Clinical outcome of adjunctive topiramate treatment in a sample of refractory bipolar patients with comorbid conditions

Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 1035 – 1039

Clinical outcome of adjunctive topiramate treatment in a sample of refractory bipolar patients with comorbid conditions Constance Guille, Gary Sachs* Harvard Bipolar Research Program, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

Abstract Topiramate, a novel antiepileptic agent, has shown promise in the treatment of bipolar disorder. Patients attending a bipolar specialty clinic and treated with topiramate were identified by chart review, and data were harvested from systematic prospective assessments used routinely in the clinic. Fourteen patients who received topiramate for an average of 22.4 weeks were identified. All but one of these patients were considered to be highly refractory to standard treatment and 13 met the criteria for at least one comorbid psychiatric condition. Nine of these patients (64%) experienced an increased level of functioning and decrease in symptom severity during treatment with adjunctive topiramate. Eleven patients remained on treatment for longer than 2 weeks. Eight of these patients (73%) experienced a significant improvement in their comorbid conditions. Patients with a body mass index (BMI) of  28 (n = 4) experienced a mean weight loss of 29.7 lb while on topiramate. Topiramate appears to be a promising agent for the treatment of bipolar disorder associated with comorbid psychiatric conditions and obesity. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Bipolar disorder; Comorbid psychiatric conditions; Refractory; Topiramate

1. Introduction The challenge of treating patients with bipolar disorder is evinced by the dramatic growth in the percentage of patients requiring polypharmacy over the last two decades. This may reflect heterogeneity of clinical populations, severity of the illness, and/or the high rate of comorbid general medical and psychiatric conditions. Data from Frye et al. (2000) indicate the percentage of patients discharged on three or more medications has increased from 9% in 1980 to 44% in 1995. Tohen et al. (2000) reported that only 30% have achieved functional recovery at 6 months and 38% at 24 months, despite access to the full range of standard treat-

Abbreviations: BMI, body mass index, weight in kilograms divided by the square root of height in meters; CGI-I, Clinical Global Impressions— Improvement; CGI-S, Clinical Global Impressions—Severity; CMF, clinical monitoring form; GAD, general anxiety disorder; GAS, Global Assessment Scale; IBS, irritable bowel syndrome; MGH, Massachusetts General Hospital; OCD, obsessive – compulsive disorder; PTSD, Posttraumatic stress disorder; SCID, Structured Clinical Interview for DSM-IV Axis I disorders. * Corresponding author. 50 Staniford Street, Floor 5, Boston, MA 02114, USA. E-mail address: [email protected] (G. Sachs).

ments. Better or additional treatments are clearly required for the effective management of bipolar disorder. Unfortunately, data from the multicenter double-blind trials required to establish efficacy often lag substantially behind clinical practice. Reports from clinical experience even when uncontrolled can provide useful direction for practitioners treating bipolar disorder. The structurally novel antiepileptic drug, topiramate, is an attractive option for treatment of bipolar disorder. Clinical trials in epilepsy suggest topiramate is more potent than other approved antiepileptic agents. This may reflect the multiple mechanisms by which topiramate can alter neuronal activity. Topiramate combines the pharmacological properties of carbamazepine and valproate. Like both compounds, topiramate blocks Na + channels in a state-dependent manner, and like valproate, topiramate augments neuronal responses to g-aminobutyric acid. In addition, topiramate antagonizes glutamate effects at a-amino-3-hydroxy-5-methylisoxazole4-propionic acid (kainate) receptors, modulates neuronal Ca2 + channel activity, and inhibits certain isoenzymes of carbonic anhydrase. These mechanisms are postulated to account for the potency of topiramate in epilepsy and may contribute to its psychotropic action (Shank et al., 2000). Therapeutic agents with these pharmacological properties including valproate, carbamazepine, and lamotrigine have

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been reported to be of benefit in the treatment of bipolar disorder (Keck et al., 2000). Several open-label trials have shown evidence of benefit with topiramate in various presentations of bipolar disorder. Vieta et al. (2000) reported apparent mood-stabilizing properties of adjunctive topiramate in a sample of refractory patients with bipolar I and II disorder. Twenty-five of 33 evaluable patients completed 6 months of follow-up. Seventy-one percent demonstrated a reduction of  50% in Young Mania Rating Scale (Young et al., 1978) scores and 69% demonstrated a reduction of  50% in Hamilton Depression Rating Scale (Hamilton, 1967) scores, using intent-to-treat analysis. Calabrese et al. (2001) found topiramate monotherapy to be an effective treatment in acute mania. Fifty percent (5/10) of acutely manic patients showed moderate to marked improvement with topiramate treatment. Grunze et al. (in press) also found an antimanic response in 72% (8/11) acutely manic in-patients following adjunctive administration of topiramate. A randomized, single-blind comparison of adjunctive topiramate and bupropion found these two agents to be equally effective in a sample of bipolar I and II patients in the depressed phase of the illness (McIntyre et al., 2000). Hussain and Chaudhury (1999) studied the use of adjunctive topiramate in refractory bipolar depression. At the end of the 6-month study, 42% (19/45) of the patients were considered to be full responders and 27% (12/45) were considered partial responders. Kusumakar et al. (1999) evaluated the use of adjunctive topiramate in rapid cycling bipolar I and II women who had failed to benefit from 12 months of treatment with two or more mood stabilizers. Fifty-five percent (15/27) of participants improved significantly within 12 weeks of starting topiramate treatment. These results suggest that in common with other putative mood stabilizers, topiramate may have antidepressant activity as well as antimanic efficacy. Based on these encouraging results, psychiatrists in our bipolar specialty clinic have prescribed topiramate for bipolar disorder. We undertook this review to determine the efficacy and tolerability of topiramate as adjunctive therapy for patients in our clinic with treatment-refractory bipolar disorder and comorbid psychiatric conditions.

2. Methods 2.1. Participants Chart review was carried out to identify all out-patients who received topiramate in the Massachusetts General Hospital (MGH) Bipolar Clinic. No identified patient was excluded. This review harvested prospective ratings routinely made as part of the medical record as per standard clinical practice at the Bipolar Clinic. The data were collected with the MGH Internal Review Board’s approval for chart review.

2.2. Data collection At each visit, trained clinicians completed a clinical monitoring form (CMF), which served as the progress note for the patient’s medical record. The CMF consisted of eight parts, including the Structured Clinical Interview for DSMIV (SCID) (First et al., 1996), current mood modules, frequency and intensity of pathological mood states, comorbid conditions (based on DSM-IV criteria), selected mental status items, medication use and compliance, adverse effects, laboratory results, narrative, and summary scores. 2.3. Assessment instruments Clinicians were instructed to use all available information in rating each item and use these ratings to determine several summary assessments including the Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-I) (Guy, 1976), the Global Assessment Scale (GAS) (Endicott et al., 1976), and Clinical Status (one of eight operationally defined states, e.g., mania, hypomania, depression, mixed, continued symptomatic, recovering, recovered, and roughening). Clinicians made all prospective ratings prior to the inception of this study. Age, sex, diagnosis, comorbid conditions, baseline and final clinical status, CGI-S, CGI-I, GAS, as well as indication for the use of topiramate, dose, and duration, were harvested from each participant’s CMFs and entered into a statistical database. 2.4. Data analyses Results presented below are insufficient for statistical analyses. Mean scores are used to summarize clinically relevant information.

3. Results 3.1. Demographics Chart review identified 14 patients. Of these, 11 met DSM-IV criteria for bipolar disorder type I (9 females), 3 met criteria for bipolar disorder type II (2 females), and 8 met criteria for rapid cycling (6 females). The mean age was 36.8 years with a range of 16 –51 years. Thirteen out of 14 patients met criteria for at least one comorbid psychiatric condition (mean 2.4, S.D. ± 1.4, range 1– 5) (Table 1). The clinicians reported a broad range of specific target indications for topiramate treatment including rapid cycling (n = 7), hypomania/mania (n = 4), mixed episode (n = 1), depression (n = 1), and obesity (n = 1). With the exception of the patient treated for obesity, clinicians recorded the indication for adjunctive treatment with topiramate as inadequate clinical response.

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Table 1 Demographics Sex

Age (years)

Diagnosis

Comorbid conditions

Indications for use of topiramate

Mean dose (mg/day)

Duration of treatment (weeks)

1

M

51

BP II

obesity

125

64

2 3

F F

50 16

BP I BP I

mania mixed

200 50

33 14

4 5

F F

34 48

BP I BP I

mania rapid cycling

100 100

25 8

6 7

F F

25 32

BP I BP I

rapid cycling rapid cycling

300 75

9 23

8 9 10 11 12 13 14

F M F F M F F

49 24 39 31 40 33 39

BP BP BP BP BP BP BP

OCD, Tourette’s syndrome, PTSD, sleep apnea OCD, alcohol abuse/dependence panic, bulimia, alcohol and substance abuse/dependence, migraine panic, bulimia, alcohol abuse/dependence panic, substance abuse/dependence, PTSD, migraine bulimia panic, alcohol abuse/dependence, PTSD, migraine, anorexia nervosa none OCD migraine GAD IBS, GAD panic, bulimia, kleptomania alcohol abuse/dependence, PTSD, migraine

rapid cycling rapid cycling depression mania rapid cycling rapid cycling rapid cycling

50 100 50 50 75 25 100

1 2 1 53 9 60 12

I I II I I II I

M = male; F = female; BP = bipolar; IBS = irritable bowel syndrome; GAD = general anxiety disorder.

The mean initial dose of topiramate was 50 mg/day, S.D. of ± 27.4 mg/day, and range of 25 –300 mg/day, and the mean dose at last observation was 100 mg/day, S.D. of ± 72.0 mg/day, and range of 25– 300 mg/day. Topiramate was added to an average of three other medications (S.D. ± 1.18, range 1 –5). The mean duration of treatment was 22.4 weeks, S.D. of ± 22.0 weeks, and range of 1 – 64 weeks. The mean number of concomitant medications at end of the study for patients continuing beyond 2 weeks was 2.38, S.D. of ± 1.32, and range of 1 –5.

Table 2 Outcome of topiramate treatment Participant

Baseline clinical status

End clinical status

End CGI

1 2 3

roughening manic mixed psychosis manic depressed cycling cycling psychosis depressed psychosis

recovered roughening mixed

2 3 4

13 4 7

hypomanic depressed cycling depressed

4 2 3 5

20 9 4 4

depressed continued symptoms recovering recovered

4 4

0 5

3 2

10 15

4 3

13 8

4

8

4 5 6 7 8 9 10 11 12 13

depressed mania, psychosis cycling cycling

14

cycling

cycling continued symptoms depressed

Change in GAF

3.2. Efficacy and tolerability Eleven patients remained on topiramate for more than 2 weeks, four of whom experienced a decrease in the severity of their bipolar illness by one or more CGI point. GAS scores improved in most individuals, nine patients experienced a 4– 15-point improvement in GAS, four had a 4– 20point decrease in GAS, and the GAS score of one patient was unchanged (Table 2). Eight out of the 11 individuals exhibited clinically significant improvements in their primary comorbid condition as measured by the CGI-I [bulimia (n = 2), obsessive –compulsive disorder (OCD, n = 2), anorexia nervosa, obesity, posttraumatic stress disorder (PTSD), and Tourette’s syndrome (all n = 1)] (Table 3). During treatment with topiramate, four patients with a body mass index (BMI)  28, experienced a mean weight loss of 29.7 lb, S.D. of ± 16.3 lb, and range of 5 – 75 lb.

Table 3 Response to topiramate: subgroup analysis Subgroup

Percent improved

n

Mania Depression Rapid cycling Alcohol and substance abuse Migraine Obesity Panic Psychotic features Any OCD spectrum OCD Bulimia Tourette’s syndrome Anorexia nervosa

50 25 38 43 40 100 40 25 57 67 50 100 100

3/6 1/4 3/8 4/7 2/5 1/1 2/5 1/4 4/7 2/3 2/4 1/1 1/1

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Five patients discontinued treatment due to adverse effects [rash (n = 2), paresthesia (n = 1), cognitive impairment (n = 1), and sedation (n = 1)]. Two patients discontinued due to lack of efficacy after less than 2 weeks of treatment with topiramate and never exceeded a dose of 50 mg/day.

4. Discussion Our review of open use of topiramate in the MGH Bipolar Clinic indicated its most common use was as an adjunctive treatment for highly refractory patients. Results reported here must be interpreted within the limitations of all open uncontrolled reports. This retrospective report cannot provide definitive conclusions but does have the strength of prospective ratings and a well-documented sample of treatment-refractory bipolar patients. In this sample, 64% (9/14) experienced an increased level of functioning and decrease in symptom severity during treatment with adjunctive topiramate. Interestingly, 73% (8/11) of patients receiving topiramate for 2 weeks or longer exhibited clinically significant improvement in comorbid conditions, i.e., bulimia, OCD, anorexia nervosa, obesity, PTSD, and Tourette’s syndrome. Overall, topiramate’s safety profile is attractive compared to other antiepileptic agents particularly due to the absence of weight gain. The observation of weight loss in four patients with a BMI  28 is important since most moodstabilizing medications are associated with weight gain (Sussmann and Ginsberg, 1999) Weight gain may lead to noncompliance and subsequently to relapse. Notably, 35% (5/14) of our topiramate treated bipolar patients discontinued treatment due to adverse effects. This is considerably higher than the previously reported incidence of adverse effects among patients treated topiramate for migraine (Edwards et al., 2000a), neuropathic pain (Edwards et al., 2000b), and bipolar disorder (McElroy et al., 2000). The high incidence of side effects observed in our clinic may be attributable to the high initial dosage and aggressive titration schedule used in several patients, and the consequence of adding another antiepileptic agent to an already complex treatment regimen. To improve tolerability, current recommendations for initiation of topiramate for outpatients suggest a starting dose of 25 mg/day. Other ways to enhance tolerability include slow titration, a lower target dose, and simplification of the treatment regime. Topiramate is a desirable candidate for combination therapy due to its relatively low potential for pharmacokinetic interactions. Topiramate interactions with other antiepileptic agents are limited to a reduction in serum concentration levels when used in combination with carbamazepine (which increases topiramate plasma clearance) (Garnett, 2000). Topiramate can reduce estrogen levels by 30% in women taking oral contraceptive medications (Rosenfeld et al., 1997). Therefore, women taking oral contra-

ceptives may require preparations of 50 mg of estrogen or barrier methods of birth control.

5. Conclusion Based on the benefits observed in this sample of highly refractory patients, topiramate appears to be a promising agent for the treatment of bipolar disorder, as well as for common psychiatric comorbid conditions and obesity. While these data are supportive of the efficacy of adjunctive topiramate for bipolar disorder and comorbid conditions, definitive conclusions require double-blind controlled clinical trials with larger patient samples.

Acknowledgements This work is supported in part by an Unrestricted Educational Grant from the Stanley Foundation.

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