RESUMO
OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.
Assuntos
Antimaníacos/farmacocinética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Compostos de Lítio/farmacocinética , Adulto , Antimaníacos/uso terapêutico , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Depressão/sangue , Depressão/tratamento farmacológico , Feminino , Humanos , Compostos de Lítio/uso terapêutico , Espectroscopia de Ressonância Magnética/métodos , MasculinoRESUMO
It has been demonstrated that lithium (Li) and valproate (VPT), first line mood stabilizers, increase BDNF content in rat hippocampus and frontal cortex, which suggests that the regulation of neurotrophic factors might be associated with their pharmacological effects. In sight of the scarcity of studies with other neurotrophins, and the possible relevance of multiple neurotrophic signaling systems in bipolar disorder we investigated the effects of Li and VPT on NT-3 levels in rat serum and hippocampus, using an animal model of mania induced by amphetamine (AMPH). In the reversal model, adult male Wistar rats received AMPH or saline for 14 days, and between the 8th and 14th days, animals were treated with Li, VPT or saline. In the prevention model, rats were pretreated with Li, VPT or saline, and between the 8th and 14th days, the animals received AMPH or saline. Li increased serum and hippocampal NT-3 levels in all conditions, whereas VPT increased hippocampal NT-3 in the prevention model only. Li reversed AMPH changes in NT-3 in the reversal model, and VPT prevented AMPH changes in NT-3 in the prevention model. These results suggest that both Li and VPT modulate serum and central (hippocampal) NT-3 levels, and further support that the regulation of neurotrophic signaling systems may be related to the mechanisms of action of mood stabilizers.