Proposal To Develop A Rapid And Cost-Effective Diagnostic Test For Schizophrenia

• ClinicalTrials.gov Identifier: NCT03781115
• Recruitment Status: Recruiting
• First Posted: December 19, 2018
• Last Update Posted: February 24, 2022
• Sponsor: University of Arizona
• Collaborator: Sidney R. Baer, Jr. Foundation
• Information provided by (Responsible Party): University of Arizona

Study Description

Brief Summary:

Schizophrenia is a severe psychotic illness of unknown cause that affects 1% of the population worldwide. Currently, there is no diagnostic test for schizophrenia. Instead, the diagnosis is typically established through a psychiatric interview of the patient, who is evaluated against a set of established criteria of signs and symptoms. It can take many months to years to establish a diagnosis of schizophrenia and achieve an appropriate treatment regimen to attain resolution of the patient's symptoms. This process is particularly challenging in areas of limited access to specialists a problem not only in third world countries and rural regions, but throughout the United States where there can be long waits to obtain an appointment with a psychiatrist. The present research experiment investigates a potential novel method for diagnosing schizophrenia.

The overall objective of the study is to test the hypothesis that patients with schizophrenia will have a heightened tolerance to the sedating effects of anti-psychotic medications, which will be reflected in differences in their electroencephalogram (EEG) when compared to healthy normal controls. The investigators expect that the schizophrenia patients will score on the "more alert" and "less sleepy" ends of these scales, and that the normal control subjects will show the opposite response. A patient that fails to become sedated or experience the sleepiness side effects, typically caused by the anti-psychotic medication, may support the existing diagnosis of schizophrenia. Measures of the subjects' level of sedation that are found to correlate significantly with EEG response and diagnosis will be used to create a diagnostic test. This simple and inexpensive test will consist of a single dosage of anti-psychotic medication, and a rapid assessment tool with scores that have a high degree of predictive validity for the diagnosis of schizophrenia.

Condition or disease	Intervention/treatment	Phase
Schizophrenia	Drug: Ziprasidone; Drug: Olanzapine; Drug: Placebo Comparator	Phase 1

Detailed Description:

The overall objective of the study is to test the hypothesis that patients with schizophrenia will have a heightened tolerance to the sedating effects of antipsychotic medications, which will be reflected in differences in the participants' electroencephalogram response (EEG), when compared to healthy control participants.The following Specific Aims are designed to test this hypothesis and create the diagnostic tool.

Specific Aim 1: The investigators will first conduct a pilot dose-response evaluation of the anti-psychotic drugs ziprasidone (Geodon) (20, 40, or 60 mg tablet) and olanzapine (Zyprexa®) (2.5, 5, 7.5, or 10 mg tablet) in non-psychiatric ill control participants to determine the optimal dosage that promotes sedation in healthy participants versus a placebo. The evaluation will comprise of a physical examination and questionnaires. The investigators will start with the lowest dose of each drug and if the dosage fails to induce sedation in healthy participants, the investigators will repeat the pilot dose-response evaluation with the next higher dose until the maximum dose is reached for both drugs. Specific Aim 2. To determine whether the pattern of EEG activity in response to a single dose of the anti-psychotic medication determined from the dose-response study from Aim 1 distinguishes schizophrenia participants from normal controls. The investigators will start with 2-4 healthy control participants to determine that the results show a discernible effect on the EEG using the dosage from Aim 1. If the dose of anti-psychotic medication fails to show an effect on the EEG the investigators will increase the dosage until the maximum dosage of the chosen medication is used. Once the dosage is identified the investigators will move onto getting IRB approval to evaluate participants diagnosed with schizophrenia.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The investigators will first conduct a dose-response evaluation of the anti-psychotic drug ziprasidone (Geodon) (20, 40, or 60 mg tablet) or olanzapine (Zyprexa®) (2.5, 5, 7.5, or 10 mg tablet) in non-psychiatric ill control individuals to determine the dosage that promotes sedation in individuals versus a placebo. The evaluation will comprise of a physical examination, drug/pregnancy screenings and sleepiness questionnaires. Once the dosage of the anti-psychotic medication is determined new healthy subjects will be recruited to ingest the medication and have an electroencephalogram (EEG) recording taken. If the dosage of medication does not show an effect on the EEG the investigators will ask the individual to come back on a different day so the next higher dose of medication can be given. Once a the healthy subject's EEG shows an effect new control subjects and individuals with a diagnosis of schizophrenia will be recruited.
• Masking: Double (Participant, Investigator)
• Masking Description: Double Blind Masking: The participant and the investigator are both blinded.
• Primary Purpose: Diagnostic
• Official Title: Proposal To Develop A Rapid And Cost-Effective Diagnostic Test For Schizophrenia
• Actual Study Start Date: November 20, 2017
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: January 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ziprasidone; The investigators will conduct a pilot dose-response evaluation of a single dose of the anti-psychotic drug ziprasidone (Geodon). The investigators will start with a single 20mg pill given to (3) subjects and will increase the dosage in sequential subjects until the desired sedation effect is achieved (i.e. 40 and 60mg tablets). If Ziprasidone causes the desired sedation effect additional healthy subjects will be recruited to take the medication and have an electroencephalogram (EEG) taken.	Drug: Ziprasidone; anti-psychotic drug proposed for use as rapid diagnostic tool; Other Name: Geodon; Drug: Olanzapine; anti-psychotic drug proposed for use as rapid diagnostic tool; Other Name: Zyprexa; Drug: Placebo Comparator; A non drug oral placebo capsule will be given as a control; Other Name: Placebo Oral Capsule
Experimental: Olanzapine; The investigators will conduct a pilot dose-response evaluation of a single dose of the anti-psychotic drug olanzapine (Zyprexa). The investigators will start with a single 2.5 mg pill given to (3) subjects and will increase the dosage in sequential subjects until the desired sedation effect is achieved (i.e. 5, 7.5, and 10 mg tablets).If olanzapine causes the desired sedation effect additional healthy subjects will be recruited to take the medication and have an electroencephalogram (EEG).	Drug: Olanzapine; anti-psychotic drug proposed for use as rapid diagnostic tool; Other Name: Zyprexa; Drug: Placebo Comparator; A non drug oral placebo capsule will be given as a control; Other Name: Placebo Oral Capsule
Placebo Comparator: Placebo Comparator; The investigators have prepared a placebo which duplicates the exact color and size of the study drug capsule to use as a non-drug control.	Drug: Ziprasidone; anti-psychotic drug proposed for use as rapid diagnostic tool; Other Name: Geodon; Drug: Placebo Comparator; A non drug oral placebo capsule will be given as a control; Other Name: Placebo Oral Capsule

Outcome Measures

Primary Outcome Measures :

1. Heart Rate [ Time Frame: up to 2 years ]
   Evaluating the heart rate of the subject every hour during all the test procedures
2. Pulse Rate [ Time Frame: up to 2 years ]
   Evaluating the pulse rate of the subject every hour during all the test procedures
3. Stanford Sleepiness Scale [ Time Frame: up to 2 years ]
   The subject will rate how sleepy they are feeling at baseline and every hour during the test using an (8) point scale (i.e. 1= feeling active, vital alert, or wide awake; 2= functioning at high levels, but not fully alert; 3= awake, but relaxed, responsive but not fully alert; 4= somewhat foggy, let down; 5= foggy, losing interest in remaining awake, slowed down; 6= sleepy, woozy, fighting sleep, prefer to lay down; 7= no longer fighting sleep, sleep onset soon, having dream-like thoughts; 8= asleep
4. Epworth Sleepiness Scale [ Time Frame: up to 2 years ]
   The subject will rate their pre-test sleepiness only once during the test using a (4) point scale (0= no chance of dosing, 1= slight chance of dosing, 2= moderate chance of dozing and 3= high chance of dozing
5. Fatigue Severity Scale [ Time Frame: up to 2 years ]
   The subject will rate their pre-test fatigue only once during the test by rating 10 questions using a slide scale between 1 and 7. A rating of 1 means the subject strongly disagrees with the statement. A rating of 7 means the subject strongly agrees with the statement.
6. Chalder Fatigue Scale [ Time Frame: up to 2 years ]
   Subjects will rate their fatigue every hour and at baseline by answering 11 questions and rating their fatigue using a 4 point scale (i.e. less than usual, no more than usual, more than usual and much more than usual)
7. Psychomotor physical computerized test [ Time Frame: up to 2 years ]
   The participants uses a computerized test to test their reflexes every hour and at baseline during the trial period. Every time a red dot appears in the middle of the screen the participant must touch the computer screen as fast as they can. This test was measured in how fast they responded (ms) and by how many attempts to touch the screen were recorded in 2 minutes
8. Hand Fatigue Scale [ Time Frame: up to 2 years ]
   A hand grip measuring device will be used to test for fatigue. A small hand held device will measure the participants hand grip strength every hour during the test and at baseline.
9. Electroencephalogram [ Time Frame: up to 2 years ]
   Electroencephalogram will be taken at baseline and after subjects have taken the anti-psychotic medication. There will be no placebo taken for this test.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria Healthy Control

1. Be between 18 and 40 years of age
2. Be able to understand English
3. Have no history of psychosis
4. Have no history of sleep apnea, heart condition or seizure
5. Have no known drug allergies
6. The ability to swallow a pill

Exclusion Criteria Healthy control

1. Refuse to sign the consent form
2. Drink caffeine or alcohol within 24 hours of the study
3. Have the EKG readout report borderline or abnormal ECG
4. Have the 12 panel urine drug screen show a positive result
5. Be pregnant

Inclusion Criteria Schizophrenic subject

1. Be between 18 and 40 years of age
2. Be able to understand English
3. Have been diagnosed with a Schizophrenia Spectrum or other psychotic disorder

4. Belong to one of three groups:

   1. Never medicated patients with a first episode of psychosis
   2. Have not received long acting injectable (depot) antipsychotic in previous 6 months
   3. Have not received oral antipsychotic (or antidepressant that has serotonergic action) in previous 2 weeks
5. Have no history of sleep apnea, heart condition or seizure
6. Have no known drug allergies
7. Be able to swallow a pill
8. Healthy as determined by teh enrolling physician(s)

Exclusion Criteria Schizophrenic subject

1. Refuse to sign the consent form
2. Drink caffeine or alcohol within 24 hours of the study
3. Have the EKG readout report borderline or abnormal ECG
4. Have the 12 panel urine drug screen show a positive result
5. Be pregnant

Contacts and Locations

Contacts

Contact: Janet Campbell, MS; 602-827-2875; janetcampbell@email.arizona.edu

Contact: Amelia Gallitano, MD/PhD; 6028272131; amelia@email.arizona.edu

Locations

United States, Arizona

Banner Alzheimer's Institute; Recruiting

Phoenix, Arizona, United States, 85006

Banner University Medical Center; Recruiting

Phoenix, Arizona, United States, 85006

Sub-Investigator: Steve Chung, MD

Sponsors and Collaborators

University of Arizona

Sidney R. Baer, Jr. Foundation

Investigators

• Principal Investigator: Amelia Gallitano, MD,PhD; University of Arizona College of Medicine

More Information

Publications:

Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry. 2001;62 Suppl 5:10-3; discussion 23-4.

Gallitano-Mendel A, Izumi Y, Tokuda K, Zorumski CF, Howell MP, Muglia LJ, Wozniak DF, Milbrandt J. The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. Neuroscience. 2007 Sep 7;148(3):633-43. Epub 2007 Aug 9.

Gallitano-Mendel A, Wozniak DF, Pehek EA, Milbrandt J. Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects. Neuropsychopharmacology. 2008 May;33(6):1266-75. Epub 2007 Jul 18.

Williams AA, Ingram WM, Levine S, Resnik J, Kamel CM, Lish JR, Elizalde DI, Janowski SA, Shoker J, Kozlenkov A, González-Maeso J, Gallitano AL. Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacology. 2012 Sep;37(10):2285-98. doi: 10.1038/npp.2012.81. Epub 2012 Jun 13.

Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014 Sep;45:233-45. doi: 10.1016/j.neubiorev.2014.06.005. Epub 2014 Jun 24. Review.

Everson G, Lasseter KC, Anderson KE, Bauer LA, Carithens RL Jr, Wilner KD, Johnson A, Anziano RJ, Smolarek TA, Turncliff RZ. The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function. Br J Clin Pharmacol. 2000;49 Suppl 1:21S-26S.

Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS One. 2011;6(8):e22662. doi: 10.1371/journal.pone.0022662. Epub 2011 Aug 9.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT03781115
• Other Study ID Numbers: 1612051594
• First Posted: December 19, 2018
• Last Update Posted: February 24, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Arizona:

schizophrenia, psychosis, ziprasidone, olanzapine

Additional relevant MeSH terms:

Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Olanzapine; Ziprasidone; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Serotonin Antagonists; Dopamine Antagonists; Dopamine Agents