Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder

doi:10.1016/j.biopsych.2004.06.012

Biological Psychiatry

Volume 56, Issue 5, 1 September 2004, Pages 340-348

https://doi.org/10.1016/j.biopsych.2004.06.012 Get rights and content

Background

Prior work reported elevated gray matter (GM) lactate and Glx (glutamate + glutamine + GABA) concentrations in unmedicated patients with bipolar disorder (BP) compared with healthy controls (HC). This study examined whether lithium (Li) and valproic acid (VPA) treatment modulated these chemicals.

Methods

A subset of previously reported BP patients were treated with Li (n = 12, 3.6 ± 1.9 months) or VPA (n = 9, 1.4 ± 1.7 months) and compared untreated HC subjects (n = 12, 2.9 ± 2.4 months) using proton echo-planar spectroscopic imaging. Regression analyses (voxel gray/white composition by chemistry) were performed at each time point, and change scores computed. Metabolite relaxation and regions of interest (ROI) were also examined.

Results

Across treatment, Li-treated BP subjects demonstrated GM Glx decreases (Li–HC, p = .08; Li–VPA p = .04) and GM myo-inositol increases (Li–HC p = .07; Li–VPA p = .12). Other measures were not significant. Serum Li levels were positively correlated with Glx decreases at the trend level.

Conclusions

Li treatment of BP was associated with specific GM Glx decreases and myo-inositol increases. Findings are discussed in the context of cellular mechanisms postulated to underlie Li and VPA therapeutic efficacy.

Section snippets

Subjects

Subjects were recruited through advertisements or direct referral to the Bipolar Research Programs at McLean and Massachusetts General Hospitals in Boston (CD, ALS) or at the University of Washington Center for Anxiety and Depression (DLD). Written informed consent, approved through the institutional review board at each site, was obtained from all subjects before study participation. Participants, a subgroup of subjects studied at baseline in the medication-free state (Dager et al 2004), were

Mood characteristics

At baseline, Li- and VPA-assigned treatment groups showed elevated HAM-D values compared with the HC group [Li 15.0 ± 9.3, VPA 24.1 ± 3.9, HC 1.3 ± 1.1; F(2,30) = 38.48, p < .001; Tukey post hoc = HC–Li p < .001, HC–VPA p < .001]. The VPA-assigned sample also demonstrated greater baseline HAM-D scores compared with the Li-assigned group (Li–VPA p = .005). For Y-MRS ratings, Li- and VPA-assigned groups were elevated compared with HC subjects but did not differ from one another [Li 4.8 ± 4.5, VPA

Discussion

In this longitudinal treatment study, Li administration decreased GM Glx concentrations at the trend level compared with the HC group and significantly in comparison to VPA subjects. The Li-treated BP subjects also exhibited a reduced Glx slope between WM and GM compartments compared with both HC and VPA groups. Lac changes were not demonstrated for either Li or VPA treatment groups. Nonsignificant changes in mI, in the opposite direction to that observed for Glx, were observed in the Li

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Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels.
We studied single voxel ¹H-MRS measures of DLPFC Glu and Glx levels of 48 healthy participants and 55 inpatients with a major depressive episode in course of Bipolar Disorder, a subset of which (N = 23) underwent three cycles of repeated TSD + LT and were evaluated before and after treatment. Treatment effects of mood and on Glu and Glx concentrations were analyzed in the context of the Generalized Linear Model (GLM), correcting for age, sex and ongoing lithium treatment.
Higher concentration of Glu (adjusted Z = −2189, p = 0,0285) and Glx (adjusted Z = −3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p < 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χ² = 4.619, p = 0.0316) and in Glx levels (LR χ² = 4.486, p = 0.0341).
A reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.
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The diagnosis and treatment of bipolar depression (BDep) poses complex clinical challenges for psychiatry. Proton magnetic resonance spectroscopy (¹H-MRS) is a useful imaging tool for investigating in vivo levels of brain neuro-metabolites, critical to understanding the process of mood dysregulation in Bipolar Disorder. Few studies have evaluated longitudinal clinical outcomes in BDep associated with ¹H-MRS metabolic changes. This study aimed to longitudinally assess brain ¹H-MRS metabolites in the anterior cingulate cortex (ACC) correlated with improvement in depression (from BDep to euthymia) after lithium treatment in BDep patients versus matched healthy controls (HC). Twenty-eight medication-free BDep patients and 28 HC, matched for age and gender, were included in this study. All subjects were submitted to a 3-Tesla brain ¹H-MRS scan in the ACC using a single-voxel (8cm³) PRESS sequence at baseline. At follow-up (6 weeks), 14 BDep patients repeated the exam in euthymia. Patients with current BDep had higher baseline Myo-inositol/Cr (mI/Cr) and Choline/Cr (Cho/Cr) compared to HC. After six weeks, mI/Cr or Cho/Cr levels in subjects that achieved euthymia no longer differed to levels in HC, while high Cho/Cr levels persisted in non-responders . Elevated ACC mI/Cr and Cho/Cr in BDep might indicate increased abnormal membrane phospholipid metabolism and phosphatidylinositol (PI) cycle activity. Return of mI/Cr and Cho/Cr to normal levels after lithium-induced euthymia suggests a critical regulatory effect of lithium targeting the PI cycle involved in mood regulation.
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Valproic acid is used to prevent mania recurrence in BD. Its preventive effect has not been exactly defined [51]. Like Li, VPA may be used as a therapeutic drug for BD patients [52].
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The neurobiological relevance for the occurrence of comorbid mood and substance abuse disorders has not been fully elucidated. Considering the high levels of individuals who experience comorbidity in these areas as well as the negative associated outcomes, this is clearly an area that requires further in-depth investigation. Furthermore, findings from this area can help to inform drug abuse prevention and intervention efforts, and especially how they relate to populations with psychiatric symptoms.

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Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder

Background

Methods

Results

Conclusions

Section snippets

Subjects

Mood characteristics

Discussion

Neurochem Int

Neuropsychopharmacology

Psychiatry Res

Biol Psychiatry

Pharmacol Ther

Biochem Pharmacol

Biochem Pharmacol

J Affect Disord

J Affect Disord

Neurosci Lett

J Affect Disord

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Lancet

Brain Res

Eur Neuropsychopharmacol

Psychiatry Res

Seizure

Psychiatry Res

Brain Res

J Am Acad Child Adolesc Psychiatry

Neurosci Lett

Biol Psychiatry

Biol Psychiatry

Neuropsychopharmacology

Gen Pharmacol

Biol Psychiatry

The effects of lithium on myo-inositol levels in layers of frontal cerebral cortex, in cerebellum, and in corpus callosum of the rat

J Neurochem

Diagnostic and Statistical Manual Disorders

Differential effects of acute and short-term lithium administration on dialysate glutamate and GABA levels in the frontal cortex of the conscious rat

Synapse

Lithium treatment and suicide risk in major affective disordersUpdate and new findings

J Clin Psychiatry

LithiumEffect on [3H]spiperone binding, ionic content, and amino acid levels in the brain of rats

Neurochem Res

Toward a crystal-clear view of lithium's site of action

Proc Natl Acad Sci U S A

Functions of N-acetyl-L-aspartate and N-acetyl-L-aspartylglutamate in the vertebrate brainRole in glial cell-specific signaling

J Neurochem

N-acetylaspartate in the vertebrate brainMetabolism and function

Neurochem Res

The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease–like rats

Neurochem Res

Reduced plasma and CSF gamma-aminobutyric acid in affective illnessEffect of lithium carbonate

Biol Psychiatry

Reproducibility of 1H-MRS in vivo

Magn Reson Med

Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy

Bipolar Disord

Two-dimensional proton echo-planar spectroscopic imaging of brain metabolic changes during lactate-induced panic

Arch Gen Psychiatry