Topiramate as an Adjunctive Treatment in Psychiatric Patients with Diabetes

Ralph Ryback, MD, Lewis Brodsky, MD, and Robert Littman, MD

Dr. Ryback is medical director of the Adolescent Sexual Offenders Program, Charter Behavioral Health/Adventist Health Care Systems, in Rockville, Maryland.

Dr. Brodsky is in private practice in Tallahassee, Florida.

Dr. Littman is medical director of the Centers for Behavioral Health in Rockville, Maryland.

Disclosure: Dr. Brodsky is a consultant to, on the advisory board of, and on the speaker’s bureau of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, Otsuka, Parke-Davis, Pfizer, Shire, and UCB.

Acknowledgment: The authors wish to thank Richard Skenk, PhD, for his help in completing this manuscript.

Please direct all correspondence to: Lewis Brodky, MD, 1407 MD Lane, Suite B, Tallahasse, FL 32305; Tel: 850-878-4885; Fax: 850-656-2853.

Abstract

Usage of topiramate, an antiepileptic medication that has been utilized for other conditions in a number of off label situations, has resulted in beneficial effects in relieving symptoms associated with diabetes. Presented here are seven case reports of type-2 diabetes and one with type-1 diabetes. As a result of modest doses of topiramate (between 50–100 mg/day), plasma glucose levels reduced substantially. Patients who were overweight enjoyed a gradual loss in body weight. The patient with type 1 diabetes realized a normalization in plasma glucose levels. Some of the benefits persisted even after discontinuation of the topiramate. Some discussion of possible mechanism of action is offered.

Introduction

The number of people diagnosed with diabetes in the United States has increased more than 6-fold from 1.6 million in 1958 to 10 million in 1997, according to the Centers for Disease Control and Prevention in Atlanta, Georgia.¹ Approximately 16 million people currently have diabetes, making it a leading cause of death in the US; yet 5 million people are unaware of their illness. Nearly 800,000 new cases of diabetes are diagnosed each year. The health complications of poorly controlled diabetes are extensive (retinal degeneration, kidney failure, cardiovascular disease, limb amputations, and nerve damage). In fact, diabetes is the leading cause of new cases of blindness in adults between 20 and 74 years of age, and accounts for 40% of people who have kidney failure. Cardiovascular disease is 2–4 times more common among people with diabetes and is the leading cause of diabetes-related deaths.¹ The risk of stroke is also 2–4 times higher in people with diabetes and 60% to 65% of diabetes patients have high blood pressure.² Type-1 diabetes accounts for 5% to 10%, while type-2 accounts for >90% of cases in the US. Gestational diabetes occurs in 3% to 5% of pregnant women in the US; these women have a >50% likelihood of eventually developing type 2 diabetes.

Monitoring blood sugar levels is a key component of managing the disease and research indicates that people who keep their blood sugar levels within individual target ranges set by their physicians stand a good chance of reducing complications.^1,2 Despite recent advances in the treatment of diabetes with oral hypoglycemic medications, there remains a need for improvement and novel treatment approaches.^1,2

Topiramate is a broad-spectrum, antiepileptic drug (AED).^3,4 Although the pharmacologic properties of topiramate at the molecular level have not been completely elucidated, several biochemical properties have been identified; these include a positive modulatory effect on the inhibitory neurotransmitter g-aminobutyric acid (GABA) at some types of GABA_A receptors^5,6 and a negative modulatory effect on the excitatory neurotransmitter glutamate at the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate subtype of ionotropic glutamate receptors.^7,8 Topiramate also exerts a negative modulatory effect on some types of voltage-activated sodium^9,10 and calcium channels,¹¹ and is a comparatively weak inhibitor of some isoforms of carbonic anhydrase.^11,12 Topiramate is highly bioavailable and readily distributes to tissues throughout the body after oral dosing.^13,14

Similar to several other broad-spectrum AEDs, topiramate may possess mood-stabilizing properties. Open-label, clinical studies suggest that topiramate may promote mood stabilization of some patients with bipolar disorder; however, the efficacy of topiramate in treating this disorder has yet to be established in double-blind, placebo-controlled clinical trials.^15-17

A more unusual property of topiramate is its tendency to cause a gradual weight loss in some patients.^3,4,15 Presented here are observations on eight patients with diabetes who were receiving topiramate for other medical conditions. This open-label case study was initially stimulated by observations of a patient undergoing therapy unrelated to diabetes, who coincidentally had type 2 diabetes. During the timeframe that these observations were recorded, some other clinical and non clinical reports appeared suggesting that topiramate may have beneficial effects on symptoms associated with diabetes.^18,19 For a synopsis of all eight case studies, please see the Table.

Case Reports

Case I

A 38-year-old married female previously diagnosed with bipolar I disorder presented. Her mood disorder was further aggravated by long-term use of large doses of prednisone 60–80 mg/day. At the time of presentation the patient weighed 168 lbs and had been previously diagnosed with type-2 diabetes and microvascular disease. Her diabetes had been unstable due to prednisone treatment for severe bronchial asthma and dietary non-compliance. She was insulin dependent. She was taking a human insulin analog that was rapid acting, as well as long-acting insulin. Nevertheless, fasting serum glucose levels were as high as 600 mg/dL. She also had type-2 hyperlipidemia, dismetabolic syndrome, and gastroesophageal reflux disease. She was placed on olanzapine 10 mg/day and gabapentin 800 mg QID. Mood stabilization occurred within a 2-week period, with no change in glycemic control, but there was a weight increase of several pounds. Topiramate was initiated at 25 mg/day and increased over a 4-week period to 50 mg BID to assist with mood stabilization and weight loss.

Over the next 7 months, the patient lost 35 lbs despite continuation of olanzapine. Plasma glucose and triglyceride levels remained within normal levels and insulin was slowly removed. Simultaneously, prednisone was decreased to 10 mg QD as her bronchial asthma improved. Her body mass index (BMI) dropped from 33.06 to 26.17, a decrease of 6.89. After 8 months olanzapine was lowered to 2.5 mg. She continued to maintain a euthymic state. Blood glucose and triglycerides continued to be controlled, her asthma continued to improve, and she returned to work. Her maintenance dose of topiramate is now 25 mg every morning and 50 mg at bedtime.

Case II

A 34-year-old married female developed gestational diabetes with a 2-hour postprandial glucose of 170 mg/dL and a fasting glucose level of 140 mg/dL in the middle of her second trimester of pregnancy. She had a cyclothymic disorder and, upon entering her third trimester, resumed treatment with oxcarbazepine 900 mg/day. At the same time, topiramate was initiated at 25 mg/day and titrated over a 3 week period to 25 mg in the morning and 50 mg at bedtime to assist with mood stabilization and weight control. Prior to delivery, she lost 10 lbs and her fasting glucose levels were maintained between 100 and 109 mg/dL. She had a normal delivery with a healthy baby.

Case III

A 51-year-old married female presented at 235 lbs (BMI=31.94) with a history of polysubstance abuse and chronic hepatitis C, and was being treated with peg-interferon aIIa. She suffered from bipolar I disorder, mixed and rapid cycling, refractory to lithium and resistant to most other medications, except olanzapine. With olanzapine 7.5 mg/day, her mood disorder was under control but she developed clinical type 2 diabetes with fasting glucose levels of >140 mg/dL. Topiramate had been added and titrated to 50 mg BID over a 7-week period, both to assist with mood stabilization as well as weight control. During this period, serum glucose levels normalized, mood stabilized further, and her body weight decreased by 10 lbs. Over the next 8 months she gradually lost 50 lbs, resulting in an almost ideal 175 lbs and her BMI decreased to 23.75. She continues to receive olanzapine 2.5 mg/day, topiramate 100 mg/day, and quetiapine 25 mg as needed at bedtime for sleep.

Case IV

A 69-year-old married mother of five presented as being moderately overweight at the time of her third psychiatric hospitalization. Her diagnosis was bipolar disorder not otherise specified, mixed. At the time, she was on lithium 600 mg and risperidone 2 mg/day. Following admission she was diagnosed as suffering from type 2 diabetes. Fasting blood glucose levels were >140 mg/dL and triglyceride levels were also elevated. Topiramate therapy was initiated at 25 mg at bedtime, and increased after 1 week to 50 mg BID for mood stabilization and weight control. Over the next 4 months her blood glucose levels normalized, her triglycerides approached the normal range and she lost 11 lbs. Her BMI dropped from 25.21 to 23.26.

Case V

A 63-year-old single white female presented with chronic undifferentiated schizophrenia with an acute exacerbation, mild cognitive impairment, type-2 diabetes, hypertension, hyperlipidemia, and a history of angioplasty. She was insulin dependent and being treated with a short-acting insulin. She was also on olanzapine 20 mg/day. Topiramate was titrated over 4 weeks to 25 mg in the morning and 50 mg at bedtime for both mood stabilization and weight control. Within a month her blood glucose levels decreased along with concomitant reduction in her insulin requirements. Four months later she no longer required insulin and her diabetes was controlled by diet and topiramate at a dose of 75 mg/day. She lost 37 lbs.

Case VI

A 45-year-old white female had a long-standing history of schizoaffective disorder bipolar type, with persistent paranoid, grandiose, and bizarre delusions, as well as episodes of mania and hypomania, which first presented in her early twenties. The patient had a chronic, disabling course with numerous hospitalizations and was treated with neuroleptics, often in combination with mood stabilizers, such as lithium carbonate and valproate. She had been diagnosed with diabetes mellitus during her mid-twenties, which went untreated for several years because she refused to acknowledge her diabetes. She was eventually unsuccessfully treated with oral hypoglycemics and required insulin therapy. Due to her “near-psychotic” denial and frequent noncompliance with antidiabetic medications and diet, she developed serious complications including bilateral cataracts, cellulitis, and skin ulceration in her thirties.

At 41 years of age, after a protracted psychiatric hospitalization, weighing 190 lbs, she was switched from fluphenazine to olanzapine, and was stabilized as an outpatient on olanzapine, valproate, fluoxetine, and lorazepam on an as-needed basis for anxiety and agitation. After approximately 1 year on this regimen she gained 22% of her body weight (41 lbs). Topiramate 50 mg/day was added to help with weight loss. Her diabetic control had been extremely poor, with fasting blood sugars via fingerstick in the 300–400 mg/dL range. Insulin requirement had been increased by approximately 75% with regards to her long-acting daily insulin. Over the next 16 weeks topiramate was increased to 125 mg/day. Although her fasting blood sugars had improved (low 200s), at week 17 she was precipitously admitted with a diagnosis of insulin coma. Blood sugar in the emergency room was 34 mg/dL and fasting blood sugars by fingerstick immediately prior to that were in the low 100s. Her endocrinologist reduced insulin requirements by one half with regards to her previous regimen. At this level, blood sugars were still at 100–150 mg/dL. With an increase in topiramate to 250 mg/day, insulin requirement was reduced again substantially, and fasting blood sugars remained in the 100–150 mg/dL range. She lost 31 lbs over that 6 month period with no change in her other psychotropic medication. The final reduction represented approximately one-third of what she had originally been taking with regards to her long-acting insulin.

Case VII

A thin, 42-year-old single male (BMI=23.1) presented with rapid mood swings and depression related to his mother’s terminal lymphoma. He had a history of difficulty with concentration and attention, and was being treated with methyphenidate 40 mg/day. He had been diagnosed 4 years earlier with type-1 diabetes. His glycemia had stabilized on a combination of long-acting and intermediate-acting insulin until his mother became terminally ill, at which time his fasting glucose, as measured by fingersticks, was between 350 and 400 mg/dL. Topiramate therapy was initiated at 25 mg at bedtime. This was increased to 25 mg BID over a 2-week period. Topiramate was initiated for mood stabilization. Over the next two months his fasting glucose levels measured by fingersticks slowly decreased to 100–150 mg/dL range despite his mother’s death. His appetite and weight remained stable and he felt well without any change in insulin requirements. Three months later the topiramate was discontinued without consequence. He remained only on methylphenidate and his prior dose of insulin.

Case VIII

A 58-year-old divorced white male presented with severe depression. Bipolar disorder had been diagnosed previously, and drug therapy at the time of presentation was valproate 500 mg BID and olanzapine 5 mg/day. He attributed his weight gain and feeling of sedation to the effects of both medications. He was also diagnosed with hypertension, hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes. The diabetes was treated with metformin BID and fasting glucose was 110–130 mg/dL. He was diagnosed as having major depressive disorder recurrent and his medications were changed to quetiapine 100 mg at bedtime and imipramine 150 mg at bedtime. His mood improved, but he gained an additional 50 lbs during the next 7 months. At this point he experienced a severe business setback, at which time his fasting blood glucose rose to 180–200 mg/dL despite an increase in the dosage of his metformin. Topiramate had been introduced at 25 mg at bedtime, and increased weekly by 25 mg to further help in stabilizing his mood.

When a dose of 50 mg BID had been achieved, his body weight had decreased by 8 lbs and fasting blood glucose was 120–140 mg/dL, as measured via fingersticks. Topiramate was increased to 75 mg BID, and over the next 2 months there was an additional loss of 30 lbs, and fasting blood glucose levels remained consistent in the 100–120 mg/dL range despite a reduction in his dosage of metformin. His blood pressure had normalized. He remained on this regimen for the next 2 months at which time he decided to discontinue the topiramate slowly. Body weight, blood pressure, and fasting glucose remained stable for the next 3 months. During the next 6 months body weight gradually increased by 13 lbs, but blood pressure and fasting glucose remained stable. This benefit continued for the next year when the patient was lost to follow-up.

Discussion

Patients in therapy within a psychiatric setting are often burdened with comorbid physical illnesses. In common with the general population in the US, there is an apparent increase in the incidence of obesity and diabetes in this patient population. Among our patients for whom topiramate was deemed appropriate to include as part of a therapeutic strategy to optimize their well-being, eight were identified as having diabetes, seven with type 2 and one was type 1. Seven of the patients were diagnosed with diabetes prior to evaluation at our clinic. The medical condition of these patients was complex and all patients were receiving multiple medications. The seven patients with type 2 diabetes were all moderately overweight or obese when initially evaluated. Six of these patients were receiving medications known to typically foster increased weight, and several patients reported an increase in weight gain following introduction of one or more of these medications. Topiramate therapy was initiated at a daily dose of 25 mg, then increased weekly or biweekly in 25 mg or 50 mg increments to a maximum daily dose of 50–250 mg. For all eight patients, fasting plasma glucose levels either normalized or decreased to near normal levels within a few months of initiating topiramate therapy. For all seven patients with type-2 diabetes there was a gradual loss in body weight. Notably, the plasma glucose levels of the patient with type 1 diabetes normalized within the 5-month period he received topiramate even though his body weight remained stable during this period. This was the only patient not overweight prior to receiving topiramate.

It is well-known that >80% of patients with type-2 diabetes are overweight and most meet criteria for obesity (eg, BMI >27).²⁰ The patient population in this case-report study is consistent with that pattern. Obesity is generally regarded as a causal factor in the development of type-2 diabetes, and often simply losing weight can ameliorate the diabetic symptoms. Therefore, the question arises as to whether the normalizing effect of topiramate fasting plasma glucose levels is solely the result of its effect on body weight. The observation that plasma glucose levels normalized in the patient with type-1 diabetes without an associated loss in body weight mitigates against this possibility. Pertinently, the patient in Cae VIII continued to have beneficial effects on blood glucose levels for >1 year after topiramate was discontinued. It is also noteworthy that in two euglycemic clamp studies using rat models of type-2 diabetes, topiramate (when administered after a period of 2–4 weeks) significantly increased the ability of insulin to promote glucose uptake and utilization by muscle tissue (JJ Wilkes, personal communication, 2004).²¹

In one study, topiramate enhanced phosphatidylinositol 3 (p1-3)-kinase and its downstream effector Akt/PKB kinase, a signal transduction pathway involved in the regulation of the insulin sensitivity.¹⁹ Consequently, topiramate may be useful as an adjunctive treatment in diabetes, and its effects may not be solely related to weight loss. Controlled clinical studies are needed to elucidate the benefits of topiramate in psychiatric patients with diabetes. PP

References

1. Bell DS. Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care. 2003;26:2433-2441.

2. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32:2426-2432.

3. Privitera MD. Topiramate: a new antiepileptic drug. Ann Pharmacother. 1997;31:1164-1173.

4. Reife R, Pledger G, Wu SC. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia. 2000;41(Suppl 1):S66-S71.

5. White HS, Brown SD, Woodhead JH, et al. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 1997;28:167-179.

6. White HS, Brown SD, Woodhead JH, et al. Topiramate modulates GABA-evoked currents in murine cortical neurons by a non-benzodiazepine mechanism. Epilepsia. 2000;41(Suppl 1):S17-S20.

7. Gibbs JW, Sombati S, DeLorenzo RJ, Coulter DA. Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia. 2000;41(Suppl 1):S10-S16.

8. Skradski S, White HS. Topiramate blocks kainate-evoked cobalt influx into cultured neurons. Epilepsia. 2000;41(Suppl 1):S45-S47.

9. McLean MJ, Bukhari AA, Wamil AW. Effects of topiramate on sodium-dependent action-potential firing by mouse spinal cord neurons in cell culture. Epilepsia. 2000;41(Suppl 1):S21-S24.

10. Taverna S, Sancini G, Mantegazza M, et al. Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J Pharmacol Exp Ther. 1999;288:960-968.

11. Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia. 2000;41(Suppl 1):S52-S60.

12. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia. 2000;41(Suppl 1):S35-S39.

13. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia. 2000;41(Suppl 1):S61-S65.

14. Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmaco-kinetics, and mechanism of action. Epilepsia. 2000;41(Suppl 1):S3-S9.

15. McElroy SL, Suppes T, Keck PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry. 2000;47:1025-1033.

16. Ernst CL, Goldberg JF. Antidepressant properties of anticonvlsant drugs for bipolar disorder. J Clin Psychopharm. 2003;23:182-192.

17. Suppes T. Review of the use of topiramate for treatment of bipolar disorders. J Clin Psychopharm. 2002;22:599-609.

18. Chengappa KNR, Levine J, Rathore D, Parepally H, Atzert R. Long-term effects of topiramate on bipolar mood instability weight change and glycemic control: a case series. Euro Psychiatry. 2001;16:186-190.

19. Richard D, Deshaies Y, Lalonde J, et al. Topiramate enhances the PI 3-kinase/Akt signaling cascade in rats fed a high fat/high sucrose diet, which may account for its beneficial effect on insulin sensitivity in insulin-resistant rats. Endocrine Society Abstracts. 2004. In press.

20. Scheen AJ. Current management strategies for coexisting diabetes mellitus and obesity. Drugs. 2003;63:1165-1184.