By Dillon McKenna, as part of the "Anxiety Disorders" group.




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Generalized anxiety disorder (GAD) manifests itself in patients as excessive, non-specific worry accompanied by additional physical symptoms[1] . A relatively common disorder, its presence in the population is estimated to be around 5%, and is connected with a notable decrease in quality of life[2] . However, the specific symptom requirements for GAD diagnosis are a source of controversy, having undergone multiple revisions since first being introduced in the DSM-III (1980)[3] , with many suggested changes for the upcoming DSM-V[4] . Despite this uncertainty, recent research has provided insight into possible anatomical[1] and immunological[5] abnormalities that may contribute to the disorder.

General Overview


Characteristics and Diagnostic Criteria

As of 2012, the symptoms used to diagnose GAD come mainly from those outlined in the DSM-IV[4] . The core symptom of GAD is an excessive and uncontrollable worry about several daily events, which occurs more often than not for at least six months[4] . This must be accompanied by several additional symptoms and requirements which are outlined in table 1. Another characteristic of GAD is its very high comorbidity with other disorders, especially majour depressive disorder (MDD), as its been reported that about 70% of GAD sufferers develop MDD, and about 90% will develop at least one other psychiatric disorder, such as bipolar disorder, in their lifetime[6] . As well, individuals with GAD tend to be more susceptible to infectious diseases[5] . In addition to the criteria outlined in the DSM-IV, there are a number of different scales that professionals can use to assess the severity of GAD when diagnosing patients[7] . These include the Hamilton Anxiety Scale (HAM-A), the Generalized Anxiety Inventory (GADI), the Generalized Anxiety Disorder Severity Scale (GADSS), and several others, all of which agree with the DSM-IV, but emphasize different criteria[7] . The present criteria listed in the DSM-IV, and the variability between diagnoses have led to considerable controversies, with many changes proposed for DSM-V.
A. Excessive anxiety and worry (apprehensive expectation), occurring
more days than not and for at least 6 months, about a number of
events or activities (such as work or school performance)

B. The person finds it difficult to control the worry

C. The anxiety and worry are associated with three (or more) of the
following six symptoms (with at least some symptoms present for
more days than not for the past 6 months). Note: only one item is
required in children
(1) restlessness or feeling keyed up or on edge
(2) being easily fatigued
(3) difficulty concentrating or mind going blank
(4) irritability
(5) muscle tension
(6) sleep disturbance (difficulty falling or staying asleep, or restless
unsatisfying sleep)

D. The focus of the anxiety and worry is not confined to features of
an Axis I disorder. Eg., the anxiety or worry is not about having a
panic attack (as in panic disorder), being embarrassed in public (as
in social phobia), being contaminated (as in obsessive compulsive
disorder), being away from home or close relatives (as in separation
anxiety disorder), gaining weight (as in anorexia nervosa),
having multiple physical complaints (as in somatization disorder),
or having serious illness (as in hypochondriasis), and the anxiety
and worry do not occur exclusively during posttraumatic stressdisorder

E. The anxiety, worry, or physical symptoms cause clinically significant
distress or impairment in social, occupational, or other
important areas of functioning.

F. The disturbance is not due to the direct physiological effects of a
substance (e.g, a drug of abuse, a medication) or general medical
condition (e.g., hyperthyroidism) and does not occur exclusively
during a mood disorder, a psychotic disorder or a pervasive
developmental disorder
TABLE 1. DSM-IV criteria for generalized anxiety
disorder. From Andrews et al, 2010.

Controversies and the Possible Future of GAD

When analyzed for diagnostic consistency, it was found that some aspects of the criteria, specifically the "significant distress" category, have poor inter-rater reliability, likely due to the high level of subjectivity inherent in this requirement[8] . Also, some have suggested that the criteria are too strict, with many sub-threshold cases existing that still have high levels of anxiety[9] . Although further research is needed before final decisions are made, it has been suggested that lowering the duration requirement would increase the inclusion of similarly impaired, treatment-seeking sub-threshold individuals[4] . Also, evidence exists that suggests a different scale be used for younger (9-20) individuals, with relaxed duration and clinical significance to better reflect the nature of anxiety in youth[9] .

Neuroanatomy Associated with GAD


Despite being a commonly diagnosed psychiatric disorder, very little is understood about the mechanisms within the brain that underlie generalized anxiety disorder[10] , as its high comorbidity makes it difficult to study and to attribute findings specifically to GAD[1] . A few recent studies however, have shed some light on the GAD brain.

Amygdala

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Structural MRI showing enlarged bilateral amygdala (left) and right dorsomedial prefrontal and anterior cingulate cortex (right) in GAD patients. From Schienle et al., 2010

The amygdalahas been shown to have structural and functional irregularities which may be linked to symptoms of GAD. A recent study using structural MRI to assess gray matter volume in adult women with GAD has shown that these subjects have enlarged bilateral amygdala relative to controls[1] . The use of fMRI has also shown differences in GAD patients relative to controls. When waiting to be shown both aversive and neutral stimuli, GAD subjects showed heightened activity in bilateral amygdala, which the authors suggest could be associated with the increased expectation of worry in those with GAD[10]. It has been suggested that this hyperactivity is causing the increase in gray matter volume, however further studies are needed[1].
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Area of the prefrontal cortex where prolonged activity was seen in GAD patients after worry inducing task. From Paulesu et al., 2010.

Prefrontal Cortex

The prefrontal cortexhas also been implicated as being involved in GAD. Specifically, the right dorsomedial prefrontal cortex was found to be enlarged when compared to controls[1]. Like the amygdala, heightened activity was also found in this region when measuring BOLD[11] . Although in this study, the hyperactivity was not seen while receiving aversive stimuli, instead activity was present for much longer following the stimuli compared to controls[11]. This prolonged activation was associated with an inability of high worriers to be able to stop worrying, or to recognize when it would be beneficial to do so, when compared to low worriers[11]. Also, patterns of activation in the medial prefrontal cortices of GAD patients during empathy provoking tasks seemed to support the idea that the prefrontal cortex contains "mirror" regions for mental activity[11] . The same area was active in GAD individuals both when viewing aversive facial expressions, and when generating internal, unprovoked worry-like thoughts, which suggested people with GAD may use worry when employing reflective mental activity, however more sensitive studies would be required to confirm this[11].

Anterior Cingulate Cortex

When assessed using the Penn state worry questionnaire, it was found that the size of the anterior cingulate cortex(ACC) was positively correlated to the amount of self-described worry, however the cause and effect of this correlation was not discovered[1]. Abnormal activity has also been suggested in the ACC when using EEG
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Regions of the brain showing increased (orange) and decreased (blue) connectivity with the amygdala in GAD patients compared to controls. From Etkin et al., 2009.

recordings to monitor error-related negativity(ERN)[12] . After being administered a Flanker task, GAD subjects showed both increased ERN activity, and a larger difference between ERN and correct-response negativity compared to controls[12]. The authors suggested this stemmed from abnormal ACC activity, which is likely the neural generator of the ERN[12]. This could support the idea that the GAD brain is hypersensitive to errors, which may contribute to some aspects of worry in those with the disorder[12].

Abnormal Connections Within the GAD Brain

Along with abnormalities seen in specific brain regions, a difference in connectivity within and between regions has also been associated with GAD. Analysis of amygdalar connections to other areas of the brain have shown significantly greater bilateral connections to many parts of the prefrontal cortex compared to controls[2] . The prefrontal cortex has been implicated as part of an "executive control" network of emotional states[2] . However, the amygdala is not usually part of this network in healthy people, which could be evidence for worry being caused by chronic activation of the amygdala when GAD patients deal with emotional experiences[2] . As further findings have shown GAD patients have an inability to recruit regulatory regions of the anterior cingulate in emotional situations, it could be that hyperconnectivity with the amygdala is compensation for this[13] . Interestingly, it was recently shown using diffusion tensor imaging that GAD patients have increased fractional anisotropy within white matter of the right primary somatosensory cortex, although it is not yet understood what effect this might have[14] .

The Immune System and GAD


It has been documented that during an infection, many characteristic behaviors, including depression, fatigue, and anxiety arise, which are believed to contribute to a reorganization of priorities during sickness[15] . However, chronic mental disorders can arise if there is long-term inflammation[15] . Recent findings point toward the relationship between inflammatory immune responses and GAD.

TH17, Inflammation and GAD

Th17 cells are a type of T helper immune cell involved in clearing bacterial infections which, when activated, secrete the cytokinesIL-17, IL-21, IL-1B, IL-6, and TNF-a[5]. Many of these act as pro-inflammatory cytokines, with IL-17 also able to inhibit the production of other T cells such as Th1 and Th2, which could increase vulnerability to infections[5] . When blood cells were cultured from both GAD and normal subjects, and the proliferation of T cells induced, it was found that GAD patients had much higher levels of Th17 cytokines, especially IL-17[5] . When similar experiments were performed, it was found that Substance P, a peptide involved in pain transmission, enhanced proliferation of Th17 cells[16] . Also, similar proliferation of TH17 cells was observed when testing peripheral, stress-related levels of dopamine[17] . These studies focused on enhanced Th17 as a culprit of increased risk of infection found in anxious individuals rather than on infection's contribution to anxious behaviour[5] [16] [17] . However, recent findings from animal models provide insight into this role. When rats were administered endotoxins to induce an immune response, an increase in pro-inflammatory cytokines, such as IL-1B, IL-6 and TNF-a, was observed[15] . These induced inflammatory responses were associated with bilateral increases in amygdalar intra-cerebral EEG activity, as well as eventual anxiety-like behaviour, suggesting the amygdala is involved in behavioural modulation when faced with an inflammatory immune response[15] . The information gained from these recent studies show that further research into the relationship that the immune system has with the anatomy and behavior of people with GAD could provide greater insight into the nature of the disorder.

Treatment


Pharmaceuticals

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Greater activity in the ACC (red) of GAD partients corresponded to better response to treatment with Venafaxine. From Nitschke et al., 2009.

A wide range of drugs have been used to treat generalized anxiety disorder. Short term treatment of acute GAD symptoms are often treated with Benzodiazepines, however their negative side effects make them undesirable for long term use[18] . Both SSRI's and SNRI's have been found to be generally effective for the treatment of GAD, however not all patients will respond to them[19] . Some recent findings however have shown that GAD patients with greater anticipatory activation of ACC tended to respond better to the SNRI Venafaxine, suggesting a possible method of treatment effectiveness prediction[10] . Interestingly, anticonvulsants, normally used to treat epilepsy, and atypical antipsychotics, normally used to treat schizophrenia, have also been shown to be effective for controlling GAD symptoms[18]. As no one drug exists that will work for everyone with GAD, it has been advised that treatment be decided on a person-by-person basis following evaluation by a professional[19] . There are also a number of non-pharmaceutical options for treating GAD.

Therapy

Two popular therapeutic programs used for treating GAD are applied relaxation (AR), which focuses on muscle relaxation techniques, and cognitive behavioural therapy (CBT), which focuses on ways to recognize and reduce worry[20] . In a study comparing the two, it was found that CBT produced better post-treatment results[20] . Other forms of therapy found to be effective with GAD include metacognitive therapy (MCT), which treats the "worrying about worrying" often found in GAD, and intolerance-of-uncertainty (IUT), which focuses on the problems people with GAD have with uncertain situations[21] . Even though there are many options for treating GAD, full recovery is only seen about half the time, therefore further research into GAD treatment is needed[20] .
rather than on infection's contribution to anxious behaviour. However, recent findings from animal models provide insight into this role. When rats were administered endotoxins to induce an immune response, an increase in pro-inflammatory cytokines, such as IL-1B, IL-6 and TNF-a (all also produced by Th17), was observed (engler). These induced inflammatory responses were associated with bilateral increases in amygdalar intra-cerebral EEG activity, as well as eventual anxiety-like behaviour, suggesting the amygdala is involved in behavioural modulation when faced with an inflammatory immune response. (engler). The information gained from these recent studies show that further research into the relationship that the immune system has with the anatomy and behavior of people with GAD could provide greater insight into the nature of the disorde
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