Clinical trial NCT04887792: Acetazolamide for Treatment Resistant Schizophrenia
Official title: A Randomized Controlled Trial of Acetazolamide for Patients With Treatment Resistant Schizophrenia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Schizophrenia
Schizo Affective Disorder
Keywords: Schizophrenia
Schizo Affective Disorder
acetazolamide
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
First posted: 2021-05-14
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study will be a randomized placebo-controlled sequential parallel comparison design (SPCD).
Primary purpose: TREATMENT

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

Detailed description: Schizophrenia (SZ) afflicts over 21 million people worldwide. Persons with SZ have a 10% suicide rate and their lifespan is curtailed by over 25 years. There is an urgent need for efficacious antipsychotic drugs (APDs), particularly, second line drugs, because only 30-40% of APD-treated patients attain remission and 30% of patients show little or no response. Currently, Clozapine is the only reliable second line APD, but it can cause serious blood dyscrasias. To fill the void, the investigators have conducted systematic reviews of prior data and in silico searches. In a prior double-blind crossover randomized placebo-controlled trial (RCT), adjunctive Acetazolamide (ACZ) caused \~20% improvement in positive and negative symptom scores when added to APDs among partially-responsive patients with SZ (ACZ 2G/day). No patients dropped out. The RCT is supported by several other open trials. ACZ also reduces weight, thus it could combat weight gain, a common APD side effect. Independently, our systematic in silico strategy based on protein networks and gene expression profiles also identified Acetazolamide (ACZ) as a repurposable drug for SZ.

ACZ crosses the blood-brain barrier. It is used to treat CNS diseases such as refractory seizures and idiopathic intracranial hypertension. Used for over 50 years, its side effects (SE) and adverse effects (AE) are well known and are manageable. It is a potent, specific inhibitor of carbonic anhydrase (CA), which catalyzes the conversion of CO2 to HCO3- and H+. CA is localized to pre-synaptic terminals and glial cells. It modulates GABAergic excitation, long-term synaptic transformation, attentional gating of memory storage and cerebrospinal fluid formation. Post-mortem brain and serological studies show raised CA levels in patients with psychotic/mood disorders. Several APDs also inhibit CA. The investigators thus postulate brain CA inhibition as the therapeutic target for ACZ in SZ.

The investigators propose a double-blind, crossover RCT for SZ using adjunctive ACZ. To maximize the risk/benefit ratio, the investigators will enroll inpatients and outpatients with treatment resistant SZ (trSZ) who meet defined criteria (N=60 RCT completers). ACZ or placebo will be added to prescribed APDs for 8 weeks utilizing the Sequential Parallel Comparison Design to maximize power. The investigators have extensive experience with RCTs. The investigators will ensure timely recruitment by approaching a large group of patients we serve, across 2 sites. If ACZ is beneficial, in future studies the investigators will pursue its implementation for trSZ, and seek variables associated with treatment response.

Eligibility criteria: Inclusion Criteria:

* Written informed consent.
* Both genders, ages 18-55 years (older patients may not tolerate high ACZ dose).
* PANSS total score \> 60 and Score \> 4 on one or more items of the 'positive' syndrome items (P1-P7), following treatment at therapeutic doses for 6 weeks with different APDs on 2 occasions.
* Stable dose of antipsychotic drug (APD) for \> 1 month, continued throughout the study.
* Not participating in another randomized controlled clinical trial (RCT).

Exclusion Criteria:

* Substance abuse in the past month/dependence past 6 months with the exception of methadone prescribed for opiate withdrawal.
* History or current medical/neurological illnesses that may lead to unstable course, e.g., epilepsy.
* Pregnancy.
* Acetazolamide (ACZ) contraindications: hypersensitivity to ACZ; history of renal hyperchloremic acidosis; Addison's disease/adrenal failure; chronic closed angle-closure glaucoma.
* Current or prior treatment with ACZ or history of hypersensitivity to ACZ.
* Intellectual disability as defined in DSM 5.

Primary outcomes:
measure: Change in positive symptoms
timeFrame: 24 weeks
Secondary outcomes:
measure: Clinical Severity
timeFrame: 24 weeks
measure: Clinical Severity
timeFrame: 24 weeks
measure: Cognition
timeFrame: 24 weeks
measure: Clinical Severity
timeFrame: 24 weeks
measure: Social Function
timeFrame: 24 weeks
measure: Global Assessment of Function
timeFrame: 24 weeks
measure: Measure of satisfaction with one's Quality of Life (Quality of Life Scale/QOLS)
timeFrame: 24 weeks
measure: Socio-Economic Status
timeFrame: 24 weeks
measure: Side Effects
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Bangalore
country: India
facility: St John's Medical College Hospital
Study officials:
affiliation: University of Pittsburgh
name: Vishwajit L Nimgaonkar, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: