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Home , Duloxetine, Laxative, Methyl cellulose, Olanzapine, Tegaserod

5-step plan to treat in psychiatric patients

Algorithm can individualize treatment when or other factors are binding

r. W, age 50, presents to the psychiatry® Dowdenclinic with Health Media obsessive-compulsive disorder (OCD) symptoms. MAt his fi rst interview, he says he spends every waking hour obsessing overCopyright whether or Fornot he doespersonal things use only “right.” These thoughts force him to compulsively check and recheck everything he does, from simple body movements to complex computer tasks. He has a history of OCD since age 8, with intermittent episodes of major depression. He reports that several years ago, he had a “miraculous” response to PSYCHIATRY for several weeks but has not responded to any other . Nevertheless, he continues taking CURRENT

clomipramine, 50 mg/d, hoping that it “might eventually FOR do some good.” He adds that when he tried to increase KELLY the dose, he suff ered from “terrible constipation” despite BLAIR regular use of a methylcellulose fi ber supplement. The psychiatrist discontinues clomipramine and starts Nathaniel S. Winstead, MD, MSPH Mr. W on , 90 mg/d. At the next visit, Mr. W com- Staff Physician, Section of Gastroenterology and Hepatology Ochsner Clinic Foundation plains that his constipation is much worse, so the psychia- Clinical Associate Professor of Medicine trist decreases duloxetine to 60 mg/d, which eventually Department of Internal Medicine provides some relief. Because Mr. W has minimal response Daniel K. Winstead, MD to duloxetine after 6 months, the psychiatrist adds olan- Professor and Chairman zapine. Although this agent is , the patient Department of Psychiatry and Neurology had responded to a previous trial of this . Soon after, Mr. W experiences severe constipation. Tulane University School of Medicine New Orleans, LA Psychiatric patients face a host of potential causes of constipation, including: • use of psychotropics and other • decreased eating or physical activity as a result of Current Psychiatry depression or another psychiatric disorder Vol. 7, No. 5 29 continued

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029_CPSY0508 029 4/16/08 11:18:47 AM Box 1 frequency of bowel movements as the only Diagnostic criteria criterion for diagnosis. Under Rome Com- for mittee for Functional Gastrointestinal Dis- orders guidelines for diagnosis of chronic 1. 2 or more of the following (or functional) constipation, patients who a. Straining* move their bowels daily may meet criteria b. Lumpy or hard stools* for chronic constipation if they experience Constipation c. Sensation of incomplete evacuation* straining, incomplete evacuation, or other d. Sensation of anorectal blockage/ symptoms (Box 1).8 obstruction* e. Manual maneuvers to facilitate Many patients who complain of con- * stipation have daily, regular bowel move- f. Fewer than 3 per week ments that produce hard, diffi cult-to-pass 2. Loose stools are rarely present stool or require straining or manual ma- unless the patient takes a neuvers. Take a careful history including: • stool frequency and quality 3. Patient does not meet criteria for • straining Clinical Point • manual maneuvers (disimpaction or * Must be present during ≥25% of defecations Patients who report Source: Reference 8 manual pelvic fl oor support) straining, incomplete • sensation of blockage or incomplete Table 1 evacuation. evacuations, or other In women, take a history of childbirth symptoms may meet Colorectal screening recommendations* and obstetric or gynecologic surgery. Also constipation criteria determine the timing of symptom onset re- despite having daily Test Frequency lated to any new prescription or over-the- counter medications or supplements. bowel movements Fecal occult testing Annually (FOBT) ‘Alarm’ symptoms. For psychiatrists, the Every 5 years most important part of the Rome guide- FOBT and sigmoidoscopy Every 5 years lines are the “alarm” symptoms: Double contrast barium Every 5 years • age ≥50 years • family history of colon cancer or pol- Every 10 years yps • family history of infl ammatory bowel * For patients age ≥50. For higher-risk patients, it is reasonable to begin screening at a younger age disease (ulcerative colitis or Crohn’s Source: Reference 10 disease) • rectal bleeding, anemia • medical comorbidities that decrease • weight loss >10 pounds gastrointestinal (GI) motility. • new onset of chronic constipation Constipation carries a tremendous cost without apparent cause in an elderly in terms of resources and quality of life.1-7 patient This condition also can make patients stop • severe, persistent constipation refrac- taking medications. You can help patients tory to conservative management.9 avoid the discomfort and quality-of-life Refer a patient with any of these symp- consequences by promptly diagnosing toms to a specialist for endoscopic or constipation and following a 5-step treat- clinical evaluation. Follow ment algorithm that has shown value in Preventative Services Task Force recom- our clinical practice. mendations for colorectal cancer screening of all patients age ≥50 (Table 1).10

What to look for When evaluating a patient who complains Determining the cause of constipation, fi rst determine what he or Common causes of constipation include Current Psychiatry 30 May 2008 she means by “constipation.” Do not rely on altered visceral sensitivity, decreased GI

030_CPSY0508 030 4/17/08 11:46:19 AM Box 2 Don’t overlook 2 easily missed constipation causes

utlet obstruction, caused by these patients often require anorectal O inappropriately contracting posterior biofeedback, which teaches them to relax pelvic fl oor muscles during defecatory the posterior pelvic fl oor.11,12 effort, is the cause of 5% to 10% of Habitually suppressing the gastrocolic constipation cases.1 Patients are not aware refl ex—the urge to defecate after eating— of this pelvic fl oor incoordination. Often, causes some patients diffi culty moving they will give a history of straining even for their bowels. Counsel these patients to sit soft or liquid stool. on the toilet for several minutes after the Consider outlet obstruction in women morning meal to relearn this behavior. Some with history of multiple vaginal childbirths or may need several weeks of daily enema pelvic or gynecologic surgery, particularly or glycerine use to retrain if they fail to respond to usual measures themselves to have bowel movements after to treat constipation. For adequate relief, the morning meal. Clinical Point motility, alterations in pelvic and anorectal strategy may be to add sodium, Patients who use musculature, and alterations in the enteric a stool softener available over-the-counter chronically . Systemic causes are less as Colace. common and include abnor- may have altered malities (hypercalcemia and ) Other psychiatric-related causes. Pa- expectations of what and endocrine disorders (hypothyroidism tients with depression may experience is normal in terms and mellitus). decreased stool output because of a lack of bowel movements Some patients’ constipation is caused by of food intake or physical activity. These involuntarily contracting the pelvic fl oor causes may be effectively addressed by muscles or suppressing the urge to def- treating the depression. ecate (Box 2).1,11,12 Suspect this in patients Give special consideration to patients who strain repeatedly to pass soft or liquid with eating disorders and those who rou- stool. tinely use laxatives. A patient who is not eating will not produce the same amount Medication side eff ects are probably the of stool as one who eats regularly. most common constipation cause psychia- Constipated patients may require esca- trists will encounter. Many psychotropics lating doses of laxatives to obtain symptom have anticholinergic effects that decrease relief; this does not constitute laxative abuse GI motility and cause constipation. The but rather tachyphylaxis. Chronic laxative most commonly implicated drugs are: use has not been shown to permanently de- • older (such as crease colonic motility,14 but patients who ) use laxatives chronically may have altered • . expectations of what is normal. Among antipsychotics, , thio- ridazine, , and CASE CONTINUED probably have the greatest anticholinergic Recurring symptoms effects.13 Many selective reuptake After discontinuing Mr. W’s olanzapine and inhibitors also can cause constipation. duloxetine, the psychiatrist prescribes poly- Older psychiatric patients with consti- ethylene glycol solution (MiraLax) and in- pation may be taking medications for med- structs Mr. W to increase his daily fl uid and fi - ical conditions—particularly alpha, beta, ber intake. Although the solution works well, and calcium channel blockers—that may Mr. W complains of the cost. He then resumes have synergistic effects on slowing bowel methylcellulose and starts taking magne- motility. For these patients you may not sium hydroxide chewable tablets (Milk of have the luxury of making multiple medi- Magnesia) every 2 to 4 days as needed for Current Psychiatry cation changes. The correct management constipation. Vol. 7, No. 5 31 continued on page 36

031_CPSY0508 031 4/16/08 11:19:01 AM continued from page 31 Algorithm Treatment algorithm A stepwise approach To minimize trial and error, we use a step- to managing constipation wise approach to treating constipation (Algorithm).8,11,15 Although many standard Step 1 recommendations have not been evalu- ated in large randomized controlled trials, Recommendation Comments they are supported by decades of observed Constipation Increase activity Not rigorously studied actions among clinicians and thus remain or daily walking in constipated patients; valuable. exercise is associated with decreased orocecal Multiple nonprescription agents are transit time15 available to treat constipation, including: • bulking agents (fi ber supplements) Increase fl uid Not rigorously studied intake in constipated patients8 • lubricating agents • stool softening agents Increase dietary Not rigorously studied in fi ber intake constipated patients8 • and osmotic laxatives (Table 2, page 38).8 Clinical Point Advise patients that they may need to Step 2 Advise constipated try multiple agents to fi nd one that is toler- Recommendation Comments patients that they able and effective. Fiber supplements compounds may need to try may be superior Steps 1 & 2. When initial attempts at in- multiple OTC agents to methylcellulose, creasing physical activity, fl uid, and di- polycarbophil, and bran11 to fi nd one that etary fi ber fail to yield a response, fi ber supplements are commonly used as a is tolerable and Step 3 second step in managing constipation. We eff ective for them Recommendation Comments advocate beginning with a supplement Over-the-counter compounds are that contains psyllium—such as Fiber- laxative pills derived from plants all or Metamucil—because psyllium has been shown to increase stool frequency. Step 4 Supplements that contain methylcellu- lose (Citrucel), polycarbophil (such as Recommendation Comments Equalactin and Mitrolan), or have Over-the-counter Milk of Magnesia is either not shown effi cacy or have not been laxative solutions very inexpensive studied rigorously enough to merit rec- ommendation.10 Some patients respond Step 5 to other fi ber products, but start a fi ber- Recommendation Comments naïve patient with a psyllium-containing Prescription causes fetal supplement. laxatives loss in animals; Fiber supplements may cause increased is available only under a gas and , so start at a low dose and treatment investigational gradually increase over several weeks to new protocol mitigate these side effects.

The psychiatrist prescribes mirtazap- Step 3. If fi ber supplements fail, try a stimu- ine for OCD symptoms, but soon stops this lant or osmotic laxative. Senna compounds regimen because Mr. W complains of wors- such as Ex-Lax and Senokot and ening constipation. Next Mr. W is started products such as Correctol and Dulcolax on fl uvoxamine, which he had tried briefl y are stimulant laxatives. For patients who many years before. The dosage is gradu- prefer natural therapies, we point out that ally titrated to 150 mg/d. Although Mr. W’s senna is derived from plants. OCD improves somewhat, he complains In our experience, patients usually have of agitation and once again of worsening tried bisacodyl before seeking treatment Current Psychiatry 36 May 2008 constipation. for constipation. Although bisacodyl may

036_CPSY0508 036 4/16/08 11:19:06 AM be effective for some patients, others may WORKING need something stronger. Many gastroen- terologists prefer prescribing osmotic or prescription laxatives. TRUTHS Step 4. Osmotic laxatives generally are liquids, including hydroxide, solution, and the pre- scription agent . Magnesium hy- droxide is inexpensive and can be taken chronically.

Step 5: Prescription medications Tegaserod is a partial 5-HT4 and stimulator of GI motility and secretion. It also decreases visceral sensitivity.16 Tegaserod’s manufacturer voluntarily withdrew the drug from the market be- cause it may increase risk of cardiovascular ischemic events, including angina, heart Adults with ADHD attack, and . Tegaserod is available only under a treatment investigational 3x more likely new drug (IND) protocol that includes ob- were taining approval from a local institutional 1 review board. We recommend that psychi- to be unemployed* atrists should not prescribe tegaserod but refer patients to experienced gastroenter- ologists or other GI specialists. The consequences may be serious. Lubiprostone is a selective chloride chan- Screen for ADHD. nel activator that works only in the gut and results in net fl uid and in- creased stool frequency. The molecule is Find out more at a prostaglandin derivative and is poorly absorbed.17 www.consequencesofadhd.com Because lubiprostone has been shown and download patient support materials, to cause fetal loss in animals (at the equiv- alent of 2 and 6 times the recommended coupons, and adult screening tools. human dose), women of reproductive age should use contraception while taking lu- biprostone and carefully consider the risks and benefi ts of lubiprostone use during *Data compiled from a study comparing the young adult adaptive . outcome of nearly 140 patients (ADHD and non-ADHD control) followed concurrently for at least 13 years.

CASE CONTINUED Reference: 1. Barkley RA, Fischer M, Smallish L, Fletcher K. Young adult outcome of hyperactive children: adaptive functioning in major life activities. J Am Acad Finding an effective strategy Child Adolesc Psychiatry. 2006;45:192-202. The psychiatrist prescribes lubiprostone, 24 mcg bid, but Mr. W once again complains of the expense and says the drug does not work well. He quickly returns to his intermittent Shire US Inc. use of tablets and oc- ... your ADHD Support Company™ casionally takes bisacodyl tablets. ©2006 Shire US Inc., Wayne, Pennsylvania 19087 A1408 10/06 continued

037_CPSY0508119_CPSY0408 119 037 4/16/083/14/08 3:41:25 11:19:10 PM AM Table 2 The primary bacterial agents are Lacto- Commonly used laxatives: bacillus species and Bifi dobacterium spe- Mechanisms of action cies. At least one Bifi dobacterium product—Activia—is being marketed in Category Agents the United States as a fortifi ed yogurt. Bulk-forming Methylcellulose (Citrucel), Because limited clinical data are avail- polycarbophil (Equalactin, able on the effect of and prebiotics Constipation Mitrolan, others), psyllium on constipation, their routine use is not (Fiberall, Metamucil, others) indicated. However, patients who prefer Lubricating Glycerin (Sani-Supp), not to take medication may wish to try magnesium hydroxide and them. Because these agents are active cells, oil (Magnolax), mineral advise patients to purchase a supplement oil (Fleet , Zymenol, others) with “live and active” cultures. Supple- ments that are shipped, stored, or sold at Stool softener Docusate sodium (Colace) room temperature likely contain very few Osmotic Magnesium hydroxide (Milk of (if any) live cultures. Clinical Point Magnesia), polyethylene glycol (MiraLax), lactulose* (Cholac Because probiotics Syrup, Constulose, others), Investigational medications. are active cells, lubiprostone* (Amitiza) is a 5HT4 receptor agonist and 5HT3 recep- tor antagonist that has shown promise in a Stimulant Bisacodyl (Correctol, Dulcolax, advise patients who 18 others), (Alphamul, pilot study and is in phase III trials. Lina- try them to purchase Emulsoil, others), senna/ clotide is a peptide that activates chloride supplements sennosides (Ex-Lax, Senokot, and bicarbonate secretion in the gut and others), containing ‘live and may reduce visceral hypersensitivity. It too and has shown promise in a pilot study.19 active’ cultures (Ceo-Two evacuant)

* Available by prescription only References Source: Reference 8 1. Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94(12):3530-40. To address Mr. W’s OCD, the psychiatrist 2. Choung RS, Locke GR 3rd, Schleck CD, et al. Cumulative adds , 0.5 mg bid, to Mr. W’s regi- incidence of chronic constipation: a population-based study men. He has a modest response in OCD symp- 1988-2003. Aliment Pharmacol Ther 2007;26(11-12):1521-8. 3. Agency for Healthcare Research and Quality. Healthcare toms—30% of his day is now symptom- free— Cost and Utilization Project (HCUPnet). Available at: http:// without worsening his constipation. hcupnet.ahrq.gov. Accessed March 19, 2008. 4. Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci 1989;34(4):606-11. 5. Sonnenberg A, Koch TR. Epidemiology of constipation in the United States. Dis Colon 1989;32(1):1-8. Probiotics and prebiotics 6. Dennison C, Prasad M, Lloyd A, et al. The health-related quality Emerging therapies for constipation in- of life and economic burden of constipation. Pharmacoeconomics 2005;23(5):461-76. clude probiotics and prebiotics, which 7. Donald IP, Smith RG, Cruikshank JG, et al. A study of constipation attempt to alter the gut fl ora and milieu. in the elderly living at home. Gerontology 1985;31(2):112-8.

Bottom Line Psychotropic use, inactivity, and other factors may make psychiatric patients susceptible to constipation. A stepwise approach to treating constipation begins with recommending increased exercise, fl uids, and dietary fi ber. Progress through fi ber supplementation to nonprescription and prescription laxatives as needed. Individual therapy for constipation often requires multiple therapeutic trials until a Current Psychiatry 38 May 2008 patient fi nds an acceptable strategy.

038_CPSY0508 038 4/17/08 11:46:24 AM Related Resources • Rome Foundation. Functional gastrointestinal disorders. IMPACTFUL www.romecriteria.org. • Bleser S, Brunton S, Carmichael B, et al. Management of chronic constipation: recommendations from a consensus panel. J Fam Pract 2005;54(8):691-8. FACTS Drug Brand Names Amitriptyline • Elavil, Endep Lubiprostone • Amitiza Chlorpromazine • Thorazine • Remeron Clomipramine • Anafranil Olanzapine • Zyprexa Clozapine • Clozaril Risperidone • Risperdal Duloxetine • Cymbalta • Mellaril • Luvox Tegaserod • Zelnorm Lactulose • Cholac Syrup, Constulose, others Disclosure Adults with ADHD The authors report no fi nancial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. were 2x more Acknowledgment This project was partially supported by grant number 5 T32 HS013852 from the Agency for Healthcare Research and likely to have been Quality. involved in 3 or 8. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130(5):1480-91. *1 9. American College of Gastroenterology Chronic Constipation more car crashes Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol 2005;(100 suppl 1):S1-4. 10. U.S. Preventive Services Task Force. Colorectal cancer screening. Available at: http://www.ahrq.gov/clinic/ 3rduspstf/colorectal. Accessed March 19, 2008. 11. Chiotakakou-Faliakou E, Kamm MA, Roy AJ, et al. Biofeedback provides long-term benefi t for patients with intractable, slow and normal transit constipation. Gut 1998;42(4):517-21. The consequences may be serious. 12. Kawimbe BM, Papachrysostomou M, Binnie NR, et al. Outlet obstruction constipation () managed by biofeedback. Screen for ADHD. Gut 1991;32(10):1175-9. 13. Richelson E. Receptor of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;(60 suppl 10):5-14. 14. Muller-Lissner SA, Kamm MA, Scarpignato C, Wald A. Find out more at Myths and misconceptions about chronic constipation. Am J Gastroenterol 2005;100(1):232-42. www.consequencesofadhd.com 15. Keeling WF, Harris A, Martin BJ. Orocecal transit during mild exercise in women. J Appl Physiol 1990;68(4):1350-3. and download patient support materials, 16. Tegaserod [package insert]. East Hanover, NJ: Pharmaceuticals; 2006. coupons, and adult screening tools. 17. Amitiza [package insert]. Bethesda, MD: Sucampo Pharmaceuticals; 2007. 18. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the effi cacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006;23(11):1655-65. *Data from a study comparing driving in 105 young adults with 19. Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5 ADHD to 64 community control adults without the disorder. days on transit and bowel function in females Reference: 1. Barkley RA, Murphy KR, DuPaul GJ, Bush T. Driving in young with constipation-predominant irritable bowel syndrome. adults with attention deficit hyperactivity disorder: knowledge, performance, Gastroenterology 2007;133(3):761-8. adverse outcomes, and the role of executive functioning. J Int Neuropsychol Soc. 2002;8:655-672.

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