e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.

 


 

This past December, the United States Food and Drug Administration approved duloxetine for the maintenance treatment of major depressive disorder in adults. Long overlooked, the issue of delaying or preventing a return of depressive illness has become a focus of both clinical and research interest. Until now, compared to acute efficacy trials, few maintenance studies have evaluated the efficacy of pharmacotherapy for the prevention of recurrence. One reason is that maintenance and relapse prevention studies take significantly longer to conduct than acute efficacy studies, making them difficult to complete and expensive. These studies, if they are done, occur after the drug is approved for acute treatment, so requiring completion of such studies at New Drug Application filing will delay approvals and patient access to novel treatments. Many patients need to be enrolled because discontinuation rates after 3 months in most studies are approximately 50%. In most trials, the drop-out rate at 6 months is 70%. In a study of the elderly, approximately one-third of patients who originally responded to paroxetine alone or in combination psychotherapy relapsed within 2 years.1 Relapse rates in the Sequenced Treatment Alternatives to Relieve Depression study were also high.2

There are many possible reasons people break through. Some include pharmacodynamic or pharmacokinetic tolerance (eg, tachyphylaxis), side effects (eg, apathy, anhedonia, emotional blunting), onset of a comorbid medical disorder, increase in disease severity or change in disease pathogenesis (eg, progression), depletion of effector substance (eg, neurotransmitter), serum drug levels that have drifted below or above that drug’s therapeutic window, accumulation of detrimental metabolites, misdiagnosis (eg, bipolar disorder), loss of placebo response.

Defective or counterfeit medication can be added to this list. For example, the FDA is currently reviewing the formulation of a generic form of Wellbutrin XL. Called Budeprion XL, the drug was found in tests to have significant bioavailability problems. The tests were conducted as a result of complaints by hundreds of patients that the drug caused severe headaches, digestive problems, anxiety, tremors, and insomnia.

Keep in mind that the active ingredient of a generic medication is chemically identical to the active ingredient of the corresponding branded medication. It is supposed to be identical, or bioequivalent, to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. However, the FDA does permit a variation of approximately 20% either way in the bioavailability of the active ingredient. In addition, any filler used in compounding the pill may be different than that found in the branded product. I have had several patients who complained of loss of efficacy or allergic reaction when switching from Wellbutrin XL to a generic preparation.

On a related note to that of bupropion above, a recent article appeared on the front page of the New York Times3 concerning increase in counterfeit products that reach pharmacies. Fake, subpotent, or adulterated drug products are reaching the market. Among counterfeit drugs recently seized by the FDA were Actonel, Arimidex, Celebrex, Crestor, Diovan, Hyzaar, Lipitor, Nexium, Propecia and Zetia. This is relevant because if there is a sudden change in a patient’s clinical status, either in terms of response or side effects, questions should be triggered about whether the medication looks different than those used or whether a new bottle of medication was started.

 In addition to thanking all the authors in this issue of Primary Psychiatry, I want to acknowledge the contribution of my colleague, Jean-Pierre Lindenmayer, MD. Dr. Lindenmayer is a member of the faculty at the New York University School of Medicine and has spent his career looking for ways to improve the treatment of individuals with schizophrenia. His article notes that patient function is often a neglected aspect of the disease. Although used in clinical trials, scales of functioning are not routinely used in clinical practice for the assessment of schizophrenia. He argues that an improved understanding of the spectrum of patient dysfunction and the development and increased use of specific assessment scales should improve long-term prognoses for schizophrenia patients.

Finally, I would like to thank the excellent and hard work of our peer reviewers, without whom we could not maintain the high standards of the journal. PP

 

References

1. Reynolds CF 3rd, Dew MA, Pollock BG, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006;354(11):1130-1138.
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
3. Bogdanich W. A Toxic Pipeline Counterfeit Drugs’ Path Eased by Free Trade Zones. The New York Times. December 17, 2007:A1.

 

Dr. Novak is assistant professor in the Department of Psychiatry at the University Health Network at the University of Toronto and associate professor at the Institute of Behavioral Sciences at Semmelweis University in Budapest.

Disclosure: Dr. Novak reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Marta Novak, MD, PhD, Department of Psychiatry, University Health Network, Toronto General Hospital, 200 Elizabeth St. EN 8-212, Toronto, ON, M5G 2C4, Canada; Tel: 416-340-3043; Fax: 416-340-4198; E-mail: marta.novak@uhn.on.ca.

 


 

This issue of  Primary Psychiatry includes articles related to psychosocial and psychiatric problems in patients with chronic kidney disease (CKD). CKD is defined by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR), that persists for >3 months.

In its early stages the condition is indolent but in more advanced stages (when the GFR is <60% and CKD stage 3–5) an increasing number of symptoms will appear. When the GFR drops ≤10% to 15%, the patient will need renal replacement therapy (RRT) in the form of peritoneal or hemodialysis, or kidney transplantation (KTx). This stage of the disease is called CKD stage 5 or end-stage renal disease (ESRD).

Currently, >1.5 million people worldwide and approximately 350,000 patients in the United States are treated with dialysis therapy. In the US, another 150,000 patients live with a functioning kidney transplant.2 The prevalence of stage 3–5 CKD is largely unknown but it may well be approximately 10–50 times higher than the prevalence of ESRD.3

CKD is a complex medical problem. Patients not only experience symptoms of the declining kidney function but also suffer from a variety of serious comorbid conditions (eg, cardiovascular disorders, diabetes, bone diseases, eye diseases). Significant restrictions in fluid intake and diet affect the everyday life and medical management of patients. The pharmacologic management of these medical conditions results in a complex system of numerous medications.

The mortality of patients with CKD is substantially increased and in stage 5 CKD it could be 10–100 times higher than in the general population. The 5-year survival of patients on dialysis therapy is <50% in the US. CKD and RRTs not only increase mortality and morbidity of these patients but they are also associated with severely impaired quality of life (QOL).

Dialysis is a stressor in itself on biologic, psychological, and social levels alike. KTx does not cure CKD either and people who live with transplants are constantly under the risk of rejection and may experience medication side effects. When the transplanted kidney fails, the patients have to return to dialysis again. Dialysis, in any form, cannot fully replace kidney function, and patients inevitably experience the symptoms of CKD chronically. Both dialysis and renal transplantation are fairly invasive, and intrusive procedures which may involve pain, discomfort, and distress for the patients and their families.

As the variety of psychosocial and mental health issues related to patients with chronic renal disease and RRT are increasingly acknowledged, psychonephrology has become an emerging interdisciplinary field between nephrology, transplantation, and psychosocial medicine and psychiatry.

Psychosocial and psychiatric aspects of CKD not only affect patients but have effects on family members and caregivers; a complex and difficult psychological and lifestyle adaptation to the disease, and its treatment is required from the individuals involved. Selected topics for this issue are important in assisting patients and families in this process and improving the care of patients with CKD.

Assessing the outcome of CKD, comparing the effectiveness of various RRTs has become increasingly important over the past decades. Istvan Mucsi, MD, PhD, notes in his article that in addition to the traditional “hard outcome measures” (ie, mortality, morbidity, and hospitalization), patient-reported outcomes and, specifically, health-related quality of life, have increasingly been recognized as equally important aspects of healthcare delivery, measures of effectiveness, and patient experience in chronic medical conditions such as CKD. He emphasizes that RRTs are very intrusive therapies and have a significant impact on patient lives. Sometimes this is similar in magnitude to the effect of the disease itself on QOL. Consequently, QOL of the patients with ESRD is substantially impaired in the physical, mental health, and social domains.

Sleep disorders clearly contribute to impaired QOL and might even affect survival in patients with CKD. Sleep disorders and complaints regarding sleep are among the most frequent problems in patients with CKD. Mark Unruh, MD, MSc, provides an overview of the most frequent and significant sleep disorders, including insomnia, sleep apnea, and restless legs syndrome. He also notes that sleep disorders are still understudied in this high risk population.

Mood disorders and anxiety are the most common psychiatric problems in patients with kidney diseases. Stressful life events can trigger depression at any point of the CKD, especially in those who are susceptible to mood disorders. Specific disease-related factors might also contribute to depression or emotional distress in these patients.

Both patients and physicians often tend to attribute the physical problems, emotional distress, and functional decline to the kidney disease, and depressive disorders may be overlooked. Treatment of depressive disorders may be one important step toward a life not fully dominated by the perceived intrusiveness of the illness. Dora M. Zalai, MD, and Marta Novak, MD, PhD, emphasize that a complex biopsychosocial approach is needed to fully understand mood disorders in medically ill patients in general, and in CKD patients in particular.

The fact that no outcome studies are available that assess the effect of depression treatment on survival or QOL in this patient population points to a disturbing clinical knowledge gap. Based on the association of depression and mortality and the well-documented relationship between depression and compliance as well as between depression and conditions such as malnutrition, cardiac events, and inflammation, we can speculate that effective treatment of depression would improve the outcome of patients with CKD. Treatment of psychiatric disorders deserves special consideration in the medically ill patient. Often, patients receive suboptimal pharmacologic management due to the lack of information in this specific area. Roger S. McIntyre, RS, MD, FRCPC, and colleagues, provide a comprehensive review on the use of psychotropic drugs in patients with impaired renal function. After a detailed theoretical overview, they discuss “tactics and strategies” with a special focus on lithium and antidepressants and an extended Table synthesizing the available information of pharmacokinetics of psychotropic medications.

It is hoped that readers will find these articles useful for everyday practice. PP

 

References

1.    National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.
2.    U.S. Renal Data System. USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007.
3.    Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41(1):1-12.

 

 

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.

 

 
 

Pharmacologic and psychosocial treatment options for mania have improved substantially as evidenced by the volume of expert opinion, guidelines, meta-analyses and reports from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. However, these sources offer little direct evidence from the treatment of older patients. The lack of data is troublesome because bipolar disorder in late life is complicated by both mental and physical comorbid conditions, making both diagnosis and treatment challenging. Given the increase in the aging adult population, the frequency with which primary care physicians (PCPs) encounter late-life mania will increase as well. What follows is a brief review of the character and control of late-life mania as well as expert inferences from the Acute Pharmacotherapy of Late-Life Mania (GERI-BD) and STEP-BD studies.

 

Introduction

Late-onset mania is often misdiagnosed and, as a result, is likely to be more common than previously reported. With the increase in the older adult population, PCPs and general psychiatrists will inevitably encounter greater numbers of patients with late-life bipolar disorders and mania. The notion that bipolar disorders “burn out” in old age is more myth than reality. Indeed, few older adults with the disorder experience a full functional recovery despite symptom remission. Although substance abuse disorders are less frequently associated with bipolar disorder than in early life,1 impairments in cognitive speed and executive dysfunction are common.2 Late-onset mania occurs equally among men and women. With the exception of less sexual preoccupation among older patients, age has little impact on the symptom profile.3

 

Diagnosis

Manic episodes in older adults often present with confusion, disorientation, distractibility, and irritability rather than elevated, positive mood. The clinical interview may be characterized by irrelevant content delivered with an argumentative, emotionally-intense yet fluent quality. Grossly unrealistic plans concerning finances or travel, inflated self esteem, and contentious claims of certainty in the face of evidence to the contrary are also seen. The unsuspecting examiner may be puzzled (or irritated) by the difficulty of the interchange until the diagnosis of mania is considered.

The presence of psychosis, sleep disturbance, and aggressiveness may lead to the mistaken diagnosis of dementia or depressive disorder rather than mania. Because mania in late life is genuinely less frequent than depression or dementia and less frequently recognized, these patients are often treated with antipsychotics, antidepressants, or benzodiazepines which provide only partial relief. Late-onset mania is more often secondary to or closely associated with other medical disorders, most commonly stroke, dementia, or hyperthyroidism; it is also associated with medications including antidepressants, steroids, estrogens, and other agents with known central nervous system properties.4 A search for treatable components that contribute acutely to the person’s disability should be pursued. Risk factors for cerebrovascular disease, including excessive use of alcohol, tobacco, suboptimal control of hypertension, and other cardiovascular risk factors should be explored.

The workup should also identify indicators such as structural brain changes or dementia that will assist in prognosis. Careful inquiry of the family may uncover repeated hypomanic episodes which did not seriously impair the individual but in retrospect are clear indications of earlier disease. The difficulties of recognizing the diagnosis, care for contributing conditions, age-related vulnerability to medication side effects, and frequency with which structural brain changes are associated all make treatment more difficult. Structural brain changes most frequently include subcortical hyperintensities seen on magnetic resonance imaging.5 Table 1 provides diagnostic criteria for manic and hypomanic episodes. Table 2 portrays diagnoses that are easily confused with mania.

 

 

 

 

Treatment of Mania

An adequate review of effective, evidenced-based psychosocial interventions for bipolar disorder is beyond the scope of this column. However, the capacity of psychosocial interventions to prevent hospitalization associated with recurrence makes awareness of these interventions crucial to good care. Readers are referred to the works of Miklowitz and colleagues6,7 for a review of the evidence. There is a growing consensus based on expert opinion,8 published guidelines,9,10 and the STEP-BD reports11,12 that antiepileptics, called mood stabilizers in this context, are preferable both for acute treatment and prevention of recurrence in late-life mania and bipolar disorder depression. The anticonvulsant divalproex is increasingly considered first choice for treatment and prevention of mania. A therapeutic level is available; while hepatic toxicity is a risk, it is infrequent. Divalproex inhibits hepatic enzymes that metabolize medications frequently used by older adults. Patients taking β-blockers, type 1c antiarrhythmics, benzodiazepines, or anticoagulants should be monitored more closely until the divalproex dose is stabilized. Dose, precautions, and therapeutic levels for other mood stabilizers appear in Table 3.

 

Due to the delay in the anti-manic effects of mood stabilizers, a 3-week period including titration to a therapeutic range is the minimum time required to establish treatment responsiveness. In the interim, people whose manic excitement is extreme, exhausting, or overly aggressive will require an antipsychotic or benzodiazepine. As shown in Table 3, numerous atypical antipsychotics are Food and Drug Administration approved for the treatment of mania. Based on meta-analyses, they appear to be equally superior to placebo13 such that the choice of an individual agent is based on side-effect profiles and patient vulnerabilities. However, the available data on the treatment of mania in the STEP-BD study as well as the meta-analyses14 includes few older adults.

On contrast, the GERI-BD study,15,16 sponsored by the National Institute of Mental Health and chaired by Robert Young, MD, included adults ≥60 years of age. They must have a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,17 diagnosis of bipolar disorder, Type 1 (manic, mixed, hypomanic), be medically stable, and be free of schizophrenia and dementia. These patients will be randomized to receive monotherapy with lithium or divalproex with dose titration to be completed within 3 weeks (Table 4). Doses are increased or decreased based on side effects as well as therapeutic levels across initial, intermediate, and final target ranges. Lithium 150 mg or divalproex 250 mg is initiated BID and is adjusted by increasing or decreasing on a step by step basis, with one step equaling one of the twice daily doses. An increase or decease of one to two steps is made depending upon where the therapeutic level falls in the initial, intermediate, or final range. Therapeutic levels, side effects, and symptomatic response or lack thereof are obtained on days 4, 9, 15, and 21 following baseline. Blood work to ensure safety is collected at baseline and weeks 3, 6, and 9 and includes complete blood count, transaminases, and amylase. Dose reduction is indicated for tremor interfering with self care, ataxia or unsteady gait, excess sedation, or bradycardia <50 beats per minute. Medications may be held or discontinued when the platelet count is <80,000 or if transaminases or amylase are two-fold or more above normal limits. The onset of diabetes insipidous (polyuria, polydipsia) may also be cause for discontinuation of lithium.

 

 

Lorazepam, then risperidone, may be added during the first 3 weeks for as needed use when agitation, aggression, anxiety, hyperactivity, or insomnia are excessive. However, if after 3 weeks of treatment symptoms remain substantial or have not declined by 20%, risperidone is added as adjunctive, combined daily therapy to either lithium or divalproex. Risperidone may be titrated up to 3 mg/day with a maximum dose of 4 mg. A score of ≥16 or a decline of <20% from baseline as measured by the Young Mania Rating Scale18 at 3 weeks is the objective severity indicator for adjunctive risperidone. Although study results are not expected to appear before 2010, the GERI-BD protocol provide an expert opinion for aggressive treatment of late-life mania.15,16   

 

Lithium

Seniors who have experienced good results with lithium should not be switched to an alternative. Nonetheless, numerous concerns argue for caution when considering lithium for the initiation of treatment. Advanced age, absence of family history of bipolar disorder, mania secondary to another medical condition (particularly stroke), or dementia predict poor response to lithium. The age-related decline in renal function means older adults are at increased risk of toxicity because lithium is cleared solely by the kidneys. Structural brain changes which may not be clinically apparent are associated with higher risk of toxicity. Drug interactions which are less dangerous and less common in younger patients complicate the use of lithium in older adults. Laboratory tests which should be checked at least annually in patients treated with lithium include fasting blood sugar, thyroid function, creatinine clearance, blood urea nitrogen, and electrolytes. Diabetes insipidous (polydipsia, polyuria), hyperglycemia, thyroid abnormalities, congestive heart failure or arrhythmia, and psoriasis are among the more frequent reasons for changing to an alternative treatment.19

Manifestations of lithium toxicity include gastrointestinal complaints, ataxia, slurred speech, delirium, or coma. Toxicity in older adults may occur at plasma levels below the therapeutic range of 1.0 mEq/L. However, mild tremor and nystagmus without functional consequences frequently accompany lithium treatment and should not be considered signs of toxicity. Toxicity may result when dehydration due to vomiting, diarrhea, fever, or sweating contracts the extracellular volume of distribution. Lithium is reabsorbed in preference to sodium leaving little margin for error. Renal failure, diuretics, reduced intake of salt or fluids, and concomitant use of nonsteroidal anti-inflammatory agents (excepting aspirin and sulindac), increase the risk of toxicity.20 Long-lasting cerebellar dysfunction is the most common neurologic sequeallae of lithium toxicity, although dementia, parkinsonism, peripheral neuropathies, and brainstem symptoms have also been reported.21 Cautious re-hydration will counter suspected lithium toxicity, but return of the patient’s mental status to baseline may be prolonged. In acute renal failure, dialysis or forced saline diuresis will be required.22

 

Electroconvulsive Therapy for Mania

Electroconvulsive therapy (ECT) has a long history in the treatment of mania and may be indicated for the severely disturbed older patient when either agitation or the threat of aggression becomes extreme. It may be particularly useful in cases of medication inefficacy or intolerance, imminent suicidal risk, or morbid nutritional status. Advanced age, concurrent antidepressants, and heart disease increase the risk of adverse reactions, with cardiovascular complications being the most frequent events. The cognitive impairment associated with ECT includes transient postictal confusion, anterograde or retrograde amnesia, and less commonly a permanent amnestic syndrome in which recall of events surrounding the treatment is blank. Treatments may be limited to twice weekly and applied bifrontally or unilaterally to the non-dominant hemisphere to minimize confusion. However, bilateral treatment may be more effective.23

 

Conclusion

With the increasely aging adult population, PCPs and general psychiatrists will inevitably encounter greater numbers of patients with late-life bipolar disorders and mania. Data specific to the treatment of older adults must await the results of the GERI-BD study.15,16 However, reliable inferences based on published guidelines,9,10 meta-analyses,13 and the STEP-BP study7,11,12,14 provide considerable guidance for both biomedical and psychosocial interventions. Initial treatment should begin with a mood stabilizer. A short-acting benzodiazepine or atypical antipsychotic may be necessary during the titration phase of mood stabilizer therapy to “rescue” the patients from intolerable or dangerous symptoms. For people who remain symptomatic or exhibit depressive symptoms despite reaching a therapeutic level of a mood stabilizer, ongoing adjunctive therapy with an atypical antipsychotic appears superior to the addition of an antidepressant. Comorbidities and polypharmacy rather than age per se are the indicators for caution. Because cognitive impairment and recurrence are frequent, family-focused psychotherapy is likely to be as crucial for mania as it is for bipolar depression.2 The risk–benefit-burden comparison of lithium to divalproex remains in question but should be resolved by results from the GERI-BD study.15,16 Table 5 provides consumer and advocacy information. PP

 

 

 

References

1.    Depp CA, Jeste DV. Bipolar disorder in older adults: a critical review. Bipolar Disord. 2004;6(5):343-367.
2.    Gildengers AG, Butters MA, Chisolm D, et al. Cognitive functioning and instrumental activities of daily living in late-life bipolar disorder. Am J Geriatr Psychiatry. 2007;15(2);174-179.
3.    Young RC, Kiosses D, Heo M, Schulberg HC, Murphy C, Klimstra S, Deasis JM, Alexopoulos GS. Age and ratings of manic psychopathology. Bipolar Disord. 2007;9(3):301-304.
4.    Young RC, Moline M, Kleyman F. Estrogen replacement therapy and late life mania. Am J Geriatr Psychiatry. 1997;5(2):179-181.
5.    McDonald WM, Krishnan KRR, Doraiswamy PM, Blazer DG. Occurrence of subcortical hyperintensities in elderly subjects with mania. Psychiatry Res. 1991;40(4):211-20.
6.    Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiatry. 2003;60(9):904-912.
7.    Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the systematic treatment enhancement program. Arch Gen Psychiatry. 2007;64(4):419-426.
8.    Keck PE, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci. 1992;4(4):395-405.
9.    Hirschfeld RM. Guideline Watch: Practice Guideline for the Treatment of Patients With Bipolar Disorder. Arlington, VA: American Psychiatric Association. Available at: www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed December 11, 2007.
10.    American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
11.    Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch on mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(9):232-239.
12.    Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms; findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
13.    Perlis RH, Weige JA, Vornik LA, Hirshfeld RM, Keck PE. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67(4):509-516.
14.    Kogan JN, Otto MW, Bauer MS, et al. Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Bipolar Disord. 2004;6(6):460-469.
15.    Treatment of Bipolar Mania in Older Adults. Available at: www.clinicaltrials.gov/ct2/show/record/NCT00254488. Accessed December 11, 2007.
16.    Young RC, Beyer J, Gyulai L, et al. A randomized controlled trial of acute treatments in late-life mania. Abstract presented at: the 6th International Meeting of the International Society Bipolar Disorder; Pittsburgh, PA; June 2005.
17.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
18.    Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978;133:429-435.
19.    McDonald WM, Nemeroff CB. The diagnosis and treatment of mania in the elderly. Bull Menninger Clin. 1996;60(2):174-196.
20.    Ragheb M. The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol. 1990;10(5):350-354.
21.    Verdoux H, Bourgeois M. A case of lithium neurotoxicity with irreversible cerebellar syndrome. J Nerv Ment Dis. 1990;178(12):761-762.
22.    Parfrey PS, Ikeman R, Anglin D, Cole C. Severe lithium intoxication treated by forced diuresis. Can Med Assoc J. 1983;129(9):979-980.
23.    Lisanby SH. Electroconvulsive therapy of depression. N Engl J Med. 2007;357(19):1939-1945.

 

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and president of Pacific Sleep Medicine Services.

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.

 


 

“There is only one thing people like that is good for them; a good night’s sleep.” —Edgar Watson Howe (1853-1937)

When I am lecturing to physician groups on treatment of insomnia, I am struck by the frequency with which I am asked about the use of “non-hypnotic hypnotics.” The question is often framed in the context of, “I always give my patients who cannot sleep [fill in the blank; eg, trazodone, amitriptyline, quetiapine] and my patients seem to do fine. Is there a problem with this?”

This desire to use medications “off label” to treat insomnia is obviously reflected in clinical practice as well. Walsh and Schweitzer1 reviewed trends in the use of medications to treat insomnia over a 10-year period from 1987–1996 and found that there had been “a dramatic shift to use of antidepressants in lieu of hypnotics for the symptomatic treatment of insomnia, despite a paucity of data regarding their efficacy and the potential for serious side effects.”1 During the period of time surveyed for this article, estimates of the numbers of prescriptions for approved hypnotics decreased by 53.7% while numbers of antidepressants prescriptions to promote sleep increased by 146%.

One component in the overall reduction in the number of hypnotics prescribed during this period was a dramatic decline in the use of triazolam, from approximately 3.2 million prescriptions in 1987 to approximately 209,000 in 1996, likely due to safety concerns. From 1987 through 1993, prior to the first full year in which zolpidem was available, all available benzodiazepine hypnotics, including flurazepam, temazepam and triazolam, showed declines in use; however, for unclear reasons, benzodiazepine anxiolytics, such as clonazepam and lorazepam, showed increases in use during this time period.

In discussing the increase in use of antidepressants and reduction in prescription of hypnotics, Walsh2 suggested that the most likely explanations were a perception that depression might be the real basis for insomnia complaints, and concerns about dependence and side effects with hypnotics. Favoring the latter hypothesis was the fact that mentions for the use of trazodone as an antidepressant fell dramatically during the time frame when overall use of trazodone was rising sharply.

Walsh2 provided updated information about trends in the pharmacologic treatment of insomnia in an editorial published in Sleep in 2004. The title of the editorial is telling: “Drugs Used to Treat Insomnia in 2002: Regulatory-Based Rather Than Evidence-Based Medicine.” Using data from a national service that tracks physician prescription activity (Verispan L.L.C.), Walsh observed that the number of prescriptions of antidepressants prescribed to treat insomnia had outstripped those of hypnotics in 2002, with approximately 5.28 million prescriptions for antidepressants compared to approximately 3.4 million for “insomnia” drugs. Trazodone, an antidepressant with no indication for the treatment of insomnia, was the most widely prescribed agent with 2.73 million prescriptions, approximately 32% greater than the most widely-used insomnia drug, with 2.07 million prescriptions.

In discussing why there should be an apparent preference for the use of antidepressants for the treatment of insomnia, Walsh2 mentioned several possible explanations. Among these were the concerns of physicians about possible risks associated with the use of hypnotics. Since all available hypnotics in 2002 were classified as Schedule IV by the Drug Enforcement Administration, physicians might have been concerned about their patients abusing these medications, or might have worried that their prescription of the “restricted” medications might lead to scrutiny of their practices by regulatory authorities.

Ironically, the 16 agents used most frequently in 2002 to promote sleep included quetiapine, at number 6, and olanzapine, at number 12. Although financial arguments were considered as possible explanations for the use of some inexpensive generic medications such as amitriptyline and trazodone, quetiapine and olanzapine are expensive, used off-label, and associated with numerous risks and side effects such as weight gain, changes in glucose metabolism with risk of diabetes, tardive dyskinesia, and (rarely) neuroleptic malignant syndrome.

Questions relating to the safest, most effective, and most appropriate treatment of insomnia were addressed in detail in an National Institutes of Health (NIH) State of the Science Conference held in 2005 in Bethesda, Maryland.3 The meeting was convened with the intent to answer several specific questions, one of particular interest in the context of this column, ie, “What treatments are used for the management of chronic insomnia, and what is the evidence regarding their safety, efficacy, and effectiveness?”

The panelists who prepared the report of findings from the conference, after “weighing all the scientific evidence,”3 expressed some very strong opinions about medications used to treat insomnia, assessing compounds approved for the treatment of insomnia (on-label use) and those not approved to treat insomnia (off-label use).

For example, the committee report observed that “the antidepressant agent trazodone is now the most commonly prescribed medication for the treatment of insomnia in the United States,” despite the fact that “there are no long-term studies on the use of trazodone for treatment of insomnia.” The report similarly noted that “all antidepressants have potentially significant adverse events, raising concerns about the risk-benefit ratio.” Although side effects associated with antidepressants are often not acknowledged by prescribing physicians, they include risk of fatal overdose, cardiac arrhythmia, orthostatic hypotension and falls with tricyclic antidepressants, and similar problems, as well as risk of priapism, with trazodone.3

Other classes of prescription agents were considered as well. Antipsychotics such as quetiapine and olanzapine were mentioned as specific examples of such agents; other compounds used similarly in an off-label fashion include antihistamines and anticonvulsants. The panelists noted that there was essentially no data supporting the use of these compounds to treat insomnia, that all were associated with significant risk, and that their use in the treatment of insomnia could not be recommended.

The use of over-the counter (OTC) medications to treat insomnia was also considered by the Food and Drug Administration panel. Antihistamines, especially diphenhydramine, were recognized as the principal active ingredients in OTC sleep medications. Although the use of diphenhydramine has been allowed by FDA since 1982 and classified as “generally recognized as safe and effective,” the NIH conference noted that adverse effect associated with diphenhydramine include residual daytime sedation, diminished cognitive function, and delirium.

Were any medications viewed favorably by the NIH panel? The panel noted that benzodiazepine receptor agonists were effective in the treatment of insomnia, were efficacious in the short-term treatment of insomnia, and had shown efficacy as well in treatment trials lasting as long as 6 months. Side effects were noted to be less frequent with these compounds than with older compounds, probably because of their shorter half-lives. They also observed that tolerance and abuse of these agents were not major problems in the general population with chronic insomnia. It should be noted that ramelteon (Rozerem), a hypnotic agent approved by the FDA without restriction of duration of use, appears to have no measurable abuse potential, is not a scheduled agent, and has no restriction on access.

Nonetheless, physicians continue to choose to use “off-label” medications, those without approval by the FDA as hypnotic medications, to treat insomnia. Are these choices rational? Strong arguments can be made that they are not, as attested to in the NIH State of the Science Conference report. The risks associated with use of these agents is rarely acknowledged, and the fact they are being used off label is ignored by insurance plans and prescription plan benefit coordinators when they consider which drugs will be made available to patients for treatment of their insomnia problems. As observed by Walsh,2 choices are being made with regard to treatment that are not supported by published scientific data, treatment guidelines, or formal FDA treatment labeling.

Beyond these observations, it is worthwhile to address how decisions are made by the pharmaceutical industry to determine for what conditions a specific agent may be useful, and by extension, in what therapeutic class it will be placed. For example, did simple marketing concerns influence Roche to decide that diazepam (Valium) and chlordiazepoxide (Librium) would be submitted for FDA approval for the treatment of anxiety, while flurazepam (Dalmane) would be a sleep medication?

This is clearly not the case. Although marketing and the perception that there is a need for a product in the marketplace are clear concerns for the pharmaceutical industry, extensive pre-clinical (animal) researchers performed on compounds that are defined as “candidates” for the treatment of various disorders. Specific tests that help to differentiate anxiolytic from hypnotic compounds are utilized, followed by animal testing to determine whether the desired effect (ie, sleep promotion or reduction of anxiety) is attained. When compounds have demonstrated appropriate profiles for safety based on animal research, human evaluation begins, leading to intensive and specific testing to ensure that compounds are well tolerated and effective, with acceptable safety profiles. Recent experience would suggest that the FDA is being increasingly vigilant in assessing the safety and efficacy of submitted compounds, leading to delays in approval of hypnotics that have been submitted (ie, indiplon) and abandonment of development of other compounds prior to submission (gaboxodol).

In summary, it would appear that physicians who choose to avoid perceived risks (such as abuse and dependence) associated with approved hypnotic medications increase risk for themselves and their patients by some of their choices. This is particularly evident if we consider the cost and side-effect profiles associated with atypical psychotics, but should be evident as well for the “off-label” use of antidepressants and antihistamines, as noted by the NIH Consensus Conference Report in 2005.3

Although some choices of medication are directed by access and cost issues, physicians need to recognize that patient safety may be compromised by some agents used on an “off-label basis” and that none of these medications are as safe as medications developed specifically for the treatment of insomnia, assessed by the FDA with regard to safety and efficacy in the treatment of insomnia, and supported by a broad and growing scientific literature showing benefits of improved sleep and daytime function associated with the use of approved hypnotics. PP

 

References

1.    Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep. 1999;22(3):371-375.
2.    Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep. 2004;27(8):1441-1442.
3.    NIH State of the Science Conference statement on manifestations and management of chronic insomnia in adults. J Clin Sleep Med. 2005;1(4):412-421.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Important psychiatric issues affecting diagnosis and management arise in patients with neurological illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurological disorder; other psychiatric symptoms as a manifestation or complication of neurological disease; and physical neurological symptoms that do not correspond to any recognized pattern of neurological disease, ie, conversion disorder or somatization disorder. In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurological disease.1,2 In previous columns, psychiatric issues in stroke3 and Parkinson’s disease and multiple sclerosis4 were reviewed. This column reviews psychiatric issues related to epilepsy.

 

Epilepsy

Epileptic seizures are the result of transient cerebral dysfunction caused by abnormal electrical activity in the brain, presenting as sudden recurring attacks of motor, sensory, or psychic manifestations with or without loss of consciousness or generalized convulsions. Consequently, psychiatrists must consider epilepsy when determining whether psychiatric symptoms are due to epilepsy, when treating psychiatric complications of epilepsy or when treating psychiatric complications of epilepsy with anticonvulsants, and when prescribing psychiatric medication that may adversely affect epilepsy or interact with anticonvulsants.

In developed countries most cases of epilepsy are idiopathic; specific etiologies include include perinatal trauma, head trauma, central nervous system (CNS) infection, CNS degenerative disorders, cerebrovascular disease, brain tumors, and substance misuse. Epilepsy is more common in developing nations, because of  increased rates of birth trauma and head injury, lack of health services,  high rates of  alcohol and substance misuse, and  poor sanitation leading to high rates of CNS infection (eg, neurocysticercosis which is the leading cause of seizures in adults in endemic areas).  In some benign childhood seizures, an anticonvulsant is unnecessary, but most patients with epilepsy require treatment with anticonvulsants which  sometimes can eventually be withdrawn and sometimes must be continued indefinitely. In approximately one-third of patients with epilepsy, anticonvulsants fail to achieve adequate control.

 

Clinical Features

Epilepsy is heterogeneous in etiology and in its clinical features, but an individual patient’s seizures are usually stereotypical. The key clinical distinction is between focal and generalized seizures. Tonic-clonic seizures usually begin with no warning and are characterized by sudden loss of consciousness and dramatic motor activity (tonic, ie, sustained muscle contractions lasting approximately 10–20 seconds, followed by clonic, ie, repetitive muscle contractions lasting approximately 30 seconds). Autonomic changes may include an increase in blood pressure and pulse rate, apnea, mydriaisis, incontinence, piloerection, cyanosis and perspiration. In the post ictal period the patient is drowsy and confused and abnormal neurological signs are often present.

Partial seizures may be simple (without impairment in consciousness) or complex (with impairment of consciousness). Simple partial seizures may be manifest in many different ways, including focal muscle contractions, somatoensory experiences (eg, numbness, paresthesias), vertigo, visual disturbances (eg, micropsia, macropsia, and visual hallucinations), other hallucinations (eg, auditory, olfactory, gustatoryl, and tactile), language disturbance, emotional outbursts, unpleasant, epigastric sensations, or motor automatisms such as bicycling or sexual movements and vocalization.

In complex partial seizures, the patient frequently experiences an aura preceding the seizure lasting seconds to minutes. The content of the aura may consist of  hallucinations; intense affective symptoms such as fear, depression, or depersonalization;  cognitive dysfunction;  dreamy states, flashbacks and distortions of familiarity with events (déjà vu or jamais vu).1 A prodrome of nervousness or irritability may begin hours or even days before a seizure. This aura is followed by disturbance of consciousness and a seizure usually lasting 60–90 seconds, which may or may not generalize into a tonic-clonic seizure. Automatisms may occur such as chewing, swallowing, lip smacking, grimacing, fumbling with objects, walking or trying to stand up. Post-ictal confusion typically lasts >10 minutes.

Absence seizures are abrupt, brief episodes of decreased awareness which occur without any warning, aura or post-ictal symptoms. A simple absence seizure is characterized by only an alteration in consciousness of around 15 seconds, ending abruptly with the patient resuming previous activity, often unaware that a seizure has occurred. A complex absence seizure includes additional signs such as change in postural tone, minor clonic movements, minor automatisms, or autonomic symptoms.

 

Differential Diagnosis

The differential diagnosis of epilepsy includes syncope, psychogenic spells associated with several different psychiatric diagnoses, transient ischemic attacks, arrhythmias, recurrent pulmonary emboli, hypoglycemia, cataplexy, acute dystonia, and other paroxysmal disorders. For attacks occurring only during sleep, night terrors, rapid eye movement sleep behavior disorder, periodic limb movements, sleepwalking, and other parasomnias should also be considered.

The most common problem in the differential diagnosis of epilepsy is its distinction from psychogenic spells. The term “pseudoseizures” is unfortunate and misleading. It is typically assigned to patients whose seizures’ phenomenology is not consistent with epilepsy and/or have been demonstrated to occur without epileptiform activity on the simultaneous EEG recording during video-EEG monitoring. Thus, “pseudoseizures” is not a diagnosis, but merely designates “not-epilepsy,” and not all “pseudoseizures” are psychogenic. The “pseudo-“ prefix carries a pejorative connotation that the patient’s symptoms are illegitimate. Prigatano and colleagues5 found that reports by health care providers that patient’s seizures were not “real” (ie, true epilepsy) restimulated feelings associated with their not being believed when they reported being sexually abused as children.

Seizure-like spells may occur as part of many psychiatric diagnoses including conversion disorder, panic disorder, hyperventilation syndrome, somatization disorder, posttraumatic stress disorder, dissociative disorders, and mental retardation, as well as in factitious disorder6 and malingering.7 The presence of confirmed epilepsy does not rule out the presence of psychogenic spells as well; it is not unusual for a patient to have both. That a spell appears to be precipitated by hyperventilation does not establish the etiology as psychogenic, because hyperventilation can induce seizures in person with epilepsy. In fact, hyperventilation has been long uitlized as a method to provoke epileptiform activity during diagnostic electroencephalography (EEG).

Distinguishing psychogenic spells from epilepsy  can often be made on the basis of a careful history and examination. Clinical clues include other symptoms and signs of  psychiatric disorders, atypical seizure phenomenology, especially the occurrence of frequent and prolonged seizures in the face of normal interictal intellectual function and EEG; seizures that mainly occur and are witnessed in medical settings  and never alone; and preservation of awareness  during an apparent generalized seizure (eg, resistance to attempted eye opening). It is widely believed that tongue-biting, urinary incontinence, and injury from seizures are diagnostic of epilepsy, but this is fallacious. A survey8 of 102 consecutive patients diagnosed with psychogenic seizures by video-EEG monitoring revealed that during typical attacks of psychogenic seizures, 40% reported injuries, 44% reporting tongue biting, and 44% reported urinary incontinence. A history of previous head injury is frequent in both epilepsy and psychogenic spells. Previous childhood sexual abuse is very common in patients with psychogenic seizures but not always present9 and not distinctive since childhood abuse is common in the general population, Rosenberg and colleagues10 found that histories of sexual and physical abuse, other traumas, and PTSD were common in patients with intractable seizures, both in those with epilepsy and those with psychogenic seizures, albeit more frequent in the latter.

The gold standard for diagnosis remains observation of attacks during video-EEG recording. A normal EEG during or immediately after an apparent generalized seizure provides strong evidence that the patient’s seizure is not epileptic, but making a specific psychiatric diagnosis requires identifying positive psychiatric evidence as well.

 

Epilepsy and Psychosis

Psychotic symptoms may be coincident with seizures when both are the result of brain disease or injury, especially with subcortical or temporal lobe lesions. Examples of acute causes of psychosis and seizures include encephalitis, CNS vasculitis, alcohol withdrawal, hyponatremia, and drug toxicity (eg, lidocaine, cocaine). But psychotic symptoms may also be a consequence of some forms of epilepsy, particularly complex partial seizures. Psychotic symptoms can occur ictally, postictally, or interictally. Brief psychotic symptoms can occur in  nonconvulsive status epilepticus, most commonly with partial complex status.11 In such cases, other features of complex partial seizures may be present as well, such as automatisms (eg, lip smacking, picking at clothes), mutism, altered consciousness, or amnesia. Postictal psychosis follows an increase in the frequency of seizures, usually with a nonpsychotic period of 1–7 days between the last seizure and the psychosis. Manic grandiosity and religious and mystical features are often present in postictal psychosis and it often resolves within a few days. Chronic interictal psychosis can occur even in the absence of frequent seizures, but usually occurs in patients with poorly controlled seizures. It is often schizophreniform including auditory hallucinations, and is usually self-limiting but can last for a few weeks. Unlike postictal psychosis, interictal psychosis is sometimes ameliorated by the occurrence of one or more seizures. Chronic interictal psychosis differs from schizophrenia in having better preservation of affect, and by mood swings, mystical experiences, and visual hallucinations.

Psychosis can also be an iatrogenic consequence of the treatment of epilepsy. Psychosis is a potential side effect of anticonvulsants, most frequently with levetiracetam and topiramate, but also with phenytoin, valproate, lamotrigine, zonisamide, pregabalin, and vigabatrin. One suggested mechanism is that control of seizures causes psychotic symptoms through “forced normalization.”12 Abrupt discontinuation of anticonvulsants can also cause acute psychosis. Finally, temporal lobectomy for medically intractable epilepsy may precipitate a schizophrenia-like psychosis. A retrospective study13 found this occurring in 11 of 320 patients, with those who had bilateral functional and structural abnormalities, particularly of the amygdala, at particular risk for the development of such psychoses.

 

Epilepsy and Depression

Depression is very common in patients with epilepsy, with its lifetime prevalence estimated between 6% and 30% in population-based studies and up to 50% among epilepsy patients in tertiary centers.14 The etiology of  depression in epilepsy is multifactorial, with neurobiological, psychological, social, and iatrogenic factors all relevant.1,15,16  The risk of depression is greater in patients with high seizure frequency and symptomatic focal epilepsy,15 especially complex partial seizures. The stress of living with a stigmatized chronic illness can  have profound negative effects on health-related quality of life. Learned helplessness giving rise to depression may occur in patients with epilepsy as a result of the unpredictability and unavoidability of seizures, further exacerbated by occupational disruption and losing driving privileges until seizure-free for an extended period. Anticonvulsants can be a cause of depression as well. The relationship between depression and epilepsy is bi-directional (ie, each is a risk factor for the other). In patients with epilepsy, depression may be a stronger predictor of health-related quality of life, than seizure frequency and severity, employment, or driving status.17 Finally, for patients with intractable epilepsy, comorbid depression may improve with vagal nerve stimulation.

 

Epilepsy and Anxiety

Similarly anxiety in epilepsy is very common and best considered as multifactorial in origin. Preexisting vulnerability, neurobiological factors including seizure focus location, iatrogenic influences (anticonvulsants, epilepsy surgery), and psychosocial factors are all likely to play a role, but with considerable individual differences The prevalence of anxiety in a community sample of adults with epilepsy was 20.5% and was associated with a current history of depression, perceived side effects of antiepileptic medication, lower educational attainment, chronic ill health, female gender, and unemployment, but was not associated with the duration of epilepsy.18 While the relationship between epilepsy and depression has received much attention, less is known about anxiety disorders in epilepsy. Anxiety can have a profound influence on the quality of life of patients with epilepsy. Anxiety in epilepsy may be ictal, postictal, or interictal.19 In particular, anticipatory anxiety about having a seizure, in the absence of a warning, can lead to agoraphobic-like symptoms and behavior, to avoid embarrassment, shame, inconvenience, and stigma.

 

Epilepsy and Violent Behavior

As noted, complex partial seizures may cause emotional symptoms and automatic motor behavior and this can very occasionally result in undirected violent behavior. However, in the overwhelming majority of cases this is in response to being restrained during a seizure. One should be very cautious before attributing other violent assaults to a seizure. True ictal violence is rare, and most cases are characterized by spontaneous, non-directed, stereotyped aggressive behaviors.  One should be very cautious before attributing violence to a seizure. Characteristics of ictal violence include: the seizure episode is sudden, without provocation, and lasts at most a few minutes; automatisms and other stereotypic phenomena of the patient’s typical seizures accompany the aggressive act, and the act is associated with these phenomena from one seizure to the next; the patient’s consciousness is impaired;  the behavior is poorly directed and is unskilled; purpose and interpersonal interaction are absent.20 To confirm that violent behavior is attributable to a seizure disorder requires documenting aggression during epileptic automatisms during video-EEG monitoring.  Non-seizure EEG abnormalities (such as sharp waves) are non-specific findings and should not be used as evidence that violence is ictal. 

 

Psychotropic Drugs and Seizure Risk

Patients with epilepsy are frequently prescribed psychotropics due to the high psychiatric comorbidity described above. Many psychotropics, especially antidepressants and antipsychotics, can lower the seizure threshold.21 Controlled studies of seizure frequency with individual psychotropics in psychiatric populations without epilepsy are infrequent, and nonexistent in patients with comorbid psychiatric disorders and epilepsy. Consequently, case reports form a large part of the available literature, so estimates of the frequency of psychotropic drugs causing seizures and aggravating epilepsy are far from precise. In general, if a patient’s epileptic seizures are well-controlled on anticonvulsants, most psychotropic drugs can be used without significant increased risk. The risk of seizure induced by a psychotropic is increased in patients with treatment-resistant epilepsy, concurrent use of other drugs that lower the seizure threshold, electrolyte and other metabolic derangements, and  blood levels that rise too high because of rapid dose titration, slow metabolism, or and drug-drug interactions.22

How much risk for increased seizures do antidepressants pose? Antidepressants at therapeutic doses in non-epileptic patients exhibit a seizure risk close to that reported for the first spontaneous seizure in the general population (≤0.1%).  The risk of seizures with bupropion SR is low at doses ≤450 mg/day. The risk of seizures with bupropion has been overstated in many sources; a systematic review concluded the risk was lower than that associated with tricyclic antidepressants and phenothiazines.23

Both typical and atypical antipsychotics can lower the seizure threshold, increasing the chances of seizure induction. Of the typical antipsychotics, chlorpromazine appears to be associated with the greatest risk of seizure provocation, while high potency typical antipsychotics like haloperidol and fluphenazine are associated with a lower risk. Among the atypical antipsychotics, clozapine is the most frequently associated with seizures, with a risk of approximately 1% to 2%. Consequently, low-potency typical antipsychotics and clozapine ideally should be avoided in patients with epilepsy.24
Cholinomimetics may also reduce the seizure threshold. While many physicians believe that psychostimulants lower seizure threshold, evidence for this is lacking. Finally, many other psychiatric drugs are potent anticonvulsants (benzodiazepines, mood stabilizers other than lithium).

 

Electroconvulsive Therapy and Epilepsy

Electroconvulsive therapy (ECT) has anticonvulsant activity, as indicated by a progressive increase in seizure threshold and decrease in seizure length during the course of ECT treatment, but this effect is  too short-lived to make it an option for treating intractable epilepsy. Rarely, ECT has induced status epilepticus, but there is no evidence that spontaneous seizure frequency increases with ECT in epileptic patients.25

A key clinical question is how to treat the patient whose psychiatric disorder requires ECT but who also has epilepsy, ie, how to elicit therapeutic seizures in the face of concomitant treatment with anticonvulsants. While there is surprisingly little published literature addressing this issue, experts suggest that most epileptic patients can be successfully treated with ECT without having to alter their anticonvulsant regimen. For those who either do not obtain seizures or have extremely short ones, a number of techniques are recommended to consider, after consultation with a neurologist.25 It is not known whether various anticonvulsants differentially affect seizure threshold and duration in ECT. PP

 

References

1.     Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and neurosurgery. In: Levenson, JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2.     Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and Neurosurgery. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007;313-342.
3.     Levenson JL: Psychiatric issues in Neurology, Part I: Stroke. Primary Psychiatry. 2007;14(9):37-40.
4.     Levenson JL: Psychiatric Issues in Neurology, Part 2: Parkinson’s disease and multiple sclerosis. Primary Psychiatry. 2007;14(11):35-39.
5.     Prigatano GP, Stonnington CM, Fisher RS. Psychological factors in the genesis and management of nonepileptic seizures: clinical observations. Epilepsy Behav. 2002;3(4):343-349.
6.     Savard G, Andermann F, Teitelbaum J, Lehmann H. Epileptic Munchausen’s syndrome: a form of pseudoseizures distinct from hysteria and malingering. Neurology. 1988;38(10):1628-1629.
7.     Beaumont G. Is it epilepsy? J Forensic Leg Med. 2007;14(2):99-102.
8.     Peguero E, Abou-Khalil B, Fakhoury T, Mathews G. Self-injury and incontinence in psychogenic seizures.Epilepsia. 1995;36(6):586-591.
9.     Binzer M, Stone J, Sharpe M. Recent onset pseudoseizures–clues to aetiology. Seizure. 2004;13(3):146-155.
10. Rosenberg HJ, Rosenberg SD, Williamson PD, Wolford GL 2nd. A comparative study of trauma and posttraumatic stress disorder prevalence in epilepsy patients and psychogenic nonepileptic seizure patients.Epilepsia. 2000;41(4):447-452.
11. Sachdev PS. Alternating and postictal psychoses: review and a unifying hypothesis. Schizophr Bull. 2007;33(4):1029-1037.
12.     Akanuma N, Kanemoto K, Adachi N, Kawasaki J, Ito M, Onuma T. Prolonged postictal psychosis with forced normalization (Landolt) in temporal lobe epilepsy. Epilepsy Behav. 2005;6(3):456-459.
13.    Shaw P, Mellers J, Henderson M, Polkey C, David AS, Toone BK. Schizophrenia-like psychosis arising de novo following a temporal lobectomy: timing and risk factors. J Neurol Neurosurg Psychiatry. 2004;75(7):1003-1008.
14.     Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry. 2003;54(3):388-398.
15.     Kimiskidis VK, Triantafyllou NI, Kararizou E, et al. Depression and anxiety in epilepsy: the association with demographic and seizure-related variables. Ann Gen Psychiatry. 2007;6(1):28.
16.     Seethalakshmi R, Krishnamoorthy ES. Depression in epilepsy: phenomenology, diagnosis and management. Epileptic Disord. 2007;9(1):1-10.
17.     Gilliam F, Hecimovic H, Sheline Y. Psychiatric comorbidity, health, and function in epilepsy. Epilepsy Behav. 2003;4(suppl 4):S26-S30.
18.     Mensah SA, Beavis JM, Thapar AK, Kerr MP. A community study of the presence of anxiety disorder in people with epilepsy. Epilepsy Behav. 2007;11(1):118-124.
19.    Beyenburg S, Mitchell AJ, Schmidt D, Elger CE, Reuber M. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav. 2005;7(2):161-171.
20.     Marsh L, Krauss GL. Aggression and violence in patients with epilepsy. Epilepsy Behav. 2000;1(3):160-168.
21.     Mula M, Monaco F, Trimble MR. Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk. Expert Rev Neurother. 2004;4(6):953-964.
22.     Hedges D, Jeppson K, Whitehead P. Antipsychotic medication and seizures: a review. Drugs Today (Barc). 2003;39(7):551-557.
23.     Ruffmann C, Bogliun G, Beghi E. Epileptogenic drugs: a systematic review. Expert Rev Neurother. 2006;6(4):575-589.
24.     Alldredge BK. Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology. 1999;53:S68-S75.
25.     Rasmussen KG, Rummans TA, Tsang TSM, Barnes RD. Electroconvulsive therapy. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:957-978.

 

 

Needs Assessment: Patients with chronic kidney disease represent a substantial and growing segment of the population. This group has a high rate of sleep complaints and has recently been shown to have a high prevalence of insomnia, sleep apnea, restless legs, and periodic limb movements.

Learning Objectives:
• Recognize the prevalence of sleep disorders among those with end-stage renal disease.
• Recognize the impact of sleep disorders on sleep quality, quality of life, and mood.
• Assess potential treatments of common sleep disorders.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 5, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Unruh is assistant professor of medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine in Pennsylvania.

Disclosure: Dr. Unruh is a consultant to Qualitymetric and receives grant support from the National Institute of Health, the National Kidney Foundation, and the Paul Teschan Research Fund.

Please direct all correspondence to: Mark Unruh, MD, MSc, Assistant Professor of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, A915 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261; Tel: 412-647-2571; Fax: 412-647-6891; E-mail: unruhm@dom.pitt.edu.

 


 

Abstract

In the chronic kidney disease (CKD) population, problems with sleep have been linked to disability days, healthcare utilization, and quality of life (QOL) for dialysis patients. The health burden associated with sleep disturbances is significant. Studies in the general population have linked these problems to greater use of health services, increased use of hypnotics, and reduced functional capabilities. The need to address sleep quality in the CKD population is highlighted by the 15% to 31% prevalence of hypnotic use. Among incident dialysis patients, patients with poor sleep quality were more likely to report poor physical and mental well being, decreased vitality, and more bodily pain. While there are many causes for poor sleep in patients with kidney disease, such as depression, insomnia, restless legs, and periodic limb movements, sleep apnea may be the most common. A significant percentage of end-stage renal disease  patients report hypersomnolence, snoring, and even witnessed apneas. Those undergoing thrice-weekly hemodialysis have been shown to have a high rate of sleep apnea, insomnia, restless legs syndrome, and excessive daytime sleepiness. In the general population, sleep disorders such as sleep apnea have been associated with premature death, cardiovascular disease, depression, and poor QOL. Emerging evidence suggests that sleep disorders may contribute to the high rates of medical and psychological comorbidity in CKD patients. The diagnosis and treatment of sleep disorders among this high-risk population remains understudied. The recommendations for therapy have been largely based on findings in the general population since studies of the CKD population have been limited in scope.

 

Introduction

Patients with kidney failure have a high rate of sleep apnea, insomnia, restless legs syndrome (RLS), and excessive daytime sleepiness.1-3 Kidney failure, or end-stage renal disease (ESRD), has been defined as having the kidney function <15 ml/minute/1.73 m2. It is associated with the inability to excrete waste products, control serum electrolytes, handle the daily dietary and metabolic acid load, and maintain fluid balance. In addition, kidney failure causes inadequate production of erythropoietin, deranged calcium and phosphorous metabolism, difficulties with high blood pressure, and accelerated progression of cardiovascular disease. In parts of the world with access to dialysis and kidney transplantation (KTx), renal replacement therapy (RRT) has been thought to be necessary when the glomerular filtration rate (GFR) decreases to <15 ml/minute. Chronic kidney disease (CKD), the term used to describe a chronic decrease in GFR, has different levels. Its prevalence is rapidly increasing worldwide, and the projections are that the number of patients with kidney failure will double in the next 10–15 years. Both sleep disorders and poor sleep quality have a negative impact on daytime symptoms of sleepiness and fatigue. Daytime sleepiness and fatigue are frequent and bothersome problems for the chronic dialysis population.4 One-hundred hemodialysis patients were surveyed regarding their willingness to perform hemodialysis more frequently. A increase in energy level (94%) and improvement in sleep (57%) were the most commonly cited potential benefits that would justify more frequent hemodialysis.5 This finding highlights the importance of sleepiness and fatigue in patients undergoing RRT. This article examines the association between kidney failure and sleep disorders, highlighting the impact of sleep disorders on health-related quality of life (HRQOL) and mood.

 

Poor Sleep Quality in End-stage Renal Disease

Self-reported sleep quality is the subjective integration of sleep disturbances and satisfaction with sleep. Studies of patients on maintenance hemodialysis have found that 50% to 80% of dialysis patients experience some sleep complaint or excessive daytime somnolence.6 The patient perception of sleep quality is important since there is neither a laboratory variable nor a polysomnography (PSG) finding that can serve as a surrogate for telling how patients feel about their sleep. Neuroimaging studies have suggested that patient self reports may reflect neurophysiologic findings a PSG does not measure.7 Furthermore, those with insomnia complaints can have PSG findings comparable to normal sleepers. Self-reported outcomes may be the most critical in patients with chronic illness, and the impact treatments have on patient perception of fatigue and sleepiness may be the most important factor in their management.5

The hemodialysis population’s sleep quality has been linked to disability days, healthcare utilization, and quality of life (QOL) for dialysis patients. The health burden associated with sleep disturbances is significant. Studies in the general population have linked these problems to greater use of health services, increased use of hypnotics, and reduced functional capabilities.8-10 The need to address sleep quality in the kidney failure population is underscored by the 15% to 31% prevalence of hypnotic use in a sample of dialysis patients.6,11 The use of hypnotics to treat sleep complaints has an economic cost and exposes patients to the medications’ side-effects. Among incident dialysis patients, those with poor sleep quality were more likely to report poor physical and mental well being, decreased vitality, and more bodily pain.11 In addition, incident hemodialysis patients with a clinically significant decline in self-reported sleep quality have been shown to have a higher risk of mortality.11 While this risk may reflect acquired sleep disorders, the impact of sleep problems on mood, or the treatment of sleep complaints, studies have demonstrated that sleep quality may be reliably measured and is clinically meaningful for patients receiving dialysis.5,6,11

The Figure advocates the approach to this high-risk group’s sleep disorders in which clinicians recognize sleep disorders using patient interviews and screening tests. The interventions used to treat sleep disorders are both graded by the severity of the complaint and tailored to this special population. Sleep disorder treatment in ESRD patients should emphasize behavioral interventions. In addition, physicians should consider the removal of aggravating medications when possible since ESRD patients take a median of eight to 10 prescription drugs daily. The response to treatment should be monitored with sensitive instruments, medical follow-ups, and assessments of the patient’s overall well being.

 

 

Insomnia Highly Prevalent in End-stage Renal Disease

Insomnia, which involves difficulty falling asleep, maintaining sleep, or waking early in the morning with associated daytime difficulties, is very common among patients with ESRD. Up to 75% of dialysis patients experience insomnia,1 but the possible connection between insomnia and RLS in this population has not been investigated. Trials of insomnia treatment for patients undergoing dialysis have not been comducted. However, several approaches could optimize sleep hygiene, screen for other sleep disorders, use a brief trial of cognitive-behavioral therapy and hypnotics, or consider a sleep study in patients that remain symptomatic. For those undergoing hemodialysis, it may be reasonable to move the shift to earlier in the day, consider thermoneutral hemodialysis, and ask the patient to avoid napping during treatments. Those using overnight peritoneal dialysis may need to adapt their regimen to avoid both frequent alarms and abdominal discomfort. Numerous studies suggest that the timing of hemodialysis treatments may impact the severity of restless legs, cardiovascular risk, and survival.12,13 Parker and colleagues14 have shown that sleep propensity increases during coronary heart disease treatments, an effect they suggest may be related to treatment-induced alterations in arousal and/or thermoregulatory processes. Overnight dialysis may change daytime experience with respect to sleep, uremia, and free time for rest and activity.

 

High Rates of Sleep Apnea in End-stage Renal Disease May Contribute to Morbidity

Sleep apnea leads to repetitive episodes of hypoxemia, hypercapnia, sleep disruption, and sympathetic nervous system activation. Sleep apnea can be obstructive if respiratory effort persists during upper airway occlusion, central if both respiratory effort and airflow cease, or a combination of the two. The most common metric for sleep apnea is the apnea-hypopnea index (AHI), which is the number of apneas and hypopneas in 1 hour of sleep. Sleep apnea causes gas exchange abnormalities, sleep fragmentation, and autonomic activation, all implicated causes of substantial adverse health effects.15 This disease commonly produces daytime sleepiness, decreased QOL, and impaired cognitive ability. In the general population, the treatment of sleep apnea with continuous positive airway pressure (CPAP) improves QOL, daytime symptoms, and blood pressure.16

Severe sleep apnea has a higher prevalence among dialysis patients than the general population. The prevalence of severe sleep apnea among a community-based sample of hemodialysis patients was four-fold higher than an age-, sex-, race-, and body mass index (BMI)-matched comparison group.17 Sleep apnea in ESRD is likely due to factors related to uremia and volume overload. In a community-based study of the general population, the risk factors for sleep apnea were obesity, male sex, and neck circumference.18 These risk factors have not been associated with sleep apnea among patients with ESRD,19 perhaps due in part to the small number of patients studied. In 49 ESRD patients, those with sleep apnea had a higher apneic threshold and a higher sensitivity to hypercapnia.20 These results suggest that central and peripheral chemoreceptor sensitivity is increased in patients with sleep apnea and ESRD, leading to destabilization of respiratory control during sleep. While alteration in chemosensitivity during sleep may explain the development of sleep apnea in ESRD patients, other factors such as extracellular fluid volume overload leading to upper airway edema21 and reduced upper airway muscle tone due to uremia compromising upper airway patency in ESRD22 likely contribute to the severity of sleep apnea in uremic patients. The contribution of uremia and volume overload to sleep apnea pathogenesis in ESRD patients has been supported by the improvement in sleep apnea following changes from hemodialysis to nocturnal hemodialysis, use of automated peritoneal dialysis, and KTx.

Sleep apnea contributes to the CKD population’s substantial morbidity and mortality. It leads to the poor daytime experiences of those on dialysis19 by causing excessive daytime sleepiness and diminished QOL.3 Among patients with ESRD, sleep apnea may contribute to fatigue, tiredness, and lack of energy. These debilitating symptoms may improve when sleep apnea is treated. Investigators have demonstrated that sleep apnea causes restless sleep and daytime somnolence as well as complaints of memory difficulties and inability to concentrate. As a result of sleepiness, the cognitive disturbances may lead to increased use of sick days at work.

Sleep apnea has been associated with decreased HRQOL, mood disturbances, and reduced libido. The high rate of sleep apnea among patients undergoing hemodialysis has been proposed to negatively impact HRQOL and cognitive function performance measures of cognitive function. Daytine functioning aspects have shown to be diminished in ESRD patients.23 Furthermore, these aspects are thought to be intimately linked to sleep and are negatively impacted by sleep apnea. Sleep apnea has been associated with lower HRQOL in patients on hemodialysis in a single study with small sample size and limited PSG.24 In this study, 21 of 31 participants had an AHI of >5 with a median AHI of 13.3. The vitality, social functioning, and mental health domains in the 36-item short-form health survey (SF-36) and the emotional reactions from the Nottingham Health Profile (NHP) were significantly higher in those without sleep apnea. Both poor social functioning from the SF-36 and emotional reactions from the NHP were independently associated with the AHI after adjusting for BMI. However, this report was limited by a small sample size and a minimal adjustment for age, gender, and comorbidity in relating the QOL results to sleep apnea. Most importantly, the eight-channel ambulatory PSG recording unit utilized in this study does not document actual sleep time; therefore, the AHI used was only an estimate. Nonetheless, these findings support the position that sleep disorders impact this population’s daytime functioning. In chronic illnesses such as kidney failure, self-reported HRQOL may be the most important treatment outcome. Despite improved medical management and increasing technologic gains in dialysis therapy, patients on hemodialysis still reported a substantially lower HRQOL than the general population.23

Sleep apnea has also been shown to increase risk of cardiovascular disease in ESRD patients. Sleep apnea in those with ESRD disrupts the normal non-rapid eye movement (REM) sleep, and vagal heart rate modulation is attenuated while sympathetic modulation predominates. Increased cardiac and peripheral adrenergic drive may help explain why sleep apnea and nocturnal hypoxemia have been associated with the ESRD population’s left ventricular hypertrophy, hypertension, and increased cardiovascular events in the ESRD population.25

A study on when to initiate therapy for sleep apnea in the ESRD population has never been conducted. Similar to the general population, one should consider the severity of sleep apnea, hypoxemia, hypertension, and daytime symptoms. In the ESRD population, CPAP was used in a very preliminary study. Eight patients showed some improvement in nocturnal oxygenation and five of six patients reported improved daytime alertness.26 It is interesting that CPAP is not widely used among patients with ESRD; <2% of patients with ESRD have the sleep apnea diagnosis (D Gilbertson PhD, United States Renal Data System; personal communication; Dec 13, 2007).

Since the sleep apnea associated with uremia may be secondary to the effects of uremic toxins, some investigators have examined dialysis’ impact on sleep apnea. Quotidian nocturnal hemodialysis partially corrects sleep apnea.27 One study examined 14 patients undergoing conventional hemodialysis who subsequently switched over to nocturnal hemodialysis.27 The patients underwent PSG before and after they switched dialysis modes, demonstrating a marked reduction in sleep apnea among seven patients.27 However, the study demonstrated that these patients continued to have frequent arousals from sleep, diminished REM time, and diminished sleep time and sleep efficiency with nocturnal hemodialysis. In addition, the study neglected to report patient-assessed outcomes. While sleep apnea was diminished, these findings suggested that overall sleep architecture did not improve with intensive nocturnal hemodialysis.27

 

Restless Legs Common Among Patients with End-stage Renal Disease

RLS is a sleep disorder common among people on dialysis. RLS is characterized by paresthesias and dysesthesias, conditions improved through the movement of the affected limb, usually in the evening.28 RLS is diagnosed based on the criteria of the International Restless Legs Syndrome Study Group (IRLSSG), including an urge to move usually due to uncomfortable sensations, motor restlessness, worsening of symptoms during relaxation, and worsening symptoms in the evening.29 Studies using a gold standard neurologist interview have found that approximately 23% to 33% of patients undergoing chronic hemodialysis have RLS.30,31 The data show a 33% prevalence of RLS among ESRD patients using a questionnaire based on IRLSSG criteria. While the estimates of RLS among the hemodialysis population range up to 10 times more frequent than the general population,30 the etiology and risk factors for RLS in those with ESRD remain unclear. In the general population, a blockade of the dopamine-2 receptor in the diencephalon has been suggested to cause RLS, while among ESRD patients other factors such as under dialysis and with hypoparathyroidism may be predisposed to the syndrome.31,32 Iron has been used to treat RLS, and ferritin has been found to be a useful marker relating RLS to iron deficiency.33 The mechanism relating iron metabolism to RLS is probably central as iron is a key catalyst in brain dopamine metabolism and serum iron levels correlate poorly with central nervous system concentrations.34

RLS has been associated with substantial morbidity and mortality in the ESRD population. In both the general population and the hemodialysis population, however, RLS has been associated with poor mental health.32 RLS symptoms were associated with a lower HRQOL among a nation-wide sample of 900 incident dialysis patients.35 In hemodialysis patients, RLS has been associated with shorter survival when the age, sex, and duration of dialysis were controlled.32,35 RLS was associated with hemodialysis nonadherence, and poor adherence to the dialysis prescription in patients with RLS may lead to increased mortality risk.32

While RLS is a syndrome diagnosed using a validated questionnaire based on standard criteria, the periodic limb movements (PLMs) diagnosis requires monitoring of leg movements overnight. PLMs are characterized by periodic episodes of repetitive and highly stereotyped movement.36 PLMs have been associated with RLS, Parkinsonism, aging, and medication use.37 The PLMs may be either measured using PSG with anterior tibialis electromyogram or estimated using actigraphy on the lower extremities. However, the use of a single time point has been shown to be subject to bias from marked day-to-day variability in PLMs. While PLMs have been frequently documented in the general population, their impact on sleep has been unclear and controversial.38 In the dialysis population, PLMs have been associated with increased sleep tendency and shorter survival in small studies that accounted for neither comorbidities nor RLS.39,40 In a study that examined both RLS and PLMs in hemodialysis, a substantial difference between those with and those without PLMs in the domains of insomnia, daytime sleepiness, depression, and HRQOL was not present.41 The effects of normalizing hematocrit in sleep disorders, sleep patterns, and daytime ability to remain awake was examined in ESRD patients. While 10 patients with sleep complaints were on recombinant human erythropoietin (rHuEPO) therapy, they were studied by PSG while moderately anemic (mean hematocrit=32.3%). The patients were studied again when hematocrit was normalized (mean hematocrit=42.3%) through increased rHuEPO dosing. All 10 subjects experienced highly statistically significant reductions in the total number of arousing PLMs (P=.002). Nine of 10 subjects showed reductions in both the Arousing PLMs Index (P<.01) and the PLMS Index (P=.03) when hematocrit was normalized. Measures of sleep quality showed trends to improved quality of sleep. Molecular weight demonstrated significant improvement in the length of time patients were able to remain awake (9.7 minutes versus 17.1 minutes; P=.04).42

Studies examining the use of intravenous iron in idiopathic RLS treatment are ongoing. The use of intravenous iron in RLS treatment among ESRD patients has been studied in a small randomized study examining both short-term changes in symptoms and adverse effects of intravenous iron.43 Hemodialysis patients who were determined to have RLS by IRLSSG criteria were administered either 1,000 mg of iron dextran or normal saline intravenous (IV) in a blind fashion. Eleven patients were randomly assigned to the iron dextran administration, and 14 patients were randomly assigned to the saline IV administration. Iron infusion was associated with a significant yet transient reduction in RLS symptoms in patients with ESRD.43 It is important to assess intravenous iron therapy’s impact on sleep quality, QOL, and survival of this population at risk.

There is no particular dialysis type recommended for patients with RLS. The timing and type of dialysis should be individualized to minimize RLS. For example, patients undergoing hemodialysis in the evening with severe symptoms of RLS may benefit from a change to the morning shift during which symptoms of RLS may be less intense. Likewise, patients using continuous cycling peritoneal dialysis—a nocturnal peritoneal dialysis—may consider switching to continuous ambulatory peritoneal dialysis which is done predominately during the day. This change permits peritoneal dialysis patients more freedom to move in the late evening. Regardless of the type or timing of dialysis treatment, it is important to treat RLS. An approach to the treatment of RLS among patients with kidney failure has been recently outlined and adapted for the Table.44 RLS patients should have both a history and a physical examination that exclude causes of pain in the extremities such as peripheral vascular disease and neuropathy. RLS severity should be clinically assessed and the clinicians should consider using a validated instrument to document RLS severity. If the patient has mild-to-moderate RLS, the team should focus on non-pharmacologic interventions, ie, using a bicycle or distracting activities. If RLS is severe, it would be important to both use a pharmacologic intervention for the improved quality of life and encourage adherence with dialysis.

 

 

Conclusion

The substantial population of patients with CKD and kidney failure will continue to increase with the population’s age. This patient population has a remarkable rate of sleep complaints and has been shown to have a much higher prevalence of sleep disorders than the general population. It may be that poor sleep and sleep disorders contribute to the substantial morbidity and mortality found in patients with kidney failure. The psychiatric field may serve to recognize and treat patients’ sleep disorders. The treatment of insomnia, sleep apnea, short sleep, and RLS may improve this population’s QOL, functional status, and mood. The recommendations for sleep disorder treatment in this high risk population reflect an evolving understanding of sleep disorders, particularly in populations with medical comorbidities. They should also serve as points for future research.

Further work and refinement should be done on both the screening tools for sleep disorders and on the role of screening in this population with an exceedingly high prevalence of sleep disorders. In addition to screening, the management of patients with ESRD and comorbid sleep disorder needs further study. If a patient has severe sleep apnea, does CPAP or changing the dialysis prescription best serve the patient? Can patients with sleep disorders tolerate nocturnal dialysis, the seemingly best treatment for uremic sleep apnea? Does the treatment of sleep apnea improve the poor sleep quality, mood, and fatigue in patients with medical comorbidity? It is important to measure, monitor, and treat sleep disorders in CKD patients. It is also important for the psychiatric field to recognize both the role of medications as potential aggravators of RLS and PLMs and the role of behavioral and non-pharmacologic interventions in the management of sleep disorders. PP

 

References

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2.    Novak M, Shapiro CM, Mendelssohn D, Mucsi I. Diagnosis and management of insomnia in dialysis patients. Semin Dial. 2006;19(1):25-31.
3.    Shayamsunder AK, Patel SS, Jain V, Peterson RA, Kimmel PL. Sleepiness, sleeplessness, and pain in end-stage renal disease: distressing symptoms for patients. Semin Dial. 2005;18(2):109-118.
4.    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):2487-2494.
5.    Ramkumar N, Beddhu S, Eggers P, Pappas LM, Cheung AK. Patient preferences for in-center intense hemodialysis. Hemodial Int. 2005;9(3):281-295.
6.    Unruh M, Hartunian M, Chapman M, Jaber BL. Sleep quality and clinical correlates in patients on maintenance hemodialysis. Clin Nephrol. 2003;59(4):280-288.
7.    Nofzinger EA. Neuroimaging and sleep medicine. Sleep Med Rev. 2005;9(3):157-172.
8.    Kapur VK, Redline S, Nieto FJ, et al. The relationship between chronically disrupted sleep and healthcare use. Sleep. 2002;25(3):289-296.
9.    Klink ME, Quan SF, Kaltenborn WT, Lebowitz MD. Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia. Arch Int Med. 1992;152(8):1634-1637.
10.    Foley DJ, Monjan A, Simonsick EM, et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep. 1999;22(suppl 2):S366-S372.
11.    Unruh M, Buysse D, Dew M, et al. Sleep quality and its correlates in the first year of dialysis. Clin J Am Soc Nephrol. In press.
12.    Bliwise DL, Kutner NG, Zhang R, Parker KP. Survival by time of day of hemodialysis in an elderly cohort. JAMA. 2001;286(21):2690-2694.
13.    Ng YH, Meyer KB, Kusek JW, et al. Hemodialysis timing, survival, and cardiovascular outcomes in the Hemodialysis (HEMO) Study. Am J Kidney Dis. 2006;47(4):614-624.
14.    Parker KP, Bliwise DL, Rye DB, De A. Intradialytic subjective sleepiness and oral body temperature. Sleep. 2000;23(7):887-891.
15.    Caples SM, Gami AS, Somers VK. Obstructive sleep apnea. Ann Intern Med. 2005;142(3):187-197.
16.    Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med. 2001;163(2):344-348.
17.    Unruh ML, Sanders MH, Redline S, et al. Sleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study. J Am Soc Nephrol. 2006;17(12):3503-3509.
18.    Young T, Shahar E, Nieto FJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Int Med. 2002;162(8):893-900.
19.    Kimmel PL, Miller G, Mendelson WB. Sleep apnea syndrome in chronic renal disease. Am J Med. 1989;86(3):308-314.
20.    Beecroft J, Duffin J, Pierratos A, Chan CT, McFarlane P, Hanly PJ. Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease. Eur Respir J. 2006;28(1):151-158.
21.    Hanly P. Sleep apnea and daytime sleepiness in end-stage renal disease. Semin Dial. 2004;17(2):109-114.
22.    Tarasuik A, Heimer D, Bark H. Effect of chronic renal failure on skeletal and diaphragmatic muscle contraction. Am Rev Respir Dis. 1992;146(6):1383-1388.
23.    Valderrabano F, Jofre R, Lopez-Gomez JM. Quality of life in end-stage renal disease patients. Am J Kidney Dis. 2001;38(3):443-464.
24.    Sanner BM, Tepel M, Esser M, et al. Sleep-related breathing disorders impair quality of life in haemodialysis recipients. Nephrol Dial Transplant. 2002;17(7):1260-1265.
25.    Zoccali C, Mallamaci F, Tripepi G. Nocturnal Hypoxemia predicts incident cardiovascular complications in dialysis patients. J Am Soc Nephrol. 2002;13(3):729-733.
26.    Pressman MR, Benz RL, Schleifer CR, Peterson DD. Sleep disordered breathing in ESRD: acute beneficial effects of treatment with nasal continuous positive airway pressure. Kidney Int. 1993;43(5):1134-1139.
27.    Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med. 2001;344(2):102-107.
28.    Chesson AL Jr, Wise M, Davila D, et al. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22(7):961-968.
29.    Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. 1995;10(5):634-642.
30.    Cirignotta F, Mondini S, Santoro A, Ferrari G, Gerardi R, Buzzi G. Reliability of a questionnaire screening restless legs syndrome in patients on chronic dialysis. Am J Kidney Dis. 2002;40(2):302-306.
31.    Collado-Seidel V, Kohnen R, Samtleben W, Hillebrand GF, Oertel WH, Trenkwalder C. Clinical and biochemical findings in uremic patients with and without restless legs syndrome. Am J Kidney Dis. 1998;31(2):324-328.
32.    Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis. 1996;28(3):372-378.
33.    O’Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23(3):200-203.
34.    Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56(2):263-265.
35.    Unruh ML, Levey AS, D’Ambrosio C, et al. Restless legs symptoms among incident dialysis patients: association with lower quality of life and shorter survival. Am J Kidney Dis. 2004;43(5):900-909.
36.    Recording and scoring leg movements. The Atlas Task Force. Sleep. 1993;16(8):748-759.
37.    Hening W. The clinical neurophysiology of the restless legs syndrome and periodic limb movements. Part I: diagnosis, assessment, and characterization. Clin Neurophysiol. 2004;115(9):1965-1974.
38.    Montplaisir J, Michaud M, Denesle R, Gosselin A. Periodic leg movements are not more prevalent in insomnia or hypersomnia but are specifically associated with sleep disorders involving a dopaminergic impairment. Sleep Med. 2000;1(2):163-167.
39.    Benz RL, Pressman MR, Hovick ET, Peterson DD. Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders. Am J Kidney Dis. 2000;35(6):1052-1060.
40.    Hanly PJ, Gabor JY, Chan C, Pierratos A. Daytime sleepiness in patients with CRF: impact of nocturnal hemodialysis. Am J Kidney Dis. 2003;41(2):403-410.
41.    Rijsman RM, de Weerd AW, Stam CJ, Kerkhof GA, Rosman JB. Periodic limb movement disorder and restless legs syndrome in dialysis patients. Nephrology (Carlton). 2004;9(6):353-361.
42.    Benz RL, Pressman MR, Hovick ET, et al. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis. 1999;34(6):1089-1095.
43.    Sloand JA, Shelly MA, Feigin A, Bernstein P, Monk RD. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis. 2004;43(4):663-670.
44.    Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: ‘Markers of inadequate dialysis?’ Kidney Int. 2006;70(10):1687-1893.

 

This interview took place on August 29, 2007, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Sadock reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

 

Dr. Sadock is Menas S. Gregory professor of psychiatry and vice chairman at the New York University (NYU) School of Medicine. He is attending psychiatrist at the Bellevue and Tisch Hospitals and is consulting psychiatrist at Lenox Hill Hospital. Dr. Sadock is diplomate of the American Board of Psychiatry and Neurology and Distinguished Life Fellow of the American Psychiatric Association. He is also president and founder of the NYU-Bellevue Psychiatric Society. He was appointed Faculty Scholar at the NYU School of Medicine in 2000. Dr. Sadock is author and editor of over 100 publications and book reviewer for psychiatric journals, including the American Journal of Psychiatry.

 

Why has the eighth edition of The Comprehensive Textbook of Psychiatry (CTP) been so successful?

Several factors account for the book’s success; first, the breadth and depth of its context. The text is truly designed to cover the field in a comprehensive manner. The book is roughly divided into three areas. The first area covers behavioral sciences, which include the neural, psychological, and and sociocultural sciences; experimental and quantitative methods in psychiatry; and theories of pesonality and psychopathology. The second, clinical area includes examination and diagnosis, classification, and the clinical disorders. A third area covers treatment approaches. Many other sections of interest such as addiction, geriatric and forensic psychiatry, and a thorough coverage of child psychiatry are included.

Each edition reflects the latest advances in the field, so the book is fresh and up to date. Our contributors are carefully chosen for expertise in their various areas and the material is edited to create a readable and coherent whole.

When it was first published in 1967, there were no textbooks in psychiatry comparable to the noted textbooks of medicine such as Russel Cecil’s Textbook of Medicine1 or Ward Nelson’s Textbook of Pediatrics.2 These were multi-contributor books with sections written by experts in their respective fields. CTP was modeled after those great textbooks. Like the first edition of CTP, the eighth edition abundantly uses illustrations, photographs, and charts, making the content easier to follow, especially in a book if this size. Over the years the textbook has come to be known as the “University Without Walls.”

 

Does the book have a primary mission? 

The goal has always been and remains to foster professional competence and to ensure the highest quality care to all those who suffer from mental illness. It is geared to provide clinicians with both the broadest and the most thorough base of knowledge so they can offer the best care for their patients. Psychiatry, like all medical fields, is an art, but it has continuously been burdened with the myth that it is all art and no science. On the contrary, the scientific base of psychiatry is growing. In the first edition, for example, there were only 40 pages on subjects like neurochemistry and neurophysiology.

Today, over 450 pages cover the neural sciences. Any young psychiatrist who has to take the American Board’s written exam will describe months of studying and memorization to accumulate that hard data. In addition, the stigma associated with mental illness exists in so many aspects of our society, including the insurance industry, government, the public, and even the medical profession. Our book hopes to eliminate that stigma. We dedicated many editions of the book to those who work and care for the mentally ill because doing so is an exceedingly difficult job.

 

What do the editors’ tasks entail?

There are many. The editors must flesh out an outline that covers the past, present, and future of psychiatry. In the beginning, the field was small enough for us to do that ourselves. Now, obtaining contributing editors is key. They provide the names of people in the field who are doing important, innovative work. The main editors outline what the contributors cover. With respect to the clinical syndromes, for example, each one is discussed starting with the definition. Every aspect of the disorder, from epidemiology to treatment, is covered. The number of pages for a topic must also be decided. One page in the textbook takes up four double-spaced, typed pages. In the manuscript of the 8th edition, a book of 4,000 printed pages contained 16,000 typed pages; this is a lot to process. The entire text must be carefully proofed and checked for readability and accuracy. Sometimes, the manuscript may have to be sent back to the contributor for revisions. Last, when the editors are finally satisfied, the manuscript is promptly delivered to the publisher.

 

How is the content for future editions of the textbook derived?

One of the most common aphorisms in gestalt psychology is if one needs to mail a letter, one is always looking for mailboxes. If one is not interested in mailing a letter, one does not even notice a mailbox. I am in the former group, constantly aware of what is happening in the field of psychiatry. Whether I am reading The New York Times, The Wall Street Journal, The Green Journal, or any other piece of literature, ideas for the book are constantly being generated.

 

Is any one aspect of editing the book more challenging than others?

It is all challenging, but the most enjoyable aspects are both getting to know and working with the contributors. They are exceptional men and women with extraordinary talent. Some of the relationships with them have endured throughout the life of the textbook. For example, John Nemiah, MD, Editor Emeritus of the American Journal of Psychiatry, has contributed to every edition of the book since its beginning. Although contributors are contacted both through e-mail and by telephone, meeting with them directly is not necessarily common. However, many contributors become friends without meeting face to face.

 

Which qualities make a good contributor?

Several qualities make a great contributor. Mainly, they are outstanding academics who have done scholarly work. In addition to recognized professional stature, they also need good writing skills. Finding a contributor with writing skills is not easy, but the editing process is heavy and improves the writing. We contact potential contributors through phone conversations because they are more personal than letters; we can get a sense of the individual’s interest in the subject matter. Contributors must also have time to work on the project and be able to meet deadlines. Doctors rarely turn down an opportunity to contribute to the textbook. Over the years, approximately 2,000 psychiatrists and behavioral scientists have contributed to the book. Approximately 50% of contributors are replaced in every edition, and new authors are invited to keep CTP vital and current. Approximately 60% of contributors have been professors, 30% associate professors, and 10% assistant professors and instructors. We always try to get young people to contribute to the book to get a sense of future leaders in the field.

 

Based on your experiences as both one of CTP’s editors and a practicing psychiatrist, what changes have you seen in psychiatry?

Much has changed since I began practicing in 1963 after I finished my residency at Bellevue; however, much has remained the same. For example, I began my career using the 1st edition of the Diagnostic and Statistical Manual of Mental Disorders3 (DSM), which had under 100 diagnostic categories. The current edition4 has over 300 diagnostic categories. Diagnostic categories seem to be increasing. For example, diagnosis of compulsive buying disorder is being considered, and I once reviewed a book in which the author suggested a diagnosis of compulsive credit card usage disorder. I think it is getting a bit out of hand.

In the 1930s, the psychiatrist Karl Menninger, MD, said that defining new syndromes is an addiction of psychiatrists. We have to be very careful to not change the DSM in terms of reliability and validity. Although it has been an amazing advance, there may have been too many editions of and changes in the manual without any real evidence-based data.

In addition, the psychopharmacologic revolution occurred during my career and transformed the practice of psychiatry. We can now provide almost immediate relief to patients with intractable anxiety, depression, and psychosis.

As for CTP, the first edition had approximately 30 pages on psychopharmacology. This last edition had over 300 pages, a direct marker of the pharmacologic advances. The advances in psychotherapy also have been tremendous; ie, cognitive, interpersonal, and dialectical behavior therapy. These are just a few that did not exist when I started practicing, and we have to make sure this trend continues. The pharmacologic revolution has diminished the role of psychotherapy. We cannot rely solely on medication with its brief follow-up visits and sacrifice the doctor-patient relationship, which is built on an in-depth knowledge of our patients. Some studies have shown that psychotherapy in combination with medication is better therapy for many disorders. We have to foster psychotherapy; it is something psychiatrists must be continually trained in so they do not lose those skills.

 

Why is group therapy a rare form of treatment?

Social workers, psychologists, and other mental health professionals often utilize group psychotherapy, which is extraordinarily effective and therapeutic. Group psychotherapy can treat more people at a lesser cost than individual psychotherapy. It remains a very important modality, but unfortunately, psychiatrists are not being trained as much as they should be in the practice.

 

Psychopharmacology produces rapid results. How much time should patients and clinicians allow to pass before trying psychotherapy?

Unlike other medical specialities, psychiatry does not have specific endpoints for cure. Criteria can be used to determine how well therapy is working, but they are not tangibly verifiable. They rely on patient-reporting more than do other fields of medicine. For example, the patient’s well-being is key in terms of determining psychotherapeutic benefit. A patient’s insight into his or her behavior is an important therapeutic goal. That insight can lead to behavioral change, a clear indicator of improvement. If a compulsive gambler stops gambling or if a compulsive drinker stops drinking, those changes are clear endpoints. Whether a patient is in short-term or long-term therapy, the same criteria apply; ie, the patient’s well-being, newly gained insight, and behavior changes. Some recent studies have shown that when the comfort level between the doctor and the patient is congruent—that is, if a patient likes his or her doctor and the doctor likes his or her patient—there are better outcomes. Incongruency reveals that something is not working. The comfort level of a good doctor-patient relationship is associated with positive results over all, regardless of the school of thought to which the psychiatrist adheres.

 

Why did you choose psychiatry as your career?

The first experience that influenced my career choice was a 3-month elective at King’s Park State Hospital in New York for which I signed up during medical school. I lived on the hospital grounds and spent each day seeing and talking to severely mentally ill patients. Since this was before deinstitutionalization, hospitals were very crowded. The areas in which the most serious cases were kept were called the “back wards.” As medical students we were not permitted to go there. Naturally, that was the first thing we did.

Few doctors or nurses were present. It was staffed by attendants only. Overly medicated with chlorpromazine, barefoot and dressed in drab hospital pajamas, patients shuffled around, oblivious to their movement disorders. Despite their condition, they were eager to talk, and I spent hours listening to  their intriguing stories. The signs and symptoms were unbelievable. Patients, some in catatonic poses, were either actively hallucinating or enveloped in strange delusional beliefs. Manic patients dressed up as clowns while schizophrenic patients wore aluminum foil on their heads to prevent themselves from being disintegrated by atomic rays. This full range of human behavior was spellbinding yet frightening.

The second influence was during my internship while I was rotating through psychiatry. I was assigned a young schizophrenic girl. Her physician encouraged me to engage her in psychotherapy. He gave me Silvano Arieti, MD’s book, Interpretation of Schizophrenia,5 in which the author describes schizophrenia in extraordinary detail. He describes how sometimes one may have to spend hours with a schizophrenic patient in order to get him or her to relate to the psychiatrist. I remember having to spend 4 hours with this withdrawn girl who would neither look at nor respond to me in any way. I spoke about anything that came to mind, essentially mundane topics such as the weather, baseball, and food. After 4 hours, she made eye contact, and it was exhilarating. I was on that rotation for 1 month, and I saw her every day for hour-long, supervised sessions. She became more outgoing, coherent, and less frightened of her environment. Unfortunately, few psychiatrists are available to do that kind of psychotherapy nowadays, and even if it were available, it would be rather expensive.

The innovators in psychotherapy such as Aaron Beck, MD, and Gerald Klerman, MD, had a profound effect on my career as it progressed. However, everybody must start with Freud. If not for Freud, we would not know psychiatry as we know it today. He is often belittled, but his contributions were amazing and profound. PP

References
1.    Cecil RL, Loeb RF, eds. A Textbook of Medicine. 10th ed. Philadelphia, PA: W.B. Saunders, 1960.
2.    Nelson WE, ed. Textbook of Pediatrics. 8th ed. Philadelphia, PA: W.B. Saunders, 1964.
3.    Diagnostic and Statistical Manual of Mental Disorders. 1st ed. Washington, DC: American Psychiatric Association; 1952.
4.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
5.    Silvano A. Interpretation of Schizoprhenia. New York, NY: Robert Brunner; 1955.

 

Needs Assessment: This article facilitates knowledge as it relates to the safe and judicious use of psychotropics in individuals with deteriorating kidney function. Also provided are tactics and strategies to the selection, sequencing, and dosing of psychotropics across disparate patient populations which share in common kidney failure.

Learning Objectives:
• Describe the effect of renal failure on psychotropic pharmacokenetics.
• Describe the effect of psychotropic drugs on kidney function in indivduals with renal failure.
• Discuss tactics and strategies for prescribing psychotropic drugs in renal failure.


Target Audience:
Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement:
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 5, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. McIntyre is associate professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit at the University Health Network at the University of Toronto in Ontario, Canada. Ms. Baghdady is a PharmD candidate at King Abdul-Aziz University in Jeddah, Saudi Arabia. Mr. Banik is a medical student at the Royal College of Surgeons in Ireland in Dublin. Ms. Swartz is a medical student at the University of Ottawa in Ontario, Canada.
Disclosure: Dr. McIntyre is on the advisory boards of AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly, the France Foundation, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Pfizer, Shire, and Solvay/Wyeth; is on the speaker’s bureaus of AstraZeneca, Biovail, Eli Lilly, Janssen-Ortho, and Lundbeck; receives grant support from Eli Lilly, the National Alliance for Research on Schizophrenia and Depression, and Stanley Medical Research Institute; and receives honoraria from AstraZeneca, Bristol-Myers Squibb, the France Foundation, i3CME, Physician’s Postgraduate Press, and Solvay/Wyeth. Ms. Baghdady, Mr. Banik, and Ms. Swartz report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Roger S. McIntyre, RS, MD, FRCPC, Head, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8; Tel: 416-603-5279; Fax: 416-603-5368; E-mail: roger.mcintyre@uhn.on.ca.

 


 

Abstract

This article provides a pragmatic and clinically accessible approach to the selection and dosing of psychotropics for individuals with suboptimal renal function (SRF). The authors conducted a PubMed search of all English-language articles published between 1977 and 2007. The key search terms selected were “renal,” “kidney,” “renal failure,” “kidney failure,” “pharmacokinetics,” “renal impairment,” and “renal insufficiency.” Each term was cross-referenced with the non-proprietary names of constituent antidepressants, antipsychotics, lithium, anticonvulsants, anxiolytics, hypnotics, and psychostimulants. Article reference lists were also reviewed. Due to heterogeneity in manuscript quality and scientific methodology as well as a dearth of available adequately powered controlled studies, an inclusive approach was taken. SRF is associated with clinically significant alterations in all dimensions of pharmacokinetics. Taken together, SRF predictably affects renal excretion of psychotropic agents with more variable effects on absorption, distribution, and metabolism. The adjudication of the safe and effective dose for any psychotropic needs to be individualized for each such agent. Strong pronouncements regarding contraindication of use for any psychotropic extends beyond available data. Nevertheless, psychotropics that depend on normal kidney function for disposal require dosing alteration and in many cases should be avoided. Specific tactics and strategies regarding the use of psychotropics in this patient population are provided.

 

Introduction

Several definitions and operational criteria have been proposed for renal disease. There are two commonly employed definitions. First, the British National Formulary has divided suboptimal renal function (SRF) into three subcategories based on glomerular filtration rate (GFR), including mild (20–50 mL/minute), moderate (10–20 mL/minute), and severe (0–10 mL/minute).1 Second, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) divided SRF into five groups, three of which were defined solely on the basis of diminished GFR; these groups include moderate (30–59 mL/minute/1.73 m2), severe (15–29 mL/minute/1.73 m2), and kidney failure (<15 mL/minute/1.73 m2; Table 1).2

 

 

Clinical studies indicate that individuals with renal disease are differentially affected by mental disorders.3 The co-occurrence of mental and renal disorders invites the need for familiarity with the safety, pharmacokinetic profile, and efficacy of psychotropics in individuals with SRF. Hitherto, the evidentiary base which informs the selection, dosing, monitoring, and sequencing of psychotropics in SRF is woefully inadequate.

This article provides a clinically accessible and pragmatic review of the effect of SRF on the handling of psychotropics. The article also includes responses to commonly encountered clinical scenarios.

 

The Effect of Suboptimal Renal Function on Pharmacokinetics

The term “pharmacokinetics” refers to the physiologic handling of pharmacologic agents and has been conventionally categorized into absorption (ie, bioavailability), distribution, metabolism, and excretion of the parent drug and its respective metabolites.4 Patients with renal failure may evince alterations in any of these pharmacokinetic parameters.5 Consequently, the risk for treatment-emergent adverse events is significantly increased (Table 2).6

 

 

Bioavailability

Bioavailability denotes the extent to which a dose of drug enters the systemic circulation. An oral dose is first absorbed from the gastrointestinal tract subsequently passing through the liver wherein metabolism and biliary excretion may occur.4,7 In SRF, a decrease in bioavailability for some agents occurs at the level of drug absorption from the gastrointestinal tract. It is hypothesized that gastric alkalinity, resulting from uremia (due to excessive urea generation by the internal urea-ammonia cycle), and changes in gastrin levels mediate the decreased absorption.4,6,8 The concurrent use of aluminium- or calcium-containing antacids, commonly prescribed in renal failure, may form non-absorbable complexes with psychotropic drugs that hinder their absorption.4,8

Rival mechanisms affecting absorption in individuals with renal failure relate to nausea and vomiting as well as increased gastric emptying time (ie, due to gastroparesis).5,9 Vitamin D deficiency and bowel edema may result in altered drug partitioning across the gastrointestinal tract membrane with a consequent decrease in the overall amount of drug absorbed.6

Alternatively, SRF (ie, uremia) may be associated with an increase in drug bioavailability. A hypothesized mechanism involves reduced functional capacity of gut cytochrome P450 (CYP) enzymes, and decreased expression and function of the two main efflux protein transporters, P-glycoprotein (Pgp) and multi-drug resistance-related protein type 2 (MDR2).9,10

 

Distribution

Following absorption, a drug is distributed across body fluids, tissues, and compartments. The two overarching factors influencing distribution are the volume of distribution and protein binding. Changes in these factors would be predicted to alter distribution of any drug administered.

Mechanisms mediating altered volume of distribution in states of SRF are edema, which is related to hypoalbuminemia and consequent fluid retention, and muscle wasting. Edema alters the apparent volume of distribution of drugs, particularly those of high hydrophilicity, by expanding the extracellular fluid volume. This effect is predicted to result in dilution of the drug and hypothetically requiring an increase in dose. Alternatively, muscle wasting, dehydration, and cachexia, all of which are commonly encountered in SRF, are predicted to decrease the apparent volume of distribution, possibly inviting the need for dose reduction.

The importance of fully understanding the effect of renal failure on protein binding is underscored by the fact that most psychotropics are highly protein bound.4 The principle plasma protein responsible for binding to acidic drugs is albumin, while α1-acid glycoprotein is the primary binding protein for alkaline drugs.11 Renal failure is characterized by proteinuria and hypoalbuminemia with the consequent accumulation of endogenous binding inhibitors (eg, organic acids and uremic toxins).6 Binding inhibitors compete with drugs for the carrier protein-binding site. Moreover, in states of SRF, albumin undergoes conformational changes with hypothesized changes in binding properties.5 Taken together, SRF results in diminished protein binding and an increase in the bioactive free fraction of acidic drugs in plasma.

Alternatively, for SRF patients undergoing renal transplant or hemodialysis, the circulating concentration of α1-acid glycoprotein may increase. As a result, there would be a decrement in the unbound circulating fraction and diminished biologic activity of the drug.12

Changes in total drug concentrations reflect both bound and unbound fractions. In most jurisdictions, laboratory evaluation does not parse out and separately evaluate the unbound and biologically active fraction. In the context of SRF, evidence indicates that alterations in free fraction may be observed.11,13

 

Elimination

Metabolism
As the glomerular filtration rate (GFR) declines, the rate of renal metabolism by the renal brush border is predicted to decrease.5 Along with these changes, emerging evidence indicates that metabolism by the liver is variably altered in SRF.6,14,15 For example, the expression and function of CYP 2C9 and CYP 3A4 were decreased in severe end-stage renal disease (ESRD).15 Preclinical studies have documented a 25% to 70% decrease in the metabolism of hepatically cleared agents in some individuals with SRF. Again, like other aspects of pharmacokinetics, an opposite effect may be observed, as some studies have documented a normal or increased activity of drug hepatic biotransformation proteins.6

Taken together, in conditions of SRF there is a decrease in hydrolysis and chemical reduction with no apparent effect on glucouridation, sulfate conjugation, and microsomal oxidation.4

Excretion
Drugs are excreted through the gastrointestinal tract by three exclusive pathways, including inabsorption, active secretion into the gastrointestinal lumen, and excretion via the biliary system.

Renal drug excretion also involves three distinct mechanisms, including glomerular filtration, active tubular secretion, and passive tubular reabsorption.7 In renal failure, all three processes are differentially affected.6 Most psychotropics are metabolized by the liver and excreted through the bile; however, some are excreted unchanged from the kidney (eg, lithium) and others are converted to active metabolites that pass through the kidney.4,6,8

 

The Effect of Suboptimal Renal Function on Pharmacodynamics

Several studies indicate that in states of SRF, the overall burden of treatment-emergent adverse events is increased. It is hypothesized that the mechanism mediating this observation relates to increased translocation of drugs from the systemic circulation across the blood-brain barrier as well as accumulation of uremic toxins.11,16-18

 

Prescribing Psychotropics in Individuals with Suboptimal Renal Function

Table 3 provides a guide to prescribing psychotropics in individuals with SRF.6,8,9,15,18-50

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

Commonly-Encountered Clinical Scenarios

How is End-stage Renal Disease Defined?

SRF can be defined as either kidney damage or GFR <60 mL/minutes/1.73 m2 that is present for ≥3 months.2 The kidney disease staging system is based on GFR (Table 1).2 The presence of SRF should be established based on the occurrence of kidney damage or the level of kidney function (ie, GFR), regardless of the specific diagnosis. Disease stage should be assigned based on the level of kidney function regardless of the principal cause of SRF.2

ESRD is defined as either a level of GFR <15 mL/minute/1.73 m2 (ie, Stage 5), which is accompanied in most cases by signs and symptoms of uremia, or as a need for initiation of kidney replacement therapy (dialysis or transplantation) for treatment of complications from decreased GFR which would otherwise increase the risk of morbidity and mortality.2 Some patients may need dialysis or transplantation at GFR ≥15 mL/minute/1.73 m2 because of symptoms of uremia. ESRD almost always follows SRF, which may exist for 10–20 years or longer before progressing to become ESRD, when kidney function is <10% of normal.51 At this point, the compromised kidney function is associated with multiple complications requiring dialysis or kidney transplantation.

 

What Determines Drug Dialyzability?

Patients receiving dialysis treatment require special attention with regard to dosing regimens and the potential need for supplemental dosing following dialysis. The need for supplemental dosing is determined by the extent to which a drug is removed by dialysis (ie, drug dialyzability). A marked lowering of blood levels will occur upon dialysis in patients receiving medication that is dialyzable (of the psychotropics, namely, lithium, gabapentin, and pregabalin). Practitioners prescribing psychotropics should obtain post-dialysis blood levels and use the information obtained to determine how much of that agent needs to be given after the dialysis run (See Table 3 for drug dialyzabilities).52

Drug dialyzability is determined primarily by several physical and chemical characteristics of the drug. These include molecular size, protein binding, water solubility, volume of distribution, and plasma clearance (ie, the sum of renal and non-renal clearance). In addition, technical aspects of the dialysis procedure (eg, dialysis membrane and flow rates) may also determine drug dialyzability. Overall, peritoneal dialysis is much less efficient at removing drugs than hemodialysis. In general, if a drug is not removed by hemodialysis, it cannot be removed by peritoneal dialysis.53

 

Lithium and Nephrotoxicity: At What Glomerular Filtration Rate Should Lithium Be Discontinued?

The predominant form of chronic renal disease associated with lithium therapy is a chronic tubulointerstitial nephropathy (CTIN). This condition is often heralded by the insidious development of renal insufficiency, with little or no proteinuria, often in the setting of chronic nephrogenic diabetes insipidus. It is unequivocally established that long-term lithium administration may induce CTIN leading to renal failure (ESRD).54 A review of lithium nephrotoxicity, including data from 14 separate studies, found that the prevalence of reduced GFR associated with chronic lithium therapy was 15%.54 An even smaller number of lithium-treated patients go on to develop renal insufficiency, ultimately leading to dialysis (ESRD).55,56

Taken together, studies indicate that a small number of patients treated with lithium develop progressive renal damage (associated with CTIN). Despite withdrawal of lithium, several patients have been reported to develop ESRD after long-term lithium exposure (ie, >20 years) requiring dialysis therapy. Nonetheless, in patients with mild-to-moderate chronic renal insufficiency from lithium, withdrawal of lithium may be associated with gradual improvement in GFR.57

Recently, an increasing number of publications have published on the hazardous effects of progressive increases in creatinine levels (“creeping creatinines”) and renal insufficiency as a result of long-term lithium therapy. Lithium was first approved for the acute treatment of mania by the United States Food and Drug Administration in 1970, which implies that there is a significant number of individuals who have received lithium therapy for >15 years.58 Uninterrupted lithium exposure decreases the kidney’s endogenous ability for cellular regeneration. With further progression of renal insufficiency, there is the appearance of renal fibrosis which may progress, despite elimination of the offending agent (ie, lithium), to ESRD.54 A consensus does not exist as to when lithium treatment should be discontinued in the context of diminishing kidney function. For example, it has been suggested that repeat serum creatinine concentrations exceeding 140 mmol/L (1.6 mg/dl) should invite the need for expert consultation.56

Prognosticating which individuals will progress to ESRD has substantial clinical importance. A single report documented that serum creatinine levels could serve as a useful biomarker in categorizing individuals at risk for progression. More specifically, after long-term lithium cessation, an initial serum creatinine of >2.5 mg/dl identified an at-risk group with a high probability of progression while individuals with a serum creatinine <2.5 mg/dl were significantly less likely to progress to ESRD requiring dialysis.59 Another study using the biomarker of estimated creatinine clearance (CrCl) (via the Cockcroft-Gault formula) identified an at-risk group; individuals with a CrCl ≤40 mL/minute had a high likelihood of continued renal deterioration at lithium discontinuation than those with CrCl >40 mL/minute.54

In addition to its predictive value for the irreversible onset of kidney failure, the GFR level is also strongly associated with the risk of complications from SRF. Based on evidence-based guidelines,2 the prevalence of complications from SRF increases at GFR levels of <60 mL/minute/1.73 m2. Complications include hypertension, malnutrition, anemia, bone disease, neuropathy, and reduced functioning and well being (eg, depression). Furthermore, the risk of progression to ESRD is considerably increased below this GFR level.

Moreover, as K/DOQI states, the risk for kidney progression should be taken into consideration, such as the rate of GFR decline and non-modifiable and modifiable risk factors. Examples include diabetes, hypertension, family history of kidney failure, and ethnicity (ie, African Americans, American Indians, Hispanic Americans). In addition, specific risk factors for impaired renal function for patients on lithium have been documented, including previous lithium intoxication; concomitant medication (ie, thiazide diuretics, angiotensin converting enzyme inhibitors, some nonsteroidal anti-inflammatory drugs), which promotes renal lithium retention and thus lithium intoxication; chronic physical illness (eg, diabetes, hypertension); and increasing age.60 The foregoing factors do not contraindicate lithium treatment but should prompt increased vigilance on the part of the practitioner and most probably an earlier cutoff point.

Side by side with prognostication interventions, strategies for minimizing the renal effects of lithium should also be implemented. This includes diligently avoiding episodes of renal toxicity; monitoring serum lithium concentrations in order to achieve optimal efficacy at the lowest possible concentration (in view of the association of renal damage with lithium toxicity); and monitoring serum creatinine levels and estimated GFR on a yearly basis, referring for expert consultation when the serum creatinine level consistently rises >1.6 mg/dl.56

It should be noted that equations estimating GFR based on serum creatinine (eg, Cockcroft-Gault formula) are more accurate and precise than estimates of GFR from serum creatinine measurements alone.2 Therefore, in a clinical setting, serum creatinine levels should be examined in addition to reporting the estimated GFR. In addition, as these prognosticating cutoffs are putative, it should not be inferred from this data that a serum creatinine <2.5 mg/dl, a CrCl >40 mL/minute, or a GFR >60 mL/minute/1.73 m2 are necessarily safe and that the declining GFR may reverse if lithium is discontinued at this point.

 

Lithium and End-Stage Renal Disease: What is the Dosing Procedure for Hemodialysis?

Given concerns over renal safety and excretion, efforts should be made to substitute other drugs for lithium in patients with SRF. However, discontinuation of lithium in long-term lithium responders often exposes individuals to the risk of severe recurrences of bipolar disorder or even an uncontrollable worsening in the course of the illness, and so the psychiatric risk also has to be taken into account despite availability of other mood stabilizers (ie, antipsychotics or anticonvulsants).58 Moreover, some bipolar patients with ESRD do not respond to the anticonvulsants or antipsychotics that are often used as alternatives to lithium. Additionally, some patients whose illness is well controlled by lithium therapy refuse to consider interruption and substitution (ie, psychological dependence). In light of the above, lithium’s use as an effective and non-toxic agent in patients with kidney failure is established.4 It can be used with caution in ESRD with careful monitoring of renal function by creatinine clearance over time, while maintaining the serum lithium level within the lower therapeutic range.4,57

In ESRD, the dosage of lithium must be reduced in order to prevent toxicity, so at low levels of renal function the dosage should be 25% to 50% of the usual dose and should be monitored carefully by blood levels (Table 3).4,53 Treatment involves administration of a single dose (usually 600 mg) after each dialysis run. A single dose will result in a steady serum level and, as a result, no supplemental lithium is required. At the next dialysis, which removes the lithium from the body, the same single dosing should be repeated.4,61 Serum lithium levels obtained before and after dialysis sessions are used to establish the proper dose. Ideally, lithium levels should be obtained immediately before dialysis and 2 hours after completion of dialysis; the level obtained immediately after dialysis will often be lower than that observed later due to a post-dialysis redistribution effect.62

 

Which Antidepressants are Preferred for Use in End-Stage Renal Disease?

 Table 3 provides a guide to which antidepressants are preferred for use in ESRD.

Effective treatment of depression in dialyzed patients with ESRD has been understudied. Only one small study was identified in a recent comprehensive Cochrane review63 of randomized clinical trials. The study compared 12 patients treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine with those given a placebo.64 The intervention did not find a difference between treatment groups, although it was certainly underpowered.65

There is some preliminary evidence that SSRIs have a role in the treatment of depression in patients with ESRD. Fluoxetine is the most studied medication in this class in ESRD. It appears to be both non-toxic and efficacious in SRF patients. A group of researchers in Korea found HAM-D scores to be significantly reduced in patients with ESRD treated with fluoxetine.34,65 Fluoxetine also has a very high therapeutic index, contributing to its non-toxic effects in ESRD. Further, the kinetic profile of single doses of fluoxetine is unchanged in anephric patients.62 Additional preliminary evidence has shown that depressive symptoms were markedly ameliorated in patients who completed a 12-week course of treatment with sertraline, bupropion, or nefazodone, despite low rates of compliance overall.34,67

There are several non-SSRI antidepressants that should be used with caution with ESRD. Tricyclic antidepressants (TCAs), although considered as potential therapeutic options and prescribed in earlier studies, have not been employed in more recent studies due to concerns of safety and tolerability.62,67,68

Venlafaxine levels are markedly increased in patients with renal failure as clearance is reduced by >50% in patients undergoing dialysis.8,69 Accordingly, lower doses of this drug are indicated in this population; the initial dosage should be reduced and slowly titrated.8,69 Additionally, hypertension, a common comorbidity in ESRD, in theory could intensify with venlafaxine treatment.68

Bupropion and its active metabolites are almost completely excreted through the kidney; these metabolites may accumulate in dialysis patients and predispose to seizures.62 Nefazodone should also be used conservatively until more is known concerning its pharmacokinetics in patients with chronically impaired renal function.68 It should not be used as first-line therapy due to potential for hepatotoxicity.8

Less is known about the use of tetracyclic antidepressants (ie, mirtazapine, trazodone, maprotiline, amoxapine) in ESRD than about the TCAs; thus, caution is advised. Moreover, trazodone can cause postural hypotension (which diabetic dialysis patients are even more prone to) and maprotiline can cause QTc prolongation.70

Individuals with ESRD receiving hemodialysis have increased plasma levels of duloxetine and particularly of its metabolites, as evidenced by single-dose studies. The area under the curve (AUC) value of duloxetine (ie, the total amount of drug absorbed by the body) was doubled in subjects with ESRD receiving hemodialysis compared to subjects with normal renal function, while the AUC values of the major circulating metabolites were 7–9 times greater.71 Additionally, the predominant route of excretion of these metabolites is through the kidneys. Taken together, duloxetine is not recommended for patients with ESRD requiring dialysis; if administered, however, a lower starting dose with gradual titration should be used.

Patients with ESRD treated with kidney transplantation are often co-administered immunosuppressive agents (eg, tacrolimus, cyclosporine). Several psychotropics are inhibiting agents (ie, increase immunosuppressant levels) of these agents, via inhibition of CYP 3A4 enzymes and Pgp. Specifically, there is potential for drug-drug interactions with fluvoxamine, fluoxetine, nefazodone, sertraline, and paroxetine (a weak inhibitor).62

 

Conclusion

Taken together, SRF predictability effects renal excretion of psychotropics with more variable effects on absorption, distribution, and metabolism. The adjudication on the safe and effective dose for any psychotropic needs to be individualized for each psychotropic agent. Strong pronouncements regarding contraindication of use for any psychotropic extends beyond available data. Nevertheless, psychotropics that depend on normal renal function for disposal require dosing alteration, and in many cases should be avoided. PP

 

References

1.    Vidal L, Shavit M, Fraser A, Paul M, Leibovici L. Systematic comparison of four sources of drug information regarding adjustment of dose for renal function. BMJ. 2005;331(7511):263.
2.    K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-266.
3.    Kimmel PL, Thamer M, Richard CM, Ray NF. Psychiatric illness in patients with end-stage renal disease. Am J Med. 1998;105(3):214-221.
4.    Levy NB. Psychopharmacology in patients with renal failure. Int J Psychiatry Med. 1990;20(4):325-334.
5.    Churchwell MD, Mueller BA. Selected pharmacokinetic issues in patients with chronic kidney disease. Blood Purif. 2007;25(1):133-138.
6.    Crone CC, Gabriel GM. Treatment of anxiety and depression in transplant patients: pharmacokinetic considerations. Clin Pharmacokinet. 2004;43(6):361-394.
7.    Buxton IL. Pharmacokinectics and pharmacodynamics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 11 ed. Toronto, Canada: McGraw-Hill; 2006:1-39.
8.    Cohen LM, Tessier EG, Germain MJ, Levy NB. Update on psychotropic medication use in renal disease. Psychosomatics. 2004;45(1):34-48.
9.    Lacerda G, Krummel T, Sabourdy C, Ryvlin P, Hirsch E. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology. 2006;67(12 suppl 4):S28-S33.
10.    Naud J, Michaud J, Boisvert C et al. Down-regulation of intestinal drug transporters in chronic renal failure in rats. J Pharmacol Exp Ther. 2007;320(3):978-985.
11.    Matzke GR, Frye RF. Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity. Drug Saf. 1997;16(3):205-231.
12.    Trzepacz PT, DiMartini A, Tringali R. Psychopharmacologic issues in organ transplantation. Part I: Pharmacokinetics in organ failure and psychiatric aspects of immunosuppressants and anti-infectious agents. Psychosomatics. 1993;34(3):199-207.
13.    Rudorfer MV. Pharmacokinetics of psychotropic drugs in special populations. J Clin Psychiatry. 1993;54(suppl):50-54.
14.    Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109(1-2):1-11.
15.    Turpeinen M, Koivuviita N, Tolonen A et al. Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites. Br J Clin Pharmacol. 2007;64(2):165-173.
16.    Ramzan IM, Levy G. Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats. J Pharmacol Exp Ther. 1987;240(2):584-588.
17.    Schmith VD, Piraino B, Smith RB, Kroboth PD. Alprazolam in end-stage renal disease. II. Pharmacodynamics. Clin Pharmacol Ther. 1992;51(5):533-540.
18.    Spina SP, Ensom MH. Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. 2007;27(3):389-398.
19.    Johnson CA. Dialysis of Drugs. Cambridge, MA: Nephrology Pharmacy Associates, Inc; 2007.
20.    Aronoff GR, Brier ME. Prescribing drugs in renal disease. In: Barry M, ed. Brenner & Rector’s The Kidney. 7th ed. Philadelphia, PA: W.B. Saunders Company; 2004: 2849-2870.
21.    Schoerlin MP, Horber FF, Frey FJ, Mayersohn M. Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function. J Clin Pharmacol. 1990;30(3):272-284.
22.    Anttila M, Sotaniemi EA, Pelkonen O, Rautio A. Marked effect of liver and kidney function on the pharmacokinetics of selegiline. Clin Pharmacol Ther. 2005;77(1):54-62.
23.    Coulomb F, Ducret F, Laneury JP, et al. Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency. J Clin Pharmacol. 2000;40(5):482-487.
24.    Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet. 2000;38(6):461-474.
25.    Westanmo AD, Gayken J, Haight R. Duloxetine: a balanced and selective norepinephrine- and serotonin-reuptake inhibitor. Am J Health Syst Pharm. 2005;62(23):2481-2490.
26.    Preskorn SH. Milnacipran: a dual norepinephrine and serotonin reuptake pump inhibitor. J Psychiatr Pract. 2004;10(2):119-126.
27.    Ereshefsky L, Dugan D. Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: focus on venlafaxine. Depress Anxiety. 2000;12(suppl 1):30-44.
28.    Wilde MI, Benfield P. Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs. 1995;49(3):411-439.
29.    Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet. 2007;46(4):281-290.
30.    Daily Med : Current Medication Information. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3317. Accessed December 14, 2007.
31.    Hobbs DC. Distribution and metabolism of doxepin. Biochem Pharmacol. 1969;18(8):1941-1954.
32.    Rosser R. Depression during renal dialysis and following transplantation. Proc R Soc Med. 1976;69(11):832-834.
33.    Ward ME, Musa MN, Bailey L. Clinical Pharmacokinetics of Lithium. J Clin Pharmacol. 1994;34(4):280-5.
34.    Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet. 1999;36(4):277-287.
35.    Ochs HR, Oberem U, Greenblatt DJ. Nitrazepam clearance unimpaired in patients with renal insufficiency. J Clin Psychopharmacol. 1992;12(3):183-185.
36.    Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004;43(4):227-238.
37.    Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol. 1999;19(4):533-552.
38.    Canal M, MacMahon M, Kwan J, Dubruc C. Amisulpride: Kinetics in Patients with Renal Failure. Eur Neuropsychopharmacol. 2000;10(suppl 3):330.
39.    Schmitt U, bou El-Ela A, Guo LJ, et al. Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp). J Neural Transm. 2006;113(7):787-801.
40.    Bressolle F, Bres J, Faure-Jeantis A. Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans. J Pharm Sci. 1992;81(1):26-32.
41.    Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De G, I, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359-388.
42.    Shen WW. The metabolism of atypical antipsychotic drugs: an update. Ann Clin Psychiatry. 1999;11(3):145-158.
43.    Thyrum PT, Wong YW, Yeh C. Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(4):521-533.
44.    Aweeka F, Jayesekara D, Horton M, et al. The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function. Br J Clin Pharmacol. 2000;49(suppl 1):27-33.
45.    Israni RK, Kasbekar N, Haynes K, Berns JS. Use of antiepileptic drugs in patients with kidney disease. Semin Dial. 2006;19(5):408-416.
46.    Bassilios N, Launay-Vacher V, Khoury N, Rondeau E, Deray G, Sraer JD. Gabapentin neurotoxicity in a chronic haemodialysis patient. Nephrol Dial Transplant. 2001;16(10):2112-2113.
47.    Randinitis EJ, Posvar EL, Alvey CW, Sedman AJ, Cook JA, Bockbrader HN. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43(3):277-283.
48.    Quinn D, Bode T, Reiz JL, Donnelly GA, Darke AC. Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. J Clin Pharmacol. 2007;47(6):760-766.
49.    Robertson P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-137.
50.    Schmith VD, Piraino B, Smith RB, Kroboth PD. Alprazolam in end-stage renal disease: I. Pharmacokinetics. J Clin Pharmacol. 1991;31(6):571-579.
51.    A.D.A.M. Medical Encyclopedia. The end-stage kidney disease page. Available at: www.nlm.nih.gov/medlineplus/ency/article/000500.htm. Accessed December 13, 2007.
52.    Levy NB. Use of psychotropics in patients with kidney failure. Psychosomatics. 1985;26(9):699-701,705,709.
53.    Aronoff GR, Brier ME. Prescribing drugs in renal disease. In: Barry M, ed. Brenner & Rector’s The Kidney. 7th ed. Philadelphia, PA: Saunders; 2004:2849-2870.
54.    Presne C, Fakhouri F, Noel LH et al. Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int. 2003;64(2):585-592.
55.    Raedler TJ, Wiedemann K. Lithium-induced nephropathies. Psychopharmacol Bull. 2007;40(2):134-149.
56.    Gitlin M. Lithium and the kidney: an updated review. Drug Saf. 1999;20(3):231-243.
57.    Braden GL. Lithium-induced renal disease. In: Greenbery A, ed. Primer on Kidney Disease. 3rd ed. San Diego, CA: Academic Press; 2001:322-324.
58.    Lepkifker E, Sverdlik A, Iancu I, Ziv R, Segev S, Kotler M. Renal insufficiency in long-term lithium treatment. J Clin Psychiatry. 2004;65(6):850-856.
59.    Markowitz GS, Radhakrishnan J, Kambham N, Valeri AM, Hines WH, D’Agati VD. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol. 2000;11(8):1439-1448.
60.    Livingstone C, Rampes H. Lithium: a review of its metabolic adverse effects. J Psychopharmacol. 2006;20(3):347-355.
61.    Phipps A, Turkington D. Psychiatry in the renal unit. Advances in Psychiatric Treatment. 2001;7:426-432.
62.    Cohen LM, Germain MJ, Tessier EG. Neuropsychiatric complications and psychopharmacology of end-stage renal disease. In: Brady HR, Wilcox CS, eds. Therapy in Nephrology and Hypertension: A Companion to Brenner and Rector’s The Kidney. 2nd ed. Philadelphia, PA: WB Saunders; 2003:731-746.
63.    Rabindranath KS, Butler JA, Macleod AM, Roderick P, Wallace SA, Daly C. Physical measures for treating depression in dialysis patients. Cochrane Database Syst Rev. 2005;(2):CD004541.
64.    Blumenfield M, Levy NB, Spinowitz B, et al. Fluoxetine in depressed patients on dialysis. Int J Psychiatry Med. 1997;27(1):71-80.
65.    Cukor D, Peterson RA, Cohen SD, Kimmel PL. Depression in end-stage renal disease hemodialysis patients. Nat Clin Pract Nephrol. 2006;2(12):678-687.    
66.    Koo JR, Yoon JY, Joo MH et al. Treatment of depression and effect of antidepression treatment on nutritional status in chronic hemodialysis patients. Am J Med Sci. 2005;329(1):1-5.
67.    Wuerth D, Finkelstein SH, Finkelstein FO. The identification and treatment of depression in patients maintained on dialysis. Semin Dial. 2005;18(2):142-146.
68.    Levy NB, Cohen LM. End-stage renal disease and its treatment: dialysis and transplantation. In: Stoudemire A, Fogel BS, Greenberg D, eds. Psychiatric Care of the Medical Patient. 2nd ed. New York, NY: Oxford University Press; 2000:791-800.
69.    Beliles K, Stoudemire A. Psychopharmacologic treatment of depression in the medically ill. Psychosomatics. 1998;39(3):S2-S19.
70.    Shah SU, Iqbal Z, White A, White S. Heart and mind: (2) psychotropic and cardiovascular therapeutics. Postgrad Med J. 2005;81(951):33-40.
71.    Eli Lilly Medication Guide for Cymbalta. Available at: http://pi.lilly.com/us/cymbalta-pi.pdf. Accessed August 5, 2007.

  

 

Needs Assessment: Twenty percent to 40% of patients on renal replacement therapy suffer from depressive disorders. These conditions increase the burden of kidney disease, adversely affect quality of life, and may increase the mortality of these patients. Despite their significance, depressive disorders are largely underdiagnosed and undertreated in the chronic kidney disease population. Physicians should know the triggers, diagnostic issues, and treatment options of depression in this special context.

Learning Objectives:
• Describe how depression effects chronic kidney disease (CKD) outcome measures.
• List the risk factors and critical periods for depression in the CKD population.
• Provide examples for the overlapping symptoms of depression and uremia.
• List the most effective interventions for depression in the CKD population.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 8, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Zalai is research fellow in the Department of Psychiatry at the University of Toronto in Ontario, Canada. Dr. Novak is assistant professor in the Department of Psychiatry at the University Health Network and University of Toronto in Ontario, Canada, and associate professor at the Institute of Behavioral Sciences at Semmelweis University in Budapest, Hungary.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors thank the Department of Psychiatry in the Center for Integrative Mood Research at the University Health Network in Toronto, Canada, and the Hungarian Kidney Foundation.

Please direct all correspondence to: Marta Novak, MD, PhD, Department of Psychiatry, University Health Network, Toronto General Hospital, 200 Elizabeth St. EN 8-212, Toronto, ON, M5T 2S8, Canada; Tel: 416-340-3043; Fax: 416-340-4198; E-mail: marta.novak@uhn.on.ca.

 

 
 

Abstract

Depressive disorders have been shown to be present in 20% to 40% of the population receiving renal-replacement therapy, and this figure may be even higher in the pre-dialysis chronic kidney disease (CKD) population. Psychosocial factors (eg, unemployment, low income, young age, female gender, low-perceived social support, lack of adjustment to the hardship of dialysis, role transitions) make patients vulnerable to depression. Although it is often impossible to tell whether some symptoms originate primary in CKD or depressive disorders, if they meet the diagnostic criteria of depressive disorders then adequate therapy should be initiated. Screening tools can help in the identification of patients with depressive disorders. Prevention and treatment of depression is crucial because it is strongly associated with several important CKD outcomes. Monitoring the presence of depressive symptoms and enhancing social support should be part of the routine care in the CKD population.

 

Introduction

Chronic kidney disease (CKD) is a progressive, life-threatening illness, and a variety of biologic, psychological, and social stressors may trigger depression at any point during this life-long illness. Certain periods of the disease cycle and biopsychosocial factors make some patients especially vulnerable to depression. The diagnosis of depressive disorders may be challenging in this population. Clinicians sometimes experience difficulties to distinguish between the symptoms of uremia and somatic symptoms of depression. Furthermore, it may be questionable whether social withdrawal, decline in vocational activities, marital discord, and sadness are all expressions of depression or of the known burden of CKD. The literature in this respect is often confusing. On the one hand, the concept of “depression” is sometimes used in terms of “depressive affect” or “high scores on self-report questionnaires” and only rarely classified according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; Table 1).1 On the other hand, there has been no consensus, whether the shared somatic symptoms of depression and uremia should be included into the assessment and diagnosis. This article reviews the information concerning the triggers and risk factors of depressive disorders and addresses the above diagnostic issues. It also summarizes evidence on the association between depressive disorders and CKD outcomes in order to shed light on the importance of accurate diagnosis of depressive disorders in this population as well as review the few treatment studies available, with special emphasis on psychotherapy. The terms depression and depressive disorders are used interchangeably.

 

 

  

Etiology of Depression in Chronic Kidney Disease

CKD is a progressive, life-threatening illness, posing a fundamental existential problem on individuals and a burden on their families. The interplay between the person’s genetic susceptibility, his or her socioeconomic circumstances, and biopsychosocial impact of the kidney disease and its treatment may trigger depression in patients at any point of the disease.

The potential biologic pathways that link CKD and depressive disorders are important issues yet to be fully explored. Presumably, several biologic conditions associated with kidney disease (ie, uremia, anemia, impaired glucose metabolism, endocrine and immunologic changes, chronic inflammation) may play a role in the pathomechanism of mood disorders in CKD. So far, the most attention has been paid to the potential pathophysiologic link between immunologic stress factors and depression. The cytokine theory of depression assumes that inflammatory cytokines can trigger depression acting on the central nervous system. Chronic inflammation is common in dialysis patients and there is evidence to suggest that depression correlates with markers of inflammation in this population.2-5 Inflammation, malnutrition, and depression may have a complex, multi-dimensional relationship in CKD; pro-inflammatory markers may contribute to mood changes and malnutrition, whereas malnutrition can lead to inflammation and depression may result in malnutrition. This triad—often referred to as inflammation-malnutrition-depression complex—is a major determinant of a patient’s health status and mortality.2,6,7

On the psychological level, starting dialysis requires a complex emotional and cognitive-behavioral adaptation from patients. Profound experience of role transitions is common among people in this period. People whose kidney functions decline fast or who are not aware of their illness until its final stage become suddenly “severely ill.” Autonomous adults who used to exercise control over their lives become dependent on healthcare professionals and on their own family members. Those used to maintain households may become unemployed. People’s roles as sexually active, fertile males and females may be damaged. Bereavement is a natural reaction to these role changes and multiple losses that can resolve sadness and lead to healing. With some patients, however, mourning may progress to a major depressive episode (MDE) that requires treatment.

Although transplantation usually results in improved quality of life (QOL) in many aspects, it also requires special behavioral adaptation and psychological adjustment. Patients’ uncertainty about their future health and finances are the two leading stressors in the post-transplant period.8 Side effects of medications and physical problems also cause psychological strain after transplantation.9-10 Data from the few studies on this issue suggest that transplantation does not necessarily alleviate depression and anxiety; in fact, it may even amplify them.9,11,12

Re-starting dialysis after a graft rejection may again be a crisis point in the CKD “disease cycle.” A comparison between people with well-functioning graft, dialysis patients on transplant waiting list, and dialysis patients with chronic graft failure found that in the latter group the incidence of depression was significantly higher (>60%) than in the other two groups.11

Female gender, unemployment, low income, and living alone are risk factors for depression both in the general and CKD populations.13-15 Dialysis patients often have to give up their jobs. Although transplantation gives more independence to patients, the vocational activity level stays low.16

The studies on the relationship between age and the psychological impact of CKD generally concluded that younger age is associated with more mental distress than older age.15,17 Younger patients may experience dramatic role transitions in areas of health, employment, family and sexual roles, and fertility, and may feel that the illness shatters their future aspirations. In contrast, elderly patients usually compare themselves to their peers who often suffer from other chronic illnesses, and the onset of CKD may be an acceptable life event at this stage of their lives.18

Perceived social support has consistently been shown to have a strong correlation with depression and CKD outcomes.5,19,20 In particular, patients with history of suicidal thoughts or attempts in the pre-transplant and post-transplant period have found to perceive less social support than those who did not think of suicide.21 Low perceived social support is also correlated with low life satisfaction. Marital problems are common in the dialysis population.22 In a sample of mostly African-American hemodialysis patients, dyadic dissatisfaction was associated with depressive symptoms, although only in women.5

Awareness of the above factors may facilitate the utilization of appropriate preventive methods. Psychotherapy was shown to support adjustment to dialysis and transplantation and to prevent psychological deterioration.23,24 The primary care physician (PCP), who has trusting relationships with the patients, can be the first healthcare professional recognizing the risk factors for depression and to whom the patients disclose their distress.

 

Prevalence of Depression in Patients with Chronic Kidney Disease

Depressive disorders and anxiety disorders are the most common mental health problems in the CKD population,12,25,26 Most epidemiologic studies in this respect suffer from small and non-representative samples and from the use of instruments that had not been validated for the particular population. The largest study so far has been the Dialysis Outcomes and Practice Patterns Study that assessed the symptoms of depression with >9,000 participants from 12 countries.15 This study, using the Center for Epidemiologic Studies Depression Scale, reported that 43% of patients had scores indicating depression. There was also a large variation in the prevalence of physician-diagnosed depression; the two extremes were Japan (2%) and the United States (21.7%). The discrepancy between the reported symptoms and physician diagnosis may reflect cultural factors and diagnostic difficulties. A study that validated the same questionnaire in hemodialysis patients found depressive disorders in 26.7% of patients, including major depressive disorder (65%; MDD), dysthymia (27%) and minor depression (8%).27 In two other recent studies using validated instruments, the prevalence of depressive disorders have been 26% and 27%, respectively; the majority of patients suffered from MDD.28,29 The few studies available in transplanted patients suggested that the prevalence of depression is similar (20% to 35%) to that of the dialysis population.11,12

The assessment of psychological distress in the earlier stages of CKD has been largely neglected. In an unpublished study by Zalai and colleagues conducted in a pre-dialysis clinic, approximately 50% of patients reported severe depressive symptoms (unpublished data, November 2005). An earlier study arrived at similar results.30

The above evidence suggest that CKD patients can be regarded as a high-risk population for depressive disorders. Considering the enormous burden of depression both for the individual and the society, its large prevalence in CKD alone calls for special attention and effective intervention.13,31,32

 

Significance of Depression in Chronic Kidney Disease

The life expectancy of dialysis patients is one-third to one-sixth of the non-dialysis patients of the same age in the United States.33 Age, comorbidity, malnutrition, anemia, and functional status have been consistently shown to be associated with mortality.34 Depressive disorders, however, are not included in the most frequently used comorbidity indexes.

The prognostic significance of depression has been the focus of several studies, but these reports arrived at conflicting conclusions. Some studies did not find an association between depression and mortality.25,35,36 However, a large international study on dialysis outcomes concluded that both physician-diagnosed depression and depressive affect were independent predictors of survival in all countries.17 In addition, depression was associated with higher withdrawal rate and higher death rate from cardiac, vascular, and infectious diseases. The shortcoming of the above studies is that depression was assessed only at one point in time. Kimmel and colleagues37 showed that depressive affect, if measured only once, was not associated with mortality, but the time variation of depressive symptoms over a period of 2–5 years predicted survival.5 A further theoretical and methodologic issue is whether MDD and depressive affect has different effects on CKD outcomes. A recent retrospective study of a large sample of male veterans receiving long-term hemodialysis did not find association between mortality and physician-diagnosed depression, whereas other authors described that current symptoms of depression were associated with fourfold increase in mortality.29,38 Further large, multi-center studies are needed to assess the impact of clinical depression and depressive affect on mortality in CKD. Depression may increase mortality through various mechanisms, including malnutrition, immunologic changes, and increased risk for coronary heart disease and myocardial infarction.

It has been suggested that incidence of suicide is 84% higher in the dialysis than in the general population and is associated with mental illnesses.39 More passive behavior forms, eg, self-neglect, non-adherence to the treatments, may be expressions of suicidal ideation. The association between hospitalization and depression is more lucid; depression was found to increase the number of hospitalizations and length of stay in the hemodialysis population.17,38

For those living with CKD for months, years, or decades, the impact of disease and of kidney replacement therapies on their lives is an essential issue. Depression and anxiety are predictors of poor QOL in the hemodialysis, peritoneal dialysis, and transplanted populations.29,40-42 Depression and anxiety have found to be a stronger impact on QOL than clinical and sociodemographic variables (ie, comorbidity, hemoglobin, albumin, age, gender, employment status) taken together.40

 

Diagnosis of Depression in Patients with Chronic Kidney Disease

The DSM-IV classifies depressive disorders into MDD, dysthymic disorder and depressive disorder not otherwise specified (NOS). MDD is characterized by MDEs (Table 1). Dysthymic disorder features non-episodic symptoms that are present for at least 2 years (Table 1). Depressive disorders NOS are disorders with depressive features that do not meet the criteria for MDD or dysthymic disorder.

MDEs are characterized with depressed mood and/or anhedonia accompanied by decreased or increased appetite, significant weight gain or weight loss, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, diminished ability to think or concentrate, feelings of worthlessness, guilt, and recurrent thoughts of death. Some of these symptoms, however, can also be attributed to CKD or can simply be regarded as understandable reactions to the overwhelming burden of this illness (Table 2).

 

 

Fatigue, for example is one of the most prevalent symptoms of stage 5 CKD, affecting approximately 70% of patients.43 It may be caused by the consequences of renal failure, including anemia, malnutrition, hemodialysis-related hypotension and electrolyte shifts, medication side effects, and sleep disorders.34 However, loss of energy is among the leading symptoms of depressive disorders.44 Sleep disturbances occur in 45% to 80% in stage 5 CKD. The most frequent sleep disorders in the dialysis population are insomnia, sleep apnea, restless-leg syndrome, and periodic limb movements.45 The relationship between sleep disturbances and depression is two-directional; sleep problems can trigger depression and depression often results in insomnia.46 It is also important to note that the neuropsychological symptoms of sleep apnea, which is very frequent in the renal population, resemble the symptoms of depression or even uremia.47

Anorexia is yet another devastating symptom in about half of the patients with advanced stages of CKD.22 Depressive disorders are also often associated with decreased appetite. Sexual problems may appear in the early stages of CKD and their prevalence increases with the progression of the disease.43 Depression is one among the multiple factors that may contribute to the development of sexual dysfunctions, especially to loss of libido. Finkelstein and colleagues2 suggested that pharmacotherapy and psychiatric counseling may improve sexual functions in CKD patients with depression.

Pain is highly prevalent from the early stages of CKD.48 Chronic pain increases the burden of CKD, decreases QOL, and correlates with psychological distress in the early stages of the CKD. The prevalence of chronic pain is >50% in end-stage CKD, but it is often under-recognized even in the dialysis settings.43,49 Pain management also seems to be inadequate; according to a Canadian study,50 >40% of those in pain (musculoskeletal, ischemic, and neuropathic of origin) report moderate-to-severe pain and nearly 75% of patients find pain analgesic treatment inadequate. In the study, the severity of pain was positively correlated with the severity of self-reported depression symptoms. Patients who reported moderate-severe pain had higher score on the Beck Depression Inventory than those who had only mild or no pain.50

The presence of cognitive-emotional symptoms can help in directing attention to an underlying depressive disorder. However, some patients may not be able to identify or express emotional distress, or may be reluctant to share these psychological problems with their physicians. In addition to this, both physicians and patients often share the belief that depression is an “understandable” or “inevitable” condition in severe chronic illness.51,52

Sadness, anhedonia, anxiety, and thoughts of death are common at the onset of severe illnesses. The distinction of depression from normal bereavement and from adjustment disorders is important. DSM-IV makes a distinction between normal bereavement and “complicated bereavement.” The former refers to a normal, profound sadness caused by the loss of a loved one, whereas complicated bereavement is a reaction that triggers MDD. DSM-IV classifies bereavement as an MDE if symptoms of bereavement last for >2 months, or if there is a marked functional impairment, psychomotor retardation, morbid preoccupation with worthlessness, suicidal ideation, or psychotic symptoms. Although DSM-IV does not exclude normal, intense sadness caused by losses other than loss of a loved person from MDD criteria, it has been proposed that these reactions be treated similarly to bereavement.53,54 In this spirit, when patients react with intense sadness to the losses associated with CKD, those symptoms could be classified as MDD if the symptoms last for >2 months or are as extreme as described above. Adjustment disorders may develop in 3 months after stressful life events such as, for example, the initiation of dialysis. Adjustment disorders may manifest with depressive symptoms, most often with depressed mood, tearfulness, and hopelessness. Other maladaptive symptoms, such as chronic denial, noncompliance with treatment, and social withdrawal may also dominate the clinical presentation. In adjustment disorder with depressed mood, the symptoms do not meet the diagnostic criteria of an MDE. Somatic symptoms and suicidal ideation are also less common than in MDD.

Depression is largely under-diagnosed in CKD populations.15,55 Full assessment of the emotional, cognitive, and somatic symptoms of depressive disorders is strongly suggested in this population. The National Institute of Health and Clinical Excellence (Canada) advised that screening for depression should include at least two questions about the mood and interest of the patients.56 Although this may be a valid, quick screening method, it is important to know that patients who cannot or do not want to disclose emotions may give denying answers for these questions.57 Self-report screening instruments can also aid the recognition of depressive disorders. These tools cannot be used for diagnosis, but help to identify people with the symptoms of depression and indicate the severity of these symptoms. Some of these instruments have already been validated in dialysis patients (Table 3).27,28,58-60 Structured interviews validated against DSM-IV can reliably aid the diagnosis of depression. Referral to a psychiatrist who has experience with the medically ill population might be necessary.

 

 

 

Therapy of Depression in Patients with Chronic Kidney Disease

Despite of the association of depression with outcomes of the disease, only a few studies have been published on the treatment of depression in CKD patients.

Antidepressant pharmacotherapy is discussed by McIntyre and colleagues.61 Preliminary evidence suggests that selective serotonin reuptake inhibitors, in particular fluoxetine, sertraline, and paroxetine, seem to be safe choices for treatment of CKD.62,63 Tricyclic antidepressants, however, may have severe side effects in patients with CKD, and should be used mainly for the treatment of insomnia and neuropathic pain, under close monitoring. Pain management and the treatment of sleep disturbances should also be considered when starting antidepressant therapy.

Non-pharmacologic therapeutic approaches, such as counseling or psychotherapy, may be a more appealing choice of treatment for patients who suffer from several medical conditions and already receive multiple medications. Cognitive-behavioral therapy (CBT) and interpersonal psychotherapy (IPT) are both effective for the treatment of mild and moderate depression in other patient populations64 and can be combined with pharmacotherapy for the treatment of severe depression. Cognitive psychotherapy aims at identifying and modifying patients’ maladaptive beliefs about the self and the world, whereas IPT focuses on the identification and resolution of the main interpersonal problem areas in the patients` lives that are assumed to be related to the onset of depressive symptoms. Supportive psychotherapy is widely used to facilitate adjustment to chronic illness. Empathetic listening, cognitive and emotional support, reinforcement of adaptive strategies, and direct environmental intervention by the therapist are its main features. Psychotherapy can be conducted either in an individual, couple, family, or group setting. Group therapy is more cost effective than individual therapy and can also have additional benefits in that, for example, patients can share experiences and develop supportive relationships. However, individual therapy may better suit those patients who find public psychological disclosure difficult or intimidating. Psychotherapy might have to be modified to meet the needs of this population. Therapy, for example, could be delivered over the phone, or conducted with dialysis patients during the dialysis sessions, although issues about privacy in that setting may present a problem.

The few studies on the effectiveness of psychotherapy have promising outcomes in different CKD treatment groups. In a recent study of hemodialysis patients, 15 weeks of CBT reduced the depressive symptoms measured with the Beck Depression Inventory, and this effect was maintained for 3 months.52 Furthermore, a Korean group showed that a combination of pharmacotherapy and supportive psychotherapy reduced depressive affect and improved nutritional status of hemodialysis patients who previously had been diagnosed with MDD.63 Appropriate counseling may also be beneficial for people at the time of diagnosis of CKD as well as before the initiation of kidney replacement therapy. Studies in this area are very much needed. For PCPs and psychiatrists, it is also important to know that >40% of married dialysis patients report moderate-to-severe marital discord.22 Counseling with spouses or main caregivers could be an important part of the prevention and treatment of depression in this subgroup of patients. Well-designed, prospective, randomized studies are badly needed to establish the effectiveness of the above interventions and treatments in the CKD population.

 

Conclusion    

Depressive disorders are common in patients with CKD. Regular screening of depressive disorders in this population is essential. Appropriate use of validated screening instruments and structured clinical interviews help identify individuals with depression. Further studies are still needed to assess the association of the different depressive disorders with outcome of CKD, but the available evidence suggests that both depressive affect and clinical depression are associated with impaired QOL and poorer survival in these patient groups. Both pharmacotherapy and psychotherapy should be considered for the treatment of depression. Individual and group psychotherapy can be applied not only as effective treatment methods but also as preventive tools during the transition to dialysis and transplantation. Spouses or main caregivers of dialysis patients often play active roles in the treatment process and share the psychological strain of the disease. Thus, involving them in the counseling sessions may also be an important element of prevention and treatment of depression. PP

 

References

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8.    Achille MA, Ouellette A, Fournier S, Marie-Josée H, Catherine G, Michel Pâquet. Impact of transplant related stressors and feelings of indebtedness on psychosocial adjustment following kidney transplantation. J Clin Psychol Med Settings. 2004;11(1):63-73.
9.    Heck G, Schweitzer J, Seidel-Wiesel M. Psychological effects of living related kidney transplantation- risks and chances. Clin Transplant. 2004;18(6):716-721.
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11.    Akman B, Özdemir FN, Sezer S, Miçozkadioglu H, Haberal M. Depression levels before and after transplantation. Transplant Proc. 2004;36(1):111-113.
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19.    Thong MS, Kaptein AA, Krediet RT, Boeschoten EW, Dekker FW. Social support predicts survival in dialysis patients. Nephrol Dial Transplant. 2007;22(3):845-850.
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21.    Soykan A, Arapaslan B, Kumbasar H. Suicidal behavior, satisfaction with life, and percieved social support in end- stage renal disease. Transplant Proc. 2003;35(4):1290-1291.
22.    Finkelstein FO, Shirani S, Wuerth D, Finkelstein SH. Therapy insight: sexual dysfunction in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2007;3(4):200-207.
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Dr. Lindenmayer is clinical professor in the Department of Psychiatry at New York University School of Medicine and clinical director of the Manhattan Psychiatric Center in New York City.

Disclosures: Dr Lindenmayer receives grant support from AstraZeneca, Azur, Bristol-Myers Squibb, Eli Lilly, the National Institute of Mental Health, Janssen, Organon, and Pfizer; and is consultant to Eli Lilly and Janssen. This manuscript was sponsored by Johnson & Johnson.

Please direct all correspondence to: Jean-Pierre Lindenmayer, MD, Clinical Director, Manhattan Psychiatric Center, New York, NY 10035; Tel: 646-672-6004; Fax: 646-672-6446; E-mail: Lindenmayer@NKI.RFMH.org.

 


 

Focus Points

• Impaired patient function is a core component of schizophrenia.
• Improving patient functioning is an important treatment goal.
• Scales that assess function should be used routinely in clinical practice.

 


 

Abstract

Functional impairment is observed in the majority of patients with schizophrenia and is now considered a core diagnostic feature of the disorder. Nonetheless, patient function has been a neglected aspect of the burden of schizophrenia. Despite the availability of numerous assessment scales, patient functioning has not been routinely assessed in clinical practice or as a major outcome in clinical trials. This article highlights the independence of functioning from the psychopathologic features of schizophrenia and its interference with patient recovery even when effective symptom control is achieved. This article details the complexity of measuring patient functioning and the need for increased use of assessment scales in clinical practice, in particular those scales that can assess functioning independent of the symptoms of schizophrenia. The ease of use of such scales should also help to promote their routine use in the attainment of improving patient function and, therefore, improving the long-term prognosis for patients with schizophrenia.

 

Introduction

Schizophrenia is a chronic disease encompassing a range of symptoms including hallucinations, delusions, social withdrawal, and anhedonia. Symptom control has been a major goal of schizophrenia treatment. Different measurement tools, such as the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions–Severity (CGI-S) scale, and the Brief Psychiatric Rating Scale (BPRS) are utilized to assess the symptoms of schizophrenia.

Schizophrenia symptoms have a measurable impact on many aspects of a patient’s life. Severe deficits in functioning are observed in daily living, family life, social interactions and employment. This article highlights both the importance of improving patient functioning as part of the overall treatment approach to schizophrenia and how the assessment of this aspect of the disease has been neglected in clinical practice and as a major outcome of clinical trials despite its importance in optimizing long-term prognosis. Also emphasized is the complexity of measuring patient functioning; its independence from and overlap with the psychopathologic features of the disease; and how the development of scales that can assess functioning independently of symptoms are necessary for the progression and assessment of new treatment options.

 

Improving Patient Functioning: An Important Treatment Goal

The importance of functioning in patients with schizophrenia was acknowledged in 1980 with its formal inclusion as one of the five axes of patient clinical status in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III)1 classification system, which was retained in the subsequent DSM-IV.2 Deficits in functioning are now described as one of the defining characteristics of schizophrenia in the DSM-IV-TR,3 broadly depicting changes in functioning in terms of work, interpersonal relations, and self care. Impairments in patient functioning can lead to decreased medication adherence, increased risk of hospitalization, and diminished ability to either engage in relationships or to maintain employment, which can further impact the disease progression. Moreover, schizophrenia is associated with considerable economic burden due to the loss in productivity as well as the costs of treatment, hospitalization, and rehabilitation.

Patient functioning is partly affected by the phase of the disease. Treatment expectations vary between individuals, but during the acute phase, they include improvement in the domains that impact basic functioning and everyday living (eg, aggressive behavior, paranoia, and the basics of self care). In stable phases, expectations of functional improvement encompass more autonomous social behavior, the ability to actively participate in rehabilitative therapy, and better functioning at work. Improvement in these domains may enable the patient to partake in relationships and increase employment opportunities.

Assessment of functioning is complex and has been a neglected aspect of the stable phase of schizophrenia. However, with each successive relapse the likelihood of patients regaining their previous level of functioning is compromised. Conversely, with persistent symptom control there is the potential for functional improvement. However, there is recognition that impairment in the symptom domains of schizophrenia is not always related to decreases in functioning. Indeed, there is increased awareness that functioning must be assessed independently of and in addition to the symptoms of schizophrenia to improve long-term treatment outcomes for the patient.

Specific functional deficits have been linked to various symptom domains of the disease, such as negative symptoms and certain cognitive impairments (eg, nonverbal social perception, attention and memory, executive functioning, and concept formation). Specifically, some studies have shown that negative symptoms have consistent associations with social problem solving and inconsistent relationships with community functioning but not with skill acquisition.4 It has been suggested that the level of cognitive functioning may predict subsequent functional outcome in the community setting, and that there may be links between cognitive deficits, autonomous living, and sustained employment.5 However, the overall concept of functioning as an outcome of schizophrenia can be independent of the psychopathology of the disease; the relationship between psychotic symptoms and social functioning is not linear and improvements in symptoms do not always result in functional improvements.4

 

Assessment of Patient Functioning in Schizophrenia

How Can We Routinely Assess Functioning in Schizophrenia?

Clinical trials that have assessed patients’ functioning have utilized various scales, including those based on the DSM-IV, and have measured different aspects/domains of functioning. Many have not been validated in schizophrenia and were not designed for use in this population. Quality of life (QOL) is generally considered an important outcome measure in schizophrenia, and scales for the assessment of QOL have been used as a measure of functioning in many studies, even though many of  these scales are not considered sensitive to the specific impact of schizophrenia on functioning.6 Scales include the Lehman Quality of Life Interview,7,8 Social Function Scale,9 Strauss-Carpenter Level of Functioning scale (SLOF),10 Quality of Well-being Scale,11 the Medical Outcomes Study Short Form-36,12 Independent Living Skills Inventory,13 and the University of California, San Diego Performance-based Skills Assessment.14

The measurement of functioning is complicated by the type of assessment used. Patient-reported assessments are regarded as necessary to provide an accurate representation of the outcome. This is especially relevant in terms of the subjective impact of treatment, particularly with respect to functioning. However, self-assessments have been shown to be unrelated to observer-rated symptom scale assessment in patients with schizophrenia. Nevertheless, patients have rated improvement in functioning as an important outcome in their treatment expectations, confirming that their opinion is valuable and should be taken into consideration. It may be argued that subject-rated outcomes are not necessarily reliable, as patients might not be able to assess or accurately report their condition owing to the inherent nature of the symptoms, including psychosis, cognitive deficits, and reduced insight. Additionally, little evidence exists in the literature regarding the reliability and validity of self-reports from patients with acute schizophrenia. Clinician-rated scales, although considered more accurate due to rating by a trained professional and generally validated, also have disadvantages: training for application of the scale is required and there is the possibility of some subjectivity of scoring by the clinician. Another complication in the assessment is the need to have an outside source available to obtain information the clinician may not have direct access to, such as work functioning, peer functioning in settings outside the clinician office, and performance of activities of daily living. This information can often only be obtained by a person who is very familiar with the day-to-day functioning of the patient. However, it may be difficult to have family members, case workers, or staff from board and care homes available at the time of the assessment by the clinician in the outpatient setting, which may be another reason why assessments of functioning are not always part of routine clinical practice.

 

Scales for Assessment of Patient Functioning in Schizophrenia

Given the present interest on those assessment instruments, which may be particularly helpful for clinical practice, this evaluation will be limited to instruments with a more global scope. Of these scales available to measure functioning in schizophrenia, those based on the DSM-IV criteria are considered to be the most clinically meaningful to clinicians and researchers and will, therefore, be the focus of this article. These clinician-rated instruments include the Global Assessment of Functioning (GAF) scale, the Social and Occupational Functioning Assessment Scale (SOFAS), and the Personal and Social Performance (PSP) scale.

The GAF has demonstrated good sensitivity to change and disorders with higher complexity; higher levels of severity are associated with lower scale scores. As one of the most frequently used scales, the GAF only assesses global functioning in terms of a single rating of overall psychological, social, and occupational functioning,15 and consequently, interpretation of specific aspects of patient functioning is difficult. The revised GAF has demonstrated improved inter-rater reliability as compared with the original GAF but considers only social and occupational functioning. There is evidence that this revised scale is more strongly related to psychiatric symptoms than to the functional capacity of the patient.16

The SOFAS, developed by the American Psychiatric Association for the DSM-IV to operationalize functioning, improved on the GAF by incorporating the impact of psychological and general medical symptoms on patient functioning.17 Although this expanded the assessment beyond a single axis and improved the ability to measure functioning independent of the severity of psychiatric symptoms, the SOFAS has been criticized for poor linguistic distinction of terms such as “serious” and “major” impairment.

The newer PSP scale18-20 has been developed as a further improvement over the GAF and SOFAS, demonstrating good reliability and validity in patients with severe mental illness in an inpatient rehabilitation program and a stable outpatient population. Unlike the SOFAS, the PSP scale specifies four areas to be rated, enabling the clinician to specifically identify where patients are impaired within the spectrum of these four functional domains that are representative of the spectrum of functioning in schizophrenia (Table).2,15-21 A single-scale rating based on these four domains can also be independently assessed. Unlike the GAF and SOFAS, the PSP scale has demonstrated an ability to measure a functional construct of the disease, showing greater correlation with SLOF than the moderate correlations with the symptom-oriented PANSS or CGI-S scale.18 Furthermore, sensitivity to change of the PSP scale has been demonstrated after treatment interventions. A change on the PSP scale has been correlated with changes in symptomatology on the CGI-S and PANSS total scales pointing to some degree of relationship between this measure of functioning and psychotic symptoms. No significant psychometric limitations of the scale have been identified, although validation assessment was only conducted over a 7-day period and, therefore, longer-term validation studies are required. Additionally, studies are necessary to determine the effect of differing amounts of information provided by patients and clinicians on PSP ratings. User-friendly training materials for the PSP scale should be developed to increase its use by non-research clinicians and practitioners.
 

Although used increasingly in clinical trials, scales of functioning are not routinely used in clinical practice for the assessment of schizophrenia. While some clinicians are beginning to use symptom rating scales such as the CGI-S or the BPRS, the use of scales such as the PANSS may be limited due to their demanding and time-consuming nature. Consistent use of functional assessment scales in clinical practice remains suboptimal.

In order to facilitate achieving more wide-reaching outcomes in schizophrenia, scales that assess patient functioning relatively independent of the disease psychopathology should be more routinely included in clinical practice. The development of schizophrenia-specific measures that reflect the improved understanding of the impact of functional deficits on the patient and the phase of the disease could provide the basis for such scales to become more widely used, allowing assessment of functioning as the disease progresses or patients improve. This will allow practitioners to focus on and to include treatment interventions that specifically target domains of impaired functioning that otherwise might be neglected. In today’s busy clinical practices, shorter and simpler scales that can be administered by different treatment team members beyond the treating psychiatrist will be more likely to be adopted for routine use. This will allow the treatment team to assess whether functional treatment goals are being reached, ultimately raising expectations for long-term prognosis and potentially promoting a more widespread acceptance of such measures.

 

Conclusion

The impaired functioning exhibited by patients with schizophrenia can impact many aspects of life. Thus, for antipsychotic and rehabilitative treatments to be considered fully effective, they should not only target symptom improvement, but also improvements in patient functioning that may be independent of the psychopathology of the disease. The routine measurement of functioning with accessible scales should increase awareness of patients’ levels of functioning and improvements following treatment. User-friendly scales shown to reliably assess functional domains independent of disease symptoms should have optimal utility and be useful across all phases of schizophrenia. The ease of use of such scales should also help to promote their routine use with the aim of focusing and improving patient function and, therefore, advancing the long-term prognoses for patients with schizophrenia. Ultimately, this should help raise expectations of treatment outcomes. PP

 

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