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

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ClinicalTrials.gov Identifier: NCT00591318
Recruitment Status : Unknown
Verified September 2009 by Research Foundation for Mental Hygiene, Inc..
Recruitment status was:  Recruiting
First Posted : January 11, 2008
Last Update Posted : September 18, 2009
Sponsor:
Collaborator:
National Alliance for Research on Schizophrenia and Depression
Information provided by:
Research Foundation for Mental Hygiene, Inc.

Tracking Information
First Submitted Date  ICMJE December 26, 2007
First Posted Date  ICMJE January 11, 2008
Last Update Posted Date September 18, 2009
Study Start Date  ICMJE August 2007
Estimated Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 26, 2007)
PANNS Score (Total and Positive Symptom) [ Time Frame: Baseline, 2, 4, 6 & 8 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00591318 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 26, 2007)
  • MR Spectroscopy [ Time Frame: Baseline and 8 weeks ]
  • MATRICS [ Time Frame: Baseline and End of Treatment ]
  • SAPS/SANS [ Time Frame: Baseline and Wk 8 ]
  • Hamilton Depression Scale [ Time Frame: Baseline and Week 8 ]
  • Side Effect Checklist [ Time Frame: Baseline & weekly through Wk 8 ]
  • Hamilton Anxiety Scale [ Time Frame: Baseline, weeks 2, 4, 6, 8 ]
  • MMSE [ Time Frame: Baseline and week 8 ]
  • CDSS [ Time Frame: Baseline, weeks 2, 4, 6, 8 ]
  • CGI Change [ Time Frame: Weekly through week 8 ]
  • YMRS [ Time Frame: Baseline and Week 8 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Placebo-controlled Efficacy Study of IV Ceftriaxone for Refractory Psychosis
Official Title  ICMJE IV Ceftriaxone for Refractory Psychosis: a Controlled Trial
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Psychosis
  • Schizophrenia
  • Schizoaffective Disorder
Intervention  ICMJE
  • Drug: ceftriaxone
    2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses
    Other Name: "Rocephin"
  • Drug: Normal Saline
    50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions.
Study Arms  ICMJE
  • Experimental: A
    IV Ceftriaxone 2 grams/day
    Intervention: Drug: ceftriaxone
  • Placebo Comparator: B
    IV Placebo (Normal Saline)
    Intervention: Drug: Normal Saline
Publications * Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005 Jan 6;433(7021):73-7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 26, 2007)
28
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)

    -

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00591318
Other Study ID Numbers  ICMJE 5418
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Brian A Fallon, MD, Research Foundation for Mental Hygiene
Study Sponsor  ICMJE Research Foundation for Mental Hygiene, Inc.
Collaborators  ICMJE National Alliance for Research on Schizophrenia and Depression
Investigators  ICMJE
Principal Investigator: Brian A Fallon, MD New York State Psychiatric Institute
PRS Account Research Foundation for Mental Hygiene, Inc.
Verification Date September 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP