Projects

Project Description

Schizophrenia (SZ) afflicts over 21 million people worldwide 1. Persons with SZ have a 10% suicide rate and their lifespan is curtailed by over 25 years 2-4. There is an urgent need for efficacious antipsychotic drugs (APDs) 5  6, – particularly, second line drugs - because only 30-40% of APD-treated patients attain remission 7, 8 and 10 - 30% of patients show little or no response 9. Currently, Clozapine is the only reliable second line APD,  but it can cause serious blood dyscrasias 10 11.  To fill the void, we 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)12.  No patients dropped out.  The RCT is supported by several other open trials 13  14 15, 16  17.  ACZ also reduces weight 18 19,  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 20. 

ACZ crosses the blood-brain barrier 21 22.  It is used to treat CNS diseases such as refractory seizures and idiopathic intracranial hypertension 21, 23-25.  Used for over 50 years, its side effects (SE) and adverse effects (AE) are well known and are manageable 73. It is a potent, specific inhibitor of carbonic anhydrase (CA), which catalyzes the conversion of CO2 to HCO3- and H+ 26, 27.  CA is localized to pre-synaptic terminals and glial cells 28-30.  It modulates GABAergic excitation, long-term synaptic transformation, attentional gating of memory storage and cerebrospinal fluid formation 30-32.  Post-mortem brain and serological studies show raised CA levels in patients with psychotic/mood disorders 33-35.  Several APDs also inhibit CA 36. We thus postulate brain CA inhibition as the therapeutic target for ACZ in SZ.

  We propose a double-blind, crossover RCT for SZ using adjunctive ACZ. To maximize the risk/benefit ratio, we will enroll inpatients and outpatients with treatment resistant SZ (trSZ) who meet defined criteria 9 (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 37.  The primary outcome will be improvement in total symptom scores using the Positive and Negative Syndrome Scale (PANSS). Secondary outcomes include cognitive function, social function and weight. Serum ACZ levels will be monitored. We have extensive experience with RCTs.  We will ensure timely recruitment by approaching a large group of patients we serve, across 2 sites. We will share all SMRI-mandated data. If ACZ is beneficial, in future studies we will pursue its implementation for trSZ, and seek variables associated with treatment response.