CLINICAL TRIAL published: 07 July 2020 doi: 10.3389/fpsyt.2020.00636 Free Thyroxine Concentrations Moderate the Response to a Cognitive Remediation Therapy in People With Early Psychosis: A Pilot Randomized Clinical Trial Francesc Estrada 1,2, Josep Maria Crosas 1,2, Maribel Ahuir 1,2, Sara Pérez-Muñoz 1,2, Wanda Zabala 1,2, Raquel Aguayo 1,2, Juan David Barbero 1,2, Itziar Montalvo 1,2, Meritxell Tost 1,2, Laura Llauradó 1,2, Armand Guardia 1,2, Diego Palao 1,2,3, José Antonio Monreal 1,2,3 and Javier Labad 1,2,3* Edited by: 1 Department of Mental Health, Institut d’Investigació i Innovació Parc Taulı´ (I3PT), Parc Taulı´ Hospital Universitari, Sabadell, Błażej Misiak, Spain, 2 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Centro de Wroclaw Medical University, Poland Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain Reviewed by: Wenche Ten Velden Hegelstad, Stavanger University Hospital, Norway Introduction: Cognitive deficits are a cause of functional disability in psychotic disorders. Laura Ferraro, Cognitive remediation therapy (CRT) might be applied to improve these deficits. We University of Palermo, Italy conducted a pilot study to explore whether thyroid hormones might predict the response *Correspondence: Javier Labad to CRT in patients with recent-onset psychosis (ROP). jlabad@tauli.cat Methods: Twenty-eight stable ROP outpatients (9 women) were randomized to receive computerized CRT (N=14) or treatment as usual (TAU) (N=14), over three months. Both Specialty section: This article was submitted to cognitive and thyroid functions were assessed at the baseline and after those three Schizophrenia, months to all patients. A full cognitive battery (CANTAB) was administered before and after a section of the journal Frontiers in Psychiatry the treatment. Serum levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) Received: 02 April 2020 were measured. FT4 concentrations were recoded into a dichotomic variable (FT4 group) Accepted: 18 June 2020 based on the median of the sample (1.2 ng/dL). Data were analyzed on an intention-to- Published: 07 July 2020 treat basis with linear mixed models. Afterwards, we offered CRT to all participants from Citation: the TAU group and seven enrolled CRT, reassessing them when finished. Secondary Estrada F, Crosas JM, Ahuir M, Pérez- Muñoz S, Zabala W, Aguayo R, analyses were repeated in a sample of 14 participants who completed the CRT (either Barbero JD, Montalvo I, Tost M, from the beginning or after the TAU period) and attended at least one third of the sessions. Llauradó L, Guardia A, Palao D, Monreal JA and Labad J (2020) Free Results: The linear mixed models showed a significant time x CRT x FT4 group effect in Thyroxine Concentrations Moderate two cognitive tasks dealing with executive functions and sustained attention (participants the Response to a Cognitive Remediation Therapy in People with higher FT4 concentrations worsened executive functions but improved sustained With Early Psychosis: A Pilot attention after CRT). In the secondary analysis including all patients assigned to CRT, Randomized Clinical Trial. Front. Psychiatry 11:636. higher FT4 concentrations were associated with a poorer response in verbal memory but doi: 10.3389/fpsyt.2020.00636 a better response in spatial working memory. Frontiers in Psychiatry | www.frontiersin.org 1 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation Conclusions: Free thyroxine concentrations moderate the response to a CRT in patients with early psychosis. Keywords: cognitive rehabilitation, memory, psychosis, thyroid, cognition INTRODUCTION sometimes contradictory. A recent review (21) has explored 18 potential moderators to have an effect on CRT; nonetheless, they Cognitive dysfunction is a core feature of schizophrenia found no high-quality replicated evidence for any of them. experienced by approximately 75% of the patients, and it may To design a tailored treatment, searching for biomarkers as occur prior to the onset of psychosis, as it is usually unaltered despite moderators or mediators of cognitive improvement with CRT in positive symptom remission (1). Actually, cognitive function at schizophrenia is an emerging field of research. First, some studies psychosis onset is what most strongly predicts worse long-term have studied several candidate genes and proteins that could overall functioning as well as worse functionality in social and predict cognitive improvement after CRT such as catechol-o- occupational areas (2, 3). methyltransferase (COMT) (22–24), brain-derived neurotrophic Without any specific medication approved to treat cognitive factor (BDNF) (25, 26), or excitatory amino acid transporter 2 impairment (4), there has been an increased interest in the (EAAT2) (27). Neuroimaging studies suggest that cortical efficacy of cognitive remediation therapy (CRT) in the last reserve, defined as grey matter volume (28), cortical thickness decade. CRT is an intervention targeting cognitive deficit using (29), and integrity of the right fronto-occipital fasciculus, right scientific principles of learning with the ultimate goal of corticospinal tract and bilateral medial lemnisci (30) can improving functional outcomes (5). It has been shown to have moderate the response to CRT in cognitive domains such as a significant impact on cognition with a medium effect size: 0.41 social cognition, verbal and non-verbal memory, attention/ in the meta-analysis of McGurk et al., and 0.45 in the one from vigilance, and executive function. However, two recent reviews Wykes (5, 6). More specifically, some studies have shown have concluded that specific biological pathways underlying improvements in early psychosis patients reporting moderate cognitive remediation are still unclear, and the authors could to large effects on cognitive outcomes, such as verbal and not provide any guidance on clinical decision-making in this working memory, visuospatial ability, psychosocial functioning, field (21, 31). problem solving, or executive functioning (7, 8). Moreover, in Another potential biomarker moderating the response to those patients, a significant functional benefit such as in CRT could be thyroid hormones, as they play an important employment and in social functioning has been found (9). role in cognitive performance in psychiatric and non- However, the impact on symptoms is almost null, as it is more psychiatric populations (32). Thyroid hormones participate in significant in less symptomatic patients (5). In fact, cognitive brain development with effects on actin polymerization, deficits appear to reduce the potential benefit of rehabilitation microfilament organization, and neuronal migration (33). programmes, contributing to higher rates of institutionalization Hence, individuals with overt hypothyroidism have mild to (10). Nonetheless, Cella et al. showed a significant effect on moderate impairment in cognition, especially in memory; negative symptoms (0.36) in established schizophrenia patients those with overt thyrotoxicosis may have reduced attention/ (11). More recently, Ventura et al. found an improvement on concentration and executive function (34), but these negative symptoms at 12 months in the first episode of symptoms are usually reversible with levo-thyroxine (L- schizophrenia patients (FEP), comparing CRT to healthy T4) treatment?. Furthermore, in chronic patients with behaviour training (12). schizophrenia, several thyroid test abnormalities have been It is important to remark that the effect of CRT appears to be described: decreased activity of the hypothalamic–pituitary– homogeneous regardless of the method used and the programme thyroid axis, euthyroidism with a low triiodothyroxine (T3) duration (5, 13); however, a study has highlighted the levels, and increased thyroid antibodies (35), where the free T3 importance of adjusting the level of computerized exercises to (FT3) levels are associated with better cognitive function as the patients’ cognitive performances (14). Nevertheless, it seems assessed by the Mini-Mental State Examination (MMSE) (36). that even with limited duration of the intervention (5–15 h), mild More specifically, our group has studied the cognitive function in improvement can be observed (15). early psychotic patients and the potential contribution of thyroid Although CRT is an effective approach, there are data hormones. Barbero et al. found that better cognitive performance showing that 25–44% of the participants receiving this in the attention/vigilance domain of the MATRICS Consensus intervention will not improve (5, 16, 17). To date, only a Cognitive Battery (MCCB) was associated with subtly increased limited number of studies have considered how individual free thyroxine (FT4) levels (37). In addition, the same group characteristics may affect treatment response. Some of them performed a 1-year follow-up study that reported a U-shaped have suggested that being younger (18, 19), reporting fewer relationship between FT4 levels and longitudinal cognitive symptoms (5) and having more severe cognitive difficulties changes. In other words, the highest and lowest FT4 values (7, 20) can contribute to benefiting more from CRT. However, were associated with worsened attention in the follow-up it seems to be limited converging evidence, and the data are assessment, suggesting that subtle differences in normal FT4 Frontiers in Psychiatry | www.frontiersin.org 2 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation levels may play a role in the attention domain in early psychotic Afterwards, patients were offered to switch arms to give access patients (38). However, other studies had reported previously to the intervention to the TAU group. At that point, only 7 from that high levels of FT3 were associated with poorer performance the 14 patients who were in TAU finally enrolled the CRT on executive functioning and processing speed with no (2ndwave). Participants were reassessed with the same cognitive association of FT4 with cognitive domains (39). battery three months later (after the CRT). We conducted per- To our knowledge, there are no studies exploring the role of protocol analyses by excluding patients who did not complete at thyroid function as a predictor of cognitive improvement after least one third of the CRT sessions. Therefore, we finally had a CRT. Thus, we aimed to conduct a pilot study to explore whether sample of 14 patients: 7 patients from the initial CRT group (1st thyroid hormone levels, particularly FT4, might moderate wave) and 7 patients added in the 2nd wave. treatment response to a CRT when compared to treatment as The flow chart of the participants of the clinical trial is usual (TAU). We also aimed to study in what degree FT4 levels depicted in Figure S1 from the Supplementary Material. predict longitudinal cognitive changes in the subsample of patients completing at least one third of CRT sessions Intervention (excluding those who did not engage in the therapy). The intervention consisted of a computerized CRT through Neuropersonal Trainer (NPT) software (40). This CRT includes two rehabilitation modules: 1) the cognition module, that addresses sustained, selective, and divided attention; verbal, MATERIALS AND METHODS spatial, visual and working memory; and executive functions including inhibition, sequence, and planning; 2) the social Participants cognition module (41), which allows working different aspects We studied a population of 28 patients (9 women) with a recent- of emotional processing, the theory of mind and cognitive biases onset psychosis (ROP) aged between 18 and 40 years old and through 43 multimedia-based tasks. Both modules have different with less than 3 years of duration of the illness. Our sample is a levels of complexity. convenience sample of patients who were consecutively recruited All exercises offered immediate success/failure feedback and a from the Early Intervention Service from Hospital Universitari final summary of the results performance. Each rehabilitation Parc Taulı́ Sabadell, (Spain). All participants were outpatients session with NPT was individualized to the cognitive needs of with stable illness [< 4 points in each positive item of the Positive each patient by an expert neuropsychologist, who adjusted the and Negative Syndrome Scale (PANSS) and being on community difficulty level in each treatment session based on the participant treatment for at least 4 weeks]. The included patients with early baseline cognitive profile and his/her task performance in psychosis fulfilled the DSM-IV-TR criteria for schizophrenia previous treatment sessions. The neuropsychologist was always (n=17), schizoaffective disorder (n=8), psychotic disorder not guiding the sessions, assuring the understanding of the different otherwise specified (NOS) (n=2) or bipolar disorder (n=1). The tasks, and individually coaching every patient to achieve the exclusion criteria were refusal to participate, severe neurological correct performance. disease or intellectual disability, pregnancy, substance-induced The training was administered in 1.5 h sessions, twice a week, psychosis, history of severe traumatic brain injury, and visual during 12 weeks (36 h of total duration). To assure a therapeutic deficits or language difficulties that could influence cognitive effect, a minimum of 12 h of training for each participant was assessment and intervention. established by clinical consensus. Ethical approval was granted by the Drug Research Ethics Committee (CEIm) from Parc Taulı́ Hospital Universitari. All Screening Visit participants received extended information about the study, and All patients were interviewed by a psychiatrist, and the OPCRIT written informed consent was obtained. The biological samples checklist version 4.0 (available at http://sgdp.iop.kcl.ac.uk/opcrit) and the clinical data were collected following the Spanish was used to obtain DSM-IV diagnoses. PANSS was used to assess legislation of data protection to ensure the confidentiality of the severity of psychotic symptoms (42). The Calgary Depression the patients. Scale (CDS) was administered to assess depressive symptoms (43). The Personal and Social Performance scale (PSP) was used Design to measure functionality (44). These scales were administered by A randomized crossover clinical trial was performed as a pilot a psychiatrist or clinical psychologist with experience in the study (NCT04418570). In a first step, participants were treatment of patients with psychotic disorders. randomized into two groups: CRT (n=14) or TAU (n=14) in Socio-demographic data, clinical variables, and substance use the Early Intervention Service. Participants included in the CRT in the last month were obtained by a semi-structured interview, arm received the same health care in the Early Intervention to assure that the two randomized groups were comparable at Service as those participants included in the TAU group. All baseline assessment. Alcohol use was measured by standard patients were assessed (clinical and cognitive assessment) and a Spanish units/day, tobacco use was measured by cigarettes/day, blood sample was obtained at baseline and after the CRT/TAU and cannabis use was measured by qualitative description (daily period, 3 months later. We conducted an intention-to-treat or sporadic). analysis for cognitive changes over the first three months All patients received antipsychotic treatment. Overall, 13 (1st wave). were on LAI treatment (11 with paliperidone and 2 with Frontiers in Psychiatry | www.frontiersin.org 3 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation aripiprazole). The rest were treated with oral antipsychotics: used as a continuous covariate for adjustment. The following aripiprazole (n=8), clozapine (n=3), paliperidone (n=2), fixed effects were tested: time (baseline vs 3-months visit), risperidone (n=1), and olanzapine (n=1). Each antipsychotic intervention (CRT vs TAU), FT4 (low vs high) and TSH. The dose was converted to chlorpromazine equivalents in mg/day following interactions were also tested: time x intervention, (45). We considered long-acting aripiprazole 400 mg as 267 mg/ time x FT4, intervention x FT4, time x intervention x FT4. day of chlorpromazine. Participants were considered random effects in the model. Restricted Maximum Likelihood (REML) was used for fitting Cognitive Assessment the model and estimating the effects of the variables included in To assess the cognitive function, we utilized the Cambridge the model. First-order autoregressive was used as the structure Neuropsychological Test Automated Battery (CANTAB) for for the within-subject covariance matrix. schizophrenia (46). This battery has 8 specific tests to assess In the second analyses (per-protocol, including all participants cognition in patients with psychosis. Those are: Attention completing at least one third of the CRT sessions during the 1st wave Switching Task (AST; assessing attention and response or the 2nd wave), the following fixed effects were considered: time, latencies); One Touch Stockings of Cambridge (OTS; assessing FT4 group, TSH, time x FT4 group. Participants were also executive functioning: spatial planning and working memory); considered random effects in the model. Paired Associates Learning (PAL; assessing visual memory and Our clinical trial was considered a pilot study. Some authors new learning); Reaction Time (RTI; assessing reaction time: have suggested the role of thumb of 12 per group for a pilot study motor and mental response speeds, as well as measures when there is no prior information (47). As we had no previous of movement time, reaction time, response accuracy and data on the moderation of FT4 concentrations on cognitive impulsivity); Rapid Visual Information Processing (RVP; changes, we decided to include a sample size of 28. This assessing sustained attention); Emotion Recognition Task sample size would be sufficient to detect moderate to large (ERT; assessing theory of mind processes); Spatial Working effects with a statistical power of 90% and two-sided 5% Memory (SWM; assessing spatial working memory: retention significance (48). However, it is important to underscore that and manipulation of visuospatial information, strategy and our study is underpowered for detecting small effects. working memory errors); Verbal Recognition Memory (VRM; Although we conducted multiple statistical analyses, we did assessing verbal memory and new learning). The description of not adjust for multiple comparisons, as it is not strictly necessary all different cognitive tasks is included in List S1 from the to adjust for multiple comparisons in exploratory studies (49). Supplementary Material. Hormonal Assessment A fasting blood sample was obtained in the morning between 8 RESULTS and 10 a.m.to determine thyroid hormones. Serum levels of thyroid-stimulating hormone (TSH) and FT4 were measured Baseline Characteristics using an electrochemiluminescence immunoassay on an Socio-demographic and clinical characteristics of the study automated analyser (Cobas 8000 e801, Roche Diagnostics, participants are presented in Table 1. Of the patients, only two Mannheim, Germany). had subclinical hypothyroidism (TSH > 5 µU/mL with normal FT4), with a TSH range of 0.63-7.91 µU/mL. These two cases Statistical Analysis were in the TAU group, which explains significant differences in The statistical analysis was conducted with SPSS version 22.0 TSH baseline levels between the two groups (p=0.038). The FT4 (IBM, USA). To assess the differences on baseline variables concentrations ranged between 0.87 and 1.68 ng/dL and were all between two groups (TAU and CRT), we used Student’s t-test within the normal range. There were no significant differences in for continuous variables, the Mann-Whitney U test for ordinal TSH or FT4 concentrations between men and women (data not variables, and a chi-squared test for categorical variables. We shown). The two randomized groups did not differ in socio- considered significance to be a p-value <0.05 (two-sided). demographic characteristics, psychopathology (although a trend Longitudinal changes in cognitive variables were analyzed towards higher negative symptom scores was found in the TAU with linear mixed models. We previously transformed cognitive group), global functionality, or substance misuse (Table 1). In scores into z-scores. Z-scores are linearly transformed data relation to CANTAB cognitive tasks at baseline visit, there were values having a mean of zero and a standard deviation of 1. no significant differences with the exception of verbal memory – We also divided all participants into two groups for FT4 immediate recall, which was better in the TAU group (30.7 ± 3.1) concentrations taking into account the median of the baseline than in the CRT group (25.8 ± 4.8, p= 0.003). measures (1.2 ng/dL): 1) high FT4 (≥ 1.2 ng/dL) and 2) low FT4 (< 1.2 ng/dL). Wave 1 Analysis (Randomized Phase, CRT In the first analyses (intention-to-treat basis, 1st wave), vs TAU; Intention-to-Treat). intervention (CRT vs TAU) was defined as a factor, being the Longitudinal cognitive changes by treatment arm are described TAU arm as the reference category. Time (visit) and FT4 group in Table 2. The estimated fixed effects of factors and covariates were also considered factors (baseline visit and low FT4 were set and interactions calculated with the linear mixed models are as the reference categories). TSH concentrations (z-scores) were reported in Table S1 from the Supplementary Material. These Frontiers in Psychiatry | www.frontiersin.org 4 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation TABLE 1 | Sociodemographic, hormonal, and clinical variables. effects, that considered z-scores for each CANTAB cognitive CRT (N=14) TAU (N=14) p Value1 variable, have been also described in Figure 1. For easing the Female sex 7 (50%) 2 (14.3%) 0.103 interpretation of these effects, those cognitive variables that show Age (years) 26.9 (5.6) 25.4 (4.9) 0.459 an inverse relationship with cognitive performance (higher scores Caucasian ethnicity 13 (92.9%) 11 (78.6%) 0.244 reflecting worse cognitive performance) have been indicated with Educational level (years of study) 10.3 (2.0) 10.8 (2.6) 0.570 an asterisk. Therefore, positive estimated fixed effects (z-scores for Alcohol use (standard unit/day) 0.7 (1.4) 0.1 (0.1) 0.081 each cognitive task) would represent cognitive improvement over Tobacco (cigarettes/day) 12.6 (6.8) 7.7 (9.5) 0.137 Cannabis Use 0.935 time in positive cognitive variables but cognitive worsening over No 5 (35.7%) 5 (35.7%) time in inverse cognitive variables (marked with an asterisk). As it Occasional 5 (35.7%) 6 (42.9%) can be seen in Figure 1, longitudinal changes in OTS Problems Daily 4 (28.6%) 3 (21.4%) Solved on First Choice (OTSPSFC), a measure of executive PANSS-positive 8 (7-13) 8 (7-14) 0.247 functioning, differed between treatment (TAU vs CRT) and FT4 PANSS-negative 9 (10-28) 15 (8-29) 0.406 PANSS-general 26 (21-42) 22 (16-40) 0.087 (low vs high) groups, as the interaction between time x CRT x FT4 CDSS 2 (0-15) 2 (0-14) 1.0 group was significant. This triple interaction is also represented in PSP 54.6 (15.0) 65.8 (17.8) 0.104 Figure 2, showing that patients with higher FT4 levels worsened in Chlorpromazine equivalent doses (mg/ 333.4 229.7 0.183 this measure in both CRT and TAU groups whereas patients with day) (179.6) (219.0) Thyroid hormones lower FT4 levels had a different pattern depending on the treatment TSH (µU/mL) 1.86 (0.80) 3.09 (1.90) 0.038 arm (worsening when receiving CRT and improvement when FT4 (ng/dL) 1.20 (0.20) 1.20 (0.21) 0.918 receiving TAU). Data represent the mean (SD), median (range) or N (%). Another significant triple interaction (time x CRT x FT4 group) CRT, Cognitive Remediation Therapy; TAU, Treatment as usual; PANSS, Positive and Negative was found for rapid visual information processing (RVPA, a Syndrome Scale; CDSS, Calgary Depression Scale for Schizophrenia; PSP, Personal and Social measure that reflects how good a subject is for detecting target Performance Scale; TSH, Thyroid Stimulating Hormone; FT4, Free thyroxine. 1 sequences). Patients with higher FT4 concentrations in the TAU Chi-square test was used for categorical variables. T-test was used for continuous variables. Mann-Whitney U test was used for ordinal variables. arm worsened in this measure (Figure 3), but improved if were TABLE 2 | Longitudinal changes in cognitive measures (raw scores) by treatment arm. CANTAB task1 CANTAB variable2 TAU (n=14) CRT (n=14) Pre Post Pre Post AST ASTLCMD* 600.7 (135.7) 565.3 (147.6) 635.2 (157.7) 642.5 (261.7) ASTLSWMD* 793.8 (185) 681.0 (199.3) 750.4 (205.3) 749.3 (231.6) OTS OTSMDLFC* 11649.0 (4637.1) 7694.8 (3398.8) 12753.4 (5709.1) 11387.9 (7419.0) OTSPSFC 9.4 (2.1) 9.5 (2.4) 9.9(2.7) 8.8 (3.5) PAL PALFAMS 14.3 (5.5) 15.9 (2.8) 11.1 (3.5) 11.0 (3.6) PALTEA* 12.4 (16.3) 6.0 (6.4) 18.9 (12.2) 17.3 (10.1) RTI RTIFMDMT* 266.4 (68.3) 281.7 (98.6) 287.7 (87.1) 297.9 (132.6) RTIFMDRT* 403.2 (65.3) 398.3 (42.9) 438.4 (67.2) 431.3 (72.4) RTISMDMT* 227.5 (65.7) 248.8 (113.3) 237.4 (81.5) 226.9 (64.5) RTISMDRT* 348.9 (58.8) 353.1 (38.4) 381.8 (87.0) 367.5 (66.2) RVP RVPA 0.84 (0.04) 0.82 (0.08) 0.83 (0.03) 0.84 (0.07) RVPMDL* 509.6 (109.5) 460.7 (83.7) 548.0 (127.2) 494.4 (135.7) RVPPFA* 0.026 (0.057) 0.014 (0.018) 0.036 (0.045) 0.055 (0.118) ERT ERTOMDRT* 1499.9 (453.2) 1356.9 (500.4) 1939.2 (651.3) 1867.8 (1534.4) ERTTH 29.14 (4.28) 26.25 (7.58) 26 (4.10) 27.54 (3.41) SWM SWMBE* 15.2 (8.0) 12.7 (8.1) 15.5 (19.8) 14.5 (7.9) SWMBE4* 1.1 (1.4) 0.8 (1.3) 1.4 (1.2) 0.8 (0.9) SWMBE6* 5.5 (3.6) 3.1 (2.1) 4.1 (3.5) 4.9 (3.5) SWMBE8* 8.5 (5.7) 8.8 (5.8) 10.2 (6.3) 9.1 (4.9) SWMS* 8.46 (2.8) 8.6 (2.5) 8.2 (2.4) 8.9 (2.3) VRM VRMDRTC 30.6 (4.5) 27.8 (5.7) 27.4 (3.7) 27.4 (3.7) VRMFRDS 6.7 (3.4) 6.0 (2.5) 4.9 (2.1) 3.8 (1.8) VRMIRTC 30.7 (3.1) 28.9 (4.4) 25.8 (4.8) 26.6 (4.3) TAU, Treatment as usual; CRT, Cognitive remediation therapy; AST, Attention Switching Task (assessing attention and response latencies); OTS, One Touch Stockings of Cambridge (assessing executive functioning: spatial planning and working memory); PAL, Paired Associates Learning (assessing visual memory and new learning); RTI, Reaction Time (assessing reaction time: motor and mental response speeds, as well as measures of movement time, reaction time, response accuracy and impulsivity); RVP, Rapid Vision Information Processing (assessing sustained attention); ERT, Emotion Recognition Task (assessing theory of mind processes); SWM, Spatial Working Memory (assessing Spatial Working Memory: retention and manipulation of visuospatial information, strategy and working memory errors); VRM, Verbal Recognition Memory (assessing verbal memory and new learning). 1 The definition of all CANTAB tasks (and CANTAB variables) is described in List S1 from Supplementary Material. 2 For all cognitive tasks, lower scores reflect better cognitive performance unlike OTSPSFC, PALFAMS, RVPA, ERTTH, and all VRM tasks (which are the opposite; higher scores reflect better cognitive performance). Reverse scores have been marked with an asterisk (*), indicating that higher scores reflect worse cognitive performance. Frontiers in Psychiatry | www.frontiersin.org 5 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation A B C D FIGURE 1 | Longitudinal changes in CANTAB cognitive tasks by CRT and FT4 groups: fixed effects dealing with time estimated with linear mixed models. Bars represent the estimated effect and standard error for each cognitive task (z-score) for the following variables and interactions: time (A), time x CRT (B), time x FT4 (C) and time x CRT x FT4 (D). The full results of the linear mixed models are also represented in Table S1 from Supplementary Material. CRT, Cognitive remediation therapy; FT4, Free thyroxine. CANTAB Cognitive tasks are described in List S1 from Supplementary Material. *Reverse scoring tasks are marked with an asterisk (higher scores representing worse cognitive performance). †p <0.05. receiving CRT. In contrast, patients with lower FT4 concentrations showed less cognitive changes in this cognitive task over time independently of their treatment arm (CRT or TAU). As it can be seen in Table S1 and Figure 1, CRT was not associated with significant changes over time in most cognitive variables (most time x CRT interactions were non-significant), and ever worsened in a two cognitive tests dealing with executive functioning (OTS) and spatial working memory (SWMBE6, a measure of working memory errors; this task has also notable executive function demands). Wave 2 Analyses (Pre-Post Changes After CRT in the Patients Completing One Third of the Sessions; Per-Protocol Analysis). In this secondary analysis, we included all patients assigned to CRT who completed one third of the sessions (N= 14 participants). There were no significant differences in CANTAB cognitive tasks between patients who did not engage in the CRT and those who completed at least one third of the FIGURE 2 | Longitudinal changes in executive function (One Touch sessions (data not shown). CRT treatment was not associated Stockings of Cambridge - Problems Solved on First Choice) by CRT and FT4 with cognitive improvement in any task (Table 3), as the time groups. F-T4, Free thyroxin; CRT, Cognitive remediation therapy; TA5U, Treatment as usual. effect was non-significant for all measures but the SWMBE6 (patients worsened in this task after CRT). A time x FT4 Frontiers in Psychiatry | www.frontiersin.org 6 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation Figures S2 and S3 from the Supplementary Material. As it can be seen in Figure S2, patients with lower FT4 concentrations made more errors in the spatial working memory task involving 6 tokens after CRT whereas patients with higher FT4 concentrations improved over time in this task after CRT. In relation to delayed verbal memory, those patients with higher FT4 concentrations worsened in this task whereas those patients with lower FT4 concentrations improved after CRT (Figure S3). DISCUSSION The present study highlights the role of hypothalamic–pituitary– thyroid axis hormones, particularly FT4, in cognitive changes over time in a sample of young patients with early psychosis who received CRT, especially in sustained attention and executive functions. In the secondary analysis, including only the patients who completed at least on third of the CRT, FT4 appeared to FIGURE 3 | Longitudinal changes in rapid visual information processing by moderate the response to the CRT in relation to spatial working CRT and FT4 groups. F-T4, Free thyroxin; CRT, Cognitive remediation memory and delayed verbal memory. therapy; TAU, Treatment as usual. Our clinical trial was designed as a pilot study to explore whether thyroid hormones could predict the clinical response to CRT. We interaction was found for two cognitive tasks dealing with spatial included a sample of ROP patients because we were interested in working memory (SWMBE6) and verbal memory (VRMDRTC, exploring the potential pro-cognitive effect of CRT in early stages of delayed recognition of words). These interactions are shown in the illness, and we also aimed to identify biomarkers that would help TABLE 3 | Results of the linear mixed models exploring longitudinal changes in cognition in the patients receiving at least one third of sessions of cognitive remediation. CANTAB task CANTAB variable2 CRT (n=14) Estimated fixed effects (calculated with z-scores) Time FT4 group TSH Time x FT4 group Pre Post Effect (SE) P Effect (SE) P Effect (SE) P Effect (SE) P AST ASTLCMD* 624.9 (158.2) 677.7 (261.2) 0.05 (0.34) 0.895 -0.01 (0.44) 0.989 0.11 (0.22) 0.638 0.01 (0.50) 0.977 ASTLSWMD* 714.1 (177.2) 720.6 (231.3) 0.13 (0.30) 0.673 0.31 (0.51) 0.550 0.34 (0.25) 0.897 -0.22 (0.45) 0.631 OTS OTSMDLFC* 11301.1 (6648.3) 11241.5 (7298.9) 0.15 (0.20) 0.466 0.12 (0.57) 0.838 -0.04 (0.28) 0.887 -0.38 (0.31) 0.247 OTSPSFC 9.21 (3.0) 9.50 (3.8) -0.19 (0.32) 0.562 -0.02 (0.52) 0.969 0.47 (0.26) 0.859 0.64 (0.48) 0.209 PAL PALFAMS 12.5 (4.9) 12.4 (3.8) -0.12 (0.41) 0.784 0.14 (0.54) 0.796 0.48 (0.19) 0.028 0.23 (0.63) 0.720 PALTEA* 16.6 (14.7) 15.0 (11.2) -0.30 (0.37) 0.431 -0.62 (0.53) 0.267 -0.49 (0.20) 0.032 0.42 (0.57) 0.474 RTI RTIFMDMT* 251.9 (68.0) 275.9 (76.8) 0.03 (0.40) 0.941 -0.08 (0.54) 0.886 0.14 (0.24) 0.562 0.70 (0.61) 0.272 RTIFMDRT* 401.3 (65.1) 414.1 (66.8) 0.71 (0.34) 0.840 0.09 (0.57) 0.876 -0.19 (0.26) 0.469 0.30 (0.53) 0.583 RTISMDMT* 227.7 (67.4) 243.0 (78.1) 0.06 (0.36) 0.864 -0.10 (0.53) 0.862 0.20 (0.25) 0.435 0.35 (0.55) 0.536 RTISMDRT* 357.5 (57.5) 363.1 (65.5) -0.04 (0.36) 0.903 -0.07 (0.55) 0.894 -0.14 (0.26) 0.591 0.32 (0.55) 0.571 RVP RVPA 0.83 (0.03) 0.86 (0.03) 0.39 (0.27) 0.176 0.22 (0.52) 0.680 0.08 (0.23) 0.721 0.79 (0.41) 0.080 RVPMDL* 535.3 (103.7) 496.0 (113.7) -0.35 (0.48) 0.476 -0.52 (0.51) 0.329 -0.37 (0.18) 0.068 -0.02 (0.73) 0.978 RVPPFA* 0.043 (0.067) 0.020 (0.018) -0.49 (0.44) 0.285 -0.35 (0.74) 0.652 -0.09 (0.09) 0.371 0.09 (0.70) 0.897 ERT ERTOMDRT* 1801.4 (614.0) 1855.1 (1462.2) 0.32 (0.38) 0.428 -0.09 (0.31) 0.766 -0.19 (0.15) 0.242 -0.62 (0.59) 0.311 ERTTH 28.4 (4.8) 28.2 (3.2) -0.09 (0.37) 0.806 -0.14 (0.64) 0.836 0.19 (0.23) 0.433 0.13 (0.57) 0.817 SWM SWMBE* 12.8 (9.6) 14.2 (8.9) 0.53 (0.34) 0.152 0.004 (0.52) 0.994 -0.38 (0.25) 0.155 -0.70 (0.53) 0.215 SWMBE4* 0.93 (1.33) 0.93 (1.0) 0.33 (0.37) 0.395 0.61 (0.63) 0.354 -0.06 (0.24) 0.813 -0.76 (0.56) 0.203 SWMBE6* 3.4 (3.4) 4.2 (3.4) 0.82 (0.23) 0.004 0.40 (0.53) 0.471 -0.23 (0.25) 0.384 -1.31 (0.35) 0.003 SWMBE8* 8.5 (6.2) 9.3 (5.5) 0.27 (0.45) 0.554 -0.33 (0.52) 0.539 -0.34 (0.23) 0.169 -0.19 (0.69) 0.790 SWMS* 7.5 (2.7) 9.0 (1.8) 0.91 (0.45) 0.067 0.12 (0.65) 0.854 0.02 (0.19) 0.903 -0.68 (0.69) 0.349 VRM VRMDRTC 28.3 (4.8) 28.4 (4.8) -0.71 (0.37) 0.084 1.69 (0.32) < 0.001 0.09 (0.16) 0.589 -1.69 (0.55) 0.010 VRMFRDS 5.5 (2.7) 4.3 (1.9) -0.69 (0.46) 0.164 -0.09 (0.68) 0.894 0.32 (0.18) 0.113 0.41 (0.71) 0.577 VRMIRTC 27.0 (5.2) 27.9 (3.6) 0.69 (0.57) 0.250 1.07 (0.60) 0.099 0.03 (0.15) 0.870 -1.14 (0.87) 0.211 CRT, Cognitive remediation therapy; TSH, Thyroid-stimulating hormone; FT4, Free thyroxine; AST, Attention Switching Task; OTS, One Touch Stockings of Cambridge; PAL, Paired Associates Learning; RTI, Reaction Time; RVP, Rapid Vision Information Processing; ERT, Emotion Recognition Task; SWM, Spatial Working Memory; VRM, Verbal Recognition Memory. 1 The definition of all CANTAB tasks is described in List S1 from Supplementary Material. 2 For all cognitive tasks, lower scores reflect better cognitive performance unlike OTSPSFC, PALFAMS, RVPA, ERTTH, and all VRM tasks (which are the opposite; higher scores reflect better cognitive performance). Reverse scores have been marked with an asterisk (*), indicating that higher scores reflect worse cognitive performance. All statistically significant domains (p < 0.05) have been highlighted in bold text. Frontiers in Psychiatry | www.frontiersin.org 7 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation to determine which patients would benefit from an early findings and to also explore whether a potential “U shape” intervention. When controlling for TSH and FT4 concentrations, pattern does also apply for the cognitive response to a CRT. we failed to detect a specific effect of the intervention (CRT) Although several classic studies have found contradictory results compared with TAU. This could be explained by several reasons between cross-sectional associations among TSH, FT4, FT3, and such as a low proportion of participation in sessions or the small cognitive performance (39, 52), there are no studies exploring the sample size, which could imply a lack of statistical power for potential role of thyroid hormones as a predictor of response to detecting small effects. Our sample comprised ROP patients; this CRT. Our study needs to be considered a pilot clinical trial and could also explain why both groups (CRT and TAU) improved over replicated before drawing definitive conclusions. The secondary time because ROP patients are known to improve in cognitive analysis conducted in the subsample with a greater attendance to abilities in the first years of the illness (50, 51). Moreover, several CRT sessions shows promising results, suggesting the potential patients became enrolled in educational or job-seeking activities, moderating effects of thyroid hormones on cognitive changes. If which could also contribute to improved cognition over time. these results are confirmed in future studies with larger samples, a Previous studies have reported that subtle deficits in working tailored therapy approach taking into account specific biomarkers memory and executive function likely exist in subclinical thyroid (e.g., FT4) to maximize its potential benefits is suggested. disease hypothesizing that the degree of cognitive dysfunction is The physiopathology connecting thyroid hormones and probably related to the degree of thyroid dysfunction and cognition is not fully known to date. It is known that thyroid subclinical thyroid disease (34). Several studies conducted in hormones have an association with the polymerization of psychiatric populations have reported poorer cognitive astrocytes. Those cells may contribute to behavioral disorders performance (in processing speed and verbal memory) in patients related to reward circuits, and reactive astrogliosis is a well- with bipolar disorder and subclinical hypothyroidism, as well as known feature of Alzheimer’s disease (53). Several studies have cognitive improvements with T3 administration in patients detected a decreased number of astrocytes in cortical and receiving lithium or electroconvulsive therapy (32). In our study, subcortical areas in patients with schizophrenia (54). Moreover, patients had FT4 levels within the normal range, which is in dystrophic and swollen astrocytes have been found in psychotic accordance with previous results from our group (37) that noted patients, and those alterations progressed with the duration of the that subtle differences in FT4 levels may be important in cognitive illness (55). Recently, O’Donovan et al. hypothesized that increased performance in people with early psychosis. The cited cross- adenosine kinase activity in astrocytes may reduce extracellular sectional study found that increased FT4 levels were associated adenosine, with subsequent hypofunction on the adenosine with better performance in the attention/vigilance domain, neurotransmitter system, which is altered in schizophrenia (56). especially in subjects with affective psychosis. In another Antipsychotic treatment is another factor that could also contribute longitudinal study from our group (38), both higher and lower to the reduction of astrocytes because astrocytes express dopamine FT4 concentrations (although within normal limits) were receptors. It could also be that antipsychotic treatment reduces the associated with poorer cognitive outcome in attention/vigilance number of astrocytes, as astrocytes express dopamine receptors, and one year later. animal studies have demonstrated a lower astrocyte number in As the sample size of our study was small, we decided to macaque monkeys chronically exposed to antipsychotics (57). compare high vs low FT4 concentrations using the median of our Thus, it seems that thyroid hormones could intervene in sample (1.2 ng/dL). For this reason, we could not explore a “U- cognitive changes through their actions on astrocytes, shaped” pattern as in our previous study (38). In our current affecting the morphology, functioning, and number of these cells study, higher FT4 levels moderated longitudinal changes in two in psychotic patients. cognitive tasks that imply attention (sustained attention and Some limitations of our study need to be addressed. Of the immediate verbal learning), although the direction differed participants in our study, a half of the sample did not engage with at depending upon the cognitive task: improved sustained least one third of the sessions of CRT. Nevertheless, these rates are attention and spatial working memory after CRT, whereas similar to those in previously published studies from other groups worsened delayed verbal memory recognition. Although this (58). This fact may be influenced by the study design because we finding might seem contradictory with our previous included a randomized phase and half of the patients received TAU. longitudinal study (38) that reported worsening in attention Several patients failed to complete the CRT because they enrolled in and vigilance in those patients with higher FT4, it is important to educational or job-seeking activities. The low proportion of underscore that cut-offs for groups differ between both studies completed CRT sessions could make the detection of a positive (1.54 ng/dL vs 1.2 ng/dL). In our current study, only two patients effect of CRT on cognitive changes over time difficult, as the first had a FT4 concentration above 1.54 ng/dL. This fact, altogether analyses (global sample, randomized phase, intention-to-treat with the finding in the study by Labad et al. (38), that reported analysis) included all patients independently of the proportion of improvements in attention in those patients with FT4 levels attended sessions. We decided to define the attendance at one third between 1.16 and 1.54 ng/dL, makes less contradictory both of the sessions as a significant treatment because previous studies results. It does suggest, however, that subtle deviations in FT4 suggest that even short interventions (5–15 h) could be associated concentrations might moderate the cognitive response to a CRT with mild cognitive improvements (15). Another limitation of our in some cognitive domains. As our study is the first of its kind in study was not including the FT3 concentrations, as previous studies people with ROP, larger studies are needed to replicate our suggest that FT3 levels are associated with better cognitive function Frontiers in Psychiatry | www.frontiersin.org 8 July 2020 | Volume 11 | Article 636 Estrada et al. Thyroid Hormones and Cognitive Rehabilitation in schizophrenia patients (36). Finally, one of the most important AUTHOR CONTRIBUTIONS limitations was the small sample size, which does not allow for conducting sub-analyses by diagnoses or by sex, due to a lack of JL designed the study, wrote the protocol, and performed the statistical power. As the sample size of our study was small, we statistical analysis. FE wrote the first draft of the manuscript, preferred not to adjust for potential covariables (e.g. negative which was supervised by JL. FE, AG, JC, SP-M, and MA symptoms, tobacco, or cannabis use) for avoiding the instability evaluated the cognitive and clinical function. WZ and JC of the model. conducted the CR intervention. RA and LL participated in the In summary, FT4 concentrations moderate longitudinal collection and processing of biological samples. JB, MT, JL, and cognitive changes over time in ROP patients, mainly in specific IM participated in the recruitment. All authors contributed to domains such as sustained attention, executive functions, and the article and approved the submitted version. verbal and working memory. It appears that FT4 concentrations may be able to predict the response to CRT in people with early psychosis; however, the pilot nature of our study makes it FUNDING necessary to replicate our findings in future studies. This study was supported by grants from the Carlos III Health Institute through the Ministry of Economy and Competitiveness DATA AVAILABILITY STATEMENT (PI15/01386) and the European Regional Development Fund (ERDF) “A way to build Europe”. JL and IM received an The original contributions presented in the study are included in Intensification of the Research Activity Grant (SLT006/17/ the article/Supplementary Material; further inquiries can be 00012; SLT008/18/00074) from the Health Department of the directed to the corresponding author. Generalitat de Catalunya. ETHICS STATEMENT SUPPLEMENTARY MATERIAL The study was reviewed and approved by the Drug Research Ethics The Supplementary Material for this article can be found online Committee (CEIm) Parc Taulí. All patients provided their written at: https://www.frontiersin.org/articles/10.3389/fpsyt.2020. informed consent to participate in this study. 00636/full#supplementary-material 9. Barlati S, De Peri L, Deste G, Fusar-Poli P, Vita A. Cognitive Remediation in REFERENCES the Early Course of Schizophrenia: A Critical Review. Curr Pharm Des (2012) 18(4):534–41. doi: 10.2174/138161212799316091 1. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and 10. Bell MD, Bryson G. Work Rehabilitation in Schizophrenia: Does Cognitive functional outcome in schizophrenia: Implications for MATRICS. Schizophr Impairment Limit Improvement? Schizophr Bull (2001) 27(2):269–79. doi: Res (2004) 72(1):41–51. doi: 10.1016/j.schres.2004.09.009 10.1093/oxfordjournals.schbul.a006873 2. 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