Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases

Abstract

INTRODUCTION Chronic kidney disease (CKD) is a common public health problem involving all ages and significantly affects the body’s overall homeostasis. It involves almost all organ systems and causes significant impairment in the quality of life. CKD is commonly caused by diabetes mellitus, hypertension, tubulointerstitial diseases, glomerulonephritis, polycystic kidney diseases, obstructive uropathy, and congenital malformations of the kidney. In CKD, there is a progressive decline in kidney function. CKD often present with appetite loss, nausea, vomiting, easy fatigability, lethargy, muscle cramps, edema of the extremities, itching, disturbed sleep, increase in blood pressure, dyspnea, chest pain, alteration of urine output. There are five stages of CKD, and a significant number of cases do reach the advanced stage of CKD called end-stage renal disease (ESRD). At this stage, patients need renal replacement therapy (RRT), maintenance dialysis (peritoneal and/or hemodialysis), and/or renal transplantation (RT). As CKD affects the individual’s functioning and produces significant disability, patients go through psychological distress. Evidence support that psychiatric comorbidities are common among patients with CKD.[1] The presence of psychiatric comorbidities in CKD affects the outcome of renal diseases as due to psychiatric comorbidity, these patients’ help-seeking behavior, lifestyle, and medication adherence becomes poor, which attribute to poor outcomes. The psychiatric comorbidities associated with CKD are summarized in Table 1.Table 1: Psychiatric comorbidities associated with chronic kidney diseasePatients with CKD often present with various psychiatric disorders. The psychiatric disorders commonly seen in patients with renal diseases are depression, anxiety disorders, and delirium.[4] Patients with ESRD go through enormous distress due to their compromised health, dependence on others, regular, frequent dialysis, continued cost of treatment, the uncertainty of renal transplant, which increases their vulnerability for mental illness. Metabolic derangements (electrolyte imbalance), anemia, renal bone disease, and hypertension associated with renal diseases also contribute to psychiatric morbidities such as depression and anxiety.[4] Similarly, several medications such as amantadine, aspirin, ciprofloxacin, steroids, phenytoin may contribute to the development of psychiatric manifestations ranging from anxiety, depression, insomnia to psychosis and delirium.[4] The use of these medications (whenever indicated) in patients with CKD and RRT needs absolute caution. Evidence supports that comorbid depression adversely affects the attitude toward medication compliance and compromises sleep quality.[5] Similarly, research suggests that patients with ESRD undergoing peritoneal dialysis and hemodialysis have deficits in cognitive function compared to the general population.[67] The deficits in cognition are evident in the domains of attention, concentration, orientation, and executive functions.[7] Similarly, reduced serum albumin level in patients with dialysis is associated with a decline in delayed memory, visuospatial skills, language ability, and general cognitive function.[6] This paper focuses on the management of psychiatric disorders in CKD with a specific focus on pharmacological management. Prescribing treatments to patients with renal diseases and those with RRT need certain careful considerations [Table 2].Table 2: Considerations while prescribing psychotropic medications in patients with renal diseases and those with renal replacement therapyRENAL PHYSIOLOGY RELEVANT FOR PSYCHIATRY Optimal renal function is required for maintaining homeostasis in the body. Renal function is required for the excretion of waste products from the body. Glomerular filtration rate (GFR) gives an estimation of renal function. GFR can be measured by checking ideal filtration markers, creatinine clearance, and Cystatin C protein.[8] Creatinine clearance test is considered as a marker of renal functioning. In a normally functioning kidney, the creatinine clearance is >60 ml/min; but, there are variations in the normal value of GFR among males and females (males >females), across different age groups and among different races.[910] Due to the cumbersome nature of the measurement of GFR, GFR is now more commonly estimated by using various formulas, which have been validated in many ethnic groups. The two most commonly used formulas for estimated GFR (eGFR) are modification of diet in renal disease and CKD-epidemiology collaboration (CKD-EPI).[1112] The severity of renal disease is broadly classified into five stages based on GFR; stage 1-eGFR ≥90 ml, stage 2-60-89 ml/min, stage 3-30-59 ml/min, stage 4-15-29 ml/min and stage 5-<15 ml/min.[13] In renal diseases, the protein binding ability of the psychotropic medications is decreased. As the unbound (free) forms of medications are responsible for the therapeutic effect and side effects, there is a need for dose adjustment in renal diseases, depending on the decrease in renal function.[9] Renal diseases also cause impairment in the excretion of certain psychotropic drugs and their metabolites that have renal excretion.[8] The formula for estimating the GFR[12] are as follows: The modification of diet in renal disease formula GFR (mL/min/1.73 m2) =175× (Scr)-1.154× (Age)-0.203× (0.742 if female) × (1.212 if African American) The chronic kidney disease-epidemiology collaboration formula GFR = 141× min (Scr/k, 1) a × max (Scr/k, 1)-1.209 × 0.993 age ×1.018 [if female] × 1.159 [if black] where: Scr: Serum creatinine in mg/dL, k: 0.7 (for females); 0.9 (for males) a:-0.329 (for females);-0.411 (for males) Min: Minimum of Scr/k or 1 Max: Maximum of Scr/k or 1 ASSESSMENT OF PSYCHIATRIC DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY Patients with CKD and RRT having psychiatric illnesses need to be assessed thoroughly. A thorough history taking is required in patients with CKD and RRT, who have a psychiatric illness. It is important to explore about the duration of illness, nature of psychopathology, severity of psychopathology, associated psychosocial issues (if any), medical comorbidities including CKD and RRT, drug history, degree of adherence to treatment, any side effects to medications, and response to treatment. Detailed physical examination (general and systemic) and appropriate investigations for medical condition (particularly kidney disease: Renal function test, GFR, urine routine and microscopic examination, serum electrolytes, serum albumin, 24-hour urine protein, and ultrasonogram of abdomen to see kidney size) and psychiatric condition (serum B12, folate, Vitamin D3 level, serum lithium [if the patient is receiving lithium], etc.) need to be done. It is important to take information about the medications prescribed for medical condition, as there is a possibility of drug-drug interaction with psychotropic medications. Figure 1 demonstrates the sequential clinical assessment that is relevant for considering appropriate psychotropic medications.Figure 1: Flow diagram showing assessment of patients with psychiatric illnesses with renal diseasesPSYCHIATRIC DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY Psychiatric disorders are commonly seen in patients with CKD, on dialysis, and renal transplants [Table 3].Table 3: Common psychiatric disorders in patients with chronic kidney disease and renal replacement therapyPrescribing antipsychotic drugs in patients with chronic kidney disease and renal replacement therapy Antipsychotic medications are the mainstay treatment modality for the management of psychosis. Although the kidney excretes few first-generation antipsychotic medications as inactive metabolites, most first-generation antipsychotics are safe in CKD and do not require dose adjustment.[9] Among the first-generation antipsychotic medications, haloperidol is safest. The phenothiazine group of antipsychotic medication increases the risk of hypotension in patients with CKD.[9] Similarly, most second-generation (atypical) antipsychotic medications are also considered safe in renal diseases as most of them are metabolized in the liver.[9] Among the atypical antipsychotics, paliperidone is excreted by the kidney in unchanged form, whereas olanzapine, risperidone, quetiapine, clozapine, and iloperidone are excreted by the kidney as their metabolites.[9] Amisulpride needs to be avoided in ESRD.[8] There is little evidence regarding any risk of worsening renal impairment or toxicity due to the metabolite with the use of aripiprazole in patients with CKD. However, it is recommended to avoid using depot preparations of aripiprazole in ESRD.[8] No evidence suggests dose reduction of asenapine till severe renal impairment; however, the use of asenapine in ESRD is poorly studied, hence better to be avoided in this condition[8] Most antipsychotic medications are safe in mild-to-moderate renal dysfunction. Dose adjustment may be required in severe to ESRD.[9] Caution needs to be exercised while using antipsychotic medications such as chlorpromazine, clozapine, flupentixol, haloperidol, lurasidone, olanzapine, risperidone, quetiapine, paliperidone, ziprasidone, pimozide, trifluoperazine, and zuclopenthixol.[8] In renal impairments, long-acting (depot) preparations of all typical and atypical antipsychotic medications need to be avoided.[8] Some evidence supports that severe mental illnesses (e.g., schizophrenia and bipolar affective disorder) increase CKD risk, and the antipsychotic medications and mood-stabilizing anticonvulsants also increase the chance of renal impairment.[8] Hence, adequate caution needs to be exercised while treating these patients. Prescribing anticholinergic drugs in patients with chronic kidney disease and renal replacement therapy Patients with psychotic illnesses receiving antipsychotic medications often have extrapyramidal side effects. Anticholinergic medications such as trihexyphenidyl and procyclidine are commonly used for the treatment of extrapyramidal side effects. However, using these anticholinergic medications may cause urinary retention and need to be avoided in conditions with obstructive genitourinary conditions.[14] Prescribing antidepressant drugs in patients with chronic kidney disease and renal replacement therapy Patients with renal diseases with depression need to be treated with special precaution. Antidepressant treatment, psychotherapy, and somatic treatments are commonly used in the treatment of depression. Cognitive behavior therapy (CBT) is a commonly practiced and evidence-based psychological treatment for the management of depression. A recent meta-analysis supports the efficacy of CBT in the management of depression in patients with renal diseases on dialysis.[15] Antidepressant medications are often metabolized in the liver and excreted by the kidney.[9] Among the selective serotonin reuptake inhibitors, fluoxetine level remains unchanged irrespective of the severity of renal impairment, whereas paroxetine concentration goes high in patients with severe renal impairment requiring dose adjustment.[9] Citalopram use increases the risk of sudden cardiac arrest when used in patients undergoing hemodialysis. The risk is significantly higher in comparison to other selective serotonin reuptake inhibitors.[8] Among the serotonin-norepinephrine reuptake inhibitors, venlafaxine and desvenlafaxine excretion are affected by renal impairment. In severe renal impairment, the plasma concentration of these medications may increase up to 50%; hence, there is a need for dose reduction.[9] However, duloxetine is safe in mild-to-moderate renal impairment. Severe renal impairment increases the blood level of duloxetine multi-folds requiring dose reduction.[9] Although the safety profile is acceptable for tricyclic antidepressants, monoamine oxidase inhibitors and bupropion in mild to moderate renal diseases, dose reduction, and slow titration is required for severe renal impairment.[9] Approximately three-fourth of the mirtazapine is excreted by kidneys in unchanged form, and renal impairment causes a decrease in the excretion of the drug, increasing plasma concentration.[8] Therefore, dose reduction is required in CKD. Vortioxetine is safe in renal disorders as the existing evidence suggests that it is minimally excreted by the kidney; however, caution needs to be followed during its use in patients with ESRD.[8] Vortioxetine is a new molecule and requires extensive research for safety. Hence, the clinician should exercise adequate caution and need to be watchful for all possible side effects, while recommending vortioxetine in patients with CKD and RRT. Tricyclic antidepressants such as amitriptyline, nortriptyline, imipramine, clomipramine, due to their anticholinergic property, may cause urinary retention, postural hypotension, sedation, and confusion like state.[8] Agomelatine has negligible renal excretion, so believed to be safe in early renal diseases; however, caution needs to be exercised in moderate to severe renal impairments.[8] Likewise, caution needs to be exercised while using dosulepin (Dothiepin) as the majority of the active metabolites of the drug are excreted through the kidney, and renal impairment causes accumulation of the metabolites resulting in excess sedation.[8] Therefore, it has been recommended that patients with GFR <20 ml/min need to be given low doses with slow escalation.[8] Trazodone also needs to be used in low doses to manage depression in patients with CKD.[8] Prescribing mood stabilizers in patients with chronic kidney disease and renal replacement therapy Mood stabilizers are the mainstay of treatment in the management of bipolar affective disorder. Mood stabilizers that are effective in managing manic episodes are lithium, valproate, carbamazepine, and oxcarbazepine, whereas for the management of depressive episodes in bipolar affective disorder, lithium and lamotrigine are found to be useful. There is a need for dose adjustment for lithium in mild-to-moderate renal impairment. Lithium use needs to be avoided, preferably in patients with severe renal diseases and ESRD.[9] Lithium is also known to produce renal disease, primarily tubulointerstitial damage. Therefore, patients receiving lithium treatment need to be regularly monitored for serum lithium levels and renal function tests in regular intervals. Valproate (or Valproic acid) is a commonly used antiepileptic medication, which also has significant mood-stabilizing properties.[16] However, valproate needs to be used cautiously in patients with renal impairment and urea cycle disorders.[1617] Evidence suggests that valproate may cause renal tubular injury and Fanconi’s syndrome.[17] Lamotrigine is another mood stabilizer commonly recommended in the management of bipolar depression. Inactive metabolites of lamotrigine are excreted by the kidney; hence there is no need for dose adjustment.[9] The data regarding the use of lamotrigine in severe renal diseases and ESRD are sparse. Dose titration may be required in such a group of patients and patients on dialysis.[9] Oxcarbazepine is metabolized by glucuronidation. Its subsequent metabolites are excreted through the kidney. Mild to moderate renal impairment does not require dose adjustment for oxcarbazepine; however, for severe renal impairment and ESRD, dose reduction of oxcarbazepine (maybe by 50% of the recommended dose) is required.[9] Prescribing anxiolytic drugs (benzodiazepines and nonbenzodiazepine anxiolytics) in patients with chronic kidney disease and renal replacement therapy Anxiety is a common comorbidity among patients with CKD, patients on dialysis, and following renal transplant. Persistent anxiety that is significantly impairing and lasts beyond a specific time period is considered an anxiety disorder. Various pharmacological and non-pharmacological treatment options are considered in patients with anxiety disorders. Among the pharmacological treatment options, antidepressants, benzodiazepines, beta-blockers, and buspirone are commonly used.[18] The active metabolites of buspirone are excreted by the kidney. In mild-to-moderate renal impairment, it should be started in a low dose with slow escalation; but, it needs to be avoided in severe renal impairment.[8] Among the benzodiazepines, chlordiazepoxide, diazepam, clonazepam, lorazepam, nitrazepam, oxazepam need to be used with caution as their active metabolite may accumulate in renal impairment, causing excessive sedation.[8] Gabapentin and pregabalin are excreted by the kidney in unchanged form; hence, dose reduction is required in renal impairment.[8] Promethazine is an with anxiolytic Therefore, it needs to be used with caution as it may produce excessive in renal impairment.[8] Antidepressant medications are commonly used in the management of anxiety disorders. The that to be exercised have been in the on the treatment of mood disorders in renal impairment Prescribing drugs in patients with chronic kidney disease and renal replacement therapy disorders like are commonly seen in the disease is a common in the with such as and are commonly used in patients with is an drug also used in the treatment of The commonly used medication, is excreted by the kidney in unchanged form; however, its clearance is not affected in renal impairment.[8] excreted by the kidney, Dose reduction is recommended beyond severe renal impairment.[8] ESRD is a for the use of It has been recommended to with a low dose and go slow to use and to manage in CKD.[8] Prescribing drugs used in management in patients with chronic kidney disease and renal replacement therapy Patients with CKD may have comorbid use disorders. like and are used in the management of use disorder. the mainstay of treatment of of is used as a in the management of use disorder. Similarly, and are commonly used in the management of use disorders. is used as a treatment modality for an is used as an for The regarding the use of bupropion and have been in this The kidney excretes in an unchanged However, CKD may cause impairment of excretion of and an increase in its plasma Therefore, may be used in doses for patients with mild to moderate renal impairment and avoided in severe renal and moderate renal impairment, the recommended dose of is in a has an important in the management of use and use disorder. The kidney excretes and its There is a of adequate on in severe renal impairment; however, caution needs to be while prescribing in severe renal impairment and is primarily metabolized and excreted by the There is no alteration of of in patients on hemodialysis. Hence, dose alteration of is not required in patients with CKD, irrespective of their and its metabolites are excreted by the kidney to However, the safety of use among patients with renal impairment is not Hence, it is recommended to use cautiously in renal impairment patients. It is to with a low dose and with frequent The of in CKD is not It has been for dose reduction of in renal impairment. Dose reduction is required more as the severity of renal impairment Similarly, dose reduction is also recommended for used to manage use with renal Prescribing drugs in the management of psychiatric disorders in patients with chronic kidney disease and renal replacement therapy and are also affected by CKD. psychiatric disorders such as disorder, are commonly an early age and The pharmacological management in disorder, and has a is recommended for the and behavior due to the condition, mood antipsychotic medications, or antidepressant medications are The to these medications in CKD has been in the The of low and go slow should be followed with regular for the side effects. Patients with are often treated with like and No data is regarding the use of and in CKD and patients on However, caution be exercised with for side effects when these medications are given in severe renal impairment and no dose adjustment is for the use of in CKD, adequate caution be while prescribing it to patients on The kidney excretes the metabolites of and use of is recommended in treating in Prescribing and drugs in patients with chronic kidney disease and renal replacement therapy are common among patients with CKD. benzodiazepines, tricyclic antidepressants, and are used to needs to be exercised while using benzodiazepines, tricyclic antidepressants, and mirtazapine in patients with CKD, as antidepressant and anxiolytic The kidney minimally excretes and no dose adjustment is Similarly, the clearance of is reduced for dose reduction is not required in patients with renal impairment.[8] Prescribing drugs used in the management of disorders in patients with chronic kidney disease and renal replacement therapy with CKD may have like and dysfunction. serotonin reuptake inhibitors are commonly used in the treatment of need to be exercised the mood while using selective serotonin reuptake for inhibitors like and are used in the management of dysfunction. is to be used with caution in patients with renal impairment. Severe renal impairment a dose reduction of A low dose may be considered the dose of for in severe renal evidence is poor it to be a However, a recent suggests the safety of in treating in ESRD patients undergoing Hence, caution and dose reduction need to be while using in CKD those with Similarly, and other psychological treatment need to be for patients to their more on OF IN RENAL REPLACEMENT THERAPY There is with to patients on RRT, which Patients for RRT or who RRT have ESRD Patients who renal on Patients with renal transplants like and Patients receiving need to avoid monoamine oxidase inhibitors and tricyclic In selective serotonin reuptake inhibitors and selective serotonin and reuptake inhibitors need to be used with caution as drugs like and the in the liver and increase the plasma level of inhibitors like and safe to use in patients are and Valproate and are the The use of these medications the concentration of and which can increase the risk of drugs such as and also found to and the of The use of with antipsychotic medication increases the risk of blood of the safety of common psychotropic medications in CKD is in Table of safety of common psychotropic medications in chronic kidney AND OF urinary diseases diseases of the and is a common of the in the by the medications such as antipsychotics (e.g., chlorpromazine, antidepressants (e.g., tricyclic antidepressants, anticholinergic (e.g., and anticonvulsants have the to cause urinary The psychotropic medications to be used in olanzapine, aripiprazole desvenlafaxine Mood valproate, carbamazepine, OF CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY general have been prescribed while using psychotropic medications in patients with renal diseases and Table the for psychotropic use in chronic kidney to these general patients on dialysis may need of drugs dialysis for drugs which are This is of the of this However, treating should for specific drugs for a of peritoneal dialysis, or RRT and drugs if Figure the safety profile of various psychotropic medications in various stages of 2: profile of common psychotropic medications in various stages of chronic kidney A the and is required to better the patients of renal diseases with mental health The use of non-pharmacological like behavior and somatic treatments like and may be in patients with chronic renal diseases and those with RRT. Similarly, the clinician needs to the of the psychotropic medications with the used in patients with renal The of appropriate psychotropic in appropriate doses in patients with CKD and RRT the and the support and of There are no of

Topics & Concepts