Psycho-pharmacologic Therapy. Objectives

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1 Psycho-pharmacologic Therapy for Functional Bowel Disorders John J. Hutchings, M.D. Assistant Professor of Medicine and Psychiatry Louisiana i State t University it School of Medicine i Department of Medicine Section of Gastroenterology Objectives Explore current theories on the pathophysiology of functional bowel disorders Analyze research which supports the use of psychopharmacologic and psychological therapies for symptom relief Identify particular psychotropic medications to utilize in common clinical situations 1

2 Definition of FGID Chronic and recurrent symptoms of the gastrointestinal (GI) tract: -without detectable structural or biochemical abnormalities -symptoms include: pain, nausea, vomiting, bloating, diarrhea and/or constipation Functional bowel disorders (FBDs) are a subgroup of functional gastrointestinal disorders Common Features of FBD Pathophysiology Role of psychosocial factors The treatment strategy 2

3 Consultation Pattern Specialists Primary care ~25% Healthcare seekers ~75% Non-healthcare seekers Adapted from Drossman and Thompson, Ann Intern Med 1992; 116(pt1):109 Irritable Bowel Syndrome Between 7-10% population has IBS 1 There are 3.6 million physician visits in the U.S. annually for IBS and it consumes over $20 billion in both direct and indirect expenditures 2 Psychiatric disorders occur in 50-60% of patients seeking care for IBS 3 1 Brandt LJ, Chey WD, Foxx-Orensetin, et al. American College of Gastroenterology IBS Task Force: An evidence-based review of the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104:S Talley NJ, Gabriel SE, Harmsen WS et al. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology. 1995;109: Creed F, et al. Outcome in severe irritable bowel syndrome with and without accompanying depressive, panic and neurasthenic disorders. British Journal of Psychiatry. (2005),

4 Rome III Criteria: IBS Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or more: improvement with defecation onset associated with a change in frequency of stool onset associated with a change in form (appearance) of stool Criteria fulfilled in the last 3 months with symptom onset at least 6 months prior to diagnosis Longstreth et al., Gastroenterology 2006; 130:1480 Pathophysiology Altered motility Visceral hypersensitivity Infection/Inflammation Brain-gut axis deregulation Brain-gut peptides 4

5 Some possible mediators of motility and visceral sensitivity Motility: serotonin acetylcholine nitric oxide substance P vasoactive intestinal peptide cholecystokinin Visceral sensitivity: serotonin Kim and Camilleri, Am J Gastroenterol 2000; 95: 2698 Grider et al, Gastroenterology 1998; 115: 370 Tachykinins, bradykinin calcitonin gene-related peptide neurokinin A, NMDA Enkephalins Psychosocial Factors History of severe physical abuse, sexual abuse, or severe posttraumatic stress disorder strongly influences the severity of symptoms and dthe clinical i l outcome 1-2 Other psychosocial factors appear to influence both the decision to seek care 3 and also health care utilization by the patient 4. These psychosocial factors can be independent predictors of HRQOL Drossman DA, et al. Sexual and Physical abuse and gastrointestinal illness: review and recommendations. Ann intern Med. 1995:123: Creed F. The relationship between psychosocial parameters and outcome in irritable bowel syndrome. Am J Med. 1999:107 (suppl): Drossman DA. Irritable bowel syndrome. Gastroenterologist. 1994; 2: Drossman DA, McKee DC, Sandler RS et al. Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology. 1988; Kettell J, Jones R, Lydeard S. Reasons for consultation in irritable bowel syndrome: symptoms and patient characteristics. Brtitsh J Gen Pract. 1992; 42: Whitehead WE, et al. Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples. Gastroenterology. 1988; 95: Smith RC, et al. Psychosocial factors are associated with health care seeking rather than diagnosis in irritable bowel syndrome. Gastroenterology. 1990; 98:

6 Current Treatment Strategies for Functional Bowel Disorder Non-pharmacologic Education and reassurance Dietary advice Lifestyle modification Behavioral modification Pharmacologic Antispasmodic / anticholinergic Anti Anti-diarrheal Laxatives Antidepressants Neurotransmitter Imbalance Dysregulation of brain-gut neuroenteric system Many neurotransmitters, neuromodulators, and neuropeptides are present in both the brain and the gut Gastrointestinal homeostasis is dependent on a functional equilibrium between the pathways that enhance and those that inhibit secretion and motility 6

the receptors on the intrinsic and extrinsic afferent neurons, as well as secretory neurons Mechanisms Enhanced perception 5% Infectious

7 Neurotransmitter Imbalance Serotonergic pathways have been a focus Greater than 95% of total body content is found within the gastrointestinal tract Intraluminal stimulation of enterochromaffin cells facilitates the release of serotonin (5-HT), which binds to the receptors on the intrinsic and extrinsic afferent neurons, as well as secretory neurons Mechanisms Enhanced perception 5% Infectious insults 5-HT Inflammatory processes 95% Altered motility Visceral hypersensitivity Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11:3 7

8 Tricyclic Antidepressants (TCAs) Used in IBS for modulation of hyperalgesia Dose for hyperalgesia is typically lower than the dose for depression TCAs modulate activity in pain centers in the CNS TCAS are anti-cholinergic agents and can induce constipation Meta-analysis: TCAs in IBS In a 2009 a meta-analysis of 9 randomized, placebocontrolled trials for functional gastrointestinal disorders with TCAs was performed These trials include a total 575 patients RelativeRisk068(056083) Risk 0.68 ( ) Meta-analysis demonstrated symptomatic improvement, NNT = 4 Ford AC, et al. Am J Gastroenterol. 2009; 104:

9 Desipramine vs. Placebo for Moderate to Severe FGIDs 12 week Trial P=0.16 NNT=8.1 Desipramine vs. Placebo for Moderate to Severe FGIDs 12 week Trial P=0.006 NNT=4 9

10 Tricyclic Antidepressants (TCAs) Antidepressant NE 5-HT ACh H 1 Amitriptyline (Elavil) Amoxapine (Asendin)* Clomipramine (Anafranil) Desipramine (Norpramin) Doxepin (Sinequan) Imipramine (Tofranil) Maprotiline (Ludiomil) Nortryptyline (Pamelor) Protryptyline (Triptyl, Vivactil) Trimipramine (Surmontil) Tricyclic Antidepressants (TCAs) Side Effects: Anticholinergic Constipation Dry Mouth Blurred Vision Urinary Hesitancy Esophageal Reflux Cardiovascular Slowed conduction Orthostatic hypotension Palpitations Hypertension Central Nervous System Sedation Tremor Stimulation Myoclonic twitches Other Weight gain Sexual dysfunction Impotence Perspiration Dose Range: mg 10

11 Selective Serotonin Reuptake Inhibitors (SSRIs) Selectively block the reuptake of 5-HT Initially increase availability of 5-HT in synaptic cleft Eventually reduce sensitivity of somatodendritic and terminal 5-HT 1A autoreceptors Increase in neurotrophin expression and enhanced transcription of neurotrophic factors, including BDNF Meta-analysis: SSRIs in IBS In a 2009 a meta-analysis of 5 randomized, placebocontrolled trials for functional gastrointestinal disorders with SSRIs was performed These trials only include a total 230 patients Relative Risk 0.62 ( ) Meta-analysis demonstrated symptomatic improvement, NNT = 4 AC Ford, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58:

12 Selective Serotonin Reuptake Inhibitors (SSRIs) Examples: Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Side Effects: Headache GI side effects (nausea, diarrhea, heartburn) Sexual dysfunction ( libido, delayed orgasm) Sleep disturbance (insomnia, somnolence) Dose Range: mg SSRIs and TCAs: Synergy Enhance effectiveness of endogenous pain inhibition and modulate hyperalgesia Both SSRIs and TCAs may be equally effective in improving IBS symptoms 1 Reported success of combination of SSRIs with TCAs for pain modulation if one alone is insufficient 2,3 1 Ford AC, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58: Drossman DA. Severe and refractory chronic abdominal pain: treatment strategies. Clin Gastroenterol. Hepatol. 2008; 6: Drossman DA. Beyond Tricyclics: new ideas for treating patients with painful and refractory functional gastrointestinal symptoms. Am. J. Gastroenterol. 2009; 6:

13 Choosing an Antidepressant (ACG) TCAs and SSRIs are more effective than placebo at relieving global IBS symptoms, and appear to reduce abdominal pain There are limited data on the safety and tolerability of these agents in patients with IBS Diarrhea TCA Constipation SSRI Brandt LJ et al. Am J Gastroenterol 2009; 104 Suppl 1: S1-35 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Examples: Desvenlafaxine (Pristiq) Venlafaxine (Effexor) Duloxetine (Cymbalta) Milnacipran (Savella) Fibromyaglia Side Effects: Same as SSRIs PLUS: potential treatment-emergent HTN tachycardia 13

14 Comparison of Agents TCAs SSRI SNRI Peripheral pain **? ** modulation Central *** * *** antinociception Anxiolysis * *** *** Motilty ** *? Visceral pain ***?? Sleep ** -? Psychiatric comorbidities ** *** *** Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19: Mirtazapine Mechanism of Action α 2 -adrenergic receptor antagonist 5-HT 2, 5HT 3 receptor antagonist Potent H 1 receptor antagonist Side Effects Dry Mouth Somnolence Sedation Weight Gain 14

15 Anxiolytics Benzodiazepines - limited anecdotal evidence of possible benefit Limited evidence even in pts with co-occurring anxiety disorder Addiction potential, worsening of associated depression, and poor safety profile make them less than attractive candidates Tollefson GD, et al. An open label trial of alprazolam in comorbid irritable bowel syndrome and generalized anxiety disorder. J Clin Psychiatry. 1991;52:502-8 Psychological Treatments Collaborative treatment of psychological symptoms with gastroenterology t and psychologists has demonstrated improvements in medical symptoms and global self assessment Gerson CD, Gerson MD. A Collaborative Health Care Model for the Treatment of Irritable Bowel Syndrome. Clinical Gastroenterology and Hepatology. 2003;1:

16 Psychological Treatment Cognitive Behavioral Therapy (CBT) seven studies done comparing CBTt to control or usual treatment. t t Total patients = 493 IBS symptoms persisted in 118 of 279 assigned to CBT or 42.3%. IBS symptoms persisted in 130 of 212 of those assigned to usual care or 61.3% NNT = 3 Ford AC, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58: Psychological Treatments Hypnotherapy 2 small studies, N=40. symptoms persisted in 15/20 (75%) of the controls and 7/20 (35%) of the hypnotherapy patients t with a NNT of 2 Relaxation therapy 5 studies, N=234. symptoms persisted in 100/112 of the controls (89.3%) and 94/192 (77.0%) of the relaxation therapy patients Psychodynamic psychotherapy 2 studies, N=273. symptoms persisted in 95/135 (70.4%) controls and 61/138 (44.2%) of the therapy patients with a NNT of 3.5 Ford AC, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58:

17 Behavioral Therapy Includes biofeedback, relaxation therapy, cognitive behavioral therapy, dynamic psychotherapy py and hypnotherapy Relaxation therapy NOT effective Grade B RCTs (poorly blinded) indicate improvement in GI and psychological symptoms in pts with comorbid psychiatric diagnosis Designs are inferior to drug trials Benefits of Collaboration Increased time with a team of physicians Thorough assessment of psychosocial factors Expanded treatment plan to include psychotropics commonly used in IBS that are dosed based on patient- specific factors as well as psychotherapy Potential to decrease visits to GI Clinic and Emergency Services 17

18 Summary The exact pathophysiology of IBS is multifactorial and incompletely understood Carefully selected psychotropic medication can be useful in patients with IBS Choosing a psychotropic is improved with a understanding of physiology and knowledge of side effect profiles 18

The Use of Antidepressants in the Treatment of Irritable Bowel Syndrome and Other Functional GI Disorders What are functional GI disorders?

The Use of Antidepressants in the Treatment of Irritable Bowel Syndrome and Other Functional GI Disorders Christine B. Dalton, PA-C Douglas A. Drossman, MD and Kellie Bunn, PA-C What are functional GI