Cognitive Impairment Characteristics and Biological Mechanisms in Untreated Severe Mental Illness

Patients with Severe Mental Illness (SMI) frequently exhibit cognitive impairment of varying degrees, involving multiple cognitive domains. These domains include working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem-solving, processing speed, and social cognition. The severity of this impairment often predicts poorer treatment adherence and serves as a crucial indicator of a patient's capacity for independent living and social reintegration. Research into the mechanisms underlying cognitive impairment offers robust theoretical support for therapeutic interventions in SMI and remains a major focus in psychiatry. However, cognitive impairment is a complex phenomenon; studies focusing on any single cognitive dimension can only reveal partial characteristics and often lack disease specificity. Therefore, there is an urgent need to integrate multiple technical modalities, focusing on a specific biological pathway related to the symptoms of cognitive impairment, to deeply elucidate the process of its onset and to screen for reliable biomarkers. This study will recruit untreated SMI patients and healthy community controls. Upon enrollment, participants will undergo comprehensive assessments including psychiatric symptom evaluation, cognitive function testing, Electroencephalography (EEG), Magnetic Resonance Imaging (MRI), and collection of research blood samples. A follow-up assessment will be conducted at 12 weeks, re-evaluating psychiatric symptoms, cognitive functions, and EEG, while collecting follow-up blood samples and medication records. By integrating these assessment indicators, we aim to identify the potential biological mechanisms underlying cognitive dysfunction in untreated SMI patients, construct a predictive and identification model for cognitive impairment, and explore the concomitant changes in biological markers during the evolution of cognitive impairment through longitudinal follow-up, thus paving the way for prospective targeted interventions.

Study Overview

• Status: Enrolling by invitation
• Conditions: Patients With Severe Mental Illness

• Study Type: Observational
• Enrollment (Estimated): 230

Contacts and Locations

Study Locations

• China
  • Tianjin, China
    • Tianjin Anding Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

This study will recruit 150 untreated severe mental illness patients and 80 healthy controls. The 150 subjects, aged 18-65, come from Tianjin Anding Hospital's inpatient/outpatient services and must consent to participate. Untreated patients must meet strict criteria: never taking antipsychotics, or taking them for ≤3 days, or >5 years of illness with <30 lifetime treatment days and no use in the last 5 years (TCM for psychosis excluded). The 80 healthy controls will be matched to patients based on age, gender, education, and residence (urban/rural).

Description

Inclusion Criteria:

• Aged 18-65 years;
• Matched to enrolled untreated patients in terms of age, sex, educational attainment, and place of residence (urban or rural).

Exclusion Criteria:

• Psychotic symptoms caused by a general medical condition or substance use;
• A history of mental retardation (estimated IQ below 70), dementia, head trauma, or brain disease, a history of seizures (epilepsy), or any history of violent or suicidal tendencies;
• Any factor that prevents the participant from providing informed consent or participating in the study.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Untreated Severe Mental Illness (SMI) Patients; We will enroll 150 patients who meet the following inclusion criteria: a current or past episode of a psychotic disorder meeting DSM-5 diagnostic criteria, including Schizophrenia, Schizoaffective Disorder, Acute and Transient Psychotic Disorder, Schizophreniform Disorder, Delusional Disorder, Other Specified or Unspecified Psychotic Disorder, or Bipolar Disorder with psychotic features; age between 18 and 65 years, inclusive; and willingness to participate and sign the informed consent form (ICF); in addition, untreated patients must meet the following specific criteria: no lifetime exposure to antipsychotic medication, or continuous use of antipsychotic medication for a period not exceeding 3 days, or a course of illness exceeding 5 years with no antipsychotic use in the last 5 years and a total lifetime cumulative use of antipsychotic medication of less than 30 days; traditional Chinese medicine used for treating psychotic symptoms will not be counted as antipsychotic medication.
Healthy Control; We will include 80 healthy controls who meet the following criteria: aged 18-65 years and matched to enrolled untreated patients in terms of age, sex, educational attainment, and place of residence (urban or rural).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Function	Cognitive function will be assessed using the MATRICS Consensus Cognitive Battery (MATRICS-CN). The following domains will be measured: processing speed, verbal learning, working memory, reasoning and problem-solving, visual learning, and attention/alertness. It possesses excellent psychometric properties, correlates with functional outcomes, and is brief, easy to administer, can be used for home-based assessments, is acceptable to participants, and has domain "robustness." The MATRICS-CN has been translated into Chinese and is available for purchase from PAR, Inc.	Baseline, week12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Symptom Scale (PANSS)	The psychiatric symptoms of schizophrenia were assessed in all enrolled patients using the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item clinician-rated scale yielding a total score ranging from 30 (least symptomatic) to 210 (symptomatic), where higher scores indicate more severe psychopathology.	Baseline, week12
Young Mania Rating Scale (YMRS)	This is an 11-item clinician-rated scale (scored from 0-4 or 0-8, depending on the items) that assesses the severity of mania and the response to treatment in patients with bipolar disorder. The assessment is based on clinical observation and patient subjective reports regarding symptoms over the past 48 hours.	Baseline, week12
Montgomery-Åsberg Depression Rating Scale (MADRS)	This is a 10-item clinician-rated questionnaire (scored 0-6 per item) that assesses the severity of depressive episodes in patients with affective disorders. The assessment is based on the patient's subjective report of their symptoms over the past week.	Baseline, week12
Global Assessment of Functioning (GAF) Scale	Primarily used to assess the subject's psychological, social, and occupational functioning. The GAF consists of only one dimension: the overall clinical severity level. It is divided into 100 levels (scored from 1-100), where a higher score indicates less severe illness.	Baseline, week12
Antisaccade Task Error Rate	The antisaccade task consists of 4 blocks of 20 trials each. Each trial begins with a central fixation cross. A peripheral visual target appears at 10° or 15° visual angle from fixation, and the fixation cross disappears 200ms after target onset. Participants are instructed to inhibit the reflexive saccade toward the peripheral target and instead generate a saccade to the mirror image location in the opposite visual field. Eye movements are recorded using an eye tracker integrated with the EEG system. The primary outcome is the error rate, calculated as the percentage of trials in which the participant fails to inhibit the reflexive saccade and looks toward the peripheral target rather than the correct mirror location.	Baseline, week12
Auditory Paired Stimuli P50 Suppression Ratio	Auditory paired stimuli are presented binaurally as 150 pairs of broadband auditory stimuli (duration 4s, 75dB). The inter-pair interval averages 9.5s (range 9-10s), and the inter-stimulus interval within each pair is 500ms. EEG is recorded continuously during the task. The P50 evoked potential is identified as the positive deflection occurring 40-80ms post-stimulus at the Cz electrode. The P50 suppression ratio is calculated as the amplitude of the response to the second stimulus (S2) divided by the amplitude of the response to the first stimulus (S1). A lower ratio indicates stronger sensory gating.	Baseline, week12
Auditory Oddball P300 Event-Related Potential Amplitude and Latency	Participants complete an auditory oddball task consisting of 567 standard tones (1000Hz) and 100 target tones (1500Hz) presented in a pseudo-random order, with an inter-stimulus interval of 1300ms. Participants are instructed to press a button upon hearing the target tone. EEG is recorded continuously. The P300 component is measured at the Pz electrode site as the largest positive deflection between 250-500ms post-stimulus. Primary outcomes are: 1) P300 amplitude (µV), defined as the peak voltage relative to a 200ms pre-stimulus baseline; and 2) P300 latency (ms), defined as the time from stimulus onset to the peak amplitude.	Baseline, week12
Resting-State EEG Spectral Power in Theta and Alpha Bands	Resting-state EEG is recorded for 5 minutes with eyes closed using a [具体设备] EEG system with electrodes placed according to the 10-20 system. Data are segmented into 2-second epochs and artifacts are removed via independent component analysis. Power spectral density (µV²/Hz) is calculated using fast Fourier transform. The primary outcomes are mean power in the theta band (4-8 Hz) and alpha band (8-13 Hz) at frontal and parietal electrode sites.	Baseline, week12
Gray Matter Volume from Structural MRI	High-resolution T1-weighted structural MRI scans are acquired using a [3T Siemens Prisma] MRI scanner. Images are preprocessed using voxel-based morphometry (VBM) with SPM12 software. Gray matter is segmented from white matter and cerebrospinal fluid. The primary outcome is the regional gray matter volume (mm³) in regions of interest, normalized for total intracranial volume.	Baseline, week12
Fractional Anisotropy from Diffusion Tensor Imaging (DTI)	Diffusion tensor imaging (DTI) data are acquired using a single-shot echo-planar imaging sequence with 30 diffusion directions (b-value = 1000 s/mm²) and one non-diffusion-weighted image (b=0). Data are preprocessed for eddy current and motion correction using FSL software. Fractional anisotropy (FA) maps are calculated, representing the directionality of water diffusion in white matter tracts. The primary outcome is the mean FA value in major white matter tracts (e.g., corpus callosum, cingulum bundle), with FA values ranging from 0 (isotropic diffusion) to 1 (completely anisotropic diffusion).	Baseline, week12
Amplitude of Low-Frequency Fluctuations (ALFF) from Resting-State fMRI	Resting-state functional MRI (fMRI) data are acquired using a gradient-echo echo-planar imaging sequence while participants are instructed to remain awake with eyes closed. Data are preprocessed including slice-timing correction, head motion correction, and spatial normalization to standard MNI space. The amplitude of low-frequency fluctuations (ALFF) is calculated as the square root of the power spectrum in the low-frequency range (0.01-0.08 Hz). The primary outcome is the mean ALFF value in predefined regions of interest, reflecting the intensity of spontaneous brain activity.	Baseline, week12
Resting-State Functional Connectivity (Seed-Based)	Using the same resting-state fMRI data described above, functional connectivity is assessed using a seed-based correlation approach. The mean time series is extracted from a seed region of interest (e.g., posterior cingulate cortex for default mode network). Pearson's correlation coefficients are calculated between the seed time series and all other voxels in the brain. Correlation coefficients are then transformed to Fisher's z-scores for normalization. The primary outcome is the strength of functional connectivity (Fisher's z) between the seed region and target brain regions.	Baseline, week12

Collaborators and Investigators

• Sponsor: Tianjin Anding Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: January 19, 2026
• First Submitted That Met QC Criteria: February 28, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: February 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: cognitive dysfunction; Untreated; longitudinal follow-up; Biological Mechanism; Patients with Severe Mental Illness
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: SMI-UT

Drug and device information, study documents

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