Cognitive Remediation Therapy in Schizophrenia: Effects on Epigenetics

Epigenetic Regulation of Brain-Derived Neurotrophic Factor (BDNF) Gene Expression According to Response to Cognitive Remediation in Schizophrenia

This study is a randomised and controlled trial that aims to investigate whether Cognitive Remediation Therapy (CRT) can modulate epigenetic mechanisms by changing methylation levels of BDNF gene in patients with Schizophrenia.

OBJECTIVES: To investigate whether Cognitive Remediation Therapy (CRT) can modulate epigenetic mechanisms by changing methylation levels of BDNF gene. It also aims to test whether BDNF valine-66-methionine (Val66Met) polymorphism influences CRT treatment outcome among people with schizophrenia. SAMPLE AND METHODS: A randomized and controlled study will be carried out with two groups: patients receiving CRT and patients in control condition without any cognitive intervention and receiving Treatment as Usual (TAU). Methylation levels of BDNF gene at different sites will be contrasted before and after treatment. Additionally, neurocognition profile, level of symptoms and psychosocial functioning will also be tested. CRT outcomes will be investigated in a mixed model for repeated measures.

Study Procedure. 60 patients with schizophrenia disorder (according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classification, determined by The Structured Clinical Interview for DSM-5 (SCID-5) interview will be recruited and randomly allocated in one of the two groups: CRT or treatment as usual control group. All participants will undergo neurocognitive testing over a 2-week period, followed by a blood draw. After random allocation, 40 participants will follow a computerized cognitive remediation program and 20 will be followed a similar period of time without any cognitive intervention. Subjects will have another blood sample drawn after completion of the cognitive therapy or the TAU. All subjects should remain on stable doses of medications while in the study (no dose change > 10%). Finally, subjects will be reassessed on PANSS and cognitive measures and social functioning by personnel blind to group assignment.

"CIRCuiTS is a web-based computerised CR therapy, delivered by a therapist but supplemented with independent sessions to facilitate massed practice. It targets metacognition, particularly strategy use, in addition to providing massed practice of basic cognitive functions. The therapist facilitates motivation, metacognitive and strategy development and generalisation of learning by encouraging the participant to learn about and regulate their cognitive performance and to transfer this learning to meet real-world goals. Therapists provide additional scaffolding for CR tasks to ensure consistent successful performance. Independent sessions involve carrying out cognitive tasks allocated by the therapist to ensure scaffolded learning" (Reeder et al.2017)

Mean methylation percentage in CpG island BDNF CpG exon I: located at chr11:27743473-27744564 in the BDNF

Mean methylation percentage of CpG region BDNF CpG exon IV: located at chr11:27723060-27723294 in exon IV, upstream of the start codon in exon VII

Total score in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery

Inclusion Criteria: Diagnosis of schizophrenia according to DSM-5 and confirmed by the semi-structured interview (SCID) for the axis 1. Presence of cognitive impairment confirmed by the neuropsychological battery Stable symptomatology at least during the last six months and the estimation of not modifying pharmacological antipsychotic treatment . Exclusion Criteria: Presence of organic-cerebral affectation due to neurological or traumatic conditions Antipsychotic dose change >10% Abuse of psychotropic substances Presence of other psychiatric symptomatology