Matthew E. Layton

Reactive oxidant species in piriform cortex extracellular fluid during seizures induced by systemic kainic acid in rats.

Kainic acid (KA) administered systemically to rats produces seizures and brain damage. We measured an increase in reactive oxidant species (ROS) during KA-induced seizures in the extracellular fluid (ECF) of the piriform cortex, a brain region known to be subsequently damaged. Intracerebral microdialysis samples were collected and assayed for isoluminol-dependent chemiluminescence before and after injection of KA (16 mg/kg, ip). Hydrogen peroxide (H2O2) concentrations were calculated from catalase-sensitive chemiluminescence, the difference between total and catalase-resistant chemiluminescence. During generalized tonic-clonic seizures, both total and catalase-resistant chemiluminescence increased significantly in samples from brain ECF. Catalase-resistant chemiluminescence, most likely produced by ascorbic acid, increased for a full hour during sustained seizure activity. H2O2 concentrations showed a trend towards elevation during seizures. Increased ROS suggest that oxidative stress occurs in brain ECF during sustained seizure activity.

Co-occurring mood disorders among hospitalized patients and risk for subsequent medical hospitalization

OBJECTIVE The objective was to determine if patients hospitalized with a primary medical diagnosis and any co-occurring serious mental illness (SMI) were more likely than patients without any co-occurring SMI diagnosis to experience a subsequent medical hospitalization. METHOD This was a longitudinal cohort study of 925,705 adult persons (aged 18+ years). Patients hospitalized in Washington State from 2004 to 2008 were followed through 2009 (for an average of 43 months). RESULTS Compared to patients hospitalized for medical conditions without co-occurring SMI, patients with co-occurring dysthymia, bipolar and major depressive disorders were at an elevated risk for long-term subsequent hospitalization. Patients in the combined co-occurring mood disorders cohort were more likely (hazard ratio=1.13; 99% confidence interval=1.10-1.16; P<.001) than patients in the reference cohort to experience a subsequent medical hospitalization. A significant interaction between substance and mood disorders that increased risk for subsequent hospitalization was also observed. CONCLUSION Hospitalized patients with co-occurring mood disorders are at high risk for repeat hospitalization for a medical reason. This high-risk population, including those with substance abuse, should be a focus of research efforts to identify and address ambulatory-care-sensitive conditions amenable to strategies that decrease complications and illness leading to subsequent hospitalizations.

Cerebral penetration injury leads to H2O2 generation in microdialysis samples

Delayed tissue damage is proposed to be caused by reactive oxygen species. We investigated the effects of microdialysis probe penetration into rat piriform cortex on hydrogen peroxide (H2O2) in brain extracellular fluid (ECF). H2O2 decreased immediately after probe insertion into the brain, but increased over 300% in samples within minutes after collection. We assessed H2O2 changes in vitro in microdialysis perfusion media containing various ascorbic acid concentrations and confirmed ascorbic acid is a source of H2O2. We conclude that decreased H2O2 concentrations in perfusion media as it passes through the brain reflect an extracellular antioxidant effect, whereas the increase in H2O2 with time after sample collection indicates that H2O2 generating substances are present in ECF. Thus, the potential for producing reactive oxygen species in brain ECF exists following penetration injury, especially if transition metals are released into the neuronal microenvironment.

Redox Changes in Perfusates Following Intracerebral Penetration of Microdialysis Probes

Microdialysis probe insertion into rat cerebral cortex significantly affects the levels of redox-active substances in brain extracellular fluid. Ascorbic acid levels are high immediately after probe insertion, decline rapidly, and then rise as the rat recovers from anesthesia 5–8 hours after surgery. Uric acid is at a low level for 5 hours and then rapidly increases in parallel with ascorbic acid. High ascorbic acid levels immediately after probe insertion are likely due to a shift from intracellular to extracellular fluids, whereas the delayed increase in uric acid may be due to increased enzymatic formation. After removal from the brain, hydrogen peroxide (H2O2) in microdialysis samples produces catalase-sensitive oxidative chemiluminescence. Microdialysis samples also produce high level catalase-resistant chemiluminescence associated with ascorbic acid levels after penetration injury. Although ascorbic acid is likely an antioxidant at concentrations estimated to be in brain extracellular fluid, it may have prooxidant effects when complexed with transition metals released into the neuronal microenvironment during traumatic brain injury.

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.

Optimum Treatment of Panic Disorder

SummaryPanic disorder is characterised by the recurrence of acute, unpredictable panic attacks, with associated fear and physiological arousal. The disorder is very common among the general population and has a high rate of associated morbidity and mortality when not treated.Both pharmacological and psychological treatment approaches are effective in alleviating symptoms of panic attacks. Various psychological treatment approaches have been advocated, with cognitive-behavioural treatment the most systematically studied and applied. A wide range of pharmacological agents are useful in treating attacks, and differ primarily in adverse effect profile, latency of onset and potential for abuse or addiction. Available agents include tricyclic anti-depressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and benzodiazepines. We consider long term use of SSRIs, in conjunction with benzodiazepines for the short term relief of symptoms, to be the optimum pharmacological management of panic disorder.

Educating Psychiatry Residents to Practice in Smaller Communities: A Regional Residency Track Model

Psychiatrists in the USA are concentrated in population-dense major metropolitan and higher income areas, particularly in the Northeast [1]. Many areas, including rural communities but also smaller cities, experience a shortage and have difficulty recruiting psychiatrists. Indeed, more than three quarters of counties in the USA have a severe shortage ofmental health providers, especially prescribers [2]. Psychiatry residency programs are located primarily in major metropolitan areas and graduates most often choose to practice in the vicinity of where they have completed graduate medical education [3]. Here, we describe a regional track model of psychiatry residency education designed to increase rates of practice in smaller communities. The University of Washington School of Medicine and Psychiatry Residency Program serve a large geographical region (the WWAMI region: Washington, Wyoming, Alaska, Montana, and Idaho) with some of the lowest physician to population ratios and graduate medical education position to population ratios in the nation. For example, the communities sponsoring the regional tracks described here (Spokane, Washington and Boise, Idaho) are in the lowest quartile nationally for physicians per capita and have 5–6 psychiatrists per 100,000 people as opposed to the national average of 10.9 [4]. The average number of graduate medical education positions per 100,000 is 35.7 nationally, but 6.8 and 3.6 per 100, 000 in Spokane and Boise, respectively [5]. Both have a severe shortage of mental health providers, poor access to mental health care, and suicide rates 46–54 % above the national average [6]. Historically, the only psychiatry residents were based in the academic medical center in Seattle, Washington, a major metropolitan center and the largest city in the region. These residents rarely practiced elsewhere in the WWAMI region after graduation, despite selection of residents from and interested in practicing in the region and the availability of several 1–3month away rotations to explore practice in smaller communities. Thus, our psychiatry residency program established two regional tracks in smaller cities in our region, located in the midst of large, underserved areas, with the goal of preparing general psychiatrists to practice in these communities. The Spokane Track was founded in 1992 and the Idaho Track in 2007. Spokane and Boise have populations of 208,916 and 205,671 (2010 census) and are 280 and 495 miles from Seattle, respectively. These regional tracks were established with the goal of 50 % retention of graduates in the regional site community. Here, we report on this outcomemeasure and, secondarily, on rates of practice of these graduates in other underserved parts of our region.