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INTRODUCTION

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  • In anxiety disorders (eg, generalized anxiety disorder and panic disorder), the most prominent features are anxiety and avoidance which are irrational or that impair functioning. In posttraumatic stress disorder, there is previous exposure to trauma and intrusive, avoidant, and hyperarousal symptoms.

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PATHOPHYSIOLOGY

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  • Noradrenergic model. This model suggests that the autonomic nervous system of anxious patients is hypersensitive and overreacts to various stimuli. The locus ceruleus (LC) may have a role in regulating anxiety, as it activates norepinephrine release and stimulates the sympathetic and parasympathetic nervous systems. Chronic noradrenergic overactivity downregulates α2-adrenoreceptors in patients with generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). This receptor is hypersensitive in some patients with panic disorder. Drugs with anxiolytic or antipanic effects (eg, benzodiazepines and antidepressants) inhibit LC firing, decrease noradrenergic activity, and block the effects of anxiogenic drugs. Hyperactive noradrenergic signaling in patients with PTSD is a consistent research finding.

  • γ-Aminobutyric acid (GABA) receptor model. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). Many antianxiety drugs target the GABAA receptor. Benzodiazepines enhance the inhibitory effects of GABA, which regulates or inhibits serotonin (5-hydroxytryptamine; 5-HT), norepinephrine, and dopamine activity. The number of GABAA receptors can change with alterations in the environment, and GABA receptor subunit expression can be altered by hormonal changes. Abnormal functioning of several neurotransmitter systems, including norepinephrine, GABA, glutamate, dopamine, and 5-HT may affect manifestations of anxiety disorders and PTSD.

  • 5-HT model. Abnormalities in serotonergic functioning may play a role in anxiety disorders. Preclinical models suggest that greater 5-HT function facilitates avoidance behavior; but primate studies show that reducing 5-HT increases aggression. GAD symptoms may reflect excessive 5-HT transmission or overactivity of the stimulatory 5-HT pathways. The selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels at the synapse and are efficacious in blocking manifestations of panic and anxiety.

  • Patients with PTSD hypersecrete corticotropin-releasing factor, but have subnormal levels of cortisol at the time of trauma and chronically. Cortisol reduces the stress response by tempering the sympathetic reaction. Dysregulation of the hypothalamic-pituitary-adrenal axis may be a risk factor for eventual development of PTSD.

  • Neuroimaging studies support the role of the amygdala, anterior cingulate cortex, and insula in the pathophysiology of anxiety. In GAD, there is an abnormal increase in the brain’s fear circuitry and increased activity in the prefrontal cortex. Patients with panic disorder have abnormalities of midbrain structures. In PTSD, the amygdala plays a role in the persistence of traumatic memory. Hypofunctioning in the ventromedial prefrontal cortex is theorized to prevent extinction in patients with PTSD and is inversely correlated with severity of symptoms. Low hippocampal volumes in patients with PTSD are likely a precursor for vulnerability for subsequent development of PTSD.

  • Glutamate signaling abnormalities may result in distortion of amygdala-dependent emotional processing under stress. Dysregulation of the processing of sensory input and memories may contribute to the dissociative and ...

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