Clinical trial NCT02034253: Glutamate, Brain Connectivity and Duration of Untreated Psychosis
Official title: Glutamate, Brain Connectivity and Duration of Untreated Psychosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Schizophrenia
Psychosis
Schizoaffective Disorder
Keywords: duration of untreated psychosis
glutamate
functional connectivity
structural connectivity
schizophrenia
psychosis
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
First posted: 2014-01-13
Enrollment: 134
Sex: ALL
Minimum age (years): 17
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The investigators expect to enroll a total of 67 male and female patients with first episode psychosis and 67 demographic matched controls.

Among patients who participate in research at the University of Alabama at Birmingham (UAB) the approximate gender, ethnic and race distribution is 75% male and 25% female; 1% Hispanic and 99% Non-Hispanic; 54% White, 44% Black, and 1% Asian/Pacific Islander. The gender distribution is consistent with that observed in clinical populations with schizophrenia.

Persons below the age of 17 and above the age of 35 are excluded to minimize the variance in cognitive functioning or brain connectivity that might be attributable to development rather than diagnosis.

Brief summary: The early stages of schizophrenia are associated with significant decreases in social and intellectual abilities, with more declines in chronic disease. Studies have identified relationships between duration of untreated psychosis (the duration between the onset of positive symptoms and treatment) and worse long term outcomes. However, the neurobiology of this phenomenon and its implications for response to antipsychotic medications remain poorly understood.

Glutamatergic excess altering brain connectivity might provide an explanation for why those with longer duration of untreated psychosis have worse clinical outcomes. The investigators propose to use neuroimaging to study 67 first episode psychosis subjects before and after sixteen weeks of treatment with risperidone, a common antipsychotic. We will measure (1) glutamate and (2) structural and functional brain connectivity and test the hypotheses that glutamatergic abnormalities are present in first episode patients and that longer duration of untreated psychosis is associated with greater connectivity abnormalities that set the stage for poor response to treatment. 67 demographic-matched controls will also be recruited as a comparison group - healthy controls will not receive antipsychotic medication.

The investigator's previous studies have made progress in the understanding of abnormalities in the glutamate system and brain connectivity in unmedicated patients with schizophrenia and modulation of these by antipsychotic medication. Two indices of glutamatergic dysfunction have been identified. While antipsychotic medications appear to modulate glutamate, the disturbance in the relationship between metabolites is not restored with treatment. In addition, the investigators found that both structural and functional connectivity abnormalities in unmedicated patients with schizophrenia predict patients' response to treatment.

To the investigator's knowledge, no other group has performed a study that uses a combination of complementary neuroimaging techniques that will allow generating a broad characterization of glutamatergic function and brain connectivity in first episode psychosis and change with treatment. The results of the proposed studies could suggest a mechanism by which the duration of untreated psychosis is associated with poor treatment response which might lead to new interventions to target the illness.


Eligibility criteria: Inclusion Criteria:

* Persons with first episode psychosis
* Healthy controls will be matched to first episode psychosis participants on a one to one basis

Exclusion Criteria:

* inability to understand and sign informed consent assessed by the Evaluation to sign Consent form
* diagnosable central nervous system illnesses
* poorly controlled acute or chronic medical conditions aside from psychosis
* history of head trauma with loss of consciousness for \> 2 minutes
* active substance abuse or dependence (exclusive of nicotine dependence)
* suspected substance induced psychotic symptoms
* clinically significant symptoms of depression, hypomania, or mania
* patients concomitantly treated with drugs known to affect glutamate, such as: valproate, topiramate, gabapentin, levetiracetam, lamotrigine, lithium, and acamprosate

Primary outcomes:
measure: Comparison of indices of glutamate as measured by 1H-MRS in unmedicated first episode psychosis patients before and after antipsychotic treatment and with healthy controls.
timeFrame: Up to 5 years
Secondary outcomes:
measure: Comparison of structural and functional brain connectivity in first episode psychosis patients before and after antipsychotic treatment and healthy controls
timeFrame: Up to 5 years
measure: Evaluation of the contribution of structural and functional connectivity to eventual antipsychotic treatment response in first episode psychosis patients.
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Sparks Center
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham, Department of Psychiatry
name: Adrienne C. Lahti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maximo JO, Briend F, Armstrong WP, Kraguljac NV, Lahti AC. Salience network glutamate and brain connectivity in medication-naive first episode patients - A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study. Neuroimage Clin. 2021;32:102845. doi: 10.1016/j.nicl.2021.102845. Epub 2021 Sep 29.
citation: Maximo JO, Nelson EA, Armstrong WP, Kraguljac NV, Lahti AC. Duration of Untreated Psychosis Correlates With Brain Connectivity and Morphology in Medication-Naive Patients With First-Episode Psychosis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Feb;5(2):231-238. doi: 10.1016/j.bpsc.2019.10.014. Epub 2019 Nov 9.
citation: Kraguljac NV, Anthony T, Skidmore FM, Marstrander J, Morgan CJ, Reid MA, White DM, Jindal RD, Melas Skefos NH, Lahti AC. Micro- and Macrostructural White Matter Integrity in Never-Treated and Currently Unmedicated Patients With Schizophrenia and Effects of Short-Term Antipsychotic Treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 May;4(5):462-471. doi: 10.1016/j.bpsc.2019.01.002. Epub 2019 Jan 23.
citation: Sivaraman S, Kraguljac NV, White DM, Morgan CJ, Gonzales SS, Lahti AC. Neurometabolic abnormalities in the associative striatum in antipsychotic-naive first episode psychosis patients. Psychiatry Res Neuroimaging. 2018 Nov 30;281:101-106. doi: 10.1016/j.pscychresns.2018.06.003. Epub 2018 Jun 9.