In vivo imaging of the pharmacodynamics and pharmacokinetics of lithium

Department of Psychiatry and Behavioral Sciences, Emory Center for Positron Emission Tomography, Atlanta, Ga, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 02/2000; 61 Suppl 9:41-6.
Source: PubMed


The therapeutic efficacy of lithium for the long-term management of bipolar disorder is well recognized, along with the risk of lithium-induced toxicity. The author describes the current findings of in vivo functional neuroimaging techniques with respect to the pharmacokinetics and pharmacodynamics of lithium and their future potential to elucidate the drug distribution and neural mechanisms that produce its therapeutic effects. Brain Li nuclear magnetic resonance spectroscopy findings have disassociated postdose brain and blood lithium concentrations and suggest a pharmacokinetic basis for lithium response and nonresponse. The application of in vivo synaptic activity and neurochemical imaging is providing new knowledge related to the distributed neural activity associated with lithium response and is contributing to the critical human testing of neuroprotective and signal transduction models of lithium's therapeutic effects.

7 Reads
  • Source
    • "We demonstrate here, for the first time, that chronic treatment of mice with Cpd-60 results in substantial effects in two behavioral tests with predictive validity for mood stabilizer and antidepressant medications. Cpd-60 treatment was associated with significant gene expression changes in prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus (HIP), brain regions involved in the regulation of mood [19], [20], through an HDAC inhibition-mediated mechanism evidenced by increased histone acetylation at gene promoter regions. Interestingly, a small subset of gene expression changes induced by Cpd-60 significantly overlap with those induced by lithium, suggesting common mechanistic elements that may play a role in altering behavior. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary - albeit often ineffective - treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.
    PLoS ONE 08/2013; 8(8):e71323. DOI:10.1371/journal.pone.0071323 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The authors' goal was to determine if there is an association between brain-to-serum lithium ratios and age. Lithium-7 magnetic resonance spectroscopy was used to measure in vivo brain lithium levels in nine children and adolescents (mean age=13.4 years, SD=3.6) and 18 adults (mean age=37.3, SD=9.1) with bipolar disorder. Serum and brain lithium concentrations were positively correlated. Younger subjects had lower brain-to-serum concentration ratios than adults: 0.58 (SD=0.24) versus 0.92 (SD=0.36). The brain-to-serum concentration ratio correlated positively with age. These observations suggest that children and adolescents may need higher maintenance serum lithium concentrations than adults to ensure that brain lithium concentrations reach therapeutic levels.
    American Journal of Psychiatry 08/2002; 159(7):1240-2. DOI:10.1176/appi.ajp.159.7.1240 · 12.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Social anxiety disorder is a common, chronic and often debilitating condition. Selective serotonin reuptake inhibitors have been widely used for the treatment of anxiety disorders, with more data currently available for paroxetine. With its beneficial side-effect profile and proven efficacy in social anxiety disorder, sertraline can be considered a valuable addition to the variety of treatments currently available for this disorder.
    Expert Review of Neurotherapeutics 11/2003; 3(6):787-95. DOI:10.1586/14737175.3.6.787 · 2.78 Impact Factor
Show more


7 Reads
Available from