This study examined whether adding structured supportive psychotherapy to risperidone treatment is more effective than risperidone alone in improving cognitive function and reducing inflammation in patients with schizophrenia.

Forty-six male patients with schizophrenia were randomly assigned to two groups: the intervention group (n=23) received risperidone 4 mg/day plus 12 sessions of structured supportive psychotherapy over 6 weeks. The control group (n=23) received risperidone 4 mg/day alone for 6 weeks.

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 6).

NOTE: This trial was retrospectively registered. The study was conducted from December 2024 to February 2025 and received ethical clearance (No. 1009/UN4.6.4.5.31/PP36/2024) from the Biomedical Research Ethics Committee, Faculty of Medicine, 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 double-blind randomized controlled trial was conducted at Dadi Psychiatric Hospital (RSJ Dadi), South Sulawesi Province, Makassar, Indonesia, from December 2024 to February 2025.

BACKGROUND:

Schizophrenia is associated with cognitive impairment and elevated inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP). Supportive psychotherapy has been proposed as an adjunctive intervention to pharmacotherapy to address these deficits. However, evidence on the combined effect of supportive psychotherapy and risperidone on both cognitive function and inflammation remains limited.

INTERVENTION:

The intervention group received risperidone 4 mg/day (2 mg twice daily) plus structured supportive psychotherapy consisting of 12 sessions delivered twice weekly over 6 weeks (15-30 minutes per session). The control group received risperidone 4 mg/day monotherapy for 6 weeks. To minimize expectation bias, supportive psychotherapy was described to all participants as "standard supportive counseling," thereby preventing identification of group allocation.

RANDOMIZATION AND BLINDING:

Participants were randomly allocated in a 1:1 ratio using a simple random number generator by an independent researcher not involved in clinical recruitment. Allocation concealment was achieved using the Sequentially Numbered Opaque Sealed Envelope (SNOSE) method, prepared by a separate research assistant and disclosed only after informed consent and baseline assessments were completed. Participants 1-23 were assigned to the intervention group and participants 24-46 to the control group. The study employed a double-blind design in which both participants and outcome assessors were blinded to group allocation. Outcome assessors evaluating MoCA-Ina scores and laboratory personnel measuring serum hs-CRP levels were fully blinded to group allocation throughout the study period.

OUTCOME MEASURES:

Primary outcomes were: (1) change in cognitive function assessed by Montreal Cognitive Assessment - Indonesian version (MoCA-Ina) from baseline to Week 6; and (2) change in serum hs-CRP level from baseline to Week 6. Secondary outcome was the correlation between delta hs-CRP and delta MoCA-Ina within each group at Week 6.

ETHICAL APPROVAL:

This study was approved by the Biomedical Research Ethics Committee, Faculty of Medicine, Universitas Hasanuddin (No. 1009/UN4.6.4.5.31/PP36/2024) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to enrollment.

NOTE: This trial was retrospectively registered. The study was conducted from December 2024 to February 2025 and received ethical clearance 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 patients diagnosed with schizophrenia according to DSM-5 criteria
• Aged 20-45 years
• Disease onset less than one year
• Insight level grade 4
• PANSS-EC score 14 or less
• Total PANSS score 60-70
• No febrile conditions, jaundice, or hepatosplenomegaly
• Willing and able to attend supportive psychotherapy sessions
• Receiving risperidone at fixed dose of 4 mg per day
• South Sulawesi ethnic origin

Exclusion Criteria:

• Organic comorbid diseases
• History of substance abuse within previous six months except caffeine and nicotine
• Comorbid personality disorders
• Obesity
• Active infectious diseases
• Use of anti-inflammatory agents, antibiotics, or antioxidant supplements
• Female sex

Participant blinding was achieved by describing the intervention to all participants as "standard supportive counseling," thereby preventing identification of group allocation and minimizing expectation bias. The structured supportive psychotherapy module used in the intervention group was not disclosed to participants. Outcomes assessors who evaluated MoCA-Ina scores and laboratory personnel who measured serum hs-CRP levels were fully blinded to participants' allocation status throughout the study period.