Orlistat

Weight gain induced by long-term psychopharmacotherapy has emerged as a relevant clinical issue because it affects compliance and long-term outcome. Weight gain is particularly associated with lithium,1-4 valproic acid,5 other anticonvulsant medications,6 and antipsychotic medications.7,8 Some antidepressants also cause weight gain in some patients.9 To date, no randomized controlled studies demonstrate the efficacy of behavioral treatment for weight gain induced by psychotropic drugs and only few studies address pharmacological treatments. Although several medications have been studied for psychotropic-induced weight gain, including metformin,3-4 phenylpropanolamine,10 and d-fenfluramine," the results have been mixed. As an added concern, anti-obesity agents (e.g., dexfenfluramine, sibutramine) hold potential for exacerbation of psychotic symptoms 12,13 and the potential for serious adverse interactions with psychotropic medications.14

Orlistat (Xenical") is a novel antiobesity drug that selectively inhibits gastrointestinal lipases so fatty foods are excreted and not absorbed.15 Because orlistat is not active in the central nervous system (CNS) and does not affect the plasma concentrations of psychotropic medications,16-18 it is a good candidate for use in a psychiatric patient population. Orlistat is approved by the United States Food and Drug Administration (FDA) for obesity, and has been shown in placebo-controlled studies to be an effective and safe weight loss agent.19-22 One published study examined its use in the treatment of psychopharmacologically-induced weight gain:23 two patients lost 13.5% of their body mass index (BMI) after using orlistat for 12 months. The medication was well tolerated and did not cause a relapse in psychiatric symptoms in either patient.23

MATERIALS AND METHODS

SUBJECTS

Data were extracted from the medical records of fourteen adult outpatients treated in a private psychiatric practice on the Butler Hospital Campus in Providence, Rhode Island. Patients were offered a trial of orlistat if they reported a substantial weight gain with their psychotropic medication, but objective verification of this criterion was not systematically established. Patients gave verbal informed consent for participation and Institutional Review Board (IRB) approval was granted for the chart review.

PROCEDURES

Patients reporting weight gain from use of psychotropic medications were treated with orlistat for up to 50 weeks. The starting dose of 120mg QD was titrated to a maximum of 120mg TID prior to meals, as tolerated. Patients were given a free two-week supply of medication samples and referred to the web-based, industry-sponsored educational program associated with Xenical® (www.xenicare.com) for dietary and nutritional advice. In addition, patients could print out, via the web site, discount coupons for a free three-month supply of pills after purchasing a three-month supply from a pharmacy.

Patients were expected to remain on stable doses of their psychiatric medications; however, the treating psychiatrist occasionally adjusted those medications during the trial. No specific exercise plan was prescribed. Data on individuals' exercise patterns were not obtained.

To capture the experience of the entire sample that began the trial, data were retrospectively divided into "acute" and "chronic" phases of treatment. The acute phase was designated as weeks 0-8, while the extended phase was defined as the start date to the endpoint [established as the time data collection was terminated (49 weeks) or when the patient stopped orlistat].

PATIENT ASSESSMENT

Patients were assessed during routine outpatient visits every 2-4 weeks. At these visits, weight, Clinical Global Impressions Scale (CGI)24 scores for illness severity and clinical change, and side-effect data were collected. A standard balance scale tracked patient weight at each visit.

STATISTICAL ANALYSIS

Paired t-tests compared baseline and endpoint assessments of weight. Side effects, as described by the treating psychiatrist, and other categorical data were analyzed with the Fisher's Exact analysis or Pearson's Chi Square. The relationship between weight and weight change was examined with Pearson's correlation coefficient. A prior alpha was set to 0.05. Positive categorical responses were defined by a CGl score at end-point of 2 ('much improved') or 3 ('very much improved.'), relative to baseline assessments.

RESULTS

DEMOGRAPHICS AND BASELINE CHARACTERISTICS

The mean baseline weight of the group was 206.7±34.5 lbs. (range 152.0 to 269.0 lbs.), corresponding to a mean BMI of 32.1±4.8 kg/m^sup 2^. Nine patients (64%) would be considered 'obese' (BMI greater than 30.0). The mean rating for baseline CGI illness severity for the group was 3.0 ± 0.6, reflecting a moderately ill population. Patients had a mean±SD age of 49.3±6.3 years. Ten patients (71.4%) were female. Twelve patients (85.7%) had a primary diagnosis of a mood disorder; two patients had non-mood disorder diagnosis (schizoaffective disorder and panic disorder with agoraphobia). Concomitant medications included various classes of antidepressants (n=13), benzodiazepines (n=6), atypical antipsychotics (n=5), anticonvulsants (n=4), thryroidsupplements (n=3), lithium (n=1), buspirone (n=1), non-benzodiazepine hyponotics (n=1), and stimulants (n=1).

DURATION OF ORLISTAT TREATMENT AND ENDPOINT DOSE

The orlistat trial lasted 4-49 weeks, with a mean duration of 7.9 ± 2.4 weeks for the acute phase and 22.9 ± 16.4 weeks for the extended trial. The final orlistat dose for the group was 188.6 ± 61.6 mg/day (range 120-240mg/day).

PRIMARY ENDPOINTS

Overall, no differences were found in the change in BMI from baseline to the end of the acute phase (Mean±SD = -2.03 ± 5.2; t=1.89, p = 0.08) or the extended trial (Mean±SD = -5.0 ± 7.5; t=2.2, p=0.06). The majority of patients (10/14 or 71%) lost weight on orlistat, but others experienced weight gain (4/14 or 29%) during the trial. The average weight loss was -6.2% of the baseline BMI, while the average weight gain was +1.55% of the baseline BMI. There was a significant correlation between the duration of the orlistat trial and the change in BMI. Results for the entire group show that weight loss was correlated with duration of orlistat trial (r=0.78, p=0.001) (Figure 1) and age (r=0.75, p=0.001).

In both the acute phase and extended trial, no differences were found between baseline and endpoint CGI severity. However, 7 patients (50%) had improved clinically at the end of the acute phase, and 4 had improved by the end of the extended phase (28.6%). There was no relationship between the severity of illness and weight loss at either the end of the acute phase (p=0.273) or full trial (p=0.926), or between psychiatric diagnosis and weight loss.

ADVERSE EVENTS/ REASONS FOR DISCONTINUING TRIAL

Side effects attributable to orlistat included flatulence and loose stools in three patients. The reasons for drug termination included undesirable side effects or concern over the drug's cost.

DISCUSSION

When all patients in our sample were considered together, orlistat did not produce significant weight loss during a short term (mean, 8 weeks) or extended trial (mean, 23 weeks). A subset of patients, who appeared more motivated for weight loss, were somewhat more successful. Since side effects (e.g. passage of unabsorbed fat and associated gastrointestinal symptoms) are directly related to the intake of fatty foods, those individuals who avoided fatty foods experienced few or no side effects and stayed on orlistat for longer. They also had lost more weight. Prospective and systematic data are needed to determine the variables which predict longer-term compliance. Providing patients with a list of the fat content of foods, supervised administration, or allowing patients to take occasional 'drug holidays' when fatty food intake is unavoidable may enhance compliance.

Limitations of out data include the small sample size, diagnostic heterogeneity, concurrent use of various psychotropic medications (including two patients using topiramate, which has been shown to cause weight loss),26 and the reliance on self-reported history of weight gain secondary to psychiatric medications. In addition, the retrospective nature of this report precluded analysis of the diet and exercise regimes of the participants.

CONCLUSIONS

Orlistat holds the potential to reduce or eliminate weight gain associated with psychotropic drugs in motivated patients. Not only would this have the potential to improve compliance with psychotropic medications, but it also might improve patient's self-esteem and promote a positive self-image. Our findings suggest a large-scale or controlled study would be useful to better delineate the utility of orlistat in treating a very common problem.

ACKNOWLEDGMENTS

A NARSAD Young Investigator Award (LLC) provided partial funding for this research project. Medication samples were provided by Rosche, Inc. The authors gratefully acknowledge Kathleen Reilly for data management support.

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LINDA L CARPENTER MD, JORDAN M SCHECTER MD, JASON SINISCHALCHI MS, ZELKO LEON MD, LAWRENCE H PRICE MD

Linda L. Carpenter, MD, is Chief, Mood Disorders Program, Butler Hospital, and Associate Professor of Psychiatry and Human Behavior, Brown Medical School.

Jordan M. Schecter, MD, is a Research Assistant, Mood Disorders Research Program, Butler Hospital.

Jason M. Siniscalchi, MS, is a Research Data Analyst, Mood Disorders Research Program, Butler Hospital.

Zelko Leon, MD. is Clinical Assistant Professor of Psychiatry and Human Behavior, Brown Medical School.

Lawrence H. Price, MD, is Professor of Psychiatry and Human Behavior, Brown Medical School.

CORRESPONDENCE:

Linda Carpenter MD

Butler Hospital

345 Blackstone Blvd

Providence, RI 02906

Phone: (401)455-6349

Fax: (401) 455-6534

E-mail: Linda_Carpenter_MD@Brown.edu

Copyright Rhode Island Medical Society Dec 2004
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