PsychosisPhase 1/2NCT00591318
A Placebo-controlled Efficacy Study of IV Ceftriaxone for Refractory Psychosis
A Phase 1/2 study testing ceftriaxone and Normal Saline in people with Psychosis and Schizophrenia, run by Research Foundation for Mental Hygiene, Inc. at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Psychosis, Schizophrenia, Schizoaffective Disorder
- What is being tested?
- ceftriaxone and Normal Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Oct 2007to 17 Mar 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Adult age 18-55 (Self Report)
- 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).
- Significant positive symptoms, including delusions and/or hallucinations. (Clinical evaluation/interview)
- Diagnosis of schizophrenia or schizoaffective disorder (DSM-IV Diagnostic Checklist)
- 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)
- Negative Urine Toxicology (Urine collection at the time of initial evaluation)
Show all 10Show fewer
- 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.)
- Patient's current treatment has been optimized (Review of medical records and conversation with treating psychiatrist)
- Patient is likely to tolerate the departure from clinical management required of study participants (Review of medical records and conversation with treating psychiatrist)
- 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) -
Who cannot join
- Penicillin or cephalosporin allergy (Self-report)
- Agitation such that patient is likely to be unable to tolerate having an IV line in place.(Behavioral Observation)
- 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).
- Inability to be an inpatient for at least 8 weeks. (Discussion with patient (\& family if indicated))
- A history of IV drug abuse. (Review of medical history)
- Inability to provide informed consent. (Capacity will be assessed by a clinical MD.)
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- Patients who had received IV antibiotic therapy within the last year (Review of medical history)
- 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)
- For subjects participating in the MRSpectroscopy component: Current or past history of claustrophobia (Interview and history)
- 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)
- 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)
- Patient is currently taking Cyclosporine (Interview and Medical records review)
- -
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Psychosis, Schizophrenia, Schizoaffective Disorder
- Being tested
- ceftriaxone, Normal Saline
- Keywords
- Ceftriaxone, Psychosis, Schizophrenia, Schizoaffective Disorder
- Medical subject headings
- Psychotic Disorders, Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ceftriaxoneDrug
Also called "Rocephin"
2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses
Normal SalineDrug
Also called placebo
50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions.
| Study group | Role | What they receive |
|---|---|---|
| IV Ceftriaxone | Experimental | IV Ceftriaxone 2 grams/day Receives: Drug: ceftriaxone |
| IV Placebo | Placebo comparator | IV Placebo (Normal Saline) Receives: Drug: Normal Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Positive and Negative Syndrome Scale - Positive Subscale
Positive and Negative Syndrome Scale (PANSS) - 7 point scale where 1 is absent and 7 is extreme The positive scale has 7 items. Altogether there are 7 items for the total score (range is a minimum of 7 to a maximum of 49). Lower scores indicate better health.
We report the Positive scale
Measured: Last observation assessed occurring from baseline through to the end of week 8
Secondary outcomes (3)
Scale for the Assessment of Positive Symptoms
Scale evaluates positive symptoms of psychosis rated on a scale of 0-5 for each of the 34 items (0 for absent and 5 for severe).
Minimum score is 0 and the maximum score is 170; higher scores are worse.
Measured: Last observation assessed occurring from baseline through to the end of week 8
Hamilton Depression Scale
This is a clinician-administered scale of depression severity with 17 items with scores ranging from 0-7 with higher scores indicating greater severity of depression.
The range is 0-119, where higher scores indicate greater depression
Measured: Last observation assessed occurring from baseline through to the end of week 8
Hamilton Anxiety Rating Scale
The Hamilton Anxiety Rating Scale is a clinician-administered scale of 14 items, with each item rated 0-4 where 4 is the most severe.
The range is 0-56 where the higher values indicate greater anxiety.
Measured: Last observation assessed occurring from baseline through to the end of week 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2008 (estimated)
- Study start10 Oct 2007
- Primary completion2 Mar 2011
- Study completion17 Mar 2011
Why it stopped: Study was terminated after enrolling 12 patients due to poor enrollment rates
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PsychosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Research Foundation for Mental Hygiene, Inc.
- Sponsor type
- University, hospital or other
- Collaborators
- National Alliance for Research on Schizophrenia and Depression, New York State Psychiatric Institute
- Responsible party
- Principal investigator, Brian A Fallon, New York State Psychiatric Institute
- Investigators
- Brian A Fallon, MD, Principal investigator, New York State Psychiatric Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00591318
- Sponsor's protocol ID
- 5418
- Status last verified
- Nov 2022
- First submitted
- 26 Dec 2007
- Last updated
- 2 Dec 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
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. doi: 10.1038/nature03180.
PubMed 15635412
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- IV Ceftriaxone for Refractory Psychosis: a Controlled Trial
- ClinicalTrials.gov ID
- NCT00591318
- Acronym / sponsor ID
- 5418
- Conditions
- Psychosis, Schizophrenia, Schizoaffective Disorder
- Keywords
- Ceftriaxone, Psychosis, Schizophrenia, Schizoaffective Disorder
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was terminated after enrolling 12 patients due to poor enrollment rates
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Research Foundation for Mental Hygiene, Inc.University, hospital or other
- Collaborators
- National Alliance for Research on Schizophrenia and Depression, New York State Psychiatric Institute
- Study start
- 10 Oct 2007 (actual)
- Primary completion
- 2 Mar 2011 (actual)
- Study completion
- 17 Mar 2011 (actual)
- First posted
- 11 Jan 2008 (estimated)
- Results
- Posted 12 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| IV Ceftriaxone | Experimental | Drug: ceftriaxoneIV Ceftriaxone 2 grams/day |
| IV Placebo | Placebo comparator | Drug: Normal SalineIV Placebo (Normal Saline) |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Adult age 18-55 (Self Report)
- 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).
- Significant positive symptoms, including delusions and/or hallucinations. (Clinical evaluation/interview)
- Diagnosis of schizophrenia or schizoaffective disorder (DSM-IV Diagnostic Checklist)
- 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)
Key exclusion criteria (13 listed)
- Penicillin or cephalosporin allergy (Self-report)
- Agitation such that patient is likely to be unable to tolerate having an IV line in place.(Behavioral Observation)
- 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).
- Inability to be an inpatient for at least 8 weeks. (Discussion with patient (\& family if indicated))
- A history of IV drug abuse. (Review of medical history)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ceftriaxoneAlso: "Rocephin"2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses | Drug | IV Ceftriaxone |
| Normal SalineAlso: placebo50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions. | Drug | IV Placebo |
Primary outcome
Positive and Negative Syndrome Scale - Positive Subscale
Time frame: Last observation assessed occurring from baseline through to the end of week 8
Positive and Negative Syndrome Scale (PANSS) - 7 point scale where 1 is absent and 7 is extreme The positive scale has 7 items. Altogether there are 7 items for the total score (range is a minimum of 7 to a maximum of 49). Lower scores indicate better health. We report the Positive scale
3 secondary outcomes
Scale for the Assessment of Positive Symptoms
Time frame: Last observation assessed occurring from baseline through to the end of week 8
Hamilton Depression Scale
Time frame: Last observation assessed occurring from baseline through to the end of week 8
Hamilton Anxiety Rating Scale
Time frame: Last observation assessed occurring from baseline through to the end of week 8
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 15635412Rothstein 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. doi: 10.1038/nature03180.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian A Fallon, MD principal investigator
New York State Psychiatric Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing ceftriaxone and Normal Saline in people with Psychosis and Schizophrenia, run by Research Foundation for Mental Hygiene, Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 2 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Positive and Negative Syndrome Scale - Positive Subscale (time frame: Last observation assessed occurring from baseline through to the end of week 8). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00591318, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2022.