Good morning everyone. My name is Arnaud Pierre and today, the topic of my presentation is going to be on generalised anxiety disorder (aka GAD). SO GAD is a persistent and common disorder where the patient has unfocused worry and anxiety which is not associated with stressful situations. According to recent studies, GAD has a lifetime prevalence rate of 4-7% and therefore, being able to understand the mechanisms triggering GAD is essential.
Let us begin with some important definitions. -Aminobutyric acid, also known as GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays the principal role in reducing neuronal excitability throughout the nervous system. GABA-A receptors are one form of GABA receptors which have ligand-gated ion channels. PBR is a secondary binding site for diazepam expressed throughout the body and brain. (definitions) Molecular Biology It is generally accepted that dynamic interactions among several different neurotransmitter systems are likely to underlie different anxiety states.
Evidence from animal and human studies suggests that alteration of function of the GABA neuronal system plays a significant role in the pathophysiology of GAD. Benzodiazepine receptors (BDZ-Rs) and GABAAreceptors are part of the same macromolecular complex. Clinical studies have shown that benzodiazepines are effective in treating patients with GAD. 42 Patients with GAD have been shown to have low levels of peripheral benzodiazepine receptors (PBR) and low levels of PBR messenger ribonucleic acid in lymphocytes. 3
These levels increased to normal after 2 months of treatment with a diazepam-related compound, and remained normal up to 1 month after discontinuing treatment. In this study, the level of PBR was also correlated with the amount of clinical improvement. These results suggest that the lower expression of PBR is a state-related biological abnormality in patients with GAD that can be remediated with appropriate treatment. However, the mechanism by which the levels of PBRS are normalized is still unknown and one must always be careful when extrapolating from studies of the PBRs to the function of the central BDZ-Rs.
Medications that affect serotonin and norepinephrine, neurotransmitters thought to be central to the pathophysiology of GAD, prove efficacious. However, research investigating these neurotransmitters is inconsistent. One study found elevated plasma levels of norepinephrine and decreased a2-adrenergic function in GAD patients. 44 The authors of that study concluded from these findings that norepinephrine activity is elevated in GAD, causing receptor downregulation.
Other studies were unable to replicate these findings. 5,46 The one investigation exploring the metabolic pathways of catecholamines failed to find a difference between GAD subjects and normal controls, 47 and studies have failed to consistently demonstrate that plasma catecholamine levels of GAD subjects are higher than normal comparison subjects. 45,46 Furthermore, research investigating catecholamine receptors in GAD patients are mixed and inconclusive. 48-50 In summary, there is little evidence suggesting abnormalities in the catecholamine system for patients with GAD. Studies investigating the role of serotonin in GAD are also inconclusive.
Both overactivity or underactivity of the serotonergic system has been hypothesized to be involved in the pathogenesis of GAD. 51,52 Some of the strongest biological evidence linking the serotonin system and GAD have been studies with the serotonin receptor agonists buspirone, ipsapirone, and gepirone. These agents decrease the firing rate of serotonergic neurons and exert anxiolytic effects in patients with GAD. 53 The hypothalamic-pituitary-adrenal axis has been implicated in other anxiety disorders and may play a role in GAD.
Cortisol, the primary hormone implicated in stress, has been shown to be elevated in GAD patients. 54 In normal subjects, exogenous cortisol induces an increase in the serotonin transporter gene transcription. 55 However, the incubation of peripheral lymphocytes from GAD patients with cortisol failed to increase serotonin transporter gene product. 55Corticotropin-releasing factor (CRH) is associated with heightened states of anxiety in animal models. However, there is no conclusive association between CRH dysfunction and GAD. 6-58 Genetics Genetic studies suggest a moderate degree of heritability for GAD.
The prevalence rate for GAD is 20%59 to 22%60 for individuals who have a first-degree relative with GAD, as compared to a 4% prevalence rate in the control sample. 59 Twin studies demonstrate that 21% of monozygotic twins are concordant for GAD, versus 13% of dizygotic twins. 61 Candidate genes for further study include those influencing norepinephrine and serotonin neurotransmission as well as GABA and CRH. Of particular interest is the serotonin transporter gene located on chromosome 17q.
One study reported that polymorphism in the second intron of this gene occurs at significantly higher rates in individuals with GAD. 62 Pharmacological treatments Benzodiazepines are a well-studied class of medications with proven efficacy in the treatment of GAD. 65 Approximately 75% of patients have either a marked (35%) or moderate (40%) response to treatment. 66 Anxious symptoms respond to benzodiazepines rapidly, with the most dramatic improvement occurring in hypervigilance and somatic symptoms, such as muscle tension, restlessness, and insomnia.
Psychological symptoms, such as worrying and fretting, are not as responsive to benzodiazepine medication, and may require additional treatment with cognitive-behavioural therapy (CBT) or another specific modality. Tricyclic Antidepressants represent another way of treating GAD. Indeed, TCAs work by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT), thereby increasing the available amount of both neurotransmitters in the synaptic cleft. The TCAs differ in their abilities to inhibit NE and 5-HT. For example, clomipramine is considered to be a “serotonergic” tricyclic.
The tricyclics, like the selective serotonin reuptake inhibitors (SSRIs), are useful in treating the patient with mixed anxiety and mood disorder, where anxiety and mood pathology coexist71. The monoamine oxidase inhibitors (MAOIs), are used in the treatment of atypical depression, panic disorder, and as an alternative therapy in treatment-resistant depression. MAOIs are known to reduce anxiety when used in the treatment of depression. They work by irreversibly inhibiting monoamine oxidase, the enzyme that breaks down NE, dopamine, and 5-HT73.
Psychotherapies Cognitive behavioural therapy also known as CBT has been demonstrated to be an effective treatment for GAD. A study comparing nondirective therapy, CBT, and applied relaxation in outpatients with GAD found that both applied relaxation and CBT were superior to nondirective therapy by the end of the study. Longer-term follow-up of the subjects determined that the nondirective therapy group had lost its treatment gains, but both CBT and applied relaxation maintained their treatment gains, with the greatest gains maintained by the CBT group. 6 Another study comparing CBT, behavior therapy, and a wait-list control group found that CBT was consistently more effective than behavior therapy on measures of cognition, mood, and anxiety. 97 Conclusion GAD is a common disorder and is highly comorbid with other psychiatric syndromes. GAD alone and GAD comorbid with other psychiatric syndromes is remarkably disabling and significantly impedes on the quality of life of individuals and their loved ones.
At this time, little is understood about the biology of GAD, but it is hoped that advances in neurobiology and genomics will enhance our knowledge about the pathogenesis of this syndrome. Patients with GAD commonly approach PCPs with somatic concerns such as headaches, backaches, and muscle spasms. Fortunately, there are safe and effective pharmacotherapies and psychotherapies for GAD. However, the longer-term prognosis for GAD is still troubling. This emphasizes the need for more longitudinal treatment research as well as exploration of alternative modalities of therapy.