Psychopharmacology (2005) 179: 838–845 DOI 10.1007/s00213-004-2117-y
ORIGINA L IN VESTI GATION
Ornah T. Dolberg . Gaby Barkai . Yigal Gross . Shaul Schreiber
Differential effects of topiramate in patients with traumatic brain injury and obesity—a case series Received: 8 August 2004 / Accepted: 3 November 2004 / Published online: 24 December 2004 # Springer-Verlag 2004
Abstract Rationale: Topiramate is an antiepileptic drug known to have effects on weight. In order to use this as a tool to treat eating disorders, it is useful to examine whether these effects can be predicted in certain patients. Objectives: To report the effects of topiramate, initiated for the treatment of epilepsy, on top of ongoing treatment, on eating patterns and weight of 17 patients with traumatic brain injury (TBI) with post-traumatic epilepsy and weight gain of various etiologies. Methods: Patients were followed up according to their usual treatment plan. Topiramate was added on top of current and stable treatment. Dose was titrated based on the patients’ neurological status. Patients were asked to report side effects. No other changes were made. Results: Of the 17 patients included, one patient dropped out. Six patients with binge eating disorder (BED) demonstrated the most pronounced effects, with marked attenuation of binges and normalizing body mass index. Less noticeable were the effects in patients with mood disorders. Topiramate was ineffective in patients whose overweight was a side effect of their medication. Side effects were rated as mild and included somnolence, paresthesias, mild cognitive disturbances and O. T. Dolberg . G. Barkai . S. Schreiber Department of Psychiatry, Tel Aviv Sourasky Medical Center and The Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel G. Barkai . Y. Gross The Neuropsychiatric Unit for Treatment and Rehabilitation, Yad Harutzim 14, Tel Aviv, Israel Y. Gross Department of Psychology, Bar Ilan University, Givat Shemuel, Israel O. T. Dolberg (*) Lundbeck Israel Ltd., P.O. Box 3088 Petach Tikva, 49130, Israel e-mail:
[email protected] Tel.: +972-3-9100100 Fax: +972-3-9100117
some gastrointestinal disturbances. Conclusions: In this report of the actual effects of topiramate in a clinical setting on weight and eating habits of 17 patients with TBI and obesity of various etiologies, topiramate seemed to be a safe intervention. Topiramate appeared to be differentially effective, with particular effects on primary pathological eating patterns. Keywords Binge eating disorder . Obesity . PTSD . Post Traumatic Stress Disorder . Topiramate . Traumatic brain injury . TBI . Weight gain . Epilepsy . Side effects
Introduction Topiramate is a structurally novel agent currently approved for the treatment of epilepsy (Wallace 2001). Topiramate appears to have a broad spectrum of activity in epilepsy (Chengappa et al. 2001a), and several possible mechanisms have been identified. This medication has been lately receiving a generous amount of attention in the medical literature due to its weight loss promoting characteristics. In addition, it is being examined for migraine prophylaxis (Young et al. 2002), bipolar disorder (Calabrese et al. 2001), eating disorders including anorexia and binge eating disorder (BED) (Appolinario et al. 2002), and obesity (Bray et al. 2003) with or without a concomitant psychiatric diagnosis. Apart from being examined for its efficacy in treating the primary disorder, it is concurrently judged for its effects on weight, and is even being considered as an option in the management of drug-induced obesity due to the use of atypical antipsychotics (Werneke et al. 2002) in patients with schizophrenia or anxiety disorders (Van Ameringen et al. 2002). Furthermore, topiramate seems to improve glycemic control in patients with diabetes. Chengappa et al. (2001b) report on three obese bipolar patients with type II diabetes who received topiramate in combination with antipsychotics and another mood stabilizer. These patients lost a considerable amount of weight, and also achieved a significant improvement in glycemic control.
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As previously stated, topiramate is being examined for its effectiveness as a primary psychiatric drug—most notably as a mood stabilizer and for the treatment of binge eating disorder. If determined to be efficacious in these disorders and in light of its effect on weight, this might prod topiramate to become a much prescribed treatment, not only in epilepsy but also in mood disorders such as bipolar affective disorder, and possibly even as an adjunct therapy in depression (Carpenter et al. 2002). In addition, topiramate might be added to the pharmacopoeia of eating disorders, most prominently for binge eating disorder (McElroy et al. 2003), and also for obesity and anorexia. Whether due to the effects of medication, or as a result of their primary psychiatric diagnosis, psychiatric patients seem to suffer from obesity more than the average population. Indeed, weight gain seems to be a prominent reason for treatment discontinuation and drug non-compliance among psychiatric patients (Weiden et al. 2003). Therefore, a solution addressing this unmet need would be most welcome. In the neuropsychiatric unit, we address the needs of patients with posttraumatic brain injuries. These patients suffer from a combination of neurological disorders, psychiatric disorders and frequently, orthopedic disabilities. These result from combat wounds, road accidents, and various intra-cranial injuries including hemorrhages, ischemic events, and tumors. These patients are notorious for their unique response to medication, often requiring minute dosages, or inversely, megadoses, long titration periods, long discontinuation periods, paradoxical responses and many other challenging pharmacological puzzles. In this case series, we present the results of patients treated with topiramate for post-traumatic epilepsy and the effect that this medication had on their weight, in view of their other medications and other psychiatric disorders.
Materials and methods The series comprised 17 patients who were admitted to the neuropsychiatric unit and treated with topiramate regardless of the etiology of their head trauma, the type of epilepsy treated, and their psychiatric diagnoses or treatment. All patients included had a BMI of at least 25, but nearly all were significantly overweight and some extremely obese. All patients were initially treated with topiramate for their epileptic disorder, following consultation with their neurologist, almost always after an EEG. The decision whether to continue topiramate treatment was based on the patient’s neurological condition and not on weight or eating parameters. The patients were followed up, as is usual for their condition, and the only change that was made was weight assessment and questions pertaining to their appetite and eating habits, which were emphasized more than usual (although these are a routine part of the patients’ follow-up program). Topiramate dosage was also adjusted according to their neurological status. However, doses were at times increased if there was a partial but positive response regarding appetite suppression or decline
in binge frequency. This was done in coordination with the patients’ neurologist, if needed. The treatment was not initiated as an anti-obesity agent or an anti-binge agent, and therefore although not a randomized or blinded study, there were no expectations raised by this treatment among the patients. Currently, these patients are still in treatment in the neuropsychiatric unit, and are still on treatment with topiramate, to the best of our knowledge. As no intervention was performed that was specific to the study, but rather treatment choices were based on clinical parameters, and follow up was routine, the ethics committee advising the neuropsychiatric unit deemed that verbal consent is sufficient for participation in this study.
Results The Neuropsychiatric Unit for Treatment and Rehabilitation addresses the total needs of these patients including but not limited to social, psychological, psychiatric, and neurological and issues pertaining specifically to rehabilitation. The unit employs psychologists, social workers, neuropsychiatrists, and rehabilitation specialists. Seventeen patients were included in this study. The characteristics of the patients are presented in Table 1. All patients suffered from severe traumatic head injury, either due to a road accident, a combat-related injury (such as a bullet hole) or an ischemic or hemorrhagic insult such as a ruptured aneurysm or a stroke. For example, patient number 8 tried to commit suicide by shooting himself in the head. Patient Number 17 suffered extensive head trauma following a dive into an empty pool. Several patients were comatose for significant periods of time and all were hospitalized in acute and then rehabilitation wards for lengthy periods of time. All patients suffer from neurological deficits and some have, in addition, significant orthopedic disabilities. A number of patients suffer from other consequences of their trauma such as splenectomies, extensive facial plastic reconstructive surgery, and artificial limbs. All patients use a number of other medications including prescription and over-the-counter (OTC) painkillers, anxiolytics, antipsychotics, antidepressants, antiepileptics, anti-spastics, sleep medication, and a myriad of other pharmacological agents including drugs for the treatment of impotence, laxatives, wakefulness promoters, artificial tears, antihypertensives and basically any medication available. Among these patients, it is not uncommon to see patients with a dozen different drugs per day. However, all patients were several years past their injury, the doses of their medication were stable, and their psychiatric conditions were stable and no changes were observed or made. Prior to the initiation of treatment, the attending physician attempted to determine the central cause of the weight gain in each individual patient. As these are complex patients with a number of diagnoses and several medications, this division is based on the clinician’s longterm acquaintance with the patients. Following this, weight gain in six patients was attributed primarily to their eating
40
21
44
32
50
48
2 F
3 F
4 F
5 M
6 M
Age
1 F
Sex
Combat
Ruptured Aneurysm Combat
MVA
Grand Mal
Partial Complex Grand Mal
Partial
Grand Mal
Grand Mal
MVA1
MVA
Type of epilepsy
Type of trauma
300
400
150
200
250
125
Dose (mg)
PTSD and organic MDD
PTSD2 and organic psychosis
Organic MDD and BED
Organic MDD and BED
Organic anxiety disorder
Organic major depressive disorder (MDD) and binge eating disorder (BED)
Neuro-psychiatric diagnosis
Table 1 Demographic and clinical details of the patients included in the study
Mirtazapine 45 mg Paroxetine 40 mg Valproate 2,000 mg Clonazepam 6 mg Paroxetine 40 mg Lorazepam 3 mg Brotizolam 7.5 mg Citalopram 40 mg Mirtazapine 7.5 mg Diazepam 4 mg Reboxetine 8 mg Valproate 600 mg Olanzapine 20 mg Valproate 1,200 mg Carbamazepine 1,000 mg Sertraline 100 mg Clonazepam 4 mg Zopiclone 7.5 mg Venlafaxine 225 mg Carbamazepine 1,000 mg Clonazepam 4 mg Etodolac 600 mg
Other medications
1.9
1.7
1.5
1.50
1.66
1.65
Height (m)
107/104
120/110
63/54
60/54
80/77
75/65
Weight (kg) pre/post
29.6/28.8
41.5/38
28/24
26.7/24
29/27.9
27.5/23.9
BMI pre/post
Somnolence
Somnolence
Nausea and fullness
Palpitations
Nausea
Side effects
840
35
32
38
42
49
51
8 M
9 F
10 F
11 M
12 F
Age
7 F
Sex
Type of epilepsy
Combat
Combat
Stroke
MVA
Suicide attempt
200
Dose (mg)
Partial
Unknown
Grand Mal
Unknown
100
600
800
250
Recent onset 200 Grand Mal
Head trauma Partial
Type of trauma
Table 1 (continued)
Post-traumatic dementia and psychosis
PTSD and MDD
Organic personality disorder
MDD with atypical features
Organic delusional disorder
Organic borderline personality disorder
Neuro-psychiatric diagnosis
Valproate 1,200 mg Lorazapam 2 mg Venlafaxine 150 mg Risperidone 2 mg Zopiclone 15 mg Venlafaxine 225 mg Eltroxin 150 mg Valproate 1,200 mg Risperidone 1 mg Citalopram 20 mg Mirtazapine 15 mg Valproate 800 mg Diazepam 10 mg Flunitrazepam 2 mg Olanzapine 5 mg Clonazepam 0.5 mg Sertraline 50 mg Eltroxin 100 mg
Other medications
1.60
1.75
1.62
1.62
1.75
1.68
Height (m)
70/70
87/80
80/82
80/73
76/76
76/80
Weight (kg) pre/post
27.3/27.3
28.4/26.1
30.5/31.3
30.5/27.9
25/25
27/28.4
BMI pre/post
Worsening of nightmares
Metallic taste
Nausea
Side effects
841
39
45
30
25
14 F
15 F
16 M
17 F
Head Trauma
Combat
MVA
MVA
MVA
Type of trauma
Partial
Grand Mal
Grand Mal
Complex Partial
Grand Mal
Type of epilepsy
2
MVA=motor vehicle accident PTSD=post traumatic stress disorder
1
30
Age
13 F
Sex
Table 1 (continued)
150
500
400
500
200
Dose (mg)
Organic personality disorder and BED
Organic bipolar disorder and Pica
Organic bipolar disorder and BED
Organic bipolar disorder and BED
Organic personality disorder
Neuro-psychiatric diagnosis
Olanzapine 2.5 mg Rofecoxib 25 mg Lithium 1,200 mg Olanzapine 7.5 mg Fluoxetine 20 mg Brotizolam 7.5 mg Lithium 1,500 mg Valproate 1,200 mg Mirtazapine 15 mg Clonazepam 6 mg Valproate 800 mg Lithium 1,500 mg Olanzapine 7.5 mg Sertraline 150 mg Etodolac 400 mg Clonazepam 2 mg
Other medications
1.68
1.83
1.73
1.65
1.6
Height (m)
75/62
100/95
83/70
80/62
65/?
Weight (kg) pre/post
26.6/22
30/28.4
27.8/23.5
29.4/23
25.4/?
BMI pre/post
Difficulty in finding words
Nausea and fullness
Withdrew due to lack of efficacy
Side effects
842
843
disorder; in five patients overweight was judged to be a consequence of their mood disorders, mostly depression, and in six patients—as drug (specifically antipsychotic)induced. Thirteen patients were overweight prior to treatment with topiramate (25
