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.

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 Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) domains, with affected patients performing approximately two standard deviations below healthy controls. A landmark network meta-analysis of 68 randomized controlled trials (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. 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 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (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 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 change in hs-CRP (Δhs-CRP, where Δ denotes Week 12 minus baseline) and change in MoCA-Ina score (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.

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

Individual participant data will not be shared publicly. This pilot RCT involved a small sample (n=44) of psychiatric inpatients, raising re-identification risk despite de-identification efforts. The study was conducted at a single center in Indonesia without institutional data-sharing infrastructure. Findings from this pilot will inform a planned multicenter trial, which will include a formal prospective data-sharing plan.