Susan Rotzinger

Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithiums efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI-cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myo-inositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myo-inositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI-cycle.

Metabolism of some "second"- and "fourth"-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine.

Abstract1. This review summarizes the major known aspects of the metabolism of second-generation (iprindole, viloxazine, bupropion, mianserin, maprotiline, and trazodone) and fourth-generation (nefazodone and venlafaxine) antidepressants.2. Discussions about specific enzymes involved and about possible pharmacokinetic drug–drug interactions, particularly as they relate to cytochrome P450 enzymes, are provided.

Human CYP2D6 and metabolism of m-chlorophenylpiperazine

BACKGROUND Metabolic drug-drug interactions can occur between drugs that are substrates or inhibitors of the same cytochrome P450 (CYP) isoenzymes, but can be prevented by knowing which isoenzymes are primarily responsible for a drugs metabolism. m-Chlorophenylpiperazine (mCPP) is a psychopharmacologically active metabolite of four different psychiatric drugs. The present experiments were designed to identify the CYP isoenzymes involved in the metabolism of mCPP to its main metabolite p-hydroxy-mCPP (OH-mCPP). METHODS The rate of production of OH-mCPP from mCPP was correlated with isoform activities in a panel of human liver microsomes, was assessed using a panel of individual complementary DNA-expressed human CYP isoenzymes, and was investigated in the presence of a specific inhibitor of CYP2D6. RESULTS OH-mCPP production correlated significantly with CYP2D6 activity in human liver microsomes. Furthermore, incubations with microsomes from cells expressing CYP2D6 resulted in OH-mCPP formation, whereas no mCPP was formed from incubations with microsomes from cells expressing other individual isoforms. Finally, when the specific CYP2D6 inhibitor quinidine was preincubated with either human liver microsomes or cells expressing human CYP2D6, there was a concentration-dependent decrease in the production of OH-mCPP. CONCLUSIONS These results confirm that CYP2D6 is the isoform responsible for the p-hydroxylation of mCPP, and indicate that caution should be exercised in coprescribing inhibitors or substrates of CYP2D6 with drugs that have mCPP as a metabolite.

RETRACTED: Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain

One of the mechanisms underlying lithiums efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myoinositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high-resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myoinositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myoinositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI cycle.

Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS

BACKGROUND The clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis. METHODS Magnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle. RESULTS Subjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects. CONCLUSIONS The present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain.

Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes

Nefazodone is an antidepressant with a relatively unique structure and mechanism of action. The current study was conducted to assess the potential for nefazodone to have metabolic drug interactions associated with cytochrome P450 (CYP) enzymes. Nefazodone is metabolised to hydroxynefazodone (OH-NEF), triazoledione (TD), and m-chlorophenylpiperazine (m-CPP), and OH-NEF is metabolised to TD and m-CPP. Correlations with enzyme activities in a panel of microsomes prepared from human livers, incubations with heterologously expressed human CYP enzymes, and incubations with enzyme inhibitors were used to study these metabolic pathways. The results suggest that the metabolism of NEF and OH-NEF to each of their active metabolites is catalysed mainly by CYP3A4, which is in agreement with clinical reports of drug--drug interactions of nefazodone with substrates and inhibitors of CYP3A4.