Trial of DMXB-A in Schizophrenia

The objective of the trial is to determine if dosing DMXB-A twice daily for 4 weeks will
improve cognition and be safe. Secondary goals are to determine if these neurocognitive
effects also have effects on neurobiological paradigms previously shown to be responsive to
nicotinic receptor stimulation: suppression of P50 auditory evoked response, saccadic
intrusions during smooth pursuit eye movements, and hemodynamic activity in the hippocampus
during smooth pursuit eye movements as measured by fMRI. The purpose of these neurobiological
measures is to assess whether the response to DMXB-A is consistent with activation of
nicotinic receptors. In addition, the investigators will assess clinical response using a
battery of clinical assessment scales and assessments of daily living functions. The purpose
of these assessments is to address the FDA requirement of a clinical effect beyond change in
laboratory neuropsychological performance. This study and the subsequent two studies will
also include assessments of the safety of DMXB-A and related compounds.

The purpose of the trial is to lay the groundwork for Phase III investigation. If this trial
finds that DMXB-A has effects at a safe dose, without tachyphylaxis, then the investigators
intend to proceed to a Phase III trial, where the clinical importance of this effect can be
measured.

The trial will be a double blind trial with placebo control. The order of doses and placebo
will be randomized.

The Phase 1 study was completed in January, 2005, with 12 non-smoking schizophrenics
subjects. The subjects were concurrently treated with neuroleptics throughout the study. They
received 3 treatments, each for 1 day, in a double-blind crossover design. The treatments
were DMXB-A (150 mg + 75 mg 2 hours later), DMXB-A (75 mg + 37.5 mg 2 hours later), and
placebo. A significant effect on neurocognition, as measured by the Repeatable Battery for
Assessment of Neuropsychological Status, and on sensory gating, as measured by P50 auditory
evoked potentials was observed. Subjects reported no significant symptoms. One subject's
white blood cell count decreased from just above normal limits on placebo to just below
normal levels on DMXBA (150 + 75 mg 2 hours later). He did not receive further exposure to
drug and his white blood cell count returned to normal at the next testing, 2 days later.

Inclusion Criteria:

- Schizophrenia

- Currently treated with neuroleptic drugs

Exclusion Criteria:

- Treatment with clozapine;

- Head injury or neurological condition;

- Cardiovascular disease;

- Substance abuse or dependence, including nicotine