Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78.
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Differential display polymerase chain reaction was used to identify genes regulated by the mood-stabilizing drug valproate (VPA). Four differentially displayed valproate-regulated gene fragments were isolated in rat cerebral cortex after i.p. injection of sodium VPA (300 mg/kg) for 3 weeks, and their expression was confirmed by Northern and slot blot analysis in rat cerebral cortex and C6 glioma cells. Sequencing analysis revealed three previously unidentified cDNA fragments in addition to a sequence with 100% homology with a molecular chaperone, 78-kDa glucose-regulated protein (GRP78). VPA treatment did not increase mRNA expression of 70-kDa heat shock protein, which is a related stress-induced molecular chaperone protein. All four candidate genes, including GRP78, showed similar VPA concentration-dependent increases in mRNA abundance. Another commonly prescribed mood-stabilizing anticonvulsant, carbamazepine, also increased GRP78 mRNA expression in C6 glioma cells, whereas lithium had no effect at doses up to 2 mM. Immunoblotting revealed that GRP78 protein levels were also increased in C6 glioma cells treated with VPA under the same conditions. Nuclear runoff analysis showed that VPA increased GRP78 gene transcription. Because GRP78 possesses molecular chaperone activity, binds Ca2+ in the endoplasmic reticulum, and protects cells from the deleterious effects of damaged proteins, the present findings suggest that VPA (and possibly carbamazepine) treatment may target one or more of these processes. (+info)
Carbamazepine-induced upregulation of adenosine A1-receptors in astrocyte cultures affects coupling to the phosphoinositol signaling pathway.
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The anticonvulsant and antibipolar drug carbamazepine (CBZ) is known to act as a specific antagonist at adenosine A1-receptors. After a 3-week application of CBZ, A1-receptors are upregulated in the rat brain. We have investigated the consequences of this upregulation for the A1-receptor-mediated signal transduction in primary astrocyte cultures from different regions of the rat brain. CBZ treatment for 10 days had no effect on adenosine A1-receptor mRNA expression in cultures with high basal A1-receptor mRNA levels, but increased A1-receptor mRNA in cultures exhibiting low basal A1-receptor mRNA levels. This upregulation of A1-receptor mRNA was accompanied by an upregulation or induction of A1-receptor-mediated potentiation of PLC activity, a property that was not found in these cultures before CBZ treatment. Thus, CBZ treatment for 10 days induces a new quality of adenosine A1-receptor-mediated signal transduction in cells that express low basal A1-receptor numbers. (+info)
Pharmacogenetics of lithium response in bipolar disorder.
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Lithium is the first-line treatment for bipolar disorder. In the past, genetic studies have attempted to identify factors associated with positive treatment response or side effects. Several research groups have shown that familial factors, family history of primary bipolar disorder, and negative family history of schizophrenia in particular, correlate well with prophylactic lithium response. Conversely, studies of lithium responsive patients and their families can assist genetic research of bipolar disorder. Lithium responders appear to suffer from a form of bipolar disorder that is more genetically based and more homogeneous. In a series of family studies, the author and his colleagues have confirmed the differences in family histories of lithium responders and nonresponders and shown that the mode of inheritance in lithium responders is compatible with a major-gene model. Subsequently, they initiated an international collaborative study to map the gene(s) predisposing to the illness or treatment response, or both, using both linkage and association strategies. To date, a sample of 32 families, 138 unrelated patients and 163 control subjects has been studied. In these studies, they found support for the role of phospholipase C in lithium responsive bipolar disorder. (+info)
Pharmacoeconomic and health outcome comparison of lithium and divalproex in a VA geriatric nursing home population: influence of drug-related morbidity on total cost of treatment.
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OBJECTIVE: Clinicians use mood stabilizers for treating agitation in older patients, but limited information is available regarding side effects and costs in clinical practice. Total costs of treatment were assessed for a subset of geriatric patients receiving either lithium carbonate or divalproex sodium for agitation. STUDY DESIGN: Retrospective cohort examination of the medical records of 72 patients, 55 years of age or older, in a Veterans Administration long-term, skilled nursing care facility, with a diagnosis of dementia or bipolar affective disorder or both. PATIENTS AND METHODS: Patients treated with lithium or divalproex during the previous 4 years (1994-1997) were evaluated. Quantitative information was collected and compared regarding routine care, including cost of treatment and laboratory monitoring; and occurrence of adverse events and associated diagnostic and treatment measurements. RESULTS: Routine care costs for the 2 groups were similar. The lower annual acquisition cost per patient-year for lithium ($15 vs $339 for divalproex) was offset by higher laboratory monitoring costs associated with its administration ($278 vs $53 for divalproex). Examining the adverse events showed that the lithium group had more medication-related adverse events (32 total) than the divalproex group (10 total) and more severe occurrences, including 6 cases requiring medical intensive care unit (MICU) hospitalization. The total mean cost of treating drug-related mild-to-moderate morbidity was $3472 for lithium and $672 for divalproex. An additional cost per admission of $12,910 ($77,462 for all 6 cases) increased total morbidity-related expenditures in the lithium group to $80,934. CONCLUSIONS: Treating geriatric patients with lithium requires careful monitoring because of side effects. Staffing and resource limitations of a skilled nursing care facility may compromise optimal lithium monitoring in elderly patients. The collected data indicated that divalproex does not result in as many as or as severe adverse events and is, therefore, a safer treatment. The use of lithium was not only more expensive (on average $2875 more per patient) than treatment with divalproex but, more importantly, it was associated with poorer patient outcomes. (+info)
Bipolar disorder in old age.
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OBJECTIVE: To review the classification, clinical characteristics, and epidemiology of bipolar disorders in old age with a special focus on neurologic comorbidity, high mortality, and management. QUALITY OF EVIDENCE: Most available data is gleaned from retrospective chart reviews and cohort studies. Treatment recommendations are based on evidence from younger populations and a few anecdotal case reports and series involving elderly people. MAIN MESSAGE: While relatively rare in the community setting, mania in old age frequently leads to hospitalization. It is associated with late-onset neurologic disorders (especially cerebrovascular disease) involving the right hemisphere and orbitofrontal cortex. Prognosis is relatively poor; morbidity and mortality rates are high. Management of bipolarity includes cautious use of mood stabilizers, especially lithium and divalproex. CONCLUSIONS: Mania in old age should trigger a careful assessment of underlying neurologic disease, especially cerebrovascular disease. Close clinical follow up is essential. (+info)
Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?
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The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs. (+info)
Asthma precipitated by cessation of lithium treatment.
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We report symptomatic asthma, associated with objective and highly significant increases in both airway responsiveness and airflow limitation, presenting de novo in a male patient 6 weeks after suddenly discontinuing lithium carbonate therapy. (+info)
Carbamazepine suppresses methamphetamine-induced Fos expression in a regionally specific manner in the rat brain. Possible neural substrates responsible for antimanic effects of mood stabilizers.
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Carbamazepine (CBZ) has been widely used for treatment of manic states. Because amphetamine produces effects in humans similar to those of idiopathic mania, acute methamphetamine administration could serve as a model of this condition. To elucidate the neurobiological substrates responsible for the antimanic effects of carbamazepine, this study investigated the effects of chronic carbamazepine administration on regional Fos protein expression induced by a single dose of methamphetamine (2mg/kg). Chronic treatment with CBZ (0.25% in food for 7 days, followed by 0.5% for 7 days; final mean serum carbamazepine concentration: 4.09 +/- 0.34 microg/ml) significantly attenuated the number of Fos-like immunoreactivity-positive nuclei induced by methamphetamine administration in the core of the nucleus accumbens and the caudate/putamen. The results indicate these brain regions are involved in the antimanic effects of carbamazepine. (+info)