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

• Sponsor: Research Foundation for Mental Hygiene, Inc. (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00591318
• Collaborator: National Alliance for Research on Schizophrenia and Depression (Other), New York State Psychiatric Institute (Other)
• Enrollment: 12
• Location: 1
• Arms: 2
• Actual Duration (Months): 41.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Psychosis; Schizophrenia; Schizoaffective Disorder	Drug: ceftriaxone; Drug: Normal Saline	Phase 1/Phase 2

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

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: IV Ceftriaxone for Refractory Psychosis: a Controlled Trial
• Actual Study Start Date: Oct 10, 2007
• Actual Primary Completion Date: Mar 2, 2011
• Actual Study Completion Date: Mar 17, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IV Ceftriaxone IV Ceftriaxone 2 grams/day	Drug: ceftriaxone; 2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses; Other Names: "Rocephin"
Placebo Comparator: IV Placebo IV Placebo (Normal Saline)	Drug: Normal Saline; 50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions.; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Positive and Negative Syndrome Scale - Positive Subscale [8 weeks]

   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

Secondary Outcome Measures

1. Scale for the Assessment of Positive Symptoms [8 weeks]

   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.

2. Hamilton Depression Scale [8 weeks]

   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

3. Hamilton Anxiety Rating Scale [8 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYS Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• Research Foundation for Mental Hygiene, Inc.
• National Alliance for Research on Schizophrenia and Depression
• New York State Psychiatric Institute

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Brian A Fallon, Professor of Clinical Psychiatry, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT00591318
• Other Study ID Numbers: 5418
• First Posted: Jan 11, 2008
• Last Update Posted: Jan 12, 2022
• Last Verified: Dec 1, 2021

• Keywords provided by Brian A Fallon, Professor of Clinical Psychiatry, New York State Psychiatric Institute: Ceftriaxone; Psychosis; Schizophrenia; Schizoaffective Disorder
• Additional relevant MeSH terms: Schizophrenia; Psychotic Disorders; Mental Disorders; Ceftriaxone

Study Results

Participant Flow

Recruitment Details	There were 12 people who signed consent but 2 opted not to start treatment and therefore are not included in the demographics or the treatment results report

Arm/Group Title	IV Ceftriaxone	IV Placebo
Arm/Group Description	IV Ceftriaxone 2 grams/day ceftriaxone: 2 grams of ceftriaxone given daily, Monday to Friday, excluding major holidays, for a total of 40 doses	IV Placebo (Normal Saline) Normal Saline: 50 cc of normal saline, daily, Monday through Friday, except for major holidays, for a total of 40 normal saline infusions.
Period Title: Overall Study
STARTED	5	5
COMPLETED	1	5
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Ceftriaxone	Placebo	Total
Arm/Group Description	Ceftriaxone Group (n=5)	Placebo Group (n=5)	Total of all reporting groups
Overall Participants	5	5	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (12.5)	38.6 (11.7)	40.5 (11.4)
Sex: Female, Male (Count of Participants)
Female	2 40%	1 20%	3 30%
Male	3 60%	4 80%	7 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	5 100%	5 100%	10 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 40%	1 20%	3 30%
White	3 60%	4 80%	7 70%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
PANSS Positive (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	16.7 (4.9)	18.2 (4.9)	17.3 (4.8)

Outcome Measures

1. Primary Outcome

Title	Positive and Negative Syndrome Scale - Positive Subscale
Description	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
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

We included all 10 people who started treatment. We used the last observation carried forward in the final analysis which included all time points from baseline through to the end of week 8.

Arm/Group Title	Ceftriaxone Arm Results	Placebo Arm Results
Arm/Group Description	This group was randomized to 2 gms of ceftriaxone given 5 days/week for 8 weeks. If participants were not at least 15% improved at 6 weeks, they were considered unlikely to respond and rated as having completed the randomized phase of treatment.	This group was randomized to receive saline given 5 days/week for 8 weeks
Measure Participants	5	5
Mean (Standard Deviation) [score on a scale]	17.6 (4.9)	18.6 (4.3)

2. Secondary Outcome

Title	Scale for the Assessment of Positive Symptoms
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

All 9 participants had ratings on this scale which were used for the results below. One placebo participant (the missing one of the 10) only had a rating at baseline and so was not included in the analysis.

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	Group randomized to Ceftriaxone	This group received IV saline
Measure Participants	5	4
Mean (Standard Deviation) [score on a scale]	27.8 (15.1)	22.7 (7.9)

3. Secondary Outcome

Title	Hamilton Depression Scale
Description	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
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

5 in the ceftriaxone group and 4 in the placebo group had ratings on this scale

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	Sample randomized to IV Ceftriaxone	Participants received IV saline
Measure Participants	5	4
Mean (Standard Deviation) [score on a scale]	15.4 (12.7)	7.7 (5.5)

4. Secondary Outcome

Title	Hamilton Anxiety Rating Scale
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Results from the analysis of data on all 10 participants are presented below

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	Sample randomized to IV Ceftriaxone	Participants received IV saline
Measure Participants	5	5
Mean (Standard Deviation) [score on a scale]	6.2 (5.4)	5.8 (2.2)

Adverse Events

Time Frame	Adverse events are reported that occurred during the time period of each participants receipt of randomized treatment (ranging to a maximum of 8 weeks)
Arm/Group Title	Ceftriaxone		Saline
Arm/Group Description	Participants randomized to Ceftriaxone		Participants randomized to saline
All Cause Mortality
	Ceftriaxone		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Ceftriaxone		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		0/5 (0%)
Psychiatric disorders
Prolongation of hospitalization	1/5 (20%)	1	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Ceftriaxone		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		1/5 (20%)
Gastrointestinal disorders
Diarrhea	2/5 (40%)	2	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Rash	3/5 (60%)	3	1/5 (20%)	1
Pain	1/5 (20%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.