Anxiety Disorders: Dager SR

Giardino ND, Friedman SD, Dager SR. · Department of Radiology, University of Washington School of Medicine, Seattle, WA 98105, USA. · Compr Psychiatry. · Pubmed #17292699 links to  free full text

Abstract: Brain functional imaging methods, such as fMRI, are sensitive to changes in cerebral blood flow (CBF) that are normally associated with changes in regional neural activation. However, other endogenous and exogenous factors can alter CBF independently of brain neural activity, thus complicating the interpretation of functional imaging data. The presence of an anxiety disorder, as well as change in state anxiety, is often accompanied by respiratory alterations that affect arterial CO(2) tensions and produce significant changes in CBF that are independent of task-related neural activation. Therefore, the effects of trait and state anxiety need to be given close consideration in interpreting functional imaging findings. In this paper, we review the dependence of most brain functional imaging methods on localized changes in CBF and the potentially confounding effects of anxiety-related alterations of respiration on interpreting patterns of functional activation. Approaches for addressing these effects are discussed.

Layton ME, Friedman SD, Dager SR. · The Center for Anxiety and Depression, University of Washington, Seattle, Washington 98105-6099, USA. · Depress Anxiety. · Pubmed #11754135 No free full text.

Abstract: Six subjects with panic disorder underwent sodium lactate infusions in conjunction with magnetic resonance spectroscopic imaging (MRSI) at study entrance when actively symptomatic and after clinical improvement while under treatment with gabapentin. MRSI was used to serially measure regional brain lactate levels from an axial section at the level of the lateral ventricles at baseline, during lactate infusion and postlactate infusion. Gabapentin treatment appeared to be effective in blocking a lactate-induced panic response but did not alter the magnitude or time course of an abnormal brain lactate response to lactate infusion in all subjects. Additionally, two subjects were reinfused while clinically improved on double-blind placebo and demonstrated a consistent pattern of abnormal brain lactate response.

Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, Taylor CB, Dager SR, Shiovitz T. · Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. · J Clin Psychopharmacol. · Pubmed #10917408 No free full text.

Abstract: A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score > or = 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder.

Han DH, Renshaw PF, Dager SR, Chung A, Hwang J, Daniels MA, Lee YS, Lyoo IK. · Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea. · J Psychiatr Res. · Pubmed #17482647 No free full text.

Abstract: OBJECTIVE: Functional imaging studies of panic disorder subjects suggest an increased activation of the cingulate regions of the brain. Aim of the current study was to explore the white matter connectivity differences between subjects with panic disorder and healthy comparison subjects. METHOD: Structural white matter connectivity, as determined from fractional anisotropy (FA) values obtained by diffusion tensor imaging, was assessed for anterior and posterior cingulate regions in 24 panic disorder patients and 24 age and sex-matched healthy comparison subjects. RESULTS: Subjects with panic disorder exhibited significantly greater FA values in left anterior and right posterior cingulate regions (by 13.3% and 19.6%, respectively) relative to comparison subjects. White matter connectivity for these two cingulate regions was also positively correlated with clinical severity, as determined by Panic Disorder Severity Scale. FA values in left anterior cingulate region negatively correlated with the time of Trail Making Tests and positively with Digit Symbol Substitution Test. CONCLUSIONS: Findings suggest a potential 'enhancement' in white matter connectivity in left anterior and right posterior cingulate regions in panic disorder, and that these changes may play an important role in mediating clinical symptoms of panic disorder.

Friedman SD, Mathis CM, Hayes C, Renshaw P, Dager SR. · Department of Radiology, 1100 N.E. 45th St., Suite 555, Seattle, WA 98105, USA. · Am J Psychiatry. · Pubmed #16585448 links to  free full text

Abstract: OBJECTIVE: Previous findings of excess brain lactate and delayed end-tidal CO(2) (pCO(2)) recovery in subjects with panic disorder during hyperventilation suggested altered acid-base regulation. Two models were posited to explain these results: 1) subjects with panic disorder demonstrate greater alkalosis to hyperventilation, implicating increased lactate as directly compensatory, or 2) subjects with panic disorder demonstrate reduced or blunted alkalosis, implicating increased lactate as overly compensatory to a normal pH response. In both models, delayed pCO(2) recovery in subjects with panic disorder could reflect slower pH normalization in the recovery phase. METHOD: Asymptomatic medicated patients with panic disorder were studied during regulated hyperventilation. Phosphorous spectroscopy was used to measure brain pH every 2 minutes. Nine subjects with panic disorder were compared to 11 healthy subjects at baseline (five scans), during regulated hyperventilation (five scans), and across recovery (10 scans). Anxiety symptoms were assessed with standard ratings. RESULTS: No subject had a panic attack before hyperventilation. Subjects with panic disorder had lower pCO(2) during hyperventilation and slower pCO(2) recovery across the posthyperventilation interval. Despite this different respiratory response in the panic disorder group, brain pH increases were not significantly greater during hyperventilation, nor was pH return to baseline slowed during posthyperventilation. A linear regression model derived from data of healthy subjects showed pH blunting in the panic disorder group. CONCLUSIONS: Although subjects with panic disorder had greater hypocapnea during hyperventilation, their observed pH response, not altered from comparison levels, implicated exaggerated buffering. It is suggested that increased lactate could account for these findings.

Nazemi H, Dager SR. · Department of Psychology, Family and Community, Seattle Pacific University, Seattle, WA, USA. · Compr Psychiatry. · Pubmed #12764706 No free full text.

Abstract: The psychological reactions and coping strategies used in response to a behavioral contingency (confinement in a magnetic resonance imaging [MRI] scanner) during a biological challenge (sodium lactate infusion) were systematically studied in 13 subjects with panic disorder (PD) and 11 control subjects using the Claustrophobia Questionnaire (CQ) and the Revised Ways of Coping Checklist (RWCCL). All participants were able to successfully complete the experimental procedure. Findings suggest between-group coping strategy differences in response to general stressors, but relative convergence of coping strategies in response to the experimental procedure, with relatively greater emphasis on problem-focused coping approaches. These observations suggest that PD patients are able to engage in effective coping strategies in response to stressful but highly structured experimental situations. An overall pre-post MR scanning reduction in the fear of restriction but not suffocation was observed for the combined sample, primarily reflecting changes in the control group. Among PD subjects, higher levels of suffocation fears were maintained despite emergence of more problem-focused coping in the experimental situation.

Strauss WL, Unis AS, Cowan C, Dawson G, Dager SR. · Center on Human Development and Disability, University of Washington, Seattle, 98105-6099, USA. · Am J Psychiatry. · Pubmed #11986128 links to  free full text

Abstract: OBJECTIVE: Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. METHOD: Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. RESULTS: A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. CONCLUSIONS: These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.

Friedman SD, Dager SR, Richards TL, Petropoulos H, Posse S. · Department of Psychiatry and Behavioral Sciences, 4225 Roosevelt Way NE-Suite 306-C, University of Washington, Seattle, WA 98105-6099, USA. · Psychiatry Res. · Pubmed #10708926 No free full text.

Abstract: Magnetic resonance spectroscopy has been used to characterize abnormal brain lactate response in panic disorder (PD) subjects following lactate infusion. The present study integrated water quantification and tissue segmentation to evaluate compartmental lactate response within brain and cerebrospinal fluid (CSF). As there is evidence of brain parenchymal pH changes during lactate infusion, water scans were collected at baseline and post-infusion to address brain water stability. Water levels remained essentially stable across the protocol suggesting internal water provides an improved reference signal for measuring dynamic changes in response to metabolic challenge paradigms such as lactate infusion. To model brain lactate changes by compartments, we took the null hypothesis that lactate rises occur only in tissue. The approach referenced lactate amplitude (potentially from both compartments) to 'voxel' water (water scan corrected for differential T(2) between CSF brain at long-echo times - synonymous to a short-echo water scan). If the magnitude of lactate rise in CSF was equal to or greater than brain, voxels with substantial CSF fractions should demonstrate an equivalent or elevated response to voxels comprised only of tissue. The magnitude of lactate increases paralleled voxel tissue fraction suggesting the abnormal lactate rise observed in PD is tissue-based. The feasibility of lactate quantification and compartmental modeling are discussed.

Dager SR, Friedman SD, Heide A, Layton ME, Richards T, Artru A, Strauss W, Hayes C, Posse S. · Department of Psychiatry, Diagnostic Imaging Sciences Center, University of Washington School of Medicine, Seattle 98105-6099, USA. · Arch Gen Psychiatry. · Pubmed #9892258 links to  free full text

Abstract: BACKGROUND: A fast, proton echo-planar spectroscopic imaging (PEPSI) technique, capable of simultaneously measuring metabolites from multiple brain regions, was used to investigate the anatomical distribution and magnitude of brain lactate responses to intravenous lactate infusion among subjects with panic disorder and control subjects. METHODS: Fifteen subjects with panic disorder and 10 control subjects were studied. All subjects were medication free and met DSM-IV criteria for panic disorder, or, for controls, no Axis I psychiatric disorder. Two-dimensional axial metabolite images having 1-cm3 spatial resolution were acquired at 61/2-minute intervals during 3 conditions: a 20-minute baseline, 20-minute 0.5-mol/L sodium lactate infusion, and 15-minute postinfusion period. RESULTS: Intravenous lactate infusion increased brain lactate levels throughout the axial brain section studied in all subjects. Panic-disordered subjects had significantly greater global brain lactate increases in response to lactate infusion. Lateralization of brain lactate response did not occur, nor were discrete regional loci of elevated lactate observed. Cerebrospinal fluid lactate changes corresponded to lactate changes in brain tissue. Severity of symptoms provoked by lactate infusion did not directly correlate with brain lactate response. CONCLUSIONS: Greater overall rises in brain lactate among subjects with panic disorder compared with controls occurred in response to lactate infusion. We were unable to detect a distinct regional pattern for magnitude differences in brain lactate rise by which to identify a specific neuroanatomical substrate underlying a lactate-induced panic response. The wide anatomical distribution of these brain lactate increases suggest metabolic and/or neurovascular mechanisms for the abnormal rise in subjects with panic disorder.