Official Title: “IV Ceftriaxone for Refractory Psychosis: a Controlled Trial”

Many patients with schizophrenia and schizoaffective disorder have symptoms that persist, including hallucinations or delusions, despite adequate pharmacotherapy with antipsychotic drug. Glutamate is a major excitatory neurotransmitter in the brain that has been implicated in several brain diseases. NMDA antagonist drugs cause symptoms of psychosis in otherwise normal persons. It is postulated that reduced NMDA receptor mediated neurotransmission leads to an increase in synaptic glutamate. Excessive synaptic concentrations of glutamate can produce excitatory neurotoxicity. Agents which reduce excess glutamate activity are neuroprotective. This therapeutic strategy has been applied to schizophrenia through the use of compounds that reduce presynaptic release of glutamate or otherwise decrease excessive postsynaptic stimulation, including lamotrigine, memantine and a m-GLU-R2 agonist (LY354740) with the hypothesized result of a reduction in psychotic symptoms.

Recently it was shown that a commonly available antibiotic (ceftriaxone) has the unique neuroprotective function of decreasing the amount of extracellular glutamate in nervous system tissue by increasing the number of glutamate transporter proteins. Our clinical experience with patients who have refractory psychosis and past Lyme disease indicates that in some patients psychosis may improve with IV ceftriaxone therapy. Whether this improvement was due to its antimicrobial or glutamate effect or a placebo effect is uncertain. In a placebo-controlled design, this study investigates the ability of ceftriaxone to decrease psychotic symptoms in patients with refractory psychotic disorders. In addition, the study will examine glutamatergic functional activity before and after treatment using brain imaging with magnetic resonance spectroscopy.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: August 2009

Intervention(s) in this Clinical Trial

• Drug: ceftriaxone
  • 2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses
• Drug: Normal Saline
  • 50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • IV Ceftriaxone 2 grams/day
• Placebo Comparator: B
  • IV Placebo (Normal Saline)

Primary Measures

• PANNS Score (Total and Positive Symptom)
  • Time Frame: Baseline, 2, 4, 6 & 8 weeks
    Safety Issue?: No

Secondary Measures

• MR Spectroscopy
  • Time Frame: Baseline and 8 weeks
    Safety Issue?: No
• MATRICS
  • Time Frame: Baseline and End of Treatment
    Safety Issue?: No
• SAPS/SANS
  • Time Frame: Baseline and Wk 8
    Safety Issue?: No
• Hamilton Depression Scale
  • Time Frame: Baseline and Week 8
    Safety Issue?: No
• Side Effect Checklist
  • Time Frame: Baseline & weekly through Wk 8
    Safety Issue?: Yes
• Hamilton Anxiety Scale
  • Time Frame: Baseline, weeks 2, 4, 6, 8
    Safety Issue?: No
• MMSE
  • Time Frame: Baseline and week 8
    Safety Issue?: No
• CDSS
  • Time Frame: Baseline, weeks 2, 4, 6, 8
    Safety Issue?: No
• CGI Change
  • Time Frame: Weekly through week 8
    Safety Issue?: No
• YMRS
  • Time Frame: Baseline and Week 8
    Safety Issue?: No

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)
-

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 55 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Research Foundation for Mental Hygiene

Overall Clinical Trial Officials and Contacts

Brian A Fallon, MD Principal Investigator New York State Psychiatric Institute  

Overall Contact: Katy M Harper, M.A. 212-543-5422 harperk@nyspi.cpmc.columbia.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00591318

Study ID Number: 5418

ClinicalTrials.gov Identifier: NCT00591318

Health Authority: United States: Food and Drug Administration