A Placebo-controlled Efficacy Study of IV Ceftriaxone for Refractory Psychosis

Patients will be screened over the telephone. Information will be gathered from the mental
health treatment team and the patient. Most patients who come to this study have had an
inadequate or insufficient improvement with clozapine. Upon arrival at the NYS Psychiatric
Institute, they review and sign consent to make sure the details of the research study are
understood. Comprehensive assessments are conducted, including neurocognitive testing, prior
to treatment onset. The treatment is randomized so patients will either receive IV
ceftriaxone or IV placebo. Treatment is given Monday through Friday to enable the patient to
have weekends off without a plastic tube (angiocath) in the vein of the arm. If after 6
weeks the patient's symptoms are not at least mildly improved, then the treatment will be
stopped. If however there are signs of improvement, the treatment will be continued another
2 weeks. If at the end of the "double-blind" part of the study a patient learns he/she
received placebo and wishes to be given ceftriaxone, we will provide 4 weeks of ceftriaxone
for those patients. The inpatient unit is located in the NYS Psychiatric Institute which is
adjacent to the Columbia Medical Center in northern Manhattan. Our new building for the NYS
Psychiatric Institute is about 10 years old so the inpatient unit is quite attractive with
beautiful views of the Hudson River and the Palisades. There is no financial cost for the
inpatient stay nor is there a financial cost for participating in this study.

Patients or family members wishing to learn more about this research study should call
212-543-6510 for more information or call Dr. Fallon directly at 212-543-5487.

Inclusion Criteria:

1. Adult age 18-55 (Self Report)

2. Persistent positive symptoms of psychosis despite at least three adequate trials of
anti-psychotics as defined by the Texas medical Algorithm Project - one of which is
clozapine unless there is a contra-indication. (Review of medical records and
conversation with prior treating psychiatrist).

3. Significant positive symptoms, including delusions and/or hallucinations. (Clinical
evaluation/interview)

4. Diagnosis of schizophrenia or schizoaffective disorder (DSM-IV Diagnostic Checklist)

5. Patients will be on a stable dose of antipsychotic medication for at least 8 weeks
prior to randomization or 4 months if Clozaril (Clinical evaluation)

6. Negative Urine Toxicology (Urine collection at the time of initial evaluation)

7. Patients on other antidepressants/mood stabilizers (except PRN benzodiazepines) will
be at the same dose for at least 2 months prior to starting this trial. (Clinical
evaluation & record review.)

8. Patient's current treatment has been optimized (Review of medical records and
conversation with treating psychiatrist)

9. Patient is likely to tolerate the departure from clinical management required of
study participants (Review of medical records and conversation with treating
psychiatrist)

10. There is no significant risk of self-injury or violence based on recent history and
current mental state (Review of medical records and conversation with treating
psychiatrist) -

Exclusion Criteria:

1. Penicillin or cephalosporin allergy (Self-report)

2. Agitation such that patient is likely to be unable to tolerate having an IV line in
place.(Behavioral Observation)

3. Current Lyme disease that has not been treated previously. Current or history of
liver, kidney, or gall bladder disease or elevated liver function test, elevated BUN
over/Cr at screening. Unstable medical illness. History of gall stones (without
subsequent cholecystectomy), hypereosinophilic syndrome, sickle cell disease,
immunodeficiency or blood clotting disorder. History of inflammatory bowel disease,
colon cancer, or C.difficile colitis. (Review of medical history, screening blood
test).

4. Inability to be an inpatient for at least 8 weeks. (Discussion with patient (& family
if indicated))

5. A history of IV drug abuse. (Review of medical history)

6. Inability to provide informed consent. (Capacity will be assessed by a clinical MD.)

7. Patients who had received IV antibiotic therapy within the last year (Review of
medical history)

8. Pregnancy or lactation. For females of child bearing age, the pregnancy test is
performed pre-randomization. Since this test cannot detect the very early stage of
pregnancy (10 day period between fertilization and implantation), an effective birth
control method or sexual abstinence is required during the 15 days before the MR scan
and randomization. (Interview & urine pregnancy test pre-randomization)

9. For subjects participating in the MRSpectroscopy component: Current or past history
of claustrophobia (Interview and history)

10. For subjects participating in the MRSpectroscopy component Metal implants or
paramagnetic objects contained within the body which may pose a risk to the subject
or interfere with the MR scan, as determined in consultation with a neuroradiologist
and according to the guidelines set forth in the following reference book commonly
used by neuroradiologists: "Guide to MR procedures and metallic objects", F.G.
Shellock, Lippincott Williams and Wilkins, NY 2001. (Interview and history)

11. History of self-injurious behaviour or other behaviour that might complicate the
insertion and maintenance of an angiocath, in the past 2 years (Interview and
History)

12. Patient is currently taking Cyclosporine (Interview and Medical records review)