Use of low-dose topiramate in substance use disorder and bodyweight control

Authors


Winston W. Shen, MD, 111 Hsin Long Road, Section 3, Taipei 116, Taiwan. Email: shenwinw@gmail.com

Abstract

Abstract  In recent years topiramate has been used for psychiatric patients, mainly for controlling substance use and food intake. A total of 46 patients who received topiramate treatment during the study period were identified from a computer database. Nineteen had received topiramate for at least 1 month. Twelve patients received topiramate for anticraving effects (alcohol, n = 9; heroin/amphetamine, n = 1; meperidine, n = 1; and nicotine, n = 1). On an average dosage of 112.5 mg/day, nine of the 12 patients (excluding three alcoholic patients) achieved complete or partial remission from the substance use disorders. The present results show that six of the nine patients achieved full or partial remission from alcohol use disorder on a dosage of 100 mg/day. Topiramate was also used to control seven patients' bodyweight (mean bodyweight change, 1.53 kg). Four of them achieved bodyweight loss in the 1-month follow up, with an average change of 2.65 kg. Based on the present findings topiramate <100 mg/day may be effective in treating patient with alcohol use disorder, and that topiramate has not shown remarkable benefit of bodyweight loss.

INTRODUCTION

Topiramate is a sulfamate-substituted monosaccharide that is derived from its d-enantiomer.1,2 Its anti-epileptic effect, which was discovered incidentally, involves multiple mechanisms, including the antagonistic effects of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-gated, sodium-ion channels and red blood cell carbonic anhydrase, as well as the agonistic effect of γ-amino butyric acidA (GABAA) transmission.1,2 Unlike carbamazepine, valproate and lamotrigine, topiramate does not have firm evidence of its effectiveness in bipolar disorder.1,2

In recent years topiramate has been reported to have an anticraving and a food intake inhibition effect. For alcohol, topiramate is thought to antagonize alcoholic patients' abuse liability by inhibiting dopamine release in the mesocorticolimbic system through facilitating GABA activity and inhibiting glutamate function. Johnson et al. have proposed that topiramate might exert antidopaminergic action through facilitating the inhibitory neurotransmitter GABA through a non-benzodiazepine receptor site and antagonizing the excitatory effects of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate glutamate receptors on A10 dopaminergic neurons at the cell body and nucleus accumbens.3 Therefore, topiramate might be a promising agent for the treatment of both nicotine and alcohol dependence.4,5

In addition to the anticraving effects, topiramate can also produce the effect of bodyweight control. Bray et al. and Appolinario et al. reported that topiramate produced a greater weight loss in healthy obese subjects compared to placebo.6,7 Thus topiramate may be an effective treatment for binge-eating disorder8–10 and bulimia nervosa.11

In recent years topiramate has been used for psychiatric patients for its anticraving and bodyweight control effects. Here, we present the clinical cases of topiramate use in the past 2 years among our psychiatric patients.

METHODS

We collected the clinic case reports of patients who had received topiramate treatment in psychiatric clinics at Taipei Medical University-Wan Fang Medical Center (TMU-WFMC) between 1 January 2004 and 30 June 2006. Excluded were patients who had epilepsy or severe renal/liver function impairment. The diagnoses were made based on DSM-IV-TR.12 We collected the case reports from a database kept at Department of Pharmacy at TMU-WFMC. We then reviewed the medical records to obtain data on sex, age, diagnosis, doses of topiramate, and efficacy and side-effect of topiramate from the progress notes.

RESULTS

We identified 46 patients from the computer database who received topiramate treatment during the study period (Fig. 1). Of them, 24 patients received topiramate without any follow-up information, and three patients reported no benefits and self-discontinued it. Table 1 shows the other 19 patients who had received topiramate for at least 1 month. Except one (patient 12), all of the patients were psychiatric outpatients. The male/female ratio was 9/10. Their average age was 40.4 years. Of those 19 patients, 12 patients received topiramate for anticraving effects for the use of substances (alcohol, n = 9; heroin/amphetamine, n = 1; meperidine, n = 1; and nicotine, n = 1).

Figure 1.

Patients who received topiramate.

Table 1.  Demographic data and the diagnoses of 19 patients
CaseGenderAge (years)Diagnosis
  1. GAD, generalized anxiety disorder; MDD, major depressive disorder.

 1M56MDD, alcohol dependence
 2M45MDD, alcohol dependence
 3M37MDD, panic disorder, alcohol dependence
 4F37MDD, GAD, alcohol dependence
 5M44MDD, alcohol dependence
 6M48GAD, alcohol dependence
 7M57MDD, alcohol dependence
 8F25MDD, panic disorder, alcohol abuse
 9M24Bipolar disorder, panic disorder, alcohol abuse
10F35MDD, meperidine dependence
11F30MDD, polysubstance abuse
12M41Schizophrenia, nicotine dependence
13F22MDD, bulimia nervosa
14F36MDD, bulimia nervosa
15F37MDD, GAD, panic disorder, bulimia nervosa
16F41MDD, GAD, panic disorder
17F55MDD, panic disorder
18F55Bipolar I disorder
19M42MDD, GAD

Their average topiramate dosage was 112.5 mg/day. As in regular clinic follow up, we used an approximate semistructured interview and self-reported information for evaluating the therapeutic effects. As shown in Table 2, nine of those 12 patients achieved complete or partial remission from the substance use disorders. The anticraving effects lasted as long as the patients were on topiramate treatment in the present study. The other three patients did not show any benefit from topiramate and continued to drink alcohol (Table 2). Newly reported side-effects included paresthesia (n = 1) and dizziness (n = 1). All 12 patients received antidepressants at the same time, and most of them received mirtazepine therapy (Table 2). The remaining seven patients received topiramate treatment for weight control. Three patients had the diagnosis of bulimia. The average dose was 157 mg/day. Four of them had the benefit of weight reduction. The average bodyweight change was 1.53 kg. The reported side-effects included paresthesia (n = 1) and sedation (n = 1). Two patients achieved partial improvement of their bulimic conditions.

Table 2.  Summary of topiramate's therapeutic and side-effects and concomitant drugs
CaseDosage (mg/day)Therapeutic effectsSide-effectConcomitant drugs
 1200Continued to use alcoholNilVenlafaxine 150 mg/day
 2100Full remissionNilMirtazepine 30 mg/day
 3100Partial remissionNilMirtazepine 30 mg/day
 4100Full remissionParesthesiaMirtazepine 30 mg/day
 5100Partial remissionNilBupropion 300 mg/day
 6100Continued to use alcoholDizzinessVenlafaxine 150 mg/day
 7100Partial remissionNilMirtazepine 30 mg/day
 8100Continued to use alcoholNilVenlafaxine 150 mg/day
 9100Full remissionNilAripripazole 20 mg/day, venlafaxine 187.5 mg/day, lamotrigine 50 mg/day
10200Full remissionNilMirtazepine 60 mg/day
11100Full remissionNilBupropion 300 mg/day,
Quetiapine 200 mg/day
12100Full remissionNilOlanzapine 15 mg/day
13150−1 kgNilVenlafaxine 187.5 mg/day
Bupropion 75 mg/day
14250−4.7 kgNilBupropion 225 mg/day
15150No changeSedationBupropion 150 mg/day
Venlafaxine 300 mg/day
16150No changeNilVenlafaxine 225 mg/day
Quetiapine 200 mg/day
17100−4 kgNilVenlafaxine 112.5 mg/day
18200+1 kgNilOlanzapine 2.5 mg/day
Lamotrigine 150 mg/day
Mirtazepine 60 mg/day
19100−2 kgParesthesiaBupropion 300 mg/day

DISCUSSION

Previous studies have demonstrated topiramate's effectiveness on self-reported drinking measures at 200 mg per day (6 weeks after the starting of topiramate).3 Johnson et al. collected 150 cases of patients with alcohol dependence. Of them, 75 were assigned to receive topiramate and 75 to have placebo. The result of that 12-week clinical trial showed that topiramate (≤300 mg/day) was more efficacious than placebo to control alcohol drinking.3 Until now, data on topiramate's effect at lower dosage in substance use disorder patient have been limited. As shown in Table 2, six of nine patients achieved full or partial remission from alcohol use disorder on ae dose of 100 mg/day. Based on this finding we suggest that topiramate dose <100 mg per day may be effective in treating patient with alcohol use disorder. Although the dosage is relatively low compared to other studies,3 we should still be vigilant for the probable side-effects, including paresthesia, dizziness, sedation or acute glaucoma.13

In humans topiramate is cleared mainly by kidney.1,2 Only approximately 20% of topiramate is metabolized in the liver, and the involved enzymes include cytochrome P450s 1A2, 2A6, 2C9, 2E1 and 3A4.1,2 Topiramate itself can inhibit CYP 2C1 activity. The clearance rate has been reported to be decreased in patients with moderate to severe renal/liver dysfunction.1,2 Considering the possibility of decreased metabolism, we excluded patients with moderate to severe renal/liver function impairment in the present study.

All 19 patients in the present study took concomitant psychiatric drugs at the same time (Table 2). Most of them received an antidepressant. To our knowledge, patients' concomitant drugs do not interfere with topiramate's concentration. In the absence of the potential drug interactions, we suggest that the concomitant drugs did not influence topiramate's therapeutic effects in the present study.

In addition to alcohol use disorder patients, the present study also included one patient with heroin/amphetamine dependence, one with meperidine dependence and one with nicotine dependence (Table 1). All three patients received topiramate (average dose 133.3 mg/day) and achieved full remission. We postulate that topiramate's anticraving effects produced its benefit in treating substance use disorders. Although not reported, topiramate may have benefits in control of other substances due to its anticraving effects.

The mechanism of topiramate's weight loss effects was unknown but may involve modulation of glutamate receptors or lipoprotein lipase activity.6,14 In the past 30 months we used topiramate to control seven patients' bodyweight (mean bodyweight change, 1.53 kg). Four of them achieved bodyweight loss in the 1-month follow up, with the average change of 2.65 kg (Table 2). Compared to its anticraving effects, topiramate did not demonstrate remarkable benefit of bodyweight loss in the present study but the present sample size was relatively small.

The limitations of the present study were small sample size, lack of a questionnaire, and not being a prospective designed study. We could not obtain total concurrent data from the patients, especially in the follow-up period. We plan to treat more patients and to increase the sample size under an IRB-approved research protocol for achieving long-term follow-up result of topiramate at 100–150 mg/day used in controlling substance use and bodyweight.

ACKNOWLEDGMENTS

This study was presented at the annual meeting of the Taiwanese Society of Psychiatry, Taichung, Taiwan, 3–4 November 2006. We are grateful to the Taipei Medical University-Wan Fang Medical Center Pharmacy Department for its support of data collection.

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