Andrew W. Goddard

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Glutamate and γ-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that unipolar, but not bipolar, depression is associated with reductions in cortical GABA levels. Antidepressant and mood-stabilizing treatments also appear to raise cortical GABA levels and to ameliorate GABA deficits in patients with mood disorders. The preponderance of available evidence suggests that glutamatergic and GABAergic modulation may be an important property of available antidepressant and mood-stabilizing agents. Future research will be needed to develop and evaluate new agents with specific glutamate and GABA receptor targets in the treatment of mood disorders.

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 γ-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.

Baseline and fear-potentiated startle in panic disorder patients ☆

The present study investigated whether patients with panic disorder had an increase in the startle response and whether this effect, if present, was specific to anticipatory anxiety. The eyeblink component of the acoustic startle reflex was measured in a paradigm involving the anticipation of electric shocks (fear-potentiated startle) in 34 patients with panic disorder and 49 healthy controls. Startle was also recorded in the absence of specific threat at the beginning and at the end of the testing. The testing consisted of three phases: adaptation, fear-potentiated startle, and recovery. In the adaptation and recovery phases, startle stimuli were delivered in the absence of threat. In the fear-potentiated startle phase, startle stimuli were delivered in threat conditions, when subjects anticipated shocks, and in safe conditions that predicted the absence of shocks. Startle was larger in the younger patients (age < 40 years old) compared to the younger controls throughout the testing. The difference reached significance only during the fear-potentiated startle phase, however. Startle was nonsignificantly reduced in the older patients (age > or = 39 years old), compared to the older controls. The results are discussed in terms of the contextual effects of the experimental setting.

SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder

BACKGROUND Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Temporal lobe volume in panic disorder } a quantitative magnetic resonance imaging study

Although previous studies have used magnetic resonance imaging (MRI) to demonstrate qualitative abnormalities of the temporal lobes in patients with panic disorder, no study to date has applied quantitative volumetric methods to evaluate brain changes in panic disorder. The purpose of this study was to measure the volume of the temporal lobe and the hippocampus in patients with panic disorder and healthy control subjects using quantitative MRI measures. The volume of the temporal lobe, hippocampus and whole brain was measured in 13 patients with panic disorder and 14 healthy subjects. The mean volume of the left and right temporal lobes was significantly smaller in panic disorder compared to healthy subjects (16770+/-909 mm(3) vs. 18343+/-1740 mm(3)). This result was significant after controlling for differences in whole brain volume. There was no significant difference in volume of the hippocampus between patients and control subjects. These findings are consistent with smaller temporal lobe volume in panic disorder despite normal hippocampal volume.

Multicenter, randomized, double‐blind, active comparator and placebo‐controlled trial of a corticotropin‐releasing factor receptor‐1 antagonist in generalized anxiety disorder

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010.

Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.

Cigarette smoking is highly destructive to individuals and society, and is moderately heritable. We completed a genomewide linkage scan to map loci increasing risk for cigarette smoking in a set of families originally identified because they segregate panic disorder (PD). One hundred forty two genotyped individuals in a total of 12 families were studied (214 subjects analyzed, including non‐genotyped individuals). Of these individuals, 69 were “affected” with habitual cigarette smoking (i.e., they smoked more than one pack per day for at least a year, or at least 1/2 pack per day for at least 10 years), 49 were “unaffected” (i.e., they smoked less than 1/2 pack per day for less than 1 year), and 24 were scored as “unknown.” Nine families from the panic series were excluded from these analyses because they lacked multiple affected individuals with habitual cigarette smoking. In an initial genomewide scan, we genotyped a total of 416 markers (398 autosomal, 18 X‐chromosome) with an average spacing of less than 10 cM, spanning the genome. Linkage analysis (pairwise, or single‐point, and multi‐point) was performed using ALLEGRO. An additional 14 markers were genotyped in a high‐density panel to follow‐up on an identified region of interest on chromosome 11p. The three highest multi‐point Zlr scores (3.43, 3.04, and 3.01; P = 0.0003, P = 0.0012, and P = 0.0013, respectively), which each reflect “suggestive” evidence for linkage, were observed in multi‐point linkage analyses using Allegro on chromosomes 11p and 9, near markers D11S4046, D9S283, and D9S1677, respectively. D11S4046 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence have previously been identified. The chromosome 9 region we identified as possibly linked to cigarette smoking in anxiety families, was previously identified as significantly linked to PD in Icelandic pedigrees. We also identified evidence supporting linkage (Zlr score > 2.3, P < 0.01) to regions of chromosomes 14, 16, and X. There was a significant phenotypic association between PD and cigarette smoking (P < 0.001). Conclusions: We identified evidence for two loci increasing risk for cigarette smoking that map to chromosomes 9 and 11. There is now evidence supporting linkage or association of chromosome 11 markers with alcohol dependence, illegal drug abuse and dependence, and cigarette smoking. Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD.

Response to meta-chlorophenylpiperazine in panic disorder patients and healthy subjects: Influence of reduction in intravenous dosage

As a further test of the hypothesis of serotonin hypersensitivity in panic disorder (PD), the serotonin agonist meta-chlorophenylpiperazine (MCPP) was administered intravenously in a dose of 0.05 mg/kg to 27 PD patients and 22 normal control subjects. This is one-half the dose used in our previous study of PD patients, where the dose may have been too high to provide evidence of hypersensitivity to the agent. Responses of anxiety and nervousness were statistically indistinguishable by analysis of variance in the two groups, replicating our previous findings. Panic attack symptom score (PASS) ratings were significantly higher in the PD group, compared with a trend toward higher PASS ratings in the 0.1 mg/kg study. Cortisol, human growth hormone, and male prolactin responses showed no significant differences in the two groups by analysis of variance. Prolactin responses were significantly blunted in the female patients. The unexpected blunted prolactin response to MCPP in female PD patients may reflect a nonspecific blunting of prolactin response to stress. The PASS data provide some evidence of serotonergic hypersensitivity in PD.

Serotoninergic mechanisms in the treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling psychiatric condition affecting 1-2% of the community. Although modern drug, behavioral and psychosurgical therapies have improved the prognosis of OCD considerably, approximately 30% of patients remain treatment-refractory. Currently, selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the drug treatments of choice for OCD. Accordingly, this review evaluates the evidence for a role of the serotonin (5-HT) neurochemical system in the treatment and pathophysiology of OCD. However, drug treatment approaches that modify function of interrelated neurochemical systems, such as the dopamine and glutamate systems, are also briefly discussed as they promise to complement and enhance SSRI treatment effects.

Genome Scan for Loci Predisposing to Anxiety Disorders Using a Novel Multivariate Approach: Strong Evidence for a Chromosome 4 Risk Locus

We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.