Inpatient Evaluation of Adults With Schizophrenia

Inpatient Evaluation of Neuropsychiatric Patients

The purpose of this study is to understand the biologic basis of schizophrenia and to determine which symptoms are related to the illness itself and which are related to medications used to treat the illness.

Schizophrenia and related psychoses are chronic brain disorders whose prognosis is often poor and whose pathophysiology remains obscure. Brain imaging technologies such s positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and magnetic resonance imaging (MRI) offer opportunities to study the pathophysiology of psychotic disorders by evaluating brain function. However, the use of anti-psychotic drugs may interfere with the results of such studies. In this study, psychotropic medication will be discontinued in patients for a short period of time to distinguish the effects of the illness on the brain without the interference of the medication's effects on the brain. Given that there is a risk that the patient's symptoms will increase, they are asked to stay on an inpatient unit where the NIMH clinical staff is available to help them 24 hours a day.

This study will be conducted in three phases. In Phase 1, participants will be admitted to the Clinical Center while continuing to take their medication and will undergo diagnostic interviews, physical and laboratory assessments, physiological monitoring, and neuropsychological testing. Behavioral ratings will also be performed and blood and urine samples will be collected. During Phase 2, participants will continue taking medications in a blinded fashion for 8 to 12 weeks. The active medications will be replaced with a placebo (an inactive pill) part of that time. PET, fMRI, and MRI scans will be used to monitor how the continuation or lack of medication affects the brain. Psychological tests will also be given to measure changes in cognition. In Phase 3, participants will have the opportunity for clinical stabilization.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

Objectives:

Schizophrenia and related psychoses are chronic brain disorders whose prognosis is often poor and whose pathophysiology remains obscure. Neuroimaging technologies such as PET (positron emission tomography), fMRI (functional magnetic resonance imaging), DTI (diffusion tensor imaging) and MRSI (magnetic resonance spectroscopic imaging) offer opportunities to elucidate the pathophysiology by studying brain function in living research subjects. The use of these techniques to study psychotic disorders is severely limited, however, by a critical methodological confound: antipsychotic treatment. The purpose of this protocol is to admit research subjects with schizophrenia and other related disorders to the Clinical Center, carefully evaluate their neuropsychiatric status, and discontinue psychotropic medications for a brief period so research subjects can be studied without the confound of antipsychotic treatment.

Study Population:

700 participants

The study will include research subjects with schizophrenia.

Study Design:

There are several phases to this protocol. The first phase is the Screening Evaluation and Stabilization Phase and includes gathering historical data, structured diagnostic interviews, general physical and laboratory assessments, basic physiological monitoring, neuropsychological testing, limited collection of blood and urine samples, and serial behavioral ratings. In the second phase (Coded Medication Phase), research subjects will receive blinded compounds that will contain inactive placebo or active antipsychotic administered in a crossover fashion. Patients and unit clinical nursing staff evaluating and caring for the patient will be blind to arm status. Each arm normally lasts 4 to 6 weeks. The total duration of this phase is 8 to 12 weeks. During the Coded Medication Phase, research subjects are enrolled in a series of neuroimaging and other approved studies designed to elucidate the neurobiology of these disorders. These include studies using neuropsychological testing, MEG, PET, fMRI, DTI, and MRSI. The antipsychotic free period is essential to distinguish the effects of illness versus medication.

Outcome Measures:

Parameters under investigation include traits that are candidate phenotypes for genetic studies and state-dependent aspects of brain function. The combined use of many neuroimaging modalities will allow us to look at the functional relationship between a variety of brain abnormalities hypothesized to play a role in schizophrenia. These include hippocampal neurochemical abnormalities, deficits in prefrontal cortical activation, and dysregulation of subcortical dopamine in a single research subject.

• Study Type: Observational
• Enrollment (Estimated): 700

Contacts and Locations

• Study Contact: Name: Vincent L Del Balzo; Phone Number: (301) 435-8974; Email: vincent.delbalzo@nih.gov
• Study Contact Backup: Name: Daniel P Eisenberg, M.D.; Phone Number: (301) 402-5483; Email: eisenbergd@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals with schizophrenia-spectrum illness from the community.

Description

• INCLUSION CRITERIA:
• Diagnosis of DSM-IV- or DSM5-defined schizophrenia spectrum disorder (including schizophrenia, schizoaffective disorder, or other specified/unspecified schizophrenia spectrum and other psychotic disorder/psychosis NOS).

Subjects with other neuropsychiatric disorders may also be admitted and participate in the protocol if there is sufficient evidence to believe they have an underlying, undiagnosed DSM-IV-or DSM5-defined schizophrenia spectrum disorder.

EXCLUSION CRITERIA:

-Currently treated with depot medications

Because of the long half-life of depot medications such as paliperidone palmitate (Invega Sustenna), applicants to our program will be excluded if they are currently receiving depot medications monthly. However, applicants may decide to switch from depot to oral medications on their own, in conjunction with their personal physician, before coming to the program. This is not part of research and we do not participate in this decision. A sufficient washout period based on the particular long-acting injectable medication s elimination half-life will be required in order for prospective participants to be eligible. Subjects may complete the last 3 months of washout in the inpatient unit while being evaluated under the standard protocol.

-Major medical illness.

Research subjects identified as having major medical problems other than their primary neuropsychiatric disorder will be excluded from admission.

• Applicants judged to be unsuitable for medication free studies will also be excluded. Possible reasons for exclusion include prior history of dangerousness to self or others, particularly when off medication.
• Applicants who are pregnant are excluded from this study. Volunteers who are found to be pregnant after testing will be terminated from study and referred to an OB-GYN for follow up care.
• Infection with syphilis, hepatitis, or HIV.
• History of any (excepting nicotine-related and cannabis-related) DSM5-defined moderate to severe substance use disorder (or DSM-IV-defined substance dependence).
• Cumulative lifetime history of any (excepting nicotine-related and cannabis-related) DSM5-defined mild substance use disorder (or any DSM-IV-defined substance abuse), either in excess of 5 years total or not in remission for at least 6 months.
• Lack of capacity to provide consent.

Exclusion Criteria for Previously Enrolled Research Subjects

• No longer satisfying the above inclusion criteria or meeting any of the above exclusion criteria
• Inability to safely participate in planned research (e.g., development of acute suicidal behavior during prior research participation)
• Unlikely to provide sufficient additional research data

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
1; Individuals with schizophrenia-spectrum illness from the community.	Drug: Sirolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To map the physiological fMRI BOLD response, the brain electrical activity through MEG response and the blood flow, presynaptic and post-synaptic dopaminergic function through PET studies during different cognitive tasks	To map the physiological fMRI BOLD response, the brain electrical activity through MEG response and the blood flow, presynaptic and post-synaptic dopaminergic function through PET studies during different cognitive tasks	ongoing
To explore the neuropsychological response in research subjects with schizophrenia under placebo conditions without the confounding effect of antipsychotics.	To explore the neuropsychological response in research subjects with schizophrenia under placebo conditions without the confounding effect of antipsychotics.	ongoing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PANSS data will be collected to determine changes or lack thereof in clinical status during the protocol.	PANSS data will be collected to determine changes or lack thereof in clinical status during the protocol.	Ongoing

Collaborators and Investigators

• Sponsor: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Daniel P Eisenberg, M.D., National Institute of Mental Health (NIMH)

Publications and helpful links

General Publications

• Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. doi: 10.1073/pnas.111134598. Epub 2001 May 29.
• Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. doi: 10.1038/nn804.
• Eisenberg DP, Kohn PD, Hegarty CE, Smith NR, Grogans SE, Czarapata JB, Gregory MD, Apud JA, Berman KF. Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia. Mol Psychiatry. 2022 Feb;27(2):1241-1247. doi: 10.1038/s41380-021-01337-1. Epub 2021 Nov 17.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 1989

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: March 11, 2024

More Information

Terms related to this study

• Keywords: Schizophrenia; Psychosis; Schizoaffective Disorder; Schizoaffective; Cognition; Neuroimaging
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 890160; 89-M-0160

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .Because a large share of the accrued dataset precludes broad sharing language in the consent, it is unlikely that sharing of only some IPD that underlie results in any given publication would be of scientific value.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No