A key role for orexin in panic anxiety.

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid levels in women with comorbid depression and panic disorder.

Major depression comorbid with panic disorder has a more severe clinical picture and adverse course than either disorder alone, and both conditions are associated with abnormalities in the serotonin system. Therefore, we hypothesized that central serotonergic function in the patients with comorbid panic disorder would be more disturbed than in major depression alone. Concentrations of cerebrospinal fluid (CSF) monoamine metabolites of serotonin, norepinephrine, and dopamine were assayed by high-pressure liquid chromatography, and compared in female subjects with DSM-IV-diagnosed major depressive disorder and a lifetime diagnosis of panic disorder (MDD+PD, n=13), major depressive disorder and no lifetime panic disorder (MDD-, n=35), and a healthy volunteer (HV, n=15) group. All subjects were free of antidepressant medication for at least 14 d prior to the lumbar puncture procedure. CSF 5-hydroxylindoleacetic acid (5-HIAA) was higher in the MDD+PD group (124.0+/-43.0 nmol/l) compared with the MDD- group (100.1+/-28.8 nmol/l, p=0.03) and the HV group (93.3+/-33.6 nmol/l, p=0.02). The MDD- group and HV group did not differ in CSF 5-HIAA. There were no group differences in the CSF metabolites of norepinephrine and dopamine, 3-methoxy-4-hydroxyphenylglycol and homovanillic acid respectively. Higher CSF 5-HIAA in women with comorbid major depressive disorder and lifetime panic disorder is indicative of greater serotonin release, increased serotonin metabolism, and/or decreased 5-HIAA clearance in this group. This difference in pathophysiology is potentially related to the greater morbidity and poorer treatment response of this group.

Modeling brain compartmental lactate response to metabolic challenge: a feasibility study.

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.

Frontal CSF enlargement in panic disorder: a qualitative CT-scan study.

Brain morphology was assessed qualitatively in CT scans of 21 patients with panic disorder and 21 normal control subjects. Patients showed significant bilateral enlargement of frontal cerebrospinal fluid (CSF) spaces. These findings suggest that alterations in brain morphology are involved in the etiology of panic disorder.

Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects.

Cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF) were measured in a group of patients with anxiety disorders and normal comparison subjects (NC) to explore the hypothesis that abnormalities in CRF neuronal regulation occur in patients with anxiety disorders. Analysis of variance (ANOVA) revealed no differences in CSF CRF concentrations between the four diagnostic categories: panic disorder (PD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and NCs. Male OCD patients had higher CSF CRF concentrations than men with PD and GAD and male NCs. CSF CRF concentration was positively correlated with age in women but not in men. These findings suggest that central neuronal CRF regulation may be affected by both age and gender.

Cerebrospinal fluid gamma-aminobutyric acid in patients with panic disorder.

Cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in 11 patients with panic disorder (PD) prior to and following 7 months of treatment with alprazolam or imipramine and in six neurological control patients. Although a clear treatment response was observed in patients with PD, neither alprazolam nor imipramine significantly changed CSF GABA during the treatment period. A negative correlation was demonstrated between baseline CSF GABA and posttreatment overt psychopathology. Low pretreatment level of CSF GABA correlated significantly with poor therapeutic outcome, judged by the amount of anxiety and depression as well as by the frequency of panic attacks at the end of follow-up.

CSF diazepam-binding inhibitor concentrations in panic disorder.

Diazepam-binding inhibitor (DBI) is a neuropeptide that has been detected in the brain and cerebrospinal fluid (CSF). Previous studies have suggested the possible role of DBI as a potential endogenous anxiogenic ligand modulating GABAergic transmission at the benzodiazepine-GABA receptor complex. The measurement of DBI immunoreactivity (DBI-IR) in CSF of panic-disorder patients and normal controls was undertaken to assess whether there were differences in the CSF concentration of this peptide to assess possible relationships with other monoamines and peptides. Lumbar CSF was obtained from 18 panic patients (4 men, 14 women) and 9 controls (5 men, 4 women). As a group, no significant differences were found between panic patients' CSF concentration of DBI-IR (1.12 +/- 0.27 pmol/mL) and normal volunteers (1.23 +/- 0.27 pmol/mL). No gender differences were demonstrated. However, we did find a positive correlation between CSF levels of DBI and CSF corticotropin releasing hormone (CRH) in our panic patients.

CSF cholecystokinin concentrations in patients with panic disorder and in normal comparison subjects.

Cholecystokinin concentrations in the CSF of 25 patients with panic disorder and 16 normal comparison subjects were ascertained by radioimmunoassay. The patients with panic disorder had significantly lower CSF concentrations of cholecystokinin, which may reflect increased CNS cholecystokinin receptor sensitivity, reduced numbers of receptors, or a compensatory reduction in cholecystokinin octapeptide secondary to theoretically increased central cholecystokinin tetrapeptide activity.