	60.9 (4.1)	2.3 (24)	0.034^*
EAT-26 total	39.1 (18.9)	21.9 (13.7)	2.6 (24)	0.014^*
EAT-26 Dieting	20.9 (12.4)	12.3 (8.3)	2.6 (24)	0.047^*
EAT-26 Bulimic	5.6 (4.3)	2.1 (2.7)	2.5 (24)	0.018^*
EAT-26 Oral control	12.5 (5.3)	7.5 (4.9)	2.5 (24)	0.014^*
EDI-2 Interoc. Awareness	9.9 (5.3)	5.2 (3.3)	2.7 (24)	0.012^*
EDI-2 Impulsivity	6.9 (3.8)	3.1 (2.6)	2.9 (24)	0.008^*
SIAB-EX	4.5 (.7)	3.2 (1.5)	3.4 (24)	0.005^*

Abbreviations: BMI = Body mass index; CGAS = Children's Global Assessment Scale; CGI-S = Clinical Global Impressions–Severity; CBCL = Child Behavior Checklist (Total score, Internalizing score); EAT = Eating Attitude Test; EDI-2 = Eating Disorder Inventory; SIAB-EX = Structured Inventory for Anorexic and Bulimic Syndromes-Expert form (Hyperactivity). *Significant difference: p < 0.05.

Of note, the course of improvement of BMI, C-GAS, and SIAB hyperactivity scores was parallel; all the three measures significantly improved after only 1 month of olanzapine treatment, and continued to improve in the next 5 months of follow up (Fig. 1). When an improvement in the EAT-26 Total score of at least 50% was considered, 7 patients were responders and 6 were nonresponders. The two groups of patients were compared to explore the underpinnings of clinical response. No significant predictive measures were found (Table 4), but when improvements were considered separately in responders and nonresponders (Table 5), data showed that in the responder group SIAB-EX mean score significantly improved from 4.7 ± 0.5 to 3.0 ± 1.3 (paired t-test, p = 0.008), whereas in nonresponders the improvement was nonsignificant, from 4.3 ± 0.8 to 3.5 ± 1.4 (paired t-test, p = 0.141). As expected, improvement in EAT-26 scores significantly differentiated responders from nonresponders, this measure being the criterion for clinical response (Table 5). All of the other changes from baseline to end point (6-month follow up) did not differentiate responders from nonresponders (Table 5).

FIG. 1.

Longitudinal course of BMI, CGAS, and SIAB-EX (Hyperactivity). (A) BMI course. (B) SIAB-EX course (Hyperactivity). (C) CGAS course. (*) Significant difference: BMI and SIAB, p < 0.005; CGAS, p < 0.000. BMI = Body mass index; SIAB-EX = Structured Inventory for Anorexic and Bulimic Syndromes–Expert form; CGAS = Children's Global Assessment Scale.

Table 4.

Comparisons of Clinical Characteristics in Adolescents Who Responded (n = 7) and Did Not Respond (n = 6) to Pharmacological Treatment

	Responders N = 7	Nonresponders N = 6	t (df )	p
Age, mean (SD)	11.9 (2.4)	13.0 (.7)	−1.0 (11)	0.326
Age at hospitalization, mean (SD)	13.3 (2.9)	14.0 (1.4)	−0.5 (11)	0.627
Mean dosage olanzapine (mg/day)	3.7 (2.1)	4.8 (3.9)	−0.6 (11)	0.549
CGI-S	5.9 (.7)	6.2 (.4)	−0.9 (11)	0.375
SIAB-EX, baseline	4.7 (.5)	4.3 (.8)	1.1 (11)	0.295
SIAB-EX, end point	3.0 (1.7)	3.5 (1.4)	−0.6 (11)	0.579
CBCL Total score, baseline	62.3 (4.3)	64.5 (9.7)	−0.5 (11)	0.597
CBCL Internalizing score, baseline	66.1 (6.9)	68.8 (12.4)	−0.5 (11)	0.630
CBCL Externalizing score, baseline	55.0 (6.9)	55.5 (9.6)	−0.1 (11)	0.915
CBCL Total score, end point	57.8 (5.6)	58.2 (6.0)	−0.1 (11)	0.903
CBCL Internalizing score, end point	60.4 (4.1)	61.5 (4.5)	−0.5 (11)	0.654
CBCL Externalizing score, end point	55.6 (6.0)	54.7 (7.3)	0.2 (11)	0.812
EAT-26 Total, baseline	40.8 (18.6)	37.0 (20.8)	0.4 (11)	0.731
EAT-26 Dieting, baseline	22.1 (12.7)	19.5 (13.1)	0.4 (11)	0.724
EAT-26 Bulimic, baseline	6.6 (4.5)	3.2 (3.5)	1.5 (11)	0.162
EAT-26 Oral control, baseline	12.1 (6.1)	13.0 (4.9)	−0.3 (11)	.778
EAT-26 Total, end point	13.3 (8.7)	32.0 (11.6)	−3.3 (11)	0.007^*
EAT-26 Dieting, end point	7.6 (6.0)	17.8 (7.4)	−2.7 (11)	0.019^*
EAT-26 Bulimic, end point	1.1 (1.2)	3.2 (3.5)	−1.5 (11)	0.162
EAT-26 Oral control, end point	4.4 (3.5)	11.0 (3.9)	−3.2 (11)	0.008^*
EDI-2 Interocept. awareness, baseline	10.3 (3.8)	9.5 (7.0)	−0.3 (11)	0.798
EDI-2 Impulsivity, baseline	6.6 (4.0)	7.3 (3.9)	−0.3 (11)	0.756
EDI-2 Interocept. awareness, end point	5.7 (3.8)	4.7 (2.9)	0.5 (11)	0.610
EDI-2 Impulsivity, end point	2.6 (2.8)	3.8 (2.6)	−0.8 (11)	0.443

Abbreviations: SD = Standard deviation; CGI-S = Clinical Global Impressions–Severity; SIAB-EX = Structured Inventory for Anorexic and Bulimic Syndromes–Expert form (Hyperactivity); CBCL = Child Behavior Checklist (Total score, Internalizing score); EAT = Eating Attitude Test; EDI-2 =Eating Disorder Inventory. *Significant difference: p < 0.05.

Table 5.

Changes from Baseline to End Point in Adolescents Who Responded (n = 7) and Did Not Respond (n = 6) to Pharmacological Treatment (Paired t-Test)

	Baseline	End point	t (df )	p
SIAB-EX
Responders (n = 7)	4.7 ± .5	3.0 ± 1.3	3.2 (6)	0.008^*
Nonresponders (n = 6)	4.3 ± .8	3.5 ± 1.4	1.7 (5)	0.141
CBCL Total score
Responders (n = 7)	62.3 ± 4.3	57.8 ± 5.6	2.0 (6)	0.082
Nonresponders (n = 6)	64.5 ± 9.7	58.2 ± 6.0	1.4 (5)	0.212
CBCL Internalizing score
Responders (n = 7)	66.1 ± 6.9	60.4 ± 4.1	2.3 (6)	0.059
Nonresponders (n = 6)	68.8 ± 12.4	61.5 ± 4.5	1.5 (5)	0.205
CBCL Externalizing score
Responders (n = 7)	55.0 ± 6.9	55.6 ± 6.0	−0.2 (6)	0.836
Nonresponders (n = 6)	55.5 ± 9.6	54.7 ± 7.3	0.2 (5)	0.869
EAT-26 Total score
Responders (n = 7)	40.9 ± 18.6	13.3 ± 8.7	6.2 (6)	<0.001^*
Nonresponders (n = 6)	37.0 ± 20.8	32.0 ± 11.6	1.0 (5)	0.359
EAT-26 D
Responders (n = 7)	22.1 ± 12.7	7.6 ± 6.0	4.4 (6)	0.005^*
Nonresponders (n = 6)	19.5 ± 13.1	17.8 ± 7.4	0.6 (5)	0.598
EAT-26 B
Responders (n = 7)	6.6 ± 4.5	1.1 ± 1.2	3.5 (6)	0.013^*
Nonresponders (n = 6)	4.5 ± 4.0	3.2 ± 3.5	0.9 (5)	0.427
EAT-26 OC
Responders (n = 7)	12.1 ± 6.1	4.4 ± 3.6	6.4 (6)	<0.001^*
Nonresponders (n = 6)	13.0 ± 4.9	11.0 ± 3.9	0.9 (5)	0.387
EDI-2 Impulsivity
Responders (n = 7)	6.6 ± 4.0	2.0 ± 3.2	2.1 (6)	0.077
Nonresponders (n = 6)	7.3 ± 3.9	2.6 ± 2.8	1.9 (5)	0.110
EDI-2 Interoceptive awareness
Responders (n = 7)	10.3 ± 3.8	6.3 ± 3.9	2.4 (6)	0.053
Nonresponders (n = 6)	9.5 ± 7.0	4.7 ± 2.9	2.3 (5)	0.069

Abbreviations: SIAB-EX = Structured Inventory for Anorexic and Bulimic Syndromes–Expert form (Hyperactivity); CBCL = Child Behavior Checklist (Total score, Internalizing score); EAT = Eating Attitude Test; EDI-2 = Eating Disorder Inventory. *Significant difference: p < 0.05.

When the role of olanzapine dosage was considered, by comparing patients assuming lower (1.25–2.5 mg/day) and higher doses of the medication (3.75–12.5 mg/day), no significant differences were found between the two groups both at 1 month and 6 months.

Discussion

The aim of this prospective study was to explore the efficacy (1-month and 6-month follow up) of low-dose olanzapine as adjunctive treatment in the context of a multimodal treatment in girls with ANr. Consistent with other reports (Malina et al. 2003; Barbarich et al. 2004; Spettigue et al. 2008), olanzapine significantly improved several outcome measures, including body weight, eating attitudes, global functioning, and internalizing symptoms. To evaluate the specific effect of olanzapine on the symptoms of the eating disorder, responders were considered according to the improvement on a specific measure of the anorectic symptomatology, the EAT-26. Seven patients (53.8%) improved by at least 50% of their EAT-26 score.

The mechanism of action of olanzapine in AN is still poorly understood. It may be the result of a positive effect of the antipsychotic medication on the “delusional” component of AN, including abnormal perception of body image and the extreme restriction of food intake. Another mechanism may be the direct action of olanzapine on appetite and food intake, a well-known side effect of olanzapine and other antipsychotic agents (Malina et al. 2003; Barbarich et al. 2004). The positive effect of olanzapine on eating attitudes is shown by the improvement of EAT-26, which indicates a better approach to dieting. Interestingly, clinical improvement, assessed with both a global measures of functioning (CGAS) and a specific measure for eating disorder (BMI), paralleled the improvement of hyperactivity, assessed with a structured measure (SIAB-EX), starting at the end of the first month of treatment and further increased in the following 5 months.

Our study suggests that the decrease of hyperactivity may be related not just to a reduction of agitation. First, it can be a result of the reduction of impulsivity, as indicated by the significant decrease on the EDI-2 Impulsivity subscale. Second, as indicated by the changes on the CBCL Internalizing score, it may result from the improvement of the internalizing symptoms (anxiety, depression). It has been suggested that patients with AN may attempt to alleviate anxiety, often associated with AN (Muratori et al. 2004; Godart et al. 2007), through exercising (Malina et al. 2003; Barbarich et al. 2004). The effect of olanzapine on hyperactivity may be related to the metabolic effects of this medication, such as the increase of leptin blood levels (Birkenaes et al. 2009), which are low when excessive exercise co-occurs in acute AN (Holtkamp et al. 2003). Interestingly, in an animal model of semistarvation induced hyperactivity in rats, exogenous application of leptin can completely suppress hyperactivity (Hebebrand et al. 2003).

When responders and nonresponders were compared according to the improvements in measures used in this study, BMI, C-GAS, EDI-2, and CBCL Total, Internalizing and Externalizing scores did not differentiate the two groups, whereas SIAB-EX significantly improved in responders, but not in nonresponders. This finding suggests that: (1) Olanzapine significantly reduces pathological hyperactivity; (2) the positive effect of clinical manifestations of ANr is not mediated by a general effect on mood and/or behavior; and (3) the weight gain may be positively affected by the reduction of hyperactivity (Meheler-Wex et al. 2008).

The hypothesis that olanzapine action is at least partly related to the improvement of hyperactivity may be important for two reasons. First, according to some authors, excessive physical activity is not only a secondary symptom of AN, but it has also an important role in its pathogenesis (Hillebrand et al. 2005); in this perspective, olanzapine action may go beyond a symptomatic effect on weight and influence one of the basic mechanisms of AN (Södersten et al. 2003). Second, excessive physical activity can disturb compliance with other treatments, and its improvement may positively affect the adherence to the treatment strategy of these difficult patients.

Regarding the dosage, we did not find significant differences between lower and higher doses of olanzapine. Consistent with other studies (Meheler-Wex et al. 2008), our data suggest that a 2.5 mg/day dose is effective and well tolerated in young patients with AN and that a higher dosage is not usually associated with a greater efficacy.

Our study presents several methodological limitations. The most important weakness is that this is neither a randomized nor a controlled study. All of the patients received multimodal treatment, including pharmacotherapy with olanzapine, so it may be difficult to disentangle the specific role of the medication in the positive outcome, as well as in the decrease of physical activity. Other mechanisms may have determined a positive effect of olanzapine, such as a direct effect on appetite and metabolism. For this reason, our study can only suggest that olanzapine has at least facilitated some response, such as the reduction in hyperactivity, in the responders. Furthermore, the sample size is small and from a single clinic, and this may limit the generalization of the findings. A possible limitation may be also a referral bias, because our tertiary-level university hospital with a nation-wide catchment may have selected the more treatment refractory patients. Finally, compliance to pharmacotherapy was not monitored through olanzapine blood levels; the medication was given and controlled directly by parents.

The strengths of our study are the sampling (girls younger than under 16 years, all with diagnosis of ANr), the assessment with standardized measures, in different moments (1 month, 6 months), and the specific assessment of hyperactivity. Most other studies explored nonhomogeneous samples in terms of age range and/or diagnosis (Davis et al. 2003; Malina et al. 2003; Meheler-Wex et al. 2008), and the follow up was usually short (Davis et al. 2003; Malina et al. 2003; Meheler-Wex et al. 2008; Spettigue et al. 2008). We believe that a “longer- term” prospective study might represent an important source of information regarding the effectiveness of treatment over extended periods of time under ordinary clinical conditions, and therefore the present findings are of particular relevance to clinical practice in adolescents with ANr.

Footnotes

Disclosure

Dr. Masi is a consultant for Eli Lilly and Shire; has received research grants from Eli Lilly; and has been speaker for Eli Lilly, Sanofi-Aventis, GlaxoSmithKline, Janssen Cilag, and Pfizer.

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