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Increased gray matter volume in lithium-treated bipolar disorder patients
Neuroscience Letters 329 (2002) 243–245 www.elsevier.com/locate/neulet
Increased gray matter volume in lithium-treated bipolar disorder patients Roberto B. Sassi a,b, Mark Nicoletti a,c, Paolo Brambilla a,c,d, Alan G. Mallinger a,e, Ellen Frank a,f, David J. Kupfer a,g, Matcheri S. Keshavan a, Jair C. Soares a,c,* a
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA b Department of Psychiatry, Institute of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil c Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA d Department of Psychiatry, University of Pavia School of Medicine, Pavia, Italy e Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA f Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA g Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA Received 19 April 2002; received in revised form 4 June 2002; accepted 6 June 2002
Abstract Lithium’s neurotrophic effects have been reported in several in vitro and ex vivo studies. Preliminary human studies with magnetic resonance imaging (MRI) and spectroscopy have recently provided evidence of lithium-induced increases in gray matter volumes and N-acetyl-aspartate levels. In order to further examine the hypothesis that lithium treatment would relate to detectable increases in gray matter brain content, we blindly measured gray and white matter volumes in MRI images of 12 untreated and 17 lithium-treated bipolar patients and 46 healthy controls. Using multivariate analysis of covariance with age and gender as covariates, we found that total gray matter volumes were significantly increased in lithium-treated (747.9 ^ 69.8 cm 3) compared with untreated patients (639.2 ^ 91.2 cm 3; F ¼ 10:6; d:f: ¼ 1; 25; P ¼ 0:003) and healthy individuals (675.8 ^ 61.8 cm 3; F ¼ 17:4; d:f: ¼ 1; 59; P , 0:001), suggesting in vivo effects of lithium on gray matter, which could possibly reflect lithium’s neurotrophic effects. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lithium; Bipolar disorder; Mood disorders; Magnetic resonance imaging; Gray matter; Neuroimaging
Bipolar mood disorder is a prevalent and life-threatening psychiatric illness, whose pathophysiology is still largely unknown. For decades, lithium has been the most effective treatment for bipolar disorder, with pronounced effects on both acute and long-term mood stabilization. Lithium exerts multiple actions on brain cells by affecting several cellular signaling pathways [3]. However, it is not clear which of these cellular actions is related to lithium’s therapeutic effects. Of major interest, lithium has been shown to have relevant neurotrophic and neuroprotective effects in vitro and ex vivo [4]. Indirect evidence from magnetic resonance (MR) studies also points to similar in vivo neurotrophic actions of * Corresponding author. Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel.: 11-210-567-5492; fax: 11-210-5673759. E-mail address: [email protected] (J.C. Soares).
lithium. Moore and colleagues [6] utilized proton MR spectroscopy to demonstrate increased levels of N-acetyl-aspartate (NAA), a brain chemical found only inside neurons, across several cortical regions, after 4 weeks of lithium treatment. Moore and colleagues [7], utilizing MR images, have also reported increased gray matter brain volume in bipolar patients after 4 weeks of lithium treatment. In order to further examine the possible influence of lithium on the volume of gray matter in the human brain, we conducted a cross-sectional study using high-resolution MRI images to measure gray and white matter volumes in 46 healthy controls (18 women; mean age ^ SD: 35.5 ^ 10.3 years), 12 untreated bipolar mood disorder patients (five women; 37.7 ^ 10.6 years), and 17 lithiumtreated bipolar patients (seven women; 31.1 ^ 8.8 years). This research study was approved by the University of Pittsburgh Institutional Review Board. All patients met the DSM-IV diagnostic criteria for bipolar disorder, without
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 61 5- 8
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R.B. Sassi et al. / Neuroscience Letters 329 (2002) 243–245
Fig. 1. Lithium-treated bipolar patients had significantly larger gray matter volume compared with untreated bipolar patients and healthy controls (MANCOVA, age and gender as covariates, P , 0:05).
other comorbid axis I diagnosis. Patients were considered untreated if they arrived at the outpatient clinic off all psychotropic medications for at least 2 weeks (in most cases, patients presented without medications due to noncompliance with prescribed treatment). The lithium-treated group had been on lithium as monotherapy for at least 2 weeks (most patients had been on lithium for several weeks; mean ^ SD: 131 ^ 250 weeks; median: 27 weeks). Patients or healthy controls with a lifetime history of alcohol or drug dependence, or alcohol or drug abuse in the 6 months preceding the MRI were excluded. 3D MRI images were obtained with a 1.5T-GE Signa magnet. Gray matter, white matter, and intracranial volumes (ICV) were measured by a trained rater, blindly to patient’s identity or group assignment, using a semi-automated method and following standardized procedures, after having achieved intra-class correlation coefficients for each of these measures of .0.90. Additional details on the utilized imaging methodology can be found elsewhere [1]. The three groups (healthy controls, untreated, and
lithium-treated bipolar patients) had comparable age (F ¼ 1:7; d:f: ¼ 2; P ¼ 0:2) and gender (x2 ¼ 0:4; d:f: ¼ 2; P ¼ 0:9) distributions. Lithium-treated and untreated bipolar patients had comparable age at onset of illness (mean age ^ SD: 21.3 ^ 7 and 17.7 ^ 7, respectively; F ¼ 0:3; d:f: ¼ 26; P ¼ 0:15), length of illness (17 ^ 10 and 14 ^ 8 years; F ¼ 0:2; d:f: ¼ 26; P ¼ 0:4), and number of previous affective episodes (16 ^ 15 and 16 ^ 18 episodes; F ¼ 0:6; d:f: ¼ 24; P ¼ 0:9). Lithiumtreated and untreated bipolar patients had comparable rates of mood disorders on a first-degree relative (eight of 17, and eight of 12, respectively; x2 ¼ 1:1; d:f: ¼ 1; P ¼ 0:3). However, there were significant differences between the two groups in mood state at the time of the MRI scan: 14 of 17 patients in the lithium-treated group were euthymic, whereas the remaining three were acutely depressed. Among the 12 untreated bipolar patients, four were euthymic, seven were acutely depressed and one was hypomanic (x2 ¼ 7:5; d:f: ¼ 2; P ¼ 0:02). Furthermore, there was a trend towards a significantly higher percentage of bipolar I patients in the lithium-treated (16 of 17) compared with the untreated (eight of 12; x2 ¼ 3:7; d:f: ¼ 1; P ¼ 0:054) group. Using age and gender as covariates, we found that lithiumtreated bipolar patients had larger intracranial and total gray matter brain volumes than untreated ones (Fig. 1). Moreover, lithium-treated patients presented larger intracranial and total gray matter brain volumes than healthy controls (Table 1). The finding of significantly increased gray matter volumes in lithium-treated bipolar patients compared with healthy controls persisted after taking into account ICV as a covariate for the analyses (multivariate analysis of covariance (MANCOVA), age, gender, and ICV as covariates; F ¼ 6:17; d:f: ¼ 1; 58; P ¼ 0:016). Furthermore, we repeated the analyses including bipolar subtype and mood status at the time of the MRI scan as covariates, and the results were similar: larger ICV (MANCOVA with age, gender, mood status and bipolar subtype (I or II) as covariates; F ¼ 5; d:f: ¼ 1; 23; P ¼ 0:03) and larger total gray matter volumes (F ¼ 9:1; d:f: ¼ 1; 23; P ¼ 0:006) in the lithium-treated compared with the untreated bipolar group. There was no correlation between lithium dose (mean ^ SD: 1111.8 ^ 356 mg/day; median: 900; range: 750–2100; Spearman’s correlation coefficient: 0.3; P ¼ 0:2) or length
Table 1 Intracranial, total gray and total white matter volumes a Groups/mean ^ SD
Healthy controls (n ¼ 46)
Untreated bipolar patients (n ¼ 12)
Lithium-treated bipolar patients (n ¼ 17)
ICV (cm 3) Total gray matter volume (cm 3) Total white matter volume (cm 3)
1458.7 ^ 126.6 675.8 ^ 61.8 476.7 ^ 68.7
1433.6 ^ 147.7 639.2 ^ 91.2 484.9 ^ 84.9
1552.6 ^ 132.6 b 747.9 ^ 69.8 b 487.9 ^ 68.7
a
MANCOVA with age and gender as covariates. Lithium-treated bipolar patients had larger intracranial (F ¼ 6; d:f: ¼ 1; 25; P ¼ 0:02) and total gray matter volumes (F ¼ 10:6; d:f: ¼ 1; 25; P ¼ 0:003) than untreated bipolar patients, and also larger intracranial (F ¼ 10:2; d:f: ¼ 1; 59; P ¼ 0:002) and total gray matter volumes (F ¼ 17:4; d:f: ¼ 1; 59; P , 0:001) than healthy controls. b
R.B. Sassi et al. / Neuroscience Letters 329 (2002) 243–245
of lithium treatment (mean ^ SD: 131 ^ 250 weeks; median: 27; range: 2–1000; Spearman’s correlation coefficient: 20.14; P ¼ 0:6) and gray matter brain volume. No significant differences in total white matter volumes were observed across the three groups (Table 1). These intriguing results are in line with previous reports of increased gray matter volume [7] and NAA levels [6] in lithium-treated subjects. Since no significant effects of lithium administration on white matter volumes were found in our sample, we believe that the increased ICV in the lithium-treated group are primarily due to an increase in total gray matter volume. It is important to consider, however, that we are not able to rule out the possibility that, for any spurious reason, our lithium-treated sample suffered from a selection bias towards larger premorbid global cerebral volumes. Considering that age and gender distribution were similar among the three groups, this possibility seems unlikely. Since we did not measure skull diameter or volume, or cerebrospinal fluid volume, we are not able to assure that increased gray matter volume is the single explanation for the increased ICV we found among the lithium-treated patients. Nonetheless, it is important to consider that the findings of increased gray matter volume in lithium-treated patients persisted even after controlling for ICV, i.e. using ICV (as well as age and gender) as a covariate in the analyses. In the present study, lithium-treated patients had total gray matter volumes greater not only than untreated patients, but also greater than age- and sex-matched healthy controls. These findings may represent detectable brain effects of lithium, and are in line with recent evidence that lithium exerts neuroprotective and neurotrophic effects, and could possibly prevent or partly reverse regional gray matter deficits that may be linked to bipolar illness. Lithium induces the expression of bcl-2 on neurons [5], an action that is also shared by another mood-stabilizer, valproate [2]. An increase in neuropil volume as a consequence of the trophic actions of bcl-2 in the brain [4] is an appealing explanation for the results we obtained. However, osmotic effects of lithium, leading to neuron swelling and consequent increased gray matter brain volume cannot be ruled out. Nonetheless, we believe that a purely osmotic action of lithium would not be restricted only to gray matter and would also influence the white matter volume; therefore, such effects appear less likely. Our results, nonetheless, should be interpreted with caution. The magnitude of the gray matter increase is somewhat higher than the difference reported by Moore et al. [7]. We believe that key methodological differences between our study and the study by Moore et al. [7] might explain these discrepancies. First, Moore et al. performed a longitudinal evaluation of the same group of patients, pre- and post-lithium treatment, whereas our study compared two distinct groups of patients in a cross-sectional fashion. Second, in the study by Moore et al., all patients received only 4 weeks of lithium treatment, whereas in our report, the
245
length of continuous lithium treatment was, in most cases, several weeks (mean ^ SD: 131 ^ 250 weeks; median: 27 weeks). Although we did not find a correlation between length of treatment and gray matter volume, perhaps due to the wide variance and relatively small sample size, it is not possible to rule out the possibility that this variable may be partially responsible for the discrepancy in the magnitude of gray matter changes between our study and theirs [7]. In a previous report with a smaller subject sample [1], we identified a trend towards increased total gray matter volume in lithium-treated when compared with drug-free bipolar patients. The inclusion of additional subjects to compose a larger sample in the present study allowed us to confirm and expand the preliminary results we reported. We are currently conducting a prospective MRI study of the effects of lithium in healthy controls, to find out if the actions of lithium on gray matter volumes are also identifiable in subjects without psychiatric disorders. Future studies should assess whether valproate and other medications also effective in the treatment of bipolar disorder cause similar increases in brain gray matter in vivo, and further investigate the clinical relevance of these findings. Furthermore, longitudinal studies that attempt to examine the effects of lithium on gray matter volumes in specific brain regions implicated in the pathophysiology of bipolar disorder will be of utmost importance. This study was supported by NIMH grants MH01736, MH29618, and MH30915, the Theodore and Vada Stanley Foundation, NARSAD, and CAPES Foundation (Brazil).
[1] Brambilla, P., Harenski, K., Nicoletti, M., Mallinger, A.G., Frank, E., Kupfer, D.J., Keshavan, M.S. and Soares, J.C., Differential effects of age on brain gray matter in bipolar patients and healthy individuals, Neuropsychobiology, 43 (2001) 242–247. [2] Chen, G., Zeng, W.Z., Yuan, P.X., Huang, L.D., Jiang, Y.M., Zhao, Z.H. and Manji, H.K., The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS, J. Neurochem., 72 (1999) 879–882. [3] Lenox, R.H. and Hahn, C.G., Overview of the mechanism of action of lithium in the brain: fifty-year update, J. Clin. Psychiatry, 61 (2000) 5–15. [4] Manji, H.K., Moore, G.J. and Chen, G., Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness, Biol. Psychiatry, 48 (2000) 740–754. [5] Manji, H.K., Moore, G.J. and Chen, G., Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness, J. Clin. Psychiatry, 61 (2000) 82–96. [6] Moore, G.J., Bebchuk, J.M., Hasanat, K., Chen, G., SerajiBozorgzad, N., Wilds, I.B., Faulk, M.W., Koch, S., Glitz, D.A., Jolkovsky, L. and Manji, H.K., Lithium increases N-acetylaspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol. Psychiatry, 48 (2000) 1–8. [7] Moore, G.J., Bebchuk, J.M., Wilds, I.B., Chen, G., Manji, H.K. and Menji, H.K., Lithium-induced increase in human brain grey matter, Lancet, 356 (2000) 1241–1242.
Increased gray matter volume in lithium-treated bipolar disorder patients Roberto B. Sassi a,b, Mark Nicoletti a,c, Paolo Brambilla a,c,d, Alan G. Mallinger a,e, Ellen Frank a,f, David J. Kupfer a,g, Matcheri S. Keshavan a, Jair C. Soares a,c,* a
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA b Department of Psychiatry, Institute of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil c Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA d Department of Psychiatry, University of Pavia School of Medicine, Pavia, Italy e Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA f Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA g Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA Received 19 April 2002; received in revised form 4 June 2002; accepted 6 June 2002
Abstract Lithium’s neurotrophic effects have been reported in several in vitro and ex vivo studies. Preliminary human studies with magnetic resonance imaging (MRI) and spectroscopy have recently provided evidence of lithium-induced increases in gray matter volumes and N-acetyl-aspartate levels. In order to further examine the hypothesis that lithium treatment would relate to detectable increases in gray matter brain content, we blindly measured gray and white matter volumes in MRI images of 12 untreated and 17 lithium-treated bipolar patients and 46 healthy controls. Using multivariate analysis of covariance with age and gender as covariates, we found that total gray matter volumes were significantly increased in lithium-treated (747.9 ^ 69.8 cm 3) compared with untreated patients (639.2 ^ 91.2 cm 3; F ¼ 10:6; d:f: ¼ 1; 25; P ¼ 0:003) and healthy individuals (675.8 ^ 61.8 cm 3; F ¼ 17:4; d:f: ¼ 1; 59; P , 0:001), suggesting in vivo effects of lithium on gray matter, which could possibly reflect lithium’s neurotrophic effects. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lithium; Bipolar disorder; Mood disorders; Magnetic resonance imaging; Gray matter; Neuroimaging
Bipolar mood disorder is a prevalent and life-threatening psychiatric illness, whose pathophysiology is still largely unknown. For decades, lithium has been the most effective treatment for bipolar disorder, with pronounced effects on both acute and long-term mood stabilization. Lithium exerts multiple actions on brain cells by affecting several cellular signaling pathways [3]. However, it is not clear which of these cellular actions is related to lithium’s therapeutic effects. Of major interest, lithium has been shown to have relevant neurotrophic and neuroprotective effects in vitro and ex vivo [4]. Indirect evidence from magnetic resonance (MR) studies also points to similar in vivo neurotrophic actions of * Corresponding author. Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel.: 11-210-567-5492; fax: 11-210-5673759. E-mail address: [email protected] (J.C. Soares).
lithium. Moore and colleagues [6] utilized proton MR spectroscopy to demonstrate increased levels of N-acetyl-aspartate (NAA), a brain chemical found only inside neurons, across several cortical regions, after 4 weeks of lithium treatment. Moore and colleagues [7], utilizing MR images, have also reported increased gray matter brain volume in bipolar patients after 4 weeks of lithium treatment. In order to further examine the possible influence of lithium on the volume of gray matter in the human brain, we conducted a cross-sectional study using high-resolution MRI images to measure gray and white matter volumes in 46 healthy controls (18 women; mean age ^ SD: 35.5 ^ 10.3 years), 12 untreated bipolar mood disorder patients (five women; 37.7 ^ 10.6 years), and 17 lithiumtreated bipolar patients (seven women; 31.1 ^ 8.8 years). This research study was approved by the University of Pittsburgh Institutional Review Board. All patients met the DSM-IV diagnostic criteria for bipolar disorder, without
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 61 5- 8
244
R.B. Sassi et al. / Neuroscience Letters 329 (2002) 243–245
Fig. 1. Lithium-treated bipolar patients had significantly larger gray matter volume compared with untreated bipolar patients and healthy controls (MANCOVA, age and gender as covariates, P , 0:05).
other comorbid axis I diagnosis. Patients were considered untreated if they arrived at the outpatient clinic off all psychotropic medications for at least 2 weeks (in most cases, patients presented without medications due to noncompliance with prescribed treatment). The lithium-treated group had been on lithium as monotherapy for at least 2 weeks (most patients had been on lithium for several weeks; mean ^ SD: 131 ^ 250 weeks; median: 27 weeks). Patients or healthy controls with a lifetime history of alcohol or drug dependence, or alcohol or drug abuse in the 6 months preceding the MRI were excluded. 3D MRI images were obtained with a 1.5T-GE Signa magnet. Gray matter, white matter, and intracranial volumes (ICV) were measured by a trained rater, blindly to patient’s identity or group assignment, using a semi-automated method and following standardized procedures, after having achieved intra-class correlation coefficients for each of these measures of .0.90. Additional details on the utilized imaging methodology can be found elsewhere [1]. The three groups (healthy controls, untreated, and
lithium-treated bipolar patients) had comparable age (F ¼ 1:7; d:f: ¼ 2; P ¼ 0:2) and gender (x2 ¼ 0:4; d:f: ¼ 2; P ¼ 0:9) distributions. Lithium-treated and untreated bipolar patients had comparable age at onset of illness (mean age ^ SD: 21.3 ^ 7 and 17.7 ^ 7, respectively; F ¼ 0:3; d:f: ¼ 26; P ¼ 0:15), length of illness (17 ^ 10 and 14 ^ 8 years; F ¼ 0:2; d:f: ¼ 26; P ¼ 0:4), and number of previous affective episodes (16 ^ 15 and 16 ^ 18 episodes; F ¼ 0:6; d:f: ¼ 24; P ¼ 0:9). Lithiumtreated and untreated bipolar patients had comparable rates of mood disorders on a first-degree relative (eight of 17, and eight of 12, respectively; x2 ¼ 1:1; d:f: ¼ 1; P ¼ 0:3). However, there were significant differences between the two groups in mood state at the time of the MRI scan: 14 of 17 patients in the lithium-treated group were euthymic, whereas the remaining three were acutely depressed. Among the 12 untreated bipolar patients, four were euthymic, seven were acutely depressed and one was hypomanic (x2 ¼ 7:5; d:f: ¼ 2; P ¼ 0:02). Furthermore, there was a trend towards a significantly higher percentage of bipolar I patients in the lithium-treated (16 of 17) compared with the untreated (eight of 12; x2 ¼ 3:7; d:f: ¼ 1; P ¼ 0:054) group. Using age and gender as covariates, we found that lithiumtreated bipolar patients had larger intracranial and total gray matter brain volumes than untreated ones (Fig. 1). Moreover, lithium-treated patients presented larger intracranial and total gray matter brain volumes than healthy controls (Table 1). The finding of significantly increased gray matter volumes in lithium-treated bipolar patients compared with healthy controls persisted after taking into account ICV as a covariate for the analyses (multivariate analysis of covariance (MANCOVA), age, gender, and ICV as covariates; F ¼ 6:17; d:f: ¼ 1; 58; P ¼ 0:016). Furthermore, we repeated the analyses including bipolar subtype and mood status at the time of the MRI scan as covariates, and the results were similar: larger ICV (MANCOVA with age, gender, mood status and bipolar subtype (I or II) as covariates; F ¼ 5; d:f: ¼ 1; 23; P ¼ 0:03) and larger total gray matter volumes (F ¼ 9:1; d:f: ¼ 1; 23; P ¼ 0:006) in the lithium-treated compared with the untreated bipolar group. There was no correlation between lithium dose (mean ^ SD: 1111.8 ^ 356 mg/day; median: 900; range: 750–2100; Spearman’s correlation coefficient: 0.3; P ¼ 0:2) or length
Table 1 Intracranial, total gray and total white matter volumes a Groups/mean ^ SD
Healthy controls (n ¼ 46)
Untreated bipolar patients (n ¼ 12)
Lithium-treated bipolar patients (n ¼ 17)
ICV (cm 3) Total gray matter volume (cm 3) Total white matter volume (cm 3)
1458.7 ^ 126.6 675.8 ^ 61.8 476.7 ^ 68.7
1433.6 ^ 147.7 639.2 ^ 91.2 484.9 ^ 84.9
1552.6 ^ 132.6 b 747.9 ^ 69.8 b 487.9 ^ 68.7
a
MANCOVA with age and gender as covariates. Lithium-treated bipolar patients had larger intracranial (F ¼ 6; d:f: ¼ 1; 25; P ¼ 0:02) and total gray matter volumes (F ¼ 10:6; d:f: ¼ 1; 25; P ¼ 0:003) than untreated bipolar patients, and also larger intracranial (F ¼ 10:2; d:f: ¼ 1; 59; P ¼ 0:002) and total gray matter volumes (F ¼ 17:4; d:f: ¼ 1; 59; P , 0:001) than healthy controls. b
R.B. Sassi et al. / Neuroscience Letters 329 (2002) 243–245
of lithium treatment (mean ^ SD: 131 ^ 250 weeks; median: 27; range: 2–1000; Spearman’s correlation coefficient: 20.14; P ¼ 0:6) and gray matter brain volume. No significant differences in total white matter volumes were observed across the three groups (Table 1). These intriguing results are in line with previous reports of increased gray matter volume [7] and NAA levels [6] in lithium-treated subjects. Since no significant effects of lithium administration on white matter volumes were found in our sample, we believe that the increased ICV in the lithium-treated group are primarily due to an increase in total gray matter volume. It is important to consider, however, that we are not able to rule out the possibility that, for any spurious reason, our lithium-treated sample suffered from a selection bias towards larger premorbid global cerebral volumes. Considering that age and gender distribution were similar among the three groups, this possibility seems unlikely. Since we did not measure skull diameter or volume, or cerebrospinal fluid volume, we are not able to assure that increased gray matter volume is the single explanation for the increased ICV we found among the lithium-treated patients. Nonetheless, it is important to consider that the findings of increased gray matter volume in lithium-treated patients persisted even after controlling for ICV, i.e. using ICV (as well as age and gender) as a covariate in the analyses. In the present study, lithium-treated patients had total gray matter volumes greater not only than untreated patients, but also greater than age- and sex-matched healthy controls. These findings may represent detectable brain effects of lithium, and are in line with recent evidence that lithium exerts neuroprotective and neurotrophic effects, and could possibly prevent or partly reverse regional gray matter deficits that may be linked to bipolar illness. Lithium induces the expression of bcl-2 on neurons [5], an action that is also shared by another mood-stabilizer, valproate [2]. An increase in neuropil volume as a consequence of the trophic actions of bcl-2 in the brain [4] is an appealing explanation for the results we obtained. However, osmotic effects of lithium, leading to neuron swelling and consequent increased gray matter brain volume cannot be ruled out. Nonetheless, we believe that a purely osmotic action of lithium would not be restricted only to gray matter and would also influence the white matter volume; therefore, such effects appear less likely. Our results, nonetheless, should be interpreted with caution. The magnitude of the gray matter increase is somewhat higher than the difference reported by Moore et al. [7]. We believe that key methodological differences between our study and the study by Moore et al. [7] might explain these discrepancies. First, Moore et al. performed a longitudinal evaluation of the same group of patients, pre- and post-lithium treatment, whereas our study compared two distinct groups of patients in a cross-sectional fashion. Second, in the study by Moore et al., all patients received only 4 weeks of lithium treatment, whereas in our report, the
245
length of continuous lithium treatment was, in most cases, several weeks (mean ^ SD: 131 ^ 250 weeks; median: 27 weeks). Although we did not find a correlation between length of treatment and gray matter volume, perhaps due to the wide variance and relatively small sample size, it is not possible to rule out the possibility that this variable may be partially responsible for the discrepancy in the magnitude of gray matter changes between our study and theirs [7]. In a previous report with a smaller subject sample [1], we identified a trend towards increased total gray matter volume in lithium-treated when compared with drug-free bipolar patients. The inclusion of additional subjects to compose a larger sample in the present study allowed us to confirm and expand the preliminary results we reported. We are currently conducting a prospective MRI study of the effects of lithium in healthy controls, to find out if the actions of lithium on gray matter volumes are also identifiable in subjects without psychiatric disorders. Future studies should assess whether valproate and other medications also effective in the treatment of bipolar disorder cause similar increases in brain gray matter in vivo, and further investigate the clinical relevance of these findings. Furthermore, longitudinal studies that attempt to examine the effects of lithium on gray matter volumes in specific brain regions implicated in the pathophysiology of bipolar disorder will be of utmost importance. This study was supported by NIMH grants MH01736, MH29618, and MH30915, the Theodore and Vada Stanley Foundation, NARSAD, and CAPES Foundation (Brazil).
[1] Brambilla, P., Harenski, K., Nicoletti, M., Mallinger, A.G., Frank, E., Kupfer, D.J., Keshavan, M.S. and Soares, J.C., Differential effects of age on brain gray matter in bipolar patients and healthy individuals, Neuropsychobiology, 43 (2001) 242–247. [2] Chen, G., Zeng, W.Z., Yuan, P.X., Huang, L.D., Jiang, Y.M., Zhao, Z.H. and Manji, H.K., The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS, J. Neurochem., 72 (1999) 879–882. [3] Lenox, R.H. and Hahn, C.G., Overview of the mechanism of action of lithium in the brain: fifty-year update, J. Clin. Psychiatry, 61 (2000) 5–15. [4] Manji, H.K., Moore, G.J. and Chen, G., Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness, Biol. Psychiatry, 48 (2000) 740–754. [5] Manji, H.K., Moore, G.J. and Chen, G., Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness, J. Clin. Psychiatry, 61 (2000) 82–96. [6] Moore, G.J., Bebchuk, J.M., Hasanat, K., Chen, G., SerajiBozorgzad, N., Wilds, I.B., Faulk, M.W., Koch, S., Glitz, D.A., Jolkovsky, L. and Manji, H.K., Lithium increases N-acetylaspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol. Psychiatry, 48 (2000) 1–8. [7] Moore, G.J., Bebchuk, J.M., Wilds, I.B., Chen, G., Manji, H.K. and Menji, H.K., Lithium-induced increase in human brain grey matter, Lancet, 356 (2000) 1241–1242.