1. The European Network for Traumatic Stress Training & Practice www.tentsproject.eu

2. The Pharmacological Treatment Of PTSD Francisco Orengo - García MD Psychiatrist Sociedad Española de Psicotraumatología y Disociación (www.sepetyd.com)www.sepetyd.com

3. Psychopharmacology: Objectives 1. To describe the theoretical basis underlying the commonly used pharmacological treatments. 2. To discuss the current evidence base for the effectiveness of pharmacological treatments for PTSD.

4. Neurobiology of PTSD What neurophysiological changes occur in PTSD? –What is the evidence for this?

5. HYPOTHALAMIC – PITUITARY - ADRENAL AXIS *There is an enhanced negative feedback in the HPA axis (1) *There are low cortisol levels in PTSD sufferers (2) *Corticotrophin Realising Factor increases locus ceruleus firing and noradrenalin release (3)

6. Some consequences of this facts are: Initial adrenergic surge may be associated with the consolidation of traumatic memories (4) and Low endogenous cortisol levels may: –promote development and symptomatology of PTSD by a disinhibition of traumatic memory retrieval (5) and –fail to contain the sympathetic stress response (6)

7. Neurobiology and drugs for the treatment of PTSD Given the neurobiology of PTSD which drugs may be effective?

8. 1. Direct Strategies to Reduce Noradrenergic Overactivity Alpha 2 adrenergic receptor agonism – e.g. clonidine (7) Postsynaptic beta adrenergic blocking – e.g. propranolol (8) Alpha 1 adrenergic receptor blocking – e.g. prazosin (9)

9. 2. Indirect Strategies to Reduce Noradrenergic Overactivity SSRIs - serotonin inhibits noradrenaline release (10,11) Mirtazapine (12,13) – increases noradrenaline - with downregulation of beta adrenergic receptors and through presynaptic blockade of alpha 2 adrenergic inhibitory autoreceptors

10. Neurobiology of PTSD: implications for treatment* Recently published studies and articles are noteworthy for advancing our understanding of the neurobiology of the traumatic stress response and PTSD as they relate to the processes of emotional memory and impairment of extinction learning (14-16). These studies provide a theoretical basis for the mechanism of action of exposure-based CBTs **as interventions that promote reprocessing and reconsolidation of emotionally laden memories of traumatic experiences and facilitate the extinction of conditioned responses to reminders of these experiences.

11. Neurobiology of PTSD: implications for treatment* 2 Studies also point to the involvement of N-methyl-D-aspartate (NMDA) receptors in the process of extinction learning, suggesting a potential role for NMDA agonists as enhancers of exposure-based psychotherapies (17,18). Trials under way at this time may augment the emerging data from pilot studies that suggest the possible benefits of NMDA agonist treatment in combination with exposure- based psychotherapies (19).

12. Indications for the pharmacological treatment of PTSD * 1 Pharmacological treatment of PTSD in adults should be considered if: PTSD clients prefer not to engage in a trauma focused psychological treatment. PTSD clients cannot start a psychological therapy because of serious ongoing threat of further trauma. Trauma focused psychological treatment has resulted in little or no benefit.

13. Indications for the pharmacological treatment of PTSD* 2 A clients ability to benefit from psychological treatment is decreased because of significant comorbid depression or severe hyperarousal (i.e., pharmacotherapy as an adjunct to psychological treatment). Treatment should be delivered by competent individuals who have received appropriate medical education.

14. Duration of treatment* Positive effects are usually present within a few weeks but often increase up to 8-12 weeks of treatment. A further decrease in symptoms has been reported up to 6 months commencement of treatment (21) with improvements maintained at 52 weeks (22; 23). It is recommended that pharmacological treatment is continued for at least 6 months, and more usually at least 12 months, if a positive response has been achieved (24). For hypnotic medication (benzodiazepines and non- benzodiazepines) short-term use only is recommended.

15. COMBAT RELATED TREATMENTS With the exception of the alfa-adrenergic antagonist prazosin, the evidence base for pharmacological intervention in combat- related PTSD has not been significantly augmented by recent studies. Indeed, these studies suggest that SSRIs may not be recommended with the previous level of confidence for the treatment of PTSD in this particular population.

16. Conclusions* 1 In consideration of the evidence, drug treatments for PTSD should not be used as a routine first-line treatment for adults in preference to a trauma focused psychological therapy (NCCMH, 2005*). A detailed and up to date overview of the state of the art on this issue is in **: http://focus.psychiatryonline.org/cgi/content/full/7/2/204

17. Conclusions* 2 There is a need for replication of previous studies in typical clinical populations, and A use of more standardized measures of outcome, as well as A need to clarify the possibility that existing types of psychotherapy might be specifically augmented by novel pharmacological agents or other forms of intervention.

18. Conclusions* 3 In pharmacologically treated PTSD in adults, the antidepressants paroxetine, mirtazepine, sertraline and amytriptiline (20) have been recommended above others (NCCMH, 2005*).