Psychiatric Aspects of Organ Transplantation

A range of psychotherapeutic and behavioral interventions have been developed specifically for solid organ transplant candidates and recipients and tested empirically. Most psychotherapeutic interventions target patients and their families during the waiting period because it is typically one of the most psychologically and physically stressful periods of the entire transplant experience (4). Interventions that focus on managing the emotional demands of waiting for the transplant while also dealing with the symptoms of advanced organ disease are most effective. Quality of Life Therapy (QOLT) is a cognitive-behavioral intervention that targets the areas of life (e.g., relationships, goals, self-esteem) the patient identifies as essential for his/her happiness and overall life satisfaction but are currently compromised (5). QOLT produced improvements in quality of life, psychological distress, and social intimacy in lung (6) and kidney (7) candidates who received weekly sessions over 8–15 weeks. Notably, caregivers of candidates receiving QOLT experienced vicarious improvements in quality of life, mood and social intimacy (8); this is an important benefit of QOLT given that candidates’ perceptions of social support have been found to decrease after waiting times greater than 3 months (9). Coping skills training and similar cognitive-behavioral therapies tailored to transplant specific needs also offer benefits for quality of life, anxiety and depressive symptoms, and perceived social support (10, 11).

Although many transplant centers offer supportive services to patients and their families during the waiting period and immediately posttransplant, psychiatrists on the transplant team have an opportunity to further optimize patients’ psychological outcomes by using these evidence-based psychotherapies. Remote intervention delivery is a viable option, and evidence supports the feasibility and efficacy of telephone-based (6, 10, 11) and web-based (12) programs. This may be a solution to the logistical challenges of delivering regular psychotherapy when many transplant patients live hundreds of miles from the transplant center and are unable to travel due to their deteriorating health.

Complementary and alternative therapies have also shown promise as strategies to improve sleep quality and duration. Sleep is a common problem for transplant patients, due to both their underlying disease and chronic immunosuppression (13) and the effects of poor sleep can carry over into mental health and well-being. Transplant recipients who participated in an 8-week mindfulness-based stress reduction program experienced improvements in quality of life and quality of sleep and decreases in anxiety and depression symptoms that were sustained up to 1 year (14, 15).

Lastly, exercise interventions have received attention because of their direct benefits on physical functioning and their indirect benefits on quality of life (16). Empirically tested exercise programs have taken forms ranging from a 3–4 week intensive inpatient rehabilitation program for long-term transplant survivors (17) to a thrice-weekly supervised cross training program for the first 3 months after discharge from the transplant hospitalization (18). The physical functioning gains demonstrated by these programs give reason to be optimistic about the potential for transplant survivors, particularly those who have survived the first year, to reach the functioning levels of the general population and, in so doing, improve their overall quality of life (19). Psychiatrists should thus encourage their transplant survivors to seek out formal exercise programs or, at the very least, establish a regular aerobic activity routine.

Following transplantation, problems psychologically incorporating the organ can lead to emotional difficulties. In part, transplant programs’ policies to preserve deceased donor confidentiality may actually facilitate better psychological incorporation of the organ, to the extent that they preclude undue focus and rumination by the recipient on donor characteristics such as race/ethnicity, specific age, or other personal characteristics. For recipients who appear distressed about their new organ, directly interviewing them may help to uncover facets that seem particularly disturbing to them or steps that they might take to become more at peace with the transplant. Recipients may also provide revealing and clinically useful information via other techniques, including a questionnaire focused on organ incorporation (20), and artwork and projective test drawings (21) have been used to bring forth emotionally laden issues (even guilt, debt, or culpability) that may not be easy for a recipient to verbalize. Through these techniques recipients of living donation may express guilt over putting someone else at risk (21). Psychological rejection of the organ may lead to poorer survival (20) and interventions based on psychological rejection should aim to change the recipient’s attitude toward the transplanted organ and thus facilitate incorporation.

There are no absolute contraindications to the use of specific psychotropic medications for transplant patients, but there is a need for greater caution with choice of agent and dosing. Prior to transplant, physiologic changes due to advanced organ disease cause alterations in pharmacokinetics affecting drug absorption, distribution, metabolism, and elimination. Patients awaiting transplantation are often seriously ill and less able to tolerate medication side effects such as nausea or sedation or physiological effects such as blood dyscrasias. Prescribing psychotropic medications before transplantation generally requires the use of lower initial doses and careful monitoring of tolerability and clinical response. Doses should be adjusted gradually. The final dose will often be lower than that used in a healthy individual. Closer monitoring, both symptomatically and physiologically, is recommended, and combining follow-up with regular pretransplant medical appointments may facilitate this. Some drugs may be less optimal to use. For example, maintaining stable nontoxic lithium levels within a narrow therapeutic window is complicated in advanced organ disease. Dehydration, congestive heart failure, cirrhosis, renal dysfunction, or cystic fibrosis reduce lithium clearance, increasing levels, while fluid overload (e.g., edema, ascites) reduces lithium levels. As another example, the use of antipsychotic medications requires additional care during the pretransplant period, as patients often have increased risk for QT prolongation and possible torsades de pointes due to electrolyte imbalances, presence of cardiac, renal, or hepatic failure, left ventricular hypertrophy, or other QT-prolonging medications (for detailed review of these issues, see Ferrando et al. [22]).

In the weeks following transplantation, some recipients will have transient physiological abnormalities that could also affect pharmacokinetics (e.g., liver congestion and/or renal hypoperfusion in heart recipients, fluid overload in renal recipients, and liver hypoperfusion and fluid overload in liver recipients). Even with normalized organ functioning, immunosuppressants and other medications increase the risk for drug-drug interactions. Most immunosuppressants have significant toxicities and narrow therapeutic indices. Adequate levels must be maintained to prevent organ rejection. The most commonly used immunosuppressants (glucocorticoids, calcineurin inhibitors [tacrolimus and cyclosporine], sirolimus, and corticosteroids) are all CYP3A4 substrates. Inhibitors and inducers of CYP3A4 may cause clinically significant drug level changes, resulting in toxicity or inadequate immunosuppression. Thus the selection of psychotropics should include consideration of agents with less potential to inhibit or induce CYP450 enzymes (see Table 1).

While there can be many possible etiologies for neuropsychiatric symptoms or changes in mental status, especially in the early posttransplant period, the possibility that symptoms reflect immunosuppressive medication side effects should always be entertained. Symptoms often diminish with reduction in immunosuppressive medications.

Most transplant programs engage social workers and additionally mental health clinicians to assist in determining the suitability of candidates for transplantation. While guidelines exist in the literature, there are no national listing criteria for either medical/surgical or psychosocial/psychiatric issues—each transplant team must decide for themselves what factors are considered relevant and their willingness to take risks on less optimal candidates. Psychiatrists are most often asked to render opinions on patients with mental health histories, especially complex patients and those with substance use disorders. Assistance with preparing potential candidates for transplant is a typical strategy, although for some the severity of their medical condition or the need for urgent transplantation simply does not allow them to accomplish necessary goals (e.g., addiction rehabilitation for an active substance user). Below we review some of the more complex scenarios and patients who could present a psychiatric challenge for the transplant team. It is important to note that with expert psychiatric management, good social supports, and a longitudinal relationship with the transplant team, even complicated patients such as those with severe psychiatric disorders can have successful posttransplant outcomes.

Perhaps due to careful psychosocial screening, relapse rates following transplantation are low relative to the general population. However, rates of any alcohol use after transplantation for alcoholic liver disease approaches 6% per year with cumulative rates of heavy use approaching 10%−15% by 5 years (23). Substance use can impair adherence to posttransplant care. Posttransplant screening for substance use is required and relapse can often be effectively elicited by direct nonjudgmental questioning during routine clinic visits.

Tobacco use is now recognized as problematic for all types of solid organ transplantation, not heart and lung alone. A significantly increased risk of malignancies, vasculopathies, infections, graft loss, and other complications are observed in posttransplant smokers. Many liver and kidney transplant programs are now also requiring patients to be tobacco-free prior to transplant listing. Despite similar emphasis on maintenance of lifelong smoking cessation in lung and heart transplantation, following lung transplantation the rates of posttransplant smoking are 4.8% per year (higher than for any other organ) and 3.2% per year for heart transplant recipients (24). Patients who are stable in methadone or suboxone maintenance programs should not be required to stop these therapies as a condition for transplant eligibility, as this increases the risk for relapse, especially during the stressful pretransplant period.

Patients referred for transplant evaluation are seen at a time they are already facing declining health, limited prognosis, disability, financial stress, role loss, and family strain. Under these circumstances, mature coping mechanisms are often compromised even in psychologically healthy individuals. Among patients with comorbid personality traits/disorders, regression to immature and inflexible defenses can compromise their ability to cope with the demands of the transplant evaluation and the long-term requirements for self-management. For example, borderline and narcissistic patients can be excessively demanding, overly critical, and may disrupt the cohesive functioning of transplant team members and other healthcare providers through splitting. While the attention to details and need for control and order may make obsessive-compulsive traits seem valuable to transplant self-management, a patient with such traits can become overly controlling about their medical care, argumentative about treatment recommendations, and intolerant of the inevitable delays or setbacks. Concerns arise with these patients regarding their ability to cope with transplantation and work collaboratively with the transplant team while adhering to medications and the necessary follow-up posttransplantation. Psychiatrists can assist transplant teams by helping them to recognize the presence of personality pathology and to develop care plans that can help to reduce miscommunication, anger, frustration, and acting out. For patients with more severe psychopathology, a behavioral contract may be needed between patient and transplant team outlining clear expectations about treatment adherence, appropriate communication with healthcare providers, involvement of their support system, and mandatory psychiatric treatment. While this is not a legal contract, it can help to define expectations between patient and transplant team, reducing miscommunication and splitting. Eligibility for transplantation can be made contingent on fulfillment of contract requirements.

Transplant teams are often hesitant to consider candidates with pre-existing psychotic disorders (e.g., schizophrenia, bipolar disorder). Their hesitance often arises from concerns about the patient’s ability to adhere to their posttransplant care and their risk of developing “steroid psychosis.” However, evidence does not suggest that these patients are at greater risk for steroid-induced neuropsychiatric complications. Limited information exists on transplant outcomes for patients with psychotic disorders. Case reports and a survey reporting on 35 patients across several transplant centers indicate successful transplantation can occur with careful psychiatric assessment and planning (25–30). According to survey findings, risk factors for posttransplant complications (e.g., suicide attempts, nonadherence) included presence of comorbid antisocial or borderline personality features, history of assault, living alone/homeless, recent positive psychotic symptoms, and family history of schizophrenia. In the survey, rates of posttransplant nonadherence with medications and laboratory testing, reduced graft function or graft loss due to nonadherence, were similar to rates observed in general transplant populations. Transplant candidates should be evaluated on an individual basis with added attention to response to psychiatric treatment, stability of psychiatric symptoms, adherence to medical and psychiatric care, and availability of support before and after transplantation. Developing a coordinated care plan is needed to ensure that there are no lapses in psychiatric treatment and follow-up, as this can easily occur both before and after transplantation given the greater focus on physical health and medical care.

In some cases, patients present emergently for transplant consideration due to fulminant organ failure and are unable to participate in a pretransplant psychosocial assessment. These patients often arrive in a dramatic fashion such as cardiogenic shock following a massive myocardial infarction or fulminant hepatic failure following an acetaminophen overdose. Patients are unable to be interviewed face-to-face and evaluation requires urgent but thorough collection of collateral information from other healthcare providers, family, friends, and other close associates. Since informed consent from the patient is not possible, discussions with family members and significant others are crucial to determine the patient’s possible interest in transplantation and ability to adjust to posttransplant life (e.g., chronic immunosuppressant therapy, side effects, lifestyle restrictions, self-monitoring, medical follow-up). The availability of support for the patient after transplant should be determined. For patients presenting with fulminant hepatic failure due to intentional acetaminophen overdose, additional information needs to be considered for transplant candidacy including circumstances surrounding the suicide attempt, presence and severity of active psychiatric symptoms, history of prior suicide attempts or psychiatric hospitalizations, comorbid substance abuse, adherence to mental healthcare, and coping skills. At times, families and friends may be hesitant to provide information that they fear may hinder the patient’s eligibility for transplant, but openness should be encouraged. For all cases of emergent transplantation, families and others will need added support to cope with the acute nature of the patient’s decline and often higher chance of poor outcome, even with transplantation. Patients who attempt suicide are at heightened risk for another attempt and posttransplant management should not neglect the need for long-term psychiatric care and risk monitoring. While many patients experience a honeymoon period in the early stages after transplant—being elated to be alive—the realities of living as an organ recipient appear quickly and such stresses can be disabling, especially for an already psychologically fragile patient.

Following transplantation, recipients must consistently take their immunosuppressive medications, have routine blood work and biopsies (if indicated), and come to all requested clinic appointments and procedures. Additional self-management skills that need to be adopted include being able to monitor their symptoms and know when to report concerning symptoms to the transplant team. Nonadherence to these components of the transplant medical regimen is a persistent problem (31) and has been consistently shown to predict transplant related morbidity and mortality (32).

Immunosuppression is the most important element of the transplant regimen and requires daily adherence. Across all organ types the average rate for immunosuppressant nonadherence is 23% annually, with kidney recipients having the highest medication nonadherence at 36% (24). Rates of nonadherence are slightly better for attending clinic appointments (6%) and getting blood work and tests (12%), but less so for self-monitoring behaviors such as monitoring vital signs (21%) (24). Nonwhite ethnicity, poorer social supports and poorer perceived health are associated with greater immunosuppressive medication nonadherence, suggesting these patients may benefit from closer monitoring by the transplant team. The magnitude of these rates is discouraging given the shortage of organs and the psychosocial screening of candidates that occurs prior to transplantation, which includes pretransplant education emphasizing the necessity of lifelong adherence to transplant directives.

While patients are informed of their postoperative self-care requirements prior to transplant, the real education begins shortly after surgery in the hospital and includes both patient and caregiver. Written materials are provided as are strategies and tools for managing the complex medication regimens. Patients and their caregivers are expected to learn and adopt these complex regimens and to be capable of monitoring symptoms and appropriately report them to the transplant team. These directives are reviewed most intensively during the early postoperative period when recipients come to clinic and are interviewed by the transplant team. As patients stabilize and have fewer, less frequent appointments with the transplant team, there is less opportunity to provide these face-to-face reinforcement sessions; at some point patients are expected to have integrated these skills without significant involvement by the transplant team. Patients will have a transplant coordinator assigned to them who will know them best and follows their course. The transplant coordinator responds to calls and questions from the patient and often knows essential information on the patient’s medication taking, pharmacy refills, appointment attendance, getting labs and biopsies as directed, and returning phone calls.

Self-report assessments by clinical interview are the standard in identifying nonadherence, and strategies that maximize the accuracy of self-reporting (e.g., establishing rapport; wording questions so that they assume that nonadherence can and will occur) are important when relying on self-report information (see Table 2). Other methods, such as electronic medicine cap monitoring, may not be as revealing (e.g., patients tire of using special pill bottles) and are expensive and labor intensive to use clinically.

Immunosuppressive medication levels are routinely checked, since maintaining adequate blood levels of these medications is critical to preventing organ rejection. In the clinical setting this is one of the primary methods of monitoring adherence. In addition to blood levels at a single time point, investigators have determined that wide fluctuations in immunosuppressive medication levels (i.e., standard deviations of ≥2) can indicate patients who have erratic or inconsistent medication taking and subsequently are at risk for rejection (26).

Strategies to improve adherence include re-education about transplant-specific directives, although additional therapies are often necessary to address psychological and psychosocial issues related to nonadherence. Patients for whom the transplant was abrupt and there was little time to adjust to the need for transplantation (such as in acute or fulminant failure) or those who have been emotionally traumatized by the experience (and may even have developed transplant-related PTSD) may be unwilling to or have difficulty with incorporating their transplant identity and struggle with following directives. Some patients find the side effects of immunosuppressive medications intolerable. Others might not perceive a need to continue taking them as they do not immediately feel any symptoms of organ rejection so they do not perceive the dangerous effects of having stopped their medications. Depression and substance use can also lead to nonadherence, so identifying and addressing psychiatric disorders may improve adherence. For some the expenses of medications, loss of insurance, transportation, or other logistical issues need to be addressed by the social worker on the transplant team.

Clinicians commonly target nonadherence by providing reading materials about immunosuppression, training patients to self-administer medications, and providing printed medication instructions and teaching patients to link medication-taking with their daily routines (33). In the literature, only five of 12 empirically-tested adherence interventions included in a 2009 review yielded adherence benefits (34). Of these, those that combined educational, behavioral, and psychological dimensions were most effective, which is consistent with the multimodal, collaborative approach to chronic disease management. More recently, mobile health technologies have been used to track adherence to all elements of the medical regimen, including medications and self-monitoring tasks such as spirometry for lung recipients. These technologies have enhanced traditional adherence interventions by facilitating communication with the transplant care team and have been well accepted even by patients who are older and less familiar with using computers (35, 36). Automated text messaging reminders delivered via mobile telephones for taking medications has been demonstrated to improve adherence to medication schedules and reduce rejection episodes (37). Other promising strategies include pharmacist-led longitudinal interventions that begin before hospital discharge and continue with quarterly meetings to discuss adherence throughout the first posttransplant year (38, 39), as well as interventions conducted before hospital discharge from the transplant surgery to educate recipients about the importance of adherence and preemptively address expected barriers and facilitators to adhering (40). Given that the most effective strategies are multimodal, there is a key role for psychiatrists on the transplant team to coordinate these efforts to promote adherence.