A Tale of 3 Cities, the Maastricht Masters & the Tryptophan Depletion story Professor Sean Hood Consultant Psychiatrist University of Western Australia Perth, Australia

Servier + Pfizer Support

City # 1: Bristol

Tryptophan Depletion in Social Anxiety Disorder. Dr Sean Hood Presented at The European Certificate in Anxiety and Mood Disorders, Santa Margherita Ligure, 2000 Explain ATD Explain disorder – specific provocations

Study Protocol Overview Tryptophan Depletion: Serotonin & Anxiety Study Protocol Overview Patient fails to respond to standard open treatment (by CGI-I score): Routine outpatient care Exclusion Criteria met: Routine outpatient care Exclusion Criteria met: Routine outpatient care Screening Day Standard open treatment 3/12+ SSRI Day 1 Day 2 Post-Study Follow-up Recruitment

#1: Autobiographical Script Tryptophan Depletion: Serotonin & Anxiety SAnD TD: Protocol #1: Autobiographical Script #2: Verbal Task #3: Neutral Script Amino acid drink Qu. +2 hr Qu. +4 hr (fasting) Time (hrs) 0 +1 +2 +3 +4 +5 +6 +7 TRP Levels TRP Levels TRP Levels TRP Levels

Subjects: n=14 SSRI-remitted SAnD (CGI 1 or 2) Challenge: Autobiog. Script, Verbal Task, N. task Measures: SSAI,VAS,LSAS,SPIN CVS

Subjects: n=14 SSRI-remitted SAnD (CGI 1 or 2) Challenge: Autobiog. Script, Verbal Task, N. task Measures: SSAI,VAS,LSAS,SPIN CVS Results: ATD

Subjects: n=14 SSRI-remitted SAnD (CGI 1 or 2) Challenge: Autobiog. Script, Verbal Task, N. task Measures: SSAI,VAS,LSAS,SPIN CVS Results: ATD Challenge  ATD x Challenge  Psychological  Physiological

I look startled. Why? Jet lag Japanese guy mixed a very strong gin and tonic Fergus’ straw hat?

City # 2: Maastricht

Coffee not wickes witte break

2004 Summer Conference of the British Association for Psychopharmacology. Harrogate, UK.

Acute Tryptophan Depletion in 5 clinical anxiety disorders: PD, SAnD, PTSD, GAD & OCD Neurotalk June 27th, 2010 Singapore Professor Sean Hood Consultant Psychiatrist University of Western Australia Perth, Australia

5 Clinical Anxiety Disorders

Acute Tryptophan Depletion: Serotonin & Anxiety Acutely Depleting Serotonin  Sx (SSRI-remitted Depression) SSRI-remitted SAnD (Social Anxiety) SSRI-remitted PD (Panic) CBT-remitted PD (Panic) SSRI-remitted PTSD Acutely Depleting Serotonin  NO Sx SSRI-remitted GAD (Generalised Anxiety) SSRI-remitted OCD (Obsessive Compulsive)

ATD in Anxiety Summary

City # 3: Perth

Serotonin – HPA

Serotonin – HPA Prolactin was also measured as it is known to be stress responsive (see Freeman et al., 2000).

Serotonin – HPA 2 CO2 inhalation produced significant bradycardia compared with air inhalation, consistent with previous findings This was not influenced by tryptophan depletion or related to plasma cortisol levels and is likely a parasympathetic response discrete from either sympathetic, HPA or arousal centres (Kaye et al., 2006; Wetherell et al., 2006).

5HT & Hypertension & Stress (N) Volunteer Studies completed Study ATD 35% CO2 SSRI Completed Pre-1: ATD Vols (Shufflebotham et al. 2006)   Pre-2: CO2 Vols (Shufflebotham et al. 2009) Pre-3: ATD CO2 Vols (Hood et al. 2006) Pre-4: ATD CO2 SSRI Vols (Hince et al. 2010)  (3 weeks) Study Pre-1: ATD Vols (Shufflebotham, Hood, Hendry, Hince, Morris, Nutt, Probert, & Potokar 2006)   Firstly, we applied our ATD procedure to a group (n=11) of normal volunteers, who were matched to a convenience sample of 18 subjects with untreated Irritable Bowel Syndrome (IBS). We have reported elsewhere that IBS patients are a chronic disease group that exhibit depressive and anxiety symptoms in the subsyndromal range (Hood et al. 2008) and found that the IBS patients’ gastrointestinal and anxiety responses to changes in tryptophan load differ from that of normal volunteers. ATD in volunteers by itself exhibited no noticeable effect on psychological or cardiovascular outcomes. Study Pre-2: CO2 Vols (Shufflebotham, Wetherell, Hince, Hood, Lightman, Nutt, Probert, & Potokar 2009) Secondly, we isolated the 35% CO2 provocation variable in a similar group of normal volunteers (n=10) matched with untreated IBS patients (n=12). The 35% CO2 inhalation lead to an increase of anxiety, systolic blood pressure and cortisol levels in both groups, although the cardiovascular effect was enhanced in the IBS group. Study Pre-3: ATD CO2 Vols (Hood, Hince, Robinson, Cirillo, Christmas, & Kaye 2006) The logical progression was to combine the challenges of Study Pre-1 and Pre-2, thus in Study Pre-3 we examined both ATD and 35% CO2 provocation in normal volunteers. Independent effects of ATD (increasing cortisol, a trend for increase blood pressure) and 35% CO2 (increase cortisol, blood pressure & anxiety) were demonstrated but there was no ATD x 35% CO2 effect noted. Study Pre-4: ATD CO2 SSRI Vols (Hince, Menon, Shadianloo, & Hood 2010) Most recently, we have extended this series by adding a 3 week SSRI (escitalopram) versus placebo arm to the design of Study Pre-3, focussing on psychological and cardiovascular effects. Although adding an SSRI had no direct effect on anxiety measures an increase in diastolic blood pressure was seen, and the SSRI appeared to attenuate the 35% CO2-induced increase on anxiety.

5HT & Hypertension & Stress (N) Volunteer Studies over Past 5 Years Significant Outcome Measures for Normal Volunteers Study Psychological Cardiovascular Endocrine Pre-1: ATD Vols (Shufflebotham, Hood, Hendry, Hince, Morris, Nutt, Probert, & Potokar 2006) Nil: ATD - Pre-2: CO2 Vols (Shufflebotham, Wetherell, Hince, Hood, Lightman, Nutt, Probert, & Potokar 2009) CO2   anxiety CO2  BP CO2  Cortisol Pre-3: ATD CO2 Vols (Hood, Hince, Robinson, Cirillo, Christmas, & Kaye 2006) Nil: ATD x CO2 ATD  BP (trend) ATD  Cortisol Pre-4: ATD CO2 SSRI Vols (Hince, Menon, Shadianloo, & Hood 2010) Nil: 3 wk SSRI Nil: ATD x 3 wk SSRI CO2 x 3 wk SSRI   anxiety Nil: 3 wk SSRI Nil: CO2 x 3 wk SSRI Messages: CO2 ... Is a powerful tool to produce psych + cvs + endocrine response in vols ATD ... Increase cortisol and maybe mild pressor, but psych effect in normals unlikely

5HT & Hypertension & Stress (N) Volunteer Studies completed & proposed Study ATD 35% CO2 SSRI Completed Pre-1: ATD Vols (Shufflebotham et al. 2006)   Pre-2: CO2 Vols (Shufflebotham et al. 2009) Pre-3: ATD CO2 Vols (Hood et al. 2006) Pre-4: ATD CO2 SSRI Vols (Hince et al. 2010)  (3 weeks) Proposed Study 1: CO2 single dose SSRI  (single dose) Study 2: ATD CO2 single dose SSRI Study 1:  To test the hypothesis that single dose SSRI treatment will increase the anxiety-inducing effects of 35% CO2 inhalation in healthy volunteers. Healthy volunteers (n=26) will be randomly allocated to either placebo or 10 mg escitalopram in a double blind manner. Three hours post ingestion of the medication (estimated to be with in the range of maximum plasma concentration for escitalopram (Sogaard B et al. 2005), participants will inhale a single breath of 35% CO2/air mixture. The psychological, cardiovascular and endocrine response to this stressor will be measured prior to and after the inhalation. We expect a greater stress response to the 35% CO2 challenge in the escitalopram group compared with the placebo group.   Study 2: To test the hypothesis that single dose SSRI treatment increases the anxiety-inducing effects of 35% CO2 inhalation in healthy volunteers by increasing synaptic serotonin availability. Healthy volunteers (n=26) will be randomly allocated to either placebo or 10 mg escitalopram in a double blind manner. All participants will be tested twice separated by one week. On one test day, participants will be depleted of tryptophan and on the other, will not be depleted on the other. Order of depletion will be randomly determined for each participant and balanced across drug group, and both researcher and participant will be blind to group allocation. Three hours post ingestion of the depletion mixture, participants will inhale a single breath of 35% CO2/air. The psychological, cardiovascular and endocrine response to this stressor will be measured prior to and after the inhalation. We expect the following order of magnitude of stress response: escitalopram/not depleted = escitalopram/depleted ≥ placebo/depleted > placebo/not depleted Study 3: To test the hypothesis that single dose SSRI treatment blocks the anxiety-inducing effects of 35% CO2 inhalation in normal volunteers due to participant expectation.  Despite the double blind designs used in the studies proposed here and conducted previously, it is difficult to exclude expectation effects as 1) participants are aware that there is a 50% chance they will be given a medication that is expected to reduce their response to a stressor and 2) some participants may be away of symptoms produced by the medication and assume this means they are on active medication. To assess the role of expectation in the effect of escitalopram, healthy volunteers (n=x) will be randomized and assessed as described in Study 1. To experimentally manipulate expectation, half of each drug group will be told they have taken placebo, and half will be informed that they have taken escitalopram. If expectation is an important factor in SSRI effect of reducing 35% CO2 induced stress response, the following order of magnitude of effects will be observed: on placebo/told placebo=on escitalopram/told placebo > on placebo/told escitalopram=on escitalopram/told placebo  consider within sub design? Would the models of SSRI action predict more anxiety with acute dose? We also need to know what acute dose does in patients I guess, although I know now practical.  This requires more thought now, as participants might expect the SSRi to reduce anxiety because they think of it as a treatment for anxiety – will depend on what we tell them.

Serotonin – Cardiovascular Cardiovascular response variables. Beat to beat blood pressure and heart rate will be recorded continuously across the challenge period using a non-invasive Task Force monitor.   Autonomic response variables. Changes in cutaneous blood flow (an indication of flushing) and electrodermal skin response (an indication of changes in sweating) will be measured, as these autonomically mediated response to stress were important features of panic attacks in hypertensive individuals (9). Changes in cutaneous blood flow in the forehead and index finger will be measured using a laser Doppler flowmeter. This non-invasive technique involves shining a laser light onto the skin and applying the Doppler frequency shift principle to the reflected light in order to quantify the increase/decrease in blood flow. Changes in the electrodermal skin response will be measured using silver-silver chloride electrodes filled with conductive paste and attached to the second and third fingers. Psychological measures: Three subjective ratings of psychological variables will be used: Visual Analogue rating Scales (VAS), measured on 100mm line, anchored from 0: “not at all” to 100: “the most ... ever”. Subjects will be trained in the use of these scales as integer measures; these scales have been extensively validated (22;23). The Panic Symptom Inventory (PSI) lists 34 symptoms related to a panic attack with the option of rating 0 = not at all, 1 = slight, 2 = moderate, 3 = severe, 4 = very severe and has been used in studies of anxiety provocation (e.g. 54). The Spielberger State Anxiety Inventory (STAI).

5HT & Hypertension & Stress Davies, Hood et al. J Clin Psychopharm.

P & H: Autonomic Dysfunction

P & H: Autonomic Dysfunction

Networking

To an aussi, being “knackered” and “stranded” in stockholm is pretty funny… especially when you are lost.

Ken orr collab

“Dr david Christmas” google search!  “Dr Who Christmas”

P & H: Autonomic Dysfunction

From Rags to Riches in 10 years: How the Maastricht Masters made me fantastically successful. Professor Sean Hood Consultant Psychiatrist University of Western Australia Perth, Australia Simon’s version