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Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study
Biological Psychiatry: CNNI
Archival Report Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study Marcio Gerhardt Soeiro-de-Souza, Maria Concepcion Garcia Otaduy, Rodrigo Machado-Vieira, Ricardo Alberto Moreno, Fabiano G. Nery, Claudia Leite, and Beny Lafer
ABSTRACT BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD. Keywords: Anticonvulsants, Bipolar disorder, Euthymia, Glutamate, Glx, Magnetic resonance spectroscopy https://doi.org/10.1016/j.bpsc.2018.02.007
The study of bipolar disorder (BD), a chronic and recurrent illness characterized by depressive and manic episodes (1), is like investigating multiple disorders in one, especially in studies including patients with bipolar spectrum disorders. This holds true because BD has multiple clinical presentations and patterns of mood instability. Among the different subtypes of BD, bipolar I disorder (BDI) has the most consistent data regarding genetic, neuroimaging, and peripheral biomarkers (2), and therefore we consider it the most appropriate subtype of BD for investigating brain metabolites. Glutamate (Glu) system dysfunctions have been consistently reported in BD by postmortem, peripheral biomarker, pharmacological (3,4), and proton magnetic resonance spectroscopy (1H-MRS) studies (5,6). This body of evidence has prompted the development of novel medications to treat mood disorders based on the Glu system (7–10). Unfortunately, studying BD by 1H-MRS, a key instrument for investigating the Glu system, has proven a
ISSN: 2451-9022
major challenge because of the unique features of BD. The multiple subtypes and mood states in BD, when mixed within the same sample, prevent a conclusive interpretation of the data (5,6) because neuroimaging markers reportedly differ between these subtypes (11,12). In this scenario, the objective of the present study was to investigate the impact of mood stabilizers on Glu using 1H-MRS in a large sample of BDI patients during euthymia. Glutamate is the major excitatory neurotransmitter of the brain (13) and is constantly recycled between neurons and glia. Glutamatergic alterations have been reported in plasma (14–16), serum (17), cerebrospinal fluid (18,19), and brain tissue (20,21) in subjects with BD. Postmortem studies have reported decreased N-methyl-D-aspartate receptor subunits NR1 and NR2A transcript expression and indicate a reduction in total number of N-methyl-D-aspartate receptors (22–24). Pharmacological studies highlight the link between BD and the
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glutamatergic system, indicating that first-line agents for treating BD, such as lithium, valproate, carbamazepine, and lamotrigine, also regulate the glutamatergic system (22,23). Excess Glu causes excitotoxicity and apoptosis (25), which is associated with higher levels of intracellular calcium and the production of mitochondrial reactive species (26,27). Excessive synaptic Glu may cause neuronal atrophy and death, but it is noteworthy that long-term treatment with lithium has been shown to partially revert these effects (28,29). Most 1H-MRS studies on BD mood episodes (mania, depression) have reported increased Glu and Glx (Glu plus glutamine [Gln]) in multiple brain voxels (5,6). Most studies of BDI and BDII patients during euthymia have reported Glx and/ or Glu increase in patients compared with control subjects in the following voxels: hippocampus (30), occipital cortex (31,32), and anterior cingulate cortex (ACC) (33,34). A study that applied the whole-brain technique as opposed to singlevoxel study in euthymic BD patients found no alterations in Glu or Glx levels (35). Among voxels, the ACC is an important area linked to mood regulation (33,34) and shows widespread functional (36) and structural abnormalities in patients with BD, also observed during euthymia, suggesting that ACC dysfunction might represent a stable trait marker of BD (37,38). Moreover, the ACC has been the most extensively studied brain voxel in BD among 1H-MRS studies (5,6). 1H-MRS studies in BDI euthymic patients indicate Glu cycle metabolite abnormalities and suggest increased Glx and Glu (30–32,39,40) and increased Gln (40–42) within at least three brain voxels processed with different 1H-MRS sequences (Table 1). Therefore, although there is an indication that Glu and/or Glx levels measured by 1H-MRS might be increased in BDI and BDII patients during euthymia compared with control subjects, the methodological variability (different voxel sizes and locations, acquisition and postprocessing
techniques in multiple mood states, and BD subtypes in the same sample) and possible medication effects preclude any further conclusions from being drawn. In this context, the objective of the present study was to investigate the association between mood stabilizers (lithium, anticonvulsants [ACVs], and antipsychotics) and ACC glutamatergic metabolites in a homogeneous sample of BDI patients during euthymia.
METHODS AND MATERIALS One hundred twenty-eight BDI subjects (86 females; 18–45 years of age) were included in the study between 2008 and 2016 (BIPUSP MRS study). These subjects were examined over a 4-year period by three research programs focused on BD. For all 128 BD subjects the same 1H-MRS sequence and ACC voxel were used. The data from these three studies have been reported in two previous articles. The first study reported the effect of B-cell lymphoma 2 on Glu levels in a sample of 40 BD patients and 40 healthy control subjects (HCs) (39). The second study reported the effect of lithium on ACC metabolites in 23 BD subjects over a 6-week period, of which only 16 achieved euthymia and were included in present study (43). We consider this an original study, given that the data for only 56 of 128 subjects have previously been published and that neither of the two articles intended to study the influence of mood stabilizers on the Glu/creatine (Cre) ratio. Diagnoses were determined by trained psychiatrists based on the Structured Clinical Interview for DSM-IV-TR (44,45). Subjects had been on stable medication regimens for at least 2 months before the scanning session. Subjects with neurological disorders; with comorbid unstable medical conditions, head trauma, or current substance abuse; or who were treated with electroconvulsive therapy in the last 6 months were excluded.
Table 1. Glutamate Proton Magnetic Resonance Spectroscopy Studies in Bipolar Disorder Euthymia Study, Year
Sample
Magnetic Echo Field Sequence Time, ms
Bhagwagar et al. (31), 2007 16 BDI euthymic vs. 18 HCs
3T
PRESS
Colla et al. (30), 2009
21 BDI euthymic vs. 19 HCs
3T
PRESS
Kaufman et al. (35), 2009
10 BDI and BDII euthymic vs. 11 HCs
4T
JPRESS
Senaratne et al. (32), 2009
12 BDI and BDII euthymic vs. 12 HCs
3T
PRESS
35
Soeiro-de-Souza et al. (39), 2013
40 BDI euthymic vs. 40 HCs
3T
PRESS
Ehrlich et al. (40), 2015
21 BDI euthymic vs. 42 HCs
3T
Soeiro-de-Souza et al. (41), 2015
50 BDI euthymic vs. 38 HCs
Kubo et al. (42), 2017
14 BDI and BDII euthymic vs. 23 HCs
26
Voxel
Parameter
Findings
Medications
OCC
Cre ratio
Increased Glx
No medications
3.8
Hippocampus
Absolute
Increased Glu
Lithium
6.2
Whole brain BG
Absolute
None
Multiple
Absolute L OCC, hippocampus, and OFC
Increased Glx OCC
Multiple
80
ACC
Increased Glx, Glu
Multiple
PRESS
80
ACC Absolute hippocampus
Increased Glu ACC Multiple and decreased Glu in hippocampus
3T
JPRESS
31
ACC
Absolute
Increased Gln and decreased Glu/Gln
Multiple
3T
STEAM
18
ACC LBG
Absolute
Increased Gln, Gln/Glu
Multiple
Cre ratio
1 H-MRS, proton magnetic resonance spectroscopy; ACC, anterior cingulate cortex; BDI, bipolar I disorder; BDII, bipolar II disorder; BG, basal gangla; Cre, creatine; Gln, glutamine; Glu, glutamate; Glx, sum of glutamate and glutamine; HC, healthy control subject; JPRESS, J-resolved spectroscopy; L, left; LBG, left basal ganglia; OCC, occipital cortex; OFC, orbitofrontal cortex; PRESS, point resolved spectroscopy; STEAM, stimulated echo acquisition mode.
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The Young Mania Rating Scale (46) and the 21-item Hamilton Depression Rating Scale (HDRS) (47) were applied to assess residual subthreshold depressive and manic symptoms. Euthymia was defined as a score of ,8 on the Young Mania Rating Scale and a score of ,8 on the HDRS. Patients also fulfilled DSM-IV-TR criteria for remission, as evaluated by the Structured Clinical Interview for DSM-IV-TR. Eighty healthy individuals (42 females; 18–45 years of age) were also included in the study and used the same 1H-MRS sequence and ACC voxel. All HCs had no current or previous history of psychiatric disorder according to the evaluation conducted by trained psychiatrists using the Structured Clinical Interview for DSM-IV-TR. In addition, HCs had no family history, in first-degree relatives, of mood or psychotic disorders and had not been taking any psychotropic medicines for at least 3 months before enrollment, according to a semistructured interview. Subjects with a history of substance abuse within the 3 months leading up to enrollment were excluded from the study. The research ethics board approved the study. Written informed consent was obtained from all study participants.
Image Acquisition Brain magnetic resonance imaging examinations were performed on a 3T scanner (Intera Achieva; Philips Healthcare, Best, The Netherlands) with an 8-channel head coil. Each brain examination included anatomical images acquired with a three-dimensional T1 fast field echo sequence (echo time = 3.2 ms; repetition time = 7 ms; inversion time = 900 ms; flip angle = 8 ; field of view = 240 mm 3 240 mm 3 180 mm; matrix = 240 3 240) and MRS acquisition. Single-voxel 1H-MRS was performed using the point resolved spectroscopy (PRESS) sequence (160 scans; repetition time = 1500 ms; echo time = 80 ms). The choice of echo time was based on results from a previous study on optimization of Glu detection (48). MRS was preceded by an automatic preacquisition that included adjustment of the transmitter/receiver, optimization of the tilt angle for water suppression, and homogenization of the field for the selected volume of interest. Voxel size was set at 2 3 2 3 2 cm3 for all patients and HCs. The voxel was positioned in the ACC using anatomical guidelines as a reference. It was placed on midsagittal T1-weighted images, anterior to the genu of the corpus callosum, with the ventral edge aligned with the dorsal corner of the genu and centered on the midline of axial images as shown in Figure 1. A water unsuppressed spectrum of the same voxel was also acquired for eddy current correction and reference purposes.
Figure 1. Anterior cingulate voxel (2 3 2 3 2 cm).
for each spectrum (Figure 2). To ensure the accuracy of the measurements obtained, only metabolite results with values of Cramér–Rao lower bound less than 20% were considered, according to technical references (50). Metabolite ratios were calculated relative to Cre concentration. Glu/Cre was considered for the statistical analysis and, for comparison with other publications, Glx/Cre was also included, where Glx represents the sum of Glu and Gln. The normal metabolic concentration varies considerably between gray matter (GM) and white matter (WM) (51), and therefore the fraction of GM in the voxel needed to be taken into account in the analysis. To this end, brain tissue in the three-dimensional T1-weighted brain images was extracted using the brain extraction tool and then segmented into GM, WM, and cerebrospinal fluid using the FAST (features from accelerated segment test) algorithm, both
1
H-MRS Quantification
Metabolites were quantified using LCModel (49) and a basis set was simulated for an echo time of 80 ms, including alanine, aspartate, Cre, phosphocreatine, gamma-aminobutyric acid, glucose, Gln, Glu, glicerophosphocholine, phosphocholine, myo-inositol, lactate, N-acetylaspartate, N-acetylaspartylglutamate, scyllo-inositol, taurine, guanidinoacetate, macromolecules, and lipid signals. Figure 2 shows an example of a typical spectrum from a patient, with the LCModel fit and residual error. To compare the spectral quality between the groups, the full width at half maximum and signal to noise ratio were noted
Figure 2. Typical spectrum for a bipolar disorder patient showing original spectrum (black) and LCModel fit (red). The line at the top displays the residual after fitting. ppm, parts per million.
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available from the open source FSL software (http://www. fmrib.ox.ac.uk/fsl). Finally, the MRS voxel mask was superimposed onto the segmented images using a Python script that was developed in-house. The GM brain tissue fraction (fGM) was calculated for each voxel [fGM = %GM/(%GM 1% WM)], and fGM was used as a covariate when comparing metabolites between groups.
Statistical Analysis Categorical variables were analyzed using c2 tests, whereas continuous variables were analyzed using t tests. Significant differences in age were observed in the sample; to prevent this potential bias from influencing results, age correction was performed in all analyses. Normality was checked using the Kolmogorov–Smirnov test. Normally distributed variables (Glu/ Cre, Glx/Cre) were compared between the two groups using analysis of covariance, in which each brain metabolite (Glu and Glx) was separately tested and entered as a dependent variable, while age, gender, medication use (ACVs, antipsychotics, antidepressants, and lithium) and fGM were entered as covariates. Medications were investigated only regarding subjects’ being on and off each class of mood stabilizers; therefore, no dosage data were included in this analysis. All statistical analyses were carried out using SPSS software (version 20; IBM Corp., Armonk, NY).
RESULTS The sample comprised 128 (86 females, 67%) euthymic BD patients and 80 (42 females, 52%) HCs. The BD group had a higher mean age (mean 6 SD, 32.1 6 9.4 years) compared with the HC group (27.9 6 8.0 years, p = .001) (Table 2).
Group Comparisons The segmentation analysis within the ACC volume of interest revealed that BD and HC groups had similar WM (p = .9), but the BD group had higher cerebrospinal fluid (p = .001) and lower GM (p , .001) content within the analyzed voxel. Therefore, fGM was included in the statistical model as a factor to correct for possible bias of lower GM in the BD group (Table 3). Table 2. Demographic and Clinical Characteristics of Participants Healthy Bipolar I Control Disorder Patients, n = 128 Subjects, n = 80
Variable Age, Years, Mean (SD) Gender, Male/Female, n Education, Years, Mean (SD)
32.04 (9.38) 42/86
38/42 13.33 (3.1)
2.01 (2.28)
Hamilton Depression Rating Scale-21, Mean (SD)
1.61 (1.96)
Disease Duration, Years, Mean (SD)
6.99 (6.02)
Anticonvulsants, n (%) (Monotherapy n = 17)
41 (31)
Lithium, n (%) (Monotherapy n = 39)
93 (70.5)
Antipsychotics, n (%) (Monotherapy n = 17)
47 (35.6)
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Medication Effects Glu/Cre ratios were lower among patients medicated with ACVs (n = 41) (ACV mean 6 SD, 0.97 6 0.12; non-ACV mean 6 SD, 1.03 6 0.11, F = 4.66, p = .03) compared with patients not taking ACVs (Figure 4). Glx/Cre ratio did not differ as a function of ACV prescription (ACV mean 6 SD, 1.06 6 0.16; non-ACV mean 6 SD, 1.09 6 0.14, F = 1.15, p = .28). Curiously, when all 41 subjects using ACV were excluded from the BD group and the analysis of covariance model comparing BDs (n = 87) and HCs (n = 80) repeated, the BD group had even stronger data, indicating higher Glu/Cre (BD mean 6 SD, 1.02 6 0.11; HC mean 6 SD, 0.99 6 0.11, F = 6.86, p = .01) and Glx/Cre ratios (BD mean 6 SD, 1.09 6 0.14; HC mean 6 SD, 1.03 6 0.14, F = 8.67, p = .004) compared with the HC group. The prescription of lithium (n = 93) (Glu/Cre with lithium mean 6 SD, 1.01 6 0.12; Glu/Cre without lithium mean 6 SD, 0.99 6 0.10), Glx/Cre (with lithium mean 6 SD, 1.08 6 0.15; without lithium mean 6 SD, 1.06 6 0.13), or antipsychotics (n = 47) (Glu/Cre with antipsychotics mean 6 SD, 1.00 6 0.11; Glu/Cre without antipsychotics mean 6 SD, 1.00 6 0.12; Glx/ Cre with antipsychotics mean 6 SD, 1.07 6 0.14; Glx/Cre without antipsychotics mean 6 SD, 1.06 6 0.15) was not found to alter Glu/Cre or Glx/Cre ratio (p . .05). Table 3. Results of Proton Magnetic Resonance Spectroscopy in the Anterior Cingulate Cortex of Patients and Healthy Control Subjects
28.13 (8.19)
13.07 (3.2)
Young Mania Rating Scale Score, Mean (SD)
A total of three spectra (2 BD and 1 HC) were excluded from the analysis to maintain Glu and Glx Cramér–Rao lower bound below the 20% threshold. Full width at half maximum was 0.044 6 0.013 parts per million (range, 0.023–0.103) for the BD group and 0.043 6 0.012 parts per million (range, 0.027–0.084) for the HC group. The signal to noise ratio was 13.8 6 2.9 parts per million (range, 5–21) for the BD group and 14.4 6 3.2 parts per million (range, 7–20) for the HC group. There was no statistically significant difference between the two groups (p = .69 and p = .22, respectively). BD subjects had higher ratios of Glu/Cre (BD mean 6 SD, 1.01 6 0.11; HC mean 6 SD, 0.99 6 0.11, F = 4.34, p = .038) and of Glx/Cre (BD mean 6 SD, 1.08 6 0.15; HC mean 6 SD, 1.03 6 0.14, F = 8.19, p = .005) compared with the HC subjects (Figure 3). Young Mania Rating Scale and HDRS symptom scales were not correlated with Glu/Cre or Glx/Cre.
Variable
Patients With Bipolar I Disorder, n = 128
Healthy Control Subjects, n = 80
Cerebrospinal Fluid, Mean (SD)
0.2223 (0.05)
0.1942 (0.05)
Gray Matter, Mean (SD)
0.6017 (0.05)
0.6308 (0.04)
White Matter, Mean (SD)
0.176 (0.03)
0.175 (0.03)
Glu/Cre, Mean (SD)
1.01 (0.11)
0.99 (0.11)
Glu CRLB, Mean (SD)
9.24 (3.9)
8.8 (2.87)
Glx/Cre, Mean (SD)
1.08 (0.15)
1.03 (0.14)
Glx CRLB, Mean (SD)
10.1 (3.8)
9.8 (3.1)
Mean values presented are not values adjusted by age, gender, and gray matter brain tissue fraction. Cre, creatine; CRLB, Cramér–Rao lower bound; Glu, glutamate; Glx, sum of glutamate and glutamine.
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Figure 3. Anterior cingulate cortex glutamate (Glu)/creatine (Cre) and Glu plus glutamine (Glx)/Cre ratios in euthymic bipolar I disorder patients (n = 128) compared with healthy control subjects (n = 80).
Disease duration and lifetime psychotic symptoms were not associated with Glu/Cre or Glx/Cre (p . .05).
DISCUSSION To the best of our knowledge, this is the largest 1H-MRS study in BD including only euthymic subjects with BDI. We reported increased ratios of Glu/Cre and Glx/Cre in BD patients compared with HC subjects. Moreover, we found that the use of ACV medication at the time of the scan was associated with lower ratios of Glu/Cre, without influencing Glx/Cre ratio. Interestingly, the data showing higher Glu/Cre and Glx/Cre in BD compared with HC subjects were strengthened after the removal of ACV from the analysis, indicating that the increase in Glu/Cre and Glx/Cre was not caused by medication use. Our data are in line with previous 1H-MRS studies that reported Glu system alterations in BD, more specifically within the ACC and during euthymia. At least four smaller studies using the same sequence used in the present study (PRESS) and examining the same volume of interest (ACC) reported similar abnormalities in Glu system metabolites (39–42). Furthermore, considering that previous studies in patients during mania (52,53) and depression (54,55) have also
Figure 4. Anterior cingulate cortex glutamate (Glu)/creatine (Cre) ratios in euthymic bipolar I disorder patients (n = 128) by anticonvulsant use.
indicated altered Glu system metabolites in BD (4), we hypothesized that this might be a trait unique to BD because it has been reported in all mood episodes. Abnormal ACC Glu metabolites might be considered an endophenotype of BD if 1 H-MRS studies confirm Glu system abnormalities in unaffected first-degree relatives of BD patients, which so far has not been the case (56). Moreover, we propose that the relationship between 1H-MRS data of Glu and Glx increase and postmortem data reporting a reduction in the number of Nmethyl-D-aspartate receptors (22–24) in BD should be analyzed together, because the reduction in number of receptors might be a consequence of long-term stimulation by life-long high Glu levels. The effect of ACV medication on Glu/Cre ratio in BD has been previously reported in the literature. In 2013, a small sample of 17 BD subjects taking ACVs were found by our group to have lower ratios of Glu/Cre and Glx/Cre compared with patients who were not prescribed ACVs (n = 23) (39). In 2015—using a JPRESS sequence that allowed the measurement of Glx subcomponents with higher accuracy than conventional PRESS—we observed that Gln was higher among subjects medicated with ACVs (n = 23) compared with those not taking ACVs (n = 27) (41). Moreover, we reported in the same article that the Glu/Gln ratio was lower in BD subjects who were taking ACVs compared with those not in taking ACVs (41). This finding might be explained by a previous study in epilepsy that demonstrated the influence of valproate on mitochondrial function, changing the balance reaction of Glu/Gln toward Gln (57). Therefore, the fact that we observed an ACV medication effect leading to lower Glu/Cre in a group reported to have elevated ratios of Glu/Cre might indicate that ACVs exert their mood stabilizing effects by decreasing brain Glu/Cre ratios. Moreover, it has been reported that lithium, another first-line treatment for mood stabilization, might also exert its therapeutic effects by reducing Glx concentrations (58), although we were unable to replicate these results in the current study with 93 patients taking lithium. Limitations of this study include the fact that most of the subjects were using pharmacological combination therapy with two drugs (Table 2), limiting the interpretation of findings on the association between anticonvulsants and lower Glu/Cre ratio. Moreover, it is important to note there was an age difference of less than 3 years between cases and control subjects, although age was included in all our analytical models.
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Conclusions We believe this study contributes to the knowledge on BD Glu system abnormalities by demonstrating that both Glu/Cre and Glx/Cre are elevated in BDI patients during euthymia, regardless of medication effects, indicating a potential biomarker that is unique to this disorder. Additional 1H-MRS studies at higher magnetic fields with more sensitive sequences should investigate specific BD subtypes and mood states to increase understanding of the Glu system in BD and help develop novel pharmacological approaches based on the glutamatergic system.
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ACKNOWLEDGMENTS AND DISCLOSURES This work was supported by the São Paulo Research Foundation and the National Council of Scientific and Technological Development. We thank the University of São Paulo for all its support and the team of researchers, patients and volunteers that participated in this 4-year study. The authors report no biomedical financial interests or potential conflicts of interest.
ARTICLE INFORMATION From the Mood Disorders Unit (MGS, RAM), Genetics and Pharmacogenetics Unit (MGS), and the Bipolar Disorders Program (BL), Department and Institute of Psychiatry, and the Laboratory of Magnetic Resonance (MCGO, CL), Department and Institute of Radiology, University of São Paulo, São Paulo, Brazil; University of Texas (RM-V), Austin, Texas; and the Department of Psychiatry and Behavioral Neuroscience (FGN), University of Cincinnati College of Medicine, Cincinnati, Ohio. Address correspondence to Marcio Gerhardt Soeiro-de-Souza, M.D., Ph.D., Dr. Ovidio Pires de Campos s/n. Hospital das Clínicas, Instituto de Psiquiatria, 3rd floor, North wing room 12, 05403-010 São Paulo, São Paulo, Brazil; E-mail: [email protected]. Received Oct 18, 2017; revised and accepted Feb 28, 2018.
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REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
990
Goodwin FK, Jamison KR (2007): Manic-Depressive Illness: Bipolar and Recurrent Unipolar Disorders, 2nd ed. New York: Oxford University Press. Sigitova E, Fi sar Z, Hroudová J, Cikánková T, Raboch J (2017): Biological hypotheses and biomarkers of bipolar disorder. Psychiatry Clin Neurosci 71:77–103. Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA (2009): Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15:1595–1611. Manji H (2008): Bcl-2: A key regulator of affective resilience in the pathophysiology and treatment of severe mood disorders. Biol Psychiatry 63(suppl 1):243S. Yüksel C, Ongur D (2010): Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 68:785–794. Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN (2012): Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: A meta-analysis. Bipolar Disord 14:478–487. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, et al. (2002): Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 7(suppl 1):S71–S80. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. (2010): A randomized add-on trial of an N-methyl-Daspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67:793–802. Zarate CA, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. (2013): A randomized trial of a low-trapping nonselective
22.
23.
24.
25.
26.
27.
28.
29.
N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 74:257–264. Park M, Niciu MJ, Zarate CA (2015): Novel glutamatergic treatments for severe mood disorders. Curr Behav Neurosci Rep 2:198– 208. Keener MT, Phillips ML (2007): Neuroimaging in bipolar disorder: A critical review of current findings. Curr Psychiatry Rep 9:512–520. Phillips ML, Swartz HA (2014): A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry 171:829–843. Govindaraju V, Young K, Maudsley AA (2000): Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13:129–153. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982): Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 232:299–304. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F (1993): Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150:1731–1733. Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, et al. (1998): Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37:124–129. Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR, Kawahara R (2006): Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 30:1155–1158. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW (2000): Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 47:586–593. Frye MA, Tsai GE, Huggins T, Coyle JT, Post RM (2007): Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol Psychiatry 61:162–166. Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, et al. (1989): Brain amino acid concentrations and Ca21dependent release in intractable depression assessed antemortem. Brain Res 494:315–324. Eastwood SL, Harrison PJ (2010): Markers of glutamate synaptic transmission and plasticity are increased in the anterior cingulate cortex in bipolar disorder. Biol Psychiatry 67:1010–1016. Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B (2003): Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 5:257–264. Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007): Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32:1888–1902. Beneyto M, Meador-Woodruff JH (2008): Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33:2175–2186. Hashimoto R, Hough C, Nakazawa T, Yamamoto T, Chuang DM (2002): Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: Involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem 80:589–597. Kumar A, Singh RL, Babu GN (2010): Cell death mechanisms in the early stages of acute glutamate neurotoxicity. Neurosci Res 66:271– 278. Gigante AD, Young LT, Yatham LN, Andreazza AC, Nery FG, Grinberg LT, et al. (2011): Morphometric post-mortem studies in bipolar disorder: Possible association with oxidative stress and apoptosis. Int J Neuropsychopharmacol 14:1075–1089. Soeiro-de-Souza MG, Dias VV, Figueira ML, Forlenza OV, Gattaz WF, Zarate CA, et al. (2012): Translating neurotrophic and cellular plasticity: From pathophysiology to improved therapeutics for bipolar disorder. Acta Psychiatr Scand 126:332–341. Zung S, Souza-Duran FL, Soeiro-de-Souza MG, Uchida R, Bottino CM, Busatto GF, et al. (2016): The influence of lithium on
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging December 2018; 3:985–991 www.sobp.org/BPCNNI
Biological Psychiatry: CNNI
ACC Glutamate and Mood Stabilizers in BD
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
hippocampal volume in elderly bipolar patients: A study using voxelbased morphometry. Transl Psychiatry 6:e846. Colla M, Schubert F, Bubner M, Heidenreich JO, Bajbouj M, Seifert F, et al. (2009): Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol. Mol Psychiatry 14:696–704, 647. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A, et al. (2007): Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 61:806–812. Senaratne R, Milne AM, MacQueen GM, Hall GBC (2009): Increased choline-containing compounds in the orbitofrontal cortex and hippocampus in euthymic patients with bipolar disorder: A proton magnetic resonance spectroscopy study. Psychiatry Res 172:205–209. Drevets WC (2000): Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126:413–431. Phillips ML, Drevets WC, Rauch SL, Lane R (2003): Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 54:504–514. Kaufman RE, Ostacher MJ, Marks EH, Simon NM, Sachs GS, Jensen JE, et al. (2009): Brain GABA levels in patients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 33:427–434. Anticevic A, Savic A, Repovs G, Yang G, McKay DR, Sprooten E, et al. (2015): Ventral anterior cingulate connectivity distinguished nonpsychotic bipolar illness from psychotic bipolar disorder and schizophrenia. Schizophr Bull 41:133–143. Liu J, Blond BN, van Dyck LI, Spencer L, Wang F, Blumberg HP (2012): Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing. Bipolar Disord 14:432–441. Foland-Ross LC, Thompson PM, Sugar CA, Madsen SK, Shen JK, Penfold C, et al. (2011): Investigation of cortical thickness abnormalities in lithium-free adults with bipolar I disorder using cortical pattern matching. Am J Psychiatry 168:530–539. Soeiro-de-Souza MG, Salvadore G, Moreno RA, Otaduy MCG, Chaim KT, Gattaz WF, et al. (2013): Bcl-2 rs956572 polymorphism is associated with increased anterior cingulate cortical glutamate in euthymic bipolar I disorder. Neuropsychopharmacology 38:468–475. Ehrlich A, Schubert F, Pehrs C, Gallinat J (2015): Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder. Psychiatry Res 233:73–80. Soeiro-de-Souza MG, Henning A, Machado-Vieira R, Moreno RA, Pastorello BF, da Costa Leite C, et al. (2015): Anterior cingulate glutamate-glutamine cycle metabolites are altered in euthymic bipolar I disorder. Eur Neuropsychopharmacol 25:2221–2229. Kubo H, Nakataki M, Sumitani S, Iga JI, Numata S, Kameoka N, et al. (2017): 1H-magnetic resonance spectroscopy study of glutamaterelated abnormality in bipolar disorder. J Affect Disord 208:139–144.
43.
44.
45.
46. 47. 48.
49. 50. 51.
52.
53.
54.
55.
56.
57.
58.
Machado-Vieira R, Gattaz WF, Zanetti MV, de Sousa RT, Carvalho AF, Soeiro-de-Souza MG, et al. (2015): A longitudinal (6-week) 3T (1)HMRS study on the effects of lithium treatment on anterior cingulate cortex metabolites in bipolar depression. Eur Neuropsychopharmacol 25:2311–2317. First MB, Spitzer RL, Williams JB (1996): Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I. Washington, DC: American Psychiatric Press. American Psychiatric Association (2000): Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed, Text Revision. Washington, DC: American Psychiatric Publishing, Inc. Young RC, Biggs JT, Ziegler VE, Meyer DA (1978): A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 133:429–435. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296. Schubert F, Gallinat J, Seifert F, Rinneberg H (2004): Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. Neuroimage 21:1762–1771. Provencher SWS (1993): Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679. Kreis R (2004): Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed 17:361–381. Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG, et al. (2006): Use of tissue water as a concentration reference for proton spectroscopic imaging. Magn Reson Med 55:1219–1226. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, et al. (2008): Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 64:718–726. Michael N, Erfurth A, Ohrmann P, Gössling M, Arolt V, Heindel W, et al. (2003): Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacology (Berl) 168:344–346. Frye MA, Watzl J, Banakar S, O’Neill J, Mintz J, Davanzo P, et al. (2007): Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 32:2490–2499. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, et al. (2004): Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 61:450–458. Hajek T, Bernier D, Slaney C, Propper L, Schmidt M, Carrey N, et al. (2008): A comparison of affected and unaffected relatives of patients with bipolar disorder using proton magnetic resonance spectroscopy. J Psychiatry Neurosci 33:531–540. Garcia M, Huppertz HJ, Ziyeh S, Buechert M, Schumacher M, Mader I (2009): Valproate-induced metabolic changes in patients with epilepsy: Assessment with H-MRS. Epilepsia 50:486–492. Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL, et al. (2014): Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 56:340–348.
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Archival Report Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study Marcio Gerhardt Soeiro-de-Souza, Maria Concepcion Garcia Otaduy, Rodrigo Machado-Vieira, Ricardo Alberto Moreno, Fabiano G. Nery, Claudia Leite, and Beny Lafer
ABSTRACT BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD. Keywords: Anticonvulsants, Bipolar disorder, Euthymia, Glutamate, Glx, Magnetic resonance spectroscopy https://doi.org/10.1016/j.bpsc.2018.02.007
The study of bipolar disorder (BD), a chronic and recurrent illness characterized by depressive and manic episodes (1), is like investigating multiple disorders in one, especially in studies including patients with bipolar spectrum disorders. This holds true because BD has multiple clinical presentations and patterns of mood instability. Among the different subtypes of BD, bipolar I disorder (BDI) has the most consistent data regarding genetic, neuroimaging, and peripheral biomarkers (2), and therefore we consider it the most appropriate subtype of BD for investigating brain metabolites. Glutamate (Glu) system dysfunctions have been consistently reported in BD by postmortem, peripheral biomarker, pharmacological (3,4), and proton magnetic resonance spectroscopy (1H-MRS) studies (5,6). This body of evidence has prompted the development of novel medications to treat mood disorders based on the Glu system (7–10). Unfortunately, studying BD by 1H-MRS, a key instrument for investigating the Glu system, has proven a
ISSN: 2451-9022
major challenge because of the unique features of BD. The multiple subtypes and mood states in BD, when mixed within the same sample, prevent a conclusive interpretation of the data (5,6) because neuroimaging markers reportedly differ between these subtypes (11,12). In this scenario, the objective of the present study was to investigate the impact of mood stabilizers on Glu using 1H-MRS in a large sample of BDI patients during euthymia. Glutamate is the major excitatory neurotransmitter of the brain (13) and is constantly recycled between neurons and glia. Glutamatergic alterations have been reported in plasma (14–16), serum (17), cerebrospinal fluid (18,19), and brain tissue (20,21) in subjects with BD. Postmortem studies have reported decreased N-methyl-D-aspartate receptor subunits NR1 and NR2A transcript expression and indicate a reduction in total number of N-methyl-D-aspartate receptors (22–24). Pharmacological studies highlight the link between BD and the
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glutamatergic system, indicating that first-line agents for treating BD, such as lithium, valproate, carbamazepine, and lamotrigine, also regulate the glutamatergic system (22,23). Excess Glu causes excitotoxicity and apoptosis (25), which is associated with higher levels of intracellular calcium and the production of mitochondrial reactive species (26,27). Excessive synaptic Glu may cause neuronal atrophy and death, but it is noteworthy that long-term treatment with lithium has been shown to partially revert these effects (28,29). Most 1H-MRS studies on BD mood episodes (mania, depression) have reported increased Glu and Glx (Glu plus glutamine [Gln]) in multiple brain voxels (5,6). Most studies of BDI and BDII patients during euthymia have reported Glx and/ or Glu increase in patients compared with control subjects in the following voxels: hippocampus (30), occipital cortex (31,32), and anterior cingulate cortex (ACC) (33,34). A study that applied the whole-brain technique as opposed to singlevoxel study in euthymic BD patients found no alterations in Glu or Glx levels (35). Among voxels, the ACC is an important area linked to mood regulation (33,34) and shows widespread functional (36) and structural abnormalities in patients with BD, also observed during euthymia, suggesting that ACC dysfunction might represent a stable trait marker of BD (37,38). Moreover, the ACC has been the most extensively studied brain voxel in BD among 1H-MRS studies (5,6). 1H-MRS studies in BDI euthymic patients indicate Glu cycle metabolite abnormalities and suggest increased Glx and Glu (30–32,39,40) and increased Gln (40–42) within at least three brain voxels processed with different 1H-MRS sequences (Table 1). Therefore, although there is an indication that Glu and/or Glx levels measured by 1H-MRS might be increased in BDI and BDII patients during euthymia compared with control subjects, the methodological variability (different voxel sizes and locations, acquisition and postprocessing
techniques in multiple mood states, and BD subtypes in the same sample) and possible medication effects preclude any further conclusions from being drawn. In this context, the objective of the present study was to investigate the association between mood stabilizers (lithium, anticonvulsants [ACVs], and antipsychotics) and ACC glutamatergic metabolites in a homogeneous sample of BDI patients during euthymia.
METHODS AND MATERIALS One hundred twenty-eight BDI subjects (86 females; 18–45 years of age) were included in the study between 2008 and 2016 (BIPUSP MRS study). These subjects were examined over a 4-year period by three research programs focused on BD. For all 128 BD subjects the same 1H-MRS sequence and ACC voxel were used. The data from these three studies have been reported in two previous articles. The first study reported the effect of B-cell lymphoma 2 on Glu levels in a sample of 40 BD patients and 40 healthy control subjects (HCs) (39). The second study reported the effect of lithium on ACC metabolites in 23 BD subjects over a 6-week period, of which only 16 achieved euthymia and were included in present study (43). We consider this an original study, given that the data for only 56 of 128 subjects have previously been published and that neither of the two articles intended to study the influence of mood stabilizers on the Glu/creatine (Cre) ratio. Diagnoses were determined by trained psychiatrists based on the Structured Clinical Interview for DSM-IV-TR (44,45). Subjects had been on stable medication regimens for at least 2 months before the scanning session. Subjects with neurological disorders; with comorbid unstable medical conditions, head trauma, or current substance abuse; or who were treated with electroconvulsive therapy in the last 6 months were excluded.
Table 1. Glutamate Proton Magnetic Resonance Spectroscopy Studies in Bipolar Disorder Euthymia Study, Year
Sample
Magnetic Echo Field Sequence Time, ms
Bhagwagar et al. (31), 2007 16 BDI euthymic vs. 18 HCs
3T
PRESS
Colla et al. (30), 2009
21 BDI euthymic vs. 19 HCs
3T
PRESS
Kaufman et al. (35), 2009
10 BDI and BDII euthymic vs. 11 HCs
4T
JPRESS
Senaratne et al. (32), 2009
12 BDI and BDII euthymic vs. 12 HCs
3T
PRESS
35
Soeiro-de-Souza et al. (39), 2013
40 BDI euthymic vs. 40 HCs
3T
PRESS
Ehrlich et al. (40), 2015
21 BDI euthymic vs. 42 HCs
3T
Soeiro-de-Souza et al. (41), 2015
50 BDI euthymic vs. 38 HCs
Kubo et al. (42), 2017
14 BDI and BDII euthymic vs. 23 HCs
26
Voxel
Parameter
Findings
Medications
OCC
Cre ratio
Increased Glx
No medications
3.8
Hippocampus
Absolute
Increased Glu
Lithium
6.2
Whole brain BG
Absolute
None
Multiple
Absolute L OCC, hippocampus, and OFC
Increased Glx OCC
Multiple
80
ACC
Increased Glx, Glu
Multiple
PRESS
80
ACC Absolute hippocampus
Increased Glu ACC Multiple and decreased Glu in hippocampus
3T
JPRESS
31
ACC
Absolute
Increased Gln and decreased Glu/Gln
Multiple
3T
STEAM
18
ACC LBG
Absolute
Increased Gln, Gln/Glu
Multiple
Cre ratio
1 H-MRS, proton magnetic resonance spectroscopy; ACC, anterior cingulate cortex; BDI, bipolar I disorder; BDII, bipolar II disorder; BG, basal gangla; Cre, creatine; Gln, glutamine; Glu, glutamate; Glx, sum of glutamate and glutamine; HC, healthy control subject; JPRESS, J-resolved spectroscopy; L, left; LBG, left basal ganglia; OCC, occipital cortex; OFC, orbitofrontal cortex; PRESS, point resolved spectroscopy; STEAM, stimulated echo acquisition mode.
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The Young Mania Rating Scale (46) and the 21-item Hamilton Depression Rating Scale (HDRS) (47) were applied to assess residual subthreshold depressive and manic symptoms. Euthymia was defined as a score of ,8 on the Young Mania Rating Scale and a score of ,8 on the HDRS. Patients also fulfilled DSM-IV-TR criteria for remission, as evaluated by the Structured Clinical Interview for DSM-IV-TR. Eighty healthy individuals (42 females; 18–45 years of age) were also included in the study and used the same 1H-MRS sequence and ACC voxel. All HCs had no current or previous history of psychiatric disorder according to the evaluation conducted by trained psychiatrists using the Structured Clinical Interview for DSM-IV-TR. In addition, HCs had no family history, in first-degree relatives, of mood or psychotic disorders and had not been taking any psychotropic medicines for at least 3 months before enrollment, according to a semistructured interview. Subjects with a history of substance abuse within the 3 months leading up to enrollment were excluded from the study. The research ethics board approved the study. Written informed consent was obtained from all study participants.
Image Acquisition Brain magnetic resonance imaging examinations were performed on a 3T scanner (Intera Achieva; Philips Healthcare, Best, The Netherlands) with an 8-channel head coil. Each brain examination included anatomical images acquired with a three-dimensional T1 fast field echo sequence (echo time = 3.2 ms; repetition time = 7 ms; inversion time = 900 ms; flip angle = 8 ; field of view = 240 mm 3 240 mm 3 180 mm; matrix = 240 3 240) and MRS acquisition. Single-voxel 1H-MRS was performed using the point resolved spectroscopy (PRESS) sequence (160 scans; repetition time = 1500 ms; echo time = 80 ms). The choice of echo time was based on results from a previous study on optimization of Glu detection (48). MRS was preceded by an automatic preacquisition that included adjustment of the transmitter/receiver, optimization of the tilt angle for water suppression, and homogenization of the field for the selected volume of interest. Voxel size was set at 2 3 2 3 2 cm3 for all patients and HCs. The voxel was positioned in the ACC using anatomical guidelines as a reference. It was placed on midsagittal T1-weighted images, anterior to the genu of the corpus callosum, with the ventral edge aligned with the dorsal corner of the genu and centered on the midline of axial images as shown in Figure 1. A water unsuppressed spectrum of the same voxel was also acquired for eddy current correction and reference purposes.
Figure 1. Anterior cingulate voxel (2 3 2 3 2 cm).
for each spectrum (Figure 2). To ensure the accuracy of the measurements obtained, only metabolite results with values of Cramér–Rao lower bound less than 20% were considered, according to technical references (50). Metabolite ratios were calculated relative to Cre concentration. Glu/Cre was considered for the statistical analysis and, for comparison with other publications, Glx/Cre was also included, where Glx represents the sum of Glu and Gln. The normal metabolic concentration varies considerably between gray matter (GM) and white matter (WM) (51), and therefore the fraction of GM in the voxel needed to be taken into account in the analysis. To this end, brain tissue in the three-dimensional T1-weighted brain images was extracted using the brain extraction tool and then segmented into GM, WM, and cerebrospinal fluid using the FAST (features from accelerated segment test) algorithm, both
1
H-MRS Quantification
Metabolites were quantified using LCModel (49) and a basis set was simulated for an echo time of 80 ms, including alanine, aspartate, Cre, phosphocreatine, gamma-aminobutyric acid, glucose, Gln, Glu, glicerophosphocholine, phosphocholine, myo-inositol, lactate, N-acetylaspartate, N-acetylaspartylglutamate, scyllo-inositol, taurine, guanidinoacetate, macromolecules, and lipid signals. Figure 2 shows an example of a typical spectrum from a patient, with the LCModel fit and residual error. To compare the spectral quality between the groups, the full width at half maximum and signal to noise ratio were noted
Figure 2. Typical spectrum for a bipolar disorder patient showing original spectrum (black) and LCModel fit (red). The line at the top displays the residual after fitting. ppm, parts per million.
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available from the open source FSL software (http://www. fmrib.ox.ac.uk/fsl). Finally, the MRS voxel mask was superimposed onto the segmented images using a Python script that was developed in-house. The GM brain tissue fraction (fGM) was calculated for each voxel [fGM = %GM/(%GM 1% WM)], and fGM was used as a covariate when comparing metabolites between groups.
Statistical Analysis Categorical variables were analyzed using c2 tests, whereas continuous variables were analyzed using t tests. Significant differences in age were observed in the sample; to prevent this potential bias from influencing results, age correction was performed in all analyses. Normality was checked using the Kolmogorov–Smirnov test. Normally distributed variables (Glu/ Cre, Glx/Cre) were compared between the two groups using analysis of covariance, in which each brain metabolite (Glu and Glx) was separately tested and entered as a dependent variable, while age, gender, medication use (ACVs, antipsychotics, antidepressants, and lithium) and fGM were entered as covariates. Medications were investigated only regarding subjects’ being on and off each class of mood stabilizers; therefore, no dosage data were included in this analysis. All statistical analyses were carried out using SPSS software (version 20; IBM Corp., Armonk, NY).
RESULTS The sample comprised 128 (86 females, 67%) euthymic BD patients and 80 (42 females, 52%) HCs. The BD group had a higher mean age (mean 6 SD, 32.1 6 9.4 years) compared with the HC group (27.9 6 8.0 years, p = .001) (Table 2).
Group Comparisons The segmentation analysis within the ACC volume of interest revealed that BD and HC groups had similar WM (p = .9), but the BD group had higher cerebrospinal fluid (p = .001) and lower GM (p , .001) content within the analyzed voxel. Therefore, fGM was included in the statistical model as a factor to correct for possible bias of lower GM in the BD group (Table 3). Table 2. Demographic and Clinical Characteristics of Participants Healthy Bipolar I Control Disorder Patients, n = 128 Subjects, n = 80
Variable Age, Years, Mean (SD) Gender, Male/Female, n Education, Years, Mean (SD)
32.04 (9.38) 42/86
38/42 13.33 (3.1)
2.01 (2.28)
Hamilton Depression Rating Scale-21, Mean (SD)
1.61 (1.96)
Disease Duration, Years, Mean (SD)
6.99 (6.02)
Anticonvulsants, n (%) (Monotherapy n = 17)
41 (31)
Lithium, n (%) (Monotherapy n = 39)
93 (70.5)
Antipsychotics, n (%) (Monotherapy n = 17)
47 (35.6)
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Medication Effects Glu/Cre ratios were lower among patients medicated with ACVs (n = 41) (ACV mean 6 SD, 0.97 6 0.12; non-ACV mean 6 SD, 1.03 6 0.11, F = 4.66, p = .03) compared with patients not taking ACVs (Figure 4). Glx/Cre ratio did not differ as a function of ACV prescription (ACV mean 6 SD, 1.06 6 0.16; non-ACV mean 6 SD, 1.09 6 0.14, F = 1.15, p = .28). Curiously, when all 41 subjects using ACV were excluded from the BD group and the analysis of covariance model comparing BDs (n = 87) and HCs (n = 80) repeated, the BD group had even stronger data, indicating higher Glu/Cre (BD mean 6 SD, 1.02 6 0.11; HC mean 6 SD, 0.99 6 0.11, F = 6.86, p = .01) and Glx/Cre ratios (BD mean 6 SD, 1.09 6 0.14; HC mean 6 SD, 1.03 6 0.14, F = 8.67, p = .004) compared with the HC group. The prescription of lithium (n = 93) (Glu/Cre with lithium mean 6 SD, 1.01 6 0.12; Glu/Cre without lithium mean 6 SD, 0.99 6 0.10), Glx/Cre (with lithium mean 6 SD, 1.08 6 0.15; without lithium mean 6 SD, 1.06 6 0.13), or antipsychotics (n = 47) (Glu/Cre with antipsychotics mean 6 SD, 1.00 6 0.11; Glu/Cre without antipsychotics mean 6 SD, 1.00 6 0.12; Glx/ Cre with antipsychotics mean 6 SD, 1.07 6 0.14; Glx/Cre without antipsychotics mean 6 SD, 1.06 6 0.15) was not found to alter Glu/Cre or Glx/Cre ratio (p . .05). Table 3. Results of Proton Magnetic Resonance Spectroscopy in the Anterior Cingulate Cortex of Patients and Healthy Control Subjects
28.13 (8.19)
13.07 (3.2)
Young Mania Rating Scale Score, Mean (SD)
A total of three spectra (2 BD and 1 HC) were excluded from the analysis to maintain Glu and Glx Cramér–Rao lower bound below the 20% threshold. Full width at half maximum was 0.044 6 0.013 parts per million (range, 0.023–0.103) for the BD group and 0.043 6 0.012 parts per million (range, 0.027–0.084) for the HC group. The signal to noise ratio was 13.8 6 2.9 parts per million (range, 5–21) for the BD group and 14.4 6 3.2 parts per million (range, 7–20) for the HC group. There was no statistically significant difference between the two groups (p = .69 and p = .22, respectively). BD subjects had higher ratios of Glu/Cre (BD mean 6 SD, 1.01 6 0.11; HC mean 6 SD, 0.99 6 0.11, F = 4.34, p = .038) and of Glx/Cre (BD mean 6 SD, 1.08 6 0.15; HC mean 6 SD, 1.03 6 0.14, F = 8.19, p = .005) compared with the HC subjects (Figure 3). Young Mania Rating Scale and HDRS symptom scales were not correlated with Glu/Cre or Glx/Cre.
Variable
Patients With Bipolar I Disorder, n = 128
Healthy Control Subjects, n = 80
Cerebrospinal Fluid, Mean (SD)
0.2223 (0.05)
0.1942 (0.05)
Gray Matter, Mean (SD)
0.6017 (0.05)
0.6308 (0.04)
White Matter, Mean (SD)
0.176 (0.03)
0.175 (0.03)
Glu/Cre, Mean (SD)
1.01 (0.11)
0.99 (0.11)
Glu CRLB, Mean (SD)
9.24 (3.9)
8.8 (2.87)
Glx/Cre, Mean (SD)
1.08 (0.15)
1.03 (0.14)
Glx CRLB, Mean (SD)
10.1 (3.8)
9.8 (3.1)
Mean values presented are not values adjusted by age, gender, and gray matter brain tissue fraction. Cre, creatine; CRLB, Cramér–Rao lower bound; Glu, glutamate; Glx, sum of glutamate and glutamine.
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Figure 3. Anterior cingulate cortex glutamate (Glu)/creatine (Cre) and Glu plus glutamine (Glx)/Cre ratios in euthymic bipolar I disorder patients (n = 128) compared with healthy control subjects (n = 80).
Disease duration and lifetime psychotic symptoms were not associated with Glu/Cre or Glx/Cre (p . .05).
DISCUSSION To the best of our knowledge, this is the largest 1H-MRS study in BD including only euthymic subjects with BDI. We reported increased ratios of Glu/Cre and Glx/Cre in BD patients compared with HC subjects. Moreover, we found that the use of ACV medication at the time of the scan was associated with lower ratios of Glu/Cre, without influencing Glx/Cre ratio. Interestingly, the data showing higher Glu/Cre and Glx/Cre in BD compared with HC subjects were strengthened after the removal of ACV from the analysis, indicating that the increase in Glu/Cre and Glx/Cre was not caused by medication use. Our data are in line with previous 1H-MRS studies that reported Glu system alterations in BD, more specifically within the ACC and during euthymia. At least four smaller studies using the same sequence used in the present study (PRESS) and examining the same volume of interest (ACC) reported similar abnormalities in Glu system metabolites (39–42). Furthermore, considering that previous studies in patients during mania (52,53) and depression (54,55) have also
Figure 4. Anterior cingulate cortex glutamate (Glu)/creatine (Cre) ratios in euthymic bipolar I disorder patients (n = 128) by anticonvulsant use.
indicated altered Glu system metabolites in BD (4), we hypothesized that this might be a trait unique to BD because it has been reported in all mood episodes. Abnormal ACC Glu metabolites might be considered an endophenotype of BD if 1 H-MRS studies confirm Glu system abnormalities in unaffected first-degree relatives of BD patients, which so far has not been the case (56). Moreover, we propose that the relationship between 1H-MRS data of Glu and Glx increase and postmortem data reporting a reduction in the number of Nmethyl-D-aspartate receptors (22–24) in BD should be analyzed together, because the reduction in number of receptors might be a consequence of long-term stimulation by life-long high Glu levels. The effect of ACV medication on Glu/Cre ratio in BD has been previously reported in the literature. In 2013, a small sample of 17 BD subjects taking ACVs were found by our group to have lower ratios of Glu/Cre and Glx/Cre compared with patients who were not prescribed ACVs (n = 23) (39). In 2015—using a JPRESS sequence that allowed the measurement of Glx subcomponents with higher accuracy than conventional PRESS—we observed that Gln was higher among subjects medicated with ACVs (n = 23) compared with those not taking ACVs (n = 27) (41). Moreover, we reported in the same article that the Glu/Gln ratio was lower in BD subjects who were taking ACVs compared with those not in taking ACVs (41). This finding might be explained by a previous study in epilepsy that demonstrated the influence of valproate on mitochondrial function, changing the balance reaction of Glu/Gln toward Gln (57). Therefore, the fact that we observed an ACV medication effect leading to lower Glu/Cre in a group reported to have elevated ratios of Glu/Cre might indicate that ACVs exert their mood stabilizing effects by decreasing brain Glu/Cre ratios. Moreover, it has been reported that lithium, another first-line treatment for mood stabilization, might also exert its therapeutic effects by reducing Glx concentrations (58), although we were unable to replicate these results in the current study with 93 patients taking lithium. Limitations of this study include the fact that most of the subjects were using pharmacological combination therapy with two drugs (Table 2), limiting the interpretation of findings on the association between anticonvulsants and lower Glu/Cre ratio. Moreover, it is important to note there was an age difference of less than 3 years between cases and control subjects, although age was included in all our analytical models.
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Conclusions We believe this study contributes to the knowledge on BD Glu system abnormalities by demonstrating that both Glu/Cre and Glx/Cre are elevated in BDI patients during euthymia, regardless of medication effects, indicating a potential biomarker that is unique to this disorder. Additional 1H-MRS studies at higher magnetic fields with more sensitive sequences should investigate specific BD subtypes and mood states to increase understanding of the Glu system in BD and help develop novel pharmacological approaches based on the glutamatergic system.
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ACKNOWLEDGMENTS AND DISCLOSURES This work was supported by the São Paulo Research Foundation and the National Council of Scientific and Technological Development. We thank the University of São Paulo for all its support and the team of researchers, patients and volunteers that participated in this 4-year study. The authors report no biomedical financial interests or potential conflicts of interest.
ARTICLE INFORMATION From the Mood Disorders Unit (MGS, RAM), Genetics and Pharmacogenetics Unit (MGS), and the Bipolar Disorders Program (BL), Department and Institute of Psychiatry, and the Laboratory of Magnetic Resonance (MCGO, CL), Department and Institute of Radiology, University of São Paulo, São Paulo, Brazil; University of Texas (RM-V), Austin, Texas; and the Department of Psychiatry and Behavioral Neuroscience (FGN), University of Cincinnati College of Medicine, Cincinnati, Ohio. Address correspondence to Marcio Gerhardt Soeiro-de-Souza, M.D., Ph.D., Dr. Ovidio Pires de Campos s/n. Hospital das Clínicas, Instituto de Psiquiatria, 3rd floor, North wing room 12, 05403-010 São Paulo, São Paulo, Brazil; E-mail: [email protected]. Received Oct 18, 2017; revised and accepted Feb 28, 2018.
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REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
990
Goodwin FK, Jamison KR (2007): Manic-Depressive Illness: Bipolar and Recurrent Unipolar Disorders, 2nd ed. New York: Oxford University Press. Sigitova E, Fi sar Z, Hroudová J, Cikánková T, Raboch J (2017): Biological hypotheses and biomarkers of bipolar disorder. Psychiatry Clin Neurosci 71:77–103. Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA (2009): Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15:1595–1611. Manji H (2008): Bcl-2: A key regulator of affective resilience in the pathophysiology and treatment of severe mood disorders. Biol Psychiatry 63(suppl 1):243S. Yüksel C, Ongur D (2010): Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 68:785–794. Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN (2012): Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: A meta-analysis. Bipolar Disord 14:478–487. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, et al. (2002): Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 7(suppl 1):S71–S80. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. (2010): A randomized add-on trial of an N-methyl-Daspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67:793–802. Zarate CA, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. (2013): A randomized trial of a low-trapping nonselective
22.
23.
24.
25.
26.
27.
28.
29.
N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 74:257–264. Park M, Niciu MJ, Zarate CA (2015): Novel glutamatergic treatments for severe mood disorders. Curr Behav Neurosci Rep 2:198– 208. Keener MT, Phillips ML (2007): Neuroimaging in bipolar disorder: A critical review of current findings. Curr Psychiatry Rep 9:512–520. Phillips ML, Swartz HA (2014): A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry 171:829–843. Govindaraju V, Young K, Maudsley AA (2000): Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13:129–153. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982): Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 232:299–304. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F (1993): Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150:1731–1733. Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, et al. (1998): Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37:124–129. Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR, Kawahara R (2006): Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 30:1155–1158. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW (2000): Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 47:586–593. Frye MA, Tsai GE, Huggins T, Coyle JT, Post RM (2007): Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol Psychiatry 61:162–166. Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, et al. (1989): Brain amino acid concentrations and Ca21dependent release in intractable depression assessed antemortem. Brain Res 494:315–324. Eastwood SL, Harrison PJ (2010): Markers of glutamate synaptic transmission and plasticity are increased in the anterior cingulate cortex in bipolar disorder. Biol Psychiatry 67:1010–1016. Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B (2003): Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 5:257–264. Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007): Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32:1888–1902. Beneyto M, Meador-Woodruff JH (2008): Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33:2175–2186. Hashimoto R, Hough C, Nakazawa T, Yamamoto T, Chuang DM (2002): Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: Involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem 80:589–597. Kumar A, Singh RL, Babu GN (2010): Cell death mechanisms in the early stages of acute glutamate neurotoxicity. Neurosci Res 66:271– 278. Gigante AD, Young LT, Yatham LN, Andreazza AC, Nery FG, Grinberg LT, et al. (2011): Morphometric post-mortem studies in bipolar disorder: Possible association with oxidative stress and apoptosis. Int J Neuropsychopharmacol 14:1075–1089. Soeiro-de-Souza MG, Dias VV, Figueira ML, Forlenza OV, Gattaz WF, Zarate CA, et al. (2012): Translating neurotrophic and cellular plasticity: From pathophysiology to improved therapeutics for bipolar disorder. Acta Psychiatr Scand 126:332–341. Zung S, Souza-Duran FL, Soeiro-de-Souza MG, Uchida R, Bottino CM, Busatto GF, et al. (2016): The influence of lithium on
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging December 2018; 3:985–991 www.sobp.org/BPCNNI
Biological Psychiatry: CNNI
ACC Glutamate and Mood Stabilizers in BD
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
hippocampal volume in elderly bipolar patients: A study using voxelbased morphometry. Transl Psychiatry 6:e846. Colla M, Schubert F, Bubner M, Heidenreich JO, Bajbouj M, Seifert F, et al. (2009): Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol. Mol Psychiatry 14:696–704, 647. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A, et al. (2007): Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 61:806–812. Senaratne R, Milne AM, MacQueen GM, Hall GBC (2009): Increased choline-containing compounds in the orbitofrontal cortex and hippocampus in euthymic patients with bipolar disorder: A proton magnetic resonance spectroscopy study. Psychiatry Res 172:205–209. Drevets WC (2000): Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126:413–431. Phillips ML, Drevets WC, Rauch SL, Lane R (2003): Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 54:504–514. Kaufman RE, Ostacher MJ, Marks EH, Simon NM, Sachs GS, Jensen JE, et al. (2009): Brain GABA levels in patients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 33:427–434. Anticevic A, Savic A, Repovs G, Yang G, McKay DR, Sprooten E, et al. (2015): Ventral anterior cingulate connectivity distinguished nonpsychotic bipolar illness from psychotic bipolar disorder and schizophrenia. Schizophr Bull 41:133–143. Liu J, Blond BN, van Dyck LI, Spencer L, Wang F, Blumberg HP (2012): Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing. Bipolar Disord 14:432–441. Foland-Ross LC, Thompson PM, Sugar CA, Madsen SK, Shen JK, Penfold C, et al. (2011): Investigation of cortical thickness abnormalities in lithium-free adults with bipolar I disorder using cortical pattern matching. Am J Psychiatry 168:530–539. Soeiro-de-Souza MG, Salvadore G, Moreno RA, Otaduy MCG, Chaim KT, Gattaz WF, et al. (2013): Bcl-2 rs956572 polymorphism is associated with increased anterior cingulate cortical glutamate in euthymic bipolar I disorder. Neuropsychopharmacology 38:468–475. Ehrlich A, Schubert F, Pehrs C, Gallinat J (2015): Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder. Psychiatry Res 233:73–80. Soeiro-de-Souza MG, Henning A, Machado-Vieira R, Moreno RA, Pastorello BF, da Costa Leite C, et al. (2015): Anterior cingulate glutamate-glutamine cycle metabolites are altered in euthymic bipolar I disorder. Eur Neuropsychopharmacol 25:2221–2229. Kubo H, Nakataki M, Sumitani S, Iga JI, Numata S, Kameoka N, et al. (2017): 1H-magnetic resonance spectroscopy study of glutamaterelated abnormality in bipolar disorder. J Affect Disord 208:139–144.
43.
44.
45.
46. 47. 48.
49. 50. 51.
52.
53.
54.
55.
56.
57.
58.
Machado-Vieira R, Gattaz WF, Zanetti MV, de Sousa RT, Carvalho AF, Soeiro-de-Souza MG, et al. (2015): A longitudinal (6-week) 3T (1)HMRS study on the effects of lithium treatment on anterior cingulate cortex metabolites in bipolar depression. Eur Neuropsychopharmacol 25:2311–2317. First MB, Spitzer RL, Williams JB (1996): Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I. Washington, DC: American Psychiatric Press. American Psychiatric Association (2000): Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed, Text Revision. Washington, DC: American Psychiatric Publishing, Inc. Young RC, Biggs JT, Ziegler VE, Meyer DA (1978): A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 133:429–435. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296. Schubert F, Gallinat J, Seifert F, Rinneberg H (2004): Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. Neuroimage 21:1762–1771. Provencher SWS (1993): Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679. Kreis R (2004): Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed 17:361–381. Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG, et al. (2006): Use of tissue water as a concentration reference for proton spectroscopic imaging. Magn Reson Med 55:1219–1226. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, et al. (2008): Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 64:718–726. Michael N, Erfurth A, Ohrmann P, Gössling M, Arolt V, Heindel W, et al. (2003): Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacology (Berl) 168:344–346. Frye MA, Watzl J, Banakar S, O’Neill J, Mintz J, Davanzo P, et al. (2007): Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 32:2490–2499. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, et al. (2004): Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 61:450–458. Hajek T, Bernier D, Slaney C, Propper L, Schmidt M, Carrey N, et al. (2008): A comparison of affected and unaffected relatives of patients with bipolar disorder using proton magnetic resonance spectroscopy. J Psychiatry Neurosci 33:531–540. Garcia M, Huppertz HJ, Ziyeh S, Buechert M, Schumacher M, Mader I (2009): Valproate-induced metabolic changes in patients with epilepsy: Assessment with H-MRS. Epilepsia 50:486–492. Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL, et al. (2014): Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 56:340–348.
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