Amantadine for weight gain associated with olanzapine treatment

European Neuropsychopharmacology 15 (2005) 13 – 21 www.elsevier.com/locate/euroneuro

Amantadine for weight gain associated with olanzapine treatment Walter Deberdt a,*, Andrew Winokur b, Patrizia A. Cavazzoni a, Quynh N. Trzaskoma a, Christopher D. Carlson a, Frank P. Bymaster a, Karen Wiener c, Michel Floris d, Alan Breier a b

a Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Drop Code 4133, Indianapolis, IN 46285, USA Department of Psychiatry, Neuropsychopharmacology Treatment, Research, and Training Center, University of Connecticut Health Center, Farmington, CT, USA c Strong Ties Community Support Center, Rochester, NY, USA d Department of Psychiatry, Hospital Notre-Dame, Tournai, Belgium

Received 26 January 2004; accepted 25 March 2004 This manuscript is dedicated to the memory of Dr. Mahmoud Parsa, who died in a car accident during this study. He was a dedicated and passionate researcher and is survived by his wife Shahin and children Morad and Setareh.

Abstract Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score V45]; treated with olanzapine for 1 – 24 months; and who had gained z5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5 – 20 mg/day) was co-administered with double-blind treatment of 100 – 300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 ( P=0.042), 12 ( P=0.029), and 16 (primary endpoint, meanFS.D.: 0.19F4.58 versus 1.28F4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety – depression scores improved comparably in both groups, and Montgomery – Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy. D 2004 Elsevier B.V. and ECNP. All rights reserved. Keywords: Olanzapine; Amantadine; Weight gain; Schizophrenia; Bipolar I disorder

1. Introduction Treatment with many antipsychotics is temporally associated with weight gain (Allison et al., 1999a; Amdisen, 1964; Lamberti et al., 1992; Peuskens, 1995; Tollefson et al., 1997; Wirshing et al., 1999). In addition, patients with mental illness tend to have a higher body mass index (BMI) than the general population (Allison et al., 1999b; Coodin, 2001). Excessive weight gain during antipsychotic therapy is undesirable for many reasons. Obesity is associated with increased rates of morbidity due to hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, and respiratory * Corresponding author. Tel.: +1-317-651-5329; fax: +1-317-2767100. E-mail address: deberdt [email protected] (W. Deberdt).

problems; and also endometrial, breast, prostate, and colon cancers (National Heart, Lung, and Blood Institute, 2003). Furthermore, weight gain temporally associated with antipsychotic treatment in patients with mental illness can lead to decreased quality of life (Strassnig et al., 2003). Most atypical antipsychotics appear to have greater association with weight gain than the majority of the conventional antipsychotics (Allison et al., 1999a). In addition, there are differential degrees of weight gain among patients treated with different atypical antipsychotics (Wirshing et al., 1999). Olanzapine is an atypical antipsychotic approved for the treatment of schizophrenia (Sch) and acute bipolar (BP) mania; similar to treatment with several other antipsychotics, olanzapine treatment is temporally associated with weight gain. In a clinical trial database containing over 3000 subjects (Kinon et al., 2001), the distribution of weight gain in 424 subjects over a 3-year

0924-977X/$ - see front matter D 2004 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2004.03.005

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period during olanzapine therapy showed that 22% either lost weight or did not gain weight, 44% gained up to 10 kg, and 34% gained more than 10 kg. Approximately 7% of subjects gained more than 20 kg over the 3-year follow-up period. The same analysis indicated that the olanzapineassociated weight gain trended toward a plateau after about 9 months of treatment. In addition, low baseline BMI was a predictor of weight gain in patients with an initial BMI lower than 23.6 gaining a mean of 9 kg during the study period and patients with an initial BMI greater than 27.6 gaining a mean of 4 kg (Kinon et al., 2001). The atypical antipsychotics interact with multiple receptors in the central nervous system and the periphery; several of these receptors may be involved in weight gain through the regulation of appetite (increased food intake or decreased satiety) or metabolism (McIntyre et al., 2001; Casey and Zorn, 2001; Baptista et al., 2002). Antagonism of serotonin receptors by atypical antipsychotics may be associated with increased food intake and carbohydrate craving (Kulkarni and Kaur, 2001). In particular, the 5-HT2C receptor subtype has been implicated in clozapine-associated weight gain (Reynolds et al., 2003) and is considered as a target for the treatment of obesity (Bickerdike et al., 1999). Histamine H1receptor antagonism in the hypothalamus of an animal model of genetic obesity has also been implicated in increased food intake (Sakata et al., 1997). In addition, some of the weightinducing effects of histamine antagonism may be mediated through sedation and decreased physical activity. a1-Adrenergic agonists reduce food intake; therefore, antagonism of a1 receptors may increase food intake (Baptista et al., 2002) as well as cause sedation. In addition to direct neurotransmitter receptor interactions that may mediate weight gain temporally associated with antipsychotic treatment, several secondary mediators including prolactin, insulin, leptin, neuropeptide Y, and steroid hormones have also been implicated in weight gain during antipsychotic treatment (Kulkarni and Kaur, 2001; Baptista et al., 2002). Amantadine is an antiparkinsonian drug commonly used for treatment of extrapyramidal side effects associated with antipsychotic drugs (Silver and Geraisy, 1996). It was originally thought to enhance monoaminergic activity by blocking uptake of norepinephrine, serotonin, and particularly dopamine (Herblin, 1972). However, amantadine has also been found to be a moderate affinity non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor complex (Danysz et al., 1997; Kornhuber et al., 1994). In vivo microdialysis studies have shown that amantadine directly increases extracellular dopamine by blocking dopamine uptake and indirectly through blockade of NMDA receptors (Mizoguchi et al., 1994). In addition, another in vivo microdialysis study showed that amantadine also increases serotonin levels in the rat hypothalamus (Baptista et al., 1997). Sibutramine and mazindol (two examples of FDA-approved weight-reducing agents) block the uptake of dopamine, norepinephrine, and serotonin. Based on amantadine’s

ability to modify dopamine and serotonin neurotransmission, it was hypothesized that it may also have weightreducing effects. A small case series and open-label studies have demonstrated the potential of amantadine treatment to limit weight gain or lead to weight loss in patients treated with antipsychotic agents (Correa et al., 1987; Floris et al., 2001; Gracious et al., 2002). Importantly, in three studies, there was either improvement (Correa et al., 1987) or no exacerbation of psychotic symptoms (Silver and Geraisy, 1996; Gracious et al., 2002) in patients co-administered with amantadine. However, in another study, amantadine cotreatment was reported to significantly increase the Brief Psychiatric Rating Scale (BPRS) scores in patients taking relatively low doses of antipsychotic medications (Wilcox and Tsuang, 1990– 1991). Based on the available evidence, amantadine appears to be well tolerated when administered to most antipsychotic-treated patients with stable psychiatric symptoms and may have distinct advantages for treatment of antipsychotic-related weight gain. The primary objective of this study was to examine the efficacy of amantadine to limit or reverse weight gain temporally associated with olanzapine treatment of subjects with schizophrenia, schizoaffective disorder, schizophreniform disorder, or bipolar I disorder. The safety and tolerability of amantadine co-treatment, including effect on stable psychiatric symptoms, were also assessed. Patients enrolled in this study had received olanzapine treatment for 1– 24 months and had gained greater than 5% of their body weight during the first 9 months of olanzapine therapy.

2. Experimental procedures 2.1. Study design This was a randomized, double-blind, parallel study of male and female inpatients and outpatients, 18– 65 years of age. Study participants had a diagnosis of schizophrenia and related disorders (schizoaffective and schizophreniform disorders) or bipolar I disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). They were not acutely psychotic, with a BPRS total score V45, and were not manic, or hypomanic, based on the clinical judgment of the investigator. At the time of study entry, subjects were required to have been treated with olanzapine (5 –20 mg/day) for at least 1 month but no more than 24 months. Patients who experienced weight gain, defined as a weight increase of z5%, during the first 9 months of olanzapine treatment, were eligible to participate in the study. Patients meeting entry requirements were randomly assigned in a 1:1 ratio into two treatment groups: olanzapine 5 – 20 mg/day in combination with amantadine 100 –300 mg/ day (Olz+Amt) or olanzapine 5 –20 mg/day in combination with placebo (Olz+Plc). Amantadine co-treatment was initiated at a dose of 100 mg/day and after 2 weeks, it could be

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increased in 100 mg/day increments to a maximum of 300 mg/day if, in the opinion of the investigator, the subject was safely tolerating the dosage but was not demonstrating an adequate response. Following randomization, all subjects received standardized nutritional counseling but this did not include any behavioral program or diet. After the 16week open-label olanzapine and double-blind amantadine or placebo co-treatment (study period 1), patients were followed in an 8-week double-blind extension period, in which patients continued to receive open-label olanzapine and double-blind co-treatment at the same doses (study period 2). Antidepressants, mood stabilizers (except carbamazepine due to its effect of increasing olanzapine metabolism, potentially decreasing olanzapine’s serum concentration), and anti-diabetic drugs were allowed in this study. However, the patient must have been taking the adjunctive medication for at least 30 days without a change in dose prior to beginning the study and had to continue taking it throughout the study. In addition, if patients in the study took a concomitant drug with a possible weight-gain effect during olanzapine therapy, this effect was required to be judged as minimal by the investigator. Furthermore, if the patient was taking one of these drugs and it was withdrawn or the dose changed, the patient was discontinued. The use of benzodiazepines/hypnotics for anxiety and anticholinergic medications for extrapyramidal symptoms (EPS) was also permitted during the study. Finally, female patients of childbearing potential using a medically accepted means of contraception were included. This study was conducted in accordance with the Declaration of Helsinki. The appropriate Institutional Review Boards approved the study protocol. 2.2. Assessments As the primary determinant of efficacy, subjects were weighed at each visit on the same type of standardized scales. Patients were also monitored for relapse of their primary psychiatric condition and were discontinued if there was any appearance of clinically significant symptoms of relapse. Different psychotic symptoms were examined by administering the BPRS (0 –6 scale), and depressive symptoms were examined with the Montgomery – Asberg Depression Rating Scale (MADRS). Furthermore, changes in the individual BPRS items, as well as in the following BPRS subscales were compared between the treatment groups: BPRS Positive subscale (items 4, 11, 12, and 15), Negative subscale (items 3, 13, and 16), and Anxiety – Depression subscale (items 1, 2, 5, and 9). Extrapyramidal symptoms were assessed by administration of the Simpson – Angus Scale (SAS), the Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS). Blood pressure, heart rate, and ECG were monitored; and corrected QT (QTc) and QRS intervals were calculated, using Fridericia’s (1920) and Bazett’s (1920) formulas. At randomization and during the study, blood samples were

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obtained while patients were under fasting conditions (no food or caloric beverages for at least 7 h prior to sampling); and standard clinical chemistry, liver enzymes, electrolytes, and hematology tests were performed. Leptin, lipid panel (including LDL fractionation and triglycerides), free fatty acids, insulin, fructosamine, and prolactin levels were also determined. 2.3. Statistical methods An analysis of variance (ANOVA) model was used to evaluate the last-observation-carried-forward (LOCF) visitwise change in weight from baseline as the primary measurement of efficacy. The ANOVA model included terms for treatment and investigator. Investigators with fewer than two patients per treatment group were pooled as specified in the protocol. A subgroup analysis for mean change (LOCF) in weight from baseline to endpoint among patients with BMI>30 versus those with BMIV30 was performed. For this subgroup analysis, both the interaction term of therapy by strata and the subgroup term were tested using an ANOVA model with terms for therapy, investigator, strata, and therapy by strata, whereas the strata term was tested using an ANOVA model with terms for treatment and investigator. Visit-wise changes (LOCF) from baseline to endpoint in psychopathology rating scale scores (MADRS total and BPRS total, subtotal, and individual items) were analyzed using ANOVA models with terms for treatment and investigator. These changes were analyzed separately for each of the following three-patient populations: all of the randomized patients, the patients with schizophrenia, and the patients with bipolar I disorder. For analyses of the changes (LOCF) from baseline to endpoint in extrapyramidal symptom scales, vital signs, ECG heart rate and intervals, and fasting laboratory analytes, ANOVA models with terms for treatment and investigator were used to compare treatment-group results. Categorical analyses of treatment-emergent adverse events, treatment-emergent extrapyramidal symptoms, potentially clinically significant changes in vital signs and weight, and change in fasting lipid laboratory values from normal at baseline to abnormal at anytime post-baseline (using criteria for abnormality from the NCEP Cholesterol Guidelines) were evaluated using Fisher’s exact tests. All analyses were done on an intent-to-treat basis. All cited P-values were two-tailed, with a significance level of 0.05 as specified in the protocol.

3. Results 3.1. Patient demographics There were no significant between-treatment-group differences in the distribution of patients with respect to sex, ethnicity, or age. In addition, there were no significant

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differences between treatment groups in the percentage of patients with schizophrenia (or related disorders) (Sch) and bipolar I disorder (BP), the duration of illness, or the duration of olanzapine treatment. Furthermore, there were no significant between-treatment-group differences in baseline weight or BMI and mean weight or BMI change from the start of olanzapine therapy to randomization in this study (Table 1). 3.2. Study medications The mean dose of olanzapine prior to randomization was similar in both treatment groups (Table 2). The mean modal dose of olanzapine during the study (periods 1 and 2) was slightly higher than the mean modal dose before randomization, but this increase was similar in both groups. The distributions of patients by modal dose of olanzapine in both groups and by amantadine in the Olz+Amt group are also presented in Table 2. Use of concomitant medications was not significantly different between treatment groups, except for a greater percentage of the Olz+Plc-treated patients receiving valproate (22% in Olz+Plc group versus 7% in Olz+Amt group, P=0.022). 3.3. Patient disposition A total of 60 patients were randomly assigned to the Olz+Amt group and 65 to the Olz+Plc group. The percen-

Table 1 Patient characteristics Characteristics

Male: n (%) Age: years, meanFS.D. Ethnicity: n (%) Caucasian African American Other Schizophrenia and related disorders: n (%) Duration of illness (years, meanFS.D.) Bipolar I disorder: n (%) Duration of illness (years, meanFS.D.) Duration of olanzapine treatment prior to randomization (weeks, meanFS.D.) Weight change from the start of olanzapine treatment to randomization (kg, meanFS.D.) BMI change from the start of olanzapine treatment to randomization (kg/m2, meanFS.D.) Baseline weight (kg, meanFS.D.) Baseline BMI (kg/m2, meanFS.D.)

Treatment group Olz+Plc (N=65)

Olz+Amt (N=60)

29 (45) 41F12

31 (52) 40F12

56 (86) 7 (11) 2 (3) 33 (51)

46 (77) 12 (20) 2 (3) 36 (60)

16F13

15F12

32 (49) 19F12

24 (40) 18F13

39F29

34F29

11.4F8.9

10.7F6.8

0.05F0.36

0.06F0.41

92.0F19.0 31.80F6.20

90.0F20.0 30.40F6.10

Olz, olanzapine; Plc, placebo; Amt, amantadine; BMI, body mass index.

Table 2 Study treatments Doses

Treatment group Olz+Plc (N=65)

Olz+Amt (N=60)

Olanzapine Dose at baseline (mg, meanFS.D.) Dose during the study (mg, mean modalFS.D.) Modal dose <10 mg 10 mg 15 mg 20 mg

10.7F5.1 11.6F5.5 26.1% 30.8% 26.2% 16.9%

12.3F5.1 13.3F5.7 18.3% 31.7% 16.7% 33.3%

Amantadine Dose during the study, mg, mean modalFS.D. Modal dose 100 mg 200 mg 300 mg >300 mg

– – – – –

235.6F87 23.7%a 18.6% 55.9% 1.7%

The en-dash ( – ) indicates ‘‘not applicable’’. Olz, olanzapine; Plc, placebo; Amt, amantadine. a These percentages do not add up to 100% due to rounding.

tages of patients discontinuing the study for various reasons are presented in Fig. 1. There were no significant betweentreatment-group differences in the percentage of patients discontinuing due to adverse events [Olz+Plc (9%) versus Olz+Amt (13%)]. Although the total number of discontinuations in the Olz+Amt group was numerically greater, more patients in the Olz+Plc group discontinued treatment in the very beginning of the study (week 1; Olz+Plc, 5 versus Olz+Amt, 1). Total discontinuations (Sch, 34.8% versus BP, 66.1%; P<0.001) and discontinuations due to adverse events (Sch, 5.8% versus BP, 17.9%; P=0.046) were significantly greater in patients with bipolar I disorder compared with patients with schizophrenia and related disorders.

Fig. 1. Patient discontinuations (study periods 1 and 2); N=125. Other=lost to follow-up, sponsor decision, and physician decision. Abbreviations: Olz=olanzapine; Plc=placebo; Amt=amantadine.

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3.4. Weight change The primary outcome of this study was amantadine’s effect on weight change during ongoing olanzapine therapy. In both treatment groups, mean weight remained relatively stable for the first 4 weeks of the study (Fig. 2). At weeks 5 and 6, weight remained stable in the Olz+Amt group, while weight began to increase above baseline weight in the Olz+Plc group. The last-observation-carried-forward analysis showed that weight change from baseline in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 ( P=0.042), 12 ( P=0.029), and 16 (primary endpoint; Olz+Amt, 0.19F4.58 kg versus Olz+Plc, 1.28F 4.26 kg, P=0.045). Weight change was minimal between week 16 and week 24 in both treatment groups; however, the difference between treatment groups was no longer statistically significant at week 24 (Fig. 2). On average, amantadine co-treatment limited weight gain in patients with a baseline BMIV30 (Olz+Plc, n=39 and Olz=Amt, n=26), while it led to weight loss in patients with a baseline BMI>30 (Olz+Plc, n=25 and Olz=Amt, n=33) (Fig. 3). In patients with a baseline BMI>30, the change in weight from baseline was significantly different in Olz+Amt-treated patients versus Olz+Plc-treated patients ( P=0.046). Similar weight changes occurred in patients with schizophrenia (and related disorders) and bipolar I disorder. 3.5. Psychiatric symptoms An important finding in the present study is that the enhanced catecholamine (particularly dopamine) neurotransmission during amantadine co-treatment did not worsen psychotic, manic, or anxiety symptoms. The stability of psychiatric symptoms was monitored in patients by admin-

Fig. 2. Weight change during study period 1. N=123; Olz+Plc, n=64; Olz+Amt, n=59. Data are presented as meanFS.D. Abbreviations: Olz=olanzapine; Plc=placebo; Amt=amantadine.

Fig. 3. Mean weight change in patients (by BMI; study period 1). N=123; Olz+Plc, n=64; Olz+Amt, n=59. Data are presented as meanFS.D. P=0.041 (Fisher’s exact test), baseline BMI>30 versus baseline BMIV30. Abbreviations: Olz=olanzapine; Plc=placebo; Amt=amantadine; BMI=body mass index.

istering the BPRS during study periods 1 and 2. In both treatment groups, mean endpoint BPRS total scores were slightly lower than baseline, and this improvement was not significantly different between treatment groups (Fig. 4). The change in BPRS total score was not significantly different between treatment groups when patients with schizophrenia (and related disorders) or bipolar I disorder were analyzed separately (Sch, meanFS.D.: Olz+Amt, 2.0F6.5 versus Olz+Plc, 2.8F8.6; BP, meanFS.D.: Olz+Amt, 1.8F7.4 versus Olz+Plc, 0.03F8.6). Moreover, the within-group, baseline-to-endpoint change in BPRS total score in BP patients treated with Olz+Amt was not significant. There were no significant differences between treatment groups in baseline-to-endpoint changes in the BPRS Positive, Negative, or Anxiety – Depression subscales, or in any of the individual BPRS items.

Fig. 4. Baseline and endpoint BPRS total scores. N=120; Olz+Plc, n=63; Olz+Amt, n=56. Data are presented as meanFS.D. Abbreviations: Olz=olanzapine; Plc=placebo; Amt=amantadine; BPRS=Brief Psychiatric Rating Scale.

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Depressive symptoms were monitored by administering the MADRS during study periods 1 and 2. There was no significant difference in the baseline-to-endpoint change in MADRS total score between treatment groups (Fig. 5). In patients with schizophrenia or related disorders, endpoint MADRS total scores were lower than baseline scores; this improvement was significantly greater in the Olz+Amt group compared with the Olz+Plc group (meanFS.D.: Olz+Amt, 2.4F6.0 versus Olz+Plc, 0.6F6.4, P=0.047). In patients with bipolar I disorder, the mean endpoint MADRS total score was higher in both treatment groups but this increase was not significantly different between treatment groups. 3.6. Safety measures There was no significant difference between treatment groups in the percentage of patients with any adverse events ( P=1.00). Adverse events that were reported significantly more often in the Olz+Amt treatment group compared with the Olz+Plc group were insomnia (22% versus 6%, P=0.017) and upper abdominal pain (7% versus 0%, P=0.028). Fatigue was reported significantly more often in the Olz+Plc treatment group compared with the Olz+Amt group (9% versus 0%, P=0.050). In addition, adverse events occurring in 10% or more of patients were headache in the Olz+Plc group and insomnia, decreased appetite, anxiety, diarrhea, dizziness, dry mouth, and constipation in the Olz+Amt group. There was no indication of an increased risk for deterioration of psychiatric symptoms in the Olz+Amt group. In both treatment groups, there were reported cases of worsening of schizophrenia (Olz+Amt, 2 versus Olz+Plc, 1), worsening of mania (one in each treatment group), worsening of depression (Olz+Amt, 2 versus Olz+Plc, 1), and suicide attempts (Olz+Amt, 1 versus Olz+Plc, 2). Baseline-to-endpoint changes in SAS, BAS, or AIMS scores did not differ significantly between treatment

Fig. 5. Baseline and endpoint MADRS total scores. N=118; Olz+Plc, n=62; Olz+Amt, n=56. Data are presented as meanFS.D. Abbreviations: Olz=olanzapine; Plc=placebo; Amt=amantadine; MADRS=Montgomery – Asberg Depression Rating Scale.

Table 3 Frequency of abnormal values at anytime during treatment in patients with normal baseline values Olz+Plc

High cholesterol, z6.21 mmol/l High triglycerides, z2.26 mEq/l High glucose, z6.99 mmol/l Weight gain >7% Weight loss >7%

Olz+Amt

P-value

N

n

%

N

n

%

18

2

11.1

25

1

4.0

0.562

22

8

36.4

23

4

17.4

0.189

48

6

12.5

52

3

5.8

0.305

64 64

6 3

9.4 4.7

59 59

5 7

8.5 11.9

1.00 0.193

groups. There were four cases of treatment-emergent dyskinesia in the Olz+Amt group versus none in the Olz+Plc group ( P=0.046). Two of these cases resolved during the study and two remained at endpoint (Olz+Amt versus Olz+Plc, respectively; P=NS). There were no significant baseline-to-endpoint changes or between-treatment group differences in heart rate and QTc or QRS intervals. In addition, patients experienced no significant between-treatment-group changes in standing and supine diastolic and systolic blood pressures. Majority of the patients presented some lipid abnormalities at baseline. Lipid values slightly improved in the Olz+Amt group, but this change was not significantly different from the Olz+Plc group, where these values remained essentially unchanged. Baseline and endpoint mean fasting glucose levels (range, 93.6 – 106.5 mg/dl [5.2 – 5.9 mmol/l]) were within the normal range. In both treatment groups, patients experienced a similar small, non-significant decrease in glycemia. Table 3 presents the total number of patients in each treatment group with normal baseline values (N) and the number (n) and percentage (n/N) of patients who developed abnormal elevations in lab values at anytime during the study. In the minority of patients who had normal fasting cholesterol and triglyceride values at baseline, there were no significant between-treatment-group differences in the percentage of patients developing abnormal lab values (The Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001) at anytime during the study (Table 3). In addition, there were no significant differences in the percentage of patients who developed elevated fasting glucose (z6.99 mmol/l) or experienced clinically significant weight gain (>7%) between treatment groups (Table 3). Furthermore, a greater percentage of Olz+Amt-treated patients experienced clinically significant weight loss (>7%) than Olz+Plc-treated patients; however, the difference was not significant between treatment groups (Table 3). There were also no clinically significant changes within treatment groups or significant betweentreatment-group differences in other lab parameters, including standard biochemistry, prolactin, leptin, fructosamine, and insulin.

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4. Discussion Many antipsychotics are temporally associated with weight gain during treatment of psychiatric disorders. The weight gain may be associated with increased appetite or decreased satiety and is potentially mediated via serotonergic, histaminergic, or dopaminergic receptor pharmacology (McIntyre et al., 2001; Casey and Zorn, 2001; Baptista et al., 2002). It would be advantageous to identify the drugs that produce weight loss in patients who have significant weight gain during antipsychotic therapy. Potentially, these agents may also be used to prevent or limit weight gain from the initiation of treatment. Several case reports or case series and a few controlled clinical trials regarding antipsychotic agents have shown some efficacy in treating patients with weight gain temporally associated with antipsychotic treatment. The degree of weight change in these studies varied widely from attenuating weight gain to a rate of weight loss of more than 4 kg/ month. Adult patients treated with amantadine lost a mean of 3.7 kg over 3 weeks during one small open-label study (Correa et al., 1987) and lost a mean of 3.5 kg over 3 –6 months of treatment in another open-label study (Floris et al., 2001). The degree of weight loss during treatment with amantadine in children and adolescents was more modest with the average loss of 0.7 kg over a mean treatment duration of 14.5 weeks (Gracious et al., 2002). In a small double-blind trial, reboxetine, a norepinephrine selective reuptake inhibitor, attenuated weight gain temporally associated with open-label olanzapine treatment in non-obese patients with schizophrenia. Patients treated with reboxetine gained significantly less weight than the placebo group (reboxetine, 2.45F2.72 kg versus placebo, 5.45F3.09 kg) with no significant between-treatment-group differences in the improvement in psychotic symptoms (Poyurovsky et al., 2003). Drugs having mechanisms of action other than influencing catecholamine neurotransmission can also be effective weight-loss agents in patients with mental illness. The anticonvulsant topiramate has been temporally associated with weight loss in patients co-administered the drug with a mood stabilizer or antipsychotic. The rate of weight loss during topiramate treatment varied from 0.9 to 4.2 kg/month in individual case reports (Dursun and Devarajan, 2000; Littrell et al., 2001; Levy et al., 2002; Chengappa et al., 2002). In a chart review of an open-label, non-randomized study, patients treated with topiramate (duration of treatment, meanFS.D.: 131F78 days) lost a mean weight of 1.2F6.3 kg (Chengappa et al., 2001). In another open-label study, patients treated with topiramate lost a mean weight of 6.2F7.5 kg over a 1-year period (McElroy et al., 2000). The histamine H2-receptor antagonist nizatidine has shown some promise in treating weight gain associated with olanzapine treatment. A case report of a patient with schizophrenia describes weight loss after addition of nizatidine to ongoing olanzapine treatment (Sacchetti et al.,

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2000). Weight loss (mean 2.4 kg) was also observed in an 8-week, open-label study of Korean patients with schizophrenia (Pae et al., 2003). In one double-blind trial examining Turkish patients with schizophrenia, addition of nizatidine to olanzapine treatment was associated with significant weight difference ( 4.5F2.2 kg) compared with placebo-treated patients (2.3F0.9 kg) (Atmaca et al., 2003). Another placebo-controlled study of olanzapine with double-blind nizatidine treatment showed that nizatidine at 300 mg b.i.d. was associated with less weight gain than 150 mg nizatidine b.i.d. or placebo treatments (Cavazzoni et al., 2003). Of the three prospective studies, the two that reported weight loss following addition of nizatidine (Pae et al., 2003; Atmaca et al., 2003) contained patients with normal or near-normal BMI (25 – 27 kg/m2). The mean weight of patients in the study that showed attenuation of weight gain (Cavazzoni et al., 2003) was approximately 10 kg higher than the other two prospective studies. Orlistat, a pancreatic lipase inhibitor that prevents absorption of lipids in the gastrointestinal tract, has been reported to decrease BMI in a patient with bipolar I disorder ( 4.9 kg/m2 after 12 months) and a patient with schizophrenia ( 3.3 kg/m2 after 3 months) (Anghelescu et al., 2000). Metformin, an anti-diabetic agent used to treat insulin resistance, has been shown to promote weight loss ( 2.9F3.1 kg after 12 weeks) in a small open-label study of pediatric patients administered psychotropic drugs (Morrison et al., 2002), but not in a small placebo-controlled, crossover study of women with schizophrenia (Baptista et al., 2001). In this study of patients with schizophrenia, schizophreniform disorder, schizoaffective disorder, or bipolar I disorder, the difference in weight change between the Olz+Amt and Olz+Plc treatment groups was modest. The weight increase in the Olz+Plc group was small (1.3F4.3 kg), potentially because the weight of many patients had already stabilized (Kinon et al., 2001) or because of the early discontinuation of some patients in the Olz+Plc group who may have been unsatisfied with the degree of weight loss. The latter hypothesis is supported by the fact that a significantly different endpoint weight was achieved in a small study (N=35) of nizatidine for the treatment of weight gain associated with olanzapine, where all placebo patients and all but one nizatidine patient completed the study (Atmaca et al., 2003). Moreover, because the mean BMI at baseline of the Olz+Amt group was slightly lower than in the Olz+Plc group ( 1.3 kg/m2), the Olz+Amt group was at a higher risk for weight gain (Kinon et al., 2001). Despite this increased risk, amantadine appeared to prevent further weight gain. After the primary endpoint at 16 weeks, the difference in mean weight change between treatment groups was not significant. Since the average weight did not change much during this study period, the loss of significance can be attributed to the increased variability of the weight change, which may be related to an increasing number of study discontinuations. Amantadine induced some weight

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W. Deberdt et al. / European Neuropsychopharmacology 15 (2005) 13–21

loss in obese patients (BMI>30); while in overweight patients (BMI=25 – 30), amantadine limited additional weight increase. This suggests that amantadine might be effective in attenuating or preventing weight gain earlier in the course of olanzapine treatment. A few limitations of the present study warrant discussion. The duration of olanzapine treatment prior to initiation to amantadine was relatively longer in most patients (Table 1) and only a few patients had a normal weight at the start of amantadine treatment. Because of these factors, this study was unable to address questions regarding the prevention of weight gain from the start of olanzapine therapy. The large number of dropouts early in the study may have led to an underestimation of amantadine’s effect on weight gain. The study also did not collect data on the effect of discontinuing amantadine treatment on subsequent weight gain. The higher frequency of valproate use in the placebo group might have been associated with more weight gain; however, limited weight gain was observed in this treatment group (Fig. 2). Finally, the tolerance and safety of amantadine cotreatment in acutely ill patients have not yet been evaluated and additional studies are needed to establish the overall safety and tolerability profile of amantadine in combination with antipsychotic treatment. Amantadine treatment of patients with severe acute symptoms or in combination with drugs with less antipsychotic activity (Davis et al., 2003) might be associated with a greater risk for exacerbation of psychotic symptoms, but this possibility awaits systematic assessment in randomized controlled trials. Weight-loss agents that act on the central nervous system may have the disadvantage of interfering with the dopaminergic antagonism possessed by antipsychotic medications, potentially resulting in an exacerbation of psychotic or manic symptoms. Amantadine has been used to control extrapyramidal symptoms in antipsychotic-treated patients by a mechanism thought to involve inhibition of dopamine reuptake and indirectly enhancing dopamine synaptic levels by antagonism of NMDA receptors. Thus, amantadine may be a unique agent from this class of drugs because in several studies it did not exacerbate psychosis when added to antipsychotic drug treatment (Correa et al., 1987; Silver and Geraisy, 1996; Gracious et al., 2002). In a study that reported an increase in psychiatric symptoms (Wilcox and Tsuang, 1990 –1991), the mean antipsychotic dose was very low (15.4 chlorpromazine equivalents), and the best predictor of increases in BPRS scores was greater symptom severity prior to amantadine co-treatment. There have been reports of onset or exacerbation of psychotic symptoms (including auditory hallucinations, paranoid delusions, suicidal ideation, agitation, and hostility) temporally associated with topiramate therapy in patients with and without a history of psychosis (Khan et al., 1999; Matthews and Miller, 2001). Orlistat may have an advantage as a weight-loss agent in this patient population because it has no central nervous system activity. However, it requires a low-fat diet and has been associated with gastrointestinal

side effects of bloating, cramping, oily discharge, and diarrhea. In this study with patients who were not acutely psychotic, manic, or hypomanic, amantadine (100 – 300 mg/ day) was safe, well tolerated, and did not impair the therapeutic effects of olanzapine (5– 20 mg/day). More prospective, long-term, controlled clinical trials are needed to determine the efficacy and safety of individual weight-loss drugs concomitantly administered with antipsychotic agents in patients with serious mental illness and to evaluate whether the weight loss observed is correlated with decreased obesity-associated comorbidities, enhanced quality of life, and better long-term outcomes. As such, amantadine warrants further study as a potential tool for weight control in patients with schizophrenia, schizophreniform disorder, schizoaffective disorder, or bipolar I disorder.

Acknowledgements This work was sponsored by Eli Lilly and Company. The authors would also like to thank Theresa Bauer and David Burnham for their assistance in coordinating the study.

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