Acetazolamide for Schizophrenia

(APTS Trial)

Recruiting at 2 trial locations

Overseen By Vinayak Sant, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vishwajit Nimgaonkar, MD PhD

Must be taking: Antipsychotics

Disqualifiers: Substance abuse, Epilepsy, Pregnancy, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a double blind adjunctive randomized controlled trial for schizophrenia using acetazolamide.

Will I have to stop taking my current medications?

No, you will not have to stop taking your current antipsychotic medication. The trial requires that you continue your stable dose of antipsychotic drugs throughout the study.

What data supports the effectiveness of the drug acetazolamide for schizophrenia?

Research shows that acetazolamide can increase blood flow in certain areas of the brain, which might help with conditions involving brain function. However, there is no direct evidence from the provided studies that it is effective for treating schizophrenia. ^{1 2 3 4 5}

Is acetazolamide generally safe for humans?

Acetazolamide is generally safe for humans, but it can cause serious allergic reactions in people with sulfonamide allergies, leading to potentially life-threatening conditions like anaphylactic shock (a severe allergic reaction). It's important to inform your doctor about any sulfonamide allergies before taking acetazolamide. ^{6 7 8 9 10}

How does the drug acetazolamide differ from other treatments for schizophrenia?

Acetazolamide is unique because it is primarily known as a diuretic and a respiratory stimulant, often used for conditions like high altitude sickness and sleep apnea, rather than for schizophrenia. Its use in schizophrenia is novel and may involve different mechanisms compared to standard antipsychotic medications. ^{11 12 13 14 15}

Research Team

Vishwajit L Nimgaonkar, M.D., Ph.D.

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for adults aged 18-55 with treatment-resistant schizophrenia, having a PANSS score over 60 and significant positive symptoms despite medication. Participants must not be in another study, have taken acetazolamide before, or have certain medical conditions like epilepsy or substance abuse issues.

Inclusion Criteria

My schizophrenia symptoms remain severe despite treatment.

I have been on a stable dose of my antipsychotic medication for over a month.

Not participating in another randomized controlled clinical trial (RCT).

Exclusion Criteria

You have used illegal drugs or abused prescription drugs within the past month, or have had a drug addiction within the past 6 months (excluding nicotine).

I have a condition like epilepsy that could make my health unstable.

I am not allergic to ACZ and do not have renal acidosis, Addison's disease, or chronic glaucoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjunctive Acetazolamide or placebo added to prescribed antipsychotic drugs for 8 weeks

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

Treatment Details

Interventions

• Acetazolamide
• Placebo

Trial Overview The trial tests if acetazolamide can help people whose schizophrenia doesn't respond to usual drugs. It's a double-blind study, meaning neither the patients nor doctors know who gets the real drug versus a placebo (a harmless pill).

Participant Groups

Group I: Acetazolamide Active Control 1 Intervention

acetazolamide capsules

Group II: Placebo Active Control 1 Intervention

Identical gelatin capsules

Who Is Running the Clinical Trial?

Vishwajit Nimgaonkar, MD PhD

Lead Sponsor

Trials

2

Recruited

220+

Stanley Medical Research Institute

Collaborator

Trials

141

Recruited

10,400+

Findings from Research

In a study involving 11 patients, acetazolamide (Diamox) significantly increased blood flow in areas affected by thalamic and crossed cerebellar diaschisis, indicating its potential to enhance vascular response in these regions.

The results suggest that Diamox may lead to increased arteriolar dilation and improved perfusion in damaged brain areas, which could be beneficial for recovery or treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide effect on vascular response in areas with diaschisis as measured by Tc-99m HMPAO brain SPECT. Matsuda, H., Tsuji, S., Sumiya, H., et al.[2019]

In a study using baboon models, the two different radio-tracers, 99mTc-HMPAO and 123I-iodoamphetamine (123I(IMP)), showed expected differences in cerebral blood flow measurements without the drug acetazolamide.

Acetazolamide significantly enhanced the uptake of 123I(IMP) compared to 99mTc-HMPAO, suggesting that 123I(IMP) may provide better diagnostic information when assessing cerebrovascular reserve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative cerebral blood flow study in a baboon model with acetazolamide provocation: 99mTc-HMPAO vs 123I(IMP). Dormehl, IC., Oliver, DW., Hugo, N., et al.[2019]

The new diazepam rectal gel (Diastat) showed rapid absorption, reaching peak plasma levels within 70 minutes and demonstrating a high bioavailability of 90.4%, making it an effective alternative to intravenous administration.

Cognitive effects were mild and temporary, with subjects experiencing slight impairments in alertness and performance on neuropsychological tests, but these effects resolved within 4 hours, indicating that Diastat is a safe option for administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam. Cloyd, JC., Lalonde, RL., Beniak, TE., et al.[2019]

The study used the 133Xe-DSPECT technique to measure regional cerebral blood flow (rCBF) in 32 healthy patients before and after administration of acetazolamide (Diamox), finding that a 1 g dose increased rCBF from 58 to 73 ml/100 g/min, indicating its efficacy in enhancing blood flow.

The research suggests that measuring both resting rCBF and the increase in rCBF (reserve capacity) can help differentiate between healthy individuals and those with reversible cerebrovascular disease, especially in patients with lower baseline rCBF values.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[133Xe-DSPECT: normal values of resting cerebral blood flow and reserve capacity]. Kreisig, T., Schmiedek, P., Leinsinger, G., et al.[2015]

In a study of 100 geriatric patients undergoing cataract surgery, those premedicated with dixyrazine experienced higher levels of anxiety compared to those given diazepam, indicating that dixyrazine may not be as effective for anxiety management in this context.

Patients receiving dixyrazine required more frequent intravenous sedatives than those on diazepam, suggesting that while dixyrazine can be used for mild sedation, it may not be suitable for patients needing more significant anxiety control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dixyrazine premedication for cataract surgery. A comparison with diazepam. Oikkonen, M., Heine, H., Salminen, U., et al.[2019]

Topical dorzolamide significantly reduces intraocular pressure (IOP) in pediatric glaucoma patients, but it is less effective than oral acetazolamide, with an average IOP reduction of 27.4% compared to 35.7% for acetazolamide.

In a study of 11 patients, all experienced an increase in IOP when switched from acetazolamide to dorzolamide, indicating that while dorzolamide is a viable alternative, it may not provide sufficient control for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. Portellos, M., Buckley, EG., Freedman, SF.[2019]

In a study involving rats, a daily oral dose of acetazolamide (1 mg for five days) did not affect tear production but significantly reduced lacrimal peroxidase secretion by 60%.

The decrease in peroxidase secretion was reversible, returning to baseline levels after stopping the medication, indicating a temporary effect on lacrimal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acetazolamide (Diamox) on tear secretion. van Agtmaal, EJ., Thörig, L., van Haeringen, NJ.[2019]

In a study involving nine patients with ocular hypertension, acetazolamide effectively reduced intraocular pressure (IOP) by 30% to 35%, with the most significant response observed at a 63 mg dose, which lowered IOP by an average of 8.2 mm Hg.

Higher doses of acetazolamide (up to 500 mg) did not produce a proportionally greater reduction in IOP, indicating that a 63 mg dose is sufficient for effective treatment, as it achieves similar results to higher doses without the need for increased plasma levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term dose response characteristics of acetazolamide in man. Friedland, BR., Mallonee, J., Anderson, DR.[2019]

Generic acetazolamide and brand-name acetazolamide (Diamox) have equivalent effects on lowering intraocular pressure and achieve comparable blood levels after a single dose.

The cost of generic acetazolamide is 37% lower than that of the brand-name version, and food intake does not affect the absorption of acetazolamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of generic acetazolamide. Ellis, PP., Price, PK., Kelmenson, R., et al.[2019]

A 66-year-old woman experienced irreversible anaphylactic shock and severe pulmonary edema after being prescribed acetazolamide for glaucoma, likely due to a cross-reaction with her known sulphonamide allergy.

This case highlights the critical importance of screening for sulphonamide allergies before prescribing acetazolamide, as such allergies should be considered a contraindication due to the chemical similarities between the two drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. Gerhards, LJ., van Arnhem, AC., Holman, ND., et al.[2017]

A highly sensitive method for analyzing acetazolamide in plasma was developed, capable of detecting levels as low as 25 ng/ml, which is crucial for monitoring drug levels in patients.

The method allows for the study of plasma level profiles of various dosage forms of acetazolamide, enhancing our understanding of its pharmacokinetics and potential therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assay for acetazolamide in plasma. Bayne, WF., Rogers, G., Crisologo, N.[2019]

Acetazolamide is effective in preventing acute mountain sickness, significantly reducing symptoms like headache and nausea, and its benefits are linked to increased arterial oxygen levels and reduced fluid retention.

While Acetazolamide can help treat established acute mountain sickness by improving oxygen levels, there is limited data on its effectiveness compared to other treatments like steroids or calcium channel blockers, and faster alternatives like Methazolamide may be more suitable in emergencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide and high altitude diseases. Bradwell, AR., Wright, AD., Winterborn, M., et al.[2013]

In a study of 12 male patients with stable systolic heart failure, acetazolamide significantly reduced the number of central apnea episodes from an average of 49 to 23 per hour, indicating its efficacy in treating central sleep apnea.

Acetazolamide also improved overall sleep quality and reduced daytime fatigue and unintentional daytime sleepiness, suggesting it positively impacts both sleep and daily functioning in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Javaheri, S.[2022]

A new high-performance liquid chromatography (HPLC) method has been developed to accurately measure acetazolamide in both tablet and injection forms, ensuring reliable quantification for clinical use.

The method utilizes a specific extraction process and a commercially available C18 cartridge column, achieving quick retention times of approximately 2.50 minutes for acetazolamide, which enhances the efficiency of drug analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of acetazolamide in dosage forms by high performance liquid chromatography. Gomaa, ZS.[2013]

A new method using stable-isotope dilution GC-MS has been developed to accurately measure acetazolamide levels in human urine, demonstrating high precision and reliability for pharmacological studies.

The method successfully quantified urinary excretion of acetazolamide after ingestion, indicating its potential for monitoring drug levels and effectiveness in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GC-NICI-MS analysis of acetazolamide and other sulfonamide (R-SO2-NH2) drugs as pentafluorobenzyl derivatives [R-SO2-N(PFB)2] and quantification of pharmacological acetazolamide in human urine. Begou, O., Drabert, K., Theodoridis, G., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Acetazolamide effect on vascular response in areas with diaschisis as measured by Tc-99m HMPAO brain SPECT. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

A comparative cerebral blood flow study in a baboon model with acetazolamide provocation: 99mTc-HMPAO vs 123I(IMP). [2019]

3. United States pubmed.ncbi.nlm.nih.gov

A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

[133Xe-DSPECT: normal values of resting cerebral blood flow and reserve capacity]. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Dixyrazine premedication for cataract surgery. A comparison with diazepam. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of acetazolamide (Diamox) on tear secretion. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Short-term dose response characteristics of acetazolamide in man. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of generic acetazolamide. [2019]

10. Netherlands pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. [2017]

11. United States pubmed.ncbi.nlm.nih.gov

Assay for acetazolamide in plasma. [2019]

12. Germany pubmed.ncbi.nlm.nih.gov

Acetazolamide and high altitude diseases. [2013]

13. United States pubmed.ncbi.nlm.nih.gov

Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Determination of acetazolamide in dosage forms by high performance liquid chromatography. [2013]

15. China pubmed.ncbi.nlm.nih.gov

GC-NICI-MS analysis of acetazolamide and other sulfonamide (R-SO2-NH2) drugs as pentafluorobenzyl derivatives [R-SO2-N(PFB)2] and quantification of pharmacological acetazolamide in human urine. [2022]