1
Psychiatric Clinics of North America
Volume 24 • Number 1 • March 2001
Copyright © 2001 W. B. Saunders Company
GENERALIZED ANXIETY DISORDER
Neurobiology of Generalized Anxiety Disorder
Praveen V. Jetty
1
MD, MRCPsych
Dennis S. Charney
2
MD
Andrew W. Goddard
3
MD
1
Substance Abuse Program, Health South Metro West Hospital, Fairfield, Alabama (PVJ)
2
Mood and Anxiety Disorders Research Program and Experimental Therapeutics and Pathophysiology Branch, National Institute
of Mental Health, Bethesda, Maryland (DSC)
3
Anxiety Disorders Program, Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health
Center, New Haven, Connecticut (AWG)
Address reprint requests to
Praveen V. Jetty, MD, MRCPsych
Substance Abuse Program
Health South Metro West Hospital
Fairfield, AL 35064
e-mail Praveen.jetty@usa.net
Generalized anxiety disorder (GAD) is a relatively new diagnostic entity first defined as a distinct category in the DSM-
III.
[7]
Two major epidemiologic studies, the National Survey of Mental Health and Well-Being
[2]
and the National
Comorbidity Survey
[120]
have shown an incidence of 3.6% and 3.1% per year, respectively. Based on the National
Comorbidity Survey data in the United States alone, more than 9 million people are afflicted with GAD at some point
during their lifetimes. Also, GAD is one of the most common psychiatric disorders seen by primary care physicians.
GAD was once considered by many clinicians to be a relatively mild condition, but new scientific data have challenged
the perception that GAD is mild and minimally disabling. GAD has been found to be associated with various adverse
social consequences, such as being more prevalent in lower socioeconomic groups, being poorly paid, being on
disability, and experiencing more marital instability and divorce than the general population.
[12]
GAD has a lifetime
comorbidity rate of 62% with major depressive disorder (MDD), 39.5% with dysthymia, 37.6% with alcoholism, and 34.4%
with social phobia. Comorbid GAD seems to be associated with an even greater level of functional impairment than GAD
alone. Follow-up studies have shown a substantial impairment and even poorer outcome among people with GAD than
among those with panic disorder.
[121]
[125]
Thus, it is evident that GAD is neither an infrequent nor mild condition but an
important public health problem that merits additional research on treatment and mechanism of illness.
The diagnostic concept of GAD, however, is somewhat controversial. Some investigators have suggested that GAD is a
residual or prodromal phase of MDD,
[92]
[98]
or a "forme fruste" of MDD.
[61]
Other investigators have observed that it is
attributable to other anxiety disorders, such as social phobia
[81]
or panic disorder.
[114]
Still others have conceptualized
GAD as a dimension of personality function, a generalized anxious temperament that, when pronounced, constitutes
psychopathology,
[4]
whereas other investigators have conceptualized GAD as a part of a general neurotic syndrome.
[113]
A well-designed 5-year longitudinal follow-up study, however, showed significant diagnostic stability for GAD,
supporting the reliability of the diagnosis.
[121]
Thus additional research must be carried out to clarify the diagnostic
boundaries of GAD so that meaningful conclusions may be drawn from research studies.
This article provides a concise picture of preclinical and clinical research pertinent to the neurobiology of GAD.
Research on functional neuroanatomy and fear circuitry; animal models relevant to GAD; research on the genetics of
GAD; and neurochemistry, neurophysiology, and functional imaging studies relevant to GAD are discussed. Finally, a
crucial discussion of several biological models of GAD is presented, and paths for future research are suggested.
2
GENETIC STUDIES
Vulnerability to anxiety disorders may be determined in part by genetic predisposition. Genes may influence the expression of key
neurotransmitters, thereby modifying behaviors. Because GAD is a relatively new diagnostic entity, and there have been major
changes in the diagnostic criteria, it is not surprising that there is disagreement over the genetic findings from work of different
researchers. There does seem to be a modest genetic contribution for the development of GAD, however, as evidenced by the
research described herein.
The various family studies of GAD that have been conducted generally point to GAD being a familial syndrome. One research
group
[89]
found that 19.5% of first-degree relatives of GAD probands had developed the disorder compared with only 3.5% of
control subjects' families, with a corresponding relative risk of 5.6, which is large compared with other anxiety disorders. Other
investigators
[103]
diagnosed GAD in 22% of first-degree relatives of 33 probands with anxiety disorders, 13 of whom had GAD, but
other investigators
[80]
found no evidence of inheritance of GAD in their family study. Other studies have suggested that GAD and
MDD cosegregate in families.
[9]
[118]
Data from epidemiologic surveys also have shown a high rate of comorbidity of this disorder.
Although family studies may discriminate the impact of individual-specific environmental factors from those of genes and the
family environment, they are unable to make the important distinction between the latter two factors. To help make this
distinction, twin and adoption studies are required. Twin studies of GAD include one conducted by Torgersen et al,
[111]
who
studied anxiety disorders in 12 monozygotic and 20 dizygotic twin pairs in Finland. None of the monozygotic and only one of the
dizygotic twins was concordant for GAD. Another group
[8]
found that 21.5% of 63 monozygotic twin pairs were concordant for
GAD compared with 13.5% of 81 dizygotic pairs, whereas another study
[104]
showed that three of five monozygotic and one of
seven dizygotic twin pairs were concordant for GAD. Large cohorts
[60]
[98]
were used to study GAD and depression in the Virginia
twin study and a sample of twins from the Swedish twin registry. In both samples, the same genetic factors accounted for both
disorders. GAD and depression were genetic, but an index monozygotic twin with either diagnosis was as likely to have a twin
with the other disorder as with the same disorder. A follow-up study by Kendler et al
[62]
showed additional support for the
hypothesis that genetic factors are relatively nonspecific in their impact on symptoms of depression and GAD. They suggested
that GAD has approximately a 30% heritability rate, but the study has been criticized on some methodologic shortcomings, with
the diagnostic criteria being loosened to gain a larger sample size (e.g., DSM-III-R 6-month duration criterion for GAD being
changed to 1 month), but this study is the largest to date, with 2352 female twin subjects. The findings suggest that the genetic
liability between the two disorders is identical and that which disorder that develops is determined entirely by the environment.
Because familial environment contributed to neither disorder, the environmental influences must be considered unique. These
findings are echoed by a family study of cotransmission of depression anxiety disorders and alcoholism,
[82]
which showed that
more than half the variance in liability for GAD and depression may be accounted for by extrafamilial influences and therefore not
caused by a shared environment. In a study of male twins to test for distinction between subjects with GAD and panic disorder,
Scherrer et al
[100]
found that the lifetime co-occurrence of GAD and panic disorder could not be explained by family environmental
influences. Thus, although evidence from some studies show that MDD and GAD share the same genotype, the expression of
these disorders seems to depend on environmental influences unique to each patient.
Molecular genetic studies of the anxiety disorders are still in their infancy. Some of the promising approaches used are molecular
genetics of personality characteristics, linkage studies in animal behavioral models, and candidate gene studies in transgenic
animals. It is hoped that these techniques will lead to a better understanding of the anxiety disorders at a molecular level. Several
genome searches have been started for panic disorder,
[26]
but so far there have been none for GAD. One GAD study focused on
the serotonin (5-HT) transporter gene located on chromosome 17q.
[91]
Significantly higher proportions of the GAD group than
controls had the Stin2.12 allele. The odds ratio was 3.61, but this result is not only specific to GAD but also seen in obsessive-
compulsive disorder and MDD. The same group
[90]
also studied a polymorphism on the catechol-O-methyl transferase gene but
found no statistically significant difference between subjects and controls. Several strategies, such as systematic genome
scanning and candidate-gene strategies, may be used for understanding linkage. The receptors in the gamma-aminobutyric acid
(GABA), norepinephrine (NE), corticotropin-releasing factor (CRF), and 5-HT systems would be considered prime candidates for
the candidate-gene strategy. Despite many weaknesses, candidate-gene studies are a reasonable strategy in that the approach
is hypothesis based, and, if a gene is found using this method, money and time would be saved.
Genetic studies of GAD consistently indicate that genes contribute to the development of GAD. Although family and twin study
data suggest this, they also demonstrate that the influence of genes is modest compared with classic Mendelian diseases or
even the more heritable polygenic diseases. So clinicians must prepare to confront genes of small effect that most likely
contribute incrementally to the threshold for GAD.
FUNCTIONAL IMAGING STUDIES
There have been few studies on functional imaging in GAD. Data from clinical imaging studies suggest the involvement of the
occipital cortex in GAD. Buchsbaum et al
[18]
found a significant decrease of occipital lobe metabolism after benzodiazepine
administration in patients with GAD. Wu et al
[123]
studied 18 patients who met DSM-III criteria for GAD and were randomized to
receive clorazepate or placebo during a series of activation and vigilance tasks. The study showed higher relative metabolic rates
for subjects with GAD in parts of the occipital, temporal, and frontal lobe metabolism and cerebellum relative to normal controls
and a decrease in basal ganglia metabolism. No right-left hippocampal asymmetry was found, as has been reported in panic
disorder. Arousal tasks resulted in activation of the basal ganglia and right parietal metabolism. After benzodiazepine therapy, a
reduction in glucose metabolism was found in the cortex, limbic system, and basal ganglia compared with the control subjects.
The investigators concluded that the findings support a role for the potential involvement of the basal ganglia in GAD. Tiihonen et
al
[110]
conducted an investigation using MR imaging and single photon emission CT to assess central benzodiazepine receptor
3
binding and distribution in subjects with GAD. Subjects with GAD had significantly decreased reduction in the density of these
receptors in the left temporal pole. Results of various studies are summarized in Table 1 . Neuroimaging studies in GAD are at an
early stage. Unfortunately, there is a paucity of literature available on the subject, and the significance of findings to date is
unclear but suggestive of brain changes in some neuroanatomic regions that are relevant in arousal and anxiety. With increasing
sophistication of technology, additional studies likely will clarify some of these ambiguities.
TABLE 1 -- FUNCTIONAL IMAGING STUDIES IN GENERALIZED ANXIETY DISORDER
Study
No. Subjects
Scan Type
(Function
Measured)
Findings Inferences
Mathew et al,
1982
[77]
GAD 9, controls, 9 Xenon
inhalation,
CBF, rCBF
Global CBF
insignificantly
decreased in GAD
patients
CBF inversely
correlated with trait
anxiety
Mathew and
Wilson, 1988
[76]
GAD, 13; controls,
13
Xenon inhalation,
CBF, rCBF
CO
2
-induced CBF
increase GAD = NC
? CBF change
inversely correlated
with state anxiety
Buschbaum et al,
1987
[18]
GAD, 18
PET, GMR, rGMR Decreased GMR in
visual cortex during
treatment;
increased rGMR in
BG and TH
Occipital lobe
involvement in
GAD; ? related to
hypervigilance
Tiihonen et al,
1997
[110]
GAD, 10; controls,
10
SPET, MR imaging Benzodiazepine
receptor binding
was decreased in
the L-temporal pole
among GAD
patients; more
homogeneous
cerebral
benzodiazepine
receptor density
distribution in
patients with GAD
Trait abnormality
that leads to
abnormal stimulus
processing in GAD
Wu et al, 1991
[123]
GAD, 18; controls,
15
PET, GMR, rGMR Basal ganglia,
temporal poles,
cortex, CG resting
rGMR GAD < NC
cerebellum, L occ-
cortex, R precentral
frontal cortex
resting GAD > NC
Involvement of
basal ganglia in
GAD; ? clue to
ruminations in GAD,
similar to the basal
ganglia-frontal lobe
circuits in OCD
BG = basal ganglia; CBF = cerebral blood flow; rCBF = regional cerebral blood flow; CG = cingulate cyrus; GMR = glucose metabolic rate; L =
left; NC = normal control; PET = positron emission tomography; Occ = occipital; R = right; rGMR = regional glucose metabolic rate; OCD =
obsessive-compulsive disorder; GAD = generalized anxiety disorder; SPET = single photon emission tomography; MR = magnetic resonance.
NEUROCHEMISTRY
gamma-Aminobutyric Acid Neuronal System
GABA is the main inhibitory neurotransmitter in the CNS and is widely distributed in all regions of the brain. The benzodiazepine
receptors and GABA
A
receptors are part of the same macromolecular complex. These receptors have different binding sites but
are functionally coupled and regulate themselves in an allosteric manner.
[70]
[74]
[126]
The hypothesis that alteration of function of
this complex may have a significant role in the pathophysiology of GAD is suggested by some lines of evidence from animal and
studies, as discussed here.
In one study,
[30]
animals exposed to long-term, inescapable stress in the form of cold swim or foot shock showed a decrease in
benzodiazepine receptor binding in frontal cortex, hippocampus, and hypothalamus--areas associated with the neural circuitry of
fear and anxiety. In another study,
[25]
gamma
2
subunit knockout mice showed enhanced behavioral inhibition toward natural
aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination. Synaptic clustering
of GABA
A
receptors in mice heterozygous for the gamma
2
subunit was reduced, mainly in hippocampus and cerebral cortex. This
model suggests GABA
A
receptor dysfunction as a potential causal predisposition to anxiety disorders, such as GAD.
The human literature also supports a role for benzodiazepine dysfunction in anxiogenesis. In one study,
[29]
normal subjects
experienced severe anxiety reactions to benzodiazepine inverse agonists, such as beta-carbolines. Another study
[96]
showed that
benzodiazepines were clinically effective in the treatment of patients with GAD. Patients with GAD have been found to have
4
abnormally low levels of peripheral lymphocyte benzodiazepine receptors (PBR), which normalize after treatment with
benzodiazepines,
[34]
[97]
suggesting that GAD might be associated with an abnormal decrease of PBRs. This finding also is seen
in obsessive-compulsive disorder but not in panic disorder, suggesting that changes in lymphocyte PBR may distinguish between
different types of anxiety states. The decrease in the PBRs in patients with GAD is paralleled by a concomitant decrease in the
relative content of mRNA encoding PBR, suggesting that the rate of synthesis of these receptors also decreases during active
illness, which reverses with successful treatment. Recent research indicates that PBRs may modulate the central GABA
A
receptor function, possibly by regulating steroidogenesis in peripheral tissues and in the brain, suggesting a mechanism by which
peripheral abnormalities may affect the CNS in GAD and other disorders. In studies of PBRs located on monocytes of patients
with GAD, the ability of the monocytes to migrate toward chemoattracting benzodiazepines is completely abolished.
[99]
This
chemotaxis still is impaired after their treatment with diazepam, with good clinical recovery and a normalization of receptor
density. The investigators explained this finding on the basis that treatment reversed the PBR decrease but that the receptor still
may be desensitized because of an impairment in the receptor-transducer coupling mechanisms and an increase of the
anxiogenic endogenous ligand, such as the diazepam binding inhibitor in GAD. Additional studies combining imaging and
molecular genetics may clarify the role of the GABA-benzodiazepine system in GAD.
Noradrenergic System
Although the role of the NE system in acute and chronic animal models of stress has been well documented,
[20]
NE also is
associated with neural mechanisms, such as sensitization
[88]
and fear conditioning, which are associated with stress.
The role of NE in the pathophysiology of GAD is unclear because the data from the studies in this area are mixed. Patients with
GAD show good response to noradrenergic drugs, such as imipramine and the norepinephrine 5-HT reuptake inhibitor (SSRI)
venlafaxine.
[33]
[102]
Platelet monoamine oxidase activity is increased in patients with GAD.
[78]
Using skin-conductance after stress,
some studies have shown a hyporesponsive and prolonged autonomic response in subjects with GAD.
[51]
Other investigators
[101]
compared NE function in patients with GAD and in those with MDD and healthy controls and found that plasma levels of NE and
free 3-methoxy-4-hydroxyphenylethelene glycol were increased in the GAD group and that the number of alpha
2
-
adrenoreceptors decreased. They concluded that NE activity is increased in subjects with GAD and that higher levels of
catecholamines may lead to a decrease of the presynaptic alpha
2
-adrenoreceptors, but other studies
[77]
[86]
did not report any
difference between patients with GAD and normal controls. Another study
[64]
found no significant differences between controls
and patients with GAD in the levels of catechol-O-methyl transferase, dopamine beta-hydroxylase, and monoamine oxidase. An
additional study
[37]
showed that subjects with GAD had increased levels of another NE metabolite, vanillylmandelic acid, in urine.
A blunted growth-hormone response to clonidine has been described by some investigators
[1]
and may be caused by presynaptic
autoreceptor hypersensitivity or postsynaptic hyposensitivity. Another focus of study on the NE system in GAD has been on the
inhibitory alpha
2
-adrenergic receptor. Inhibition of these receptors presynaptically results in increased NE activity and anxiety
behaviors in animals. Other investigators
[22]
used an alpha
2
-adrenergic antagonist to study difference in response and found that
subjects with panic disorder or posttraumatic stress disorder (PTSD) were abnormally sensitive to generating anxiety responses
but that patients with GAD were not. So, overall, the results of studies of the NE system in GAD have been inconsistent. The
available data are limited to draw meaningful conclusions, and future studies will need to address the issue of evaluating direct
CNS indices of NE function. Also, with the changing taxonomy and diagnostic criteria, studies will have to use DSM-IV criteria to
arrive at a coherent formulation.
Serotonin
Another neurotransmitter associated with the pathogenesis of GAD is 5-HT. In animals, threatening situations seem to increase
synaptic 5-HT levels, and cortical and limbic regions may use this input to analyze and react to the situation.
[45]
In animal studies,
5-HT receptor subtypes 5-HT
1A
, 5-HT
2A
, and 5-HT
3
have been associated with fear behavior and consequently have been of
most interest in human anxiety disorders, such as GAD. Mice bred without 5-HT
1A
receptors (i.e., 5-HT
1A
knockout mice) show
decreased exploratory activity and increased fear of aversive environments, suggesting heightened anxiety.
[94]
The 5-HT
1A
receptor agonists, such as buspirone, ipsapirone, and gepirone, which selectively decrease the firing rate of 5-HT neurons in
animal models,
[109]
have been shown to be of help in treating GAD.
Evidence for the possible role of 5-HT involvement in GAD comes from the following clinical studies. One study found decreased
platelet paroxetine binding in patients with GAD.
[54]
Another study
[36]
showed a distinction between patients with GAD and those
with panic disorder by showing that the urinary levels of the lysosomal enzyme N-acetyl-beta-glusosaminidase were significantly
higher in patients with GAD. N-acetyl-beta-glusosaminidase levels are thought to be an indirect marker for 5-HT activity. Another
study
[37]
found that elevated urinary levels of the 5-HT metabolite 5-hydroxyindoleacetic acid predicted higher anxiety levels in
patients with GAD, implying increased 5-HT metabolism in more anxious patients with GAD. On the other hand, one study found
that the 5-HT synthesis inhibitor, PCPA, was anxiogenic in humans, implying an association between decreased 5-HT levels and
anxiety. Hence, the relationship between 5-HT levels and anxiety has been inconsistent, so attention has focused on receptor
subtypes. Studies have supported the role of 5-HT
2C
and 5-HT
2A
receptor subtypes in GAD as reviewed by Kahn et al.
[57]
Also,
patients with GAD have shown greater anger and anxiety responses to the mixed postsynaptic 5-HT agonist-antagonist meta-
chlorophenylpiperazine than control subjects.
[38]
Examining the differences in slow-wave sleep (which may be influenced by
serotonergic activity) between patients with GAD and normal controls using ritanserin, some investigators
[27]
found no significant
differences, but the sample size was small, and although they did not find evidence to support the hypothesis that there is a
generalized hypersensitivity of brain 5-HT
2
receptors, they believed that their data could not exclude the presence of a regionally
specific change in this receptor. Clinical data show efficacy of 5-HT
1
receptor partial agonists, such as buspirone,
[106]
and 5HT
2
blockers, such as nefazodone, in GAD. Thus, although the general trend for the findings is that of 5-HT dysfunction in people with
5
GAD, the question of hyperactivity or hypoactivity of 5-HT is unclear. Future studies (e.g., imaging studies of receptor subtypes
and the 5-HT transporter) may elucidate the picture.
Neuropeptides
Cholecystokinin
Much research has associated neuropeptides with normal anxiety responses in animal models and in pathologic anxiety in
humans. Of particular relevance is the cholecystokinin (CCK) system. CCK is one of the most abundant and widely distributed
peptide neurotransmitters in the brain, and the CCK-B (brain) receptors are found with high densities in the hypothalamus, limbic
system, basal ganglia, hippocampus, cortex, and brain stem, all of which have been associated with animal fear behaviors. There
are several different CCK peptides, but CCK-4 and CCK-8 are of most interest in the study of anxiety.
[75]
CCK-B is widely
distributed in the brain and seems more directly involved in animal models of anxiety.
[47]
Observed responses to CCK-B receptor
agonists include decreased exploratory activity in mice and rats, submissive and restless behavior in monkeys, and defensive
attack in cats. Pretreatment with CCK-B antagonists, such as L-365,260, and CI-988 blocks the anxiogenic activity of CCK
agonists.
[122]
CCK activates NE neurons in the locus ceruleus by peripheral CCK receptors in vagal efferent pathways. CCK also
interacts with the GABA system, and withdrawal from long-term diazepam administration is associated with an increase of CCK-8
binding in frontal cortex of rats. Endogenous CCK release enhances or amplifies stress responses that are 5-HT mediated.
Researchers have tried to uncover the role of CCK in the modulation of anxiety and stress responses in human subjects. Studies
have shown that intravenous injection of the CCK-B agonists CCK-4 and pentagastrin in subjects with panic disorder were
panicogenic compared with control subjects.
[14]
Another study
[15]
showed that intravenous pentagastrin induces higher rates of
panic attacks in patients with GAD (71%) than in age-matched and sex-matched control subjects (14%). One study
[63]
explored
the genetic basis of panic disorder and suggested a link between CCK-B receptor gene polymorphism and panic disorder. The
precise mechanism of CCK induced anxiety, however, is unclear. In response to the research associating CCK with anxiety and
fear behaviors, anxiolytic drug development efforts have focused on the therapeutic potential of CCK-B receptor antagonists.
Although preclinical studies have shown promise, studies in clinical trials in patients with GAD have proved disappointing,
[3]
and
the ability of CI-988 to block anxiety in lactate-induced panic and CCK-4-induced panic has been limited, perhaps because of its
poor bioavailability.
[39]
In another study, in patients with GAD, the CCK-B antagonist CI-988 did not show any anxiolytic effects,
[39]
and neither did another CCK-B antagonist, L-365,260, in subjects with panic disorder.
[105]
Nevertheless, if agents from this class
of compounds were found to be clinically effective in subjects with GAD, then they would have significant advantages over
available pharmacotherapies in view of low abuse potential and rapid onset of action.
Corticotropin-Releasing Factor
CRF is widely distributed in the brain, with highest concentrations found in the hypothalamus, where it is produced and secreted
by the parvocellular neurons of the hypothalamic paraventricular nucleus. It is the major hypophysiotropic factor regulating basal
and stress-induced release of adrenocorticotropic hormone, beta-endorphin, and other proopiomelanocortin-derived peptides.
[115]
Moderate and low levels of CRF also are present in cortical and limbic structures, respectively. The effects of CRF are mediated
by two specific G-protein-coupled, seven-transmembrane domain receptors called CRF-1 and CRF-2. CRF-1 receptor expression
is most abundant in neocortical, cerebellar, and limbic structures, whereas CRF-2 receptor expression is typically localized in
subcortical structures, notably in the lateral septum and various hypothalamic areas. CRF-2alpha subtype is primarily expressed
within the brain, whereas the subtype CRF-2beta is found in the CNS and periphery.
[73]
CRF may contribute significantly to the
behavioral responses to stress and the emotional behavior.
[65]
Intracerebroventricular administration of CRF in animals increases the concentrations of CRF in the CNS, produces physiologic
and behavioral alterations virtually identical to those observed in laboratory animals in response to stress, including increases in
heart rate and mean arterial pressure, suppression of exploratory behavior, induction of grooming, and reduction in feeding
behavior. Additional actions include potentiation of acoustic startle responses, facilitation of fear conditioning, and enhancement
of shock-induced freezing.
[43]
These effects do not occur after systemic administration of CRF and are not blocked by
hypophysectomy, adrenelectomy, or pretreatment with dexamethasone, suggesting that these actions of CRF do not involve
activation of the pituitary-adrenal axis but are mediated by CRF receptors present in the CNS. Several of these effects of CRF
seem mediated by activation of the central NE system. Microinjection of CRF directly into the locus ceruleus of rats has been
found to produce defensive withdrawal responses from a novel environment.
[19]
Similarly, intra-amygdala infusion of CRF has
been shown to produce anxiogenic behavior in the open field test and increase grooming in rats. Investigators used a transgenic
mouse model overexpressing CRF and found that the mice exhibited a behavior state akin to anxiety,
[66]
but in a study of CRF
knockout mice, no differences between mutant and normal mice in 1997 were found.
[83]
This may be because of compensation by
other peptidergic mechanisms, but overall, CRF seems to have a significant in anxiety-related and stress-related states.
Clinical data suggesting a role for CRF in anxiety disorders has been accumulating for many years. Cerebrospinal fluid (CSF)
levels of CRF have been shown to be elevated in patients suffering with obsessive-compulsive disorder
[6]
and PTSD but not panic
disorder.
[56]
Baseline CSF studies of CRF levels, however, have not shown significant differences between control subjects and
patients with GAD, panic disorder, or obsessive-compulsive disorder,
[35]
suggesting no tonic hypersecretion in people with these
disorders. CRF may be episodically hypersecreted and may initiate fear responses in some contexts, however. In this regard,
KOOB proposed a model that stress activates two types of CRF-NE interactions. Stress may activate CRF release in the region
of the locus ceruleus, activating it and releasing NE in forebrain terminal projections, which, in turn, stimulates the release of
CRF. Accordingly, a powerful feed-forward system, akin to kindling,
[65]
may be triggered by episodic or chronic stress.
The past few years have seen important advances in the understanding of CRF and its mechanisms of action in modulating
responses to stress. The finding that CRF stimulation increases anxiety-related behaviors in various animal models suggests that
agents acting at CRF receptors may have therapeutic value in anxiety disorders. Industry is actively pursuing the development of
nonpeptide and lipophilic CRF receptor antagonists as novel anxiolytics, and data on their efficacy should be available soon.
[43]
6
Neuropeptide-Y (NPY) is one of the most abundant peptides in the body. There are at least three NPY receptors, classified as
Y
1-3
.
[117]
High densities of Y
1
and Y
2
receptors are found widely in the CNS. The presence of NPY and its receptors in brain
regions that are activated during stress (e.g., the amygdala and hypothalamus) has provided a rationale for studying NPY and
related peptides in animal models of anxiety.
Several studies in rats have shown that intracerebroventricular injections of NPY produce a behavioral profile consistent with an
anxiolytic-like action in various anxiety models. One study
[17]
showed that the anxiolytic activity is comparable to that of
chlordiazepoxide. A series of studies have shown that intracerebroventricular infusion of high-affinity Y
1
agonists, including
(Gly
[121]
, Glu
[26]
, Lys
[18]
, Pro
[70]
, Leu
[110]
)-NPY, yielded anxiolytic activity. Y
2
receptor analogues have been found to be inactive
in anxiety models in many studies, leading to the conclusion that the anxiolytic-like effects of NPY may be mediated primarily by
activation of the Y
1
receptors.
A few studies have shown that NPY might be involved in human anxiety but not in GAD. For example, one study
[119]
found that
the lowest CSF concentrations of NPY in depressed patients were among those who had the most severe anxiety; another
study
[13]
showed higher plasma NPY-like immunoreactivity in patients with panic disorder compared with healthy controls. Other
investigators,
[107]
however, did not find significant differences between controls and subjects with panic disorder or social phobia
at basal and during stress stimulation. The reasons for these discrepancies are unknown but underscore the need for additional
study of NPY in anxiety disorders in general. The robust anxiolytic effects observed with Y
1
agonists in preclinical research
suggest that these compounds may become an alternative to benzodiazepines for the treatment of anxiety disorders, but
additional work on searching for selective nonpeptide Y
1
receptor agonists is needed to potentially provide new drugs for the
management of anxiety disorders.
Tachykinins
Tachykinins are a group of neuropeptides that include substance-P, neurokinin-A, and neurokinin-B. The biological effects of
tachykinins are mediated by the NK
1-3
receptors. NK
1
and NK
2
receptors are widely distributed in the CNS and are found in
significant density in brain regions traditionally associated with control of fear and anxiety, such as the amygdala, hypothalamus,
and the periaqueductal gray.
Substance-P, when injected in picomolar concentrations, is anxiogenic and anxiolytic depending on the dose and the brain region
in which it is injected. Studies using a range of NK
1
antagonists have indicated that they possess anxiolytic activity, albeit some of
them weakly, but studies on NK
2
receptor antagonists in animal models have invariably shown anxiolytic activity, which is robust.
The most studied drugs in this group are GR-159897
[11]
and SR-48968, which show anxiolytic activity similar to that of
benzodiazepines but do not produce behavioral suppression at higher doses. Although the anxiolytic effects of NK
2
receptor
antagonists are compelling, these effects have been obtained only in exploration tests. Research is needed using these in conflict
paradigms to compare their efficacy to classic anxiolytics.
Other Peptide Systems in Anxiety
The natriuretic peptide system consists of the atrial, brain, and C-type. Although several preclinical studies have shown that
natriuretic peptides display anxiolytic activity, the potential of these compounds must be evaluated in more preclinical paradigms
and in clinical anxiety disorders.
One of the primary behavioral effects of uncontrollable stress is analgesia, which results from the release of endogenous opioids.
Most clinical research on opiates in treating anxiety disorders has focused on PTSD. Most studies support a hypothesis of
increased release of endogenous opiates with stress in PTSD. This hypothesis also has been supported by a finding of elevated
levels of beta-endorphin in CSF in PTSD. Opioids are powerful suppressors of the NE system. They decrease hyperarousal in
many patients with PTSD.
[16]
Opioids may be used as a treatment paradigm because increased NE activity is considered one of
the causes of anxiety. There has been a lack of studies in other anxiety disorders, and this area requires research.
Glutamate
The glutamate receptors mediate excitatory neurotransmission in the brain. Glutamate neurotransmission also is important in
neuronal plasticity, as exemplified by long-term potentiation in the hippocampus, a mechanism of relevance in the
pathophysiology of anxiety.
[87]
Stress activates cortical and limbic glutaminergic systems.
[67]
CNS circuitry mediating response to
stress is heavily dependent on glutaminergic pathways. Stress-related animal models of depression have shown an increase in
N-methyl-d-aspartate (NMDA) NR
1
subunit gene expression in the ventral tegmental area and regionally selective increases in
NMDA binding or function.
[124]
Chronic administration of NMDA antagonists and glycine-B partial agonists reduces behavioral
deficits in animal models of anxiety and depression.
[112]
NMDA antagonists prevent fear conditioning and have direct anxiolytic
activity.
[84]
Stress seems to stimulate glutamate release in the hippocampus, in part because of the effects of glucocorticoids.
[85]
Studies in healthy human subjects suggest that NMDA antagonists produce disturbances in identity and perception resembling
dissociation. Lamotrigine, a drug that reduces glutamate release in humans, attenuates the dissociative effects of ketamine in
humans. The efficacy of NMDA antagonists in the treatment of human anxiety disorders has not been explored. Industry has
already begun clinical testing of metabotropic glutamate receptor agonists at the GLU
2/3
receptor in GAD and other anxiety
disorders. Research using the startle paradigm, which is influenced by NMDA receptors, will be of interest because startle
reactivity may be a vulnerability marker for the development of anxiety disorders. Research is needed to determine whether the
inhibition of glutamate release by drugs such as lamotrigine or metabotropic agonists will help people with anxiety disorders.
Neuroactive Steroids
Neurosteroids are synthesized in the CNS and peripheral nervous system, particularly but not exclusively in myelinating glial
cells, from cholesterol or steroidal precursors. They include pregnenolone and dehydroepiandrosterone (DHEA) and their
sulphates and metabolites. These compounds may act as allosteric modulators of neurotransmitter receptors.
[10]
7
Allopregnanolone is of great significance for psychiatric research because it binds with high affinity at nanomolar concentrations
to GABA
A
receptors and potently facilitates GABA action at these receptors.
[44]
DHEA has been reported to act as a functional
antiglucocorticoid. In animal studies, chronic exposure to DHEA-S impairs contextual fear conditioning 24 hours after conditioning
but not immediately after conditioning, which is similar to adrenalectomy. In mice, DHEA and DHEA-S show anxiolytic activity in
the plus-maze test,
[79]
and the investigators in this study believed that neurosteroids were involved in the termination of stress
responses. Also, allopregnanolone had anxiolytic activity, and the central nucleus of the amygdala is the key region involved in
the mechanism.
[5]
Acute foot-shock stress and carbon dioxide inhalation elicit a time-dependent increase in progesterone,
allopregnalanolone, and allotetrahydrodeoxycorticosterone in rat brain and plasma and antagonism with abecarnil, an anxiolytic
beta-carboline derivative, blocks this increase. Other investigators have studied DHEA-S-cortisol ratio values in subjects with
panic disorder and found that subjects with panic disorder seemed to have a markedly increased DHEA-S-cortisol ratio value
compared with control subjects.
[32]
No studies have been done in human subjects with GAD, and this may be an area for future
research in view of the possibility of developing novel treatments.
Lactate and Carbon Dioxide Challenge Paradigms
Pharmacologic challenge strategies are considered an increasingly important investigational method in studying anxiety
disorders. Carbon dioxide-induced and lactate-induced anxiety have been studied with a view to distinguishing GAD from panic
disorder. Studies found that many patients with panic disorder have panic attacks while rebreathing 5% carbon dioxide, whereas
those with GAD did not.
[40]
[53]
[76]
Other investigators found, however, that when 35% carbon dioxide was inhaled (single-
inhalation) by subjects with GAD, they had less anxiety and fewer panic attacks than did patients with panic disorder, but that
both groups had similar increases in somatic symptoms.
[116]
Another study evaluated the response of patients with GAD to the
administration of sodium lactate
[24]
and showed patients with GAD panicked at a lower rate (11% v 41%) after lactate infusion
than did patients with panic disorder but that patients with GAD reported significantly more anxiety symptoms than did normal
controls. Another study showed lactate-induced panic rates of 26% for patients with panic disorder compared with 13% of those
with GAD.
[68]
Rapee et al
[95]
reported that 15 minutes of breathing 5.5% carbon dioxide caused patients with panic disorder to
develop a greater subjective response than in patients with GAD (49% v 21%), who, in turn, had a greater response than did
control subjects (0%).
[95]
A history of panic attacks may be an important factor in determining anxiety sensitivity to challenge
paradigms. Overall, the results of these challenge studies demonstrate that GAD and panic disorder are discrete disorders but
that they share a common sensitivity to some physiologic stressors. These findings also imply that both of these disorders might
derive from a dysregulation of the self-preserving response such as that elaborated in Klein's suffocation alarm theory.
NEUROBIOLOGICAL MODELS
The large body of work previously reviewed has contributed to the generation of hypotheses concerning the pathogenesis of GAD
and other anxiety disorders. Biological and psychosocial factors seem to contribute to the development of GAD. Various
biological models of anxiety have been proposed that provide a framework for understanding the phenomenology and
neurobiology of GAD.
An elegant model of human anxiety has been articulated by Gray,
[42]
based on preclinical data focusing on states of "behavioral
inhibition" seen in animals facing threat. The primary anatomic components of this behavioral inhibition system include the
septohippocampal areas, locus ceruleus, and median raphe nuclei. Also, the prefrontal cortex may modulate septohippocampal
activity. In this model, the septohippocampal system assesses the potential threat value of stimuli, and, when appropriate,
activates the behavioral inhibition circuit, which, in turn, increases the monitoring of sensory stimuli for additional evidence of
danger and suppresses motor activity. Gray postulates that theta electric rhythms transmitted from the septum to the
hippocampus suppress hippocampal activation, acting as an "all-clear" signal, which also finds validation in clinical studies.
[108]
Increased NE output to the septum inhibits theta transmission, causing the hippocampus to maintain a state of heightened
activity. Also, serotonergic stimulation of the septohippocampal area further activates this system. Under conditions of acute
stress, 5-HT and NE activity are increased and amplify septohippocampal activity. Chronic activation of the behavioral-inhibition
system may produce a chronic state of fear in animals. This consequent state of hypervigilance and increased arousal is
analogous to the chronic anxiety in humans with GAD. In this model, antianxiety medications are said to exert their effects by the
reduction of the NE and 5-HT inputs into the septohippocampal region. Benzodiazepine anxiolytics theoretically would reduce
function in these systems by acting at the presynaptic GABA
A
receptors in the raphe nuclei, in the locus ceruleus, and
postsynaptically in hippocampal formation.
The strengths of the Gray model in explaining the pathogenesis GAD include the fact that it is well grounded in the preclinical
literature. Also, it has direct clinical implications in relation to the psychological concept of behavioral inhibition, which has been
identified as a risk factor for adult anxiety disorders.
[50]
Behavioral inhibition would be expected to be associated with decreased
behavioral activity and relatively decreased activity in the basal ganglia. This prediction has been observed in human studies of
moderate anxiety states (e.g., GAD) that show a generally enhanced level of cortical activity and decreased basal ganglia
activity,
[18]
[123]
in contrast to severe anxiety states (e.g., panic), which tend to enhance basal ganglia activity to support the fight-
or-flight response. These data may be caused by alterations in focal cerebral metabolism or may be explained by changes in
regional cerebral blood flow secondary to moderate anxiety.
[55]
Some human studies also have shown an increased cortisol
output in states of moderate anxiety, with no change or a decrease of plasma cortisol levels in panic disorder,
[52]
consistent with
the prediction of chronic NE hyperactivity suggested by the Gray model. Taken together, these human data provide support for
Gray's model. A weakness of this model is that some of the effective treatments for GAD, such as buspirone and the SSRIs,
result in a net increase serotonergic function in the long term, apparently contradicting the idea that decreasing 5-HT input would
8
decrease clinical anxiety. Also, in terms of its face validity, Gray's model seems to account best for situational anxiety and
exacerbations of a chronic illness brought on by stress. How the model accounts for the maintenance of a chronic anxiety state is
unclear.
A developmental-vulnerability model was proposed for conceptualizing the etiopathogenesis of the anxiety disorders.
[49]
In this
model, adverse experiences early in life predispose individuals to anxiety and mood disorders in adult life. A genetic
predisposition, coupled with early stress in crucial phases of development, may result in a phenotype that is neurobiologically
vulnerable to stress and may lower an individual's threshold for developing anxiety or depression on additional stress exposure.
The model is based on results from preclinical studies, which show that stress early in life results in persistent central CRF
hyperactivity and increased stress reactivity in adulthood.
[72]
[93]
The strengths of the Nemeroff model (i.e., the developmental
vulnerability model) include its attempt to describe the neurobiological impact of early life stressors. It fits well with preclinical
research linking sensitization to stressors with an increase of central CRF and NE function
[65]
and with research showing that
chronic stress by CRF may alter hippocampal structure and function.
[41]
A potential limitation of this model is its nonspecificity with
regard to GAD because the model may be equally well applied to the pathogenesis of MDD and PTSD.
Another model focuses on inherited abnormalities in neurotransmitter systems, which express personality traits that may manifest
as GAD.
[23]
It conceptualizes personality as a combination of three heritable temperament dimensions--novelty seeking, harm
avoidance, and reward dependence--which may be determined by neurotransmitter activity. Harm avoidance has been proposed
to be associated with a high level of 5-HT activity and with anxiety. A high level of harm avoidance may predispose individuals to
feel that they are in danger and to worry constantly, which may lead to generalized anxiety. Studies attempting to link candidate
genes in these three neurotransmitter systems and behavioral traits have provided some empiric support for this model. Some
research has suggested a link between the 5-HT transporter polymorphism and harm avoidance
[58]
and in research using
prolactin response to 5-HT
1A
agonists, which suggests that serotonergic activity and harm avoidance are positively correlated.
[46]
Investigators have worked on the 5-HT transporter system,
[48]
[71]
and observed that a short variant of the transporter occurring
because of a polymorphism shows decreased transcription of the gene, reduced synthesis of the transporter molecule, and
decreased uptake of 5-HT in vitro. Individuals who have the short variant have higher neuroticism scores on the NEO-PI (a
commonly used objective test of personality traits). Kendler's
[59]
model (discussed later) also provides some support for this
observation. Although this model accounts for harm avoidance mediated by inhibiting 5-HT uptake, it does not account for the
action of SSRIs, which also reduce anxiety by inhibiting 5-HT uptake, but the action of SSRIs is more complex than acutely
increasing 5-HT in the synaptic cleft. Another limitation is how it would account for adult-onset GAD.
The interaction of inheritance and the environment in the pathogenesis of GAD has been emphasized by other investigators.
[59]
The Kendler
[61]
group proposed that the genotype for GAD and MDD are similar if not identical but nonspecific in their impact on
the expression of either disorder, which is determined entirely by the environment. Kendler observed that the common genetic
diathesis was strongly linked to neuroticism, suggesting that this shared genetic factor tends to respond poorly to stress and
therefore to experience frequent and intense episodes of distress and negative affect.
[60]
[61]
Merikangas et al
[82]
found that more
than half the variance in the liability for GAD and depression could be accounted for by extrafamilial influences and not by a
shared environment. The limitation of the Kendler model is that it does not incorporate some of the current neurochemical and
neuroanatomic data.
Other groups (i.e., Charney et al
[21]
) have focused on fear circuitry and the role of the amygdala in this circuitry in human anxiety.
This model draws on the preclinical work of many investigators,
[28]
[31]
[69]
who have explicated the neural basis of fear
conditioning and contextual conditioning. Neural processes, such as long-term potentiation in the central nucleus of the
amygdala, may mediate the development of fear conditioning. Contextual conditioning involves the hippocampus to first create a
representation of the environment using information received from the subiculum and the entorhinal cortex. Then the information
is relayed through the basal or accessory basal nuclei of the amygdala and then to the central nucleus. The bed nucleus of the
stria terminalis also may be involved in this process. Lesions in the basal nucleus of the amygdala attenuate contextual fear
conditioning. In humans, the prefrontal cortex is necessary for the association of new sensory input with the memory of the type
of emotional state usually associated with the type of situation in prior experience. The amygdala-prefrontal cortex-locus ceruleus
interactions may be responsible for the establishment of the appropriate emotional valence in a given situation and thus are
associated with pathologic fear and anxiety. Fear responses are implemented by the locus ceruleus, hippocampus, dorsal motor
nucleus of the vagus, parabrachial nucleus, trigeminal nucleus, facial motor nucleus, striatum, and periaqueductal gray (the
effector part of the circuit).
The strength of this theory is its ability to integrate the numerous neural areas associated with fear and anxiety. GAD symptoms
might be explained by contextual conditioning processes that occur in the extended amygdala and hippocampus. The Charney
model accounts for several symptoms of GAD, including hyperarousal, increased motor tension, stress sensitivity, and avoidance
behavior. Limitations of this model include that it does not directly address which factors predispose one to a specific disorder
and that it does not specify the effects of genetic influences. Additional research into the role of specific neural structures are
required to address this issue. The amygdala-fear circuitry model of anxiety, though, offers a comprehensive model by which
neural structures initiate and propagate anxiety disorders.
SUMMARY
On reviewing the literature on GAD and trying to summarize the various developments in the field of neurobiology of GAD, we
see that a range of hypotheses try to explore and integrate the observations found into potentially meaningful theories. Abnormal
serotonergic and GABAergic function occur in many patients with GAD. Functional imaging data have shown increased cortical
activity and decreased basal ganglia activity in patients with GAD, which reverses with treatment, but it is apparent that no one
theory is sufficiently comprehensive to propose a unitary hypothesis for the development of GAD and other anxiety disorders.
9
GAD is a relatively new diagnosable condition, first introduced into the classification system of psychiatric disorders in 1980, and
since then has undergone a series of changes in its conceptualization, with some investigators questioning the existence of the
condition as a distinct entity. Any inferences that may be drawn from various studies must be guarded, and it is appropriate to
compare studies using the same diagnostic criteria. Significant research has been done and may lead to exciting new discoveries
in the treatment of anxiety disorders in general and GAD in particular. Gray's model of behavioral inhibition, in which the
septohippocampal system acts by assessing stimuli for the presence of danger and, when that is detected, activates the
behavioral-inhibition circuit, provides a neuroanatomic conceptualization that has been expanded by preclinical research. Some
exciting work has been done on CRF and the concept of development, vulnerability, and kindling and some investigators have
contributed to this area of interest. This concept supports the hypothesis that a genetic predisposition, coupled with early stress,
in the crucial phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an
individual's threshold for developing anxiety or depression on additional stress exposure. The pharmaceutical industry is
exploring treatment options using CRF antagonists, and research on other neuropeptides, especially NPY, will be of interest.
Research on neurosteroids also may bring the opportunity for pharmacologic treatment approaches. Future research on the
startle reflex and on the NMDA and the metabotropic glutamate receptors is important. Future studies of a more homogenous
patient population and using more sophisticated techniques, such as molecular genetic strategies and better imaging techniques,
may answer some of the outstanding questions.
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