PSYCHIATRIC CONSULTANT

Series Editor Judith A. NeugroschI, MD

Chronic kidney disease Psychosocial impact of chronic pain Sara N. Davison, MD, MHSc, FRCP(C)

Chronic kidney disease (CKD) affects more than 19 miilion peopie in the United States, and prevalance of CKD is expected to doubie within 10 years. Additlonaliy, a significant number of predominantiy elderly patients have end stage renal disease, necessitating dialysis or kidney transplant. Perception of chronic pain, especially in elderly dialysis patients, may be greatly underrecognized. As a result, management of pain, as weil as depression and other physical and mental symptoms, may not be adequately addressed in the primary care setting. Ciinicai interventions, such as psychiatric evaluation, pain management, and therapy to improve physical and mental symptoms, may markedly impact well-being for CKD patients. Constant reassessment is criticai when treating CKD patients. Such an approach may significantiy better elderly patients health-related quality of life. Davison SN. Chronic kidney disease. Psychosociai impact of chronic pain. Geriatrics 2007; 62(Feb):17-23.

Key words: chronic kidney disease iife • depression

dialysis • health-related quality of

Drugs discussed: amitryptyllne • buproplon • citalopram • cyciosporine fluoxetine • Imlpramlne • litiiium • noripenephrlne • paroxetine sertrallne • tacrollmus • venlafaxine

C

hronic kidney disease (CKD) is a major public health concern affecting more than 19 million people in the United States.' More than 453,000 patients, predominantly elderly, have end stage renal disease (ESRD) requiring dialysis or kidney transplantation.^ Of the 336,000 patients on dialysis, 63% are age >60 and approximately 14% are age >80. In 2004, more than 102,000 patients

started dialysis in the United States: the majority (60%) were over age 60, and the proportion of patients age >75 had increased from 7.6% in 1980 to more than 25%, representing the fastest-growing group of new dialysis patients.^ Given the aging population and increasing incidence of diabetes and hypertension, the prevalence of CKD is projected to nearly double in the next decade.

Dr. Davison is assistant professor of nnedicine, division of nephrology and immunology, University of Aiberta, Edmonton, Aiberta, Canada. Disclosure: The author has no reai or apparent confiict of interest with the subject under discussion.

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The role of pain in elderly dialysis patients' perception of their health-related quality of life (HRQL) appears to be greatly underappreciated. In fact, the number and severity of physical and mental symptoms (eg, pain, nausea, anorexia, shortness of breath, insomnia, anxiety, depression) reported by elderly dialysis patients is similar to that reported by patients hospitalized in palliative care settings with cancer.^ The literature suggests approximately 50% of dialysis patients over age 55 experience chronic pain and that pain management is suboptimal, with 82% of these patients rating pain as moderate to severe.'*'^ Even in the last day of life, pain is present in 42% of patients withdrawing from dialysis.^ The burden of pain and other physical and mental symptoms, as previously mentioned, can account for more than one-third of the impairment observed in mental HRQL in dialysis patients.^'^ Worsening of symptom burden explains 46% of the deterioration in patients' mental HRQL.^ The lack of significant association between various clinical parameters, such as dialysis adequacy, calcium and phosphorous balance, or hemoglobin and HRQL, reinforces the relative importance from a patient perspective of symptom burden on patients' perception of HRQL. Pain, depression, and other physical and mental symptoms are not adequately recognized, diagnosed and treated in CKD.'*'^ Clinical interventions (eg, pain management, psychiatric evaluation, therapy for improv-

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PSYCHIATRIC CONSULTANT

Table 1 Causes o( pain in dialysis patients Etiology*

Percentage

Osteoarthritis + osteoporosis

31%

Inflammatory arthritis

7%

Renal osteodystrophy

5%

Peripheral polyneuropathy

13%

Carpal tunnel

2%

Peripheral vascular disease

9%

Discitis/osteomyelitis^

2%

Related to dialysis procedure

14%

Not yet diagnosed

18%

Other (trauma, PCKD, malignancy, calciphylaxis)

18%

* Many patients have nnore than 1 cause for their pain. Adapted for Geriatrics based on information from reference 4,

ing subjective assessment of physical and mental symptoms) would have a significant impact on well-being for CKD patients, and are critical components of comprehensive care for this patient population.

Chronic pain in CKD The causes of pain in CKD have not been well studied but have been described in a recent study (table I)."* Pain may be due to concurrent comorbidity; while dialysis sustains life, underlying systemic diseases and painful syndromes (eg, ischemic limbs, neuropathies) persists. Pain may also be due to CKD itself as there are numerous painful syndromes unique to CKD (eg, calcific uremic arteriolopathy, renal osteodystrophy). Pain may result from the primary renal disease itself (eg, polycystic kidney disease) or from the dialysis procedure. Painful chronic infections (eg, osteomyelitis, discitis) are complications from central lines used for dialysis access, and arteriovenous fistulas can lead to painful ischemic neuropathies.'* Pain is a multidimensional phenomenon with physical, psychological and social components. It is widely recognized that chronic pain is associated

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with depressive disorders, psychological distress, impairment of interpersonal relationships, excessive use of health care, significant activity limitations in work, family and social life, and adoption of a chronic sick role. Several recent reviews have reported that the prevalence of major depression in pain clinics often exceeds 20%.'" In the general population, depressive symptoms are positively associated with pain severity, and patients with chronic pain and concurrent depression are likely to experience the highest levels of pain-related impairment and psychosocial disability.'"" Recent research in CKD suggests that elderly dialysis patients' perceptions of physical symptoms, especially pain, are associated with depression, anxiety, insomnia, and greater difficulty coping with stressful situations.'^ In fact, physical and mental symptom burden appear more important than objective assessments, including assessments of dialysis adequacy, bone mineral metabolism, and anemia, in determining CKD patients' HRQL. Although loss of satisfaction with life, sense of burden on others, and a loss of control are the most common reasons for considering withdrawal from dial-

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ysis, regardless whether patients experience pain, patients are almost three times more likely to consider withdrawal from dialysis if they suffer from chronic pain.'^

Depression in CKD Although no large-scale, well-designed, epidemiologic studies of depression in patients with CKD have been conducted, depression appears to be a common and often underdiagnosed problem with a prevalence of 5% to 50% in dialysis patients.'^"'" The wide variation in prevalence of depression has been ascribed to the different methods and criteria for the diagnosis of depression. Differences among ethnic groups may also play a role in the variation. Most studies of depression in CKD have looked at elderly dialysis patients (average age: 60-65). Self-reported depression as well as Beck Depression Inventory (BDI) scores are associated with decreased HRQL as well as increased risks of mortality and hospitalization for dialysis patients. '^''^ Depression in CKD is likely multifactorial although is typically attributed to feelings of loss and dependence.'^ Although depression can occur at any time during the course of CKD, there are times of increased likelihood of a depressive episode, such as the time leading up to and the first year following initiation of dialysis, particularly if kidney transplantation is not an option due to advanced age and/or comorbidity. During this period, patients are required to make decisions regarding treatment modality and to make multiple and radical lifestyle changes, all of which impact their occupation, familial role, relationships, and leisure activities. They are expected to assimilate information that is foreign and frightening. Patients often feel unprepared for the decisions they must make and experience feelings of helplessness and deep personal loss, which can easily develop into a severe depressive

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PSYCHIATRIC CONSULTANT

Table 2 The essentials of pain assessment and management • The essentials of pain assessment include: 1. Believe the patient's report of pain. 2. Assess pain in its site, character, severity, reiieving and aggravating factors, and temporal relationships. 3. Use a simple assessment tool, such as the ESAS, which utilizes a numerical scale of 0 to 10. A. Educate patients or their caregivers on pain assessment and charting at home. ^ Patients may have more than one kind of pain; a pain management strategy must address each syndrome. *• Aim to achieve control at a level acceptable to the patient. It may not be necessary or possible to make the patient completely pain-free. >• The pain threshold may be aggravated by associated psychosocial symptoms.The psychological state of the patient must be assessed and treated with equal concern and is best managed by an interdisciplinary team. 1. Psychological factors typically have a stronger influence on outcome than do biomedical factors. 2. Better management of psychological reactions at early stages of treatment has the potential for reducing distress and preventing unnecessary chronicity. 3. Spiritual counseling may be useful in that spirituality may help the patient think beyond self and cope with pain better. >• Have knowledge of opioids and adjuvants to opioids.The five essentials of opioid (analgesic) dosing are: 1. "By mouth": whenever possible, drugs should be given orally. 2. "By the clock": schedule doses over 24 hours on a regular basis. Additional "breakthrough" medication should be available on an "as needed" basis. 3. "By the ladder": use pain medicines "stepwise" according to the World Health Organization analgesic ladder. 4. "For the individual": there is no standard dose of strong opioids. The "right" dose is the dose that relieves pain without causing unacceptable side effects. 5. Attention to detail: pain changes over time, thus there is the need for constant assessment and reassessment. • Refer for non-pharmacological interventions (such as transcutaneous nerve stimulation, hot and cold therapy, exercise, and neuromuscular massage) where appropriate. • Educate patients and their caregivers on the goals of therapy, management plan, and potential complications. This wiil help minimize non-compliance. Source: Created for Geriatrics by SN Davison, MD.

episode.'* Other particularly stressful times include the period leading to the failure of a transplanted kidney, and non-selection after having completed the work-up for a kidney transplant.'*

Pain and depression in CKD Despite the aforementioned reasons for depression, the role of chronic pain in depression in the elderly patient population has been greatly underappreciated. In a recent study, elderly dialysis patients with moderate or severe chronic pain were 2.3 times more likely to suffer from depression than elderly dialysis patients with no or mild chronic pain.'^ The prevalence of depression as defined by a BDI score of ^19 was 34%

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in patients with moderate to severe pain, compared with 18% in patients with no or mild pain (jxO.OY). The prevalence of insomnia was also significantly higher in patients with moderate or severe pain (74%), compared with patients with mild or no pain (53%, /7<0.01, OR 2.3). Potential confounders for depression (eg, time on dialysis, gender, insomnia, comorbidity), were not predictive of depression.'^ The results are also consistent with the general population in which chronic pain and depression frequently coexist. In the National Health and Nutrition Epidemiologic Follow-up Study, depressive symptoms were found to be the variable most closely linked to chronic musculoskeletal pain."

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The relationship between chronic pain and depression is complex and not entirely clear. Pain itself may be the cause of depressive symptoms by imposing limits on activities that are intrinsically rewarding or by altering perceptions of control over one's life. The reporting of pain as a symptom of depression, or as an expression of "masked depression," has also been considered, although this remains controversial. Perceptions of life control, or more specifically, lack of control, may be a mediating factor among CKD patients who develop depression, especially in the context of chronic pain. The nature of the pain, the context of its occurrence, and the ways in which patients cope with pain are

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PSYCHIATRIC CONSULTANT Ukely central to understanding the great variability across patients in their ability to function with pain. In CKD, pain is often experienced in the context of multiple, complex symptoms and end-of-life issues which may interfere markedly with psychological, social and physical coping skills. This concept is well stated in the term "total pain," which emphasizes the contribution of psychological (anxiety and depression), spiritual (search for meaning and purpose), social (isolation and abandonment), and fmancial (fear of burdening the family) factors to the pain experience. Psychosocial, financial, and spiritual issues enter into a cycle of interacting with and perpetuating physical symptoms and suffering of the patient. The pain threshold and response to pain therapy may largely depend on these patient-related factors rather than the potency of analgesics.^"'^' Although the causal link between chronic pain and depression is not clear, the presence of a psychiatric disorder has been shown to complicate treatment and rehabilitation of patients with chronic pain in other patient populations.^^ The clinical implication is that health care providers need to pay more attention to diagnosing and treating depression along with other psychosocial and spiritual issues if they are to provide adequate pain management. Conversely, attention to pain assessment and management will likely have a significant positive impact on depressive symptomatology and mental HRQL in these patients.

Symptom assessment in CKD Given the high burden of symptoms, regular screening for physical and mental symptoms must be incorporated into routine care for patients with CKD. The modified Edmonton Symptom Assessment System (ESAS) is a reliable, valid, simple and useful method for regular screening of physical and psychological symptoms in this patient population and can even be used effec-

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tively with geriatric patients near the end of life.^ It consists of 10 visual analog scales with a superimposed 0-10 scale for pain, activity, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, and pruritis. The scale for each symptom is anchored by the words "No" and "Severe" at 0 and 10, respectively. The assessment and management of chronic pain is beyond the scope of this review and have recently been reviewed elsewhere.'^'^•' However, several essential components of this process are outlined in table 2. Several instruments are helpful in the diagnosis and monitoring of depression in the general population. These include clinical impression, selfreports, the BDI, the multiple affect

should be incorporated into routine care for patients with CKD adjective checklist, and the DSM IVTR. However, their use in advanced CKD can be problematic as the common somatic symptoms, such as fatigue, anorexia, and changes in sleep patterns in depression, mimic those found in CKD. CKD patients, therefore, tend to score higher than established norms, and it has been suggested that elevated cut-off scores for depression should be used. The BDI has been used extensively in CKD and is a useful clinical screening tool. The BDI assesses physiological symptoms of depression (eg, weight

and appetite changes, sleep disturbances, fatigue, and loss of energy) in addition to alterations in affect and cognitive processes. Despite this, a BDI score of >!5 has been shown to have a high diagnostic sensitivity and specificity for major depression in dialysis patients.^'' The cognitive Depression Index (CDI) is a subscale of the BDI in which the somatic items have been deleted. Because it is less confounded by the effects of physical illness, it may be more helpful as a screening tool for depression in CKD prior to fuller diagnostic interviewing. Like the BDI, CDI scores are associated with mortality in CKD.^^ Although the Geriatric Depression Scale (GDS) has not been used in CKD it may be an appropriate tool for this population since it has been validated for the elderly, is not particularly dependent on physical symptoms of depression, and is available in many languages. Treatment of depression in CKD It is typically recommended that depression in patients with CKD be treated because of the dramatic impact of depression on HRQL and its potential adverse effects on the management of CKD.26 Further, treatment of depression with antidepressants has been shown to improve HRQL.^^ When a pain syndrome and a depressive disorder occur together, it is usually necessary to treat these disorders concurrently for any lasting relief from chronic pain to occur, even if the pain and depression are unrelated. If depression is moderate or severe, it may complicate the treatment of chronic pain and interfere with the patient's ability to cope with pain. There are, however, a minority of patients with severe depression accompanied by suicidal ideation, in which pain treatment must be delayed until the depressive disorder has been treated or for whom the concurrent treatment should take place in an inpatient setting. The underrecognition and inadequate treatment of depression in CKD

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PSYCHIATRIC CONSULTANT is due, in part, to the lack of training and experience in psychiatric care, as well as a poor understanding of the contributing factors for depression in CKD. Psychiatric disorders, especially depression, may be unrecognized at the beginning of dialysis as depressive symptoms such as fatigue, irritability, apathy, anorexia, and inability to concentrate may be attributed solely to uremia. Patients can also hinder the timely diagnosis and management of depression. Many patients with chronic pain become defensive about discussing psychological symptoms and may deny them altogether, believing that an acknowledgement of such symptoms would suggest that their pain is caused by psychological factors. In addition, chronic pain and depression are frequently misdiagnosed and undertreated in the elderly due to false assumptions by health professionals and patients that both are normal consequences of aging, a concern with polypharmacy, and the misconception that the elderly do not respond well to either pharmacological or psychological treatment approaches. The optimal approach to depression in the general population combines concomitant psychological therapy and medication. Although management of depression in CKD may be similar, emphasis should be placed on concomitant symptom management, an understanding of the unique challenges faced by elderly CKD patients, especially those nearing or on dialysis, and the changes in pharmacokinetics and pharmacodynamics of psychotropic drugs in CKD. Patients with CKD not only have decreased renal clearance of the parent drug and metabolites, but may have altered absorption, increased volume of distribution, and reduced protein binding leading to increased available drug levels. Therefore, pharmacologic therapy should be closely monitored for therapeutic and toxic effects. Selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are effective antide-

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pressants in CKD.^*-^^ Although often used in CKD, SSRIs have not been systemically researched. SSRIs are hepatically metabolized by the cytochrome P-450 enzyme system and the metabolites are excreted principally by the kidneys. Only small percentages of the parent drugs are excreted unchanged in the urine. Fluoxetine is the best-studied medication in this class and appears to be both nontoxic and efficacious.^^ Renal function does not significantly alter fluoxetine or norfiuoxetine serum levels. Like fluoxetine, sertraline and citalopram are widely prescribed and kinetics appears minimally changed in patients with CKD. Interestingly, plasma concentra-

u mm Eiime

depressive symptoms can be significantly reduced

tions of paroxetine hydrochloride are increased in CKD patients.'^ Dose adjustment is probably not necessary in mild-moderate kidney failure. However, because of the possibility of accumulation of active metabolites, it is recommended that these agents be initiated at low doses (about half the usual starting dose) with careful titration for elderly patients and those with ESRD.^^'^" The literature suggests depressive symptoms can be significantly reduced in CKD by low doses of SSRIs.^ In addition, the SSRIs tend to have relatively mild side-effect profiles, even in CKD, although they can be associated with sexual dysfunction, which is already compromised in CKD.'^ Care must be taken with patients receiving concur-

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rent drugs metabolized by the cytochrome P-450 enzyme system (eg, tacrolimus, cyclosporine) when using antidepressants, which are inhibitors of these isoenzymes. Tricyclic antidepressants (TCAs) (eg, imipramine, amitriptyline) are effective for analgesia in neuropathic pain and are frequently prescribed in low doses for this indication in dialysis patients. However, their use for the management of depression should be reserved for treatment-resistant depression unless there is an additional indication (eg, painful peripheral neuropathy, insomnia). TCAs are metabolized in the liver and the metabolites excreted via the kidney. The hydroxylated metabolites of TCAs contribute to the therapeutic and toxic effects in CKD. Although it is not absolutely necessary to reduce the dose for patients with CKD,^' TCAs are not well tolerated in the elderly or those with CKD due to the anticholinergic, histaminergic and adrenergic properties resulting in symptoms such as urinary retention, dry mouth, orthostatic hypotension, and somnolence, symptoms that already trouble many CKD patients. In addition, CKD patients show greater unpredictability and interpatient variability in their response to TCAs. TCAs are also highly protein bound with a large apparent volume of distribution, therefore are not effectively removed by dialysis. If TCAs are to be used, it has been suggested that they be initiated at low doses, given in divided daily doses, and titrated slowly until a therapeutic or toxic effect is seen.^* Several antidepressant medications should be used with caution or avoided. The serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and the norepinephrine dopamine reuptake inhibitor (NDRI) bupropion hydrochloride, along with their metabolites, are eliminated primarily in the urine and lower doses are required in CKD.^^In addition, clinical experience with these other classes

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PSYCHIATRIC CONSULTANT of antidepressants is lacking in CKD. For the relatively few bipolar patients on dialysis who require lithium, treatment involves administration of a single dose (usually 600 mg) after each dialysis run. Because lithium is a small molecule that is readily dialyzed,^^ serum lithium levels obtained before and after dialysis sessions are required to establish the therapeutic dose. Summary Elderly patients with CKD have a high symptom burden. Chronic pain and clinical depression is widespread in this patient population and unfortunately often unrecognized and untreated by health care professionals. Routine screening and more vigorous treatment of physical and mental symptoms, especially chronic pain and depression, is required. The use of a simple, standardized, self-report tool, such as the modified ESAS, is ideal for initial symptom screening. Because depressive disorders are an integral part of the experience of chronic pain, patients with chronic pain should be carefully evaluated as pain is unlikely to be controlled unless these associated symptoms or unmet needs are addressed. Constant reassessment is necessary: as you treat one symptom successfully, others may improve allowing for successful weaning of therapy. For example, when pain and functional limitations are successfully addressed, the symptoms of depression may improve. This approach to chronic pain and depression has the potential to dramatically improve elderly CKD patients' HRQL. 8 References 1.

2.

Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the aduit US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003; 41(1):1-12. U.S.Renal Data System, National Institutes of Health, Nationai Institute of Diabetes and Digestive and Kidney Diseases. 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD:

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U.S. Renal Data System, 2005. 3.

Davison SN, Jhangri GS, Johnson JA. Cross sectional vaiidity of a modified Edmonton Symptom Assessment System (ESAS) in dialysis patients: A simple assessment of symptom burden. Kidney Int 2006; 69(9);1621-5.

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Davison SN. Pain in hemodialysis patients; Prevalence, cause, severity, and management. Am J Kidney Dis 2003; 42(6);1239-47.

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Weisbord SD, Fried LF, Arnold RM, et al.Prevalence, severity, and importance of physical and emotional symptoms in chronic hemodialysis patients. J Am Soc Nephrol 2005; 16(8);2487-94.

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Cohen LM, Germain M, Poppel DM, Woods A, Kjellstrand CM. Dialysis discontinuation and paiiiative care. Am J Kidney Dis 2000; 36(l):140-4.

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Merkus MR Jager KJ, Dekker FW, de Haan RJ, Boeschoten EW, Krediet RT. Physical symptoms and quality of life in patients on chronic diaiysis: Results of The Netherlands Cooperative Study on Adequacy of Dialysis (NECOSAD). Nephrol Dial Transplant 1999; 14(5):1163-70.

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Davison SN, Jhangri GS, Johnson JA. Longitudinai vaiidation of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients. Nephrol Diai Transpiant 2006; 21(ll);3189-95.

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Finkelstein FO, Finkeistein SH. Depression in chronic diaiysis patients: assessment and treatment. Nephroi Dial Transpiant 2000;

10. Wiison KG, Eriksson MY, D'Eon JL, Mikail SF, Emery PC. Major depression and insomnia in chronic pain. Ciin J Pain 2002; 18(2):77-83. 11. Fishbain DA, Cutier R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997; 13(2):116-37. 12. Davison SN, Jhangri GS. The impact of chronic pain on depression, sleep, and the desire to withdraw from dialysis in hemodiaiysis patients. J Pain Symptom Manage 2005; 30(5):465-73. 13. O'Donneii K, Chung JY. The diagnosis of major depression in end-stage renal disease. Psychother Psychosom 1997; 66(l):38-43. 14. Smith MD, Hong BA, Robson AM. Diagnosis of depression in patients with end-stage renal disease. Comparative analysis. Am J Med 1985; 79(2); 160-6. 15. Kimmei PL, Peterson RA, Weihs KL, et ai. Multiple measurements of depression predict mortality in a iongitudinai study of chronic hemodiaiysis outpatients. Kidney int 2000; 57(5):2093-8. 16. Lopes AA, Bragg J, Young E, et al. Depression as a predictor of mortality and hospitaiization among hemodiaiysis patients in the United States and Europe. Kidney Int 2002; 62(l):199-207.

Merskey H. Chronic abdominal pain and depression. Epidemiologic findings in the United States. Hispanic Heaith and Nutrition Examination Survey. Pain 1992; 49(l):77-85. 20. Gatchel RJ. Psychological disorders and chronic pain; Cause and effect relationships. In: Gatchel RJ, Turk DC, eds. Psychological Approaches to Pain Management: A Practitioner's Handbook. New York: Guilford Publications, 1996: 33-54. 21. Hunwitz EL, Goldstein MS, Morgenstern H, Chiang LM. The impact of psychoiogicai factors on neck pain and disability outcomes among primary care patients: Results from the UCLA Neck Pain Study. Disabil Rehabil 2006; 28(21):1319-29. 22. Burns JW, Johnson BJ, Mahoney N, Devine J, Pawi R. Cognitive and physical capacity process variables predict long-term outcome after treatment of chronic pain. J Consult Clin Psychoi 1998; 66(2):434-9. 23. Davison SN. Chronic pain in end-stage renal disease. Adv Chronic Kidney Dis 2005; 12(3):326-34. 24. Craven JL, Rodin GM, Littiefield C. The Beck Depression inventory as a screening device for major depression in renal dialysis patients. Int J Psychiatry Med 1988; 18(4):365-74. 25. Kimmei PL. Psychosocial factors in dialysis patients. Kidney int 2001; 59(4):1599-613. 26. Tossani E, Cassano RFava M. Depression and renal disease. Semin Dial 2005; 18(2):73-81. 27. Turk S, Atalay H, Altintepe L, et ai. Treatment with antidepressive drugs improved quality of iife in chronic hemodiaiysis patients. Ciin Nephroi 2006; 65(2);113-8. 28. Cohen LM, Germain M, Tessier EG. Neuropsychiatric complications and psychopharmacology of end-stage renal disease. In: Brady HR, Wiicox CS, eds. Therapy of Nephroiogy and Hypertension, 2nd ed. A Companion to Brenner and Rector's The Kidney. Philadelphia, PA. WB Saunders, 2003: 731-46. 29. Biumenfield M, Levy NB, Spinowitz B, et ai. Fiuoxetine in depressed patients on dialysis. Int J Psychistry Med 1997; 27(l):71-80. 30. McEvoy G, ed. AHFS Drug information 2000. Bethesda, MD: American Society of HeaithSystem Pharmacists, 2000. 31. Aronoff GR, Berns JS, Brier ME, et al. Drug prescribing in renai faiiure; Dosing Guidelines for Aduits, 4th ed. Phiiadeiphia, PA: American Coiiege of Physicians, 1999. 32. Troy SM, Schuitz RW, Parker VD, Chiang ST, Blum RA. The effect of renai disease on the disposition of venlafaxine. Ciin Pharmacol Ther 1994; 56(1);14-21. 33. Port FK, Kroli PD, Rosenzweig J. Lithium therapy during maintenance hemodialysis. Psychosomatics 1979; 20(2);130-2.

17. Fabrazzo M, De Santo RM. Depression in chronic kidney disease. Semin Nephrol 2006; 26(l):56-60. 18. Chambers EJ, Germain M, Brown E, eds. Supportive Care for the Renal Patient. New York, NY; Oxford University Press, 2004. 19. Magni G, Rossi MR, Rigatti-Luchini S,

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