Psychotic Disorders Clinical Trial
Official title:
Hormonal and Inflammatory Biomarkers and Response to a Cognitive Remediation Therapy in Recent-onset Psychosis: Randomized, Cross-over, Single-blind, Pilot Clinical Trial
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.
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.
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