Acetazolamide for Antipsychotic-Associated Weight Gain in Schizophrenia.

To the Editors

Acetazolamide is a sulfa-like moiety, a potent nonspecific inhibitor of carbonic anhydrase enzymes.[1] It came to medical use in 1952. It is a safe, effective, very economically priced, generic drug, which is in the World Health Organization list of essential drugs. Acetazolamide is available in oral and intravenous form.[2] Acetazolamide is indicated for centrencephalic epilepsies, idiopathic intracranial hypertension, secondary glaucoma, and preoperatively in acute angle closure glaucoma where delay of surgery is desired to lower intraocular pressure.[2] It appears to have beneficial effect in psychogenic polydipsia.[3] Common adverse effects of acetazolamide include tingling,palinopsia, dizziness, diuresis, tiredness, confusion, anorexia, and weight loss. One of the common adverse effects of the antipsychotic drugs is weight gain and metabolic adverse effects.[4]

Given the treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.[5] Body weight and metabolic risk profile in patients receiving atypical antipsychotic medications need to be effectively managed with a weight control program including physical activity, which is difficult in illness such as schizophrenia.[6] Topiramate is an anticonvulsant that reportedly confers weight loss in patients receiving doses up to 300 mg/d.[7] Topiramate appears to inhibit specific carbonic anhydrase enzymes II and V compared with azetazolamide, which is a nonspecific inhibitor of carbonic anhydrase enzymes and has been demonstrated to decrease lipogenesis in adipose cells in vitro cell culture studies.[1]

Zonisamide, another antiepileptic drug, also a carbonic anhydrase inhibitor,[8] is known to cause weight loss in adolescents[9] and adults.[10]

Patients with idiopathic intracranial hypertension and mild visual loss assigned to either acetazolamide or placebo, all of whom received a 6-month telephone-based weight loss intervention, lost an average of 5.9% of initial body weight, consistent with the NHLBI (National Heart Lung and Blood Institute) guidelines of 5% to 10% of body weight loss for clinically significant health benefit.[11] Ophthalmologists have concerns that acetazolamide retards weight gain when given to children. In a retrospective chart review, 22 well children with glaucoma taking oral acetazolamide for 3 months or more showed poor weight gain in a small subset of children.[12] Fifteen consecutive female patients with idiopathic intracranial hypertension associated with obesity were studied to determine the weight loss associated with resolution of papilloedema. Patients underwent weight loss on treatment with acetazolamide during the 24-week period. Weight loss of 3.3% ± 0.5% (mild) was observed among patients having a 1-grade change in papilloedema and 6.2% ± 0.6% was associated with a 3-grade (marked) change in papilloedema. Approximately 6% weight loss was associated with resolution of marked papilloedema in these patients.[13] A young obese lady gained significant weight after commencing risperidone and later developed headache and blurred vision. She was diagnosed to have benign intracranial hypertension due to risperidone usage. Withdrawing the offending drug and addition of acetazolamide 500 mg twice daily (given for benign intracranial hypertension) led to weight loss and drastically improved her symptoms within a month. Acetazolamide probably helped in recovery by diuresis.[14] A 49-year-old obese patient who was started on acetazolamide 250-mg twice daily had significant weight loss of 11.5 lb (5.21 kg) over 4 weeks similar to topiramate.[1]

In a study, when acetazolamide was given to 30 patients of which puberal periodic psychosis (6 cases), presenile atypical psychosis (7 cases), atypical psychosis (8 cases), atypical manic-depressive psychosis (2 cases), and atypical schizophrenia (7 cases), some extent of therapeutic effects of acetazolamide (500–1000 mg) as an antipsychotic was obtained in approximately 70% of the patients. High therapeutic effects were particularly observed in puberal periodic psychosis, presenile atypical psychosis, and atypical psychosis. Acetazolamide showed effectiveness in 10 of the 13 cases to which lithium carbonate and carbamazepine were ineffective. Acetazolamide was considered to have antipsychotic and prophylactic effects on atypical psychosis. Adverse effects were rarely observed in the study, and acetazolamide had a high safety margin.[15] Twenty-four chronic schizophrenia patients were treated successfully with the addition of acetazolamide plus thiamine to their unchanged existing therapies in a double-blind, placebo-controlled cross-over study. Therapeutic effects were measured by the scale for the assessment of positive symptoms and the scale for the assessment of negative symptoms. Overall 50% of the patients showed improvement on all the assessment scales.[16]

CONCLUSIONS

Several clinical studies have reported weight loss as an adverse effect of acetazolamide, and it has shown some beneficial effects in treating psychosis (hence no risk of increasing the primary illness). We conclude, based on the associated weight loss and the apparent improvement in psychotic symptoms, that randomized controlled clinical trials of acetazolamide in antipsychotic-related weight gain are indicated to confirm the associations.