Hormonal and Inflammatory Biomarkers and Response to Cognitive Remediation in Recent-onset Psychosis
Condition: Psychotic Disorders
MeSH terms: Psychotic Disorders; Mental Disorders
Study type: Interventional

Summary: 
      This study aims to explore whether hormones or inflammatory markers are associated with
      cognitive changes following cognitive remediation therapy (CRT) in people with a recent-onset
      psychotic disorder.

      The following biomarkers for treatment response will be considered: hormones related to the
      hypothalamic-pituitary-adrenal (HPA) axis (plasma cortisol, cortisol awakening response,
      diurnal cortisol slope, salivary cortisol at assessment), free thyroxine (F-T4), prolactin,
      or inflammatory markers.

      This study was designed as a pilot clinical trial in order to know the feasibility of the
      intervention and to calculate the effect sizes of different hormonal and inflammatory
      variables on cognition. This approach would allow the design of future larger clinical trials
      to test specific hypotheses generated with this study.
    

Detailed description: 
      Cognitive dysfunction is a core feature of schizophrenia experienced by approximately 75% of
      the patients. It may occur at the early stages of psychosis, and it is usually unaltered
      despite positive symptom remission. Cognitive function at psychosis onset is what most
      strongly predicts worse long-term overall functioning as well as worse functionality in
      social and occupational areas. Cognitive remediation therapy (CRT) is an intervention
      targeting cognitive deficit using scientific principles of learning with the ultimate goal of
      improving functional outcomes. It has been shown to have a significant impact on cognition
      with medium effect sizes. Some studies have shown improvements in recent-onset psychosis
      patients reporting moderate to large effects on cognitive outcomes, such as verbal and
      working memory, visuospatial ability, psychosocial functioning, problem-solving, or executive
      functioning.

      Although CRT is an effective approach, there are data showing that 25-44% of the participants
      receiving this intervention will not improve. To date, only a limited number of studies have
      considered potential biomarkers that could predict the treatment response. Hormones and
      inflammatory markers are potential biomarkers that could moderate the response to CRT because
      they play important roles in cognitive function in psychiatric and non-psychiatric
      populations. Previous studies have suggested that hypothalamic-pituitary-adrenal axis
      hormones (e.g. cortisol), prolactin, thyroid hormones, and inflammatory markers are
      associated with cognitive performance.

      Twenty-eight patients with a recent-onset psychosis aged between 18 and 40 years old and with
      less than 3 years of duration of the illness will be recruited. Psychotic disorders will
      include the following DSM-IV diagnosis: schizophrenia, schizoaffective disorder, bipolar
      disorder, or psychotic disorder not otherwise specified. The patients will be recruited from
      the Early Intervention Service from Hospital Universitari Parc Taulí Sabadell, (Spain). All
      participants will be outpatients with stable illness (<4 points in each positive item of the
      Positive and Negative Syndrome Scale (PANSS) and being on community treatment for at least 4
      weeks).

      A randomized crossover clinical trial will be performed: one group will first receive
      computerized CRT (n=14) for three months, and the other group will receive treatment as usual
      (TAU) in the Early Intervention Service (n=14). Afterward, patients will switch arms to
      receive alternative intervention.

      The intervention will consist of a computerized CRT through Neuropersonal Trainer software
      (Fernandez-Gonzalo et al. 2015). This includes two rehabilitation modules: 1) the Cognition
      Module, that addresses the following cognitive domains: on sustained, selective and divided
      attention; verbal, spatial, visual and working memory; and executive functions including
      inhibition, sequence and planning; and 2) the Social Cognition Module, which allows working
      different aspects of emotional processing, the theory of mind and cognitive biases through 43
      multimedia-based tasks. Both modules have different levels of complexity. Each CRT session
      will be individualized to the cognitive needs of each patient by an expert neuropsychologist.
      The professional can adjust the difficulty level in each treatment session based on the
      participant baseline cognitive profile and his/her task performance in previous treatment
      sessions. The neuropsychologist will be guiding the sessions, assuring the understanding of
      the different tasks, and individually coaching every patient to achieve the correct
      performance.

      A fasting morning blood sample (drawn between 8 a.m. and 10 a.m.) will be obtained for all
      participants at baseline, at 12 weeks and at 24 weeks of follow-up, for determining cortisol,
      prolactin, hypothalamic-pituitary-thyroid axis hormones (thyroid-stimulating hormone [TSH]
      and free thyroxine [F-T4]), and inflammatory markers (IL-6, TNF-alpha, leukocyte count).
      Saliva samples will be collected for exploring hypothalamic-pituitary-adrenal axis measures
      (cortisol awakening response, circadian cortisol slope, cortisol levels at cognitive
      assessment) at each visit (baseline, week 12, and week 24).

      Repeated measurements at the same time points will be obtained with a neurocognitive battery
      based on the CANTAB cognitive battery for schizophrenia, that includes 8 cognitive tasks:
      Attention Switching Task (AST; assessing attention and response latencies); One Touch
      Stockings of Cambridge (OTS; assessing executive functioning: spatial planning and working
      memory); Paired Associates Learning (PAL; assessing visual memory and new learning); Reaction
      Time (RTI; assessing reaction time: motor and mental response speeds, as well as measures of
      movement time, reaction time, response accuracy and impulsivity); Rapid Vision Information
      Processing (RVP; assessing sustained attention); Emotion Recognition Task (ERT; assessing
      theory of mind processes); Spatial Working Memory (SWM; assessing Spatial Working Memory:
      retention and manipulation of visuospatial information, strategy and working memory errors);
      Verbal Recognition Memory (VRM; assessing verbal memory and new learning). Cognitive
      assessment will be performed between 3 p.m. and 5 p.m. Psychopathological assessment at each
      visit (baseline, 12 weeks and 24 weeks) will be assessed with the Positive and Negative
      Syndromes Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). The social
      performance will be assessed at each visit with the Personal Performance Scale (PSP).
      Assessments will be conducted by trained personnel who will remain blind to the group
      assignment.

      Linear mixed models will be used to explore whether hormonal or inflammatory biomarkers are
      associated with cognitive changes after the intervention (CRT). The model will test the fixed
      effects for the intervention (CRT vs TAU), time (baseline visit vs 3-month visit), and the
      studied hormones, as well as their interactions. Random effects will be considered for each
      participant. Two analyses will be conducted:

        1. Primary analysis: randomized parallel phase (intention-to-treat analysis; CRT vs TAU;
           first 3 months).

           All participants will be included, independently of whether they completed CRT or not.

        2. Secondary analysis: pre-post changes in CRT (per-protocol analysis; CRT only; 3 months).

      This secondary analysis will include a subgroup of patients who have completed at least
      one-third of the CRT sessions. For this analysis, those patients receiving CRT in the first
      wave (randomized parallel phase) or second wave (after the cross-over) will be grouped.
    

Intervention name(s): cognitive remediation; attendance to an Early Intervention Service for Psychosis
Intervention type(s): Behavioral; Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: early psychosis; cortisol; inflammation; thyroid; prolactin; cognitive rehabilitation; cognitive remediation