A Pilot Study of Adjunctive Structured Supportive Psychotherapy in Schizophrenia (PILOT RCT-SCZ)

Effects of Adjunctive Structured Supportive Psychotherapy on Cognitive Function and Serum High-Sensitivity C-Reactive Protein in Schizophrenia: A Pilot Randomized Controlled Trial

This pilot randomized controlled trial examined whether adding structured supportive psychotherapy to risperidone treatment is more effective than risperidone alone in improving cognitive function and reducing peripheral inflammation in stabilized inpatients with schizophrenia.

Forty-four male and female inpatients with schizophrenia were randomly assigned to two groups: the intervention group (n=22) received risperidone 4 mg/day plus 12 individual sessions of structured supportive psychotherapy (45-60 minutes per session, once weekly) over 12 weeks. The control group (n=22) received risperidone 4 mg/day plus 12 sessions of unstructured supportive conversation (attention-matched) over the same 12-week period.

Cognitive function was measured using the Montreal Cognitive Assessment - Indonesian version (MoCA-Ina) and inflammation was measured using serum high-sensitivity C-reactive protein (hs-CRP) levels, both assessed at baseline (Week 0) and after treatment (Week 12).

NOTE: This pilot randomized controlled trial was retrospectively registered. The study was conducted from March 2025 to June 2025 and received ethical clearance (PROTOKOL-UH24100793) from Komite Etik Penelitian Universitas Hasanuddin, prior to study initiation. Registration was performed after study completion due to the investigator's initial unawareness of prospective registration requirements. No outcome measures, study design, or statistical analysis plan were modified following data collection.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Neuroinflammation; Cognitive and Executive Dysfunction
• Intervention / Treatment: Behavioral: Structured supportive psychotherapy; Drug: Risperidone 2 mg; Drug: Risperidone 2 mg; Behavioral: Standard Clinical Care with Active Control

Detailed Description

This single-center, assessor-blinded, parallel-group pilot randomized controlled trial (RCT) was conducted at a national-level referral psychiatric hospital in South Sulawesi, Indonesia, with laboratory analyses performed at a university-affiliated molecular research laboratory in the same province, from March 2025 to June 2025.

BACKGROUND:

Schizophrenia affects approximately 23.6 million individuals globally and is associated with significant cognitive impairment spanning seven MATRICS domains, with affected patients performing approximately two standard deviations below healthy controls. A landmark network meta-analysis of 68 RCTs confirmed that no antipsychotic yields cognitive benefits superior to placebo, establishing a clear pharmacological ceiling. Converging evidence further implicates neuroinflammatory dysregulation as a key mechanistic contributor to cognitive burden, with elevated levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) inversely associated with performance across five cognitive domains. hs-CRP is consistently elevated in schizophrenia and tracks illness-stage severity, establishing it as a biologically plausible peripheral neuroinflammatory biomarker. While structured psychosocial interventions demonstrate meaningful adjunctive benefits in low-resource settings, no published RCT had examined whether adjunctive structured supportive psychotherapy simultaneously improves cognition and reduces peripheral neuroinflammatory burden in schizophrenia. This pilot RCT was designed to address that gap.

INTERVENTION:

Both groups received fixed-dose risperidone 4 mg/day throughout the 12-week trial period, with adherence ensured via direct nursing observation. The intervention arm additionally underwent 12 individual structured supportive psychotherapy sessions delivered once weekly over 12 weeks, each lasting 45-60 minutes (total therapist contact time approximately 540-720 minutes), conducted by three board-certified psychiatrists each with over five years of psychotherapy experience, using the nationally validated Indonesian supportive psychotherapy module for schizophrenia (Suhuyanli et al., 2022). The active control arm received an equivalent number of individual sessions over the same 12-week period (12 sessions, once weekly, each lasting 45-60 minutes), delivered by three board-certified psychiatrists with equivalent clinical experience, yielding comparable total therapist contact time of approximately 540-720 minutes per participant. Control sessions consisted of unstructured supportive conversation without a session manual, predetermined therapeutic modules, structured psychoeducation, or a fidelity protocol.

PARTICIPANTS AND ELIGIBILITY:

Eligible participants were male and female inpatients aged 20 to 45 years, diagnosed with schizophrenia according to DSM-5-TR criteria, who were in a post-acute stabilized residual phase on a fixed dose of risperidone 4 mg/day, and scored between 60 and 70 on the total Positive and Negative Syndrome Scale (PANSS). Exclusion criteria included febrile conditions, organic comorbidities, active infections, obesity (body mass index ≥ 30 kg/m²), personality disorders, concurrent anti-inflammatory or antioxidant medications, and substance use disorder within the preceding 6 months.

RANDOMIZATION AND BLINDING:

Participants were allocated 1:1 to intervention or control using a computer-generated random number sequence managed by an independent researcher not involved in clinical recruitment. Allocation concealment was maintained through sequentially numbered opaque sealed envelopes (SNOSE), opened only after baseline assessments were completed. Randomization was not stratified by sex or baseline biomarker values in this pilot; stratified allocation will be incorporated in the planned multicenter trial. The study employed an assessor-blinded design. Outcome assessors evaluating MoCA-Ina scores and laboratory personnel measuring serum hs-CRP levels were strictly blinded to group assignments throughout the study period. Both arms received equivalent standard inpatient psychiatric care, equivalent therapist contact time, and equivalent therapist qualification, with group assignment differing solely in the presence or absence of structured manualized therapeutic content. As is inherent to psychotherapy research, participant blinding was not possible; however, participants were not formally asked to guess their allocation. The integrity of assessor blinding was not quantitatively evaluated in this pilot, a limitation to be addressed through formal blinding index assessment in future trials.

OUTCOME MEASURES:

Co-primary outcomes were: (1) change in cognitive function assessed by the Montreal Cognitive Assessment - Indonesian version (MoCA-Ina) from baseline (Week 0) to Week 12; and (2) change in serum hs-CRP level from baseline to Week 12. An exploratory secondary outcome was the Spearman correlation between Δhs-CRP and ΔMoCA-Ina within each group at Week 12. PANSS change scores were also assessed as an additional secondary outcome to evaluate differential symptomatic improvement between arms.

ETHICAL APPROVAL:

This study was approved by Komite Etik Penelitian Universitas Hasanuddin (PROTOKOL-UH24100793), and conducted in accordance with the 2013 Declaration of Helsinki. Written informed consent was obtained from all participants or their legally authorized representatives prior to enrollment, with explicit assurance that withdrawal at any point would carry no adverse consequence. This manuscript contains no individually identifiable participant information.

NOTE: This pilot randomized controlled trial was retrospectively registered. The study was conducted from March 2025 to June 2025 and received ethical clearance (PROTOKOL-UH24100793) from Komite Etik Penelitian Universitas Hasanuddin, prior to study initiation. Registration was performed after study completion due to the investigator's initial unawareness of prospective registration requirements. No outcome measures, study design, or statistical analysis plan were modified following data collection.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Indonesia
  • South Sulawesi
    • Makassar, South Sulawesi, Indonesia, 90245
      • Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Jl. Perintis Kemerdekaan Km. 10, Tamalanrea Makassar 90245, South Sulawesi, Indonesia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female inpatients diagnosed with schizophrenia according to DSM-5-TR criteria
• Aged 20 to 45 years
• In a post-acute stabilized residual phase
• Total PANSS score between 60 and 70
• Receiving risperidone at a fixed dose of 4 mg per day
• Willing and able to attend individual psychotherapy sessions throughout the 12-week trial period

Exclusion Criteria:

• Febrile conditions at time of screening
• Organic comorbid diseases
• Active infectious diseases
• Obesity (body mass index ≥ 30 kg/m²)
• Comorbid personality disorders
• Concurrent use of anti-inflammatory medications or antioxidant supplements
• Substance use disorder within the preceding 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Structured Supportive Psychotherapy plus Risperidone; The intervention arm additionally underwent 12 individual structured supportive psychotherapy sessions delivered once weekly over 12 weeks, each lasting 45-60 minutes (total therapist contact time approximately 540-720 minutes), conducted by three board-certified psychiatrists each with over five years of psychotherapy experience, using the nationally validated Indonesian supportive psychotherapy module for schizophrenia (Suhuyanli et al., 2022)	Behavioral: Structured supportive psychotherapy; Structured supportive psychotherapy using the Supportive Psychotherapy Module for Schizophrenia (Suhuyanli et al., 2022), nationally validated in the Indonesian population. Sessions progressed across three structured phases: Sessions 1-3 established therapeutic alliance and clinical formulation; Sessions 4-9 addressed psychoeducation, coping strategies, reality testing, and adherence reinforcement; and Sessions 10-12 consolidated treatment gains and planned relapse prevention. Protocol fidelity required completion of at least 10 of 12 sessions, monitored by an independent rater using a structured checklist (inter-rater agreement κ = 0.84).; Drug: Risperidone 2 mg; Risperidone 4 mg/day (2 mg tablet twice daily, oral administration) for 12 weeks.; Drug: Risperidone 2 mg; Risperidone 4 mg/day (2 mg tablet twice daily, oral administration) for 12 weeks
Active Comparator: Active control arm; The active control arm received an equivalent number of individual sessions over the same 12-week period (12 sessions, once weekly, each lasting 45-60 minutes), delivered by three board-certified psychiatrists with equivalent clinical experience, yielding comparable total therapist contact time of approximately 540-720 minutes per participant. Control sessions consisted of unstructured supportive conversation without a session manual, predetermined therapeutic modules, structured psychoeducation, or a fidelity protocol.	Drug: Risperidone 2 mg; Risperidone 4 mg/day (2 mg tablet twice daily, oral administration) for 12 weeks.; Drug: Risperidone 2 mg; Risperidone 4 mg/day (2 mg tablet twice daily, oral administration) for 12 weeks; Behavioral: Standard Clinical Care with Active Control; Participants in the active control arm received an identical schedule of individual sessions over the 12-week period, administered by three board-certified psychiatrists of comparable clinical expertise. This design ensured an equivalent total contact time of approximately 540-720 minutes per participant, consisting strictly of Standard Clinical Care with Active Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cognitive Function (MoCA-Ina Score)	Change in cognitive function assessed by the Montreal Cognitive Assessment - Indonesian version (MoCA-Ina) from baseline to Week 12. Score range 0-30; higher scores indicate better cognitive function. The MoCA-Ina is a WHO-aligned, nationally validated instrument with substantial inter-rater reliability (κ = 0.820) and domain-level inter-rater agreement (κ = 0.817-1.000). Scores ≥26 indicate normal cognitive function.	Baseline (Week 0) and post-intervention (Week 12)
Change in Serum hs-CRP Level	Change in serum high-sensitivity C-reactive protein (hs-CRP) level (mg/L) from baseline to Week 12, quantified using a sandwich ELISA kit (Elabscience® Human hs-CRP ELISA Kit, catalog no. E-EL-H5134; detection range 15.63-1000 pg/mL; sensitivity 9.38 pg/mL; intra-assay CV 4.47-4.64%; inter-assay CV 6.44-8.95%).	Baseline (Week 0) and post-intervention (Week 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation Between Delta hs-CRP and Delta MoCA-Ina	Correlation between change in serum hs-CRP level (delta hs-CRP) and change in cognitive function score (delta MoCA-Ina) within each treatment group at Week 12. Analyzed using Spearman rank correlation coefficient (ρ), with 95% confidence intervals derived via Fisher z-transformation. Delta values calculated as Week 12 minus Week 0 for each measure.	Week 12 (end of intervention)
Change in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores	Change in total PANSS score and subscale scores (positive, negative, and general psychopathology) from baseline to Week 12, assessed to evaluate differential symptomatic improvement between the intervention and active control arms. Between-group differences in change scores analyzed using independent-samples t-test or Mann-Whitney U test based on normality assessment (Shapiro-Wilk). Delta values calculated as Week 12 minus Week 0 for each subscale.	Baseline (Week 0) and Week 12 (end of intervention)

Collaborators and Investigators

• Sponsor: Hasanuddin University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2025
• Primary Completion (Actual): June 30, 2025
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: June 22, 2026
• First Submitted That Met QC Criteria: June 22, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 22, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Schizophrenia; Neuroinflammation; C-Reactive Protein; Cognition; Psychotherapy
• Additional Relevant MeSH Terms: Nervous System Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Pathologic Processes; Inflammation; Pathological Conditions, Signs and Symptoms; Neuroinflammatory Diseases; Schizophrenia; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pyrimidinones; Risperidone
• Other Study ID Numbers: PILOT-HSCRP-2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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