Abstract
To The Editor:
T
Topiramate, an FDA-approved anticonvulsant for epilepsy treatment and migraine prophylaxis, has also been shown to be effective for treating several psychiatric disorders. Appetite suppression and weight loss are commonly seen as “side effects” in patients treated with topiramate.
Studies of the safety and effectiveness of topiramate in subjects with ASD have yielded inconsistent results. An open-label retrospective study (mean duration of treatment=25±16 weeks) was conducted on 15 children and adolescents with ASD who were treated with topiramate (mean daily dose=235±88 mg) (Hardan et al. 2004). Eight subjects had a favorable response to topiramate, with lessening of irritability, hyperactivity, and inattention. Three subjects discontinued the medication because of treatment-limiting side effects, including disorientation and skin rash. Side effects of “cognitive dulling” were described in two subjects, including impaired concentration and memory, clouded thinking, and word-finding difficulties. Subjects in this study lost an average of 0.64 kg of weight.
To evaluate the use of topiramate to reverse antipsychotic-associated weight gain in children and adolescents with ASD (and intellectual disability), a prospective open-label study was conducted on 10 subjects (mean age, 12.6 years) (Canitano 2005). Eight of the subjects were undergoing long-term treatment with risperidone, and one was receiving pimozide; the other subject was not on an antipsychotic, but had a history of prior use. The total observation period was 18 months. The starting dose of topiramate was 0.5 mg/kg/day and the dose was increased by 0.5 mg/kg weekly to a maintenance dose of 1–3 mg/kg/day, although one subject was treated with a higher dose of up to 6 mg/kg/day. The average daily dose of topiramate was 2.1 mg/kg. Four participants dropped out of the study after 1–2 weeks. Three of these discontinued treatment because of adverse behavioral effects, and one discontinued because of minimal response. Behavioral side effects included increases in psychomotor agitation, hyperactivity, and irritability. Of the six participants who completed the study, two showed significant weight loss (4.5–5 kg), two had only moderate weight reduction, and two gained weight after add-on therapy with topiramate.
An 8-week double-blind, placebo-controlled trial was conducted on 40 children and adolescents with ASD to determine the benefit of adding topiramate to risperidone for treatment of symptoms of irritability (Rezaei et al. 2010). Participants were randomly assigned to either receive “risperidone+topiramate” or “risperidone+placebo” from the beginning of the trial. The dose of risperidone was based on the patients' weight, with a maximum daily dose of 2 mg for patients weighing between 10 and 40 kg and a maximum daily dose of 3 mg for patients weighing >40 kg. The maximum daily dose of topiramate was 200 mg. “Risperidone+topiramate” resulted in a significantly greater reduction in irritability, stereotypic behavior, and hyperactivity than “risperidone+placebo.” There was a higher frequency of somnolence and decreased appetite among the topiramate group, but the amount of weight loss was not quantified.
To date, there are no reports describing the effective use of topiramate for weight loss in young adults with ASD. We present two cases of the use of topiramate in young adult women with ASD and concurrent mood disorder, in order to show that it can be highly effective for weight loss in this patient population, with minimal side effects, including a lack of “cognitive dulling.”
Case Reports
Case 1
Ms. A was a 19-year-old female with Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) diagnoses of ASD and cyclothymic disorder (American Psychiatric Association 2013). Her full scale intelligence quotient (IQ) was 108 on the Wechsler Intelligence Scale for Children, 4th ed. (WISC-IV), with a greater verbal than performance split. She presented with a history of aggression towards other, particularly her mother, as well as property destruction and temper tantrums. These symptoms of irritability began when she was 12 years old, and had led to inpatient psychiatric hospitalizations. Ms. A had also struggled with chronic depression and rapid fluctuations in mood. Previous psychotropic medication trials of adequate duration included atomoxetine, methylphenidate extended-release (ER), lisdexamfetamine dimesylate, guanfacine, citalopram, escitalopram, clomipramine, mirtazapine, aripiprazole, risperidone, and lithium. All trials were discontinued because of lack of effectiveness and/or treatment-limiting side effects. Aripiprazole, risperidone, and lithium led to significant weight gain, although the exact amount was not quantified.
At baseline, at the initiation of treatment with topiramate, Ms. A's medications included bupropion 75 mg b.i.d. for depression, fluvoxamine 200 mg daily for anxiety, methylphenidate ER 36 mg daily for inattention and “fidgetiness,” and guanfacine ER 2 mg daily for motor hyperactivity. She was also taking divalproex sodium 1500 mg daily, quetiapine 200 mg daily, and quetiapine XR 400 mg daily for irritability. Before beginning treatment with topiramate, Ms. A weighed 83.73 kg. Her body mass index (BMI) was 31.7 kg/m2, classifying her as obese. She reported being bullied and teased at school because of her obesity.
Topiramate was begun at 25 mg daily for 1 week, and was then increased by 25 mg per week in a twice-daily dosing schedule. The maximum daily dose of topiramate was 75 mg b.i.d. and was in addition to the medications Ms. A was taking concurrently, which have been described. After 17.5 months of treatment with topiramate, Ms. A's weight dropped from 83.73 kg to 46.27 kg, for a total weight loss of 37.47 kg. Her BMI dropped to 17.8 kg/m2 (Table 1). She experienced no side effects from topiramate other than reduced appetite and weight loss. Specifically, no cognitive dulling was noted either on mental status examination, or through reporting by family members or school personnel. As a result, in part because of improved behavioral symptom control, Ms. A was transitioned to a different school and placed in a classroom with higher functioning students. She was noted to be less argumentative with her mother, and was less irritable and aggressive. Subsequently, over the course of treatment, the dose of topiramate was gradually decreased to 50 mg b.i.d., then to 25 mg b.i.d., and then eventually discontinued because of continued weight loss and the patient's having achieved a BMI within the normal range.
Weight loss noted after initiating adjunctive treatment with topiramate in two young adult women with autism spectrum disorder and concurrent mood disorder.
BMI, body mass index.
Case 2
Ms. B was a 20-year-old female with DSM-5 diagnoses of ASD, cyclothymic disorder, and mild intellectual disability. She did not have a history of physical aggression or temper tantrums, but did exhibit frequent mood swings and significant verbal aggression. Ms. B would also become preoccupied with particular topics, such as polar bears. She did not like change, did poorly with transitions, and engaged in repetitive questioning when anxious. Previous adequate psychotropic medication trials administered when she was in elementary school included methylphenidate, methylphenidate ER, and dextroamphetamine, which were ineffective for treatment of inattention and motor hyperactivity.
At baseline, at initiation of treatment with topiramate, Ms. B's medications included fluvoxamine 150 mg daily for irritability, dysphoric mood, and anxiety; metformin 500 mg t.i.d. for insulin resistance, and norgestimate and ethinyl estradiol for regulation of menstrual cycles. Before treatment with topiramate, Ms. B weighed 87.36 kg. Her BMI was 33.1 kg/m2, classifying her as obese. She was noted to have a ravenous appetite and her mother had a difficult time controlling her food intake.
Topiramate was begun at 25 mg twice daily for 1 week, and then increased in 25 mg increments each week to a maximum daily dose of 400 mg divided b.i.d. After 24 months of treatment with topiramate, Ms. B's weight decreased from 87.36 kg to 61.82 kg, representing a 25.54 kg weight loss. Her BMI after treatment was 23.4 kg/m2 (Table 1). Other than reduced appetite and weight loss, there were no reported side effects from topiramate, and there was no appreciable change in her clinical or functional cognitive ability. The dose of metformin was able to be reduced because of the patient's weight loss, and was eventually discontinued. In addition, the fluvoxamine was gradually reduced and discontinued with no increase in irritability, dysphoria, or anxiety.
Discussion
This report illustrates the effective use of topiramate for weight loss in two young adult women with ASD and concurrent mood disorder. Previous studies on the use of topiramate for weight control in subjects with ASD have not only produced inconsistent results, but have been limited to children and adolescents.
Drugs other than topiramate have been studied for the treatment of psychotropic medication-associated weight gain in adults and children. Metformin, an FDA-approved drug for the treatment of type 2 diabetes mellitus, has a well-established safety profile for treating diabetes in both adults and children. The most common side effects of metformin include nausea, vomiting, and diarrhea; lactic acidosis, a side effect of great concern, is an extremely rare finding (Correll et al. 2013). The efficacy of metformin for weight loss in adults and children with psychiatric illness receiving psychotropic medications has been studied, but results have not been consistent. With regard to children, the Improving Metabolic Parameters of Antipsychotic Child Treatment (IMPACT) study will evaluate metformin and another intervention in children and adolescents ages 8–19 years with schizophrenia spectrum disorder, bipolar spectrum disorder, psychotic or nonpsychotic major depressive disorder, or irritability associated with ASD, who have experienced weight gain with atypical antipsychotic treatment in the 3 years prior to the study (Reeves et al. 2013). There are currently no reports describing metformin's safety and efficacy to treat weight gain in children or adults with ASD.
This article is the first report on the use of topiramate for weight loss in young adults with ASD. To date, all available literature on this topic has been focused on topiramate's use in children and adolescents with ASD. This article describes the effectiveness of topiramate for weight loss in two young adult females with ASD and concurrent mood disorder. The extension of the use of topiramate to treat weight gain in young adults with ASD (as opposed to children and adolescents) is a unique and important factor. For adults with ASD who have average intellectual ability, there is a powerful societal stigma in place (McDougle 2013). It is often difficult for these adults to obtain jobs and fit in socially with their peers. Because obesity is common in this population, the issues of societal acceptance and decreased self-esteem can be paramount. Because adults are more likely to have been on antipsychotic treatment for a longer period of time than children, they are more susceptible to the long-term metabolic effects associated with weight gain. Evidence suggests that antipsychotic-induced metabolic side effects increase the 10-year risk for cardiovascular disease, as well as the mortality from cardiovascular disease (Daumit et al. 2008). Topiramate appears to be a safe and effective option for weight loss in young adults with ASD, and can be used successfully with minimal cognitive and noncognitive side effects.
This report has a number of limitations. These include the open-label nature of the treatment, the small number of subjects included, and the lack of a control group. Additionally, both subjects were taking several other medications for their neuropsychiatric comorbidities. Considering the significant use of atypical antipsychotics for treating symptoms of irritability in adults with ASD (McDougle et al. 1998), and the increasing rate of obesity in this population (Curtin et al. 2014), double-blind, placebo-controlled trials of topiramate for excessive weight gain appear warranted.
Disclosures
No competing financial interests exist.