Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression.
ABSTRACT Proton magnetic resonance spectroscopy ((1)HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline (1)HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR=30/3000 ms, 3 x 3 x 3 cm(3) and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.
- SourceAvailable from: Marcus V Zanetti[Show abstract] [Hide abstract]
ABSTRACT: Hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolites levels in bipolar depression under treatment with lithium. Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol and glutamate levels were assessed in the left hippocampus before (week 0) and after lithium treatment (week 6) using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (= 0.50mmol/L) (n=10) showed an overall increase in glutamate concentrations over time. These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels. Clinical trial number NCT01919892. © The Author 2014. Published by Oxford University Press on behalf of CINP.10/2014;
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ABSTRACT: The anterior cingulate cortex (ACC), consisting of the perigenual ACC (pgACC) and mid-ACC (i.e., affective and cognitive areas, respectively), plays a significant role in the performance of gambling tasks, which are used to measure decision-making behavior under conditions of risk. Although recent neuroimaging studies have suggested that the γ-aminobutyric acid (GABA) concentration in the pgACC is associated with decision-making behavior, knowledge regarding the relationship of GABA concentrations in subdivisions of the ACC with gambling task performance is still limited. The aim of our magnetic resonance spectroscopy study is to investigate in 20 healthy males the relationship of concentrations of GABA and glutamate+glutamine (Glx) in the pgACC, mid-ACC, and occipital cortex (OC) with multiple indexes of decision-making behavior under conditions of risk, using the Cambridge Gambling Task (CGT). The GABA/creatine (Cr) ratio in the pgACC negatively correlated with delay aversion score, which corresponds to the impulsivity index. The Glx/Cr ratio in the pgACC negatively correlated with risk adjustment score, which is reported to reflect the ability to change the amount of the bet depending on the probability of winning or losing. The scores of CGT did not significantly correlate with the GABA/Cr or Glx/Cr ratio in the mid-ACC or OC. Results of this study suggest that in the pgACC, but not in the mid-ACC or OC, GABA and Glx concentrations play a distinct role in regulating impulsiveness and risk probability during decision-making behavior under conditions of risk, respectively. Copyright © 2015. Published by Elsevier Inc.NeuroImage 01/2015; 109. · 6.13 Impact Factor
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ABSTRACT: Background: Glutamate system is modified by ethanol and contributes both to the euphoric and the dysphoric consequences of intoxication, but there is now growing evidence that the glutamatergic system also plays a central role in the neurobiology and treatment of mood disorders, including major depressive disorders and bipolar disorders. We speculate that, using acamprosate, patients with bipolar depression (BIP-A) can take advantage of the anti-glutamate effect of acamprosate to "survive" in treatment longer than peers suffering from non-bipolar depression (NBIP-A) after detoxification. Method: We retrospectively evaluated the efficacy of a long-term (six-month) acamprosate treatment, after alcohol detoxification, in 41 patients (19 males and 22 females), who could be classified as depressed alcoholics, while taking into account the presence/absence of bipolarity. Results: During the period of observation most NBIP-A patients relapsed, whereas a majority of BIP-A patients were still in treatment at the end of their period of observation. The cumulative proportion of 'surviving' patients was significantly higher in BIP-A patients, but this finding was not related to gender or to other demographic or clinically investigated characteristics. The treatment time effect was significant in both subgroups. The treatment time-group effect was significant (and significantly better) for bipolar patients on account of changes in the severity of their illness. Limitations: Retrospective methodology and the lack of DSM criteria in diagnosing bipolarity. Conclusions: Bipolarity seems to be correlated with the efficacy of acamprosate treatment in inducing patients to refrain from alcohol use after detoxification (while avoiding relapses) in depressed alcoholics. Placebo-controlled clinical trials are now warranted to check the validity of this hypothesis.International journal of environmental research and public health 12/2014; 11. · 1.61 Impact Factor
Increased Anterior Cingulate/Medial Prefrontal Cortical
Glutamate and Creatine in Bipolar Depression
Mark A Frye*,1, June Watzl2, Shida Banakar2, Joseph O’Neill1, Jim Mintz1, Pablo Davanzo1, Jeffrey Fischer1,
Jason W Chirichigno1, Joseph Ventura1, Shana Elman1, John Tsuang3, Irwin Walot2and M Albert Thomas4
1UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA;2Department of Radiology Harbor-UCLA Medical Center,
Los Angeles, CA, USA;3Department of Psychiatry Harbor-UCLA Medical Center, Los Angeles, CA, USA;4UCLA Department of Radiology,
Los Angeles, CA, USA
Proton magnetic resonance spectroscopy (1HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug
mechanism of action. This study evaluated baseline1HMRS spectra of bipolar depressed patients and whether the level of cerebral
metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control
subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5T MRI
scanner using single-voxel PRESS (TE/TR¼30/3000ms, 3?3?3cm3and post-processed offline with LCModel. Baseline CSF-corrected
absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher
in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the
melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to
non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased
energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to
determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.
Neuropsychopharmacology (2007) 32, 2490–2499; doi:10.1038/sj.npp.1301387; published online 11 April 2007
Keywords: bipolar; depression; glutamate; lamotrigine; MR spectroscopy
As originally proposed by Papez (1937), the cingulate cortex
is a brain region linked to the cognitive and emotional
aspects of affect regulation (Vogt, 2003, 2005; Devinsky
et al, 1995; Allman et al, 2001) and has been implicated in
the pathophysiology of bipolar disorder.
Key findings in bipolar disorder have specifically
included the subgenual anterior cingulate cortex (sACC,
Vogt, 2003, 2005). This is the subregion of the cingulated
gyrus that lies ventral to the genu of the corpus callosum. In
comparison to controls, below-normal glial cell number
(O¨ngur et al, 1998), (left-sided) volume (Drevets et al, 1997;
Hirayasu et al, 1999; Sassi et al, 2004), and regional cerebral
blood flow (Drevets et al, 1997) have been reported in the
sACC in bipolar disorder. There is additional evidence for
bipolar medial prefrontal abnormalities outside the sACC
including the pregenual anterior cingulate cortex (pACC,
subregion of the cingulate just anterior to the genu),
anterior middle cingulate cortex (aMCC, subregion of the
cingulate dorsal to the genu), and medial aspects of the
superior frontal cortex. Post-mortem pathology in bipolar
disorder in these regions have included reduced neuronal
(Benes et al, 2001; Bouras et al, 2001) and synaptic marker
density (Eastwood and Harrison, 2001).
Additional neuroimaging findings in bipolar disorder in
these regions included reduced volume of superior frontal
cortex (Lopez-Larson et al, 2002), (left-sided) reduced
activation of medial frontal cortex (Strakowski et al,
2004), increased regional blood flow of left aMCC (Blum-
berg et al, 2000; Rubinsztein et al, 2001), correlations of
glucose metabolic rate in medial prefrontal cortex with
clinical depression severity (Osuch et al, 2000), post-
treatment regional blood flow response to transcranial
magnetic stimulation in left aMCC and medial prefrontal
cortex (Speer et al, 2000), and increased levels of myo-
inositol (mI) and choline compounds (Cho) in anterior
cingulate (Davanzo et al, 2001; Moore et al, 2000c).
1HMRS is an in vivo, non-invasive brain imaging
technique that can detect alterations in brain biochemistry
in the presence of apparently normal anatomy. As reviewed
elsewhere (Moore and Galloway, 2002; Stork and Renshaw,
2005; Stanley, 2002; Strakowski, 2005), resonances in the
1HMR spectrum can be reliably quantified for several
Received 4 May 2006; revised 30 January 2007; accepted 5 February
Presented at the 6th International Conference on Bipolar Disorder,
17 June, 2005 Pittsburgh Pennsylvania and the 61st Annual Meeting
of the Society of Biological Society 18–20 May, 2006, Toronto.
*Correspondence: Dr MA Frye, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905, USA, Tel: +507 775 1475, Fax: +507 255
9416, E-mail: email@example.com
Neuropsychopharmacology (2007) 32, 2490–2499
& 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00
metabolites with brain concentrations in the millimolar
range including N-acetyl-aspartate (NAA), a marker of
neuronal viability; the excitatory amino-acid glutamate
(Glu); glutamine (Gln), the glial cell reservoir storage form
of glutamate; the sum of Glu and Gln (Glx); creatine+
phosphocreatine (Cr), a measure of energy utilization
which, given its relative stability, has historically been used
as an1HMRS internal standard; choline related compounds
(Cho) including glycerophosphocholine, phosphocholine,
and acetylcholine some of which are involved in membrane
metabolism; and myo-inositol (mI), a component of the
cellular phosphoinositol-cycle second-messenger system.
In contrast to other functional imaging technologies, MR
spectroscopy seems to be uniquely positioned to investigate
biochemical-based psychotropic drug mechanisms of ac-
tion. For example, lithium treatment has been shown to
increase gray matter volume and NAA (Moore et al,
2000a,b). This work has been extended with a recent report
of increased gray matter only in those bipolar depressed
subjects who had a treatment response associated with
lithium (Moore et al, 2005). It has been proposed that this
neuroprotective/neurotrophic action of lithium, as mea-
sured by NAA, could occur via decreased glutamate-
mediated neurotoxicity in pre-clinical ischemic models
(Nonaka and Chuang, 1998) and increased expression of
the cytoprotective protein bcl-2 (Moore et al, 2000c).
Lamotrigine is an FDA-approved agent for the maintenance
phase of bipolar I disorder (Bowden et al, 2003; Calabrese
et al, 2003). There are additional controlled data demonstrat-
ing acute efficacy in bipolar depression (Frye et al, 2000;
Obrocea et al, 2002; Calabrese et al, 1999). As reviewed by
Frye et al (2000) and Ketter et al (2003) lamotrigine has been
shown to block voltage-sensitive sodium channels with the
subsequent inhibition of the presynaptic excitatory amino
acids aspartate and glutamate. Like lithium, lamotrigine
reduces cell damage (eg, in the hippocampal CA1 region) in
ischemic neuroprotective models (Crumrine et al, 1997; Lee
et al, 2000). Although glutamatergic dysregulation has been
less well studied in mood disorders (Frye et al, 2007; Kugaya
and Sanacora, 2005), this investigation was conducted to
evaluate whether lamotrigine may modulate glutamatergic
tone in bipolar depression that is clinically relevant and
objectively measured by MR spectroscopy.
This study was approved both by the UCLA and the UCLA
Harbor Medical Center IRB. After obtaining written
informed consent, all subjects were diagnosed using the
Structured Clinical Interview for DSM-IV (SCID, First et al,
1997); this diagnostic interview was administered by trained
raters who had participated in an ongoing quality assurance
program to prevent rater drift (Ventura et al, 1998). The
inclusion criteria for this study was a DSM-IV current
diagnosis of bipolar I or II depression with at least moderate
symptom severity as measured by a Montgomery-Asberg
Depression Rating Scale (MADRS) score X16 (Montgomery
and Asberg, 1979). Melancholic vs non-melancholic subtype
was confirmed by DSM-IV criteria. All ratings were
conducted by the principal investigator (MAF) or inter-
rater reliable assistants (JF or SE). Exclusion criteria
included active suicidality, current psychosis, current
alcohol or substance abuse or dependence (within the last
6 months), active unstable medical condition, clinically
relevant abnormal laboratory test, history of adverse
reaction to lamotrigine, and antipsychotic treatment within
4 weeks as these agents have been known to increase NAA
in selected regions (reviewed by Bertolino et al, 2001).
Of the 34 bipolar depressed (BP Dep) subjects who
provided written informed consent, eight (five M/three F)
were screen failures; therefore, 26 BP Dep (19 M/seven F) &
12 healthy controls (seven M/five F) underwent1HMRS. As
described below, three bipolar subjects had non-viable
spectra and thus demographics, as presented in Table 1, are
on 23 depressed subjects. Five out of twenty-three (12%)
bipolar depressed subjects were on lithium at the time of the
scan; as lithium treatment has been shown as to increase
NAA (Moore et al, 2000a), all baseline spectroscopic
analyses were done with and without these five subjects.
At the time of scan, depressive, and manic symptom
severity was assessed utilizing the MADRS and the YMRS
(Young et al, 1978) respectively.
Bipolar depressed subjects underwent a second MRS scan
after a 12-week open trial of lamotrigine. The lamotrigine
titration schedule was 25mg p.o. q.d.?2 weeks, 50mg p.o.
q.d.?2 weeks, 100mg p.o. q.d. (orally, daily)?2 weeks,
150mg p.o. q.d.?2 weeks, and 200mg p.o. q.d. for the
remaining 4 weeks. This was a slower titration than current
guidelines to simplify prescription dispensation in our research
pharmacy. The dose of the study medication could be reduced
for side effects or maintained at a lower dose for early clinical
response. Of the original 23 subjects, five dropped out of
the study before the second scan (n¼1 hospitalization for
depression, n¼2 rash (full resolution with drug discontinua-
tion), n¼1 administrative discharge, n¼1 declined second
scan) and one did not have viable MRS spectrum for the
second scan. Remission of bipolar depressive symptoms was
defined as a MADRS o8 at the last visit/second scan.
Healthy subjects did not receive medication but underwent
a second MRS scan at the same time point 12 weeks later to
assess for normal variability in metabolites over time.
MRI/MRS Acquisition and Processing
Scans were conducted at the UCLA Harbor Brain Imaging
Center on a 1.5T GE MRI Scanner (GE Medical Systems,
Waukesha, WI) with echo-speed gradients using a head
transmit/receive coil. The scans were acquired in the following
order: (1) Sagittal whole-brain scout for general orientation
and positioning of subsequent scans, (2) T1-weighted and
inversion-recovery (IR) weighted axial images (TR/TE¼800/
8ms, 35 slices, 4mm thickness with no gap for MRS voxel
Table 1 Subject Demographic Profile (7SD)
N/gender 17M/6F7M/5FF¼0.18, p¼0.67
Age (years) 35.6711.2
Glutamate and creatine in BD
MA Frye et al
placement, (3) Single-voxel water-suppressed (Haase et al,
1985) PRESS (Bottomley, 1987)
number of averages¼256, voxel size 3?3?3cm3) of
anterior cingulated/medial prefrontal cortex. PRESS was
acquired with the GE proton brain examination (PROBE)
technique, whereby four unsuppressed water free-induction
decays were co-acquired for eddy current compensation,
phase-correction, and normalization of local absolute meta-
bolite levels. The voxel location was guided by the T1 and IR
weighted sagital images as shown in Figure 1.
A systematic approach to referencing voxel position to
identifiable anatomical landmarks was employed based on
a human brain reference atlas (Mai et al, 1997), anterior
cingulate anatomy (Vogt, 2003, 2005), and on our earlier
report (Davanzo et al, 2001, see Figure 1). Laterally, the
3?3?3cm3voxel was centered on the interhemispheric
fissure. The dorsal and ventral boundaries of the voxel were
the cingulate sulcus and the inferior margin of the genu of
the corpus callosum respectively. The anterior boundary
of the voxel approximated the frontal pole and the posterior
boundary was the gray/white-matter interface at the margin
of the corpus callosum with the cingulate gyrus. This voxel
contained bilateral pregenual anterior cingulate cortex
(pACC), anterior midcingulate cortex (aMCC), and medial
pre-frontal cortex (superior frontal gyrus). The relatively
large voxel was used to allow comparison of this 1D MRS
data with 2D MRS acquisitions developed in our laboratory
(Thomas et al, 2001), which will be reported in a future work.
Images were transferred to a Sun Ultra 10 workstation (Sun
Microsystems, Palo Alto, CA), and analyzed using an in-house
developed image processing package which made use of
software toolkits developed for medical image analysis (Brown
et al, 1998). These toolkits enabled the display and manipula-
tion of MR images, the representation of anatomic region of
interest (ROI) and the calculation of the properties of the ROI.
Multi-slice T1 MRIs were combined into a single file. The MRS
voxel (3?3?3cm3) co-ordinates recorded during acquisition
were used as the input values and the image analysis package
used the multi-slice image file to calculate the percentages of
tissue (gray matter+white matter) and cerebrospinal fluid
(CSF) in each MRS voxel. Absolute metabolite levels were
corrected for voxel CSF content.
The spectroscopic raw data were transferred to an SGITM
O2workstation (Silicon Graphics Inc, San Jose, CA) and
processed using the LCModel package (Provencher, 1993,
2001). The basis set for TE¼30ms was provided by the
vendor for quantification. LC Model is an operator-
independent commercial software package that fits in vivo
metabolite spectra in the frequency domain using model
resonances acquired under comparable scanning conditions
from multiple compounds in standard phantom solutions.
Using LC Model, resonances fitted with 420% variance
were rejected. The entire spectrum was rejected if the signal-
to-noise ratio (SNR) was less than three or the full-width
at half-maximum (FWHM) was greater than 8 Hz. This
occurred in three bipolar depressed subjects at baseline
scan, one bipolar subject at second scan, and two controls at
second scan; 91% of total scans acquired in this study were
accepted. N-acetylaspartyl-glutamate (NAAG) and macro-
molecules (MM1–MM7) were included in LC model post
processing, but were not statistically analyzed.
Water-suppressed frequency-domain data were analyzed
between 0.2 and 4.0ppm without further T1 or T2 correction.
An example spectrum is presented in Figure 2. Absolute
concentrations of N-acetyl-aspartate (NAA), glutamate (Glu),
glutamine (Gln), the sum of glutamate+glutamine (Glx),
creatine+phosphocreatine (Cr), choline+phosphocholine
(Cho), and myo-inositol (mI), corrected for voxel CSF
content, are reported and denoted by brackets [
bolite levels were also reported as ratios to creatine.
T-tests and analysis of variance were used to compare
baseline demographic differences between bipolar de-
pressed subjects vs controls and lamotrigine remitters vs
non-remitters. T-tests were used to compare baseline
spectroscopic differences between melancholic (n¼14) vs
atypical (n¼9) depression subtypes. A 2?2 group?time
mixed effects repeated measures ANOVA assuming random
attrition was conducted for spectroscopic differences
between bipolar depressed subjects (n¼23) vs controls
(n¼12) at baseline and lamotrigine-treated bipolar subjects
(n¼16) vs controls (n¼10) at second scan 12 weeks
later. Effect sizes (Cohen’s, 1988) were calculated for all
statistically significant results. Pearson’s correlation was
used to evaluate associations between baseline spectra and
clinical demographic variables.
The lamotrigine-associated remission (n¼7) and non-
remission (n¼9) groups were compared on post-treatment
spectroscopic data using analysis of covariance with base-
line as the covariate and remission status as the indepen-
dent variable. A preliminary analysis tested the assumption
of homogeneity of the regressions of post-treatment on
baseline by including the interaction of baseline and remit
status. If not significant, the interaction was dropped from
the model. If the interaction was significant, the covariate
by treatment interaction effect was retained in the model. In
that case, group means were estimated and compared using
t-tests at the minimum, mean, and maximum values of the
baseline covariate (Littell et al, 1996). Owing to the small
sample size, only those resonances hypothesized to be
associated with lamotrigine’s preclinical mechanism of
prefrontal cortex 1H-MRS single-voxel acquisition (3cm3).
T1-weighted sagittal MRI location for anterior cingulate/medial
Glutamate and creatine in BD
MA Frye et al
action (the inhibition of extracellular release of aspartate
and glutamate (NAA, Glx, Glu, Gln)) were analyzed.
As presented in Table 1, there were no significant
differences in gender, age, or years of education between
BP Dep and control subjects. For bipolar depressed
subjects, the mean index episode length and years ill was
10.2710.5 weeks and 17.4710.4 years respectively. The
mean MADRS and YMRS were 27.576.2 and 1.771.9
respectively. Five out of twenty-three (4M/1F) bipolar (bp)
depressed subjects were on lithium (mean dose 1170mg,
mean serum level¼0.83mmol/l). At baseline scan, there
was no difference in bp depressed patients (n¼23) vs
controls (n¼12), in % gray matter (bp¼70.572.71%;
matter (bp¼25.876.3%; control n¼23.772.2%; t¼2.04,
p¼0.16). As presented in Table 2a, there were no significant
differences in the mean percentage voxel CSF or CSF
corrected concentrations of [NAA], [Gln], [Cho], and [mI]
in BP Dep subjects vs controls. However, CSF-corrected
absolute concentrations of [Glx], [Glu], and [Cr] were
significantly higher in BP Dep vs controls (Table 2a,
Figure 3). When the five BP depressed subjects on lithium
were removed, the effects for CSF-corrected absolute
concentrations of [Glx] (t¼2.60, p¼0.02), [Glu] (t¼2.45,
p¼0.02), and [Cr] (t¼2.36, p¼0.03, all df¼28) remained
significant. Also, when the five BP depressed subjects on
lithium were removed, there were no new CSF-corrected
differences in any other spectroscopic resonances in
subjects vs controls. Glx/Cr and Glu/Cr ratios in BP Dep
subjects were not significantly different from those of
controls, presumably because [Cr] was also significantly
elevated in BP Dep subjects. There were no other significant
group differences in metabolite ratios (Table 2b).
As presented in Figure 4, the non-melancholic depressed
subjects had significantly higher [Glx] and [Glu] than the
melancholic depressed subjects. In all BP Dep subjects there
was no significant correlation between any clinical demo-
graphic variable (MADRS, episode duration, or age of illness
onset) and CSF-corrected absolute concentrations of [Glx]
(MADRS n¼23, r¼?0.30, p¼0.17; episode duration
r¼0.002, p¼0.99; age mood onset r¼0.11, p¼0.63), [Glu]
(MADRS n¼23, r¼?0.08, p¼0.70; episode duration
r¼0.13, p¼0.63; age mood onset r¼0.08, p¼0.75), and
[Cr] (MADRS n¼23, r¼0.27, p¼0.22; episode duration
r¼?0. 26, p¼0.31; age mood onset r¼?0.14, p¼0.54).
At the second scan 12 weeks later, there was no difference,
bp patients (n¼16) vs controls (n¼10), in % gray matter
(bp¼69.277.1%; control¼67.678.1%; t¼2.1, p¼0.63) or
% white matter (bp¼26.177.0%; control n¼27.3577.9%;
t¼2.1, p¼0.69). The only significant group differences
were a significantly higher [Gln] and significantly lower
NAA/Cr in BP Dep subjects vs controls (Table 2a and b).
For bipolar depressed subjects, the overall remission rate
was 38% (n¼7/18). There was one serious adverse event for
depression associated with hospitalization and two rashes
that resolved with drug discontinuation. For those subjects
with viable pre- and post-MRS scans, there was no significant
difference in mean index episode length, baseline MADRS,
and end point lamotrigine dose between remit (n¼7) and
non-remit (n¼9) groups (episode length: remit¼1276.2
weeks vs non-remit¼8.7576.6 weeks, df¼1,14 t¼0.49,
p¼0.63; baseline MADRS: remit¼3175.3 vs non-remit¼
Figure 2Raw (fine black), baseline (thick black), and LCModel fit (red) MR spectra localized in the anterior cingulate (27cm3) of 18-year-old male.
Glutamate and creatine in BD
MA Frye et al
2676.4, t¼1.85, p¼0.09; end point lamotrigine dose:
t¼1.13, p¼0.28) groups. The end point MADRS was
significantly lower in the remit (mean¼3.771.5) vs
non-remit group (mean¼16.7879.7, df¼1,14, t¼3.50,
The preliminary analysis of covariance revealed a signi-
ficant interaction between remit status and baseline [NAA]
Table 2a CSF Corrected Absolute Concentrations [mM] in BP Dep vs Controls at Baseline and Time 2 (12 weeks)
Baseline Time 2
BP Dep vs
BP LTG vs
[Glx]8.1670.35 6.6670.488.3870.54 6.8270.71
[Gln]2.5070.262.0470.37 2.7270.3 1.5770.44
[Cr] 5.7870.195.1470.26 5.6370.175.4070.23
[Cho] 1.3370.05 1.2170.08 1.2970.06 1.2170.08
2?2 group?time mixed effects repeated measures analysis of variance assuming random attrition.
BP, Bipolar; DEP, Depression; LTG, Lamotrigine.
aAll statistics BP DEP vs. Control baseline n¼35, df¼1,34, mean7SE.
*Cohen’s D¼0.9, **Cohen’s D¼0.81, ***Cohen’s D¼.72, ****Cohen’s D¼0.82.
Table 2b Metabolite Ratios/Creatine in BP Dep vs Controls at Baseline and Time 2 (12 Weeks)
Baseline Time 2
BP Dep vs
BP LTG vs
Glx/Cr 1.4270.051.2870.07 1.4970.09 1.2370.13
Glu/Cr 0.9870.040.9070.05 0.9970.050.9770.06
2?2 group?time mixed effects repeated measures analysis of variance assuming random attrition.
BP, Bipolar; DEP, Depression; LTG, Lamotrigine.
aAll statistics BP DEP vs control baseline n¼35, df¼1,34, mean7SE.
Glutamate and creatine in BD
MA Frye et al
(F¼5.66, df¼1,14, p¼0.03). Estimated at the baseline
minimum (4.6mM), the percent changes in [NAA] at time
of second scan were 6.2% for non-remitters and 40.1% for
remitters (t¼2.78, df¼1,14, p¼0.017). At the baseline mean
(6.9mM), the estimated percent changes in [NAA] were 2.9%
for non-remitters and 5.8% for remitters (t¼1.92, p¼0.08).
At the baseline maximum (8.6mM), the estimated percent
changes in [NAA] were 9.7% for non-remitters and ?19.6%
for remitters (t¼1.19, p¼0.26).
The interaction between remit status and baseline level
was not significant for Glx (F¼3.35, p¼0.09), Glu (F¼0.36,
p¼0.56), or Gln (F¼1.25, p¼0.29, all df¼1, 14). As
presented in Table 3, controlling for baseline differences,
[NAA], [Glx], and [Glu] were not significantly different at
study end point between remit and non-remit subjects.
However, [Gln] was significantly lower in remit vs non-remit
subjects (remit baseline¼2.3870.76, percent change¼
?0.1770.5 vs non-remit baseline¼3.0471.33, percent
change¼0.46+70.98, F¼4.84, p¼0.046); the large mean
percent change in the non-remit group was driven by one
outlier who had a 293% increase. The median percent
change was 17%, more in line with the baseline and post-
treatment means. Reanalysis using an analysis of covariance
on ranks (Conover and Iman, 1982) yielded a trend group
difference (F¼3.94, df¼1,13, po0.07).
These findings of increased anterior cingulate/medial
prefrontal cortical glutamate (quantified as [Glx] and as
[Glu] itself) and creatine [Cr] suggest that bipolar depres-
sion is characterized by an increased excitatory amino-acid
signal coupled with increased energy expenditure. The effect
sizes of the Glx (d¼0.9), Glu (d¼0.8), and Cr (d¼0.7) are
quite large despite the small sample size. As the glutamate-
glutamine cycle (Shen and Rothman, 2002) and energetic
metabolism (Magistretti et al, 1993) involve neurons and
glia, our two findings may reflect dysregulation of neurons
and/or glia in bipolar depression. In a mixed outpatient
group of bipolar patients studied by Dager et al (2004), gray
matter lactate and Glx (glutamate+glutamine) were in-
creased; the authors proposed that these increases might
suggest a dynamic shift in energy redox state from oxidative
phosphorylation towards glycolysis. [Glx], [Glu], and [Cr]
levels in our sample may be coupled in a similar manner.
In MR spectroscopic research, the absolute level of
creatine+phosphocreatine (Cr), a measure of energy
utilization, has tended to be stable in most studies and
conventionally has been used as an internal standard in
spectroscopic research. In this study, however, [Cr] was
significantly higher in bipolar depressed subjects at the first
baseline scan and was not significantly different from
controls at the second scan. This would suggest that Cr may
not be a stable resonance to be used as an internal standard
or reference ratio in bipolar depression research. This
certainly warrants further investigation as the current
literature in bipolar disorder, although different in meth-
odology, mood state, and brain region, has reported
increased creatine (Deicken et al, 2001; Michael et al,
2003Ftrend, Hamakawa et al, 1999Fmen only), decreased
creatine (Deicken et al, 2003), or no change in creatine
(Hamakawa et al, 1998; Friedman et al, 2004; Cecil et al,
2002; Brambilla et al, 2005; Frey et al, 2005).
Our findings of increased glutamate confirm previous
spectroscopic studies in bipolar disorder. As mentioned
above, Dager et al (2004) found above-normal Glx in left
cingulate. In bipolar patients with acute mania, dorsolateral
prefrontal cortical [Glx] and [Cr] (trend only) were
increased in comparison to age-matched controls (Michael
et al, 2003). Frontal cortex and basal ganglia Glx elevations
have also been reported in pediatric bipolar disorder; the
acute mood state and Cr levels were not reported (Castillo
et al, 2000). In contrast, below-normal anterior cingulate
[Glx] has been reported in unipolar depression with
(Rosenberg et al, 2005; Mirza et al, 2004) or without (Auer
et al, 2000; Pfleiderer et al, 2003) below-normal [Cr].
Despite phenomenologic similarities between bipolar and
unipolar depression, the epidemiology, course of illness
(age of onset, associated comorbidities), and potential
liability of antidepressant treatment suggest that these are
in fact, two different disease states (Bowden, 2005). Further
study is encouraged to evaluate whether anterior cingulate/
medial prefrontal cortex [Glx] and/or [Cr] are potential
biomarkers differentiating bipolar and unipolar depression.
It will be important for future studies to not only confirm
differential diagnostic criteria of bipolar vs unipolar
depression, but also to delineate subtype of depression by
melancholic vs atypical phenotype. Our data suggest that
vs controls. *Glx, F¼6.4, p¼0.016, Cohen’s D¼0.9. **Glu, F¼5.2,
p¼0.029, Cohen’s D¼0.81. ***Cr, F¼4.01, p¼0.05, Cohen’s D¼0.72.
Mean (7SE) 1H-MRS CSF-corrected spectra: BP depressed
spectra in melancholic subtype vs Non-melancholic bipolar depression.
*Glx t¼?2.98, p¼0.006 **Glu t¼?1.87 p¼0.07.
Mean (7SE) 1H-MRS CSF-corrected Glx, Glu, and Gln
Glutamate and creatine in BD
MA Frye et al
non-melancholic depressed bipolars have a significantly
higher glutamate signal than melancholic bipolar depressed
subjects. It is unclear if the potential for1HMRS anterior
cingulate glutamate to distinguish bipolar from unipolar
depression is related to the different disease state (bipolar
glutamate increase/unipolar glutamate decrease) or to the
current phenomenologic presentation (atypical glutamate
increase/melancholic glutamate decrease). The unipolar
studies that reported reduced anterior cingulate [Glx]
(Rosenberg et al, 2005; Mirza et al, 2004; Auer et al, 2000;
Pfleiderer et al, 2003) did not report glutamate levels based
on subtype or pattern of depression.
Our preliminary results are in contrast to the Sanacora et al
(2004) study which found below-normal glutamate and above-
normal GABA in the occipital lobes in melancholic unipolar
patients. It is important to emphasize however, that the two
studies differ in primary cohort (bipolar vs unipolar) and
brain region of interest (anterior cingulated/medial prefrontal
cortex vs occipital lobe). Nonetheless, recent preclincal data
have highlighted that CRF1 receptors (activation associated
with anxiogenic behavior; Liebsch et al, 1995) and CRF2
receptors (activation involved in stress mediated coping
behavior; Liebsch et al, 1999) differentially regulate glutamate
transmission (Liu et al, 2004). In the central nucleus of the
amygdala, CRF decreased glutamatergic transmission through
a CRF1 mediated post-synaptic action; conversely, in the
lateral septum mediolateral nucleus, CRF caused a CRF1
mediated facilitation of glutamatergic transmission. It may be
that CRF-mediated glutamate transmission may be differen-
tially regulated in bipolar vs unipolar disorder or in atypical vs
melancholic depressive subtypes.
These data also suggest that lamotrigine-associated remis-
sion of bipolar depression may be associated with a
reduction in glutamine. Although the sample size is small,
the effect size is quite large and is consistent with the a priori
defined mechanism of drug action (ie inhibition of extra-
cellular release of glutamate decreasing the glial cell reservoir
of glutamine). Further research is encouraged to understand
the clinical implications of these findings and to evaluate
whether baseline glutamate levels could predict treatment
response or predict the subsequent reduction of glutamine
when given an antiglutamatergic drug such as lamotrigine.
Once glutamate has been released into the synapse, glial
cells re-uptake glutamate by excitatory amino-acid (EAA)
transporters (Shegeri et al, 2004; Mathews and Diamond,
2003). EAA one and two shuttle glutamate into astrocytes
where it is converted to glutamine by glutamine synthetase
(GS). Glutamine is then released, taken up by the neuronal
terminals, and is reconverted to glutamate and GABA by
glutaminase (GLS) and glutamic acid decarboxylase (GAD1)
respectively. It is not known if there is differential
enzymatic regulation of the glutamate–glutamine cycle in
bipolar disorder patients who respond vs do not respond to
treatment, but there are data suggesting reduced activity of
GS in area 24 of anterior cingulate in depressed subjects
(Choudary et al, 2005). There are also findings of decreased
glutamate–glutamine cycling in the plasma and cerebrosp-
inal fluid of depressed patients (Cryan and Kaupmann,
2005) and epileptic human hippocampus (Petroff et al,
2002). Theoretically, downregulation of GS could account
for the increased Glx and Glu resonances reported here
guish extracellular vs intraneuronal glutamate.
Our data also suggest that lamotrigine treatment may be
associated with an increase in NAA for those subjects with
low levels at baseline; this increase was approximately 40% in
remitters and was significantly greater than non-remitters
(6%). The differential increase in NAA as a function of remit
status was not present when estimated at the either baseline
mean or baseline maximum. This means that the difference
between remit and non-remit groups in NAA increase
appears to exist only in those who start with a baseline deficit.
This is consistent with recent data with lamotrigine in
adolescent bipolar disorder (Chang et al, 2005). Eleven
adolescent bipolar depressed subjects underwent an 8-week
open label trial of lamotrigine (mean dose 136728mgqd).
At study end point, there was a significant increase in left
dorsal lateral prefrontal cortex NAA/Cr (1.5970.13 to
1.6670.1, p¼0.04). Like the Chang study, our data show
a spectral change (ie increased NAA) consistent with the
1HMRS technology is unable to distin-
Table 3 CSF-Corrected [NAA], [Glx], [Glu], and [Gln] at Baseline and 2nd Scan in Lamotrigine (LTG) Associated Remission vs
LTG Remission (n¼7) LTG Non-Remission (n¼9)
[mM] Baseline2nd scan % ChangeBaseline2nd scan% Change ANCOVA
[NAA]^ 7.1670.97.1970.5 +0.0270.26.7571.4 6.5371.1
[Glx]8.0470.9 8.1372.0 +0.0170.2 8.3571.9 9.1471.9+15270.4
[Glu]5.6670.9 6.1371.1 +0.170.2 5.3271.8 5.3771.2+0.11970.5
?0.1770.5 3.0471.3 3.7771.3+0.4670.98
CSF-corrected absolute concentration mean7SD.
*The effect size (Cohen’s D) of the unadjusted means¼0.79. The effect size of the adjusted means¼1.16.
^Analysis of covariance revealed a significant interaction between remit status and baseline [NAA] (F¼5.66, df¼1,14, p¼0.03). Estimated at the baseline minimum
(4.6mM), the percent changes in [NAA] at time of 2nd scan were 6.2% for non-remitters and 40.1% for remitters (t¼2.78, df¼1,14, p¼0.017). There were no
significant differences in percent change at baseline mean (6.9mM) and baseline maximum (8.6mM).
Glutamate and creatine in BD
MA Frye et al
drug mechanism of action (ie blocking the extracellular
release of aspartate thereby increasing intraneuronal levels).
The difference in our study vs the Chang study is that the
increase in our cohort was only identified in those subjects
with low levels at baseline. The baseline NAA by remit
status interaction is as well consistent with the hypothesis
originally proposed by Brambilla et al, (2004) whereby
treatment-associated increases in NAA may only be
identified in NAA deficient disease states. In their study,
lithium administration to healthy controls was not asso-
ciated with an increase in NAA. It may be that psychotropic
drug treatment-associated increases in NAA may only be
possible in subjects where NAA baseline deficits are present.
NAA metabolism is maintained via a unique tricellular
pathway involving a neuron, an astrocyte, and an oligoden-
drocyte proximal to a glutamatergic neuronal synapse (Baslow,
2000). NAA synthesis occurs in the neuronal mitochondrion
through the NAA-synthase-catalyzed union of acetyl-CoA with
aspartate: Acetyl-CoA+Asp-NAA+CoAsh (Baslow, 1997;
Patel and Clark, 1979). Thus, inhibition of aspartate release
may increase intracellular synthesis of NAA. It will be
important to replicate these NAA spectroscopic changes
associated with lamotrigine in a larger, placebo-controlled
investigation. Furthermore, it would be valuable to evaluate
whether baseline levels of NAA predict lamotrigine-associated
increases in NAA or treatment response.
There are several limitations to this study including the
large voxel size and lack of gray- vs white-matter tissue
segmentation. The large voxel size was chosen a priori to
standardize the 1D MRS data presented here to subsequent
2D MRS data currently being analyzed (Thomas et al, 2001).
Second, given the size of the voxel, our region of interest
expands beyond a single anatomic region of interest and
includes bilateral pregenual anterior cingulate (pAC),
anterior midcingulate cortex (aMCC), and medial pre-
frontal cortex (superior frontal gyrus). A future study, with
a smaller voxel size and careful regional volumetric analysis
might determine which, if either, cingulate subregion or
medial prefrontal cortex is driving the present results.
Uncertainties, particularly at 1.5T, attend the quantifica-
tion of overlapping resonances of Glx, Glu, and Gln.
Generally, the Glx resonance is comprised of glutamate
(60–70%) and glutamine (20–30%; Pouwels and Frahm,
1998). In this study, acceptably reliable peaks, as defined by
LCModel quality control criteria, were recorded consistently
for each of these. Thereby, the Gln resonance was smaller and
relatively more variable than Glx and Glu, as has been seen
by others (Auer et al, 2000; Rosenberg et al, 2005). Higher
field strength may better quantify Gln and separate it from
Glu as evidenced by a 4-T study of left anterior cingulate
finding reductions in both Glu and Gln in schizophrenia
(Theberge et al, 2003). Furthermore, in addition to the Glu
and Gln included in the LCModel fit of the Glx signal, some
authors include a GABA contribution since their curve fitting
algorithms do not differentiate GABA from the overlapping
Glx peaks (Sanacora et al, 1999); nonetheless, this contribu-
tion is considered to be quite small.
A further limitation of our study was lack of segmentation
of brain tissue into gray and white matter, although CSF was
distinguished from these two. Fortunately, the midline
anterior cingulate placement of the MRS voxel assured a
low contribution of white matter (B10% or less). None-
theless, the ability to segment gray and white matter from
each other might help further localize our findings vis-a `-vis
These limitations notwithstanding, this report suggests
that elevated anterior cingulate [Glx] and/or [Cr] may
represent an important metabolic concommittant of bipolar
depression, possibly even distinguishing it from unipolar
depression. Confirmatory studies are in order.
We acknowledge the support of Dr Mathew Brown and
Dr Nathaniel Wykoff in the segmentation of gray/white vs
CSF and Ms Donna McGee for conducting the MRI/MRS
acquisitions. This study was supported by an educational
grant from GlaxoSmithKline.
Mark A Frye, MD
Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb,
Eli Lilly and Co., GlaxoSmithKline, Janssen-Cilag, Johnson
& Johnson PRD, Novartis, Ortho McNeil, Otsuka Pharma-
ceuticals, Pfizer Inc., Shire Pharmaeuticals, Solvay Pharma-
Abbott Laboratories, American Foundation for Suicide
Prevention Cephalon, GlaxoSmithKline, National Institute
of Mental Health, Pfizer Inc., Solvay Pharmaceuticals,
Stanley Medical Research Institute.
Astra Zeneca Pharmaceuticals, Bristol Myers Squibb, Eli
Lilly and Co., Otsuka Pharmaceuticals, Pfizer.
Financial interest/stock ownership/royalties
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