Wayne L. Strauss

Single-voxel 1H-MRS investigation of brain metabolic changes during lactate-induced panic.

Intravenous sodium lactate infusion is a robust laboratory technique for eliciting panic in susceptible individuals. The objective for this study was to replicate previous work which found differential brain lactate rises among lactate-sensitive panic subjects relative to control subjects using single-voxel 1H-magnetic resonance spectroscopy (MRS). Single-voxel 1H-MRS was used to measure brain lactate changes in the insular cortex region among 13 panic disorder subjects and 10 healthy control subjects during the infusion. One panic subject prematurely terminated the study due to a panic response during lactate infusion. Data from two additional control subjects and one panic subject were lost due to technical problems. Four panic subjects were reinfused with lactate while panic-free under treatment with fluoxetine (20 mg/day). At the time of initial infusion, all subjects were medication-free for at least 1 month. Ten panic subjects, but no control subjects, panicked during lactate infusion. In comparison to control subjects, panic subjects demonstrated significantly greater and prolonged brain lactate rises in the insular cortex region. Three of four medicated panic subjects experienced blockage of panic symptoms during lactate reinfusion but all exhibited persistent excesses in brain lactate rise. Consistent with our prior observations, greater and prolonged lactate rises in the insular brain region occur during and following lactate infusion among panic subjects compared to control subjects. This differential brain metabolic response did not appear to normalize when a small subset of panic patients were reinfused following resolution of panic symptoms during treatment over 3-4 months with fluoxetine.

Characterization of human brain pharmacokinetics using a two-compartment model

We developed a two-compartment pharmacokinetic model to systematically characterize 19F magnetic resonance spectroscopy (19F MRS) data on the concentration time course of psychotropic compounds measured in human brain. Using this model, brain volume of distribution and clearance were calculated for fluvoxamine as an index compound. Our interest in formalizing a multicompartment model was motivated by recent advances in the field of brain spectroscopy that allow the noninvasive characterization of brain uptake and elimination half-lives of fluorinated psychotropic compounds. Differences between central compartment single-dose and steady-state half-lives and the peripheral elimination half-life at steady state were used to formulate the model. Application of the model is illustrated using previously published data on the elimination half-lives of fluvoxamine from plasma and brain at steady state, along with the literature values for single-dose plasma elimination half-life. Applying the model, brain volume of distribution (1.12 L/kg +/- 0.2 SEM) and clearance (1.01 L/hour +/- 0.12 SEM) were calculated for fluvoxamine. The bioavailability of fluvoxamine to the brain from plasma was 1.85 +/- 0.23 SEM. The underlying multicompartment pharmacokinetics of fluvoxamine were reflected by the difference between brain and plasma elimination half-lives from steady state. This method to derive pharmacokinetic parameters using 19F MRS measurements of drug concentration in brain can be applied to characterize the pharmacokinetics of other fluorinated psychotropic compounds.