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

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

3. SSRIs and Generalized Anxiety Disorder Generalized Anxiety Disorder Involves: Chronic and excessive worry about non-specific events or activities. 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. 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. Associated with significant distress and impairment in social and occupational functioning. At a physiological level, it involves a state of chronic over arousal. At a physiological level, it involves a state of chronic over arousal. Overview - GAD

4. SSRIs and Generalized Anxiety Disorder Prevalence: Lifetime prevalence of 5.1% in the United States (Approximately 23 million people). Lifetime prevalence of 5.1% in the United States (Approximately 23 million people). Second most frequent psychiatric disorder in the primary care setting. Second most frequent psychiatric disorder in the primary care setting.Impact: Impairment equivalent in magnitude to major depression. 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. 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). Fortunately, current pharmacological treatments extremely effective (SSRIs).

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

6. SSRIs and Generalized Anxiety Disorder The Neurobiology of GAD (Neural Structures): Research has demonstrated that GAD is associated with: 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.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.Increased cortical activity and decreased basal ganglia activity. Raphe Nucleus: Abnormalities in the serotonergic activity of the dorsal and median raphe nucleus (varied).Abnormalities in the serotonergic activity of the dorsal and median raphe nucleus (varied).

7. SSRIs and Generalized Anxiety Disorder 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. 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). There is some similarity in the regions associated with GAD and other disorders, especially depression (ie: Hippocampus).

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

9. SSRIs and Generalized Anxiety Disorder Benzodiazepines: Traditionally, anxiety disorders were treated with benzodiazepines. Traditionally, anxiety disorders were treated with benzodiazepines. Benzodiazepines have a number of disadvantages: Benzodiazepines have a number of disadvantages: They have high risks of dependence.They have high risks of dependence. They do not address the high comorbidity of GAD with depression and 5-HT abnormalities.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). 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). Pharmacotherapy

10. SSRIs and Generalized Anxiety Disorder SSRIs: Correlation between anxiety, 5-HT, and depression led to research into the use of SSRIs for the treatment of anxiety disorders. 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. 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). 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: Of all antidepressant therapies, paroxetine is licensed for the widest range of anxiety disorders: Obsessive Compulsive DisorderObsessive Compulsive Disorder Panic DisorderPanic Disorder Social Anxiety DisorderSocial Anxiety Disorder Generalized Anxiety DisorderGeneralized Anxiety Disorder Post-Traumatic Stress DisorderPost-Traumatic Stress Disorder

11. SSRIs and Generalized Anxiety Disorder Efficacy (Paroxetine): Benzodiazepines show more immediate results (within first two weeks), however paroxetine shows greater reductions of GAD symptoms by week 4 onwards. 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. 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. 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. 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. 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. Generally speaking, remission rates increase the longer the course of treatment.

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

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

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

15. SSRIs and Generalized Anxiety Disorder 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.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:SSRI discontinuation syndrome: Can occur during or following discontinuation of regular SSRI use.Can occur during or following discontinuation of regular SSRI use. Often begins between 24 hours to one week.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:SSRIs are not addictive in the conventional sense, but sudden discontinuation is known to produce both somatic and psychological symptoms: Sexual dysfunction. Sexual dysfunction. Paresthesia. Paresthesia.

16. SSRIs and Generalized Anxiety Disorder Conclusion SSRIs generally, and paroxetine specifically, are highly effective and well tolerated pharmacological treatment options for GAD. 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 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. 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 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. The mechanisms which underlie GAD, including 5-HT, are still relatively obscure, and further research is required to elucidate them.

17. SSRIs and Generalized Anxiety Disorder Questions