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PRIORITY COMMUNICATION
Lithium Increases N-Acetyl-Aspartate in the Human
Brain: In Vivo Evidence in Support of bcl-2’s
Neurotrophic Effects?
Gregory J. Moore, Joseph M. Bebchuk, Khondakar Hasanat, Guang Chen,
Navid Seraji-Bozorgzad, Ian B. Wilds, Michael W. Faulk, Susanne Koch,
Debra A. Glitz, Libby Jolkovsky, and Husseini K. Manji
Background: Recent preclinical studies have shown that
lithium (Li) robustly increases the levels of the major
neuroprotective protein, bcl-2, in rat brain and in cells of
human neuronal origin. These effects are accompanied by
striking neuroprotective effects in vitro and in the rodent
central nervous system in vivo. We have undertaken the
present study to determine if lithium exerts neurotrophic/
neuroprotective effects in the human brain in vivo.
Methods: Using quantitative proton magnetic resonance
spectroscopy, N-acetyl-aspartate (NAA) levels (a putative
marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medicationfree bipolar affective disorder patients and 9 healthy
volunteers). Regional brain NAA levels were measured at
baseline and following 4 weeks of lithium (administered in
a blinded manner).

Results: A significant increase in total brain NAA concentration was documented (p , .0217). NAA concentration increased in all brain regions investigated, including
the frontal, temporal, parietal, and occipital lobes.
Conclusions: This study demonstrates for the first time
that Li administration at therapeutic doses increases brain
NAA concentration. These findings provide intriguing
indirect support for the contention that chronic lithium
increases neuronal viability/function in the human brain,
and suggests that some of Li’s long-term beneficial effects
may be mediated by neurotrophic/neuroprotective events.
Biol Psychiatry 2000;48:1– 8 © 2000 Society of Biological Psychiatry
Key Words: bcl-2, lithium, bipolar mood disorder, magnetic resonance spectroscopy, neuroprotection, N-acetylaspartate

From the Departments of Psychiatry and Behavioral Neurosciences (GJM, JMB,
KH, GC, NS-B, IBW, MWF, SK, DAG, LJ, HKM), Radiology (GJM), and
Pharmacology (HKM) and the Cellular and Clinical Neurobiology Program
(GJM, HKM), Wayne State University School of Medicine, Detroit, Michigan.
Address reprint requests to Gregory J. Moore, Ph.D., Wayne State University
School of Medicine, Dept. of Psychiatry and Behavioral Neurosciences, 4201
St. Antoine UHC 9B-28, Detroit MI 48201.
Received July 13, 1999; revised December 28, 1999; accepted December 31, 1999.

© 2000 Society of Biological Psychiatry

Introduction

B

ipolar affective disorder (BD, manic-depressive illness) is a common, severe, chronic, and life-threatening illness (Goodwin and Jamison 1990). Despite the
devastating impact that this illness has on the lives of
millions, there is still a dearth of knowledge concerning its
etiology and pathophysiology. The discovery of lithium’s
efficacy as a mood-stabilizing agent revolutionized the
treatment of patients with BD. Indeed, it is likely that the
remarkable efficacy of lithium served to spark a revolution
that has reshaped not only medical and scientific but also
popular concepts of severe mental illnesses. After more
than three decades of use in North America, lithium
continues to be the mainstay of treatment for this illness,
both for the acute manic phase and as prophylaxis for
recurrent manic and depressive episodes (Goodwin and

Jamison 1990). Interestingly, long-term lithium treatment
not only reduces the excessive mortality from suicide
observed in the illness but also reduces cardiovascular
mortality (Baldessarini et al 1999). The effect on the
broader community is highlighted by one estimation that
the use of lithium saved the United States $4 billion in the
period 1969 –1979, by reducing associated medical costs
and restoring productivity (Reifman and Wyatt 1980).
Despite its role as one of psychiatry’s most important
treatments (Goodwin and Jamison 1990), the biochemical
basis for lithium’s therapeutic effects remains to be fully
elucidated (Jope 1999; Manji et al 1995). It has been
increasingly appreciated in recent years that the long-term
treatment of complex neuropsychiatric disorders likely
involves the regulation of gene expression in critical
neuronal circuits. In this context it is noteworthy that a
recent mRNA reverse transcription polymerase chain reaction differential display study has shown that chronic
(4-week) lithium administration robustly increases the
levels of the neuroprotective protein bcl-2 in rat frontal
cortex (Chen et al 1999). Subsequent studies have shown

that chronic lithium also increases the levels of bcl-2 in
areas of hippocampus and striatum in vivo, as well as in
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G.J. Moore et al

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rodent and human neuronal cells in culture (Chen and
Chuang 1999; Manji et al 1999).
Bcl-2 is the acronym for the B-cell lymphoma/leukemia-2 gene; this gene was first discovered because of its
involvement in B-cell malignancies, where chromosomal
translocations activate the gene in the majority of follicular non-Hodgkin’s B-cell lymphomas (Adams and Cory
1998; Bruckheimer et al 1998 and references therein;
Merry and Korsmeyer 1997). A role for bcl-2 in protecting
neurons from cell death is now supported by abundant

evidence; thus, bcl-2 has been shown to protect neurons
from a variety of insults in vitro, including growth factor
deprivation, glucocorticoids, ionizing radiation, and oxidant stressors, such as hydrogen peroxide, tert-butylhydroperoxide, reactive oxygen species, and buthionine sulfoxamine (Adams and Cory 1998; Bruckheimer et al
1998). In addition to these potent in vitro effects, bcl-2 has
been shown to prevent cell death in vivo in a variety of
experimental paradigms. In transgenic models, bcl-2 overexpression has been shown to prevent motor neuron death
induced by facial nerve axotomy and sciatic nerve axotomy, and to protect from the deleterious effects of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or focal
ischemia; interestingly, neurons that survive ischemic
lesions or traumatic brain injury in vivo show upregulation
of bcl-2 (Chen et al 1997; Lawrence et al 1996; Merry and
Korsmeyer 1997; Yang et al 1998, and references therein).
Overexpression of bcl-2 has also recently been shown to
prolong survival and attenuate motor neuron degeneration
in a transgenic animal model of amyotrophic lateral
sclerosis (Kostic et al 1997). Most recently, it has been
clearly demonstrated that not only does bcl-2 overexpression protect against apoptotic and certain types of necrotic
cell death, it can also promote regeneration of axons in the
mammalian central nervous system (CNS), leading to the
intriguing postulate that bcl-2 acts as a major regulatory

switch for a genetic program that controls the growth of
CNS axons (Chen et al 1997).
Consistent with the robust increases in bcl-2 levels,
lithium has recently been shown to protect neurons from
the deleterious effects of a variety of insults both in vitro
and in vivo. Thus, lithium robustly protects against the
toxic effects of glutamate, N-methyl-D-aspartate (NMDA)
receptor activation, low potassium, serum/nerve growth
factor deprivation, thapsigargin, and 1-methyl-4-phenylpyridinium–induced cell death (reviewed in Chen and
Chuang 1999; Manji et al 1999 and references therein;
Nonaka et al 1998a). Lithium’s protective effects against
the deleterious effects of glutamate and NMDA receptor
activation have also been demonstrated to occur in hippocampal and cortical neurons in culture, and in addition
to these “harsh insults,” lithium has been shown to exert
protective effects in a more “naturalistic” paradigm, age-

induced cerebellar granule cell death (Nonaka et al
1998b). Most recently, chronic lithium was shown to exert
dramatic protective effects against middle cerebral artery
occlusion, reducing not only the infarct size (56%), but

also the neurological deficits (abnormal posture and
hemiplegia)(Nonaka and Chuang 1998).
Our study was undertaken to determine if lithium may
also exert neurotrophic/neuroprotective effects in the human brain in vivo. Proton magnetic resonance spectroscopy (MRS) is a tool which provides a noninvasive
window to functional brain neurochemistry. N-Acetylaspartate (NAA) is one of the many neurochemical compounds that can be quantitatively assessed via MRS. NAA
is the predominant resonance in the proton MRS spectrum
of the normal adult human brain, and although the functional role of this amino acid has not been definitively
determined, NAA is a putative neuronal marker (Birken
and Oldendorf 1989), localized to mature neurons and not
found in mature glial cells, cerebrospinal fluid (CSF), or
blood. A relative decrease in this compound may reflect
decreased neuronal viability, neuronal function, or neuronal loss (for an excellent recent review of NAA see Tsai
and Coyle 1995). In this prospective longitudinal study,
we have utilized quantitative in vivo proton MRS to test
the hypothesis that similar to the preclinical findings in the
rodent brain and in human neuronal cells in culture,
chronic lithium increases neuronal viability/function in the
human brain in vivo, as evidenced by increased CNS
levels of NAA in both medication-free BD patients and
healthy subjects.

Methods and Materials
Subjects
BIPOLAR DISORDER PATIENTS (N 5 12). Adult patients
who gave written informed consent as approved by the institutional review board were eligible for this study. In addition, all
eligible patients were required to meet diagnostic criteria for
Bipolar Mood Disorder Most Recent Episode Depressed. The
diagnosis was determined using the structured interview for
DSM-IV (SCID). Patients were excluded if they met diagnostic
criteria for any other DSM-IV Axis I disorder during the 21⁄2
years preceding the index episode. In addition, patients with
Psychoactive Substance Abuse or Dependence within 1 year of
the index episode were excluded. Patients were also excluded
from the study if they had any of the following medical
conditions, which may put them at greater risk for side effects
from lithium: 1) renal disease; 2) hepatic disease; 3) hematological disease; or the MRS procedure: 1) a cardiac pacemaker; 2)
brain surgery for an aneurysm; 3) recent major surgery; 4) the
presence of ferromagnetic implanted devices, such as neurostimulators; or 5) metal fragments in or near the eye or brain.
The effects of lithium on regional brain NAA levels were
investigated in 12 patients (mean age 36.3 years, range 22–56

Lithium Increases N-Acetyl-Aspartate

years, seven female, five male) who met the criteria outlined
above. Eleven of these patients had a diagnosis of Bipolar I
(history of Major Depression plus Mania) and one had a
diagnosis of Bipolar II (history of Major Depression and Hypomania). Upon admission to the inpatient research unit, the
subjects were administered blinded research capsules four times
per day, tapered off any previous medications (through these
capsules), and underwent a minimum 14-day drug washout
period (depending on the half-lives of the previous treatment
medications). On completion of the washout period, the patients
had their affective symptomatology reassessed with the Hamilton
Depression Rating Scale (HAM-D; Hamilton 1967) by trained
blinded raters. All patients remained depressed following the
washout period (HAM-D mean 18.75, range 11–29). The patients
then underwent a baseline MRS scan (see neuroimaging methods
described below) prior to the initiation of lithium treatment again
through blinded research capsules. Lithium treatment was initiated and titrated to obtain a therapeutic plasma level
(;0.8meq/L) over the first week of treatment. Quantitative

proton (1H) MRS was utilized to measure brain NAA levels in
the patients at baseline and after chronic (;4 weeks) blinded
lithium administration.
HEALTHY VOLUNTEERS (N 5 9). Healthy adult subjects
who gave written informed consent as approved by the institutional review board were eligible for this study. Subjects were
free of any personal or family history of psychiatric disorders,
including psychoactive substance abuse or dependence. In addition, they were healthy and free of any significant neurological,
cardiovascular, respiratory, or endocrine disorders and had no
history of head trauma. The subjects were free of all medications
(including health food supplements) for at least 2 weeks before
beginning the study and had no factors (described above) that
would preclude lithium administration or MR scanning. A total
of nine healthy adults (mean age 27.1 years, range 18 – 48 years,
6 female, 3 male) completed the identical lithium administration
and MRS scanning protocol with the timetable described above.

MRS Protocol
Quantitative single voxel 1H MRS exams were performed using
a 1.5T clinical scanner (GE Signa/Horizon 5.7, Milwaukee, WI).
A Stimulated Echo Acquisition Mode (STEAM) pulse sequence

(Frahm et al 1987) was used to acquire spectra using the
following acquisition parameters and also included unsuppressed
water reference scans for neurochemical quantitation: an echo
time of 30 msec, a modulation time of 13.7 msec, a repetition
time of 2 sec, 8 step phase cycle, 2048 points, a spectral width of
2500 Hz, and 128 averages for a total acquisition time of
approximately 5 min. Spectra were acquired from approximately
8 mL regions of interest (ROIs) in the right frontal, left temporal,
central occipital, and left parietal lobes (see Figure 1). Special
care was taken to place the ROIs in identical locations for the
exams (baseline and 4 weeks of lithium) using a systematic
approach that referenced voxel position to readily identifiable
anatomical gyral landmarks within the brain.
Additional procedures were undertaken to evaluate the precision of the voxel placement from scan to scan in this longitudinal

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study and to control for potential partial voluming effects, which
may potentially confound any MRS findings. We utilized a
simple robust semi-automated image segmentation approach to
determine the relative percentage of the various components,
namely gray matter (GM), white matter (WM), and CSF making
up the voxel (Moore et al, in press).

Quantitative MRS Anaylsis
The NAA resonance at 2.02 ppm, which also includes a minor
contribution from N-acetyl-aspartyl-glutamate (Koller et al
1984), was identified in each of the spectra. The area under the
resonance is proportional to the concentration of the compound.
Individual peak areas were fit using time domain analysis
software (deBeer et al 1992; van den Boogaart et al 1994) and the
concentration of NAA is reported in arbitrary quantitative units
as a ratio to brain water concentration (3104/water). This water
referencing method has been used in the field for over a decade
and has been validated by a number of research groups (Barker
et al 1993; Christiansen et al 1993; Frahm et al 1990; Hennig et
al 1992; Hetherington et al 1996; Klose 1990; Soher et al 1996;
Thulborn and Ackerman 1983). The analysis software is publicly
available (http://carbon.uab.es/mruiwww) and eliminates much
of the subjectivity previously involved in determining spectral
peak areas.
Briefly, the software performs an automated fit of the unsuppressed water peak to determine its peak area and also uses the
phase of the water peak to apply an automated zero order phase
correction to the metabolite data. Following this, the user enters
a priori information regarding the neurochemical data, to give the
software starting values for its fitting process. The a priori
information given includes the expected chemical shifts for each
of the major chemical compounds appearing in the typical proton
brain spectrum as well as a starting linewidth determined by the
corresponding water linewidth. The chemical shift values given
to the program are based on literature values (Barker et al 1994;
Frahm et al 1989; Kreis et al 1993; Michaelis et al 1993;
Narayana et al 1989). With this input, the software then attempts
to fit the spectrum and then displays the results both visually and
in a file that can then be pasted into a spreadsheet analysis
program. The visual and quantitative results are inspected for
goodness of fit and either accepted or reiterated for improvement.
Most spectra (approximately 80%) required only one iteration to
achieve a satisfactory fit, with the majority of the others being
successful after two iterations. The analyzers were trained to
accept a fit if the residual showed predominately unstructured
noise. The areas of the water peak and neurochemical peaks are
then entered into a spreadsheet for analysis, and quantitative
neurochemical concentrations are then reported in arbitrary units
relative to brain water concentration. We specifically did not
attempt to correct for water and neurochemical relaxation effects
with this technique, as obtaining these values on each of our
subjects would have been time prohibitive (measurement time
would take an additional 2 hours in each subject). We have,
however, utilized acquisition parameters that minimize the uncertainty in our neurochemical concentration estimates due to
relaxation effects. Specifically, we used a short echo time of 30
msec to minimize T2 signal decay and a standard repetition time

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G.J. Moore et al

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Figure 1. Voxel placement for each region investigated with proton magnetic resonance spectroscopy. (a) Frontal lobe. (b) Parietal
lobe. (c) Occipital lobe. (d) Temporal lobe.

of 2 sec to minimize T1 error resulting from collecting spectra
under less than fully relaxed conditions. This is a common
trade-off in clinical research studies.
Two research assistants trained in nuclear magnetic resonance
spectral analysis using this protocol evaluated the data in this
study. The individuals were blind to the study information and to
each others’ results. Intra-class correlation coefficient analysis
revealed an inter-rater reliability of greater than 98% for in vivo
quantitative measurement of brain NAA concentration.

Data Analysis
Changes in the NAA concentration with lithium administration
were assessed using a within-subjects repeated measures analysis
of variance design (RM-ANOVA). Reported p values are two
tailed. N-Acetyl-aspartate values were normalized to baseline to
control for individual differences among subjects and diagnostic
groups and the known regional variability of NAA in the
different brain regions (Kreis et al 1993). N-Acetyl-aspartate
changes are reported as a percent difference compared to
baseline values for all analyses. Comparisons among groups
were performed using t tests.

Results
Of the 168 potential in vivo proton brain spectra (four
brain regions at two time points for each of the 21
subjects), 146 (87%) were available and judged to be of
adequate quality to undergo quantitative analysis. Two
subjects (both BD patients) failed to complete the chronic
time point scans (loss of eight spectra), and 14 other
spectra were discarded because of poor quality due to
inadequate water suppression, subject motion during the
scan, or magnetic susceptibility artifacts. The output of the
spectral analysis program and a typical MR spectrum is
shown in Figure 2. Voxel content within each ROI
remained stable across the two time points, repeated
measures analysis of variance revealed there was no
significant differences over time for GM, WM, or CSF.
Individual analysis of the combined data for voxel tissue
content over time demonstrated that voxel content was
highly correlated and highly significant (baseline vs.
chronic r 5 0.93, p , .0001).
No significant differences in baseline NAA concentra-

Lithium Increases N-Acetyl-Aspartate

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5

Figure 3. Total brain N-acetyl-aspartate (NAA) concentration is
plotted for the two time points (baseline and chronic lithium
treatment [;4 weeks]). *p 5 .0217 vs. baseline.

Figure 2. Typical frontal lobe proton magnetic resonance spectroscopy spectrum from a bipolar patient and example of quantitative analysis method. The bottom trace is the original proton
magnetic resonance spectrum. The spectral analysis software
models the entire spectrum (next trace up), followed by a fit of
the individual peaks (next trace up). The uppermost trace in each
panel shows the residual component, which remains after the
peak fitting procedure is completed. Ideally this should consist
only of unstructured noise to achieve optimal quantitative results.
MI, myo-inositol; Cho, choline compounds; Cr, creatine/phosphocreatine; Glx, glutamate/glutamine/g-aminobutyric acid;
NAA, N-acetyl-aspartate.

(74%) had increased NAA levels, 1 (5%) showed no
change (61%), and 4 (21%) showed a small decrease.
Examining data on a regional basis again together with
voxel gray matter content segmentation results, revealed
an interesting finding that the percentage of NAA increase
per voxel gray matter content was highest in the frontal
lobe region. Furthermore, examining the BD patient data
separately revealed an NAA increase per voxel gray
matter content two-fold higher in both the frontal and
temporal lobe regions compared to the parietal and occipital regions; however, these regional findings should be
considered speculative as they failed to reach statistical
significance in this small sample.

Discussion
tion were found between the healthy volunteer and patient
groups (using unnormalized NAA concentrations), so data
from both groups were combined to increase the power of
the study. Four weeks of lithium administration resulted in
a small (;5%) but significant increase of total brain NAA
concentration (RM-ANOVA, F 5 5.528, p 5 .0217; see
Figure 3). There was no correlation between lithium levels
and NAA increases. All brain regions investigated demonstrated an increase in NAA over the course of the study
(Figure 4).
When regional brain NAA increases were examined
together with the regional voxel image segmentation data,
we noted a significant positive correlation between increased NAA and the voxel gray matter content (r 5
0.967, p 5 .033; Figure 4), indicating that NAA increases
were occurring primarily in CNS gray matter. The percentage of the NAA increase with lithium administration
was not significantly different between the volunteer and
patient groups either on a total brain or regional basis. Of
the 19 completing both the acute and chronic scans, 14

This study demonstrates for the first time that chronic Li
administration at therapeutic doses increases NAA concentration in the human brain in vivo. These findings
provide intriguing indirect support for the contention that,
similar to the findings observed in the rodent brain and in
human neuronal cells in culture, chronic lithium increases
neuronal viability/function in the human brain, and suggests that some of Li’s long-term beneficial effects may be
mediated by neurotrophic/neuroprotective events.
Although the magnitude of the increase in brain NAA
with lithium administration over the course of this 4-week
trial is small (;5%), a recent in-depth study by Brooks
and colleagues (Brooks et al 1999) investigating the
reproducibility of in vivo proton MRS in repeated scans
convincingly documented that with 20 subjects, in vivo
proton MRS can reliably detect a mean change in NAA
concentration of 3% between two scans. The acquisition
protocol and data processing used in the Brooks study are
identical to the protocols used in this study, and we have
obtained similar or greater reliability measures in our own

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G.J. Moore et al

Figure 4. N-Acetyl-aspartate (NAA) increases on a regional basis (left); NAA increase positively correlates with percent voxel gray
matter content (right). -■-, occipital; -●-, temporal; -Œ-, frontal; -}-, parietal.

test-retest quality assurance measurements both in phantoms and in normal volunteers.
A number of studies have now shown that initial
abnormally low brain NAA measures may increase and
even normalize with remission of CNS symptoms in
disorders such as demyelinating disease, amyotrophic
lateral sclerosis, mitochondrial encephalopathies, and human immunodeficiency virus (HIV) dementia. (Davie et al
1994; De Stefano et al 1995a, 1995b; Ellis et al 1997;
Holshouser et al 1995; Kalra et al 1998; Pavlakis et al
1998; Salvan et al 1997; Takanashi et al 1997; Vion-Dury
et al 1995). In the case of temporal lobe epilepsy in which
proton MRS often reveals abnormal NAA measures in the
contralateral hippocampus, several studies have shown
normalization of these measures following successful
neurosurgical removal of the ipsilateral anterior temporal
lobe to control seizures (Cendes et al 1997; Da Silva et al,
unpublished data, 1999; Hugg et al 1996;). In the majority
of these studies, the magnitude of increase in NAA
reported is quite similar to that reported in our study.
There is now considerable literature support from a variety
of sources demonstrating significant reductions in regional
CNS volume and cell numbers (both neurons and glia)
associated with mood disorders. Thus, volumetric neuroimaging studies have demonstrated reduced basal ganglia volume and reduced temporal lobe volume (including the
hippocampus) in mood disorders (reviewed in Ketter et al
1997; Soares and Mann 1997). Within the frontal lobe,
volumetric neuroimaging studies have also consistently
shown reduced volumes in mood disorders. In particular,
recent volumetric MRI studies in familial bipolar depressives
and familial unipolar depressives have demonstrated reductions in the mean gray matter volume of approximately 40%

in the prefrontal cortex ventral to the genu of the corpus
callosum (Drevets et al 1997). Intriguingly, lithium-treated
subjects demonstrate smaller reductions in prefrontal cortical
volumes (personal communication from W. Drevets to H.K.
Manji, March 1999). In addition to the accumulating neuroimaging evidence, recent postmortem studies of the prefrontal cortex have also demonstrated reduced CNS volume and
cell numbers in mood disorders. Rajkowska (1997) has used
three-dimensional cell counting and morphological techniques to demonstrate significantly reduced sizes and densities of both neurons and glia in several distinct areas in mood
disorder subjects (Rajkowska et al 1999). Intriguingly, neuronal dimunition was especially pronounced in layer II of the
rostral orbitofrontal region (Rajkowska et al 1999), an area
where we have observed among the largest lithium-induced
increases in bcl-2 immunoreactivity (Chen et al 1999; Manji
et al 1999). Also in the prefrontal cortex, Ongur and colleagues (Ongur et al 1998) have recently reported a histological study examining the cellular composition of area sg24
located in the subgenual prefrontal cortex. They found
striking reductions in glial cell numbers in patients with
familial major depression (24% reductions) and BD (41%
reductions), compared to controls. This is a particularly
striking finding, as it is consistent with neuroimaging findings showing cortical volume loss in this same region on
volumetric magnetic resonance imaging in a similar diagnostic group (Drevets et al 1997). Together, the preponderance
of the data from the neuroimaging studies and the growing
body of postmortem evidence presents a convincing case that
there is indeed a reduction in regional CNS volume, accompanied by cell atrophy/loss, in mood disorders; these findings, along with the results of our study, raise the possibility
that chronic lithium may exert some of its long term benefits

Lithium Increases N-Acetyl-Aspartate

via hitherto underappreciated neurotrophic/neuroprotective
effects.
Interestingly, recent findings from Duman and associates have demonstrated that chronic administration of a
variety of antidepressants increases the expression of
BDNF (brain derived neurotrophic factor), and its receptor
trkB in certain populations of neurons in the hippocampus
(Duman et al 1997). Moreover, Smith and associates
(Smith et al 1995) have also recently demonstrated that
antidepressants increase the locus coeruleus expression of
another neurotrophic factor, neurotrophin 3.
In conclusion, we report here the novel observation that
chronic lithium administration increases brain NAA levels.
Clearly a larger longitudinal study with a follow-up of BD
patients over a period of years will be required to determine
if lithium indeed has a long term neurotrophic/neuroprotective effect in BD patients. The increases in NAA levels, the
robust increases in bcl-2 levels, as well as the clear evidence
for neuroprotective effects in preclinical studies also suggest
that lithium may have utility in the long term treatment of
certain neurodegenerative disorders.
Supported in part by a NARSAD Young Investigator grant to GJM and
grants from the Theodore and Vada Stanley Foundation, the State of
Michigan (Joseph Young, Sr.), and the National Institutes of Health
(NIMH MH-59107) to HKM and GJM.
The authors acknowledge the invaluable assistance of the Nursing and
Research Staff of the Neuropsychiatric Research Unit, and Ms. Caroline
Zajac Benitez for outstanding editorial assistance.

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