Free thyroxine levels are associated with cognitive abilities in subjects with early psychosis
Introduction
Subjects with schizophrenia and other psychotic disorders may suffer from negative, positive, affective and cognitive symptoms, which may coexist in a multidimensional syndrome (Van Os et al 2010). Of all the different symptom dimensions of psychosis, cognitive impairment plays a crucial role in the functional outcome of the illness (Pandina et al., 2013). Alterations in cognitive functioning appear before the onset of psychotic symptoms (Davidson et al., 1999, Reichenberg et al., 2005). The underlying biological process of cognitive impairment in psychosis is not well known. Among different biological factors, hormones may play an important role in the pathogenesis of cognitive impairment in psychotic disorders. Most studies have focused on cortisol (Walder et al., 2000), although others, such as thyroid hormones, are also important. Thyroid hormones play an important role in the differentiation and growth of a healthy human brain and consequently in cognition. They have genomic and non-genomic actions on the brain, and participate in brain development with effects on actin polymerization, microfilament organization and neuronal migration (Leonard, 2008).
Individuals with hypothyroidism show deficits in cognitive abilities, such as attention, memory, language, visual perception and executive functions. Cognitive disturbances have also been reported in patients with mild or subclinical hypothyroidism (Osterweil et al., 1992, Monzani et al., 1993, Zhu et al., 2006). Such alterations can occur in the elderly and younger individuals and are reversible with exogenous thyroxine. Studies of cognitive functioning in patients with hyperthyroidism have reported discordant findings. For example, one study found augmented cerebral activation in areas of the brain associated with memory and executive functions (Burmeister et al., 2001), but another reported no difference among euthyroid individuals (Elberling et al., 2003). Few studies have investigated the relationship between normal levels of pituitary–adrenal–thyroid axis hormones and cognitive performance, which found inconsistent and contradictory results in healthy individuals. Thyroid-stimulating hormone and FT4 levels have been positively associated with scores of verbal learning and memory in the elderly (Wahlin et al., 1998), although other studies have failed to show any relation between thyroid status and cognitive functions (Gussekloo et al., 2004).
Other studies have explored the relationship between thyroid autoimmunity and cognitive performance. Elevated levels of antiperoxidase antibodies (TPO-Abs) are thought to be a risk factor of Alzheimer disease in healthy elderly adults (Ewins et al., 1991) and are associated with poorer executive functioning in healthy, euthyroid women (Grigorova and Sherwin, 2012). The mechanistic pathways linking thyroid autoimmunity and cognitive functioning are not well known. A recent study showed that TPO-Abs are involved in the pathogenesis of Hashimoto's encephalopathy by binding to cerebellar astrocytes (Blanchin et al., 2007), which suggests a potential role for TPO-Abs in cognition.
Although hypothalamic–pituitary–thyroid axis hormones and thyroid antibodies are candidate biomarkers that may be associated with cognitive dysfunction in psychosis, no previous studies have explored this topic. Most studies have focused on other clinical aspects of the illness and show a close relationship between thyroid abnormalities and psychosis in general (Othman et al., 1994). Moreover, the most significant findings were associated with affective psychosis (bipolar disorder) rather than non-affective psychosis (schizophrenia) (Carta et al., 2004).
We aimed to study whether hypothalamic–pituitary–thyroid axis hormones or thyroid autoimmunity modulate cognitive functioning in subjects with an early psychosis. We also used a categorical approach (i.e., affective vs. non-affective psychosis). The main hypothesis of our study was that patients with thyroid abnormalities (reduced FT4 or positive thyroid autoimmune antibodies) will have poorer cognitive performance.
Section snippets
Participants
We studied a population of 70 outpatients, aged between 18 and 35 years, of the Early Intervention Service from Hospital Universitari Institut Pere Mata (Reus, Spain), who had a psychotic disorder at an early stage (< 3 year duration). 49 of these patients (70%) were first episodes of psychosis. We used a control population of 37 healthy subjects (HS), matched by sex and age, who were recruited from the community by advertisement.
The included patients with an early psychosis fulfilled DSM-IV
Results
Socio-demographic and clinical characteristics of the study individuals are presented in Table 1. Patients had lower education and reported more cannabis, alcohol and tobacco consumption than healthy controls. No differences were found on thyroid function (FT4 and TSH levels) and thyroid autoimmunity (TPO-Abs and TG-Abs) between the patients and HS. In terms of MCCB cognitive domains, patients had poorer cognitive performance in all domains than HS. We tested all of these comparisons
Discussion
Our study underscores the role of hypothalamic–pituitary–thyroid axis hormones, particularly FT4, on cognitive performance in the attention/vigilance domain, in subjects with an early psychosis. Patients had FT4 levels within the normal range. Thus, our study suggests that subtle differences in normal FT4 levels may be important for attention performance. It also suggests that this association is more evident in subjects with a diagnosis of an affective psychosis. We did not observe an
Conclusions
In summary, our study shows that FT4 plays a positive role on cognitive abilities (particularly in the attention and vigilance domain) of patients with a psychotic disorder at the early stages of the illness. Patients with a diagnosis of an affective psychosis (bipolar disorder or schizoaffective disorder) seem to be more prone to this beneficial effect. Future studies are needed to investigate the molecular mechanistic pathways by which thyroid hormones affect brain functioning to further the
Role of the funding source
This work was supported by grants from Instituto de Salud Carlos III (FIS, PI10/01607) and from Fundació La Marató de TV3 (092230/092231). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Contributors
Javier Labad and Alfonso Gutiérrez-Zotes designed the study and wrote the protocol. Javier Labad performed the statistical analysis. Juan D. Barbero wrote the first draft of the manuscript, which was supervised by Javier Labad, Gemma Garcia-Parés and Elisabet Vilella. Juan D. Barbero and Itziar Monalvo managed the literature searches. Maria José Algora participated in the collection and processing of biological samples. Itziar Montalvo, Marta Creus, Montse Solé and Ángel Cabezas participated in
Conflict of interest
Javier Labad and Itziar Montalvo have received honoraria for lectures or advisory boards from Janssen-Cilag, Otsuka or Lundbeck. The rest of the authors have no biomedical financial interests or potential conflicts of interest.
Acknowledgments
We thank Antoni Trill for their help in analyzing plasma samples.
References (40)
- et al.
A depression rating scale for schizophrenics
Schizophr. Res.
(1990) - et al.
Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy
Schizophr. Res.
(2015) - et al.
Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes
J. Neuroimmunol.
(2007) - et al.
Thyroid hormones and cognitive functioning in healthy, euthyroid women: a correlational study
Horm. Behav.
(2012) Global assessment of functioning. A modified scale
Psychosomatics
(1995)- et al.
Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys
Biol. Psychiatry
(2008) Non-genomic actions of thyroid hormone in brain development
Steroids
(2008)- et al.
Cognitive functioning in first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) Profile of Impairment
Schizophr. Res.
(2014) - et al.
Identification of clinically meaningful relationships among cognition, functionality, and symptoms in subjects with schizophrenia or schizoaffective disorder
Schizophr. Res.
(2013) - et al.
Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia
Biol. Psychiatry
(2000)
Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for Schizophrenia
Schizophr. Res.
Thyroid stimulation test in healthy subjects and psychiatric patients
Acta Psychiatr. Scand.
Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates
Am. J. Psychiatry
The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later?
Schizophr. Bull.
The MATRICS consensus cognitive battery in patients with bipolar I disorder
Neuropsychopharmacology
Hypothyroidism and cognition: preliminary evidence for a specific defect in memory
Thyroid
The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future
BMC Psychiatry
Applied Multiple Regression/Correlation Analysis for the Behavioural Sciences
Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents
Am. J. Psychiatry
TRH response pattern in adolescent schizophrenic males
Br. J. Psychiatry
Cited by (19)
The association between plasma thyroxine levels and neurocognitive impairment in early-onset schizophrenia and other psychosis spectrum disorders
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryAssessment of the relationships between genetic determinants of thyroid functions and bipolar disorder: A mendelian randomization study
2022, Journal of Affective DisordersThyroid hormones in persons with schizophrenia: A systematic review and meta-analysis
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :All of these studies were based on drug-naïve or antipsychotic-naïve persons. In one study, medicated persons with early psychosis were recruited (illness duration shorter than 3 years) (Barbero et al., 2014). Other studies were based on persons with MES, who had been drug- or antipsychotic-free (Banki et al., 1984; Baumgartner et al., 2000; Boral et al., 1980; Jose et al., 2015; Loosen et al., 1977; Prange et al., 1979; Roy et al., 1989; Wahby et al., 1988) or medicated (Bratek et al., 2015; Extein et al., 1982; Lin et al., 2019; Telo et al., 2016; Zhu et al., 2020).
Association of altered thyroid hormones and neurometabolism to cognitive dysfunction in unmedicated bipolar II depression
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Thyroid hormones are essential for brain development and there has a connection between alterations in HPT and neuropsychological deficits. For instance, TSH and FT4 are positively associated with verbal learning and memory in a normal older adult population (Wahlin et al., 1998); suppressed thyroid hormone secretion is associated with a decrement in delayed verbal recall (Burmeister et al., 2001) and working memory (Zhu et al., 2006); and, higher FT4 levels are associated with enhanced attention/vigilance and overall cognition in individuals with affective psychosis at the early stages of the illness (Barbero et al., 2015). Other studies have found high TSH levels to be associated with worse working memory (Zhu et al., 2006; Samuels et al., 2007).
Free thyroxine levels are associated with cognitive changes in individuals with a first episode of psychosis: A prospective 1-year follow-up study
2016, Schizophrenia ResearchCitation Excerpt :FT4 levels seem to modulate cognitive functioning in FEP patients but not HS. In our previous cross-sectional study (Barbero et al., 2015), a linear association was found between FT4 levels and attention performance. Interestingly, the relationship between FT4 levels and longitudinal cognitive changes showed a U-shaped pattern (highest and lowest FT4 values were associated with worsened attention one year later, whereas middle FT4 values were associated with improved attention).