Transplant Psychiatry: Issues for Clinicians

Table 1

Table 2

Table 3

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The downside of success is that demand for organ transplants has risen substantially but the number of donors has not kept pace. As of July 25, 2014, there were 134,290 patients in the US waiting for organs, yet the number of donors in 2013 was only 14,257 (8268 were deceased and 5989 were living).¹

Role of the transplant psychiatrist

Transplant psychiatrists screen for absolute and relative psychiatric contraindications and treat psychological conditions before (eg, anxiety, depression) and after (eg, delirium, PTSD) transplant. They also provide assessments of both transplant and donor candidates to determine capacity to consent to the surgery, recent stressors and coping skills, social supports and availability of caregivers, and whether there are psychological or substance abuse issues that would affect outcomes.

Education and support of both patients and family members are also part of the process during the evaluation, waiting, and postoperative periods. Candidates for transplant may have behavioral problems that predisposed them to the illness, such as alcohol or drug addiction, smoking, or (more recently) eating disorders with morbid obesity that has resulted in a surge of nonalcoholic steatohepatitis.

Recent research trends

There has been increasing interest in whether psychiatric factors predict survival and quality of life after transplant. Findings from Baranyi and colleagues² indicate that patients who had poorer psychosocial functioning as measured by the Transplant Evaluation Rating Scale (TERS) before transplant, had more total mental distress on the Global Severity Index of the Symptom Checklist-90-Revised (SCL-90-R) and decreased health-related quality of life as measured by the 36-Item Short Form Health Survey (SF-36) after transplant. However, Abbey and colleauges³ have found that selfreported questionnaires may underestimate distress that is otherwise apparent in face-to-face qualitative interviews. Only about 20% of heart transplant recipients reported poor quality of life on self-report questionnaires, but 52% showed pervasive distress by visual methodology.

Research findings suggest that psychiatric diagnoses, such as depression, may be risk factors for nonadherence to immunosuppressive drugs, morbidity, and mortality after transplant and may be associated with infection, organ rejection, and malignancies.^4,5 The risk of posttraumatic stress symptoms after solid organ transplant was seen in 15.5% of recipients and was associated with age, long-term benzodiazepine use, preexisting psychiatric comorbidity, history of retransplant, and type of transplant.⁶

Personality traits have been investigated in heart transplant recipients. The results showed a significant association between optimism and a better quality of life, although scores on the optimism-pessimism scale did not correlate with duration of survival.⁷ Candidates with mental retardation have been assessed and have had good outcomes with organ transplant if they are in stable living situations with family members or caregivers who ensure adherence to immunosuppressive therapy and follow-up care.⁸

Patients with psychotic disorders are presenting more often for evaluation. Evidence has shown that living alone and more recent psychotic symptoms may predict both poor outcomes because of lapses in adherence to immunosuppressive drugs and suicide.^9,10 However, transplant candidates with stable bipolar disorder or schizophrenia may do well if they have strong family support and social stability. Patients with suicidal behavior who present for transplant evaluation after an overdose of acetaminophen may be acceptable candidates depending on psychiatric diagnoses and history.¹¹

Trajectories of patients after organ transplant have been investigated for anxiety, depression, and alcohol use as well as for quality of life. Dew and colleagues¹² provided the first prospective data on anxiety and depression in lung transplant recipients. They report that in the first 2 years after transplant, the rates of panic disorder were higher in patients who received lungs than in those who received hearts (18% vs 8%). There was no significant difference in the rates of generalized anxiety disorder (4% vs 3%), transplantassociated PTSD (15% vs 14%), and MDD (30% vs 26%). Risk factors for affective or anxiety disorders included avoidant coping, female sex, poor caregiver support and psychiatric history before transplant, longer waiting time for an organ, and early health problems after transplant.

Dew and colleagues also investigated early trajectories of depressive symptoms in liver transplant recipients; they found 3 trajectories in the first year after transplant: survival at 10 years was 43% for the high depression group, 46% for the increasing depression group, and 66% for the low depression group. Whether long-term survival could be affected by treatment remains an area for research.

Little long-term systematic follow-up has been done for composite organ transplant recipients because of the small number of limb transplants being done. Systematic follow-up is rare in facial transplant but has been done for the past 5 years, with good outcomes. The question of whether the risks of long-term immunosuppression are justified by improved psychological well-being and quality of life in composite transplant recipients can only be answered by standardized data collection.

In efforts to standardize patient selection, several instruments have been used, including the Psychosocial Assessment of Candidates for Transplantation (PACT), the TERS, and more recently, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT).^13-15 Although specific for transplant, these instruments are not universally used because they are time-consuming and include information generally obtained in the transplant psychiatric evaluation. Initial assertions that the SIPAT predicts outcomes have been questioned when applied to organ transplants other than liver transplant. These instruments were proposed to provide a standardized psychosocial assessment format and may be used as shorthand by some teams who have informal cutoff scores. Other teams do not use these instruments at all.

Psychotropic drugs in the transplant setting

Antidepressants. Many patients referred for transplant have preexisting depression, so they may be taking antidepressants at the time of referral. In other patients, depression may develop during the workup, while waiting for the organ if the wait is prolonged, or after transplant because corticosteroids can foster mood changes.

Certain antidepressants, such as mirtazapine, may be used to promote weight gain or sleep in patients awaiting transplant or in the postoperative period. In general, the main interactions are between antidepressants and the calcineurin inhibitors (CNIs): cyclosporine, sirolimus, and tacrolimus via cytochrome P-450 (CYP) 3A4, particularly with desmethylvenlafaxine (alone or as a metabolite of venlafaxine), fluvoxamine, and nefazodone (Table 1). There have been a few cases of serotonin syndrome with venlafaxine and cyclosporine or tacrolimus.¹⁶ Fluoxetine does not generally interact with CNIs.

Citalopram or escitalopram oral concentrate can be useful for patients with short-bowel syndrome before small-bowel transplant, as can mirtazapine orally disintegrating tablets. Sertraline also has a liquid preparation, but it often causes GI upset and occasionally diarrhea, which resulted in rejection in a renal transplant patient (personal observation). In patients with poor renal function, the dosage of sertraline may need to be lowered because the half-life may be prolonged.

Neurotoxicity of CNIs includes akinetic mutism, ataxia, confusion, dysarthria, grand mal seizures (especially in posterior reversible encephalopathy syndrome), and even paralysis. Switching to another CNI drug may alleviate the symptoms that can occur even at low dosages.

Anxiolytics. Many patients may have anxiety during the assessment period and particularly during the waiting period after being listed. This is an especially stressful time because of the shortage of organs and the uncertainty of whether an organ will be available in time. If patients have rejection after transplant or repeated hospitalizations with complications, an anxiolytic may be useful (Table 2).

Although buspirone can be useful, especially in ventilator-dependent patients after lung transplant because of the lack of respiratory depression, mean plasma levels may be affected by itraconazole (13-fold). This can affect cognitive function on the Digit Symbol Substitution Test and increase drug adverse effects. Itraconazole is both a CYP3A4 and P-glycoprotein inhibitor, and like other triazole antifungals (ketoconazole, posaconazole), it may interact with various psychotropic agents. CYP3A4 inhibitors can also modestly affect plasma concentrations of oral alprazolam, diazepam, midazolam, and triazolam. Lorazepam is only mildly affected by liver or renal dysfunction.

Special caution is required when using benzodiazepines in patients with chronic obstructive pulmonary disease, because doses of alprazolam above 0.125 mg or clonazepam or lorazepam above 0.25 mg can result in carbon dioxide retention and a Pco2 of 80 mm Hg or even higher and consequent intubation. For panic attacks, SSRIs are preferred to benzodiazepines. Buspirone is generally safer than benzodiazepines for patients who have anxiety (personal observation).

Mood stabilizers. More patients with bipolar spectrum disorders are being referred for transplant; therefore, drug-drug interactions between mood stabilizers and immunosuppressants are becoming more important to consider (Table 3). The use of lithium in transplant patients who are receiving a CNI requires very close monitoring. For example, the dosage required for a therapeutic level of lithium may drop from 600 mg twice daily to as low as 150 mg daily, especially in the elderly with limited glomerular filtration. Lithium can cause leukocytosis, which may confuse the picture in transplant patients because corticosteroid boluses, yeast infection, and tuberculosis can also cause leukocytosis.

Carbamazepine, phenobarbital, and valproate are potent CYP3A4 inducers and can affect the levels of immunosuppressive drugs. In 3 kidney recipients who were receiving mycophenolate, valproate decreased the area under the curve (AUC) by 54% for mycophenolate; when valproate was discontinued, the AUC for mycophenolate increased 1.8- to 2.2-fold.^17,18 Less potent CYP3A4 inducers include other barbiturates, modafinil, oxcarbazepine, and topiramate. Many of the anticonvulsant mood stabilizers are significantly affected by renal clearance for elimination, such as lamotrigine and oxcarbazepine. Others are significantly cleared via dialysis, such as valproate, which may increase risk of seizures.

Antipsychotics. Use of antipsychotics bears caution, since those drugs prolong QTc. In particular, because of CNIs, ziprasidone can potentially prolong QTc, so synergistic effects with antipsychotic drugs are of concern following transplant. Aripiprazole is useful because it generally shortens QTc by 80 milliseconds. Moreover, it does not require dosage adjustment in renal or hepatic failure, whereas risperidone requires a 50% dose reduction in renal failure. Lurasidone also does not require dose adjustment for hepatic or renal impairment, but it is mainly metabolized via CYP3A4, so it could interact with the CNIs. There is evidence that risperidone is metabolized via CYP2D6 and that CYP3A4 is also a significant pathway for risperidone metabolism.¹⁹ Oral risperidone is about twice as strong as oral paliperidone. Drug-drug interaction information with paliperidone is limited, but it appears to be primarily excreted renally (roughly 80%).

Many newer antipsychotic drugs are metabolized through CYP3A4, including aripiprazole, perospirone, quetiapine, risperidone, sertindole, ziprasidone, and zotepine. Pharmacokinetics of some drugs (eg, olanzapine, quetiapine, risperidone, paliperidone, ziprasidone) are not significantly affected by hepatic impairment. Neither amisulpride nor ziprasidone is affected by aging, but amisulpride’s half-life is increased and clearance is decreased in renal failure.

Quetiapine is often used for delirium in intensive care settings after transplant and is not thought to be a substrate for P-glycoprotein, unlike other atypical antipsychotics. Olanzapine orally disintegrating tablets may help with appetite if mirtazapine is contraindicated. Asenapine also is available in sublingual tablets and may cause less weight gain than olanzapine, although it can cause orthostatic blood pressure changes and has similar effects on prolactin. Asenapine has some drawbacks: it is dosed twice daily, is inactive if swallowed, and requires no oral ingestion of food or liquids for 10 minutes after dosing. There is no independent verification of its efficacy or safety aside from the manufacturer’s reports.²⁰

Clozapine is contraindicated with mycophenolate mofetil because of the increased potential for agranulocytosis. Leukopenia may be caused by carbamazepine; it is also seen with cytomegalovirus infection in transplant recipients. Use of herbal medications is generally discouraged for transplant patients. Use of St John’s wort in depression may drop CNI levels by 50%, increasing the risk of rejection.²¹ Herbs that contain salicylates, such as Arnica montana, can cause stomach erosions in patients receiving prednisone (personal observation).

Conclusion

Organ transplant may one day be replaced by new technologies, including bioartificial devices, 3-D printing of organs, xenografting, and perhaps even growing replacement organs using the patient’s own stem cells. However, as technology expands, the need will also grow for development of the ethical underpinnings and understanding of the psychological effects of this technology on the recipients.

The upswing in referral of patients with bipolar disorder and schizophrenia as well as those with eating disorders and nonalcoholic steatohepatitis and cirrhosis requires careful psychosocial evaluation. Comprehensive psychiatric assessment for patient selection and follow-up to provide continuity of care remain essential for long-term patient and graft survival. Future directions for research include long-term psychological factors that determine outcomes across the various organ transplant types.

Disclosures:

Dr Coffman is staff psychiatrist in the department of psychiatry and psychology at the Cleveland Clinic in Ohio. She reports no conflicts of interest concerning the subject matter of this article.

References:

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