LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
Vesta Steiblienė
THE THYROID AXIS FUNCTION IN
ACUTE PSYCHOTIC EPISODE
Doctoral Dissertation
Biomedical Sciences, Medicine (06B)
Dissertation was prepared at the Institute of Behavioral Medicine, Lithua-nian University of Health Sciences, Medical Academy, during 2008-2012
Scientific Supervisor
Dr. Habil. Robertas Bunevičius
CONTENT
CONTENT ... 3
INTRODUCTION ... 8
1. REVIEW OF LITERATURE ... 12
1.1. Acute psychosis in schizophrenia and other psychiatric disorders ... 12
1.2. Thyroid axis hormones and the brain ... 16
1.2.1. Thyroid axis hormones secretion and metabolism ... 17
1.2.2. Tissue markers of thyroid hormone actions ... 18
1.2.3. Thyroid hormones transport to the brain ... 19
1.2.4. Thyroid hormone receptors and homeostasis in the brain ... 20
1.2.5. Genetic determination of the thyroid function ... 21
1.3. Thyroid axis function and psychiatric disorders ... 22
1.3.1. Hypothyroidism and psychiatric disorders ... 22
1.3.1.1. Unrecognized severe hypothyroidism manifested as an acute psychotic episode ... 24
1.3.1.2. “Myxedema Madness”: everyday clinical practice ... 25
1.3.2. Thyroid axis function during acute psychotic episode ... 29
1.3.4. Thyroid axis function and schizophrenia ... 30
1.4. Effect of Antipsychotic Medication on Thyroid Axis Hormones 34 1.5. Thyroid axis hormones in treatment of mental disorders ... 36
2. MATERIAL AND METHODS... 38
Ethics... 38
2.1. Study population ... 38
2.1.1. A clinical trial (Study III) ... 40
2.1.2. A cross-sectional study (Study I) ... 44
2.1.3. A prospective study (Study II) ... 47
2.2. Methods ... 48
2.2.1. Psychiatric evaluations ... 48
2.2.2. Endocrine measurements ... 50
2.3. Statistical analysis ... 51
3. RESULTS ... 54
3.1. Thyroid axis function in psychotic patients during hospital admission (Study I) ... 54
3.1.1. Thyroid axis hormone concentrations in acute psychotic patients comparing to blood donor controls ... 54
3.1.3. Thyroid axis hormone concentrations in psychotic patients upon hospital admission: effects of prior psychiatric medication use ... 58 3.1.4. The Factor Structure of the Brief Psychiatric Rating
Scale (BPRS) in acute psychotic patients ... 59 3.1.5. An association between thyroid axis hormone
concentrations and severity of psychiatric symptoms in acute psychotic patients during hospital admission ... 61 3.2. Thyroid axis function during in-patient treatment of acute
psychotic episode (StudyII) ... 63 3.2.1. Thyroid axis hormone concentrations before and after acute psychotic episode treatment with antipsychotics ... 63 3.2.2. Associations between changes in thyroid axis hormone concentrations and changes in severity of psychotic symptoms ... 66 3.2.3. Factors predicting changes in thyroid axis hormone
concentrations and changes in psychiatric symptoms during acute psychotic episode treatment ... 66 3.2.4. The direction and magnitude of thyroid axis hormone
concentrations changes during acute psychotic episode
treatment with antipsychotics ... 70 3.3. Sex hormone binding globulin (SHBG) concentrations during in-patient treatment of acute psychotic episode (Study II) ... 75
3.3.1. Sex hormone binding globulin concentrations before and after acute psychotic episode treatment with
antipsychotics ... 75 3.3.2. The direction and magnitude of thyroid axis hormone
concentrations changes during acute psychotic episode
treatment with antipsychotics ... 76 3.3.3. Associations between changes in sex hormone binding
globuline concentrations and changes in severity of psychotic symptoms before and after acute psychotic episode treatment with antipsychotics ... 77 3.4. The effects of adjuvant treatment with L–triiodthyronine (T3) on acute schizophrenia treatment with risperidone (Study III) ... 79
3.4.1. The efficacy of adjuvant treatment with T3 on acute
schizophrenia treatment with risperidone ... 79 3.4.2. The safety of RIS+T3 combinations during acute
schizophrenia treatment ... 84 3.4.3. The effect of RIS+T3 combination on thyroid axis
4.1. Thyroid axis function in acute psychotic patients during
hospital admission ... 89
4.2. Stabilization of thyroid axis hormone concentrations and changes in SHBG concentrations during acute psychotic episode treatment with antipsychotics ... 91
4.3. The accelaration and enhancement effects of adjuvant treatment with L–triiodthyronine (T3) on acute schizophrenia treatment with atypical antipsychotic risperidone ... 97
CONCLUSIONS ... 100
SCIENTIFIC SIGNIFICANCE OF THE STUDY ... 101
ACKNOWLEDGEMENTS... 104
REFERENCES ... 106
PUBLICATIONS ON THE DISSERTATION THEME ... 128
LIST OF ABBREVIATIONS
AITD – Autoimmune thyroid disease
AHDS – Allan-Herndon-Dudley syndrome
BP – Blood presure
BPRS – Brief Psychiatric Rating Scale Beta, β – Standardised regression coefficient
CGI-I – Clinical Global Impression, Improvement scale CGI-S – Clinical Global Impression, Severity of illness scale
CNS – Central nervous system
CIDI – Composite International Diagnostic Interview
CSF – Cerebrospinal fluid
D1 – Type- I deiodinase
D2 – Type- II deiodinase
D3 – Type- III deiodinase
DSM-IV-TR – Diagnostic and Statistical Manual of Mental Disord-ers, Fourth Edition, Text Revision
ECT – Electroconvulsive therapy
FT3 – Free triiodothyronine
FT4 – Free thyroxine
GABA – δ - aminobutyric acid
HPT axis – Hypothalamic-pituitary-thyroid axis HNF4A – Hepatocyte nuclear factor 4 alpha
IQR – Interquartile range
MCT 8 – Monocarboxylate trasporter-8 MCT 10 – Monocarboxylate trasporter-10
MINI–Plus – Mini International Neuropsychiatric Interview Ver-sion 5.0.0.
MRI – magnetic resonance imaging
MRS – Magnetic resonance spectroscopy
OATP1c1 – Organic anion transporter protein 1c1
p/o – Per os
PLB – Placebo
Pro – Prolactin
rT3 – Reverse T3
RIS – Risperidone
SCID – Structured Clinical Interview for DSM-IV
SD – Standard deviation
SHBG – Sex hormone binding globulin
SSRI – Selective serotonin reuptake inhibitor TPOAb – thyroid peroxidase antibody
TRH – Thyrotropin-releasing hormone
TSH – Thyroid-stimulating hormone
T3 – Triiodothyronine
T4 – Thyroxine
TRs – T3 receptors
TAAR – Trace-amine-associated receptor
T1AM – 3-iodothyronamine
INTRODUCTION
Acute psychosis such as schizophrenia and other schizophrenia spectrum disorders have a life time prevalence up-to 2–3 % in general population [245], evoke strong consequences on social functioning and quality of life of the patient and are associated with a huge economical burden for the society [155].
An improved understanding of the etiology and pathophysiology of schizophrenia and other psychosis gave the opportunity to develop prevention strategies and treatments based on this enhanced knowledge. In view of the heterogeneity of risk factors, the potential contribution of pharmacogenomics and other biological markers to optimizing individual treatment and outcome in the future are evaluated. In this context potential psychopatho-logical treatment targets are discussed [239].
Dysfunction of the thyroid gland, either hyper-function or hypo-function, is frequently associated with mental disorders, including psychoses that sometimes resemble schizophrenia [38]. An increased prevalence of thyroid function abnormalities has been reported in families of patients with schizophrenia [65], suggesting possible genetic linkage between the endocrine and mental disorders. Nevertheless, most schizophrenic patients are euthyroid with normal basal concentration of thyroid stimulating hormone (TSH) and normal TSH response to thyrotropin-releasing hormone (TRH) challenge [23, 182].
The fluctuations in the levels of thyroid hormones at various times during human development and throughout life can impact on psychiatric disease manifestation and response to treatment (Santos, 2011). It is well known that illness, certainly including mental illness, may affect the thyroid axis, and this affect is often noted when acute psychotic patients are admitted to the hospital. Several studies have reported elevated serum concentrations of thyroxine (T4), but not of triiododthyronine (T3), in acute psychiatric dis-orders, an abnormality that usually resolves during recovery and is called transient hyperthyroxinemia [24, 198]. However, data on the prevalence of hyperthyroxinemia in acute psychotic patients are scanty and need further evaluations. Moreover, factors predicting hyperthyroxinemia needs to be studied.
liver production of sex hormone binding globulin (SHBG) [186]. However, there are no data pertaining to serum SHBG concentrations in patients with acute psychoses.
Introduction of second-generation, atypical antipsychotic drugs brought new options; however, their efficacy advantage was not so high as expected [135]. A better understanding of the mechanisms related to the efficacy and side effects of antipsychotic drugs may open new venues preventing side effects and advancing treatment of acute psychosis. Some studies reported that treatment with atypical antipsychotic quetiapine may decrease thyroid hormone concentrations [114, 119]. One study reported decrease in SHBG concentrations after treatment with the atypical antipsychotic olanzapine [29].
The behavioral disturbances, physical and psychological signs and symp-toms of hypothyroidism usually respond to adequate replacement treatment with thyroid hormones [258]. The majority of patients subjectively prefer combined treatment with T4 and T3 [36, 71]. Several trials have confirmed the clinical value of thyroid hormones in the treatment of depression [4, 9, 12, 56] and improvement of psychological wellbeing [206]. Despite the fact that the majority of schizophrenic patients are euthyroid, thyroid hormones have been tried as a treatment of schizophrenia as well as depression.
AIM AND OBJECTIVES
The aim of the study was to evaluate thyroid axis function in acute
psy-chotic patients.
The objectives of the study:
1. To evaluate thyroid axis hormone concentrations in acute psychotic patients compared to blood donor controls, to severity of psychosis, and to prior use of psychiatric medication.
2. To evaluate changes in thyroid axis hormone concentrations during antipsychotic treatment of acute psychotic episode in relation to base-line hormone concentrations and to clinical characteristics of psy-chotic episode.
3. To evaluate changes in sex hormone binding globuline concentrations during antipsychotic treatment of acute psychotic episode in relation to baseline hormone concentrations and to clinical characteristics of psychotic episode.
4. To evaluate efficacy and safety of adjuvant treatment with L-triiodthyronine (T3) on acute schizophrenia treatment with risperi-done.
Scientific novelty of the study
The findings of this study generated in naturalistic setting, but with care-ful attention to background of thyroid illness and to prior drug use supported the finding of earlier investigators about the case prevalence of euthyroid hyperthyroxinemia in acute psychotic patients, furthermore, it also revealed novel findings about higher psychotic male patients SHBG concentrations; and a possible interaction between euthyroid hyperthyroxinemia and SHBG secretion in the liver.
(SHBG) concentrations and revealed that the treatment led to endocrine ab-normalities such as decrease in SHBG concentrations, especially when women were treated with typical antipsychotic haloperidol.
Results of our study for the first time demonstrated the efficacy and safe-ty of adjuvant treatment with triiodthyronine (T3) on acute schizophrenia treatment with atypical antipsychotic risperidone in randomized, double blind, parallel group, placebo controlled trial design.
1
. REVIEW OF LITERATURE
1.1. Acute psychosis in schizophrenia and other psychiatric disorders
Acute psychosis is defined as mental disorder with grossly impaired real-ity testing. Psychotic patients incorrectly evaluate the accuracy of their per-ceptions and thoughts and make incorrect inferences about external reality, even in face of contrary evidence. During acute psychosis severe impair-ment of social and personal functioning is characterized by social withdraw-al and inability to perform the usuwithdraw-al household and occupationwithdraw-al roles [202].
Psychosis (or psychotic episode) is not exclusive to schizophrenia and occurs in various diagnostic categories of psychotic disorder [67, 82, 176]. In schizophrenia, schizoaffective, schizophreniform, brief psychotic, delu-sional disorders and psychotic disorders related to general medical condi-tions psychotic symptoms could include delusions, any prominent hallucina-tions, disorganized speech, and disorganized or catatonic behavior. These disorders are conventionally characterized by having psychotic symptoms as the defining feature. In clinical picture of bipolar disorder and major depres-sive disorder psychotic symptoms also could present. The criteria used in DSM-IV-TR to distinguish between these different categories of psychotic disorder are based on duration, dysfunction, bizarreness of delusions, and presence of other medical condition, depression or mania [10].
Acute schizophrenia consists of various degrees of psychosis, characte-rized by the sudden onset of personality disorganization. Positive symptoms include delusions, which may be bizarre in nature; hallucinations, especially auditory; disorganized speech; inappropriate affect; and disorganized beha-vior. Negative symptoms include flat affect, lack of volition, alogia, and an-hedonia. Episodes appear suddenly in persons whose previous behavior has been relatively normal and are usually of short duration. Recurrent episodes are common, and in some instances a more chronic type of the disorder may develop [10, 105]. About 1% of the population is affected by schizophrenia [158], which associated with progressing personality deficits and frequently life-long course, is a mental illness that evokes strong consequences on so-cial functioning and quality of life of the patient and appeares among the world's top ten leading causes of disease-related disability [150, 159] and is linked to a huge economical burden for the society [139, 155].
dur-ing this period did not show great changes and in 2011 we counted 24.5 new cases of schizophrenia spectrum disorders per year/100000 inhabitants. A total number of patients with schizophrenia spectrum disorders in Lithuania during the last 6 years is increasing gradually over 24 000 patients and we counted prevalence (morbidity) of schizophrenia spectrum disorders in 2011 as 745.1/100 000 inhabitants. Figure 1.1.1 shows the changes in the inci-dence and the morbidity of patients with schizophrenia spectrum disorders during 2006-2011years period.
689.1 695.5 707.9 714.2 740 745.1 24.5 26.5 24.7 24.1 22.4 26.1 0 100 200 300 400 500 600 700 800 2006 2007 2008 2009 2010 2011 p er 1 0 0 0 0 0 i n h ab it an ts
The morbidity The incidence
Figure 1.1.1. The incidence and the morbidity of patients with
schizophre-nia spectrum disorders during 2006-2011 (per 100 000 inhabitants) Despite an increasing use of second-generation antipsychotic drugs, the effectiveness of schizophrenia spectrum disorders treatment is not sufficient and the patients are experiencing psychosis relapse; dynamics of the last 6 year in Lithuania shows only a slight decline in rate of hospital treatment. In 2011 8639 patients were hospitalised for the acute psychotic episode treat-ment, in which 5037 were hospitalised for the treatment of acute schizoph-renia. Overall 436 964 hospital days were spent for the acute schizophrenia spectrum psychotic episodes treatment in 2011.
2006 2007 2008 2009 2010 2011 First lifetime diagnosis of acute psychotic episode, n* 887 757 810 824 870 803
Of which: First lifetime diagnosis of acute schizophrenia, n* 376 329 353 408 431 401 The incidence of schizophrenia spectrum disorders
(new cases per year/100000 inhabitants) 26.1 22.4 24.1 24.7 26.5 24.5 Diagnosis of schizophrenia spectrum disorders, n* 23325 23412 23714 23777 24010 24172
Of which: Number of patients with schizophrenia diagnosis* 16029 15884 15844 15790 15851 13522 The morbidity of schizophrenia spectrum disorders, n
(per 100000 inhabitants) 689.1 695.5 707.9 714.2 740.0 745.1 Hospitalization for the acute psychotic episode treatment, n** 9655 8811 8823 7413 8681 8639
Of which: Hospitalization for the acute schizophrenia
treat-ment, n** 5933 5369 5392 4734 5301 5037
Hospital days for the acute psychotic episodes treatment** 445938 438374 450219 370348 431073 436964 Disability due to schizophrenia, n 7552 8479 7373 7455 7014 6506
Of which: For the first time disability due to schizophrenia, n 188 255 206 250 186 200
*Data from outpatient health care centers in Lithuania; ** Data from the psychiatric hospitals in Lithuania; n, number of patients
Despite the high costs of schizophrenia and schizophrenia spectrum psy-chotic episodes treatment, the treatment effectiveness remains questionable, because every second patient with schizophrenia diagnosis have distur-bances in social and work functioning, and level of disability. In 2011 6506 patients had disability due to schizophrenia and among them 200 had for the first time disability due to schizophrenia.
There are different primary psychotic episodes in DSM-IV-TR clasifica-tion. A Brief psychotic disorder is defined by DSM-IV-TR as a psychotic episode that involves the sudden onset of psychiatric symptoms which lasts 1 day or more, but less than 1 month. The first psychotic episode patients, even with schizophrenia symptoms, have diagnosis of brief psychotic dis-order or schizophreniform disdis-order. Schizophreniform disdis-order is similar to schizophrenia, except that it symptoms last at least 1 month but less than 6 month. In contrast for the patient to meet the diagnostic criteria for schi-zophrenia, the symptoms must have been present for at least 6 month. The schizoaffective disorder has features of both schizophrenia and affective disorders. During bipolar disorder, severe with psychotic features or major depressive disorder, severe with psychotic features psychotic symptoms-delusions or hallucinations are mood-congruent or mood-incongruent [10]. Acute psychosis such as schizophrenia and catch-all diagnostic categories of psychotic disorders revealed a life time rate of 2–3% of population [245].
There is not a full consensus how to classify various psychosis spectrum disorders into etiological and pathophysiological based categories [46, 59]. Most diagnostic categories of psychotic disorders may have common under-lying etiology, overlap in genetic liability and pathophysiological mechan-isms among themselves [42, 157, 245]. Epidemiological and molecular ge-netic studies support the hypothesis that acute psychotic episode a clinical phenotype with multifactorial etiologies [43, 238].
in-flammation and oxidative stress [44, 86, 112, 115, 137, 211]. In acute psy-chotic episode some endocrine changes are described [237] and changes in thyroid axis function in schizophrenia patients were found [220, 266]. It is known that thyroid hormones are not only essential for normal development of the central nervous system, but also regulate the expression of many neu-rotransmitters, their synthesizing enzymes and receptors. Functional and po-sitional candidate genes include brain thyroid hormone receptors and dei-odinases, which synthesize triiodothyronine, involved in their inactivation, so thyroid hormones could serve as bridges between genes and environment in schizophrenia [167].
An improved understanding of the etiology and pathophysiology of schi-zophrenia gave the opportunity to develop prevention strategies and treat-ments based on this enhanced knowledge. In this context potential psycho-pathological treatment targets are discussed. In view of the heterogenity of risk factors, the potential contribution of pharmacogenomics and other bio-logical markers to optimizing individual treatment and outcome in the future are evaluated [239]. Schizophrenia and other psychoses are linked to unique etiological and pathophysiological processes that may yield unique treat-ment targets. Innovative approaches are needed to elucidate the biological substrates of these entities because such clarity is vital for replicable re-search. Identifying the critical gaps in the knowledge, and unmet needs in our approaches to care, and outline steps that can move the field forward [160].
Clinical experience as well as controlled treatment trials suggests that acute psychosis across many diagnostic categories including schizophrenia, bipolar disorder, psychotic depression, functional and organic psychoses show a similar pharmacological treatment response [45, 46]. Although the introduction of second-generation antipsychotics for schizophrenia over the past two decades brought new options for the treatment of acute psychosis and generated considerable optimism about possibilities for recovery, their treatment until now remains unsatisfactory [5, 88]. There is a need for truly innovative treatments and strategies that can make significant advantages for persons with schizophrenia and related psychotic disorders [57, 135].
1.2. Thyroid axis hormones and the brain
thyroid axis-related proteins, such as deiodinases, thyroid hormone transpor-ters and receptors; and timing of events. Interaction of these factors contri-butes to the development of the brain as well as to presentation of psychia-tric symptoms and disorders in mature brain. Clinical and subclinical thyro-id dysfunction, thyrothyro-id autoimmunity as well as indivthyro-idual genetic varia-tions and mutavaria-tions of thyroid axis-related proteins may contribute not only to presentation of psychiatric symptoms and disorders, but also to response to psychiatric treatments. A better understanding of genomic and non-genomic mechanism related to thyroid hormone metabolism in the brain opens new venues for finding new markers, new targets, and new agents for the treatment of mental disorders [39].
1.2.1. Thyroid axis hormones secretion and metabolism
Secretion of thyroid hormones is regulated by the pituitary thyroid-stimulating hormone (TSH), which is stimulated by hypothalamic thyrotro-pin-releasing hormone (TRH) and suppressed by negative feedback from serum thyroid hormones. In serum more than 99% of thyroid hormones are bound to specific proteins, but only free hormones are active. The thyroid gland secretes several hormones, including thyroxine (T4), triiodothyronine (T3) and metabolically inactive reverse T3 (rT3) [38].
The main secretion of the thyroid gland is T4.The thyroid gland is the on-ly source of this hormone. Synthesis of T4 also requires the active uptake of dietary iodine by the gland.
Triiodothyronine (T3) is the most biologically active thyroid hormone, but no more than 20% of this hormone is secreted by the thyroid gland.T3 is produced in other tissues by removal of iodine from the T4 molecule by en-zyms, called deiodinases [28], which exist in several forms and are located in cells.
Type–I deiodinase (D1) is located primarily in the liver and kidney and is responsible for producing as much as 80% of circulating T3. Type–II deiodinase (D2) is located primary in brain glial cells, including astrocytes, and in muscles and mainly accounts for T3 tissue concentrations. Deiodinases type I and II are differentially regulated in order to protect the brain from T3 excess or deficiency. In accordance, during hypothyroidism, type I deiodinase is downregulated while type II is upregulated; the opposite occurs in hyperthyroid conditions. Therefore, the activity of deiodinases is a key step to regulate the availability of active T3.
The major cause of disturbed thyroid hormone secretion is autoimmune thyroid disease (AITD), when auto-antibodies against the normal elements of the thyroid axis are produced. Results of biopsy as well as autopsy show that up to 40% of women have AITD [255]. There are two major forms of AITD: Graves’ disease, a common cause of hyperthyroidism; and autoimmune thyroiditis, a common cause of hypothyroidism [174]. Other major causes of hyperthyroidism are toxic nodular goiters and adenomas; other major causes of hypothyroidism are treatments of thyroid disorders (radiation, thyroidectomy), thyroid dysgensesis and iodine deficiency. In overt hyperthyroidism thyroid hormone secretion is increased and thyroid-stimulating hormone secretion is suppressed. In overt hypothyroidism thyroid hormone secretion is decreased and thyroid-stimulating hormone secretion is augmented. In subclinical thyroid dysfunction only thyroid-stimulating hormone secretion, but not thyroid hormone secretion is altered [39].
1.2.2. Tissue markers of thyroid hormone actions
Thyroid hormones affect almost all peripheral target tissues: T3 and T4 act on pituitary gland as central target organ. In addition, they affect the peripheral target tissues, like muscle, the heart and the liver.
Tissue responses to changes in thyroid hormone concentrations may be better indicators of the significance of thyroid axis activity than thyroid hormone concentrations themselves. The circulating hormone levels, as measured in patients, do not always reflect the clinical effects at the target tissues. Response of the anterior pituitary gland, evident by changes in TSH concentrations, is a sensitive marker of thyroid dysfunction. Another sensi-tive tissue marker of thyroid activity is liver production of sex hormone binding globulin (SHBG) [186].
SHBG is a glycoprotein. Reference range for serum concentrations of SHBG is different for men and women. SHBG binds sex hormones, mainly estradiol and testosterone, regulating their free concentrations. The hepatic synthesis of SHBG is stimulated by thyroid hormones. Latest studies supposed that SHBG is regulated by nuclear receptor hepatocyte nuclear factor-4alfa (HNF-4a) in response to changes in the metabolic state of the liver; and T3 and T4 increased SHBG production indirectly by increasing HNF-4A gene expression [212].
are applications for the tissue markers in the borderline conditions, such as subclinical hypothyroidism and subclinical hyperthyroidism before and after some treatment with different medications. Tissue marker is indispensable tool for the clinical research reflecting the cellular action on thyroid hormones and providing informations about the metabolic status of thyroid dysfunction in humans. So thyroid function tests have achieved the highest level of perfection for diagnosis of thyroid dysfunction, as they have been obtained at the molecular and metabolic levels [230]. The measure of SHBG concentration has diagnostic values for detecting even mild thyroid hor-mones changes and showing the biological effect of thyroid horhor-mones at the tissue level [36, 207]. Even borderline elevations of thyroid hormones can show marked effects on the organs, producing severe clinical pictures [232].
1.2.3. Thyroid hormones transport to the brain
The genomic actions of T3 are mediated by nuclear T3 receptors (TRs) [268]. Because the active sites of the deiodinases and the TRs are located intracellularly, thyroid hormones metabolism and action require transport of the hormone from extracellular compartments (e.g. the bloodstream) across the plasma membrane. Until recently, it was assumed that cellular entry by free thyroid hormones was mediated via passive diffusion because of their lipophilic nature. Now it is recognized that thyroid hormones enter target cells mainly through transporters [1, 104, 108, 268]. Several thyroid hormones transporter families have been identified, however, only monocarboxylate trasporter–8 (MCT8), monocarboxylate trasporter-10 (MCT10) and organic anion transporter protein 1c1 (OATP1c1) have been shown to be specific thyroid hormones transporters [250].
To enter the brain thyroid hormones must cross the blood–brain barrier or the choroid-plexus-cerebrospinal fluid (CSF) barrier. OATP1c1 is distributed widely in the human brain and specifically transport T4 across the blood–brain barrier [79, 108, 250]. MCT10 demonstrated a substantial uptake of T3 and T4 by cells [78]. MCT8 may transport T3 as well as T4 [78]. In brain T4 enters astrocytes, where it is converted to T3 by local D2. T3 is generated in the astrocytes as well as T3 from the general circulation is transported into neurons via MCT8, where after completion of its action, it is degraded by D3 [235, 262].
resemblance to patients with Allan-Herndon-Dudley syndrome (AHDS) [80, 81, 170]. Sijens et al. 2008 used brain MRI in two children with MCT8 mutation [219]. MCT8 gene mutation resulted in deviant myelinization and in general atrophy of the brain. Different mutations in the MTC8 transporter led to different expression of dysmyelinization and magnetic resonance spectroscopy (MRS) showed the different changes in brain metabolism. In fact, MCT8 mutations were found in all families with AHDS, providing a molecular basis for this syndrome [250] and also importance of transporter MCT8 function in normal brain development.
1.2.4. Thyroid hormone receptors and homeostasis in the brain
The T3 moves into the cell nucleus, where it binds nuclear thyroid hormone receptors (TRs). TRs are the members of the steroid/thyroid family. TRs have two isoforms: thyroid hormone receptor–alpha and thyroid hormone receptor-beta. Most thyroid-hormone-mediated actions are controlled by transcriptional regulation [19, 269]. T3 interacts with TRs that function as ligand-activated transcription factors. Two genes encode TRs, THR-alfa and THR-beta, and for each there are splicing variants with distinct developmental and tissue distribution patterns. Within the nucleus, TRs recognize hormone response elements in target genes. The metabolism of thyroid hormones is linked through their main mechanism of action at the transcription level [174].
In the mature brain thyroid hormones regulate expression of several genes that may affect mood and cognition, including genes for neurotro-phins, such as nerve growth factor and brain–derived neurotrophic factor. By genomic and possibly non-genomic mechanisms T3interacts with sever-al important neurotransmitters such as serotonin and norepinephrine, which are crucial for mood regulation, and with acetylcholine, which is essential for cognition [136].
1.2.5. Genetic determination of the thyroid function
Circulating thyroid axis hormone concentrations in euthyroid individuals have much greater inter-individual than intra-individual variation, in which genetic variations play a major role. Although the population reference ranges for these parameters are wide, each individual appears to have their own set point within this. The levels of TSH only fluctuate within a very narrow range in response to changing free T4 [11]. This has significant implications given that small changes in thyroid function, even within the population reference range, have been shown to have clinically detectable effects on phenotypes as varied as cholesterol, mood [206] and longevity [95].Therefore at what point an individual started within the range is very important when one is trying to determine if an alteration in thyroid function has resulted in a clinical problem.
Findings from twin studies show that each person has a genetically determined FT4–TSH set point [100]. For TSH set point approximately 65%, but perhaps less for FT4 and FT3 (both around 40–50%). These findings suggest that individual thyroid function set points are mainly genetically derived, however,the genes responsible have until recently not been known [168].
It is clear that a significant proportion of TSH, FT4 and FT3 variation is genetically derived. Polymorphisms within three genes have been shown to be associated with thyroid function in healthy subjects at genome-wide levels of significance: phosphodiesterase 8B (PDE8B), iodothyronine deiodinase 1 (DIO1) and F-actin-capping protein subunit beta (CAPZB). A polymorphism in the TSH receptor gene (TSHR) has been shown to have associations with thyroid function in multiple studies in different populations [168]. Whilst only a few genes have been found to influence thyroid function, it has become clear that genes involved in thyroid hormone action can have clinically detectable effects with no effect on circulating thyroid hormone concentrations. There are many elements which can affect the final binding of T3 to the TR in the cell nucleus, and therefore circulating (measureable) concentrations of thyroid hormones may be a poor reflection of individual tissue levels. This may be particularly pertinent in tissues such as the brain in which there are mechanisms in place to protect the local tissue from swings in circulating levels [168].
It was found an association between rs225014 and psychological well–being [169].
Genetic variation in deiodinase enzymes and thyrotropin receptors causes alteration in the balance of circulating thyroid hormones and their tissue concentrations affecting thyroid hormone-related endpoints [175] including physiological consequences.
1.3. Thyroid axis function and psychiatric disorders 1.3.1. Hypothyroidism and psychiatric disorders
Hypothyroidism is the most common clinical condition caused by the inadequate production of thyroid hormone or inadequate action of thyroid hormone in target tissues [8]. Hypothyroidism affects from 0.5% to 18% of population and incidence rate varies 10-fold in women than in men; it is more common in elderly. [72, 128, 196]. It is most often caused by some disorder of the thyroid gland that leads to a decrease in thyroidal production and secretion of thyroxyne (T4) and triiodthyronine (T3), in which case it is referred to as primary or thyroidal hypothyroidism. Primary hypothyroidism is invariable accompanied by increased thyroid-stimulating hormone (TSH) secretion. Most common causes of primary hypothyroidism are chronic autoimmune thyroiditis or infiltrative thyroid diseases, radioactive iodine treatment or external radiation therapy, thyroidectomy, drugs with antithyroid actions or iodine deficiency. Iatrogenic hypothyroidism caused by lithium preparations or antipsychotics is also described [41, 146, 180].
Much less often hypothyroidism is caused by decreased thyroidal stimulation by TSH, which is reffered to as central or secondary hypothyroidism. Secondary hypothyroidism may be caused by pituitary or hypothalamic disease, causing deficiency of thyroid–releasing hormone (TRH). It is usually accompanied by low or inappropriately normal serum TSH concentrations. Althought most of the daily production of T3 occurs in extrathyroidal tissue, and extrathyroidal T3 production is decreased and serum T3 concentrations are low in patients with nonthyroidal illness, the decrease in T3 production in these patients is accompanied by few if any manifestations of hypothyroidism [32].
increase in rT3 concentration are the most common changes in non-thyroid illness, which is often referred to as the low T3 syndrome. Sometimes low T3 syndrome has also been called euthyroid sick syndrome, tending to minimize its clinical significance. An alternative designation, which does not presume metabolic significance, is nonthyroidal illness syndrome. A principal mechanism underlying low serum concentration of T3 in patients with non-thyroidal illness syndrome is reduced activity of the D1 enzyme in liver. Increased concentration of cytokines, such as inteleukin–6 and tumor necrosis factor-alpha, are responsible for impaired expression of hepatic D1. Other mechanisms involved in the pathogenesis of the syndrome include a decrease in concentration of thyroid hormone binding proteins and decreased secretion of TRH [30, 39, 122].
The underlying problem in hypothyroidism is slowing of many physiological processes: slow movements, bradycardia, dry skin, hyporeflexia, cold intolerance, weight gain, decreased appetite, constipation, menstrual disturbances. Spectrum of symptoms of hypothyroidism is broad: patients with subclinical hypothyroidism have few or no symptoms and the other extreme is myxedemic coma. Hypothyrosis affects major body changes as well as mental disorders [196]. Links between hypothyroidism and mental illness were described by Richard Asher (1949) [15] as “myxedema madness” and focused much needed clinical attention on its treatment. Hypothyroidism is frequently accompanied by psychiatric symptoms such as diminished cognition, inability to concentrate, slowing in thought process, inability to calculate and understand complex questions, fatique, weakness and drowsiness [111, 194]. Memory for recent events is frequently poor and eventually memory for remote events also may become impaired with decreased ability to perform everyday tasks [258].
Hypothyroidism seems to be especially related to depression with melancholic features, crying, loss of appetite, insomnia, delusions of self-reproach and suicidal ideations; even sub-clinical hypothyroidism may affect mood [94]. The picture is not consistently one of depression; disorganized agitated state also has been described; also patients with psychosis, hyperactivity, irritability, anger, auditory and visual haliucinations are described, other patients become fearfull, suspicious and delusional [93, 53, 154, 161].
Hypothyroidism is also observed in manic patients [117, 241], bipolar patients [254], especially in women with the rapid-cycling form of the disorder [21].
after surgical interventions [141]. It has been also described in other mental disorders such as major depression [185] and schizophrenia [266].
The psychoses that occur in patients with hypothyroidism are nonspecific, they may mimic schizophrenic, paranoid and affective psychoses. Even though confusion occurs in acute schizophrenia, together with distractibility and visual haliucinations. In patients with affective psychoses, cognitive impairment or pseudodementia is more common, especially in elderly persons, in whom it may dismissed as the dementia of the old age. The symptoms of hypothyroid psychosis may closely mimic severely psychotic-affective states [154, 161, 258].
1.3.1.1. Unrecognized severe hypothyroidism manifested as an acute psychotic episode
Although hypothyroidism is a common endocrine disorder characterized by thyroid hormone insuficiency and related to a wide spectrum of physical and mental disorders, the onset of disease may lead to misdiagnosis, on particular, if psychiatric disorders are present. Psychiatric disorders, such as acute psychosis, depression, bipolar disorder, acute mania or cognitive disorders may be a manifestation of hypothyroidism, even in the absence of clear physical symptoms. Endocrine dysfunction may be associated with many symptoms; it may also complicate the treatment of psychiatric disorder. Therefore, it is important to make a timely diagnosis of hypothyroidism and administer an adequate treatment when the disease manifest with psychiatric disorders.
During our study we evaluated the case about the patient with severe hypothyroidism, manifested as an acute psychotic episode.
Acute psychosis symptoms lessened after 10 days of treatment with typical antipsychotic haloperidol. However, lability of emotions did not disappear: either the patient was tearful or becoming euphoric. She suffered from consistent fatigue, sleeplessness, poor concentration; reported having „bad memory“, limited interests and activities. The results of thyroid axis hormones concentrations were received after the patient was discharged from the hospital: increased serum TSH concentrations more than 50
µIU/ml (reference range: 0.17–4.05 µIU/ml) and decreased FT4
concentrations – 1.4 pmol/l (reference range: 11.5–23.0 pmol/l) and FT3 concentration – 0.8 pmol/l (reference range: 2.5–5.8 pmol/l) with normal SHBG concentration – 48.5nmol/l. These results revealed that the patient had severe hypothyroidism and this threatening pathology of thyroid gland was not previously diagnosed, as the real cause of acute psychotic episode. High serum TPOAb concentrations – 41.2 IU/ml, (reference range for TPOAb < 20 IU/ml) indicated autoimmune thyroid disease. Moreover, acute psychotic episode treatment with typical antipsychotic haloperidol significantly affected thyroid hormone concentration – FT4 concentration decreased after treatment and was 0 pmol/l, FT3 concentration decreased and was 0.6 pmol/l and TSH remained more than 50 µIU/ml.
The patient was started on thyroid hormone replacement and the treatment reversed the effects of hypothyroidism; after few months of treatment most of physical and mental symptoms such as sluggishness, emotional lability, reduced energy and decreased interests resolved. The patient became active, communicable again; signs of anemia were also corrected.
But the insufficiency of thyroid function was diagnosed too late, and the patient could not receive a complete treatment with thyroid hormones since the onset of the disease. Acute psychotic episode treatment with typical antipsychotic haloperidol decreased the concentration of thyroid hormones and even greater influenced the severe hypothyroidism.
1.3.1.2. “Myxedema Madness”: everyday clinical practice
secondary anaemia, caused by the number of reduced erithrocytes, and hypoatremia. Manifestation of psychiatric symptoms in the presence of hypothyroidism is common, and their spectrum ranges from slight attention concentration disorder to dramatically presented agitated delirium or paranoid psychosis. However, psychiatric symptoms are commonly determined prior to hypothyrosis diagnosis. The associations between insufficient thyroid function and psychiatric symptoms are not rare but are frequently not recognized and evaluated as behavioural affective or cognitive disorders.
Our case report hypothesized that insuficient thyroid function could be related to the onset of acute psychotic epidode and the thyroid axis could be influenced during acute psychotic episode treatment.
In 1949 R. Asher wrote that “hypothyroidism is one of the most important, little known and frequently forgotten cause of acute psychosis – important, because it responds to adequate treatment, little known, since it is not frequntly mentioned, and forgettable as description of clinical hypothyrosis is a rule with many exceptions” [15]. To describe this hypothyrosis-related psychosis Asher coined the term „myxedematous maddness“ and presented 14 clinical cases during which he observed manifestation of symptoms of hypothyroidism and acute psychosis at the same time. All patients were women. Although doubts were raised over diagnoses since thyroid hormone concentration was not investigated, only physical examination was carried out, measurements of photography, cholesterol level, metabolic parameters, pulse and arterial blood pressure were evaluated – in all cases treatment with only thyroid hormone thyroxine was administered. Out of 14 patients, 9 fully recovered, two patients showed just a partial improvement, one patient‘s condition remained unchanged, and two patients died. Asher stated that there were no any specific psychoses – clinical picture of paranoid syndrome was common for all patients. Asher's study and resulting description of myxedema madness has been often cited as a typical example of psychosis secondary to hypothyroidism.
concentrations was found. The patient was started on low doses of thyroid hormones and risperidone, visual and auditory hallucinations were gradually resolving, and over a two-three-week period, psychiatric disorders disappeared. When risperidone was discontinued, recurrence of psychosis was not observed. To evaluate the caurse of psychosis authors recommended to investigate psychotic patients’ TSH, which is the most sensitive indicator in detecting of primary hypothyroidism.
The similar case of a 39-year-old patient who was diagnosed with paranoid syndrome, hypothyroidism and vitamin B12 deficiency was decribed. Paranoid symptoms resolved after treatment with thyroid hormones and vitamin B12, moreover, improvement in patient‘s cognitive functions was seen [154]. In our case report the treatment with thyroid hormones also showed reduction in complaints about the decline in cognition.
The case of a patient with a history of chronic paranoid schizophrenia, diagnosis of chronic thyroditis and Grade I hypothyroidism was described [61]. The course of psychosis showed improvement following treatment with thyroid hormones. Manifestation of both diseases at the same time did not allow evaluate existing personality disorder that led the patient to suicide. According to the authors, the differential diagnosis between hypothyroidism, primary axis I psychotic and depressive symptoms has always been problematic. When personality disorders are also present, the diagnostic dilemma is increased.
Some clinical cases presented the manifestation of acute psychotic symptoms in associations with bipolar disorder and hypothyroidism. A poorer response to antidepressants is likely to occur in the presence of the depressive phase of bipolar type I disorder when level of FT4 is lower and level TSH is higher (although within normal range). Hypothyroidism is also thought to be a risk factor for the development of rapid cycle bipolar disorder. Although hypothyroidism is more associated with depression, 10 unusual cases of the link between hypothyroidism and mania episodes in literature are presented [118].
The case report when acute mania manifested in a young woman with hypothyroidism in the absence of classical symptoms of hypothyrosis was presented [233]. This case underscored the importance of thyroid screening in patients with mood and psychotic disorders, including patients who lack the classical psychiatric features of thyroid dysfunction.
highlights the importance of screening for organic causes of psychiatric symptoms presenting for the first time in older patients as well as the importance of ascertaining thyroid function in patients with affective and behavioural symptoms. In our case first time psychosis in older patient also required the exclusion of organic causes, but during hospital treatment period hypothyroidism was not diagnosed.
The case of bipolar mania patient followed by primary hypothyroidism and unresponsive treatment with lithium and antipsychotics during a period of mania was decribed [18]. Similar to our case, only additional levothyroxine treatment of the primary hypothyroidism in this bipolar mania case resulted in rapid and complete recovery.
The significance of the evaluation of thyroid status for patients who manifest affective, psychotic and cognitive disorders even in the absence of the symptoms of thyroid disease is shown. Examination of thyroid function of all psychiatric patients would help to avoid misdiagnoses or delayed treatment. Although there is no uniform opinion on the subject, the majority of psychiatrists traditionally are likely to examine thyroid hormone concentration in hospitalized patients with a history of acute psychotic episode or affective disorders. As in our described case, only random examination helped to determine hypothyroidism and the origin of psychosis.
According to the literature, all reported cases about acute psychotic episode and hypothyroidism improved clinically after use of levothyroxine and psychotropic medications [118]. Thyroid hormone replacement therapy in hypothyroidism and psychotic episode not only reduces physical symptoms of hypothyroidism, but also significantly contributes to an improvement of symptoms of psychiatric disoders [36]. Supplementary antipsychotic medication contributes to a faster remission of psychosis symptoms than only monotherapy of thyroid hormone replacement [48].
As in our case, patients with hypothyroidism frequently experience a wide variety of neuropsychiatric sequelae. The range of physical and psychiatric presentations and their potential subtle manifestations make the diagnosis of hypothyroidism easy to miss. Since psychiatric complaints may be one of the earliest manifestations of hypothyroidism, they are often misdiagnosed as functional psychiatric disorders, rather than a psychiatric disorder due to a general medical condition. This confusion leads to delayed treatment and a high likelihood of increased morbidity. The frequency of misdiagnosis and mistreatment and the potential for poor prognosis point to the importance of a high degree of suspicion of thyroid dysfunction and the need for thyroid screening in psychiatric patients.
1.3.2. Thyroid axis function during acute psychotic episode
Dysfunction of the thyroid gland, either hyper-function or hypo-function, is frequently associated with mental disorders, including psychoses that sometimes resemble schizophrenia [38] Bunevicius and Prange, 2010]. An increased prevalence of thyroid function abnormalities has been reported in families of patients with schizophrenia [65], suggesting possible genetic lin-kage between the endocrine and mental disorders. Relevance of thyroid dis-ease to schizophrenia was discussed, according to findings of higher inci-dence of thyroid disease in mothers of schizophrenia patients than in control [140].
Large numbers of studies have investigated parameters of the thyroid axis in depressive disorders. In contrast, the thyroid hormone concentrations of acutely ill schizophrenic patients have been measured much less. The re-ports of the studies showed high rates of thyroid dysfunction in acute psy-chiatric inpatient [76, 102, 156, 164, 220, 229], but findings are quite con-troversial. Most of studies have reported results for all psychiatric inpa-tients, without explanation about medications used or ratings of mental state [147, 156, 198, 229].
Some studies [50, 102, 220, 229] have found a significant elevation of both thyroid hormone concentrations in acute psychiatric patients. Other studies [164, 190] have found decreased thyroid hormone concentrations during acute psychotic episode. Mason et al. 1989 observed significant dif-ference in the FT4 levels between acute schizophrenia and acute mania pa-tients and even hypothesized about potential usefulness of FT4 levels in the differential diagnosis of these two disorders [145].
Nevertheless, tissue responses to changes in thyroid hormone concentra-tions may be better indicators of the significance of thyroid axis activity than thyroid hormone concentrations themselves. Response of the anterior pituitary gland, evident by changes in TSH concentrations, is a sensitive marker of thyroid dysfunction. Most schizophrenic patients are euthyroid with normal basal concentration of thyroid stimulating hormone (TSH) and normal TSH response to thyrotropin-releasing hormone (TRH) challenge [23, 24, 84, 138, 182, 199]. Another sensitive tissue marker of thyroid activ-ity is liver production of sex hormone binding globulin (SHBG) [186]. However, there are no data pertaining to serum SHBG concentrations in pa-tients with acute psychoses, though one study reported decrease in SHBG concentrations after psychosis treatment with the atypical antipsychotic olanzapine [29].
Several studies described that increased levels of thyroid hormones are correlated with severity of acute psychiatric symptomatology [198, 220] and have found relations between overall symptom severity and changes in FT4 levels during clinical recovery [226].
1.3.4. Thyroid axis function and schizophrenia
Schizophrenia is one of the most severe psychiatric disorders with a chronic course and many patients responding poorly to medication and suffering frequent and disrupting relapses. This disorder arises from the interaction of a range of deviant genetic traits and environmental factors, which may begin to act in the prenatal period [139]. The clear understanding of schizophrenia’s molecular mechanisms is elusive and no biological marker has been identified. In effect, a biomarker may be difficult to find if the disease results from a subtle deregulation in a biological network with impact on mental health and behavior. In this context, modulators of transcriptional activity and their carriers/receptors are good candidates in bridging the genetic and environmental determinants of schizophrenia. Among these are thyroid hormones [167].
are regulated by thyroid hormones. These include differentiation of the ce-rebellum, axonal migration and myelination [62, 64, 74, 87, 98, 113, 210], transcriptional regulation of enzymes, receptors and transporters of the neu-rotransmitter cascades [26]. Thyroid hormones have been directly impli-cated in the processes of learning and memory [270], which is intricately involved not only in language production, but also in schizophrenia [152]. Major thyroid hormone deficiency during pregnancy results in cretinism, while mild hypothyroidism is associated with poorer cognitive development. Even euthyroid hypothyroxinemia during pregnancy has been shown to im-pair proper neuronal migration in the somatosensory cortex and hippocam-pus in rodents [129]. Euthyroid hypothyroxinemic mice display increased exploratory activity and reduced signs of depressive like behavior [225]. Follow up of thyroid function throughout pregnancy and evaluation of the psychomotor development of the offspring, possibly until adulthood, would clearly be a more relevant indication of a relationship between thyroid hor-mones and behavior disorders such as schizophrenia [167].
It is known that thyroid hormone fluctuations in adults are associated with pathophysiology of mood disorders [21], and normal brain metabolism adapts in order to avoid thyroid hormones excess or deprivation [28]. Defi-ciency of thyroid hormones in neurodevelopment is known to result in im-paired proliferation, migration and differentiation of hippocampal and cor-tical neurons [16, 129]. The expression of TRH in humans is predominant in the left hemisphere [31]. The asymmetries have been described for several neuroendocrine systems, including the thyroid axis [85]. The deficitof suc-cessful social communication is a failure of segregation of right from left hemisphere functions and such pathologies have been demonstrated in schi-zophrenia [152].
The researches have revealed the thyroid hormones modulation of crucial brain neurotransmitter systems [6, 22, 149, 259] including the dopaminer-gic, serotonerdopaminer-gic, glutamatergic and GABAergic networks [44, 86, 112, 224, 259]. The disregulation of these pathways as well as the participation of myelination and cytokines is of particular relevance in the schizophrenic brain [44, 62, 139, 179].
to subclinical hypothyroidism [142], and that hypothyroidism can lead to increased dopamine receptor sensitivity [60]. The serum levels of dopamine were found to be elevated in acutely ill schizophrenic patients, while levels of TSH and T4 were decreased [190].
The increased dopaminergic activity was hypothesized to affect the pitui-tary secretory function, and decreased beta-adrenergic activity was inferred as consequence of decreased serum TSH concentration. The adrenergic ca-techolamines could be involved in maintaining deiodinase activity and thus brain thyroid status [120]. Type-1 deiodinase impairment may result in a drop in T3 levels, with unchanged T4, and type-2 or 3-deiodinase impair-ment may be reflected in decreased T4 metabolization.
As we know, the enhanced serotonergic signaling via serotonin type 2A receptors is involved in the pathology of schizophrenia specifically during the early phases of psychoses [86, 216] and deficient central 5–HT functions may underlie some of the negative symptoms in schizophrenic patients [2]. CSF concentrations of the major metabolites of serotonin and dopamine cor-related with thyroid hormones concentrations [233]: the concentration 5– hydroxyindolacetic acid (5–HIAA) significantly and negatively correlated with plasma TSH and total T3 and homovanillic acid (HVA) significantly and negatively correlated with plasma TSH, total T3 and FT3. Such findings establish links between interactions of the serotonergic system and thyroid hormones.
According to the glutamatergic hypothesis of schizophrenia [109], Mendes-de-Aguiar et al. [149] proposed by some authors, who studied the role of T3 in the CNS, specifically on regulation of glutamate uptake; and concluded that T3 is capable of regulating extracellular glutamate levels by modulating the astrocytic glutamate transporters and by promoting neuronal development and neuroprotection.
The role for the δ-aminobutyric acid-ergic (GABA-ergic) system in the pathogenesis of schizophrenia derives mostly from neuropathologic studies [133], but upregulation of the postsynaptic GABA-A receptors was de-scribed in schizophrenic patients [7]. GABA-ergic systems are related to thyroid dysfunction. The effect of thyroid hormones on the GABA-ergic system can take place at multiple levels: circuit formation, enzymes in-volved in synthesis and metabolism of GABA and glutamate, GABA release and reuptake, and GABA receptors [259].
psy-chotic symptoms of people with severe hypo- and hyper-thyroidism and those of schizophrenic patients [15]. Elevated and normal total T4 levels have been reported in drug naive and acute schizophrenic patients and are described to normalize or decrease, respectively, as a response to treatment with different drugs [25, 114, 144, 190, 195]. Also low T3 concentrations are found in schizophrenia [266]. Other studies reported a positive correla-tion between circulating free T4 and free T3 with severity of disease [220]. These are a competition between thyroid hormones and medication for common metabolic pathways, and the downstream effects of therapeutic medication targets on the pituitary–thyroid axis. Increased dopaminergic activity inhibits TSH pituitary secretion [190], and dopamine blockers result in subclinical hypothyroidism [142] while hypothyroidism induces creased dopamine receptor sensitivity [60]. Studies in mentally healthy in-dividuals showed that the pituitary–thyroid state correlated with central do-paminergic and serotonergic activity [233].
The role of thyroid hormones in the pathophysiology of schizophrenia is more so noteworthy when considering the possible function of thyroid mones as neurotransmitters. Given the distribution pattern of thyroid hor-mones in the brain and the strong co-localization with the noradrenergic sys-tem and T3 itself might behave as a neurotransmitter [200]. It was explored a similar neurotransmitter function for 3-iodothyronamine (T1AM), which was identified as endogenous derivative of thyroid hormones. T1AM was found to block the transporters for the neurotransmitters dopamine, norepi-nephrine and serotonin. T1AM binds with high affinity to the trace-amine-associated receptor (TAAR) [209].
Thyroid hormone involvement in susceptibility to schizophrenia might result either from mutations or polymorphisms in genes of their metabolism or whose expression they regulate, but may also result from the altered ex-pression of these normal genes. An increased prevalence of thyroid function abnormalities was reported in families of patients with schizophrenia [65], suggesting possible genetic linkage of two disorders. Association with thy-roid disease and schizophrenia has been reported with a polymorphism on the human opposite paired (HOPA) gene, which is located on chromosome X, is linked to both hypothyroidism and schizophrenia [177, 227]. Muta-tions on the NR4A2 gene have been described in Swedish, but not American Caucasian patients with schizophrenia [33].
nucleotide polymorphisms (SNPs) in TRAR4/TAAR6 have been identified in schizophrenia [66]. Other genome-wide scan studies implicate chromo-somal regions harboring several genes involved in thyroid hormone meta-bolism, namely deiodinase type I on chromosome 1p32.3 [73], THRB on 3p24.2 [187] and UDP glucuronosyltransferases on 2q37.1 [132, 261]. Therefore, the loci of the thyroid hormone metabolic cascades and genes whose expression they regulate have been often implicated in schizophrenia. Relevant support for this involvement comes from studies in rodents in which the expression of nuclear receptors and genes involved in thyroid hormone metabolism is influenced by subchronic and acute treatment with drugs such as haloperidol and clozapine [69, 126, 257].
Several candidate genes recently singled out as significantly contributing to increased vulnerability in schizophrenia [98, 99, 101, 121, 217] are di-rectly or indidi-rectly regulated by thyroid hormone. Among these are ERBB4, the receptor for neuregulin 1 [163]; neuropeptide Y [143]; NOTCH4 [267]; DRD2 [203]; PHOX2B, a transcription factor for RGS4 [91, 91]; dysbindin (through retinoid regulationof the expression of dystrophin-associated pro-tein complex [47]; prohormone convertases 1 and 3 [215]; and amyloid-beta protein [249] and myelin-related genes [98, 265].
1.4. Effect of Antipsychotic Medication on Thyroid Axis Hormones
The introduction of antipsychotics was an important step managing acute psychoses; however, the therapeutic effect of the treatment was counterba-lanced by side-effects. The second-generation of antipsychotic drugs brought new options; however, their efficacy advantage was not so high as expected [135]. In acute psychotic episode [237] as well as in patients with chronic schizophrenia [220, 266] some endocrine changes including changes in thyroid function and thyroid autoimmunity are described. Endo-crine function is often affected by antipsychotic medications as well as by mental disorder itself. Atypical antipsychotics of the second-generation have even a higher risk of metabolic adverse effects than the first-generation agents [240]. A better understanding of the mechanisms related to the effi-cacy and side effects of antipsychotic medications may open new venues preventing side effects and advancing treatment of acute psychosis.
whether acting upon norepinephrine, dopamine, or serotonin synthesis, me-tabolism, uptake, or receptors [125, 130, 189, 208, 248].
Some widely used psychoactive drugs, such as typical antipsychotics phenothiazines exhibit different side effects on the thyroid. Chlorpromazine decreases iodine uptake and it may lead to iatrogenic hypothyroidism [208]. Acting on hypothalamo-pituitary-thyroid (HPT) axis chlorpromazine and thioridazine were shown to decrease thyroid-stimulating hormone (TSH) response to thyroid releasing hormone (TRH) stimulation without altering basal TSH levels [124]. In other studies patients treated with phenothiazines (chlorpromazine, thioridazine, or trifluoperazine) displayed low T4 levels with normal or increased T3 levels, with no other change in TSH and with-out clinical hypothyroidism symptoms. As the HPT axis could be assumed as being intact, this could be due to an abnormal synthesis of T3 or an in-creased conversion of T4 into T3 [97, 144]. A study of schizophrenic pa-tients who were treated with phenothiazine antipsychotic perazine revealed a decrease in serum T4 and rT3 concentrations but altered function of T3 concentration [25]. Contrary to other phenothiazines, perphenazine induces an increase of T4 blood levels with no clinical signs of hyperthyroidism [173]. Antipsychotic phenothiazine such as alimemazine was shown to de-press thyroid hormone production and enhance thyroiditis when animals were fed with these drugs [107, 236].
Some studies showed that phenothiazines could induce thyroid autoim-munity [130, 248]. Alimemazine could play a role in the induction of thyro-id autoimmune disorders [236]. In a cross-sectional study [181] increased prolactinemia was associated with an increased prevalence of thyroid au-toantibodies in schizophrenic outpatients. In the latest review was concluded that phenothiazines could induce a hypothyroid state through either their deiodination effect or their thyroid autoimmune-inducing activity. In all tients receiving phenothiazines, regular monitoring of thyroid function pa-rameters is recommended owing to the direct interference of these drugs with thyroid functioning [116].
The commonly used butyrophenone drug, typical antipsychotic haloperi-dol can induce specific changes in deiodinase activities in rat brain [69]. Treatment with haloperidol in humans declined serum concentrations of T4 and fT4 [23, 110, 195]. Accordingly, typical antipsychotic drugs, whether they were phenothiazines or not, can induce autoimmune thyroid abnormali-ties and ATPO increment [116].
clozapine treatment TSH response to TRH is significantly decreased; whe-reas the basal level of TSH remains unaltered [173].
There some studies about thyroid effects of second generation antipsy-chotics. After administration of amisulpride TSH levels significantly ele-vated compared to TSH levels after placebo administration [181]. Also pa-tients with schizophrenia treated with amisulpride showed a significant ele-vation in TRH-stimulated TSH secretion in comparison to patients treated with typical antipsychotic, thioxanthene drug flupentixol [92].
Significant decrease in T4 levels was observed in the patient group re-ceiving quetiapine, whereas other patients rere-ceiving risperidone and fluphe-nazine had no change in their thyroid hormone levels [114, 119]. Quetiapine treatment is even associated with development of hypothyroidism [75, 134, 180, 188]. Church and Callen 2009 described myxedema coma possibly as-sociated with combination aripiprazole and sertraline therapy [51]. Howev-er, a clinical role of the effects of treatment with antipsychotic medications on thyroid hormone concentrations in acute psychotic patients is not well understood. One study reported decrease in SHBG, sensitive tissue marker of thyroid activity is liver concentrations after treatment with the atypical antipsychotic olanzapine [29].
1.5. Thyroid axis hormones in treatment of mental disorders
