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URI [dataset] University of Southampton Faculty of Medicine Sexual functioning in patients with anxiety disorders: an investigation of the potential influence of neuroinflammatory and endocrine factors by Hesham Yousry Elnazer MBBCh MRCPsych ORCID ID https://orcid.org/0000-0002-3508-684X Thesis for the degree of Doctor of Medicine September 2019 Abstract University of Southampton Abstract Faculty of Medicine School of Clinical and Experimental Sciences Thesis for the degree of Doctorate of Medicine Sexual functioning in patients with anxiety disorders: an investigation of the potential influence of neuroinflammatory and endocrine factors By Hesham Yousry Elnazer Previous studies have revealed complex associations between sexual dysfunction, depressive symptoms, and treatment with antidepressant drugs, and provide evidence linking depression, neuroinflammation and hypothalamo-pituitary-axis (HPA) dysregulation. However, little is known about the prevalence of sexual dysfunction or incidence of treatment-emergent sexual dysfunction in patients with anxiety disorders. Published studies have found contrasting evidence of the association between anxiety symptoms and disrupted levels of inflammatory markers, and investigations of HPA function in anxiety disorders have produced inconsistent findings. Augmentation with COX-2 inhibitors in patients with depression can reduce depressive symptoms and improve quality of life, but the potential therapeutic benefit of COX-2 inhibitors in patients with anxiety disorders is uncertain. This thesis includes a systematic review of the utility of the Arizona Sexual Experiences scale (ASEX) and a series of investigations in patients with anxiety disorders (n=35), with exploration of sexual function, anxiety symptoms, neuroinflammation and HPA dysregulation, at baseline, after six weeks of treatment, and after six weeks of augmentation with the COX-2 inhibitor celecoxib. The ASEX appears reliable, valid, and sensitive to change, and acceptable in a broad range of clinical settings. Cross-sectional findings indicate a point prevalence of sexual dysfunction of 57.1% at Baseline, 75.1% at Week 6 and 39.3% at Week 12. Sexual dysfunction was significantly positively correlated with the severity of anxiety symptoms, and significantly negatively correlated with mental wellbeing at Baseline, Week 6 and Week 12. There were low levels of IL-12p70 and low IL-2 but a high level of TNF-α at Week 6. At Week 12, there were low levels of IL-1β, low IL-12p70 and IL-13, a high level of TNF-α (regardless of augmentation with celecoxib) but low IL-2 levels in the non- augmentation group. At Baseline, patients with panic disorders with agoraphobia had a high hair cortisol concentration (HCC). Longitudinal analysis found worsening of sexual function at Week 6, but significant improvement in anxiety symptoms, wellbeing and sexual function at Week 12 in the celecoxib augmentation group. There was a significant reduction in IL-2 level from Week 6 to Week 12 in the augmentation group, a reduction of HCC from Baseline to Week 6, and a slight elevation at Week 12, although changes in HCC were not statistically significant. Investigating sexual dysfunction as part of the clinical assessment of patients with anxiety disorders, is important to facilitate better management and well-being. Augmentation with celecoxib can improve clinical outcomes, yet further research is needed to retest this. More research is needed to explore HCC in anxiety disorders in larger clinical samples. i Table of Contents Table of Contents Table of Contents .......................................................................................................... i Table of Tables ............................................................................................................ vii Table of Figures ............................................................................................................ix List of Accompanying Materials ....................................................................................xi Research Thesis: Declaration of Authorship ................................................................ xiii Acknowledgements ..................................................................................................... xv Definitions and Abbreviations .................................................................................... xvii Chapter 1 Introduction ............................................................................................... 1 1.1 General Introduction .................................................................................................. 1 1.2 Anxiety Disorders ....................................................................................................... 2 1.3 Hypothalamic-pituitary-adrenal (HPA) axis................................................................ 3 1.4 Cortisol Levels in Patients with Anxiety Disorders ..................................................... 5 1.4.1 Method for the Literature Review ..................................................................... 5 1.4.2 Panic Disorder and Agoraphobia ........................................................................ 5 1.4.3 Generalised Anxiety Disorder (GAD) ................................................................ 20 1.4.4 Specific (Simple) Phobia ................................................................................... 25 1.4.5 Obsessive Compulsive Disorder (OCD) ............................................................. 29 1.4.6 Social Anxiety Disorder (Social Phobia) ............................................................ 32 1.4.7 Pharmacological challenge and cortisol in anxiety disorders .......................... 44 1.4.8 Summary .......................................................................................................... 45 1.5 Human sexual response ........................................................................................... 47 1.5.1 Background ....................................................................................................... 47 1.5.2 Physiological and molecular mechanisms in erection ..................................... 47 1.5.3 Physiological and molecular mechanisms in detumescence ........................... 49 1.5.4 Renin angiotensin system ................................................................................ 51 1.5.5 Tumour Necrosis Factor (TNF) ......................................................................... 52 1.5.6 Endothelin-1 (ET-1)........................................................................................... 53 1.5.7 Interleukins ....................................................................................................... 53 1.5.8 Prostaglandins .................................................................................................. 54 1.5.9 Damage-associated molecular patterns (DAMPs) ........................................... 54 i Table of Contents 1.5.10 Modulators and potential therapeutic targets ................................................ 54 1.5.11 Summary .......................................................................................................... 57 1.6 Sexual function and anxiety ..................................................................................... 59 1.6.1 Background ...................................................................................................... 59 1.6.2 Influence of treatment with psychotropic medications on sexual function ... 60 1.6.3 Management of sexual dysfunction in mood disorders .................................. 64 1.7 Neuro-inflammation and anxiety disorders ............................................................ 67 1.7.1 Background ...................................................................................................... 67 1.7.2 Method for the Literature Review ................................................................... 71 1.7.3 Panic disorder and Agoraphobia...................................................................... 71 1.7.4 Generalised anxiety disorder (GAD) ................................................................ 74 1.7.5 Other anxiety disorders ................................................................................... 82 1.7.6 Anti-inflammatory treatment and anxiety disorders ...................................... 82 1.7.7 Summary .......................................................................................................... 83 1.8 Hypotheses