Association Between Antipsychotics and Body Mass Index When Treating Patients with Tics

Abstract

Objective:

Treatment with antipsychotics can be associated with weight gain, and second-generation (atypical) antipsychotics (SGAs) can increase the risk for diabetes and dyslipidemia. These risks have not been assessed in patients with tics, who receive lower doses than those used to treat psychosis. The objective of this study is to investigate the relationship between antipsychotic use and weight in tic patients and compare the effects of SGAs to first-generation (typical) antipsychotics (FGAs).

Methods:

We studied the association between antipsychotic use and body mass index (BMI) in consecutive patients with tics seen in a specialty Movement Disorders clinic.

Results:

Height and weight were recorded on 198 patients, average age 19.9 years±14.0 years, 128 treated and 70 not treated with antipsychotics. Standardized measures of BMI were significantly higher in the antipsychotic-treated patients compared to the untreated patients (0.56±1.10) treated vs. untreated (−0.31±0.82). This difference remained significant after controlling for age, gender, stimulant medications, and co-morbidities such as attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Concomitant medications did not independently influence weight, and there was no difference between FGAs and SGAs. Antipsychotic dose, expressed in chlorpromazine (CPZ) equivalents, and treatment duration did not influence weight.

Conclusion:

Patients with tics on either FGAs or SGAs have higher BMI values compared to patients on no antipsychotics. Better knowledge of this risk should guide physician decision making when treating patients with tics.

Introduction

T ourette's disorder (TD) is a childhood-onset disorder characterized by motor and vocal tics (American Psychiatric Association 1994). Antipsychotics, with dopamine-blocking properties, are used to treat tics and include both the traditional first-generation (typical) antipsychotics (FGAs) (Shapiro et al. 1989) and the newer second-generation (atypical) antipsychotics (SGAs) (Onofrj et al. 2000; Bruggeman et al. 2001). Other drugs, including clonidine, guanfacine, and benzodiazepine derivatives, are also used, although the evidence base for efficacy is strongest for the antipsychotics (Robertson and Stern 2000). Whereas antipsychotics are effective in suppressing tics, a very high proportion of patients eventually discontinue this therapy, largely because of side effects (Silva et al. 1996). One of the most disturbing side effects of antipsychotics is weight gain. Although frequently observed in clinical practice, weight gain has not been systematically studied in tic patients.

Increasing numbers of reports on obesity, diabetes, and lipid dysregulation in psychiatric patients treated with SGAs have raised substantial health-related concerns (Allison et al. 1999; Allison and Casey 2001; Casey et al. 2004; Newcomer 2005; Newcomer and Haupt 2006). Increased weight is associated with many adverse physiological effects, including decreased insulin sensitivity and changes in plasma glucose and lipid levels (Clinton Smith 2004; Newcomer 2005).

To date, even though several reports document weight gain during antipsychotic treatment in tic patients (Shapiro and Shapiro 1984; Gilbert 2004; Stephens et al. 2004), there are no systematically collected data regarding the association of antipsychotic treatment and weight in tic patients. Additionally, patients with tics usually take lower doses of antipsychotics compared to psychiatric patients and have frequent co-morbidities, such as attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) that can be associated with weight problems, either directly or indirectly through the medications used to treat them.

We conducted a systematic study of weight and height of the patients with tics seen in a movement disorders clinic to determine whether patients on antipsychotic medications are more overweight and obese compared to patients on no antipsychotics. Additionally, we investigated whether patients on FGAs were more frequently overweight and obese compared to patients on SGAs.

Methods

Design

The study population included consecutive patients with chronic tic disorder or TD seen at the Movement Disorders clinic of Rush University Medical Center between March of 2005 and April of 2008. TD and chronic motor or vocal tic disorder were defined according to Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM-IV) criteria (American Psychiatric Association 1994). Both children and adults were included in the study. Patients on antipsychotics were included in the analysis if they were on antipsychotic medications for at least 3 months. Patients in the nontreated group were off antipsychotics for at least 3 months, but could be on other medications, including selective serotonin reuptake inhibitors (SSRIs), stimulants, and alpha-2 agonists. FGAs included pimozide, haloperidol, and fluphenazine. SGAs were classified as SGA-1 (clozapine, olanzapine), SGA-2 (risperidone, quetiapine), and SGA-3 (aripiprazole, ziprasidone).

The study was approved by the Institutional Review Board of the hospital. All weights and heights were assessed during a routine clinical visit. Additional data collected included age, gender, age at tic onset, co-morbid conditions (ADHD, OCD, and affective disorder, including both depression and anxiety disorders), current tic medications, past tic medications, and other current medications used to treat co-morbidities or other medical conditions. The co-morbid conditions were defined according to DSM-IV criteria following an evaluation by our neuropsychologist. Besides DSM-IV and clinical interview, additional tools used by our clinic neuropsychologist were the Hamilton Depression Rating Scale (HAM-D) for adults, Children's Depression Rating Scale, Revised (CDR-R) for children, to assess severity of depression, and the Leyton Obsessional Inventory to assess severity of OCD in children and adults. The Yale Global Tic Severity Scale (YGTSS) was obtained, and the total severity score (0–50) was used as a measure of tic severity.

All antipsychotics were converted to chlorpromazine (CPZ) equivalents (Rey et al. 1989; Woods 2003), and the cumulative dose was calculated as the product of the daily dose (mg) at the time of visit and the duration of treatment with the specific agent (months).

Statistical analyses

Body mass index (BMI) data were calculated from standard conversion charts for height and weight using Centers for Disease Control (CDC) normalized tables as weight in kilograms divided by the height squared in meters. The standardized values for height for individuals over 20 years old were calculated based on the CDC values for individuals between 19 and 20 years of age. Underweight was defined as BMI of less than 18.5, normal weight 18.5–24.9, overweight 25–29.9, and obese >30. All BMI scores were converted to standardized scores (Z scores) based on the mean and standard deviation of BMI in the sample. Frequency counts and chi-squared statistics were used for descriptive purposes. Differences between patients currently receiving antipsychotics versus those not receiving antipsychotics were analyzed using chi-squared, independent sample t-tests, analysis of variance, and analysis of co-variance when appropriate. The influence of age, antipsychotic usage, co-morbid diagnoses (coded as present or absent for OCD, ADHD, pervasive developmental disorder [PDD], affective disorder, psychotic disorder or learning disability), and concomitant medications (coded as present/absent for stimulants, SSRIs, alpha-2 agonists, or benzodiazepines) was assessed using a regression model, with age and antipsychotic usage entered as the first predictor variables and co-morbid diagnoses and concomitant medications entered the next predictor variables. Age was entered as a continuous variable and antipsychotic exposure was entered as present/absent. For all analyses, significance levels were set at an alpha level of 0.05.

Results

We identified 206 patients who met entry criterion on their regular office visit. Of those, 8 did not participate because they had been taking antipsychotics for less than 3 months at the index visit. Of the remaining 198 patients, 40 were female and 158 were male with an average age of 19.9 years±14.0 years (range 5–72 years) and an average age of tic onset of 8.1 years±5.9 years.

In this cohort, 128 (65%) patients were currently not receiving antipsychotic treatment for tics, while 70 (35%) patients were receiving antipsychotic treatment. Only 1 patient on antipsychotics had a history of diabetes. The antipsychotic-treated patients were older than the untreated group (24.8±14.4 vs. 17.3±13.1 years: t[196] = 3.75, p < 0.0005), had an older age of tic onset (9.9±6.7 vs. 7.2±5.0 years: t[196] = 3.25, p = 0.001), they were more likely to be receiving concurrent treatment with a SSRI (46.2% vs. 8.6%: χ² = 34.14, p < 0.0005) and more frequently received a benzodiazepine (18.5% vs. 7.8%: χ² = 3.84, p = 0.05). They were also more likely to carry a concurrent diagnosis of affective disorder (36.6% vs. 18.0%, χ² = 10.18, p = 0.003) or OCD (37.1% vs. 21.9%: χ² = 4.58, p = 0.03). All other demographic and disease-related variables were not significantly different between the groups (Table 1).

Table 1.

Demographic and Disease-Related Differences Between Tourette's Disorder Patients Currently Treated with Antipsychotics Versus Those Not Currently Treated

Variable	Untreated (%)	Treated (%)	t or χ²	p
Age (years)	17.3 (13.1)	24.8 (14.4)	3.75^a	<0.0005
Age-at-onset (years)	7.2 (5.0)	9.9 (6.7)	3.28^a	0.001
YGTSS	16.3 (8.7)	19.1 (9.5)	1.88¹	0.06
Gender	20.3% Female	20.0% Female	<1^b	0.99
Stimulant medication use	9.4%	7.8%	<1^b	0.72
SSRI use	8.6%	46.2%	34.14^b	<0.0005
A² agonist use	16.4%	16.9%	<1^b	0.89
Benzodiazepine use	7.8%	18.5%	3.84^b	0.05
Concurrent diagnosis ADHD	29.7%	34.3%	<1^b	0.46
Concurrent diagnosis OCD	21.9%	37.1%	4.58^b	0.03
Concurrent diagnosis PDD	0.8%	1.4%	<1^b	0.66
Concurrent diagnosis LD	4.7%	11.4%	2.19^b	0.09
Concurrent diagnosis affective disorder	18.0%	38.6%	9.11^b	0.003

Independent t-test.

χ².

Abbreviations: YGTSS = Yale Global Tic Severity Scale; SSRI = selective serotonine reuptake inhibitors; ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive compulsive disorder; PDD = pervasive developmental disorder; LD = learning disability.

Standardized BMI was significantly higher in the antipsychotic-treated patients compared to the untreated patients (0.56±1.10 vs. −0.31±0.82; t[196] = 6.41, p < 0.0005). This difference remained significant after controlling for the effects of age differences between the groups (F[2,195] = 25.62, p < 0.0005). Restricting the sample to those less than 20 years of age did not alter the results (no antipsychotic treatment mean zBMI = −0.22±0.86; antipsychotic treatment mean zBMI = 0.59±1.12: t[134] = 4.47, p < 0.0005). There was no significant difference in standardized BMI measures for the two genders (F[2,194] < 1.00, p = 0.96) in the whole cohort, including both treated and untreated patients. When weight and height were considered independently in both treated and untreated groups, the antipsychotic-treated group had higher weight (p < 0.0005) but there was no difference in height. In the whole sample, 1.5% of patients were underweight, 47.5% were normal weight, and 51% were overweight or obese. When untreated patients were looked at as a group (n = 128), 0.8% were underweight, 57.8% were normal weight, and 41.4% were overweight or obese. In the 70 patients on antipsychotics, 2.9% were underweight, 28.6% were normal weight, and 68.5% were overweight or obese. There were significantly more overweight and obese patients in the antipsychotic-treated group compared to the untreated group (68.5% vs. 41.4%, χ²[3] = 20.00, p < 0.0005).

Recognizing that some patients who were not currently on antipsychotics might have had previous antipsychotic exposure, we compared the standardized BMI of those who had current and/or past exposure (n = 123) to those who had never been exposed to antipsychotics (n = 75). There was still a significant difference in standardized BMI, with the group that had previous or current exposure to antipsychotics (mean = 0.24, ±1.02) scoring significantly higher than the group that had never been exposed to antipsychotics (mean = −0.39, ±0.83); t[196] = 4.53, p < 0.0005).

For those patients receiving antipsychotic treatment, there was no significant difference in BMI between FGAs (n = 34) and SGAs (n = 35) (F[2,65] < 1.0, p = 0.85). Furthermore, there was no difference between SGA-2 and SGA-3 (SGA-2 = 0.62±1.07, SGA-3 = 0.41±1.08: F[2,32] < 1, p = 0.58). There was only a single patient taking SGA-1.

Mean CPZ equivalent dose was 166.41 (standard deviation [SD] 218.13) mg and mean treatment duration was 42.37 (±56.11; range 3–252) months. The doses of the most frequently used antipsychotics were as follows: Pimozide, mean = 3.35, ±3.08; haloperidol, mean = 18.50, ±23.33; Prolixin, 1.60, ±0.49; aripiprazole, 7.60, ±5.55; risperidone 2.02, ±1.60; ziprasidone 85.00, ±47.26; quetiapine137.50, ±69.44.

The influence of antipsychotic treatment duration, cumulative dose exposure, presence of co-morbidities, and concomitant medications on BMI measures was assessed using a regression model. In this model, age was entered as the first predictor variable. Following age, duration of antipsychotic exposure and CPZ equivalents were entered into the model in a stepwise fashion. The overall model was significant (F[1,67] = 19.65, p < 0.005). As expected, age was a significant predictor of standardized BMI (t[196] = 4.43, p < 0.0005), whereas duration of antipsychotic exposure (t[196] < 1.00, p = 0.70), CPZ equivalents (t[196] = 1.12, p = 0.27), presence of co-morbidities (t[196] = 1.07, p = 0.43), and concomitant medications (t[196] < 1.00, p = 68) were not significant predictors.

Discussion

In this consecutive cohort of tic patients seen in a specialty clinic, patients treated with either FGAs or SGAs were significantly heavier than those not treated with this class of medications. Antipsychotic dose, expressed as CPZ equivalents, and cumulative dose, expressed as a function of dose and treatment duration, did not influence these results further. Co-morbidities, such as ADHD, OCD, and affective disorders, did not significantly affect BMI either. Concurrent medications, such as stimulants, SSRIs, alpha-2 agonists, or benzodiazepines did not significantly influence BMI either.

Overweight and obesity are leading public health concerns in the United States and throughout the Western world. Between 1980 and 2002, obesity prevalence doubled in adults aged 20 years or older and overweight prevalence tripled in children and adolescents aged 6–19 years (Flegal et al. 2002; Ogden et al. 2002). During 2003–2004, 66.3% of U.S. adults were overweight or obese using data from the National Health and Nutrition Examination Survey (NHANES) (Ogden et al. 2006). During the last half-century, the epidemic of obesity has been classified as among the biggest health challenges facing our nation. It has been identified as among the most important modifiable risk factors for many disease states. In our sample, 51% were overweight and obese when the whole cohort was considered. When patients not treated with antipsychotics were looked at as a group, 41.4% were still overweight or obese, and when antipsychotic-treated patients were considered, 68.5% were overweight or obese. Of interest, the rate of overweight or obesity in the untreated group is lower than the reported national average. This though should be viewed with caution because our population is both children and adults and no standardized comparison with population means for different age groups was done.

There is considerable evidence, particularly in patients with schizophrenia, that treatment with SGAs can cause a rapid increase in body weight in the first few months of treatment that may not reach a plateau even after 1 year of treatment (Newcomer 2005). When multiple doses assessed in the clinical trial programs are pooled, aripiprazole and ziprasidone (SGA-3) are associated with a mean weight gain of about 1 kg per year, quetiapine and risperidone (SGA-2) with a gain of 2–3 kg over 1 year, and olanzapine (SGA-1) with a gain of >6 kg over 1 year (Newcomer and Haupt 2006).

According to a consensus recommendation by the American Diabetes Association, the American Association of Clinical Endocrinologists, the North American Association for the Study of Obesity, and the American Psychiatric Association, given the serious health risks, patients taking SGAs should receive appropriate baseline screening and ongoing monitoring (American Diabetes Association 2004). Our results indicate that, when treating patients with tics, BMI monitoring should be done with patients treated with either FGAs or SGAs.

The primary limitation of this study is its cross-sectional design, which does not allow us to postulate a causative relation between antipsychotics and weight gain, because we do not have baseline values for weight for the patients treated with antipsychotics. Furthermore, because we are examining a single point in time, we cannot totally account for previously used medications, although patients were included only if they were on the specific treatment arm for at least 3 months prior to the index visit. It is still possible that some of these patients had been on other treatments that could have influenced their weight before the index visit. Adherence/compliance to the prescribed medications was not assessed either, although there was no mention of such an issue in the chart in any of the cases. Furthermore, based on experience with psychiatric patients, although weight increases are greatest over the initial treatment period, weight gain occurs throughout an 1-year treatment period or more (Newcomer 2005). Overall, our mean duration of exposure was 42.37±56.11 months, which would be sufficient to make specific effects evident. Finally, because SGA-1 medications were not used in our clinic, a reflection of clinical practice, the subclass with the reportedly worst impact on weight was not included in the analysis, introducing a possible bias into our results.

When one tries to extrapolate all of the data derived from treating psychiatric patients with antipsychotics to patients with tics and TD, the question arises whether patients with TD bear a different risk burden for weight problems, based on the biology of their disease. Is the metabolic syndrome seen with antipsychotics driven only by the drugs or by disease as well? Are TD patients different in responding to antipsychotics in terms of drug metabolism, dose tolerance, physical exertion due to tics, or presence of co-morbid disorders?

Tic patients usually receive lower doses of antipsychotics compared to psychiatric patients. Although dose calculated as chlorpromazine equivalents did not influence the results in our cohort, our overall dosing range is far below the usual CPZ equivalents of antipsychotics used to treat psychiatric illnesses like schizophrenia and bipolar disorder (BD). Additionally, TD patients have co-morbidities that could influence weight, such as OCD, which can be associated with impulse control problems, and ADHD, which can lead to increased caloric consumption associated with hyperactivity and impulsivity. In our model, however, these co-morbid conditions did not directly influence BMI controlling for effects of age and antipsychotic exposure. Finally, TD patients may be receiving concomitant medications that could affect weight, such as stimulants, SSRIs, alpha-2 agonists, and benzodiazepines. Although benzodiazepines were found to be associated with higher BMI, this association was dependent upon antipsychotic use, and its contribution to the variance was only 1.5%. One can postulate that this statistical artifact is probably a reflection of the use of antipsychotics and is not independently significant. Nevertheless, the presence of a pharmacological effect, i.e., a synergistic effect between the two classes, cannot be excluded.

This study attempts to define the association of FGA and SGA use with weight problems and BMI in patients with tics and TD. To date, there is no systematic report of weight gain as a result of treatment with antipsychotics in TD. Future directions should be geared toward investigating the longitudinal effects of both FGAs and SGAs on weight, blood glucose, and lipid profile in patients with tics. Establishing the effect of treatment with antipsychotics on weight and the metabolic profile of patients with tics will allow clinicians to estimate risk–benefit ratios with more accuracy and breadth than is currently available. This information will facilitate the participation of patients and families in the decision-making process regarding use of antipsychotics and guide the physician on monitoring tools during treatment.

Footnotes

Disclosures

Dr. Kompoliti has received personal compensation from: Glaxo Smith Kline as a speaker, Solstice as a consultant, and Boehringer Ingelheim as a consultant and speaker. She has received research support from TEVA Pharmaceutical, Glaxo Smith Kline, Solstice, and Boehringer Ingelheim. Dr. Stebbins has received personal compensation for consulting from Boehringer Ingelheim and Novartis Pharmaceuticals, and has received research support from the National Institutes of Health (NIH), the Michael J. Fox Foundation, the Fragile X Foundation, and the Kinetics Foundation. Dr. Goetz has received personal compensation for activities with Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc., Ceregene, EMD Pharmaceuticals, Impax Pharmaceuticals, I3 Research, Juvantia Pharmaceuticals, Kyowa Pharmaceuticals, GlaxoSmithKline, Inc., Merck KaGA, Merck & Co., Inc., Neurim Pharmaceuticals, Novartis Ovation Pharmaceuticals, Oxford Biomedica, Schering-Plough Corporation, Solstice Neurosciences, Solvay Pharmaceuticals, Synergy/Intec, and Teva Neuroscience as a consultant and advisory board member. He has received royalty payments from Oxford University Press and Elsevier Publishers and has received personal compensation in an editorial capacity for Movement Disorders. Dr. Goetz has received research support from the National Institutes of Health, Michael J. Fox Foundation, Kinetics Foundation, and the Parkinson's Disease Foundation. Wenqing Fan has no conflict of interest or financial ties to report.

References

Allison

, Casey

. Antipsychotic-induced weight gain: A review of the literature. J Clin Psychiatry, 62,Suppl 7:22–31. 2001.

Allison

, Mentore

, Heo

, Chandler

, Cappelleri

, Infante

, Weiden

. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry, 156:1686–96. 1999.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th(DSM-IV)Washington (DC): American Psychiatric Association, 1994.

American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27:596–601. 2004.

Bruggeman

, van der Linden

, Buitelaar

, Gericke

, Hawkridge

, Temlett

. Risperidone versus pimozide in Tourette's disorder: A comparative double-blind parallel-group study. J Clin Psychiatry, 62:50–56. 2001.

Casey

, Haupt

, Newcomer

, Henderson

, Sernyak

, Davidson

, Lindenmayer

, Manoukian

, Banerji

, Lebovitz

, Hennekens

. Antipsychotic-induced weight gain and metabolic abnormalities: Implications for increased mortality in patients with schizophrenia. J Clin Psychiatry, 65,Suppl 7:4–18quiz 19–202004.

Clinton Smith

. The current epidemic of childhood obesity and its implications for future coronary heart disease. Pediatr Clin North Am, 51:1679–1695. 2004.

Flegal

, Carroll

, Ogden

, Johnson

. Prevalence and trends in obesity among US adults, 1999–2000. JAMA, 288:1723–1727. 2002.

Gilbert

, Batterson

, Sethuraman

, Sallee

. Tic reduction with risperidone versus pimozide in a randomized, double-blind, crossover trial. J Am Acad Child Adolesc Psychiatry, 43:206–214. 2004.

10.

Newcomer

. Second-generation (atypical) antipsychotics and metabolic effects: A comprehensive literature review. CNS Drugs, 19,Suppl 1:1–93. 2005.

11.

Newcomer

, Haupt

. The metabolic effects of antipsychotic medications. Can J Psychiatry, 51:480–491. 2006.

12.

Ogden

, Flegal

, Carroll

, Johnson

. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA, 288:1728–1732. 2002.

13.

Ogden

, Carroll

, Curtin

, McDowell

, Tabak

, Flegal

. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA, 295:1549–1555. 2006.

14.

Onofrj

, Paci

, D'Andreamatteo

, Toma

. Olanzapine in severe Gilles de la Tourette syndrome: A 52-week double-blind cross-over study vs. low-dose pimozide. J Neurol, 247:443–446. 2000.

15.

Rey

, Schulz

, Costa

, Dick

, Tissot

. Guidelines for the dosage of neuroleptics. I: Chlorpromazine equivalents of orally administered neuroleptics. Int Clin Psychopharmacol, 4:95–104. 1989.

16.

Robertson

, Stern

. Gilles de la Tourette syndrome: Symptomatic treatment based on evidence. Eur Child Adolesc Psychiatry, 9,Suppl 1:I60–I75. 2000.

17.

Shapiro

, Shapiro

. Controlled study of pimozide vs. placebo in Tourette's syndrome. J Am Acad Child Psychiatry, 23:161–173. 1984.

18.

Shapiro

, Shapiro

, Fulop

, Hubbard

, Mandeli

, Nordlie

, Phillips

. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry, 46:722–730. 1989.

19.

Silva

, Munoz

, Daniel

, Barickman

, Friedhoff

. Causes of haloperidol discontinuation in patients with Tourette's disorder: Management and alternatives. J Clin Psychiatry, 57:129–135. 1996.

20.

Stephens

, Bassel

, Sandor

. Olanzapine in the treatment of aggression and tics in children with Tourette's syndrome—a pilot study. J Child Adolesc Psychopharmacol, 14:255–266. 2004.

21.

Woods

. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry, 64:663–667. 2003.