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|A pilot open-label study of oral acetazolamide for sodium valproate-associated weight gain in bipolar affective disorder
Mathews Joseph Panicker1, Anil Kakunje1, Vishwajit L Nimgaonkar2, Smita Deshpande3, Triptish Bhatia3, Shashwath Sathyanath1
1 Department of Psychiatry, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka, India
2 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
3 Department of Psychiatry, ABVIMS, Ram Manohar Lohia Hospital, New Delhi, India
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|Date of Submission||03-May-2021|
|Date of Acceptance||22-Jun-2021|
|Date of Web Publication||23-Nov-2021|
Background: Bipolar affective disorder (BD) is a chronic recurrent disorder having a definite link with metabolic abnormalities, including obesity, dyslipidemia, and insulin resistance. Drugs approved for the treatment of BD include sodium valproate but have weight gain as a metabolic side effect. An increase in weight is one of the common reasons for discontinuation of mood stabilizers. There is a need for a weight loss agent which will not increase mood symptoms in bipolar disorder. This study looks at the effect of acetazolamide on weight when combined with sodium valproate in patients diagnosed with BD in remission.
Materials and Methods: This pilot quasi-experimental open-label 8-week follow-up study was conducted in a tertiary care teaching hospital following clearance from the institutional ethics committee. Thirteen outpatients with BD who reported weight gain on sodium valproate monotherapy received oral acetazolamide 500 mg/day. A specialized pro forma was used to record demographic and physical data with side effects.
Results: The mean baseline weight was 70.15 ± 8.75 kg and the mean baseline body mass index was 25.09 ± 2.61. The mean sodium valproate dose of the study population was 692 mg/day. Ten of 11 individuals who completed the study showed some reduction in weight and nine showed a slight decrease in abdominal girths.
Conclusion: There was a nonsignificant decrease in weight and abdominal circumferences at the end of 8 weeks, however, since it is a small pilot study, we need more evidence.
Keywords: Acetazolamide, bipolar disorder, sodium valproate, weight
|How to cite this URL:|
Panicker MJ, Kakunje A, Nimgaonkar VL, Deshpande S, Bhatia T, Sathyanath S. A pilot open-label study of oral acetazolamide for sodium valproate-associated weight gain in bipolar affective disorder. Arch Ment Health [Epub ahead of print] [cited 2021 Dec 7]. Available from: https://www.amhonline.org/preprintarticle.asp?id=330925
| Introduction|| |
Bipolar affective disorder (BD) is a severe chronic recurrent psychiatric disorder characterized by fluctuations in mood, energy, and functional ability., A relationship has been established between BD and definite metabolic abnormalities, including obesity, dyslipidemia, and insulin resistance.,,,,,, Sodium valproate is one of the favored first-line treatments for BD. Given the complication (metabolic risk profile, weight gain, and obesity) associated with sodium valproate therapy, the treating physician must ensure frequent weight monitoring throughout the course and take necessary management options including usage of adjunctive medications, switching over to medications with more favorable side effect profiles or manage efficiently with a weight control program, and/or lifestyle modifications such as diet and physical activity which may be quite the challenge in an illness like BD.,,
Acetazolamide is a sulfa-like moiety, a potent nonspecific inhibitor of carbonic anhydrase enzymes which came to medical usage around 1952. It is a safe, effectual, economically priced, generic drug listed among one of the essential drugs by the World Health Organization. Acetazolamide is available in many preparations including oral and intravenous forms. Acetazolamide is indicated for centrencephalic epilepsies, idiopathic intracranial hypertension, secondary glaucoma, and also to lower intraocular pressure preoperatively in acute angle-closure glaucoma. Side effects of acetazolamide include tingling, tiredness, dizziness, diuresis, fatigue, confusion, anorexia, and weight loss. Topiramate and zonisamide are examples of mood stabilizers which are also known to cause weight loss and have a mechanism of action similar to that of acetazolamide, i.e. they are carbonic anhydrase enzyme inhibitors, which has weight loss property. Some studies have shown that acetazolamide has mood-stabilizing properties where its addition in BD patients has resulted in improved prophylactic efficacy and hence can be a good contender to promote weight loss in BD.,,,, In a recent bioinformatics study done to identify drugs which can be repurposed for use as an antipsychotic, it was observed that the protein target network of acetazolamide was closely related to various neuropsychiatric disorders. Acetazolamide has high inhibitory activity against human CA2 (hCA II), the ubiquitous cytosolic enzyme (inhibition constant, Ki = 12 nM), and human CA7 (Ki = 2.5 nM), the brain-specific form of the enzyme. This is one of the drugs which has the potential to be repurposed for use as an antipsychotic. Our study was to see if the addition of acetazolamide leads to weight loss in outpatients diagnosed with BD in remission who are on treatment with sodium valproate monotherapy. This pilot study was the first such attempt according to the authors.
| Materials and Methods|| |
This was a quasi-experimental open-label study carried out at a tertiary care teaching hospital over a period of 20 months from March 2019 to October 2020. All recruited patients were followed up for a period of 8 weeks from the time of enrollment.
The study included patients of both gender above 18 years and below the age of 60 diagnosed as bipolar affective mood disorder in remission using ICD-10 criteria and only on sodium valproate monotherapy who presented either to the outpatient department or who were referred to the department of psychiatry. Participants reported recent weight gain while on valproate. The dose of sodium valproate was not changed during the study period. Patients with any preexisting comorbid medical conditions or psychiatric illness other than nicotine and those with a history of allergies to sulfa drugs or hypersensitivity reaction to drugs were excluded. A larger study was planned, however, due to the COVID pandemic, we completed this pilot project. We screened 18, and a total of 13 outpatients were recruited in this pilot study.
The institutional ethical committee approved the study with protocol no YEC-1/2018/247. The study was registered under the Clinical Trials Registry-India (CTRI), with reference number CTRI/2019/05/019075. Written informed consent was obtained from all participants after explaining the details of the study, and data collection was done ensuring privacy and confidentiality. The data on various sociodemographic variables were recorded. The patients were given the study medication, tablet acetazolamide, initially 125 mg BD, gradually hiked to a maximum tolerable dose or up to 500 mg maximum whichever is lower over a period of 4 weeks (approved maximum dose of Acetazolamide is 2000mg /day). Patients were monitored for side effects serially at each visit using adverse effects monitoring sheet. Height in centimeters and weight in kilograms were measured using the same digital scale, abdominal girth in centimeters at the level of umbilicus, were measured and recorded at baseline (Visit 1), 2 weeks (Visit 2), 4 weeks (Visit 3), and at the end of 8 weeks (Visit 4). The total assessment took around 30 min. The flowchart of the methodology is explained in [Table 1].
| Results|| |
A total of 13 outpatients diagnosed with BD were included in the current study [Table 2], of which four were male (30.8%) and nine were female (69.2%). Two patients dropped out of the study: one patient developed tiredness, nausea, and lightheadedness as side effects and withdrew consent and the other person was lost to follow-up. These patients were excluded during analysis, and a total of 11 patients who completed were included in the final analysis.
The mean baseline weight of the study population was 70.15 ± 8.75 kg and the mean baseline BMI was 25.09 ± 2.61. The mean dose of sodium valproate was 692 mg/day with a range of 500 mg–1000 mg/day. The mean duration in months of sodium valproate intake at baseline was 31 months.
The P value was found to be 0.103 (confidence interval 95%: ‒2.73–26.00) when the difference between mean weights recorded at Visit 1 and Visit 4 was computed (mean = 1.94) [Table 3]. Out of 11 participants, 10 showed some reduction in weight when weight at the fourth visit was compared to the first visit whereas one individual was found to have the same weight.
|Table 3: The difference in mean weights measured during the four visits using paired t-test (n=11)|
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The abdominal girths were measured at the first visit as well as the follow-up visits, as shown in [Table 4]. Out of 11 participants, 9 showed some reduction in abdominal girth when abdominal girth at the fourth visit was compared to the first visit whereas two individuals were found to have an increase in abdominal girth.
|Table 4: The difference in mean abdominal girths measured during the four visits using paired t-test (n=11)|
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BMI was recorded in the first visit for a total of 13 patients, of which 2 individuals discontinued. There were nine individuals of overweight category and two in the normal/underweight, as shown in [Table 5]. This change in number of individuals was analyzed using Fisher's exact test and was found to be nearly statistically significant (P = 0.051).
|Table 5: Shift of individuals across body mass index categories over the follow-up period using Fisher's exact test (n=11)|
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[Figure 1] and [Figure 2] show using line diagram the changes in weight and BMI during the study period.
|Figure 1: Change in weight of participants over the study duration (Visit 1 to Visit 4)|
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|Figure 2: Change in body mass index of participants over the study duration (Visit 1 to Visit 4)|
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| Discussion|| |
Weight gain is a common finding in patients with BD, however, there are several factors that play a role adding up to weight gain which include unhealthy dietary patterns, genetic predisposition, sedentary lifestyle, and prolonged use of psychotropics like mood stabilizers, for example, sodium valproate. To the authors' knowledge, this is the first study looking at weight changes when acetazolamide is combined with sodium valproate. We recruited patients who were remitted and on a stable dose of sodium valproate monotherapy only. In our study at baseline, most patients belonged to the overweight group with BMI >25 amounting to 72.7% of the total participants.
In our study following the administration of acetazolamide, the differences in mean weights were recorded at Visit 1, Visit 2, Visit 3, and Visit 4. However, the difference was not found to be statistically significant. Nonetheless, out of 11 patients, 10 showed some reduction in weight after 8 weeks of trial with acetazolamide. Similarly, the abdominal girths too were recorded at Visit 1 and the difference of it was calculated with Visit 2, Visit 3, and Visit 4. The difference in abdominal girths was also not found to be statistically significant. Among 11 participants, 9 of them showed some reduction in abdominal girths at the end of the study. The reasons for these findings could be that the weight gain which was expected to be solely due to the effect of sodium valproate was not as expected probably due to the effect of acetazolamide which also reflected in other parameters such as reduction in abdominal girth. There was only slight decrease in weight and abdominal girths in our study, and the reason is probably owing to the fact that only a maximum of 500 mg of acetazolamide was given to participants, as this was the first study, although the maximum dose can be given up to 2000 mg/day. There were nine individuals in the overweight category and two in the normal/underweight category at Visit 1. By the end of the study, it was found that eight participants remained in the overweight category, however, one individual showed a change in BMI which led to a shift of that participant from the obese category to the normal category. This change in weight could probably be attributed to the negating effect of the interventional drug, acetazolamide, on weight gained while on sodium valproate. An interesting finding noted in a study done by Cates et al. where topiramate was given to 41 subjects who gained weight on psychotropic drugs showed that there was a mean reduction of 2.2 kg in weight among all participants. A decrease in BMI was also noted among the participants with a mean reduction of 0.5.
In addition to the above findings in our study, it is important to keep in mind that weight loss generally takes a longer time and 8 weeks in our study is short to see a noticeable difference. Few adverse effects, to name a few, of sodium valproate are anorexia, nausea, vomiting, tremors, hair loss, and weight gain.,, Some of the common adverse effects of acetazolamide seen in this study as reported by patients were tiredness, dizziness, gastritis, nausea, and weight loss which were assessed during follow-up, i.e., at the end of 2 weeks, 4 weeks, and 8 weeks of treatment. We suggest careful watch for side effects by laboratory monitoring and careful clinical examination at higher doses.
This is one of the first studies looking at the effect of acetazolamide on weight in patients who were on sodium valproate for dipolar disorder. In addition, there were no concomitant drugs which would have had an influence on weight. The study was an initial open-label pilot study. In our study, only a low dose of acetazolamide was given to the participants as compared to a maximum dose of 2000 mg, and the study was conducted only for a duration of 8 weeks which is short to see changes in weight. Participants were on various doses of valproate as decided by their treating clinician. Other factors which had an effect on weight such as family history, diet, and exercise were not controlled in our study which is another limitation. Hence, it is suggested that further larger sample randomized longitudinal studies including obese patients be conducted with a higher dose of acetazolamide which will help us to observe more significant changes and improve generalization of the findings, however, we should be watchful of the side effects.
| Conclusion|| |
There was a nonsignificant reduction in weight, BMI, and abdominal circumferences among patients on sodium valproate administered with acetazolamide. The weight and abdominal girths between first and follow-up visits were found to decrease as time duration increased, however, it was not found to be significant. We need further studies in this area.
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Conflicts of interest
There are no conflicts of interest.
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Department of Psychiatry, Yenepoya Medical College, Yenepoya University, Mangalore
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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