psy prblm 2 esrd

WISCONSIN MEDICAL JOURNAL

Wisconsin Medical Journal 2004 • Volume 103, No. 664

Psychiatric Comorbidity in Epilepsy and End Stage Renal Disease

David B. Bresnahan, MD

Doctor Bresnahan is an assistant clinical professor of Psychiatryand Behavioral Medicine at the Medical College of Wisconsin. Heis on staff at Froedtert Memorial Lutheran Hospital and RogersMemorial Hospital, with clinical interests in geriatric psychiatry,medical psychiatry, and psychopharmacology. Please address cor-respondence to: Medical College of Wisconsin, Department ofPsychiatry Clinics at Tosa Center, 8701 Watertown Plank Rd,Milwaukee, WI 53226.

INTRODUCTIONMany chronic serious medical conditions are associ-ated with increased psychiatric comorbidity. Two suchconditions are epilepsy and chronic renal failure.While specialists are often involved in the care of thesepatients, well-established primary care remains an im-portant part of their treatment. When psychiatric con-ditions arise, primary care providers will often be thefirst to see these disorders. These can be very compli-cated patients, and coordination of care between pri-mary care physicians, specialists, and other health careproviders is essential. Recognition, treatment initia-tion, and referral when needed are reviewed in this ar-ticle.

EPILEPSYEpilepsy is a complex disorder afflicting approximately1% of the population. New treatment modalities haveexploded in recent years, giving patients more optionsand a greater chance of becoming seizure free. These in-clude newer anticonvulsants, vagus nerve stimulation,and epilepsy surgery. Comorbid psychiatric disordersof a wide variety occur in epilepsy to a greater degreethan in the general population.1 These include variousforms of depression, anxiety, and psychosis. In generalthese comorbid disorders are classified based on theirtemporal relationship to the ictal event or seizure.Preictal symptoms occur hours to days before a seizureand represent a prodrome of a coming seizure. Ictalsymptoms represent an actual simple partial seizure,usually of a temporal lobe origin. Postictal symptomslast hours to days—usually occurring after a volley ofseizures—are time limited, and rarely require treat-

ment. Interictal depression, anxiety, and psychosis aremore chronic and typical disorders, not occurring in re-lation to seizures. These are far more likely to be en-countered in a primary care setting, and will be themain focus of this review.

Depression in EpilepsyDepression is the most frequently occurring comorbidpsychiatric condition in epilepsy. While patients withepilepsy face many well-documented psychosocial dif-ficulties (work discrimination, driving restrictions, etc)it is a mistake to view depression in epilepsy as a purelyreactive phenomenon.2 The influence of anti-epilepticdrugs (AED) and the neurobiology of epilepsy itselfcontribute to the etiology of depression in these pa-tients. There is a substantially increased risk of suicidefor epileptic patients experiencing depressive disorders(DD).3 Further, impaired quality of life (QOL) inepilepsy is strongly linked to mood disorders, makingrecognition and treatment of depression in these pa-tients especially important.

The incidence of depression in epilepsy far exceedsthe general population and also exceeds patients withchronic illness or other neurological conditions.Depression occurs more frequently in partial epilepsywith a temporal or frontal lobe focus.2 Stigmas associ-ated with mental illness often lead patients to under-report their symptoms. Interictal DD are by far themost common and most likely to require treatment.While interictal DD are common, they frequently donot meet DSM-IV criteria for major depression, oftenleading to lack of recognition. These disorders oftenpresent as a less severe chronic depression with someendogenous depressive features and an intermittent orwaxing and waning course.3 If depressive symptoms aresevere enough to disrupt normal activities, relation-ships, or impair QOL they should be treated.

AED selection may strongly influence the develop-ment of depression in epileptic patients. Barbiturates(i.e. phenobarbital) can cause depression and have beenassociated with suicidal ideation. Other AEDs known

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to be associated with depression include vigabatrin,topiramate, and tiagabine.4 Conversely, carba-mazepine, valproic acid, and lamotrigine have moodstabilizing properties, and their decrease or discontin-uation can be associated with depression.2 A reason-able initial approach is to look at whether the develop-ment of depression is closely associated with a recentchange in AEDs. Maintaining good seizure control isalways clinically a first priority. If it is feasible to de-crease or eliminate an offending agent (i.e. phenobarbi-tol), or restore a favorable drug (i.e. lamotrigine), thisby itself may alleviate depression. When these types ofadjustments in AED therapy are not possible, pro-ceeding with antidepressant treatment is indicated.

When antidepressants are needed, a number of fac-tors guide selection, including proconvulsant proper-ties and drug-drug interactions. Most antidepressants,even tricyclics, can be safely used to treat depression inepilepsy. With careful selection of medication, clini-cians need not be dissuaded from adequately treatingdepression by fear of antidepressant-induced seizures.2

Three antidepressants, clomipramine, bupropion, andmaprotiline should be avoided because of their exces-sive seizure risk.5 Clinically relevant drug interactionsrelate primarily to metabolism of antidepressants andAEDs by cytochrome P-450 (CYP 450) isoenzymes.Several AEDs (phenobarbital, phenytoin, and carba-mazepine) are strong inducers of these enzymes andcan lead to accelerated metabolism of antidepressants.3

For example, serum concentrations of most tricyclicantidepressants can be lowered by concurrent treat-ment with barbiturates or carbamazine.6 Conversely,several selective serotonin reuptake inhibitors (SSRIs),including paroxitene, fluoxetine, and fluvoxamine areinhibitors of one or more CYP 450 enzymes and canlead to elevated or toxic AED levels.3 For example, car-bamazepine levels may be elevated or toxic when con-currently administered with fluvoxamine. More fre-quent monitoring of AED levels may be needed withthe addition of some antidepressants. Many authorsrecommend SSRIs with low metabolic interaction (ser-traline or citalopram) as first line treatment for DD inepilepsy.2

Psychosis in EpilepsyPsychosis in epileptic patients occurs more frequentlythan in the general population.1 Interictal psychosis,often referred to as schizophrenia-like psychosis ofepilepsy (SLPE), is a more common and chronic psy-chotic illness, not temporally related to the occurrenceof seizures.1 Risk factors include temporal lobe focus(left > right), complex partial seizures, early age of

onset of epilepsy, duration of epilepsy greater than 10years, and family history of psychosis.7 Clinicallythese patients often have prominent delusional fea-tures, and visual hallucinations occur more frequentlythan auditory. These patients often show an absenceof the affective blunting, thought disorder, and deteri-oration that often accompanies schizophrenia.1 Unlikeictal or postictal psychoses, interictal psychosis gener-ally requires treatment with antipsychotic medication.With the exception of clozapine, which carries a sig-nificantly elevated seizure risk, the atypical antipsy-chotics can be safely used in these patients.8 In general,patients with a psychotic illness should have a psychi-atric referral.

Anxiety and Pseudoseizures in EpilepsyAnxiety disorders occur far more frequently inepileptic patients than in the general population.Interictal anxiety often presents as typical anxietydisorders such as panic disorder (PD), generalizedanxiety disorder (GAD), obsessive compulsive disor-der (OCD), and post-traumatic stress disorder(PTSD). Panic disorder is particularly common andpresents some difficulties in differential diagnosis.Specifically, panic disorder and temporal lobeepilepsy share many overlapping symptoms, can bedifficult to distinguish, and can co-exist in the samepatient.9 If patients with panic disorder fail standardmanagement (SSRI, alprazolam) psychiatric referralshould be considered. Further, if what appears to bepanic disorder is accompanied by odd or atypical fea-tures (impaired consciousness after attacks, stereo-typed behavior, absence of anticipatory anxiety, oragoraphobia), neurological referral may be helpful. Ingeneral, the SSRIs as a class are effective for theseanxiety disorders, though they have not been studiedsystematically in patients with epilepsy. Potential in-teractions between SSRIs and AEDs are outlined inthe earlier section on depression. Venlafaxine is ap-proved for use in GAD. Benzodiazepines offer fur-ther alternatives (clonazepam approved for PD, al-prazolam approved for PD and GAD) and offer theadvantage of not lowering seizure threshold.9

Pseudoseizures, more correctly termed non-epilepticseizures (NES), are especially challenging, even forspecialists.10 Among patients with epilepsy, up to 10%may also have NES. The diagnosis of NES can bevery difficult, and usually relies on video EEG moni-toring coupled with other observations.11 If NES issuspected clinically, referral to a neurologist with ap-propriate monitoring capability can be essential toconfirm the diagnosis. Once a diagnosis of NES is



confirmed, it is best to refer to a psychiatrist or psy-chologist familiar with the disorder.10

END STAGE RENAL DISEASERates of end stage renal disease (ESRD) have substan-tially increased in recent years. The number of patientsstarting dialysis has doubled since the early 1990s.12

Rates of hospitalization for psychiatric illness are muchhigher in dialysis patients than in the general public.13

Comorbid psychiatric illness is significant in the ESRDpopulation, and successful identification and treatmentcan lead to improved clinical outcomes and QOL forthese patients. Psychiatric problems include depres-sion, organic mental disturbances, substance abuse, andanxiety. Special considerations exist for transplant re-cipients.

Depression in ESRDDepression is the most common comorbid psychiatricdisorder in ESRD patients.12 The impact of depressioncan be significant in these patients and is associatedwith increased rates of peritonitis, hypoalbuminemia,non-compliance, missed dialysis, and overall highermortality.12,14 There can be significant overlap betweensymptoms of depression and renal failure, making thediagnosis more difficult. For example fatigue, anorexia,weight loss, and insomnia are common in both condi-tions. Attention to the cognitive aspects of depression(hopelessness, guilt, low self esteem, suicidal thoughts)can help confirm the diagnosis of depression.15 Someauthors have found the Beck Depression Inventory(BDI) to be a useful tool to screen for depression inESRD patients. Scores of 11 or greater on the BDI areassociated with high rates of clinical depression andwarrant further evaluation and possible treatment.16

The BDI is a 21-item self-rating scale used for measur-ing depression.17

Despite the additional burden of illness associatedwith ESRD, all evidence suggests that these patientsrespond well to treatment for depression. Social sup-port can be extremely important, and correlates withimproved levels of depression. Measures that improvesocial support (i.e. social service consult, home careservices, increased family involvement) can help re-duce depression. Antidepressant medications are safeand effective in these patients as long as a few guide-lines are followed. The SSRIs can be used in doses sim-ilar to the general population. An exception is paroxe-tine, in which dose reductions of 50%-75% arerecommended due to elevated plasma concentrationsthat occur in ESRD.18 A number of the newer non-SSRI antidepressants require caution in ESRD pa-

tients. Venlafaxine is primarily eliminated in the urineleading to reduced clearance in renal disease. Carefuldose adjustments and regular blood pressure monitor-ing are also recommended. Bupropion has activemetabolites that are primarily eliminated through renalexcretion. Nefazodone kinetics in renal disease is notwell understood.19 Tricyclic antidepressants (TCA) areeffective in ESRD, but should be considered secondline agents due to their cardiac, sedative, and anti-cholinergic properties. Depression that is severe, asso-ciated with suicidal ideation or psychosis, or fails torespond to reasonable treatment should have psychi-atric referral.

Organic Mental Disorders in ESRDRenal failure patients are at increased risk for delir-ium and dementia, and these conditions are fre-quently responsible for hospitalization.19 Higher ratesof dementia are due mainly to vascular disease in thispopulation. Optimizing treatment for concurrentconditions associated with cerebrovascular disease(hypertension, diabetes, arrhythmia, and co-aguopathies) can improve prospects for preservingcognition. Specific medications for treatment of pri-mary degenerative dementia (cholinesterase in-hibitors, NDMA antagonists) are available, but theiruse and pharmacokinetics have not been systemati-cally evaluated in ESRD. Features that distinguishdelirium from dementia include a fluctuating course,impaired sensorium, and reversibility when the of-fending cause is treated. Common causes of deliriumin renal failure include uremia, electrolyte disorders(especially hypercalcemia), and drug effects due toimpaired renal clearance (morphine, metoclopromide,illicit drugs). For management of acute agitation inthese patients, oral or parenteral haloperidol remainsa common drug of choice.19

Alcohol and Drug Abuse in ESRD The substance abuse rate among some dialysis popula-tions is extremely high. Alcoholism in urban hemodi-alis groups exceeds 25% in some reports.20 Heroin andcocaine use can lead to renal failure through specificdrug-induced nephropathies.21 Illicit drug use in thesepatients frequently continues once formal dialysis hasbegun. Many clinicians struggle to provide care forwhat is clearly a difficult population. The impact of se-rious substance abuse in these patients, and its appro-priate treatment, is not well studied. Even basic ques-tions such as the effect this has on compliance needmuch further study. Efforts should be made to get pa-tients into traditional drug and alcohol treatment pro-grams.

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Anxiety and Insomnia in ESRDAnxiety is common in patients with renal disease andcan range in severity from mild situational anxiety tofrank panic disorder. Mild anxiety is best handled withreassurance and by addressing any underlying causes.More severe anxiety may be seen in relation to dialysistreatments. Rapid shifts in fluids and electrolytes canlead to nausea, vomiting, hypotension, and musclecramps, and may be associated with significant anxi-ety.22 Standard doses of benzodiazepines given beforeor during dialysis are often effective. Because they aremetabolized in the liver, dose reduction of benzodi-azepines is usually not necessary. Busparone, com-monly used for more chronic anxiety, must be carefullyused in ESRD due to prolonged half-life in these pa-tients.19 For more sustained or severe anxiety (panic dis-order, generalized anxiety, social phobia) SSRIs may beused in doses similar to those used to treat depression(see depression section). Insomnia is common in pa-tients with renal failure, and may be related to suchproblems as muscle cramps, restless leg syndrome, andpain associated with peripheral neuropathy.19 Successfultreatment of these conditions may alleviate insomnia.Attention to sleep hygiene, regular exercise, and elimi-nating daytime napping can improve sleep withoutsedative hypnotics. If necessary, sleep medications(zolpidem, temazepam) can be used on a short-termbasis without dose reduction. With more chronic in-somnia, or when substance abuse is a concern, sedatingantidepressants (trazadone, mirtazepine) can be veryeffective sleep aids.

Renal TransplantationWhile renal transplant improves life expectancy andoverall QOL, comorbid psychiatric disorders, espe-cially depression and anxiety, remain high. Depressionin renal transplant recipients is associated with in-creased risk of rejection, return to dialysis, and deathby suicide.23 Psychotherapy has been shown to improveoverall emotional states and to decrease levels of depression in transplant patients.24 Selection of psy-chotropic medications is mainly limited by drug inter-actions with cyclosporine and tacromalus. Antidepres-sants nefazodone and fluvoxamine can lead to toxiclevels of these drugs and should be avoided.25 Mostother antidepressants and anxiolytics can be used safelyfollowing renal transplant. Finally, neuropsychiatric ef-fects of commonly used transplant medications need tobe considered. Corti-costeroids, such as prednisone,are associated with a wide variety of symptoms rangingfrom simple anxiety and depression to delirium and

mania. Tacrolimus and cyclosporine are associated withanxiety, insomnia, disorientation, and psychosis.

CONCLUSIONComorbid psychiatric disorders of a wide variety occurin epilepsy and renal disease to a much greater degreethan healthy populations. Each of these disorders hasspecial conditions (drug-drug interactions, effect ofconcurrent medications, etc.) that need to be taken intoaccount before initiating treatment. Primary carephysicians can play an important role by recognizingthese co-morbid disorders, initiating treatment, and re-ferring when necessary.

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