The Use of SSRIs in the Treatment of Generalized Anxiety Disorder.

1. The Use of SSRIs in the Treatment of Generalized Anxiety Disorder. By: Cameron Thompson Neuropsychology of Abnormal Behaviour

2. Outline Outline • Overview - Generalized Anxiety Disorder (GAD) • Overview - Generalized Anxiety Disorder (GAD) • The Neurobiology of GAD • Pharmacotherapy (Paroxetine) • Conclusion SSRIs and Generalized Anxiety Disorder

3. Overview - GAD Generalized Anxiety Disorder Involves: • Chronic and excessive worry about non-specific events or activities. • Must occur more days than not for at least 6 months, and must be experienced as difficult to control and intrusive. • Associated with significant distress and impairment in social and occupational functioning. • At a physiological level, it involves a state of chronic over arousal. SSRIs and Generalized Anxiety Disorder

4. Prevalence: • Lifetime prevalence of 5.1% in the United States (Approximately 23 million people). • Second most frequent psychiatric disorder in the primary care setting. Impact: • Impairment equivalent in magnitude to major depression. Prognosis: • The course of GAD tends to be chronic and recurrent, with less than one half of cases remitting without treatment. • Fortunately, current pharmacological treatments extremely effective (SSRIs). SSRIs and Generalized Anxiety Disorder

5. The Neurobiology of GAD The Neurobiology of Anxiety: • Amygdala – Neural structure associated with anxiety. • Well suited to establishing conditioned fears. • Thought to influence: • Autonomic fear responses. • Cortical interpretation of potentially frightening stimuli. • Startle reflex. • Research has demonstrated that damage to these regions in lab animals results in decreased fear related behaviour. SSRIs and Generalized Anxiety Disorder

6. The Neurobiology of GAD (Neural Structures): • Research has demonstrated that GAD is associated with: Limbic and Cortical Regions: • Changes in blood flow in a number of parts of the limbic system and frontal cortical regions. Basal Ganglia: • Increased cortical activity and decreased basal ganglia activity. Raphe Nucleus: • Abnormalities in the serotonergic activity of the dorsal and median raphe nucleus (varied). SSRIs and Generalized Anxiety Disorder

7. The Neurobiology of GAD (Neural Structures) Cont… • Neuroimaging suggests that underlying GAD is a neuronal circuit that incorporates several areas of the cortex as well as the basal ganglia and parts of the limbic system and thalamus. • There is some similarity in the regions associated with GAD and other disorders, especially depression (ie: Hippocampus). SSRIs and Generalized Anxiety Disorder

8. The Neurobiology of GAD (Neurotransmitters): • Serotonin (5-HT) is highly implicated. • Activation of 5-HT-sub(2C) receptors within the amygdala found to be anxiogenic. • Current research generally suggests that low levels of 5-HT are associated with GAD. • However, evidence often contradictory. • Possibly two forms of anxiety: • 1) Conditioned anxiety - Targeted to external cues. • 2) Unconditioned anxiety - Innate fears. • Some theorize that 5-HT might worsen conditioned anxiety, while alleviating unconditioned anxiety. SSRIs and Generalized Anxiety Disorder

9. Pharmacotherapy Benzodiazepines: • Traditionally, anxiety disorders were treated with benzodiazepines. • Benzodiazepines have a number of disadvantages: • They have high risks of dependence. • They do not address the high comorbidity of GAD with depression and 5-HT abnormalities. Antidepressants: • In 1993, a major double-blind, placebo-controlled study found that antidepressants were more effective than benzodiazepines at alleviating anxiety symptoms in a number of anxiety disorders (tricyclics). SSRIs and Generalized Anxiety Disorder

10. SSRIs: • Correlation between anxiety, 5-HT, and depression led to research into the use of SSRIs for the treatment of anxiety disorders. • SSRIs: Block reuptake of serotonin by the presynaptic terminal. Paroxetine (Paxil): • The only drug of this class to have been investigated for treatment of GAD and approved by the Food and Drug Administration (as of 2003). • Of all antidepressant therapies, paroxetine is licensed for the widest range of anxiety disorders: • Obsessive Compulsive Disorder • Panic Disorder • Social Anxiety Disorder • Generalized Anxiety Disorder • Post-Traumatic Stress Disorder SSRIs and Generalized Anxiety Disorder

11. Efficacy (Paroxetine): • Benzodiazepines show more immediate results (within first two weeks), however paroxetine shows greater reductions of GAD symptoms by week 4 onwards. • Patients treated with paroxetine show a significantly greater mean change from baseline compared with patients taking placebo. • One study reported a 50% reduction in the severity of GAD symptoms within 8 weeks. • Significantly greater rates of remission are achieved relative to placebo. • Patients with placebo were five times more likely to relapse than patients on a continuous paroxetine regimen. • Generally speaking, remission rates increase the longer the course of treatment. SSRIs and Generalized Anxiety Disorder

12. Other Advantages: • Paroxetine also has the following advantages over many other pharmacotherapeutic approaches: • The control of anxiety and co-morbid depression with the use of a single medication. • Decreased risk of dependence or withdrawal symptoms. • More tolerable side effects. • Reduced interaction potential with alcohol. • Low lethality in overdose. SSRIs and Generalized Anxiety Disorder

13. Tolerability: • Nausea. • Headache with initial treatment. • Diarrhea. • Initial increase in anxiety. • Sedation. • Sweating. • Small blood pressure elevations. • Modest weight gain. • Sexual dysfunction. SSRIs and Generalized Anxiety Disorder

14. Other disadvantages: • Many patients expect immediate improvement, and discontinue treatment before paroxetine can exert its effects. • They typically take two to three weeks to take effect. • Overall, benzodiazepines have the most rapid effects. • The relapse rate following discontinuation is considerable. SSRIs and Generalized Anxiety Disorder

15. SSRIs are inhibitors of hepatic cytochrome p450 isoenzymes. As a result, SSRIs drive up the blood levels of other medications metabolized by these isoenzymes. Can affect the metabolism of tricyclics and neuroleptics. • SSRI discontinuation syndrome: • Can occur during or following discontinuation of regular SSRI use. • Often begins between 24 hours to one week. • SSRIs are not addictive in the conventional sense, but sudden discontinuation is known to produce both somatic and psychological symptoms: • Sexual dysfunction. • Paresthesia. SSRIs and Generalized Anxiety Disorder

16. Conclusion • SSRIs generally, and paroxetine specifically, are highly effective and well tolerated pharmacological treatment options for GAD. • They have proven effective at encouraging remission, preventing relapse, and ameliorating co-morbid depressive symptoms. • They improve the working, social, and family life experienced by sufferers. • The length of time required for SSRIs to take effect, however, indicates the need for temporary use of fast-acting medications, such as benzodiazepines. • The mechanisms which underlie GAD, including 5-HT, are still relatively obscure, and further research is required to elucidate them. SSRIs and Generalized Anxiety Disorder

17. Questions SSRIs and Generalized Anxiety Disorder