Journal of Affective Disorders 180 (2015) 162–169

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Research report

The correlation between biochemical abnormalities in frontal white matter, hippocampus and serum thyroid hormone levels in first-episode patients with major depressive disorder Yanbin Jia a,n,1, Shuming Zhong a,1, Ying Wang b, Tao Liu a, Xiaoxiao Liao a, Li Huang b a b

Department of Psychiatry, First Affiliated Hospital of Jinan University, Guangzhou 510630, China Medical Imaging Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China

art ic l e i nf o

a b s t r a c t

Article history: Received 21 November 2014 Received in revised form 3 March 2015 Accepted 2 April 2015 Available online 10 April 2015

Background: Previous neuroimaging studies found evidence of potential brain biochemical abnormalities in patients with major depressive disorder (MDD). Abnormal serum thyroid hormone levels were also found in MDD patients, which may correlated with the abnormal biochemical metabolism of brain. However, they rarely excluded the compounding effects of medication, and brain degeneration. This study sought to investigate the relationship between the biochemical metabolism and the serum thyroid hormone levels in first-episode, treatment-naive, non-late-life patients with MDD. Methods: 26 first-episode, treatment-naive, non-late-life patients with MDD and 13 healthy controls were enrolled in this study. Participants underwent two-dimensinal multivoxel proton magnetic resonance spectroscopy (1H MRS) [repetition time (TR) ¼1000 ms; echo-time (TE)¼144 ms] at 1.5 T to obtain bilateral metabolite levels from the white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. The ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline containg compounds (Cho)/creatine (Cr) were calculated. Morning serum free triiodothyronine (FT3), free thyroxin (FT4), total triiodothyronine (T3), total thyroxin (T4), and thyroid-stimulating hormone (TSH) were measured before antidepressant treatment. Results: On the comparison of brain biochemical changes, MDD patients had a significantly lower NAA/Cr ratio in the left WMP, and lower NAA/Cr and Cho/Cr ratios in the right WMP when compared to the controls. There were no significant differences in the metabolite ratios in the bilateral ACC, and hippocampus. On the comparison of serum thyroid hormone levels, MDD patients had a significantly decreased T3 and TSH levels. On the comparison of correlation of brain biochemical changes and serum thyroid hormone levels in patients with MDD, the NAA/Cr ratio in the right WMP was positively correlated with the level of TSH. Conclusion: These findings suggest that biochemical abnormalities and thyroid dysfunction may emerge early in the course of MDD. Dysfunction of neuronal function in the WMP may correlate with the abnormal TSH in patients with MDD, which may be related to the neuropathology of depression. & 2015 Elsevier B.V. All rights reserved.

Keywords: Major depressive disorder Proton magnetic resonance spectroscopy Serum thyroid hormone

1. Introduction Major depressive disorder (MDD) is one of the most common psychiatric disorders, which is characterized by episodes of sustained depressed mood accompanied by low self-esteen, and loss of interest or pleasure in normally enjoyable activities. In the U.S., MDD affects more than 13% of adults during their lifetime (Hasin et al., 2005). It has been a significant cause of disability and public health concern (Smoller et al., 2013), which has placed a heavy

n

Corresponding author. Tel.: þ 86 20 38688120; fax: þ 86 20 38688888. E-mail address: [email protected] (Y. Jia). 1 These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.jad.2015.04.005 0165-0327/& 2015 Elsevier B.V. All rights reserved.

burden on the society (Kessler et al., 2005), However, we do not yet understand fully the underlying pathogenesis of MDD. The multi-voxel proton magnetic resonance spectroscopy(1H MRS)offers a unique non-invasive and non-radioactive approach to measurement of important metabolites in brain regions. It can give more detailed information about neuronal abnormalities at the cellular and metabolic levels than relatively gross volumetric estimates. It has been increasingly used to examine neurochemistry in depressive patients in recent years. Our preliminary neuroimaging studies have showed the biochemical abnormalities may occur in some brain sites, such as white matter in prefrontal (WMP) lobe, hippocampus in MDD patients, and the changes of N-acetylaspartate (NAA)/creatine (Cr) ratios in prefrontal white matter may occur early in the course of MDD, it may be related

Y. Jia et al. / Journal of Affective Disorders 180 (2015) 162–169

to the neuropathology of depression (Wang et al., 2012; Ying et al., 2012). Other studies also revealed that the prefrontal lobe plays a role in mood regulation and cognitive function, which may be involved in the pathogenesis of depression patients (Bae et al., 2006; Fossati et al., 2002; Tekin and Cummings, 2002). Other 1H MRS study has also shown alteration of specific metabolites in dorsolateral prefrontal cortex in depression patients (Brambilla et al., 2005). Gruber et al. (2003) found that NAA/Cr ratios decreased within the bilateral frontal lobes of MDD patients, other study found the level of choline containg compounds (Cho)/Cr in the prefrontal cortex also decreased in depressed patients (Caetano et al., 2005). However, the cause of biochemical metabolism changes has not been fully investigated. MDD may be associated with various endogenous circadian rhythms abnormalities such as diurnal mood variation, abnormalities in core body temperature, cortisol secretion (Monteleone., 2009). In addition to these circadian dysfunctions, MDD has been linked to the hypothalamic-pituitary-thyroid (HPT) axis disturbances (Michael et al., 2013). The patients with dysfunction of HPT axis had susceptibility to difficulty in falling asleep, weight loss and gastrointestinal symptoms. The dysfunction of HPT axis was associated with the severity of depression (Constant et al., 2001). Thyrotropin-releasing hormone (TRH) could promote the synthesizing and releasing of thyroid-stimulating hormone (TSH) in pituitary. Depressed patients usually had enhanced activities of TRH, and TSH responses to TRH (Fraser et al., 2004). The activity of HPT axis would increase in acute stage of depression and then decrease in chronic stage (Bschor et al., 2003). Thyroid hormones levels were associated with suicide attempts in psychiatric patients (Maurizio, et al., 2012), further studies may help in understanding how these findings can be used by clinicians in assessing suicide risk. In addition, there is evidence that augmentation with thyroid hormones can be effective in treating depression (Hage and Azar., 2012). The successful treatment of affective disorders with thyroid hormone suggested the interrelationship between endocrine and neuronal systems in these disorders. As we all know, thyroid hormone is essential for brain maturation, regulating neuronal differentiation and migration, myelination, and synaptogenesis. In recent years, the influence of thyroid hormone on the regulation of mood and behavior in the adult becomes the focus of research. Previous study found no associations between HPT axis and brain function, or cerebral blood flow and glucose metabolism in depressed patients (Constant et al., 2001; Xie et al., 2012), a possible reason is the impact of medication, and another possible reason is that they did not exclude the effects of aging. However, it still suggested a novel imaging approach to reveal the association between HPT axis and brain function. In this study, a semi-quantitative analysis was preformed to quantify the concentrations of NAA, Cho and Cr of bilateral WMP, anterior cingulate cortex (ACC), and hippocampus in first-episode, treatment-naive, non-late-life patients with MDD, which used a ratio rather than an absolute quantification of metabolites. Serum free triiodothyronine (FT3), free thyroxin (FT4), total tri-iodothyronine (T3), total thyroxin (T4), and thyroid-stimulating hormone (TSH) were also measured before antidepressant treatment in patients with MDD. We hypothesized that the abnormalities of serum thyroid hormone levels and biochemical levels occurred at the early stage of depression, and these abnormalities of serum thyroid hormone may correlated with the biochemical metabolism of WMP, ACC, and hippocampus, such as ratios of NAA/Cr and Cho/Cr.

2. Methods 2.1. Participants A total of 26 MDD patients were recruited at the Department of Psychiatry in the First Affiliated Hospital of Jinan University,

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Guangzhou, China (Shuming et al., 2014). The age of all participants was restricted to 18–45 years to diminish the interference of aging and vascular disease. All participants met DSM-IV criteria based on the Structured Clinical Interview for DSM-IV Patient Edition (SCID-P) (Spitzer et al., 1994) for MDD with a score of 18 or greater on the 17-item Hamilton Depression Rating Scale (HDRS). Exclusion criteria included the presence of (1) other Axis I psychiatric disorders and symptoms, (2) a history of the use of any psychotropic medication, psychotherapy or electroconvulsive therapy, (3) a history of neurological or organic brain disorder, (4) alcohol/substance abuse within 6 months preceding study entry, (5) any physical illness demonstrated by personal history or clinical or laboratory examinations, pregnancy and postpartum depression. Thirteen age- and gender-matched healthy controls (six males) were studied (Shuming et al., 2014). Healthy controls were carefully screened through a diagnostic interview, the Structured Clinical Interview for DSM-IV Nonpatient Edition (SCID-NP), to rule out the presence of current or past history of substance abuse/dependence or any psychiatric illness in self or in first-degree relatives. All participants were right-handed and were submitted to MRI scanning within 48 h of initial contact. Blood samples were obtained in the second morning. The study was approved by the Ethics Committee of First Affiliated Hospital of Jinan University, China. All participants signed informed consent forms after a full written and verbal explanation of the study. 2.2. Image acquisition Both magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) were performed on a clinical 1.5 T GE Signa MR system (General Electric, Milwaukee, WI, USA) with a conventional gradient system. A standard eight-channel head coil was used for radiofrequency transmission and reception of the MR signal. Participant was lying in the supine position; nasion served as a landmark. Ear plugs and foam pads were used to reduce noise and minimize head motion. Routine axial T1weighted fluid attenuation inversion recovery (T1 Flair) [repetition time (TR) ¼1800 ms, echo-time (TE)¼ 24 ms] and fast spin echo T2-weighted MR images (TR¼ 4500 ms, TE ¼120 ms) were obtained to confirm the absence of any structural and signal abnormality of the brain. In this study, all the spectra were acquired using 2D multivoxel technique. Axial T2-weighted MR images were used for anatomic localization (TR¼5000 ms, TE¼113 ms, slice thickness¼5 mm without a gap). For 1H MRS studies, Figs. 1 and 2 showed the location of the prefrontal lobe volume of interest (VOI) and hippocampus VOI. The prefrontal lobe VOI was localized at the midline and included the dorsolateral prefrontal white matter and anterior cingulate gray regions bilaterally avoiding the striatum, ventricle, scalp, skull base, or sinuses. The posterior boundary of the VOI was placed adjacent to the anterior margin of the frontal horn of the lateral ventricle. The hippocampus VOI was localized in normal-appearing hippocampal tissue at the midbrain level. The VOIs were placed in a uniform manner by the same investigator. The size of the VOI was including 50 nominal voxels (7.5  7.5  10 mm3). Single section 2D multivoxel 1H MRS was acquired using a point resolved spectroscopy sequence (PRESS) with water suppression by a chemical shift selective saturation (CHESS) pulse. The acquisition parameters were the following: TR¼ 1000 ms; TE¼144 ms; numbers of excitation¼1; spatial matrix¼18  18; field of view¼240  240 mm2; slice thickness¼ 10 mm; a nominal voxel size of 7.5  7.5  10 mm3. Additional saturation bands were placed outside the VOI to minimize lipid contamination from the scalp. Automatic pre-scanning was performed before each spectroscopic scan to achieve an optimal full width half-maximum of 10 Hz. As a general quality standard spectra

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Fig. 1. Magnetic resonance image (MRI) scan of healthy control subject showing location of magnetic resonance spectroscopy (MRS) of volume of interest (VOI) placed in the dorsolateral prefrontal white matter, and the proton magnetic resonance spectra in the left and right dorsolateral prefrontal white matter. The large white boxes represent the VOIx for MRS acquisition, and small white boxes depict the individual VOIs for spectral analysis. Note: NAA, N-acetylaspartate; Cho, choline containg compounds; Cr, creatine.

Fig. 2. Magnetic resonance image (MRI) scan of healthy control subject showing location of magnetic resonance spectroscopy (MRS) of volume of interest (VOI) placed in the hippocampus, and the proton magnetic resonance spectra in the left and right hippocampus. The large white boxes represent the VOIx for MRS acquisition, and small white boxes depict the individual VOIs for spectral analysis. Note: NAA, N-acetylaspartate; Cho, choline containg compounds; Cr, creatine.

with a line width above 10 Hz or water suppression above 98% were excluded. Each participant underwent scanning twice, once the prefrontal lobe and then detected the hippocampus, the time of each detection was 5 min and 28 s, total acquisition time for 1H MRS sequence was10 min and 56 s. Voxels were repositioned in the predefined (left and right) brain areas: dorsolateral prefrontal white matter, anterior cingulated gray matter, and hippocampus. A trained radiologist who was blind to the diagnosis of each participant carried out voxel placements for spectroscopy.

2.3. Thyroid function test A 5 mL blood sample was obtained 7.00–8.00 a.m. by routine venipuncture from all participants before initiating any treatment, and blood samples were sent to a centralized laboratory that performed analysis following standard procedures. A direct chemiluminescence method was used to determine the concentrations of

FT3, FT4, T3, T4, and TSH. All samples of an individual were measured in the same assay run. 2.4. Measures 2.4.1. Clinical variables Four clinical variables (HDRS score, duration of illness, age, age of onset) were included in this study to investigate their possible correction with brain biochemical metabolic changes and serum thyroid hormone levels. 2.4.2. Biochemical metabolite ratios The analysis of the spectral dataset were performed with the manufacturer-supplied software package program of the MR system (GE Advantage Workstation:AW4.2_07). Each spectrum was evaluated for the peak area of Cho at 3.22 ppm, Cr at 3.03 ppm, and NAA at 2.02 ppm. The values of the NAA/Cr, Cho/Cr ratios on both left and right side of three locations (WMP, ACC, and hippocampus) were used for analysis of brain biochemical changes.

Y. Jia et al. / Journal of Affective Disorders 180 (2015) 162–169

2.4.3. Serum thyroid hormone levels The tests of FT3 (pg/ml), FT4 (ng/dl), T3 (ng/ml), T4 (μg/dl), and TSH (mIU/L) were done in our study. All the tests were performed on a Siemens ADVIA Centaur XP Chemiluminescence Immunoassay Analyzer. 2.5. Statistical analysis All data analysis was performed using SPSS for Windows software, version 15.0 (SPSS Inc., Chicago, III, USA). Two-tailed significance level was set at p o0.05. One-way analysis of variance (ANOVA) was used to determine whether groups displayed differences in terms of two metabolite ratios (NAA/Cr and Cho/Cr on both left and right brain of three VOIs: WMP, ACC, and hippocampus and five thyroid hormone levels T3, T4, FT3, FT4, and TSH). Spearman's correlation analyses were used to determine whether four clinical variables correlated to the brain biochemical metabolite ratios (NAA/Cr, Cho/Cr) and the thyroid hormone levels (T3, T4, FT3, FT4, and TSH). It also used to determine whether the brain biochemical metabolite ratios correlated to the thyroid hormone levels. The significant level was set at po 0.05.

Table 2 Comparison of metabolite ratios in the three cerebral regions between MDD patients and healthy controls [mean (SD)].

NAA/Cr WMP Lef Right ACC Left Right Hippocampus Left Right Cho/Cr WMP Left Right ACC Left Right Hippocampus Left Right

MDD (n ¼ 26)

Control (n¼ 13)

F

p

1.77(0.45) 1.57(0.35)

2.10(0.30) 1.97(0.34)

4.933 8.493

0.033n 0.006n

1.54(0.29) 1.5 (0.23)

1.52(0.27) 1.52(0.31)

0.020 0.000

0.889 0.990

1.46(0.47) 1.54(0.49)

1.39(0.26) 1.37(0.37)

0.065 3.636

0.800 0.065

1.36(0.52) 1.16(0.23)

1.54(0.25) 1.35(0.18)

1.510 4.500

0.228 0.041n

1.22(0.30) 1.23(0.27)

1.19(0.16) 1.22(0.23)

0.089 0.013

0.767 0.908

1.34(0.24) 1.43(0.25)

1.28(0.28) 1.32(0.26)

1.691 0.892

0.202 0.352

MDD: major depressive disorder. NAA/Cr: N-acetylaspartate/creatine. Cho/Cr: Choline containg compounds/creatine. WMP: white matter in prefrontal (WMP) lobe. ACC: anterior cingulated cortex.

3. Results 3.1. Demographic result

n

Table 1 shows the demographic and clinical data of all study participants. We included 26 MDD patients (11 males and 15 females) with a mean age of 32.88 7 8.39 (range 18–45) years and 13 healthy controls (6 males and 7 females) with a mean age of 28.10 78.57 (range 18–45) years. The mean number of education years was 13.27 77.41 years for patients and 15.60 74.12 years for controls. There were no significant differences in sex, age, and educational status between the MDD group and the healthy control group. For the MDD patients, the mean duration of illness was 30.38 731.46 months and the mean HDRS score was 25.12 75.07. 16 of them have psychotic features, 6 of them have family history. 3.2. Comparisons of biochemical metabolite ratios (NAA/Cr and Cho/ Cr) in terms of WMP, ACC, and hippocampus Table 2 shows the result of comparison of the NAA/Cr, Cho/Cr ratios in the bilateral WMP, ACC, and hippocampus in MDD patients and healthy control participants. MDD group showed significantly lower NAA/Cr ratio in the left WMP (F¼ 4.933, p ¼0.033), and lower NAA/Cr and Cho/Cr ratios in the right WMP

Table 1 Demographic and clinical data of the subjects [mean (SD)].

Age (year) Age range (year) Age of onset (year) Gender (male/female) Education (year) Duration of illness (month) Number of episodes Psychotic features Family history HDRS score

165

MDD (n¼ 26)

Control (n¼ 13)

32.88(8.39) 18–45year 30.42(8.46) 11/15 13.27(7.41) 30.38(31.46) 1.96(1.82) 16 6 25.12(5.07)

28.10(8.57) 18–45year

MDD: major depressive disorder. HDRS: Hamiltion Depression Rating Scale.

6/7 15.60(4.12)

p o 0.05 significant.

when compared to the healthy controls at the confidence level of po 0.05 (F¼8.493, p ¼0.006; F¼4.500, p ¼0.041). There were no significant differences in the ratios of NAA/Cr and Cho/Cr in the bilateral ACC and hippocampus between the MDD group and the healthy controls. 3.3. Comparisons of serum thyroid hormone levels (FT3, FT4, T3, T4, and TSH) Table 3 shows the result of comparisons of the concentrations of FT3, FT4, T3, T4, and TSH. MDD group showed significantly decreased T3 and TSH levels when compared to the healthy controls at the confidence level of po 0.05 (F¼12.225, p ¼0.001; F¼4.603, p ¼ 0.039). There were no significant differences in the concentrations of FT3, FT4, and T4 between the MDD group and the healthy controls. 3.4. Correlation among clinical variables, biochemical metabolite ratios, and thyroid hormone levels For the MDD group, we only found that the NAA/Cr ratio in the right WMP was positively correlated with the level of TSH (F¼0.397, p ¼0.045) (Fig. 3). There was no significant correlation between the two metabolite ratios and four clinical variables. There was no significant correlation between the five thyroid hormone levels and four clinical variables.

4. Discussion To the best of our knowledge, this study is one of the very early studies using multi-voxel 1H MRS to investigate the relationship between the biochemical abnormalities in the bilateral WMP, ACC, hippocampus and the thyroid function in first-episode, treatmentnaïve, non-late-life patients with MDD.

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4.1. Comparison of biochemical metabolite ratios in terms of WMP, ACC, and hippocampus Previous studies have found morphometrical and functional alterations of the frontal lobes in patients with MDD. In our study, MDD patients showed significantly lower NAA/Cr ratios in the bilateral WMP when compared to the healthy controls. NAA is localized mostly in neurons, oligodendrocyte precursors mature oligodendrocytes, which is the second most abundant amino acid in the central nervous system. NAA is used in clinical and experimental MRS studies as a marker of neuronal/axonal tissue that includes functional aspects of formation and/or maintenance of myelin, dendritic and synaptic proliferation (Urenjak et al., 1993; Bhakoo and Pearce, 2000). Our result indicated that MDD patients may have reduced neuronal function in the WMP. Reduced NAA/Cr and NAA values were revealed in either younger or older patients with MDD in the frontal lobes (Gruber et al., 2003; Venkatraman et al., 2009; Olvera et al., 2010). However, negative findings have also been reported (Yildiz-Yesiloglu and Ankerst, 2006; Kaymak et al., 2009; Nery et al., 2009). The reason of these inconsistencies is probably because of the age, illness duration, drug administration, and methods of imaging data processing and analysis. One major environmental influence that is consistently seen with 1H MRS studies of the brain biochemical metabolism is the impact of medication. NAA levels increased Table 3 Comparison of serum thyroid hormone levels between MDD patients and healthy controls [mean (SD)].

FT3 (pg/ml) FT4 (ng/dl) T3 (ng/ml) T4 (μg/dl) TSH (mIU/L)

MDD (n ¼26) Control (n ¼13) F

p

Reference range

2.34(0.57) 1.10(0.22) 0.78(0.20) 7.39(1.79) 1.28(0.65)

0.286 0.762 0.001n 0.242 0.039n

2.10–3.80 0.82–1.63 0.79–1.58 4.90–11.00 0.38–4.31

2.55(0.35) 1.12(0.26) 1.02(0.27) 8.33(2.80) 2.00(1.36)

MDD: major depressive disorder. FT3: free tri-iodothyronine. FT4: free thyroxin. T3: total tri-iodothyronine. T4: total thyroxin. TSH: thyroid-stimulating hormone. n

po 0.05 significant.

1.173 0.093 12.225 1.417 4.603

significantly from baseline in MDD patients after antidepressant treatment (Gonul et al., 2006). It increased early in the course of treatment (Taylor et al., 2012). In our study, lower Cho/Cr ratio was also found in the right WMP in patients with MDD. Negative finding has also been reported (Kaymak et al., 2009), and other study found increased Cho in depressive patients (Kumar et al., 2002). Cho is a marker of cell membrane integrity (Strakowski et al., 2005), and Cho is enormously present in oligodendrocytes (Urenjak et al., 1993). It may demonstrate decreased membrane turnover, or impaired intracellular signal transduction systems in MDD patients. We have found that decreased Cho/Cr in the left prefrontal white matter was occurred in the early stage of disease without interference of medication in depressive patients (Ying et al., 2012), and speculating that decreased membrane turnover, or impaired intracellular signal transduction systems in the left WMP may play an important role in the pathophysiology of MDD. In this study, the biochemical abnormalities could also occurred early in the right WMP in the MDD patients, and there were no significant differences between the right and left WMP (p 40.05). These findings support that the abnormalities of biochemical metabolism in the left and right WMP may be related to an alteration in oligodendrocytes. ACC involved in attention and reward-based learning has been suggested in both human and macaque studies (Hayden et al., 2011; Rushworth et al., 2011). Some of the symptoms of MDD, such as cognitive deficits and apathy, could be related to cingulate dysfunction or to its neurocircuitry. However, we found no significant differences in NAA/Cr and Cho/Cr ratios in the bilateral ACC in patients with MDD, which is in agreement with the majority of publications (Gruber et al., 2003; Mirza et al., 2004; Coupland et al., 2005). We failed to observe some neurochemical abnormalities in the bilateral hippocampus of patients with MDD in this and the previous study. Other study found that NAA/Cr ratios in the hippocampus were lower in drug-naive post-stroke depression patients than in controls (Huang et al., 2010), and changed hippocampal metabolites at first onset and with recurrent episodes of MDD (Milne et al., 2009). These divergent results may be explained by age, illness duration, number of acute episodes, and so on. According to our data, we cannot rule out the possibility that NAA or Cho concentrations within the ACC and hippocampus differed between MDD patients and healthy controls.

Fig. 3. Correlation between NAA/Cr ratio in the right frontal white matter and TSH level in major depressive disorder (MDD) patients. Note: MDD, major depressive disorder; NAA/Cr, N-acetylaspartate/creatine; TSH, thyroid-stimulating hormone; WMP: white matter in prefrontal (WMP) lobe.

Y. Jia et al. / Journal of Affective Disorders 180 (2015) 162–169

4.2. Comparison of serum thyroid hormone levels A portion of depressive patients were found to have overt thyroid diseases, the association between changes of HPT axis and depression has been widely reported (Stipcevic et al., 2008). The effect on the HPT axis in depressive patients appears to be weaker than in healthy subjects. Our study found that the levels of T3 and TSH were significantly decreased in MDD group when compared to the healthy controls. The results may suggest that HPT axis functions are abnormal in patients with MDD in the first-episode. In this study, the serum T3 concentration was significantly lower than that of healthy controls, which were in agreement with the previous studies (Stipcevic et al., 2008). On the other hand, a recent study has demonstrated that the levels of hair T3 was significantly lower in patients with depression in disease episode than that in healthy controls (Jinxue et al., 2014). 80% of T3 is derived from local conversion of T4 by deiodination, It has been hypothesized that depression leads to the increasing in cortisol levels, which inhibit the type-2 deiodinase (D2) enzyme responsible for conversion of T4 into T3 (Nemeroff, 1989). Most studies found that total and free T4 levels were slightly higher or in the upper range of normal in depressed patients when compared to healthy or psychiatric controls (Hage and Azar., 2012). A possible explaining is the activation of hypothalamic TRH producing neurons and subsequent increase in thyroid function secondary to the rise in cortisol associated with depression (Baskin et al., 2002; Bahls and De Carvalho, 2004). Decreased TSH in MDD group was also found in our study. A new cohort study identified low-normal TSH as an important risk factor for depression, especially in the elderly (Marco et al., 2014), and most of them were females (Wenjiao et al., 2012). Other study found a disparity in depressive symptoms manifestations and severity among patients with a low-normal TSH versus those with a high-normal TSH (Joffe and Levitt, 2008). Moreover, the serotonin (5-HT) transporter was expressed by thyroid follicular cells. When the 5-HT activity in depression decreased, the TRH would prolong release which may be seen as a compensatory response to normalize 5-HT function and maintain normal levels of thyroid hormones. So the effects of TSH may be modulated by the local secretion of 5-HT. However, other study found a higher serum total T3 and TSH in the depressed group (Brouwer et al., 2005), and higher TSH could reduce the increase of serum brain-derived neurotrophic factor level during antidepressant treatment in patients with MDD (Baek et al., 2014). We found no significant differences in the concentrations of FT3, FT4, and T4 between the MDD group and the healthy controls. Many factors may contribute to these inconsistent results, including the heterogeneity of depression, in- or outpatient status, and periodic changes of serum thyroid hormones concentration with circadian rhythms (Russell et al., 2008). There might be a difference in the severity of depression between inand outpatients. Someone also observed an increased level of TSH with age (Surks and Hollowell, 2007). Another factor may be the use of antidepressant medication. There was no evidence that baseline thyroid function was related to overall antidepressant response or response to T3 augmentation (Steven et al., 2012). But, it has been shown that elevated serum T4 levels fall after successful treatment of depression. Basal serum TSH level may predict antidepressant efficacy in MDD patients, subtle thyroid axis modifications being associated with lower antipressant response. There were complex interactions between baseline serum TSH and antidepressant response (Corruble et al., 2010). 4.3. Correlation among clinical variables, biochemical metabolite ratios, and thyroid hormone levels 1

H MRS is a relatively new method that allows the investigation of important metabolites in brain regions, giving more detailed

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information about neuronal abnormalities at the cellular and metabolic levels. Most of the 1H MRS studies focused on metabolism abnormalities in prefrontal cortex, amygdala, and hippocampus, the relationships between brain and endocrine function are little known. In our previous study, we found no significantly higher serum cortisol levels in MDD patients, and no correlation between morning serum cortisol levels and bilateral hippocampal NAA/Cr or Cho/Cr (Ying et al., 2012). The alterations of HPT axes are important neuroendocrine abnormalities in depression. We aimed to identify some potential associations among clinical manifestations of depression, biochemical metabolism and serum thyroid hormone levels in first-episode, treatment-naive, nonlate-life patients with MDD. These findings might provide some evidences for the pathogenesis, clinical diagnosis and treatment of depressed patients according to the associations. To the best of our knowledge, few studies have been focused on the potential correlation between these abnormal biochemical metabolism and thyroid dysfunction of depression. Therefore, in this present work, we identified these potential associations in a considerable sample of Chinese patients with MDD. In our study, we found that the NAA/Cr ratio in the right WMP was positively correlated with the level of TSH in patients with MDD. Brain metabolism and regional cerebral blood flow changes have been reported in hypothyroidism (Bauer et al., 2009; Schraml and Beason-Held, 2010), and a positron-emission tomography (PET) study showed a direct relationship between the brain metabolism and TSH (Bauer et al., 2009). In Hashimoto's thyroiditis with depression, researchers found thyroid peroxidase antibodies correlated with increased gray matter density in right amygdala by using 3-T magnetic resonance imaging (MRI) (Eva et al., 2014). Antibody positive members of general population have a heightened risk for depression (Grabe et al., 2005). Our data may demonstrate that the dysfunction of neuronal function in the right WMP may correlate with the abnormal TSH in first-episode patients with MDD. We believed that the alterations of neuronal function and thyroid dysfunction existed early in the course of MDD, which may be related to the pathogenesis of depression. We did not find significant correlation between the metabolite ratios and four clinical variables, several studies demonstrated that neurometabolite levels changed with illness and chronicity (Michael et al., 2003; Brambilla et al., 2005). There was no significant correlation between the five hormone levels and four clinical variables, while there was a finding showing an association between higher FT4 and depression scores (Quinque et al., 2013). The inconsistent correlation results may be because of the small sample size.

5. Conclusion Reduced NAA/Cr in the left WMP, and lower NAA/Cr and Cho/Cr in the right WMP in this study indicated dysfunction of neuronal viability, and membrane turnover, or impaired intracellular signal transduction systems in the deep white matter in MDD patients. Decreased T3 and TSH indicated thyroid dysfunction in MDD patients. Furthermore, the dysfunction of neuronal function in the WMP may correlate with the abnormal TSH in patients with MDD, which may be related to the neuropathology of depression. There are some limitations apart from the small sample size. First, we used a ratio rather than absolute concentration levels of metabolites due to technical limitation. Second, we could not resolve the smaller 1H MRS peaks, such as mlns and Glx. Our study is an early one to investigate the relationship between the biochemical metabolism and the serum thyroid hormone levels in first-episode, treatment-naive, non-late-life patients with MDD. The correlation results are necessarily preliminary. Further study

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with larger, clinically homogenous groups of patients and better technologies will be investigated in the future.

Role of funding source Funding for this work was provided by Educational Commission of Guangdong Province, China (No: 2013KJCX0025), Humanities and Social Sciences Planning Fund (No: 13YJA190008), National Science Foundation of China (No: 81471650), Natural Science Foundation of Guangdong Province, China (No: 2014A030313375) and Planned Science and Technology Project of Guangdong Province, China (No: 2013B021800160). The funders have not played any roles in study design, data collection, analysis, manuscript writing and decision to publish.

Conflict of interest The authors declare that they have no conflict of interest.

Acknowledgments This work was supported by grants from the Educational Commission of Guangdong Province, China (No: 2013KJCX0025), Humanities and Social Sciences Planning Fund (No: 13YJA190008), National Science Foundation of China (No: 81471650), Natural Science Foundation of Guangdong Province, China (No: 2014A030313375) and Planned Science and Technology Project of Guangdong Province, China (No: 2013B021800160).

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The correlation between biochemical abnormalities in frontal white matter, hippocampus and serum thyroid hormone levels in first-episode patients with major depressive disorder.

Previous neuroimaging studies found evidence of potential brain biochemical abnormalities in patients with major depressive disorder (MDD). Abnormal s...
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