CHAPTER 29

Organ Transplantation

Andrea F. DiMartini, M.D.

Akhil Shenoy, M.D.

Mary Amanda Dew, Ph.D.

Solid organ transplantation began in 1954, with a successful kidney transplant in a patient whose identical twin was the donor. For most patients, however, an identical-twin donor was not an option, and more than a decade passed before immunosuppressive medications were available to conquer the immunological barrier. In 1967, the first successful liver transplant was performed, followed a year later by the first successful heart transplant. Even though surgical challenges of solid organ transplantation had been overcome, it was not until the early 1980s, with the advent of improved immunosuppression, that organ transplantation changed from an experimental procedure to a standard of care for many types of end-stage organ disease.

In that decade, the National Organ Transplant Act established the framework for a U.S. national system of organ transplantation, and the United Network for Organ Sharing (UNOS) began to administer the nation’s only Organ Procurement and Transplantation Network. In addition to facilitating organ matching and allocation, UNOS collects data about every transplant performed in the United States and maintains information on every organ type (e.g., wait-list counts, survival rates) in an extensive database available online (https://optn.transplant.hrsa.gov).

Although immunological barriers still exist, the greatest obstacle to receiving a transplant is the shortage of donated organs. The number of wait-listed individuals has increased far beyond the availability of donated organs. Currently, nearly 130,000 persons are active on the U.S. waiting list. Patients awaiting kidney transplant (the most common transplant performed) account for 80% of wait-listed patients. By contrast, slightly less than 15,000 patients are waiting for a liver, 4,000 for a heart, and nearly 1,500 for a lung. The numbers of patients receiving transplants in 2016 for each solid organ type (Organ Procurement and Transplantation Network 2017a) were as follows: 147 for intestine, 215 for isolated pancreas, 2,327 for lung, 3,191 for heart, 7,841 for liver, and 19,060 for kidney. In Europe, Eurotransplant, an international collaborative of eight European countries, reported 14,533 wait-listed candidates in 2016 but only 6,129 transplants performed in that year, with kidney candidates representing 72% of the wait list and over 50% of transplants (https://eurotransplant.org/cms/index.php?page=home).

For some transplant types (e.g., kidney, liver), living organ donation has become an option to address the organ shortage (see subsection “Living Donor Transplantation” later in this chapter). Although the percentage of living donors who have died due to donation is less than 1%, the numbers of living kidney donors have somewhat declined in recent years. Initiatives to increase the number of kidney donors have met with limited success. Following several highly publicized U.S. liver donor deaths beginning in 2002, the numbers of living liver donors decreased by about 50%. It appears that liver donation rates are beginning to rebound somewhat. In the absence of an identified living donor, transplant candidates may wait years for an organ. The median wait-listed time depends on the organ type and the recipient’s blood type and severity of illness and, for some organs, body size. Kidney candidates have the longest wait times, with a median wait of 4.2 years, whereas the median wait for lung candidates is only 4 months (Organ Procurement and Transplantation Network 2017a). While on the waiting list, 4%–10% of organ candidates become medically unsuitable and are removed from the list, and 10%–15% die (Organ Procurement and Transplantation Network 2017a).

Following transplantation, living-donor kidney and liver recipients experience the highest long-term survival rates (78% and 73%, respectively, are still alive at 10 years posttransplantation) (Figure 29–1) (US DHHS Health Resources and Services Administration 2012). Recipients of deceased-donor kidneys, livers, and hearts have somewhat lower 10-year survival rates (63%, 61%, and 58%, respectively), and intestine and lung recipients have the poorest 10-year survival rates (47% and 30%, respectively) (Organ Procurement and Transplantation Network 2017a). Advances in technology, immunosuppression, and medical care will most likely provide better survival rates for future recipients. However, overall graft survival rates are significantly lower than patient survival rates (e.g., graft survival rates after 10 years are 49% for kidneys and 45% for livers), which means that many transplant recipients may have to face a second transplant 5–10 years after their first (Organ Procurement and Transplantation Network 2017a). In addition, among other risk factors, chronic exposure to nephrotoxic immunosuppressive medication contributes to a 7%–21% 5-year risk of chronic renal failure after transplantation of a nonrenal organ (Ojo et al. 2003), requiring some patients to pursue an additional kidney transplant.

FIGURE 29–1. Survival rates of transplant recipients, by organ type.

Source. U.S. Department of Health and Human Services, Health Resources and Services Administration, Scientific Registry of Transplant Recipients: Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR) 2011 Annual Data Report. Rockville, MD, U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, 2012. Available at: https://srtr.transplant.hrsa.gov/annual_reports/2011/Default.aspx. Accessed September 26, 2017.

These stark facts highlight the enormous stresses facing transplant candidates, recipients, and their caregivers. These issues have also created an environment in which hospitals must evaluate, treat, and select patients for organ transplantation. The scarcity of donated organs has driven efforts to select candidates believed to have the best chance for optimal posttransplant outcomes.

Pretransplant psychosocial evaluations are commonly requested to assist in candidate and living donor selection, and psychiatric consultation is often needed for clinical input during the pre- and posttransplant phases. A wide body of knowledge on the clinical care of transplant candidates and recipients has been accumulated, and longitudinal research is increasingly available to answer questions about long-term outcomes and the impact of psychiatric factors—whether assessed pretransplant or in the early years posttransplantation—on outcomes. Research has focused primarily on kidney, heart, and liver transplantation.

In this chapter, we outline the essential information for psychiatric consultants and other mental health clinicians involved in the care of transplant patients—pretransplant assessment and candidate selection, emotional and psychological aspects of the transplant process, therapeutic issues, patients with complex or controversial features, psychopharmacological treatment, and neuropsychiatric side effects of immunosuppressive medications. Specific transplantation issues are also discussed in Chapter 17, “Heart Disease”; Chapter 18, “Lung Disease”; Chapter 19, “Gastrointestinal Disorders”; Chapter 20, “Renal Disease”; and Chapter 32, “Pediatrics.”

Pretransplantation Issues

Psychosocial/Psychiatric Assessment

Pretransplant psychosocial assessment has been a traditional role of consultation–liaison psychiatrists. These assessments are frequently used to assist in the determination of a candidate’s eligibility for transplantation and to identify psychiatric and/or psychosocial problems and needs that must be addressed to prepare the candidate and family for transplantation. These evaluations are also critical for identifying psychiatric, behavioral, and psychosocial risk factors that may portend poor transplant outcomes (Crone and Wise 1999; Dew et al. 2000, 2015).

Transplant programs often refer for pretransplant psychosocial evaluation those candidates with a known history of psychiatric problems, substance use disorders (including tobacco), and other poor health conditions and behaviors (e.g., obesity, treatment noncompliance). The process and conduct of the psychosocial evaluation varies by program and available staff. Social workers often provide an initial screening, and candidates identified as having psychiatric issues are referred to the mental health team for further evaluation. Some centers employ screening batteries of patient-rated measures to identify candidates with elevated levels of psychological distress, who then undergo a full psychiatric evaluation. Screening instruments can provide baseline cognitive, affective, and psychosocial information on candidates; use of these instruments may help maximize staff resources and minimize costs. For example, using this strategy, Jowsey et al. (2002) identified 20%–44% of potential liver transplant candidates who endorsed symptoms on a range of screening measures, which prompted a higher level of evaluation.

Transplant programs vary considerably in their psychosocial assessment criteria and procedures (see Levenson and Olbrisch 2000 for a review of methodological and philosophical issues). In general, however, psychosocial evaluations have 10 objectives (although a given assessment may not include all 10), as enumerated in Table 29–1 (see Levenson and Olbrisch 2000).

TABLE 29–1. Goals of psychosocial screening

1.	Assess coping skills; intervene with patients who appear to be unable to cope effectively.
2.	Diagnose comorbid psychiatric conditions; provide for pre- and posttransplant monitoring and treatment.
3.	Determine the candidate’s capacity to understand the transplant process and to provide informed consent.
4.	Evaluate the candidate’s ability to collaborate with the transplant team and to adhere to treatment.
5.	Assess substance use/abuse history, recovery, and ability to maintain long-term abstinence.
6.	Identify health behaviors that may influence posttransplant morbidity and mortality (e.g., tobacco use, poor eating or exercise habits) and evaluate the candidate’s ability to modify these behaviors over the long term.
7.	Help the transplant team to understand the patient better as a person.
8.	Evaluate the level of social support available to the candidate for pre- and posttransplant phases (including stable family/others committed to assisting the candidate, adequate insurance and financial resources, and logistical support).
9.	Determine the psychosocial needs of the patient and family and plan for services during the waiting, recovery, and rehabilitation phases of the transplant process.
10.	Establish baseline measures of mental functioning in order to be able to monitor postoperative changes.

Source. Adapted from Levenson J, Olbrisch ME: “Psychosocial Screening and Selection of Candidates for Organ Transplantation,” in The Transplant Patient. Cambridge, UK, Cambridge University Press, 2000, p. 23. Used with permission.

Because information on all of these domains may not be obtainable during a single clinical interview, a follow-up interview and reassessment may be necessary to clarify relevant issues, solidify a working relationship with the patient and family, and resolve problems. Collateral information may be required from the medical record and other medical and psychiatric providers. A multidisciplinary approach is often used, with input from psychiatrists, psychologists, psychiatric nurse clinical specialists, addiction specialists, social workers, transplant physicians, and transplant coordinators, to construct a comprehensive picture of the patient and develop a coordinated treatment plan. As in any psychiatric evaluation, verbal feedback provided to the patient and family will serve to reiterate the expectations of the transplant team and the requirements of the patient for transplant listing. Some centers also use written “contracts” to formalize these recommendations (Cupples and Steslowe 2001; DiMartini et al. 2011; Masson et al. 2014). In difficult cases, these contracts document expectations, thereby minimizing misinterpretation. These contracts are particularly useful with candidates who have substance use disorders, because they specify the transplant program’s requirements for addiction treatment, monitoring of adherence (e.g., documented random negative blood alcohol levels), and length of abstinence (see subsection “Alcohol” under “Substance Use Disorders” later in this chapter). Potential candidates may be requested to engage in treatment and return for reevaluation to determine if transplant treatment goals have been met.

Psychosocial Instruments and Measures

Instruments that have been used to evaluate transplant candidates and monitor their posttransplant recovery include transplant-specific instruments (e.g., Psychosocial Assessment of Candidates for Transplantation [PACT; Olbrisch et al. 1989], Transplant Evaluation Rating Scale [TERS; Twillman et al. 1993], Stanford Integrated Psychosocial Assessment for Transplant [SIPAT; Maldonado et al. 2008]); disease-specific instruments (e.g., Miller Health Attitude Scale for cardiac disease [Miller et al. 1982], Chronic Respiratory Disease Questionnaire [Guyatt et al. 1987]); and disorder-specific instruments (e.g., High-Risk Alcohol Relapse Scale for alcoholism [Yates et al. 1993]). These instruments have been used in conjunction with general instruments for rating behavior, coping, cognitive and affective states, and quality of life (QOL) (Corbett et al. 2013). Psychosocial instruments can be used to identify individuals who require further assessment (as described in the previous subsection) or to pursue evaluation of patients already identified as requiring additional screening. The evaluator’s purpose for using such instruments will determine the type and specificity of the instruments chosen (e.g., the use of neuropsychiatric tests to aid in the identification of cognitive impairment). Some instruments are more applicable to transplant populations than others. For example, although many instruments and measures are available for assessing alcoholism, they all are focused on general issues of detection and treatment of addiction rather than on issues important in evaluating appropriateness for transplantation. Formal cognitive testing may be appropriate to delineate cognitive deficits, taking into consideration the potential contribution of deficits that may be transient and related to the current degree of illness (e.g., delirium; see subsection “Cognitive Disorders and Delirium” later in this chapter). (For a systematic review of the utility of psychological measures in predicting liver transplant outcomes, see Fineberg et al. 2016.)

Because psychosocial selection criteria differ significantly by program and organ type, development and use of structured evaluation instruments may help to direct and standardize the transplant selection protocols used nationally. The Structured Interview for Renal Transplantation (SIRT; Mori et al. 2000) is a structured yet flexible interview tool designed to guide the clinician efficiently through a comprehensive interview of pertinent information for potential renal transplant candidates. Use of the SIRT requires sound clinical judgment. The instrument can also be used for training clinicians and for research (Mori et al. 2000). This instrument is not scored, and there are no ratings for transplant candidacy. Three other instruments commonly used to assess candidates for transplantation are the PACT, the TERS, and the SIPAT. Different from structured interviews with specific items or questions, these instruments can serve as heuristic tools to aid clinicians in considering and integrating the data gathered from their interviews in the candidacy determination.

Unique Role of the Psychiatric Consultant

Unlike in most clinical interviews, the psychiatrist performing the pre-transplant assessment while identifying the needs of the transplant candidate will also be proposing what psychiatric issues, if any, are conditional for listing. These requirements may be specific to transplantation, and the psychiatric consultant must be candid with the patient about the consultant’s role of providing the transplant team with psychiatric recommendations regarding the patient’s candidacy. Careful delineation of specific transplant-related expectations, explanation of the importance of these requirements to the success of transplantation, and exploration of the implications of these criteria for the individual candidate serve to establish a meaningful dialogue with the patient from which the therapeutic alliance necessary for future intervention can develop.

For the clinician, this role can be uncomfortable or even anxiety provoking. This is especially true if the clinician is not recommending the candidate for transplantation. Fortunately, many programs do not reject patients outright for psychosocial reasons; rather, they offer such patients the opportunity to work to bring their problematic areas into alignment with the recommendations (i.e., through addiction counseling, behavioral changes, psychiatric treatment, identification of appropriate social supports) and to then undergo reevaluation for candidacy. In these cases, the psychiatric consultant can often function as an advocate for the patient and assist in referral for appropriate treatment if indicated. Rather than being a “gatekeeper,” the mental health clinician has the role of optimizing the preparation of the patient. A team makes a determination regarding whether a patient with complex psychosocial issues can be successfully transplanted at their program. Nevertheless, some patients will be unable to comply with the specified transplant requirements or will not survive to complete their efforts to meet candidacy requirements.

Philosophical, moral, ethical, legal, and therapeutic dilemmas are inherent in the role of transplant psychiatrist, as conflicting team opinions present themselves with potential transplant candidates. Team discussions and consultation with other colleagues are the rule in complicated cases. In these instances, team discussions not only aid in resolving candidacy quandaries but also can help alleviate team members’ anxiety and discomfort over declining a patient for transplantation. Group or team debriefing may also be desirable, and occasionally consultation with the ethics committee (or consult service), risk management, and/or the legal department of the hospital is needed (e.g., when a candidate is challenging candidacy requirements or the team’s candidacy decision). Thorough documentation is essential in order to delineate the issues involved, the expectations of the team for transplantation candidacy, and the efforts to work with the patient.

Psychological and Psychiatric Issues in Organ Transplantation

Psychiatric Symptoms and Disorders in Transplant Patients

Similar to other medically ill populations, transplant candidates and recipients experience a significant amount of psychological distress and are at heightened risk of developing psychiatric disorders. Following transplantation, 20% of kidney, 30% of liver, and up to 60% of heart recipients develop mood and anxiety disorders within the first year (Corbett et al. 2013). Reported prevalence rates for anxiety disorders after transplantation have ranged from 3% to 33% (Dew 2003; Dew et al. 2000), but there are too few studies to identify rates for specific anxiety disorders. Clinicians should consider and screen for posttraumatic stress disorder (PTSD) related to the transplant experience; studies estimate that 3%–15% of transplant recipients develop PTSD or posttraumatic stress symptoms, with associated poorer QOL (Baranyi et al. 2013; Corbett et al. 2013; Jin et al. 2012). In a prospective study that followed 178 lung recipients and 126 heart recipients for the first 2 years after transplantation, the cumulative prevalence rates for psychiatric disorders were 58% and 47%, respectively, for any disorder, including 25% and 30%, respectively, for major depressive disorder; 18% and 8%, respectively, for panic disorder; and 15% and 14%, respectively, for PTSD (Dew et al. 2012). Whereas new onset of panic disorder or PTSD was limited to the first year posttransplantation, new onset of major depressive disorder occurred over the entire 2-year period. Lung recipients were at significantly heightened risk for panic disorder. Other factors that increased the cumulative risk for psychiatric disorders included a pretransplant psychiatric history, female gender, longer wait for transplant, early posttransplant health problems, and psychosocial characteristics (e.g., poorer caregiver support, use of avoidant coping). Studies have found that a pattern of high depression rates in candidates awaiting transplant (across all organ types), with improvements in the short term after transplantation, was associated with better QOL (Akman et al. 2004; Fusar-Poli et al. 2007; Miller et al. 2013). However, dramatic increases in depressive symptoms can accompany early graft loss (Akman et al. 2004) or can develop with long-term (>3 years) decline in functional status (Dew and DiMartini 2011; Fusar-Poli et al. 2005, 2007). In lung transplant recipients, contributors to depression included male gender, comorbid personality disorders, poor coping strategies, life stressors, physical complications, corticosteroid use in the short term after transplantation, and lack of psychosocial support (Fusar-Poli et al. 2007).

Studies show that clinically significant depression or depressive symptoms, whether assessed prior to (Smith et al. 2014) or following transplant (Farmer et al. 2013; Smith et al. 2014), can be associated with negative clinical outcomes following transplant. In one of the few prospective studies to focus on this topic, Rosenberger et al. (2016) used a structured DSM-IV-TR (American Psychiatric Association 2000) interview to identify anxiety and depression in a cohort of lung transplant recipients; they found that posttransplant depression predicted not only poorer patient and graft survival but also the development of chronic rejection (bronchiolitis obliterans syndrome). Anxiety, however, was not associated with poorer outcomes. A meta-analysis of studies examining whether depression or anxiety affected risk for posttransplant morbidity and mortality found that depression, either pre- or posttransplant, predicted poorer survival (Dew et al. 2015). Morbidity was less often studied than mortality but also appeared to be negatively affected by depression, especially death-censored graft loss. In the meta-analysis, few studies examined the effects of anxiety; although anxiety was modestly associated with increased mortality, the association did not reach significance (Dew et al. 2015). A study of heart transplant recipients found that pretransplant major depressive disorder was a significant independent predictor of posttransplant malignancies (Favaro et al. 2011). It is unclear whether treatment of psychiatric disorders will affect patient outcomes, although one study suggested that adequate psychotropic treatment of depression may improve patient outcomes (Rogal et al. 2013). Regardless of whether treatment improves medical outcomes, the role of the psychiatrist in evaluating, diagnosing, and treating psychiatric disorders both pre- and posttransplantation remains critical.

Adaptation to Transplantation

Transplant candidates typically experience a series of adaptive challenges as they proceed through evaluation, waiting, perioperative management, postoperative recuperation, and long-term adaptation to life with a transplant (Dew and DiMartini 2011; Olbrisch et al. 2002; Rosenberger et al. 2012) (Figure 29–2). With chronic illness, there can be progressive debility and gradual loss of vitality and of physical and social functioning. Patients may progressively lose their ability to work, participate in social/family activities, and drive, and may even require assistance with activities of daily living. With these losses of functioning will come the loss of important roles in the family (e.g., breadwinner, parent, spouse, caregiver). Adapting to these changes can elicit anxiety, depression, anger, avoidance, and denial and requires the working through of grief (Olbrisch et al. 2002). Patients may express their distress or ambivalence by missing appointments or procedures or by failing to complete requirements for transplant listing. Patients who are wait-listed may develop contraindications to transplantation (e.g., infection, serious stroke, progressive organ dysfunction), and both patients and families should be made aware that a candidate’s eligibility can change over time for many reasons (Stevenson 2002). During this phase, psychiatrists may provide counseling to patients and families to help them navigate these transitions and prepare for either transplantation or death.

FIGURE 29–2. Organ transplantation timeline: discrete time periods with attendant issues for transplant patients.

Note. Eval.=evaluation; TX=treatment, specifically transplantation.

Source. Adapted from Dew MA, DiMartini AF, Kormos RL: “Organ Transplantation, Stress of,” in Encyclopedia of Stress, 2nd Edition, Vol 3. Edited by Fink G. Oxford, UK, Academic Press/Elsevier, 2007b, pp. 35–44.

The summons for transplantation can evoke a mixture of elation and great fear. Patients can develop anticipatory anxiety while waiting for the call from the transplant team. Patients may experience panic when they are called for transplantation, and some—due to anxiety, fear, ambivalence, or not feeling ready—may even decline the offer of an organ.

Much of illness behavior depends on the coping strategies and personality style of the individual. In our experience, the adaptive styles of adult transplant recipients often depend on whether patients’ pretransplant illness experience was chronic or acute, as delineated in the following broadly generalized profiles.

Patients who have dealt with chronic illness for years may adapt psychologically to the sick role and can develop coping strategies that perpetuate a dependency on being ill (Olbrisch et al. 2002). For these patients, transplantation may psychologically represent a transition from one state of illness to another, and such patients can have difficulty adjusting to or transitioning into a “state of health.” They often complain that the transplant team is expecting too fast a recovery from them, and they may describe feeling pressured to get better. Some patients may develop unexplained chronic pain or other somatic complaints or may begin to evince nonadherence to transplant team directives.

For patients with good premorbid functioning who become acutely ill, with only a short period of pretransplant infirmity, the transplant can be an unwelcome event. These patients can experience a heightened sense of vulnerability, and they may deny the seriousness of their medical situation (Olbrisch et al. 2002). They often wish to return to normal functioning as quickly as possible posttransplantation, and they may recover more rapidly than the transplant team expects; however, they may suffer later as a result of pushing themselves too much (e.g., returning to work before they are physically ready). They may resent being transplant recipients, with the inherent restrictions and regimens, and may act out their anger or denial in episodes of nonadherence (Olbrisch et al. 2002).

Treatment Modalities With a Focus on Transplant-Specific Issues

Patients with psychological or psychiatric issues can benefit from traditional psychotherapies (reviewed in this section) and pharmacotherapy (reviewed later in chapter). Many programs employ educational groups to prepare patients for transplant and recovery. Patients identified as having psychosocial problems during these sessions or during the psychosocial evaluation are commonly referred to local providers for assistance. Psychotherapeutic treatments will likely focus on transplant-specific issues, and because local transplant expertise may not be available, consultation psychiatrists may need to educate therapists on how to address these issues. For example, in a prospective study of kidney transplant recipients, three recurring psychological themes were expressed by patients: 1) fear of organ rejection, 2) feelings of paradoxical loss after surgery despite successful transplantation, and 3) psychological adaptation to the new kidney (Baines et al. 2002). The study demonstrated that individual psychotherapy was effective in resolving transplant-related emotional problems, with significant reductions in depressive symptoms after therapy. Other transplant-specific themes, such as perceiving a loss of control over outcomes and/or attributing outcomes to chance, can be associated with depressed affect (Cukor et al. 2008) and may offer a focus for intervention.

In addition to traditional therapies, various innovative strategies have been employed to deal with specific transplantation issues and also to address logistical issues (e.g., distance from program, transportation, physical debility, lack of local expertise) and staffing resources. Two studies of wait-listed candidates successfully demonstrated the use of telephone therapy to overcome logistical barriers and deal with transplant-specific themes (e.g., uncertainty management, QOL, caregiver support) (Bailey et al. 2017; Rodrigue et al. 2011). Peer mentoring has become increasingly popular and is available at some transplant programs and through online resources (e.g., http://www.americantransplantfoundation.org/programs/mentorship-program-2/). Mentorship by a transplant recipient can augment patient care by providing information and support from a peer perspective (Wright et al. 2001). At the University of Toronto mentoring program, the four topics most commonly discussed between mentors and mentees were postoperative complications, medications, wait on the transplant list, and the surgery itself (L. Wright et al. 2001). To increase patient satisfaction with a mentor program, Wright et al. (2001) recommend early introduction of a mentor and matching of mentors with mentees according to demographics and clinical course. One innovative three-pronged intervention was designed to improve kidney recipients’ QOL using 1) proactive, patient-initiated care to prevent transplant-related morbidities (education on self-assessment, Web-based and learning library materials); 2) employment/vocational counseling with a rehabilitation counselor; and 3) enhancement of social support (trained peer-mentors, support group, social worker counseling on support network) (Chang et al. 2004). Not only was the intervention cost-effective, but the patients in the intervention had significantly better QOL and had more quality-adjusted treatment-free days.

Group psychotherapy for organ transplant patients and family members has also been successfully used. Abbey and Farrow (1998) described a program in which group psychotherapy was organized along three dimensions: course of illness (pre- vs. posttransplantation), homogeneous versus heterogeneous group membership (e.g., separate groups for patients and caregivers vs. integrated groups, organ-specific groups vs. cross-organ groups), and group focus (issue-specific vs. unstructured). Group therapy participants reported decreases in negative affect, increases in positive affect and happiness, less illness intrusiveness, and improved QOL. Transplant coordinators also reported that patients in group therapy required less contact, both in clinic and by telephone for social support.

Internet resources for transplant patient information and support are increasing, but few studies have examined the impact of Internet-delivered transplant interventions for mental health issues. Dew et al. (2004) designed and evaluated an Internet-based psychosocial intervention for heart transplant recipients and their families. This multifaceted intervention included stress and medical regimen management workshops, monitored discussion groups, access to electronic communication with the transplant team, and information on transplant-related health issues. Compared with recipients without access to the Web site, intervention patients and their caregivers reported significant reductions in symptoms of mental distress, and patients also experienced improvements in QOL and medication adherence (Dew et al. 2004). A recent review of studies examining mobile health interventions for organ transplant patients identified several apps designed to improve pretransplant knowledge and QOL, as well as educational apps targeting posttransplant medication regimen adherence, but the studies were limited to measuring feasibility and identifying themes for future interventional studies (Fleming et al. 2017). Most mobile apps target adherence to transplant directives (see “Posttransplant Regimen Adherence” subsection below).

Patients With Complex or Controversial Psychosocial and Psychiatric Issues

The stringency of selection criteria for transplantation appears to depend on the type of organ transplant being considered, and transplant programs often have strongly ingrained beliefs about the suitability of candidates with certain types of mental illness. Cardiac transplant programs are more likely than liver transplant programs to consider psychosocial issues as contraindications, and liver transplant programs in turn are more stringent than kidney transplant programs (Butt et al. 2014b). These differences may be attributable to the relative availability of specific types of organs (Yates et al. 1993); alternatively, the extent of experience with specific organ transplants may allow programs to feel more comfortable with less stringent criteria (e.g., kidney transplantation, with more than three decades of experience and more than 400,000 kidney transplants performed in the United States) (Organ Procurement and Transplantation Network 2017a). In addition, for kidney transplantation, cost-effectiveness research has clearly demonstrated the long-term cost savings of kidney transplantation relative to dialysis; with such unequivocal evidence, insurance payers have a strong financial incentive to refer patients early for preemptive transplantation, before the high costs of dialysis begin to accumulate (Eggers 1992). In such a setting, psychosocial factors may have less impact on transplantation candidacy. Other issues influencing the selection process include moral and ethical beliefs, societal views, personal beliefs, and even financial constraints. One study of kidney candidates found that those with a history of mental disorders or nonadherence were less likely to even complete the transplant workup within 2 years of referral (Mucsi et al. 2017).

Although each additional indicator of poor prognosis present during the perioperative period may increase the risk of nonadherence posttransplantation (Fine et al. 2009; Nevins et al. 2017; see “Posttransplant Regimen Adherence” below), it should be emphasized that candidates with any one of these features are not categorically poor recipients and, conversely, that patients without any of these features do not categorically make the best candidates. However, clinical assumptions that patients with certain personality disorders, substance use disorders, poor coping skills, poor adherence, and poor social supports will have worse posttransplant outcomes are increasingly supported by research. Nevertheless, case reports have demonstrated that even some patients who might seem inappropriate for transplant—for example, patients with active psychosis (DiMartini and Twillman 1994; Shapiro 2005), severe personality disorders (Carlson et al. 2000), or intellectual disability (Samelson-Jones et al. 2012)—can successfully undergo transplantation and maintain adequate adherence to medication regimens after the procedure. Patients with such conditions should be carefully assessed before transplantation, with optimization of their condition followed by ongoing psychiatric monitoring and treatment after transplantation. These cases demonstrate that with expert management, good social support, and a longitudinal relationship with the transplant team, even complicated patients, such as those with severe psychiatric disorders, can have positive long-term outcomes. An analysis of 822 solid organ transplants in the U.S. Veterans Administration system found that 17% of transplant recipients suffered from a serious mental illness (including schizophrenia and other psychotic disorders, bipolar disorder, major depressive disorder, and severe PTSD), and another 30% carried other psychiatric diagnoses (Evans et al. 2015). The investigators found no differences among those with serious mental illnesses, other mental illness, and no mental health diagnosis in attendance at follow-up appointments, frequency of filling immunosuppressant prescriptions, or 3-year mortality. On the other hand, if optimal management is not provided in complex cases, patient and graft survival can be adversely affected (Abbott et al. 2003).

Posttransplant Regimen Adherence

Lifelong immunosuppression is a prerequisite for maintaining graft function, and nonadherence to immunosuppressive medication regimens is often associated with late acute rejection episodes, chronic rejection, graft loss, and death. It might be assumed that transplant patients, in general, constitute a highly motivated group and that their adherence levels would be high. Unfortunately, in common with other patients living with chronic disease, organ recipients often experience difficulty in maintaining high levels of adherence to the multiple components of their regimens (DeVito Dabbs et al. 2016; Dew et al. 2007a). In a meta-analysis involving nearly 150 studies of all organ types, average annual nonadherence rates ranged from 1–4 cases per 100 patients for substance use (including tobacco, alcohol, and illicit drugs) to 19–25 cases per 100 patients for a variety of other areas of noncompliance (immunosuppressant medication, diet, exercise, and other transplant health care requirements) (Dew et al. 2007a). Medication nonadherence was especially high, and clinicians can expect to see 23 nonadherent patients for every 100 individuals seen during a given year of follow-up. Immunosuppressant nonadherence was highest in kidney recipients (36 cases per 100 patients annually, vs. 7–15 cases per 100 patients for recipients of other organs).

Nonadherence to immunosuppressive medications impairs both life quality and life span; it is a major risk factor for graft-rejection episodes and may be responsible for up to 36% of graft loss after the initial recovery period (Fine et al. 2009; Laederach-Hofmann and Bunzel 2000). Nonadherence leads to waste, as it reduces the potential benefits of therapy and adds to the costs of treating avoidable consequent morbidity. Graft loss from nonadherence is also tragic, given the large numbers of patients on the waiting lists. Global assessment of posttransplant regimen adherence is difficult, and patients can manifest varying degrees of adherence to medical recommendations. Moreover, the medical recommendations pertain to a multifaceted regimen of care. For transplant recipients, adherence to immunosuppressants is typically the chief area of focus. Even occasional missing of a dose can have deleterious consequences, with some studies suggesting that less than 95% adherence is sufficient to produce poorer outcomes (Fine et al. 2009; Nevins et al. 2017). Studies using electronic monitoring of pill taking through special medicine containers have demonstrated that medication nonadherence can begin shortly after transplant and increases over time (Fine et al. 2009; Nevins et al. 2017).

Given the extent and critical nature of nonadherence, research has focused on efforts to predict and prevent it. Factors associated with posttransplantation nonadherence include younger age (i.e., adolescence or young adulthood), pretransplant nonadherence, depression and anxiety, substance misuse, poor coping, poorer perceived self-efficacy, poorer perceived health, poor support, poor health literacy, lower socioeconomic status, greater regimen complexity, and differences in health care systems (Calia et al. 2015; Dew et al. 2007a; Fine et al. 2009; Nevins et al. 2017). One study revealed that when risk factors accumulate, adherence problems are likely to rise dramatically (Dew et al. 1996). However, clinical observation of individual patients reveals that there can be many reasons for nonadherence, and an attempt to identify, understand, and correct the reasons is required. Patients may require ongoing or remedial education about the need for lifelong adherence to immunosuppressants. Often, the symptoms of chronic rejection are silent, and recipients may not recognize that they are developing complications because they do not initially feel any adverse effects from discontinuing their medications. Discomfort with medication side effects should be elicited and alleviated if possible. Problems with insurance prescription coverage or other financial issues should be assessed. Additionally, symptoms of depression and anxiety should be identified and treated. Methods to identify nonadherence, measures of medication taking, and tools to explore barriers to adherence have been reviewed by Lam and Fresco (2015). Although self-report can overestimate adherence, it is the most commonly used technique and can provide critical information (Nevins et al. 2017) (Table 29–2).

Inquire about patients’ adherence routinely, both early posttransplant and in ensuing years. Consider asking:

How often did you miss a dose of your immunosuppressive medication in the past 4 weeks?

Did you miss more than 1 consecutive dose of your immunosuppressive medication in the past 4 weeks?

Recognize that posttransplant adherence involves multiple activities:

Taking medication

Attending clinic appointments

Self-monitoring of symptoms and vital signs

Completing required tests

Adhering to lifestyle requirements (e.g., diet, exercise)

Avoiding alcohol, illicit drugs, and tobacco

Collect evidence from multiple sources: the patient, spouse/significant other/family, transplant coordinator, laboratory data, and pharmacy records.

Inquire about correlates of nonadherence (e.g., psychological distress/psychiatric disorders, patient/family supports, insurance/financial issues).

Consider psychological, characterological, and other behavioral factors and coping strategies that are possibly playing a role in nonadherence.

Keep in mind that solutions may require multifaceted interventions to address not only nonadherence but also these other contributory factors.

Source. Adapted from Dew et al. 2009 and Nevins et al. 2017.

Adherence in Pediatric Populations

Adherence in pediatric transplant recipients can be additionally complicated by developmental stage, attempts at autonomy/individuation, parental control/support, and parental stress. In a meta-analysis, Dew et al. (2009) found (across all organ types) that nonadherence to clinic appointments and tests was the most common type of nonadherence in pediatric patients, at 12.9 cases per 100 patients annually. The rate of nonadherence to immunosuppressants was 6 cases per 100 patients annually. Older age of the child, worse family functioning (e.g., greater parental distress, lower family cohesion), and poorer psychological status of the child (e.g., poorer behavioral functioning, greater distress) were significantly but only modestly correlated with poorer adherence.

Nonadherent adolescents report poorer health perceptions, lower self-esteem, and more limitations in social and school activities (Fredericks et al. 2008). Better knowledge of medication regimens, using a pillbox to organize medications, and parental involvement in medication administration all contribute to improved adherence among adolescent renal transplant candidates (Zelikovsky et al. 2008).

In an attempt to develop a clinically useful measure of adherence in adolescents and children, Stuber et al. (2008) calculated the standard deviation of tacrolimus blood levels over a 1-year period and found that rather than a one-time “snapshot” or a single abnormal blood level, a threshold-value standard deviation of 2.5 in the tacrolimus level over the year predicted rejection episodes. The reader is also referred to Chapter 32, “Pediatrics,” for additional information on adherence in adolescents.

Interventions to Improve Medication Adherence

A systematic review of the literature on interventions intended to improve medication adherence in transplant patients found that a combination of cognitive, educational, counseling, and psychological interventions at the patient, health care provider, setting, and system levels was more likely than any single intervention to be effective in the long term (De Bleser et al. 2009). This finding is consistent with the intent underlying the multimodal collaborative approach to chronic disease management. Other studies emphasize the need for patient involvement in the selection of strategies to improve adherence, the importance of patient education, and the value of allowing patients with support to make their own decisions about their care (Chisholm-Burns et al. 2013; Dobbels et al. 2017; Joost et al. 2014; Popoola et al. 2014). Patients may benefit from motivational interviewing or problem-solving therapies to address barriers to adherence. Technology-based strategies for monitoring and supporting adherence are gaining popularity. These strategies include a variety of mobile phone apps, electronic pill monitoring with feedback, and automated text messaging, all of which are well accepted by transplant patients and have been demonstrated to improve adherence (DeVito Dabbs et al. 2009; Dobbels et al. 2017; McGillicuddy et al. 2013; Reese et al. 2017). However, because adherence tends to deteriorate over time (De Geest et al. 2014), interventions without booster sessions or a maintenance plan are not likely to be effective over the long term.

Substance Use and Disorders

Alcohol

Compared with other solid-organ transplant candidates, liver transplant (LT) candidates more often require psychiatric consultation for substance abuse assessment, due to the prevalence of alcoholic liver disease (ALD) and viral hepatitis transmitted through contaminated needles. An estimated 50% of LT recipients have a pre-LT history of alcohol and/or drug abuse/dependence (DiMartini et al. 2002). ALD is the leading indication for liver transplant in Europe. Although it remains the second most common indication for liver transplant in the United States, it could become the leading indication in the next decade, because of more effective treatment for hepatitis C. Moreover, there are high rates of alcohol use disorder in patients who undergo transplantation for viral hepatitis. The outcomes for patients who undergo liver transplantation for ALD are better than those for patients who undergo transplantation for hepatitis C and are similar to those for transplant patients with all other conditions (Lucey 2014).

In the optimal situation, the psychiatrist is an integral member of the transplant team and can identify problems and integrate the addiction treatment plan into the patient’s pre- and posttransplant care. In a prospective study of alcohol consumption follow-up after liver transplantation in which patients were consecutively evaluated by their hepatologist and an addiction specialist, the addiction specialist was able to uncover problematic alcohol use in 41% of posttransplant patients irrespective of the reason for their transplant; in contrast, the identification rate was 22% by the hepatologist (Donnadieu-Rigole et al. 2017). Psychiatric consultation provides a thorough evaluation of the candidate’s substance history, the stability of his or her recovery, the candidate’s understanding of his or her substance use (especially in the context of his or her health and need for transplantation, lifelong abstinence, and further or ongoing addiction treatment), and the presence of other psychiatric disorders. Family and social support for patients’ continued abstinence both pre- and posttransplantation must also be evaluated. The identification of alcohol use disorder in the context of transplantation is complex. Psychological barriers that are common in this disorder, such as shame, guilt, and denial, are heightened in patients seeking transplantation (DiMartini and Dew 2012). The Alcohol Use Disorders Identification Test—Consumption (AUDIT-C; Bush et al. 1998) is a screening tool used at some centers, but collateral information and random toxicological screening are essential for identification of pre- and posttransplant alcohol use. Hepatic encephalopathy and other conditions affecting cognition, such as alcoholic brain damage, can also interfere with the assessment. These transplant candidates often do not perceive a need for help with their addiction because they are focused on the end-organ damage and its management. Motivational enhancement therapy can aid in overcoming resistance to treatment (Weinrieb et al. 2011). Although there is no evidence that an “alcohol contract” confirming the transplant candidate’s commitment to abstinence affects alcohol consumption after liver transplant (Masson et al. 2014), not surprisingly those who receive addiction treatment before and after transplant may have the lowest relapse rates (Rodrigue et al. 2013). In one LT center, the introduction of an embedded alcohol addiction unit was associated with a decrease in posttransplant relapse rates (16.4% after vs. 35.1% before introduction of the unit) and an improvement in the 5-year mortality rate in patients who underwent LT for alcoholic cirrhosis (Addolorato et al. 2013).

Relapse rates of 15%–25% have been reported in wait-listed LT candidates, with most relapses identified by biological testing (DiMartini and Dew 2012; Webzell et al. 2011). Blood alcohol level is the most widely used and available test, but due to the fast elimination of ethanol, this test can only detect very recent use. Methanol may provide a longer window of detection and retain specificity, whereas carbohydrate-deficient transferrin can be falsely elevated in liver disease. Ethyl glucuronide, tested in hair, may be useful in LT candidates (Sterneck et al. 2014); this test can detect alcohol use for up to a week and is highly specific. Ultimately, a combination of patient interviews, independent caregiver reports, and biochemical monitoring may be the optimal strategy for identification of alcohol and other substance use in transplant candidates.

A meta-analysis of 50 studies of LT recipients identified an average annual rate of 5.6% for any alcohol use after transplant and 2.5% for heavy use (Dew et al. 2008). Although these rates may appear relatively low, they are cumulative over time, such that by 5 years after transplant, 28% of recipients with ALD will have relapsed to at least some alcohol use, and 12.5% will have engaged in heavy use. Studies from single centers have reported rates of relapse to harmful drinking that can impact outcomes of around 20%–25% (Cuadrado et al. 2005; DiMartini et al. 2010; Dumortier et al. 2015). In one study, one-third of liver recipients who relapsed to heavy alcohol use developed cirrhosis in less than 5 years (Dumortier et al. 2015). In a retrospective study, excessive drinking was associated with increased graft damage and worsened long-term survival (Rice et al. 2013). In another study, by 10 years posttransplant, relapsers drinking more than 30 grams of ethanol a day had significantly poorer survival compared with nonrelapsers (45.1% vs. 85.5%) (Cuadrado et al. 2005). Thus, whereas mild to moderate drinking may not affect outcomes, heavy drinking has demonstrated negative effects. Additionally, in light of the organ shortage, any return to drinking may adversely affect public perceptions of the suitability of allocating organs to patients at high risk for relapse (Neuberger et al. 1998), and transplant teams’ morale can be negatively impacted by related poor outcomes (Lee et al. 2017).

Predictors of posttransplant alcohol use have been difficult to identify. This may be due to the heterogeneity of the ALD transplant population and the potential for selection bias (whereby the most stable candidates are chosen), making this population different from the general population of individuals with alcohol abuse/dependence (DiMartini et al. 2002). In addition to the presence of alcohol use disorder, risk factors for relapse include shorter duration of pretransplant sobriety, family history of alcoholism, a diagnosis of alcohol dependence, and low social support (Dew et al. 2008; DiMartini et al. 2010; Rustad et al. 2015). With regard to duration of sobriety, the commonly used 6-month cut point does not appear to be definitive. In general, the longer the duration of sobriety, the lower the risk, with no clear threshold. In some cases, good outcomes are possible with shorter lengths of sobriety. For example, in patients with severe alcoholic hepatitis at high risk for mortality without transplantation, liver transplantation in highly selected cases has resulted in survival and relapse rates comparable to rates of patients in sustained remission (Im et al. 2016; Mathurin et al. 2011).

After transplantation, maintaining an open, nonjudgmental dialogue with transplant recipients may be the most effective way to identify alcohol and/or other substance use, and most recipients are open to discussing their substance use habits with the transplant team (DiMartini et al. 2001; Weinrieb et al. 2000). A review of liver enzymes and biopsy results and a candid discussion of the damage caused by alcohol and other substances provide an opportunity to explore the patient’s denial of the consequences of their use. Even in the most difficult cases, patients wish to maintain their health and are willing to listen to advice and recommendations on addiction treatment. In our experience, transplant team personnel are able to establish powerful emotional bonds with recipients. Many patients who have resumed substance use were relieved to learn that the transplant team would not abandon them. On the other hand, it is important not to condone or dismiss small amounts of alcohol or other substance use. What may seem supportive can be distorted by the patient with an addiction and become a tacit permission to use more regularly.

Medications that may reduce cravings and potentially diminish relapse risk for alcohol (e.g., acamprosate, ondansetron, naltrexone) or for opioids (e.g., naltrexone) have not been studied in transplant patients. One study that attempted to use naltrexone in actively alcohol-relapsing LT recipients found that patients were reluctant to use naltrexone because of its potential, albeit small, risk of hepatotoxicity (Weinrieb et al. 2001). Naltrexone can be a direct hepatotoxin at dosages higher than recommended (>300 mg/day) and is not recommended for patients with active hepatitis or liver failure. Baclofen was found in a randomized controlled trial to be safe and efficacious in patients with end-stage liver disease (Addolorato et al. 2007). In nontransplant populations, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) can stabilize mood and improve abstinence rates in depressed relapsing alcoholic individuals (Cornelius et al. 2003). Anecdotally, acamprosate has been safely used in a number of LT recipients, with some success in decreasing cravings and alcohol use. Because acamprosate is renally excreted, the dosage must be adjusted in renal insufficiency.

Tobacco

Smoking by organ transplant patients has a major impact on outcomes. Despite the availability of effective counseling and pharmacotherapies for smoking cessation, rates of return to smoking after transplant remain high, at 10%–40% (Corbett et al. 2012; Duerinckx et al. 2016). Two meta-analyses of posttransplantation adherence reported annual tobacco use rates of 3.4% among patients in the general transplant population and 10% among transplant recipients with substance use histories (Dew et al. 2007a, 2008). Tobacco use coupled with immunosuppressive therapy, which also increases cancer risk (Nabel 1999), results in higher rates of oropharyngeal and lung cancers, as well as of other malignancies. Tobacco suppresses immunity and can aggravate many disease states, resulting in higher rates of infections, vascular thrombosis, and atherosclerosis. Atherosclerosis is especially problematic for transplant recipients already at risk for hypertension, hyperlipidemia, and hyperglycemia induced by immunosuppressive medication. A meta-analysis across all organ types found that posttransplant smokers had higher rates of newly developed cardiovascular disease and nonskin malignancies, shorter survival times, and higher odds of mortality (Duerinckx et al. 2016).

Studies of heart transplant recipients have reported that 27%–50% of smokers resume smoking after transplantation (Botha et al. 2008; Corbett et al. 2012). Compared with nonsmokers, smokers had higher rates of vasculopathy, malignancies, and renal dysfunction, and significantly worse survival (Arora et al. 2009; Corbett et al. 2012; Duerinckx et al. 2016). Graft coronary artery disease and malignancy attributable to tobacco use have been found to be frequent causes of death following cardiac transplant (Botha et al. 2008). A study of heart transplant recipients found that elevated posttransplant anxiety was associated with a higher risk of resuming smoking (Dew et al. 1996).

A cross-sectional retrospective study of renal transplant recipients identified cigarette smoking as a factor in the progression of kidney disease (Zitt et al. 2007). Compared with nonsmokers, smokers had significant increases in the risk of cardiovascular events, renal fibrosis, graft rejection and graft failure, diabetes, and malignancies (Corbett et al. 2012; Zitt et al. 2007), and showed a fourfold increase in the risk of arteriopathy (Zitt et al. 2007). Previous smoking was also found to be a risk factor for graft failure after kidney transplant (Van Laecke et al. 2017). A study of LT recipients found that smoking cessation 2 years prior to transplantation reduced the incidence of vascular complications by 58% (Pungpapong et al. 2002).

Although historically most cardiothoracic transplant teams have required tobacco and even nicotine discontinuation prior to transplant, only slightly more than 20% of abdominal transplant programs now consider current smoking to be an absolute contraindication to transplant (Butt et al. 2014a). However, given that tobacco use is a modifiable risk factor that has demonstrated significant and negative effects on both patient and graft outcomes and survival, psychiatric consultants should make tobacco use a routine part of their assessments and should provide smoking cessation assistance when necessary. Given the beneficial effects on outcomes, cessation of all tobacco use prior to transplantation is strongly recommended, with close posttransplant monitoring because of the high risk that patients will resume use posttransplantation. Similar to findings regarding pretransplant alcohol use, the shorter the period of pretransplant tobacco abstinence, the higher the risk of relapse posttransplant (Corbett et al. 2012; Duerinckx et al. 2016; Ruttens et al. 2014). Self-reported tobacco use underrepresents actual use, and measurement of urinary cotinine, a metabolite of nicotine, can aid in identification (Corbett et al. 2012; Duerinckx et al. 2016). Treatments for smoking cessation include varenicline, bupropion, nicotine replacement (patches, gum, lozenges, and aerosolized formulations), and behavioral therapies (Hurt et al. 1997; Jorenby et al. 1999). Nicotine replacement strategies have been safely used in patients with advanced liver and lung disease, but severe renal disease may affect nicotine clearance. Nicotine replacement is relatively contraindicated in patients with serious heart disease due to the potential for worsening angina, increasing heart rate, and possibly exacerbating arrhythmias. When nicotine replacement therapy has been combined with bupropion, cases of severe hypertension have been reported, so careful monitoring of blood pressure is indicated. Bupropion should be used cautiously in transplant recipients, who are already at increased risk for seizures from immunosuppressive medications, specifically during the early posttransplant period, when immunosuppressive levels are higher. Because varenicline is eliminated by renal clearance, dosage reductions are necessary for patients with renal insufficiency or on dialysis. Varenicline’s side effects of nausea and vomiting may be problematic in transplant patients.

Other Substances

Compared with LT candidates with alcohol dependence, LT candidates with polysubstance dependence are more likely to have multiple prior addiction treatments; more likely to be diagnosed with personality disorders, especially those in Cluster B (antisocial, narcissistic, histrionic, borderline); and less likely to have stable housing, a consistent work history, or reliable social support (Fireman 2000). Despite evidence that this specific population could be at higher risk for relapse, there are few outcome studies addressing posttransplant nonalcohol substance use. Most studies have investigated the rates of relapse only in ALD recipients who also had a nonalcohol substance use disorder. One of the few studies to investigate all patients with a pre-LT addiction history found not only that patients with a pre-LT history of polysubstance use disorders had a higher relapse rate compared with those with alcohol dependence alone (38% vs. 20%) but also that the majority of polysubstance users demonstrated ongoing post-LT substance use (Fireman 2000). In a meta-analysis of eight studies including liver, kidney, and heart recipients, the annual rate of relapse to illicit drug use was 3.7% (Dew et al. 2008). Interestingly, this rate was significantly lower in liver recipients versus other organ recipients (1.9% vs. 6.1%).

Transplant program acceptance of opioid-dependent patients receiving methadone maintenance treatment (MMT) is a controversial issue. Several studies have examined candidate selection processes and posttransplant outcomes for this population. A survey of LT programs (Koch and Banys 2001) found that of the 56% of programs that reported accepting patients for evaluation who were taking methadone, a surprising 32% required patients to discontinue their methadone use prior to transplantation. Of even more concern was the overall lack of experience that programs had with such patients (i.e., only 10% of the programs had treated more than five MMT patients). Although there are no studies of pretransplant methadone cessation in LT patients, abundant evidence suggests that tapering methadone in stable methadone-maintained patients results in relapse to illicit opiate use in up to 82% of these individuals (Ball and Ross 1991). In our opinion, an attempt to taper a recovering opiate addict from methadone should not be made at a time when the patient is struggling with the stresses and pain associated with end-stage liver disease. Until data to the contrary emerge, requiring methadone tapering in stable opiate-dependent patients as a prerequisite for transplant candidacy could be considered unethical. Tapering heightens the risk for relapse, and those who relapse would be denied transplantation.

In regard to posttransplant outcomes of MMT patients, Koch and Banys (2001) found that among approximately 180 transplant patients on MMT, fewer than 10% relapsed to illicit opiate use. In general, regardless of patients’ illicit drug use, the transplant programs did not consider that immunosuppressive medication nonadherence (with rates <23%) necessarily affected outcomes, and the transplant coordinators’ impressions were that only 7 of the 180 patients had poor outcomes (Koch and Banys 2001). In two small series of MMT LT recipients (N=5 for each), overall long-term patient and graft survival in these recipients were found to be comparable to those in other LT recipients at the transplant centers, with none of the MMT patients evidencing posttransplant nonadherence or relapse to illicit drug use (Hails and Kanchana 2000; Kanchana et al. 2002). Liu et al. (2003), in a study of the largest single cohort (N=36) of MMT LT recipients to date, concluded that patient and graft survival were comparable to national averages (this study did not use a control group, however). Although four patients (11%) reported isolated episodes of heroin use posttransplantation, relapses were not considered to have resulted in poorer outcomes.

An important clinical consideration is pain management for patients on MMT. These patients may require higher-than-average doses of narcotic analgesics postoperatively. In one specific example, patients on MMT in whom methadone was also used as the posthospitalization pain medication required an average methadone dose increase of 60% posttransplantation, presumably to adjust for chronic downregulation of μ opioid pain receptors from chronic methadone exposure (Weinrieb et al. 2004) and improvement in metabolism after transplantation. Many clinicians consider methadone to be a useful choice for pain management rather than introducing another narcotic that may inadvertently precipitate a relapse.

Listing patients with active marijuana use has also led to controversy, partly because few data exist about the effects of marijuana in transplant recipients. In a large survey of heart transplant providers from 26 countries, two-thirds supported listing patients who use legal medical marijuana, but just under one-third supported listing patients who use legal recreational marijuana (Neyer et al. 2016). In 2015, California passed the Medical Cannabis Organ Transplant Act, which prohibits discrimination against medical cannabis patients in the organ transplant process unless a doctor has determined that medical cannabis use is clinically harmful in transplant. Several other states have followed this example. In the Neyer et al. (2016) survey, there was considerable heterogeneity in providers’ individual opinions about denying transplant to medical marijuana users despite being from regions that prohibit such practice. Smoked cannabis, however, may expose immunocompromised patients to infectious agents, as suggested by a number of case reports of fungal lung infections in cannabis smoking transplant recipients (Coffman 2008; Marks et al. 1996). New evidence suggests that inhaled/vaporized marijuana may be the source of these infections (Thompson et al. 2017). A recent study of medicinal dispensaries cultured multiple fungi (including Aspergillus and Cryptococcus) and bacteria (including Klebsiella, Enterobacter, Pseudomonas, and Bacillus) from their cannabis samples (Thompson et al. 2017), confirming that viable infectious organisms can be recovered from cannabis. Because medicinal dispensaries do not have quality/purity oversight (Wilkinson and D’Souza 2014), their marijuana can raise risks for immunocompromised patients.

Personality Disorders

Personality disorders are characterized by persisting and inflexible maladaptive patterns of subjective experience and behavior that may create emotional distress and interfere with an individual’s interpersonal relationships and social functioning. The requirements of successful transplantation can be too difficult for such individuals, as the process requires a series of adaptations to changes in physical and social functioning and significant ability to work constructively with both caregivers and the transplant team. By identifying personality disorders, the psychiatrist can potentially predict patterns of behavior, recommend treatment, develop a behavioral plan with the team to work constructively with the patient, and render an opinion as to the candidate’s ability to proceed with transplantation. Patients with personality disorders can require excessive amounts of time from the transplant team, which raises the issue of resource allocation as a potential selection criterion (Carlson et al. 2000). Not all personality disorders should be viewed similarly, however, because the behavioral and coping styles of different disorders can present varying degrees of concordance with the needs of transplantation. For example, the need for structure and orderliness of a candidate with obsessive-compulsive personality disorder would be more adaptive to the demands of transplantation than the coping style of a patient with borderline personality disorder.

The incidence of personality disorders in transplant populations is similar to that in the general population, ranging from 10% to 26% (Chacko et al. 1996; Dobbels et al. 2000), although in some cohorts, estimates have been as high as 33% (in a cohort of heart and lung transplant recipients) (Stilley et al. 2005) or even 57% (predominantly in those with a history of substance abuse) (Stilley et al. 1997). Case reports of patients with severe character pathology demonstrate the extent of adherence problems that can arise from these disorders, resulting in significant morbidity and mortality (Surman and Purtilo 1992; Weitzner et al. 1999). The disturbances in interpersonal relationships that can occur with personality disorders also can decrease the likelihood that patients will have stable and reliable social supports during the pre- and posttransplant phases (Yates et al. 1998). Of the personality disorders, borderline personality disorder is considered to represent the highest risk for posttransplant nonadherence (Laederach-Hofmann and Bunzel 2000). Among internal medicine outpatients, those with borderline personality symptoms had poorer adherence across a range of health care behaviors than those without (Sansone et al. 2015).

Sociopathy has not consistently been associated with substance relapse in the addiction literature (Vaillant 1997). However, in a study of 91 patients transplanted for ALD and followed for up to 3 years, 50% of the 18 patients who were identified as exhibiting antisocial behavior returned to either alcohol (n=6) or prescription narcotic addiction (n=3) posttransplantation, a rate that was significantly higher than the 19.8% return to alcohol use by the total group (Coffman et al. 1997). In a prospective study of 125 heart transplant recipients, personality disorders were associated with posttransplant adherence problems and a higher incidence of graft rejection (Shapiro et al. 1995).

Using the Type D (for “distressed”) personality construct (based on two broad and stable personality traits—negative affectivity and social inhibition), Denollet et al. (2007) found significantly higher rates of mortality and early allograft rejection in heart recipients with Type D personality than for those with non–Type D personality. Although Pedersen et al. (2006) found that those with Type D personality were also more likely to have worse physical and mental health–related QOL (3 and 6 times greater risk, respectively), the connection between this personality and posttransplant outcomes has not been further studied.

Patients with personality disorders do best with ongoing pre- and posttransplant psychotherapy, specifically cognitive and behavioral interventions to promote adherence to the care regimen and to establish a working alliance with transplant team members (Dobbels et al. 2000). These patients should be given clear and consistent instructions on rules and requirements of transplantation, reinforced by regular outpatient appointments. A limited number of transplant center personnel should maintain contact with each patient, and staff members should communicate regularly among themselves and with the outpatient psychiatric team (Carlson et al. 2000) to coordinate care and to reduce opportunities for cognitive distortions and splitting by the patient. A formal written contract can document the expectations of the transplant team and serve as a therapeutic treatment plan whereby the patient and team agree to work together toward common goals for the transplant recipient’s health (Dobbels et al. 2000).

Psychotic Disorders

Although chronic and active psychosis is thought by many to be incompatible with successful transplantation, case reports (Goracci et al. 2008; Krahn et al. 1998; Shapiro 2005) and a case series of 10 transplant recipients (Zimbrean and Emre 2015) demonstrate that carefully selected patients with psychosis can successfully undergo transplantation and with expert management survive after the procedure. Two sources—a survey of transplant psychiatrists at 12 national and international transplant programs (which identified only 35 cases of pretransplant psychotic disorders in transplant recipients) (Coffman and Crone 2002) and a historical cohort study of transplant recipients in the U.S. Renal Data System (which showed a 1.5% prevalence of psychosis requiring hospitalization among renal transplant recipients) (Abbott et al. 2003)—suggest that such patients are highly underrepresented among transplant recipients. The survey confirmed previously expressed stipulations that patients with psychotic disorders should be carefully screened before acceptance. Candidates should have demonstrated good adherence to both medical and psychiatric follow-up requirements; possess adequate social supports, especially in-residence support; and be capable of establishing a working relationship with the transplant team.

The survey by Coffman and Crone (2002) found that risk factors for problems with adherence after transplantation included antisocial or borderline personality disorder features, a history of assault, living alone, positive psychotic symptoms, and a family history of schizophrenia. Posttransplant nonadherence to nonpsychiatric medications was found in 20% of patients (7 of 35), and noncompliance with laboratory tests was found in 17% (6 of 35); however, these numbers are similar to percentages of medication and laboratory testing nonadherence in general transplant populations. Overall, nonadherence was responsible for rejection episodes in 5 patients (14%) and reduced graft function or loss in 4 patients (12%). Thirty-seven percent of patients experienced psychotic or manic episodes posttransplantation (not necessarily associated with immunosuppression), 20% attempted suicide (with two completed suicides), 20% experienced severe depression or catatonia, 5.7% committed assaults, 5.7% were arrested for disorderly conduct, and 8.6% required psychiatric commitment.

A recent review found no evidence of poorer posttransplant adherence in patients with psychotic disorders than in patients without (Price et al. 2014). A review of the Irish National Renal Transplant Programme database identified fewer than 1% of kidney recipients with bipolar disorder or schizophrenia, with no significant differences between these recipients and the general renal transplant group in length of transplant hospitalization, frequency of acute rejection episodes, graft function, or patient or graft survival (Butler et al. 2017). However, a historical cohort study of 39,628 renal transplant recipients in the U.S. Renal Data System showed substantially higher rates of death, graft loss, and nonadherence-related graft loss among patients hospitalized for psychosis, a finding that may have been at least partially mediated by undertreatment by medical providers or patient nonadherence (Abbott et al. 2003).

Concerns have been raised in regard to the potential of immunosuppressive medications to produce or exacerbate psychotic symptoms in patients with a prior psychiatric history. Antipsychotics are usually adequate to manage these symptoms if they emerge. Because transplant teams often overlook the early postoperative reinstitution of antipsychotics, it is essential that the psychiatrist devote careful attention to this issue. If quick reintegration of patients into their pretransplant outpatient psychiatric treatment regimen is not possible because of infirmity, interim in-home psychiatric follow-up care may be needed.

Special Issues in Transplantation

Intestinal Transplantation

Isolated small-bowel transplantation and multivisceral transplantation including the bowel are still relatively uncommon procedures, with total parenteral nutrition (TPN) remaining the primary therapeutic option for short-gut syndrome (Ceulemans et al. 2016). Candidates for intestinal transplantation typically have experienced complications such as repeated episodes of sepsis or dehydration, early liver disease, or loss of central venous access (Fishbein 2009). For parenteral-nutrition-dependent patients without complications who seek to improve their QOL, the decision to transplant is controversial, and the limited data suggesting improvements in QOL are from studies with less-than-optimal methodological rigor (Ceulemans et al. 2016). A review by the Intestinal Transplant Registry, representing 82 international intestinal transplant programs covering 2,887 transplants prior to 2013, reported survival rates of 76%, 56%, and 43% at 1, 5, and 10 years, respectively (Grant et al. 2015). Perhaps because of small numbers and poor long-term survival of patients, few studies have investigated outcomes beyond the immediate postoperative course and survival. Earlier studies examining psychiatric characteristics in the patient population showed patients to be a complex group, often with character pathology and drug and/or alcohol dependence histories and with iatrogenic dependence on high-dose narcotics (DiMartini et al. 1996). Some of these features could be ascribed to the difficulties of living with a chronic debilitating illness prior to transplantation, the severity and extent of the transplant surgery, and the prolonged posttransplantation hospitalizations marked by frequent setbacks.

Patients and their caregivers should be prepared for long and frequent hospitalizations, especially during the first years following transplantation (DiMartini et al. 1996), although substantial reductions in length of the initial hospitalization and need for readmission have occurred in recent years (Grant et al. 2015; Langnas 2004). A literature review of QOL in adults who had undergone intestinal transplant found that patients experienced improvement in QOL compared with pretransplant, as well as further improvement with longer posttransplant follow-up. Compared with TPN patients, patients who underwent transplant had fewer gastrointestinal symptoms and better energy, social functioning, and travel ability (Ceulemans et al. 2016; Pironi et al. 2012). For candidates or recipients who lack adequate gut absorption, the use of psychotropics without parenteral formulations is challenging, and other nonenteral routes of administration may need to be considered (Thompson and DiMartini 1999; see also “Alternative Routes of Administration” in Chapter 36, “Psychopharmacology”). Weaning patients from high-dose narcotics following successful transplantation may be difficult (DiMartini et al. 1996).

Cognitive Disorders and Delirium

Throughout the pre- to posttransplant phases, patients frequently experience cognitive dysfunction ranging from subclinical or mild symptoms to frank delirium. Impairment in cognitive function often results from physiological consequences of end-stage organ disease but may also be secondary to other comorbid disease processes (e.g., cerebrovascular disease from diabetes or hypertension), damage from prior alcohol or drug exposures, or previous structural damage to the brain (e.g., head trauma). (See Chapter 4, “Delirium,” for a general review of the evaluation and treatment of delirium.) The reversibility or progression of deficits may in part depend on age, the homeostatic reserve of the brain, prior central nervous system (CNS) insults, and the ability to withstand future transplant-related stressors (e.g., prolonged anesthesia, use of cardiac bypass, hemodynamic fluctuations, posttransplant immunosuppressive medications). Identification of cognitive impairment is critical to evaluating the candidate’s capacity to comprehend, make decisions, and follow medical directives. Caregivers also are impacted by the patient’s cognitive deficits, because they may be responsible for providing oversight, direct patient care, or assistance with activities of daily living. Although the restoration of normal organ function and physiology after transplantation may be expected to correct reversible cognitive impairments, such deficits may take months to years to resolve and may not resolve completely (Kramer et al. 1996; Sotil et al. 2009).

In heart failure, low cardiac output and CNS hypoperfusion can contribute to cognitive impairment. Even in the absence of acute cerebrovascular events, impaired cerebrovascular reactivity and ischemia may result. CNS microemboli are common in pre–heart transplant patients, especially in those on ventricular assist devices (VADs). In renal disease, accumulation of uremic toxins—in addition to hormonal elevations, electrolyte imbalances, malnutrition, and decreased γ-aminobutyric acid (GABA) and glycine activity—contributes to encephalopathy. Removal of uremic toxins via hemodialysis, correction of electrolyte imbalances and anemia, and treatment of malnutrition can improve cognition. For patients with end-stage lung disease, hypoxia and hypercapnia may cause mild to severe cognitive deficits, particularly in executive functions, attention, and memory (Parekh et al. 2005). Oxygen therapy may improve cognitive function for some lung candidates, and these patients can benefit from lung transplantation, but the extent to which these deficits are reversible is unclear (Parekh et al. 2005). Hepatic encephalopathy and adverse events related to VADs are two specific areas considered in detail below.

Hepatic Encephalopathy

Hepatic encephalopathy (HE), a neuropsychiatric syndrome commonly encountered in LT candidates, manifests a constellation of signs and symptoms, including alterations of consciousness (including stupor or coma), cognitive impairment, confusion/disorientation, affective/emotional dysregulation, psychosis, behavioral disturbances, bioregulatory disturbances, and physical signs such as asterixis. (HE is also addressed in Chapter 19, “Gastrointestinal Disorders.”) Identification of HE is important, because it directly affects patient quality and quantity of life; fulminant HE is associated with intracranial hypertension, cerebral edema, and death pretransplant (Ferenci et al. 2002). Even subclinical HE is clinically important, because it can impair patient safety (Schomerus et al. 1981) and is associated with persistent cognitive deficits post-LT (Tarter et al. 1990). By definition, subclinical HE is not identifiable on a typical clinical examination; detection may require additional neuropsychological tests of psychomotor speed, praxis, concentration, and attention. The Trail Making Test and the Digit Symbol and Block Design subtests from the Wechsler Adult Intelligence Scale—Revised are commonly used to identify subclinical HE, but neurocognitive testing is often not employed in gastrointestinal clinics due to lack of time and expertise. One study validated a smartphone application for delivering the Stroop cognitive screening test to detect minimal HE (Bajaj et al. 2013). A self-scoring algorithm and mobile device app potentially allow prospective monitoring even from home (Bajaj et al. 2013).

Because of their facility with cognitive examinations and testing, psychiatric consultants are often the clinicians who recognize and monitor HE symptoms and make recommendations regarding initiation of or improvement in treatment. Patients who undergo shunting procedures to relieve portal hypertension are at increased risk of ammonia buildup with subsequent HE (in one study, 45% of patients had at least one episode of HE following a shunting procedure [Riggio et al. 2008]), and they and their caregivers should be educated on monitoring for HE. Treatment should strive to normalize ammonia levels, despite the fact that blood ammonia levels are not well correlated with symptoms of HE (Riordan and Williams 1997). Treatment strategies include administration of lactulose (an osmotic laxative to flush out ammonia) and nonabsorbable antibiotics (to reduce levels of intestinal bacteria that convert protein to ammonia). Medications that potentially contribute to symptoms of encephalopathy—anticholinergic drugs, tranquilizers, and sedatives—should be avoided.

Ventricular Assist Devices in Heart Transplantation

Progress in the development of mechanical circulatory support (MCS) devices, including VADs and total artificial hearts, has dramatically improved both the physical and the psychological health of potential cardiac transplant candidates, and MCS devices are increasingly used as bridges to transplant or as permanent therapy in patients who do not meet criteria for transplant. (See also Chapter 17, “Heart Disease.”) These devices can reduce cognitive impairment from low cardiac output but also can cause adverse neurological and psychiatric events. The newer nonpulsatile continuous-flow MCS devices provide improved survival and reduced morbidity compared with the older pulsatile devices and are half as likely to lead to neuropsychiatric sequelae (Kirklin et al. 2013). A small prospective study that followed patients with heart failure before and after VAD implantation found no psychopathology (e.g., anxiety or depression), and patients’ memory actually improved, while other cognitive domains remained stable (Mapelli et al. 2014). MCS patients often experience improvements in QOL within months postimplantation, and these improvements are sustained (Grady and Dew 2012; Park et al. 2012).

Patients on MCS devices can undergo physical and physiological rehabilitation, develop exercise tolerance, and rebuild muscle mass, thus stabilizing their cardiac condition (Eshelman et al. 2009; Grady and Dew 2012). The lack of mobility restriction means that patients often can return to work and engage in activities such as dancing and driving (Catanese et al. 1996). With the urgency for transplantation diminished, the transplant team can wait for an optimal donor organ.

However, there continue to be risks and drawbacks with either temporary or permanent MCS therapy. The logistics of arranging outpatient care require a well-trained medical team whose members are available at all times, resulting in significant patient, caregiver, and medical system burden. Patient and caregiver responsibilities for MCS require the ability to perform daily inspections and as-needed maintenance, monitor for complications, and respond to alarms (for comprehensive reviews, see Caro et al. 2016 and Eshelman et al. 2009). Although patients using MCS devices have improved cerebral perfusion, they are at high risk of microembolic events. These events may be clinically silent (Thoennissen et al. 2005), but their cumulative effects on cognitive function may be significant over time, and periodic cognitive testing may be helpful in monitoring changes (Komoda et al. 2005). The risk of such events appears to be lower with the newer-generation MCS devices, but given that implantation periods have lengthened, routine care of MCS recipients requires consideration of cognitive status and identification of any developing deficits (see also Chapter 17, “Heart Disease”).

In posttransplantation comparisons with heart recipients who did not receive a VAD (either biventricular or left ventricular assist device), patients who were bridged to transplantation with a VAD showed similar improvements in physical functioning and emotional well-being, significantly lower rates of anxiety, but poorer cognitive status (Dew et al. 2001). The cognitive impairments observed in these VAD recipients were believed to be attributable to neurological events (e.g., microemboli, strokes) that occurred during the period of VAD support, and these events occurred at a higher rate among VAD recipients relative to non-VAD patients during the waiting period before transplantation. Although mild, these impairments appeared to persist during the first year following transplantation and were associated with a reduced likelihood of returning to employment.

Living Donor Transplantation

Despite the physical risks, discomfort and pain, expense and inconvenience, and potential psychological consequences of donating an organ, significant numbers of people volunteer to become living donors. Given the organ shortage and the improved survival rates of recipients of living organ donations, transplant programs are increasingly considering living donation. Living kidney donations are the most common type of living organ donation in the United States, accounting for more than one-third of all kidney transplants each year (around 5,600 donations per year). It is also possible to donate a portion of the liver and (in rare instances) a lobe of a lung or a portion of the pancreas or intestine (Organ Procurement and Transplantation Network 2017a).

Donation of an organ—putting one’s life at risk to help another—is an incredibly generous and altruistic gift. Yet the evaluation of such donors is a complex process requiring assessment of the circumstances and motives of the donor, the dynamics of the relationship between donor and recipient, the severity of the recipient’s illness, and family and societal forces. Current practice guidelines require a psychosocial evaluation for each potential donor to thoroughly examine these and other issues (Table 29–3) (Dew et al. 2007b, 2007c; Olbrisch et al. 2001; Surman 2002). In all U.S. centers, living-donor medical evaluation protocols include a predonation psychosocial assessment (performed by a psychiatrist, a psychologist, or a master’s-level or licensed clinical social worker) documenting the elements listed in Table 29–3 (Organ Procurement and Transplantation Network 2017b). The Live Donor Assessment Tool was developed to cover all of the potential areas of assessment and is being tested prospectively for validity (Iacoviello et al. 2017). Also, the recently developed Donor Cognition Instrument has been found to be reliable in assessing cognitions surrounding living organ donation (e.g., donor benefits, idealistic incentives, gratitude, worries about donation), which may facilitate psychosocial donor evaluation by mental health care professionals (Wirken et al. 2017). Donor assessments are designed to screen out potential donors with significant psychiatric morbidity (including substance abuse or dependence) and those unwilling or unable to give informed consent (due to the presence of coercion, likely financial gain, and/or impaired cognitive capacity). This screening process, combined with rigorous medical evaluation, ensures that living donors are very healthy before donation. Additionally, donors must be fully willing, independently motivated, and completely informed about the surgery. For all donors, and for liver donors in particular, long-term sequelae that may affect the donor’s future health, functioning, and even ability to obtain health insurance (due to the presence of a preexisting condition) are not fully known. Donor decision-making aids, standardized computerized education, and other educational interventions can lead to better-informed donors (Freeman et al. 2013) and living donor recipients (Waterman et al. 2014).

TABLE 29–3. Components of living donor evaluation

Psychosocial areas of assessment	Specific requirements for U.S. living donation from Organ Procurement and Transplantation Network policy 14a
Donor’s knowledge about the surgery	The determination that the living donor understands the short- and long-term medical and psychosocial risks for both the living donor and the recipient associated with living donation Identification of factors that warrant educational intervention prior to final donation decision
Motivation Ambivalence Evidence of coercion/inducement	An assessment of whether the decision to donate is free of inducement, coercion, and other undue pressure by exploring the reasons for donating and the nature of the relationship, if any, to the transplant candidate
Attitudes of significant others toward the donation
Availability of support Financial resources Work- and/or school-related issues (if applicable)	A review of the donor’s occupation, employment status, health insurance status, living arrangements, and social support The determination that the donor understands the potential financial implications of living donation
Psychiatric disorders Personality disorders Coping resources/styles Pain syndromes Prior psychological trauma/abuse Substance use/abuse	An evaluation of the donor’s psychological health, including any mental health issues that might complicate the donor’s recovery and that could be identified as risk factors for a poor psychosocial outcome Identification of factors that warrant therapeutic intervention prior to final donation decision An assessment for the presence of behaviors that may increase risk of disease transmission, as defined by the U.S. Public Health Service (Seem et al. 2013) A review of the living donor’s history of smoking and of alcohol and drug use, including past or present substance use disorders
Ability to provide informed consent	An assessment of the living donor’s ability to make an informed decision and ability to cope with the major surgery and related stress; this includes evaluating whether the donor has a realistic plan for donation and recovery, with social, emotional, and financial support available as recommended

^aAdapted from Organ Procurement and Transplantation Network 2017b.

Living liver donation is a much more surgically complex and invasive procedure than kidney donation and is therefore potentially more dangerous. Although mortality rates have been less than 1% for both kidney and liver donors (both adult-to-adult and adult-to-child) (Abecassis et al. 2012; Dew et al. 2017), nearly 40% of liver donors have complications within the first year, and serious complications occur in 3%–16% of donors (Abecassis et al. 2012; Dew et al. 2017). In the United States, transplant programs are required to have an independent living-donor advocate (i.e., someone who is not a member of the transplant team responsible for the recipient’s care and who is independent of the decision to transplant the potential recipient) to serve as a safeguard for patient autonomy, readiness to donate, and informed consent (Abecassis et al. 2000; Conti et al. 2002) to avoid conflicts of interest. The qualifications of these advocates must include knowledge of living organ donation, transplantation, medical ethics, informed consent, and the potential impact of family or other external pressures on the potential living donor’s donation decision (Organ Procurement and Transplantation Network 2017b).

Kidney donors should expect to miss 4–6 weeks of work and liver donors 8–12 weeks of work, especially if their jobs involve heavy lifting. Laparoscopic donor nephrectomy can result in overall quicker recovery times, as well as more favorable cosmetic results. For all donor types, the issue of donor financial hardship is becoming an increasingly prominent concern. Although recipients’ insurance covers the evaluation and immediate postoperative medical care, donors frequently report out-of-pocket costs, and some may have difficulties in obtaining or retaining health and life insurance (Boyarsky et al. 2014; Dew et al. 2007c; DiMartini et al. 2017). In a multisite study of liver donors (N=271), 44% reported that the out-of-pockets costs were burdensome, and 5% had difficulty getting or keeping health insurance (DiMartini et al. 2017). Kidney donors reported financial stresses from lost work and wages for both themselves and their family caregivers; costs incurred for household services they could not perform by themselves while recovering; and direct costs incurred for dependent care, transportation, and housing, with 30% reporting a loss exceeding $2,500 U.S. dollars (Rodrigue et al. 2015, 2016).

Living donors almost uniformly report that they do not regret having donated, that they would donate again if that were possible, and that they feel a deep sense of gratification at being able to help another person (Dew et al. 2014b). Moreover, generic health-related QOL assessments show that—at least in the early years postdonation—donors’ well-being, on average, meets or exceeds that reported in the general population (Dew et al. 2014b, 2017).

In a large multicenter study (“Adult-to-Adult Living Donor Liver Transplantation Cohort Study [A2ALL]” 2003) that prospectively followed hundreds of liver donors for up to 10 years after donation, 30% of donors reported improved family/spousal relationships, and more than 50% reported an improved relationship with the recipient (DiMartini et al. 2017). Some donors reported experiencing personal psychological growth as a result of the donation experience (Dew et al. 2016). The study also identified low rates (generally <5%) of major depressive, alcohol abuse, and anxiety syndromes in the first 2 years following donation (Butt et al. 2017). However, while 90% of donors surveyed 3–10 years (average 6 years) after donation felt positive about donation and would make the same decision again to donate, nearly 50% reported concerns about donation-related health issues, and 15% reported current donation-related health problems (Dew et al. 2016). A similar large multicenter study—the Renal and Lung Donors Evaluation Study—found that the majority of kidney donors reported being satisfied with their lives postdonation (Messersmith et al. 2014) and that depression rates in donors were comparable to rates in the general population (Jowsey et al. 2014). Predictors of depressive symptoms included nonwhite race, younger age at donation, longer duration of recovery after donation, greater financial burden, and feeling morally obligated to donate (Jowsey et al. 2014). A predonation intervention targeting donor risk factors for poorer psychosocial outcomes showed that donors in the intervention experienced lower rates of physical and psychological symptoms following donation (Dew et al. 2013). However, an alarming finding from a large multicenter study was that three liver donors had attempted suicide, with one completed suicide, following donation (Trotter et al. 2007). Trotter et al. (2007) estimated the suicide rate in liver donors at 2 cases per 1,000 donors, although the contribution of the donation to these events is unclear.

Altruistic (or nondirected) donors—individuals who donate an organ to an unknown recipient—pose one of the most complex challenges to transplant evaluation. In these cases, the psychosocial evaluation has particular importance in determining the suitability of the donor, and some believe that the medical standards for such donors should be higher (Ross 2002). These donors account for 1%–2% of all living organ donations (Organ Procurement and Transplantation Network 2017a). Altruistic donors are commonly viewed with some skepticism and are evaluated with greater caution than are related donors (Kazley et al. 2016). A detailed evaluation is critical, both to understand the motives of the donor and the psychological meaning of the donation to the donor and to identify any financial or other types of compensation expected for the donation. (See Dew et al. [2007b] and Dew et al. [2014a] for issues and guidelines relevant to the psychosocial evaluation and informed consent of unrelated donors.) One study of nondirected donors reported 360 inquiries over a 6-year period, of which 60 were declined on preliminary telephone interview (22% declined for psychosocial reasons); of the 51 serious candidates who came for partial or full evaluations, 8 (16%) were declined for psychosocial reasons (Jacobs et al. 2004). A postdonation study of directed and nondirected kidney donors found no differences in depression, anxiety, stress, self-esteem, physical outcomes, regret, or well-being between the groups, but nondirected donors were more engaged in other altruistic behaviors (P<0.001) (Maple et al. 2014).

Posttransplant Organ Function and Pharmacological Considerations

Although many transplant-specific psychological stresses can be appropriately managed with psychotherapeutic techniques, pharmacotherapy is an essential component in the psychiatric care of transplant patients. Given the high prevalence of psychiatric disorders in transplant candidates and recipients and the potential for untreated psychiatric disorders to influence outcomes, including adherence, pharmacological treatment is often required. Unfortunately, psychotropic medications are often not provided because of concerns about their potential risks and patients’ medical fragility. End-stage organ disease alters most aspects of drug pharmacokinetics, including absorption, bioavailability, metabolism, and clearance. For a full review of the pharmacokinetics of psychotropic drugs in general, and of pharmacokinetic changes in hepatic, renal, bowel, heart, and lung disease in particular, see Chapter 36, “Psychopharmacology”; see also Robinson and Levenson (2001) and Trzepacz et al. (2000). Here we discuss important aspects of pharmacokinetics in the newly transplanted patient during the recovery period (see Fireman et al. 2017 for further pharmacological considerations in transplant patients).

Although organ function may deteriorate slowly over the time before transplantation, following transplantation, for the majority of recipients, the newly transplanted organ functions immediately, so that normal physiological parameters are quickly restored and pharmacokinetic abnormalities resolve. Within the first month following transplantation for patients who have stable liver or kidney function, the clearance and steady-state volume of distribution of drugs can be similar to those in healthy volunteers (Hebert et al. 2003). Many transplant recipients can be treated with normal therapeutic drug dosing once they have recovered from immediate postoperative complications (e.g., delirium, sedation, ileus). With the resumption of normal organ function after transplantation, any psychotropic medications prescribed at lower dosages prior to transplant to accommodate diminished metabolism or elimination may need to be adjusted to higher levels.

For some transplant recipients, however, the transplanted organ does not assume normal autonomous physiological function immediately, or the organ may slowly regain normal function over time. Studies of posttransplantation pharmacokinetics have been mostly conducted in liver and kidney recipients due to the relevance of these organs to drug pharmacokinetics. Additionally, these studies have focused exclusively on immunosuppressive medications because of the need to achieve and maintain stable immunosuppressive medication levels to prevent organ rejection, the ability to monitor serum levels, and the narrow therapeutic range of these drugs. Nevertheless, data from these studies provide general guidelines on medication prescribing for specific types of posttransplant organ dysfunction.

Delayed Graft Function and Rejection

The most common allograft complication affecting pharmacokinetics in the immediate posttransplantation period is delayed graft function (DGF). DGF occurs in 10%–25% of liver and kidney recipients, although rates can reach 50% of cases if marginal organs are used (Angelico 2005; Shoskes and Cecka 1998; U.S. Renal Data System 2008). Liver recipients with DGF may require one-half of the typical immunosuppressive medication dose (Hebert et al. 2003; Lück et al. 2004). For kidney transplant recipients, DGF is deemed to have occurred if the recipient requires dialysis within the first week after transplant. For kidney recipients, DGF alters pharmacokinetics by mechanisms that increase the free fraction of parent drugs and renally excreted metabolites (Shaw et al. 1998). Severe or acute impairment in renal function after transplant can result in immunosuppressive levels 3–6 times higher than those in nonimpaired recipients for renally excreted drugs and their metabolites (Bullingham et al. 1998; Shaw et al. 1998). Acute cellular rejection occurs in 20%–70% of LT recipients, typically within the first 3 weeks posttransplant, resulting in transient graft dysfunction. Sixty-five percent to 80% of cases are effectively treated with high-dose steroids, and most episodes do not lead to clinically significant alterations in liver histology or architecture (Lake 2003). Chronic graft rejection, which occurs in 5%–10% of liver recipients, tends to respond poorly to treatment. Loss of liver synthetic function may not occur until very late in the course of chronic rejection (Lake 2003).

Among kidney recipients, 25%–60% will experience acute rejection, most often within the first 6 months after transplantation. Treatment of an identified rejection episode typically restores prerejection functioning; however, subclinical rejection that remains undetected can lead to gradually worsening renal function over time, with eventual graft loss (Rush et al. 1998).

If the episode of graft rejection is acute and resolves quickly, no specific changes in psychotropic dosages would be required (this is true across all organ types). Chronic rejection tends to evolve over time, with gradual deterioration in organ function and eventual loss of metabolic/elimination capacity. For all organ types, chronic graft rejection is potentially reversible in the early stages but not once chronic dysfunction has set in and progressive graft failure occurs. In these cases, pharmacokinetics may be similar to those in the pretransplant state.

General Issues

In addition to DGF or acute rejection, some recipients will experience transient physiological abnormalities in the weeks following transplant that could also affect pharmacokinetics (e.g., liver congestion and/or renal hypoperfusion in heart recipients, fluid overload in renal recipients, resolving hepatorenal syndrome in liver recipients). The mechanisms causing these derangements are complex and can include perioperative hemodynamic and fluid instability; graft-related factors such as graft harvesting; ischemic or reperfusion injury; or use of marginal organs. Thus, in addition to the status of the transplanted organ, evaluation of the recipients’ total physiological status is important in drug consideration and dosing.

Finally, in transplants of all organ types, calcineurin-inhibiting immunosuppressants are nephrotoxic with chronic use. Although there may be cumulative causes for renal failure in organ recipients, chronic use of immunosuppressants leads to renal failure in 7%–21% of recipients by 5 years posttransplant (Ojo et al. 2003). Thus, the state of the patient’s renal function should always be considered in decisions about medication usage, particularly in long-term transplant recipients and especially if the medication chosen requires renal clearance.

Neuropsychiatric Side Effects of Immunosuppressive Agents

Advances in the understanding of immunology and the development of newer strategies for immunosuppression may significantly reduce the need for—if not obviate completely—long-term maintenance immunosuppression. In the future, transplant recipients of all organ types may require immunosuppressant dosages only one or two times a week, or not at all (Starzl 2002). This achievement would remove the final obstacle to long-term successful outcomes for transplant recipients, given that the majority of long-term morbidity and mortality is due to chronic immunosuppression (e.g., infections, renal failure, cancer). Additionally, reduced requirements for immunosuppressants would facilitate medication adherence and would relieve some of the financial burden of long-term immunosuppression. However, for now, transplant recipients will continue to require immunosuppressive therapy and to be subject to these drugs’ potential neurotoxic and neuropsychiatric side effects. Psychiatrists should be familiar with the signs, symptoms, differential diagnosis, neuroimaging findings, and management of immunosuppressive neurotoxicity and secondary psychiatric disorders in solid organ recipients (Strouse et al. 1998) (see DiMartini et al. 2010 for further discussion of neuropsychiatric side effects of immunosuppressants).

Calcineurin-Inhibiting Immunosuppressive Medications

Cyclosporine

Cyclosporine is used as a primary immunosuppressive agent. Side effects are usually mild and include tremor, restlessness, and headache (Wijdicks et al. 1999). About 12% of patients on cyclosporine experience more serious neurotoxicity, characterized by acute confusional states, psychosis, seizures, speech apraxia, cortical blindness, and coma (de Groen et al. 1987; Wijdicks et al. 1995, 1996; Wilson et al. 1988).

Serious neurological side effects are associated with intravenous administration and higher dosages (Wijdicks et al. 1999). Cyclosporine trough levels correlate poorly with cyclosporine neurotoxicity, although in most studies, symptoms resolved when cyclosporine was discontinued and subsequently reinstated at a lower dosage (Wijdicks et al. 1999). Anticonvulsants can successfully treat cyclosporine-induced seizures but are not required long-term (Wijdicks et al. 1996), and seizures may cease with dosage reduction or discontinuation of cyclosporine. A few patients with serious clinical neurotoxic side effects have been found to have diffuse white matter abnormalities, predominantly in the occipitoparietal region, on computed tomography (CT) scans (de Groen et al. 1987; Gijtenbeek et al. 1999; Wijdicks et al. 1995) (see discussion of posterior reversible [leuko]encephalopathy syndrome [PRES] in the next subsection). In one case, symptoms of cyclosporine-induced cortical blindness resolved with drug discontinuation, although pathological evidence of CNS demyelination persisted for months after the episode (Wilson et al. 1988).

Tacrolimus

Tacrolimus is used as primary immunosuppressive therapy, as rescue therapy for patients who fail to respond to cyclosporine, and as treatment for graft-versus-host disease. In response to evidence that higher frequency of dosing was associated with poorer medication adherence (Weng et al. 2005), extended-release formulations were developed. Although tacrolimus is more potent and possibly less toxic than cyclosporine, the neuropsychiatric side effects of the two drugs appear to be similar (DiMartini et al. 1991; Freise et al. 1991). With tacrolimus, as with cyclosporine, neuropsychiatric side effects are more common with intravenous administration and diminish with oral administration and dosage reduction. Common symptoms include tremulousness, headache, restlessness, insomnia, vivid dreams, hyperesthesias, anxiety, and agitation (Fung et al. 1991). Cognitive impairment, coma, seizures, dysarthria, and delirium occur less often (8.4%) and are associated with higher plasma levels (DiMartini et al. 1997; Fung et al. 1991). Tacrolimus can produce symptoms of akathisia (Bernstein and Daviss 1992).

Tacrolimus is believed to cross the blood–brain barrier in humans. More serious neurotoxic side effects (e.g., focal neurological abnormalities, speech disturbances, hemiplegia, cortical blindness) may occur from higher CNS levels in patients who have a disrupted blood–brain barrier (Eidelman et al. 1991). In a study of 294 consecutive transplant recipients taking tacrolimus, those with preexisting CNS damage (e.g., from stroke, multiple sclerosis) were at higher risk of neurotoxic side effects (Eidelman et al. 1991). Both cyclosporine and tacrolimus are associated with posterior reversible (leuko)encephalopathy syndrome (PRES), an uncommon neurotoxic syndrome involving demyelination (particularly in the parieto-occipital region and centrum semiovale) (Ahn et al. 2003; Bartynski and Boardman 2007; Small et al. 1996). PRES typically occurs early postoperatively, often within the first months (Cruz et al. 2012), but can also occur years later. The presentation is variable and can include mental status changes, focal neurological symptoms, or generalized seizures without a clear metabolic etiology. Thus, moderate to serious symptoms of neurotoxicity warrant investigation with brain imaging. Characteristic neuroradiological abnormalities (low attenuation of white matter on CT scan or hyperintense lesions on T2-weighted magnetic resonance imaging [MRI]) are most commonly seen in the cortical and subcortical white matter, typically involving the posterior lobes (parietal and/or occipital), although cases have been reported involving the anterior brain, cerebellum, and brain stem (Bartynski and Boardman 2007). MRI may be better than CT for identifying the radiographic changes that characterize PRES (DiMartini et al. 2008). Like other serious neurotoxic side effects, PRES is not associated with the absolute serum level of tacrolimus but does resolve on discontinuation of the drug (Small et al. 1996). Multifocal sensorimotor polyneuropathy can occur with long-term immunosuppressive medication use and may require either dosage reduction (if possible) or medication treatment for painful peripheral neuropathy.

Other Agents for Adjunctive Immunosuppression or Treatment of Graft Rejection

Corticosteroids

Although chronic corticosteroid use has become less essential in immunosuppression for most patients posttransplantation, high dosages of corticosteroids are still employed in the early postoperative phase and also as “pulsed” dosages to treat acute rejection. Behavioral and psychiatric side effects of corticosteroids are common, but conclusions regarding the incidence or characteristics of these effects—or the specific dosages required to cause such effects—are not well established. These side effects are reviewed elsewhere in this volume, particularly in Chapter 7, “Depression”; Chapter 9, “Psychosis, Mania, and Catatonia”; Chapter 21, “Endocrine and Metabolic Disorders”; and Chapter 24, “Rheumatology.”

Sirolimus and Everolimus

The side effects of sirolimus and its analog everolimus do not include neurotoxicity (Watson et al. 1999). However, a systematic evaluation of sirolimus neurotoxicity has yet to be conducted.

Azathioprine

Azathioprine is primarily used as an adjunctive immunosuppressant and is less widely used today. Specific neuropsychiatric side effects have not been reported. Several reports of depressive symptoms in patients receiving azathioprine have been confounded by the concurrent use of other medications (specifically cyclosporine and prednisone) that may have contributed to the mood disturbance.

Mycophenolate Mofetil

Few neuropsychiatric symptoms have been reported with mycophenolate mofetil. Adverse reported CNS events (with incidence ranging from >3% to <20%) included anxiety, depression, delirium, seizures, agitation, hypertonia, paresthesias, neuropathy, psychosis, and somnolence (Roche Pharmaceuticals 2003); however, because the patients in whom these symptoms occurred were receiving mycophenolate mofetil in combination with cyclosporine and corticosteroids, the precise contribution of mycophenolate mofetil to the symptoms is difficult to interpret.

Monoclonal Antibodies

Monoclonal antibodies to T cells are used for induction immunosuppression or adjunctive therapy when a transplant recipient is experiencing an episode of rejection. Neuropsychiatric side effects, including headache, weakness, dizziness, tremor, and anxiety, are generally mild for these agents, with the exception of muromonab-CD3 (OKT3), which often causes more severe headache, tremor, agitation, and depression. OKT3 may also cause cerebral edema and encephalopathy, with confusion, disorientation, hallucinations, and seizures (Alloway et al. 1998). Rituximab has been associated with progressive multifocal leukoencephalopathy (Kranick et al. 2007). Basiliximab has been associated with insomnia, tremor, and headaches in more than 10% of patients.

Drug Interactions Between Psychotropic and Immunosuppressive Medications

Most of the immunosuppressants (e.g., tacrolimus, cyclosporine, sirolimus, everolimus, mycophenolate mofetil and corticosteroids) are metabolized by cytochrome P450 3A4 (CYP3A4); thus, psychotropics that strongly interact with CYP3A4 should be used cautiously or avoided in patients taking these immunosuppressants. Most immunosuppressants have significant toxicities and narrow therapeutic indices. Inhibitors and inducers of CYP3A4 may cause clinically significant drug-level changes, resulting in either toxicity or inadequate immunosuppression. Specific CYP3A4 inhibitors capable of interacting adversely with immunosuppressants, in decreasing order of inhibition, are as follows: fluvoxamine, nefazodone > fluoxetine > sertraline, TCAs, paroxetine > venlafaxine. Nefazodone has been implicated in several case reports (Campo et al. 1998; Helms-Smith et al. 1996; Wright et al. 1999) as causing toxic calcineurin inhibitor immunosuppressant levels, leading to acute renal insufficiency and delirium, and in two cases as causing elevated liver enzymes (Garton 2002). In a case report of a patient on stable dosages of nefazodone and sirolimus with therapeutic sirolimus levels, blood levels of sirolimus became undetectable when the nefazodone was stopped (Michalski et al. 2011). In a study in which fluoxetine or TCAs were used to treat depressed transplant recipients, no differences in cyclosporine blood level–dosage ratios and dose–response relationships were found between those treated and those not treated with antidepressants (Strouse et al. 1996). This finding suggests that antidepressants with less CYP3A4 inhibition may not have clinically meaningful drug interactions with immunosuppressants. Potent inducers of CYP3A4 (e.g., modafinil, St. John’s wort, carbamazepine) may lower the levels of immunosuppressive medications and thereby increase the risk of graft rejection (Fireman et al. 2017).

Several side effects relevant to immunosuppressant–psychotropic combinations deserve mention. Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) are common adverse effects of immunosuppressants, occurring in more than 60% of patients, and additional requirements for supplemental magnesium may aggravate these symptoms (Pescovitz and Navarro 2001); therefore, use of psychotropic medications with similar gastrointestinal adverse effects (e.g., SSRIs, venlafaxine) should be avoided. Immunosuppressants have significant metabolic side effects (e.g., weight gain, glucose intolerance, hyperlipidemia), suggesting the need to avoid psychotropics that cause these same metabolic effects. Tacrolimus and other immunosuppressants are associated with QT prolongation (Ikitimur et al. 2015) and should be used carefully in combination with QT-prolonging psychotropics.

References

Abbey S, Farrow S: Group therapy and organ transplantation. Int J Group Psychother 48(2):163–185, 1998 9563237

Abbott KC, Agodoa LY, O’Malley PG: Hospitalized psychoses after renal transplantation in the United States: incidence, risk factors, and prognosis. J Am Soc Nephrol 14(6):1628–1635, 2003 12761265

Abecassis M, Adams M, Adams P, et al; Live Organ Donor Consensus Group: Consensus statement on the live organ donor. JAMA 284(22):2919–2926, 2000 11187711

Abecassis MM, Fisher RA, Olthoff KM, et al: Complications of living donor hepatic lobectomy—a comprehensive report. Am J Transplant 12:1208–1217, 2012 22335782

Addolorato G, Leggio L, Ferrulli A, et al: Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370(9603):1915–1922, 2007 18068515

Addolorato G, Mirijello A, Leggio L, et al; Gemelli OLT Group: Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center. Alcohol Clin Exp Res 37(9):1601–1608, 2013 23578009

Adult-to-adult living donor liver transplantation cohort study (A2ALL). Hepatology 38(4):792, 2003 14512864

Ahn KJ, Lee JW, Hahn ST, et al: Diffusion-weighted MRI and ADC mapping in FK506 neurotoxicity. Br J Radiol 76(912):916–919, 2003 14711782

Akman B, Ozdemir FN, Sezer S, et al: Depression levels before and after renal transplantation. Transplant Proc 36(1):111–113, 2004 15013316

Alloway RR, Holt C, Somerville KT: Solid organ transplant, in Pharmacotherapy Self-Assessment Program, 3rd Edition. Kansas City, MO, American College of Clinical Pharmacy, 1998, pp 219–272

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

Angelico M: Donor liver steatosis and graft selection for liver transplantation: a short review. Eur Rev Med Pharmacol Sci 9(5):295–297, 2005 16231593

Arora S, Aukrust P, Andreassen A, et al: The prognostic importance of modifiable risk factors after heart transplantation. Am Heart J 158(3):431–436, 2009 19699867

Bailey DE Jr, Hendrix CC, Steinhauser KE, et al: Randomized trial of an uncertainty self-management telephone intervention for patients awaiting liver transplant. Patient Educ Couns 100(3):509–517, 2017 28277289

Baines LS, Joseph JT, Jindal RM: Emotional issues after kidney transplantation: a prospective psychotherapeutic study. Clin Transplant 16(6):455–460, 2002 12437627

Bajaj JS, Thacker LR, Heuman DM, et al: The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology 58(3):1122–1132, 2013 23389962

Ball J, Ross A: The Effectiveness of Methadone Maintenance Treatment. New York, Springer-Verlag, 1991

Baranyi A, Krauseneck T, Rothenhäusler HB: Posttraumatic stress symptoms after solid-organ transplantation: preoperative risk factors and the impact on health-related quality of life and life satisfaction. Health Qual Life Outcomes 11:111, 2013 23822659

Bartynski WS, Boardman JF: Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 28(7):1320–1327, 2007 17698535

Bernstein L, Daviss SR: Organic anxiety disorder with symptoms of akathisia in a patient treated with the immunosuppressant FK506. Gen Hosp Psychiatry 14(3):210–211, 1992 1376291

Botha P, Peaston R, White K, et al: Smoking after cardiac transplantation. Am J Transplant 8(4):866–871, 2008 18324978

Boyarsky BJ, Massie AB, Alejo JL, et al: Experiences obtaining insurance after live kidney donation. Am J Transplant 14(9):2168–2172, 2014 25041695

Bullingham RES, Nicholls AJ, Kamm BR: Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34(6):429–455, 1998 9646007

Bush K, Kivlahan DR, McDonell MB, et al: The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med 158(16):1789–1795, 1998 9738608

Butler MI, McCartan D, Cooney A, et al: Outcomes of renal transplantation in patients with bipolar affective disorder and schizophrenia: a national retrospective cohort study. Psychosomatics 58(1):69–76, 2017 27887740

Butt Z, Levenson J, Olbrisch ME: Policies on tobacco and marijuana smoking among U.S. cardiac, kidney, and liver transplant programs. Presentation at the annual meeting of the Society of Behavioral Medicine, April 26, 2014a

Butt Z, Levenson J, Olbrisch ME: Psychosocial screening practices and criteria for kidney transplantation: a survey of U.S. transplant centers. Presentation at the annual meeting of the Society of Behavioral Medicine, April 26, 2014b

Butt Z, Dew MA, Liu Q, et al: Psychological outcomes of living liver donors from a multicenter prospective study: results from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2). Am J Transplant 17(5):1267–1277, 2017 27865040

Calia R, Lai C, Aceto P, et al: Emotional self-efficacy and alexithymia may affect compliance, renal function and quality of life in kidney transplant recipients: results from a preliminary cross-sectional study. Physiol Behav 142:152–154, 2015 25680476

Campo JV, Smith C, Perel JM: Tacrolimus toxic reaction associated with the use of nefazodone: paroxetine as an alternative agent. Arch Gen Psychiatry 55(11):1050–1052, 1998 9819077

Carlson J, Potter L, Pennington S, et al: Liver transplantation in a patient at psychosocial risk. Prog Transplant 10(4):209–214, 2000 11232551

Caro MA, Rosenthal JL, Kendall K, et al: What the psychiatrist needs to know about ventricular assist devices: a comprehensive review. Psychosomatics 57(3):229–237, 2016 27005723

Catanese KA, Goldstein DJ, Williams DL, et al: Outpatient left ventricular assist device support: a destination rather than a bridge. Ann Thorac Surg 62(3):646–652, discussion 653, 1996 8783988

Ceulemans LJ, Lomme C, Pirenne J, et al: Systematic literature review on self-reported quality of life in adult intestinal transplantation. Transplant Rev (Orlando) 30(2):109–118, 2016 27066940

Chacko RC, Harper RG, Gotto J, et al: Psychiatric interview and psychometric predictors of cardiac transplant survival. Am J Psychiatry 153(12):1607–1612, 1996 8942458

Chang CF, Winsett RP, Gaber AO, et al: Cost-effectiveness of post-transplantation quality of life intervention among kidney recipients. Clin Transplant 18(4):407–414, 2004 15233818

Chisholm-Burns MA, Spivey CA, Graff Zivin J, et al: Improving outcomes of renal transplant recipients with behavioral adherence contracts: a randomized controlled trial. Am J Transplant 13(9):2364–2373, 2013 23819827

Coffman KL: The debate about marijuana usage in transplant candidates: recent medical evidence on marijuana health effects. Curr Opin Organ Transplant 13(2):189–195, 2008 18685302

Coffman KL, Crone C: Rational guidelines for transplantation in patients with psychotic disorders. Curr Opin Organ Transplant 7(4):385–388, 2002

Coffman KL, Hoffman A, Sher L, et al: Treatment of the postoperative alcoholic liver transplant recipient with other addictions. Liver Transpl Surg 3(3):322–327, 1997 9346758

Conti DJ, Delmonico FL, Dubler N, et al: New York State Committee on Quality Improvement in Living Liver Donation: a Report to New York State Transplant Council and New York State Department of Health. December 2002. Available at: https://www.health.ny.gov/professionals/patients/donation/organ/liver/. Accessed September 26, 2007.

Corbett C, Armstrong MJ, Neuberger J: Tobacco smoking and solid organ transplantation. Transplantation 94(10):979–987, 2012 23169222

Corbett C, Armstrong MJ, Parker R, et al: Mental health disorders and solid-organ transplant recipients. Transplantation 96(7):593–600, 2013 23743726

Cornelius JR, Bukstein O, Salloum I, et al: Alcohol and psychiatric comorbidity. Recent Dev Alcohol 16:361–374, 2003 12638646

Crone CC, Wise TN: Psychiatric aspects of transplantation, I: evaluation and selection of candidates. Crit Care Nurse 19(1):79–87, 1999 10401293

Cruz RJ Jr, DiMartini A, Akhavanheidari M, et al: Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management. Am J Transplant 12(8):2228–2236, 2012 22494636

Cuadrado A, Fábrega E, Casafont F, et al: Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 11(4):420–426, 2005 15776421

Cukor D, Newville H, Jindal R: Depression and immunosuppressive medication adherence in kidney transplant patients. Gen Hosp Psychiatry 30(4):386–387, 2008 18585547

Cupples SA, Steslow B: Use of behavioral contingency contracting with heart transplant candidates. Prog Transplant 11(2):137–144, 2001 11871049

De Bleser L, Matteson M, Dobbels F, et al: Interventions to improve medication-adherence after transplantation: a systematic review. Transpl Int 22(8):780–797, 2009 19386076

De Geest S, Burkhalter H, Bogert L, et al; Psychosocial Interest Group; Swiss Transplant Cohort Study: Describing the evolution of medication nonadherence from pretransplant until 3 years post-transplant and determining pretransplant medication nonadherence as risk factor for post-transplant nonadherence to immunosuppressives: the Swiss Transplant Cohort Study. Transpl Int 27(7):657–666, 2014 24628915

de Groen PC, Aksamit AJ, Rakela J, et al: Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 317(14):861–866, 1987 3306386

Denollet J, Holmes RVF, Vrints CJ, et al: Unfavorable outcome of heart transplantation in recipients with type D personality. J Heart Lung Transplant 26(2):152–158, 2007 17258149

DeVito Dabbs A, Dew MA, Myers B, et al: Evaluation of a hand-held, computer-based intervention to promote early self-care behaviors after lung transplant. Clin Transplant 23(4):537–545, 2009 19473201

DeVito Dabbs A, Song MK, Myers BA, et al: A randomized controlled trial of a mobile health intervention to promote self-management after lung transplantation. Am J Transplant 16(7):2172–2180, 2016 26729617

Dew MA: Anxiety and depression following transplantation. Presented at the Contemporary Forums Conference on Advances in Transplantation, Chicago, IL, September 2003

Dew MA, DiMartini AF: Transplantation, in Oxford Handbook of Health Psychology. Edited by Friedman HS. New York, Oxford University Press, 2011, pp 522–559

Dew MA, Roth LH, Thompson ME, et al: Medical compliance and its predictors in the first year after heart transplantation. J Heart Lung Transplant 15(6):631–645, 1996 8794030

Dew MA, Switzer GE, DiMartini AF, et al: Psychosocial assessments and outcomes in organ transplantation. Prog Transplant 10(4):239–259, quiz 260–261, 2000 11232552

Dew MA, Kormos RL, Winowich S, et al: Quality of life outcomes after heart transplantation in individuals bridged to transplant with ventricular assist devices. J Heart Lung Transplant 20(11):1199–1212, 2001 11704480

Dew MA, Goycoolea JM, Harris RC, et al: An Internet-based intervention to improve psychosocial outcomes in heart transplant recipients and family caregivers: development and evaluation. J Heart Lung Transplant 23(6):745–758, 2004 15366436

Dew MA, DiMartini AF, De Vito Dabbs A, et al: Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation 83(7):858–873, 2007a 17460556

Dew MA, Jacobs CL, Jowsey SG, et al; United Network for Organ Sharing (UNOS); American Society of Transplant Surgeons; American Society of Transplantation: Guidelines for the psychosocial evaluation of living unrelated kidney donors in the United States. Am J Transplant 7(5):1047–1054, 2007b 17359510

Dew MA, Switzer GE, DiMartini AF, et al: Psychosocial aspects of living organ donation, in Living Donor Organ Transplantation. Edited by Tan HP, Marcos A, Shapiro R. New York, Taylor & Francis, 2007c, pp 7–26

Dew MA, DiMartini AF, Steel J, et al: Meta-analysis of risk for relapse to substance use after transplantation of the liver or other solid organs. Liver Transpl 14(2):159–172, 2008 18236389

Dew MA, Dabbs AD, Myaskovsky L, et al: Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Transplantation 88(5):736–746, 2009 19741474

Dew MA, DiMartini AF, DeVito Dabbs AJ, et al: Onset and risk factors for anxiety and depression during the first 2 years after lung transplantation. Gen Hosp Psychiatry 34(2):127–138, 2012 22245165

Dew MA, DiMartini AF, DeVito Dabbs AJ, et al: Preventive intervention for living donor psychosocial outcomes: feasibility and efficacy in a randomized controlled trial. Am J Transplant 13(10):2672–2684, 2013 23924065

Dew MA, Boneysteele G, DiMartini A: Unrelated donors, in Living Donor Advocacy: An Evolving Role Within Transplantation. Edited by Steel JL. New York, Springer, 2014a, pp 149–167

Dew MA, Myaskovsky L, Steel JL, et al: Managing the psychosocial and financial consequences of living donation. Curr Transplant Rep 1(1):24–34, 2014b 24592353

Dew MA, Rosenberger EM, Myaskovsky L, et al: Depression and anxiety as risk factors for morbidity and mortality after organ transplantation: a systematic review and meta-analysis. Transplantation 100(5):988–1003, 2015 26492128

Dew MA, DiMartini AF, Ladner DP, et al: Psychosocial outcomes 3 to 10 years after donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study. Transplantation 100(6):1257–1269, 2016 27152918

Dew MA, Butt Z, Humar A, et al: Long-term medical and psychosocial outcomes in living liver donors. Am J Transplant 17(4):880–892, 2017 27862972

DiMartini AF, Dew MA: Monitoring alcohol use on the liver transplant wait list: therapeutic and practical issues. Liver Transpl 18(11):1267–1269, 2012 22887916

DiMartini A, Twillman R: Organ transplantation in paranoid schizophrenia. Psychosomatics 35(2):159–161, 1994 8171175

DiMartini A, Pajer K, Trzepacz P, et al: Psychiatric morbidity in liver transplant patients. Transplant Proc 23(6):3179–3180, 1991 1721399

DiMartini A, Fitzgerald MG, Magill J, et al: Psychiatric evaluations of small intestine transplantation patients. Gen Hosp Psychiatry 18 (6 suppl):25S–29S, 1996 8937920

DiMartini A, Trzepacz PT, Pajer KA, et al: Neuropsychiatric side effects of FK506 vs. cyclosporine A. First-week postoperative findings. Psychosomatics 38(6):565–569, 1997 9427854

DiMartini A, Day N, Dew MA, et al: Alcohol use following liver transplantation: a comparison of follow-up methods. Psychosomatics 42(1):55–62, 2001 11161122

DiMartini A, Weinrieb R, Fireman M: Liver transplantation in patients with alcohol and other substance use disorders. Psychiatr Clin North Am 25(1):195–209, 2002 11912940

DiMartini A, Fontes P, Dew MA, et al: Age, model for end-stage liver disease score, and organ functioning predict posttransplant tacrolimus neurotoxicity. Liver Transpl 14:815–822, 2008 18508372

DiMartini A, Dew MA, Day N, et al: Trajectories of alcohol consumption following liver transplantation. Am J Transplant 10(10):2305–2312, 2010 20726963

DiMartini A, Crone C, Dew MA: Alcohol and substance use in liver transplant patients. Clin Liver Dis 15(4):727–751, 2011 22032526

DiMartini A, Dew MA, Liu Q, et al: Social and financial outcomes of living liver donation: a prospective investigation within the Adult-to-Adult Living Liver Cohort Study-2 (A2ALL-2). Am J Transplant 17(4):1081–1096, 2017 27647626

Dobbels F, Put C, Vanhaecke J: Personality disorders: a challenge for transplantation. Prog Transplant 10(4):226–232, 2000 11216178

Dobbels F, De Bleser L, Berben L, et al: Efficacy of a medication adherence enhancing intervention in transplantation: the MAESTRO-Tx trial. J Heart Lung Transplant 36(5):499–508, 2017 28162931

Donnadieu-Rigole H, Olive L, Nalpas B, et al: Follow up of alcohol consumption after liver transplantation: interest of an addiction team? Alcohol Clin Exp Res 41(1):165–170, 2017 27936489

Duerinckx N, Burkhalter H, Engberg SJ, et al; B-SERIOUS consortium: Correlates and outcomes of post-transplant smoking in solid organ transplant recipients: a systematic literature review and meta-analysis. Transplantation 100(11):2252–2263, 2016 27479162

Dumortier J, Dharancy S, Cannesson A, et al: Recurrent alcoholic cirrhosis in severe alcoholic relapse after liver transplantation: a frequent and serious complication. Am J Gastroenterol 110(8):1160–1166, quiz 1167, 2015 26169514

Eggers P: Comparison of treatment costs between dialysis and transplantation. Semin Nephrol 12(3):284–289, 1992 1615249

Eidelman BH, Abu-Elmagd K, Wilson J, et al: Neurologic complications of FK 506. Transplant Proc 23(6):3175–3178, 1991 1721398

Eshelman AK, Mason S, Nemeh H, et al: LVAD destination therapy: applying what we know about psychiatric evaluation and management from cardiac failure and transplant. Heart Fail Rev 14(1):21–28, 2009 18214674

Evans LD, Stock EM, Zeber JE, et al: Post-transplantation outcomes in veterans with serious mental illness transplantation. Transplantation 99(8):e57–e65, 2015 25706275

Farmer SA, Grady KL, Wang E, et al: Demographic, psychosocial, and behavioral factors associated with survival after heart transplantation. Ann Thorac Surg 95(3):876–883, 2013 23374446

Favaro A, Gerosa G, Caforio AL, et al: Posttraumatic stress disorder and depression in heart transplantation recipients: the relationship with outcome and adherence to medical treatment. Gen Hosp Psychiatry 33(1):1–7, 2011 21353121

Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35(3):716–721, 2002 11870389

Fine RN, Becker Y, De Geest S, et al: Nonadherence consensus conference summary report. Am J Transplant 9(1):35–41, 2009 19133930

Fineberg SK, West A, Na PJ, et al: Utility of pretransplant psychological measures to predict posttransplant outcomes in liver transplant patients: a systematic review. Gen Hosp Psychiatry 40:4–11, 2016 26947255

Fireman M: Outcome of liver transplantation in patients with alcohol and polysubstance dependence. Presented at Research Society on Alcoholism: Symposium on Liver Transplantation for the Alcohol Dependent Patient, Denver, CO, June 2000

Fireman M, DiMartini A, Crone C: Organ transplantation, in Psychopharmacology of the Medically Ill, 2nd Edition. Edited by Ferrando SJ, Levenson JL. Arlington, VA, American Psychiatric Publishing, 2017, pp 597–632

Fishbein TM: Intestinal transplantation. N Engl J Med 361(10):998–1008, 2009 19726774

Fleming JN, Taber DJ, McElligott J, et al: Mobile health in solid organ transplant: the time is now. Am J Transplant 17(9):2263–2276, 2017 28188681

Fredericks EM, Magee JC, Opipari-Arrigan L, et al: Adherence and health-related quality of life in adolescent liver transplant recipients. Pediatr Transplant 12(3):289–299, 2008 18282211

Freeman J, Emond J, Gillespie BW, et al; A2ALL Study Group: Computerized assessment of competence-related abilities in living liver donors: the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Clin Transplant 27(4):633–645, 2013 23859354

Freise CE, Rowley H, Lake J, et al: Similar clinical presentation of neurotoxicity following FK 506 and cyclosporine in a liver transplant recipient. Transplant Proc 23(6):3173–3174, 1991 1721397

Fung JJ, Alessiani M, Abu-Elmagd K, et al: Adverse effects associated with the use of FK 506. Transplant Proc 23(6):3105–3108, 1991 1721372

Fusar-Poli P, Martinelli V, Klersy C, et al: Depression and quality of life in patients living 10 to 18 years beyond heart transplantation. J Heart Lung Transplant 24(12):2269–2278, 2005 16364881

Fusar-Poli P, Lazzaretti M, Ceruti M, et al: Depression after lung transplantation: causes and treatment. Lung 185(2):55–65, 2007 17393235

Garton T: Nefazodone and CYP450 3A4 interactions with cyclosporine and tacrolimus1. Transplantation 74(5):745, 2002 12352898

Gijtenbeek JM, van den Bent MJ, Vecht CJ: Cyclosporine neurotoxicity: a review. J Neurol 246(5):339–346, 1999 10399863

Goracci A, Fagiolini A, Calossi S, et al: Quetiapine in post-transplant acute mania/bipolar disorder NOS. Int J Neuropsychopharmacol 11(5):723–724, 2008 18346295

Grady KL, Dew MA: Psychosocial issues in mechanical circulatory support, in Mechanical Circulatory Support: A Companion to Braunwald’s Heart Disease. Edited by Kormos RL, Miller LW. Philadelphia, PA, Elsevier, 2012, pp 194–205

Grant D, Abu-Elmagd K, Mazariegos G, et al; Intestinal Transplant Association: Intestinal Transplant Registry report: global activity and trends. Am J Transplant 15(1):210–219, 2015 25438622

Guyatt GH, Berman LB, Townsend M, et al: A measure of quality of life for clinical trials in chronic lung disease. Thorax 42(10):773–778, 1987 3321537

Hails KC, Kanchana T: Outcome of liver transplants for patients on methadone. Poster presented at the 153rd annual meeting of the American Psychiatric Association, Chicago, IL, May 13–18, 2000

Hebert MF, Wacher VJ, Roberts JP, et al: Pharmacokinetics of cyclosporine pre- and post-liver transplantation. J Clin Pharmacol 43(1):38–42, 2003 12520626

Helms-Smith KM, Curtis SL, Hatton RC: Apparent interaction between nefazodone and cyclosporine (letter). Ann Intern Med 125(5):424, 1996 8702104

Hurt RD, Sachs DP, Glover ED, et al: A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337(17):1195–1202, 1997 9337378

Iacoviello BM, Shenoy A, Hunt J, et al: A prospective study of the reliability and validity of the Live Donor Assessment Tool. Psychosomatics 58(5):519–526, 2017 28526401

Ikitimur B, Cosansu K, Karadag B, et al: Long-term impact of different immunosuppressive drugs on QT and PR intervals in renal transplant patients. Ann Noninvasive Electrocardiol 20(5):426–432, 2015 25367596

Im GY, Kim-Schluger L, Shenoy A, et al: Early liver transplantation for severe alcoholic hepatitis in the United States—a single-center experience. Am J Transplant 16(3):841–849, 2016 26710309

Jacobs CL, Roman D, Garvey C, et al: Twenty-two nondirected kidney donors: an update on a single center's experience. Am J Transplant 4(7):1110–1116, 2004 15196069

Jin SG, Yan LN, Xiang B, et al: Posttraumatic stress disorder after liver transplantation. Hepatobiliary Pancreat Dis Int 11(1):28–33, 2012 22251467

Joost R, Dörje F, Schwitulla J, et al: Intensified pharmaceutical care is improving immunosuppressive medication adherence in kidney transplant recipients during the first post-transplant year: a quasi-experimental study. Nephrol Dial Transplant 29(8):1597–1607, 2014 24914089

Jorenby DE, Leischow SJ, Nides MA, et al: A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340(9):685–691, 1999 10053177

Jowsey SG, Taylor M, Trenerry MR: Special topics in transplantation: psychometric screening of transplant candidates. Oral presentation presented at the annual meeting of the Academy of Psychosomatic Medicine, Tucson, AZ, November 2002

Jowsey SG, Jacobs C, Gross CR, et al; RELIVE Study Group: Emotional well-being of living kidney donors: findings from the RELIVE Study. Am J Transplant 14(11):2535–2544, 2014 25293374

Kanchana TP, Kaul V, Manzarbeitia C, et al: Liver transplantation for patients on methadone maintenance. Liver Transpl 8(9):778–782, 2002 12200777

Kazley AS, Amarnath R, Palanisamy A, et al: Anonymous altruistic living kidney donation in the US: reality and practice. International Journal of Transplant Research and Medicine 2(2):021, 2016

Kirklin JK, Naftel DC, Kormos RL, et al: Fifth INTERMACS annual report: risk factor analysis from more than 6000 mechanical circulatory support patients. J Heart Lung Transplant 32(2):141–156, 2013 23352390

Koch M, Banys P: Liver transplantation and opioid dependence. JAMA 285(8):1056–1058, 2001 11209177

Komoda T, Drews T, Sakuraba S, et al: Executive cognitive dysfunction without stroke after long-term mechanical circulatory support. ASAIO J 51(6):764–768, 2005 16340365

Krahn LE, Santoscoy G, Van Loon JA: A schizophrenic patient’s attempt to resume dialysis following renal transplantation. Psychosomatics 39(5):470–473, 1998 9775708

Kramer L, Madl C, Stockenhuber F, et al: Beneficial effect of renal transplantation on cognitive brain function. Kidney Int 49(3):833–838, 1996 8648927

Kranick SM, Mowry EM, Rosenfeld MR: Progressive multifocal leukoencephalopathy after rituximab in a case of non-Hodgkin lymphoma. Neurology 69(7):704–706, 2007 17698796

Laederach-Hofmann K, Bunzel B: Noncompliance in organ transplant recipients: a literature review. Gen Hosp Psychiatry 22(6):412–424, 2000 11072057

Lake JR: Liver transplantation, in Current Diagnosis and Treatment in Gastroenterology, 2nd Edition. Edited by Friedman SL, McQuaid KR, Grendell JH. New York, McGraw-Hill, 2003, pp 813–834

Lam WY, Fresco P: Medication adherence measures: an overview. Biomed Res Int 2015:217047, 2015 26539470

Langnas AN: Advances in small-intestine transplantation. Transplantation 77 (9 suppl):S75–S78, 2004 15201690

Lee BP, Chen P-H, Haugen C, et al: Three-year results of a pilot program in early liver transplantation for severe alcoholic hepatitis. Ann Surg 265(1):20–29, 2017 27280501

Levenson J, Olbrisch ME: Psychosocial screening and selection of candidates for organ transplantation, in The Transplant Patient. Edited by Trzepacz PT, DiMartini AF. Cambridge, UK, Cambridge University Press, 2000, pp 21–41

Liu LU, Schiano TD, Lau N, et al: Survival and risk of recidivism in methadone-dependent patients undergoing liver transplantation. Am J Transplant 3(10):1273–1277, 2003 14510701

Lucey MR: Liver transplantation for alcoholic liver disease. Nat Rev Gastroenterol Hepatol 11(5):300–307, 2014 24393837

Lück R, Böger J, Kuse E, et al: Achieving adequate cyclosporine exposure in liver transplant recipients: a novel strategy for monitoring and dosing using intravenous therapy. Liver Transpl 10(5):686–691, 2004 15108262

Maldonado J, Plante R, David E: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT). Oral presentation presented at the annual meeting of the Academy of Psychosomatic Medicine, Miami, FL, November 22, 2008

Mapelli D, Cavazzana A, Cavalli C, et al: Clinical psychological and neuropsychological issues with left ventricular assist devices (LVADs). Ann Cardiothorac Surg 3(5):480–489, 2014 25452908

Maple H, Chilcot J, Burnapp L, et al: Motivations, outcomes, and characteristics of unspecified (nondirected altruistic) kidney donors in the United Kingdom. Transplantation 98(11):1182–1189, 2014 25099701

Marks WH, Florence L, Lieberman J, et al: Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient. Transplantation 61(12):1771–1774, 1996 8685958

Masson S, Marrow B, Kendrick S, et al: An “alcohol contract” has no significant effect on return to drinking after liver transplantation for alcoholic liver disease. Transpl Int 27(5):475–481, 2014 24533687

Mathurin P, Moreno C, Samuel D, et al: Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 365(19):1790–1800, 2011 22070476

McGillicuddy JW, Gregoski MJ, Weiland AK, et al: Mobile health medication adherence and blood pressure control in renal transplant recipients: a proof-of-concept randomized controlled trial. JMIR Res Protoc 2(2):e32, 2013 24004517

Messersmith EE, Gross CR, Beil CA, et al; RELIVE Study Group: Satisfaction with life among living kidney donors: a RELIVE study of long-term donor outcomes. Transplantation 98(12):1294–1399, 2014 25136843

Michalski LS, Bhuva D, Pakrasi A, et al: Sirolimus and nefazodone interaction in a renal transplant patient. Eur J Psychiatry 25(3):119–121, 2011

Miller LR, Paulson D, Eshelman A, et al: Mental health affects the quality of life and recovery after liver transplantation. Liver Transpl 19(11):1272–1278, 2013 23959592

Miller P, Wikoff R, McMahon M, et al: Development of a health attitude scale. Nurs Res 31(3):132–136, 1982 6918917

Mori DL, Gallagher P, Milne J: The Structured Interview for Renal Transplantation—SIRT. Psychosomatics 41(5):393–406, 2000 11015625

Mucsi I, Bansal A, Jeannette M, et al: Mental health and behavioral barriers in access to kidney transplantation: a Canadian cohort study. Transplantation 101(6):1182–1190, 2017 27467541

Nabel GJ: A transformed view of cyclosporine. Nature 397(6719):471–472, 1999 10028962

Neuberger J, Adams D, MacMaster P, et al: Assessing priorities for allocation of donor liver grafts: survey of public and clinicians. BMJ 317(7152):172–175, 1998 9665895

Nevins TE, Nickerson PW, Dew MA: Understanding medication nonadherence after kidney transplantation. J Am Soc Nephrol 28(8):2290–2301, 2017 28630231

Neyer J, Uberoi A, Hamilton M, et al: Marijuana and listing for heart transplant: a survey of transplant providers. Circ Heart Fail 9(7):e002851, 2016 27413036

Ojo AO, Held PJ, Port FK, et al: Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 349(10):931–940, 2003 12954741

Olbrisch ME, Levenson JL, Hamer R: The PACT: a rating scale for the study of clinical decision making in psychosocial screening of organ transplant candidates. Clinical Transplantation 3(3):164–169, 1989

Olbrisch ME, Benedict SM, Haller DL, et al: Psychosocial assessment of living organ donors: clinical and ethical considerations. Prog Transplant 11(1):40–49, 2001 11357556

Olbrisch ME, Benedict SM, Ashe K, et al: Psychological assessment and care of organ transplant patients. J Consult Clin Psychol 70(3):771–783, 2002 12090382

Organ Procurement and Transplantation Network: Data. 2017a. Available at: https://optn.transplant.hrsa.gov/data/. Accessed September 26, 2017.

Organ Procurement and Transplantation Network: Policies. 2017b. Available at: https://optn.transplant.hrsa.gov/governance/policies/. Accessed September 26, 2017.

Parekh PI, Blumenthal JA, Babyak MA, et al; INSPIRE Investigators: Gas exchange and exercise capacity affect neurocognitive performance in patients with lung disease. Psychosom Med 67(3):425–432, 2005 15911906

Park SJ, Milano CA, Tatooles AJ, et al; HeartMate II Clinical Investigators: Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy. Circ Heart Fail 5(2):241–248, 2012 22282104

Pedersen SS, Holkamp PG, Caliskan K, et al: Type D personality is associated with impaired health-related quality of life 7 years following heart transplantation. J Psychosom Res 61(6):791–795, 2006 17141667

Pescovitz MD, Navarro MT: Immunosuppressive therapy and post-transplantation diarrhea. Clin Transplant 15 (suppl 4):23–28, 2001 11778784

Pironi L, Baxter JP, Lauro A, et al: Assessment of quality of life on home parenteral nutrition and after intestinal transplantation using treatment-specific questionnaires. Am J Transplant 12 (suppl 4):S60–S66, 2012 22958831

Popoola J, Greene H, Kyegombe M, et al: Patient involvement in selection of immunosuppressive regimen following transplantation. Patient Prefer Adherence 8:1705–1712, 2014 25525347

Price A, Whitwell S, Henderson M: Impact of psychotic disorder on transplant eligibility and outcomes. Curr Opin Organ Transplant 19(2):196–200, 2014 24553499

Pungpapong S, Manzarbeitia C, Ortiz J, et al: Cigarette smoking is associated with an increased incidence of vascular complications after liver transplantation. Liver Transpl 8(7):582–587, 2002 12089709

Reese PP, Bloom RD, Trofe-Clark J, et al: Automated reminders and physician notification to promote immunosuppression adherence among kidney transplant recipients: a randomized trial. Am J Kidney Dis 69(3):400–409, 2017 27940063

Rice JP, Eickhoff J, Agni R, et al: Abusive drinking after liver transplantation is associated with allograft loss and advanced allograft fibrosis. Liver Transpl 19(12):1377–1386, 2013 24115392

Riggio O, Angeloni S, Salvatori FM, et al: Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts. Am J Gastroenterol 103(11):2738–2746, 2008 18775022

Riordan SM, Williams R: Treatment of hepatic encephalopathy. N Engl J Med 337(7):473–479, 1997 9250851

Robinson MJ, Levenson JL: Psychopharmacology in transplant patients, in Biopsychosocial Perspectives on Transplantation. Edited by Rodrigue JR. New York, Kluwer Academic/Plenum, 2001, pp 151–172

Roche Pharmaceuticals: CellCept (Mycophenolate Mofetil) Product Information. Nutley, NJ, Roche Laboratories, 2003

Rodrigue JR, Mandelbrot DA, Pavlakis M: A psychological intervention to improve quality of life and reduce psychological distress in adults awaiting kidney transplantation. Nephrol Dial Transplant 26(2):709–715, 2011 20603243

Rodrigue JR, Hanto DW, Curry MP: The Alcohol Relapse Risk Assessment: a scoring system to predict the risk of relapse to any alcohol use after liver transplant. Prog Transplant 23(4):310–318, 2013 24311394

Rodrigue JR, Schold JD, Morrissey P, et al; KDOC Study Group: Predonation direct and indirect costs incurred by adults who donated a kidney: findings from the KDOC study. Am J Transplant 15(9):2387–2393, 2015 25943721

Rodrigue JR, Schold JD, Morrissey P, et al; KDOC Study Group: Direct and indirect costs following living kidney donation: findings from the KDOC study. Am J Transplant 16(3):869–876, 2016 26845630

Rogal SS, Dew MA, Fontes P, DiMartini AF: Early treatment of depressive symptoms and long-term survival after liver transplantation. Am J Transplant 13(4):928–935, 2013 23425326

Rosenberger EM, Dew MA, DiMartini AF, et al: Psychosocial issues facing lung transplant candidates, recipients and family caregivers. Thorac Surg Clin 22(4):517–529, 2012 23084615

Rosenberger EM, DiMartini AF, DeVito Dabbs AJ, et al: Psychiatric predictors of long-term transplant-related outcomes in lung transplant recipients. Transplantation 100(1):239–247, 2016 26177087

Ross LF: All donations should not be treated equally: a response to Jeffrey Kahn’s commentary. J Law Med Ethics 30(3):448–451, 2002 12497705

Rush D, Nickerson P, Gough J, et al: Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 9(11):2129–2134, 1998 9808101

Rustad JK, Stern TA, Prabhakar M, Musselman D: Risk factors for alcohol relapse following orthotopic liver transplantation: a systematic review. Psychosomatics 56(1):21–35, 2015 25619671

Ruttens D, Verleden SE, Goeminne PC, et al: Smoking resumption after lung transplantation: standardised screening and importance for long-term outcome. Eur Respir J 43(1):300–303, 2014 23988766

Samelson-Jones E, Mancini DM, Shapiro PA: Cardiac transplantation in adult patients with mental retardation: do outcomes support consensus guidelines? Psychosomatics 53(2):133–138, 2012 22424161

Sansone RA, Bohinc RJ, Wiederman MW: Borderline personality symptomatology and compliance with general health care among internal medicine outpatients. Int J Psychiatry Clin Pract 19(2):132–136, 2015 25410155

Schomerus H, Hamster W, Blunck H, et al: Latent portasystemic encephalopathy, I: nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 26(7):622–630, 1981 7249898

Seem DL, Lee I, Umscheid CA, Kuehnert MJ; United States Public Health Service: PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 128(4):247–343, 2013 23814319

Shapiro PA: Heart transplantation in a schizophrenia patient. Am J Psychiatry 162(11):2194–2195, 2005 16263872

Shapiro PA, Williams DL, Foray AT, et al: Psychosocial evaluation and prediction of compliance problems and morbidity after heart transplantation. Transplantation 60(12):1462–1466, 1995 8545875

Shaw LM, Mick R, Nowak I, et al: Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function. J Clin Pharmacol 38(3):268–275, 1998 9549665

Shoskes DA, Cecka JM: Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 66(12):1697–1701, 1998 9884262

Small SL, Fukui MB, Bramblett GT, et al: Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506). Ann Neurol 40(4):575–580, 1996 8871576

Smith PJ, Blumenthal JA, Carney RM, et al: Neurobehavioral functioning and survival following lung transplantation. Chest 145(3):604–611, 2014 24233282

Sotil EU, Gottstein J, Ayala E, et al: Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation. Liver Transpl 15(2):184–192, 2009 19177446

Starzl TE: The saga of liver replacement, with particular reference to the reciprocal influence of liver and kidney transplantation (1955–1967). J Am Coll Surg 195(5):587–610, 2002 12437245

Sterneck M, Yegles M, Rothkirch von G, et al: Determination of ethyl glucuronide in hair improves evaluation of long-term alcohol abstention in liver transplant candidates. Liver Int 34(3):469–476, 2014 23829409

Stevenson LW: Indications for listing and de-listing patients for cardiac transplantation (Chapter 233 [Cardiac Transplantation], reviews and editorials), in Harrison’s Online. 2002. Available at: http://harrisons.accessmedicine.com. Accessed September 26, 2017.

Stilley CS, Miller DJ, Tarter RE: Measuring psychological distress in candidates for liver transplantation: a pilot study. J Clin Psychol 53(5):459–464, 1997 9257224

Stilley CS, Dew MA, Pilkonis P, et al: Personality characteristics among cardiothoracic transplant recipients. Gen Hosp Psychiatry 27(2):113–118, 2005 15763122

Strouse TB, Fairbanks LA, Skotzko CE, et al: Fluoxetine and cyclosporine in organ transplantation. Failure to detect significant drug interactions or adverse clinical events in depressed organ recipients. Psychosomatics 37(1):23–30, 1996 8600490

Strouse TB, el-Saden SM, Glaser NE, et al: Immunosuppressant neurotoxicity in liver transplant recipients. Clinical challenges for the consultation-liaison psychiatrist. Psychosomatics 39(2):124–133, 1998 9584538

Stuber ML, Shemesh E, Seacord D, et al: Evaluating non-adherence to immunosuppressant medications in pediatric liver transplant recipients. Pediatr Transplant 12(3):284–288, 2008 18331387

Surman OS: The ethics of partial-liver donation (comment). N Engl J Med 346(14):1038, 2002 11932469

Surman OS, Purtilo R: Reevaluation of organ transplantation criteria. Allocation of scarce resources to borderline candidates. Psychosomatics 33(2):202–212, 1992 1557485

Tarter RE, Switala JA, Arria A, et al: Subclinical hepatic encephalopathy. Comparison before and after orthotopic liver transplantation. Transplantation 50(4):632–637, 1990 2219286

Thoennissen NH, Schneider M, Allroggen A, et al: High level of cerebral microembolization in patients supported with the DeBakey left ventricular assist device. J Thorac Cardiovasc Surg 130(4):1159–1166, 2005 16214534

Thompson D, DiMartini A: Nonenteral routes of administration for psychiatric medications. A literature review. Psychosomatics 40:185–192, 1999 10341530

Thompson GR3rd, Tuscano JM, Dennis M, et al: A microbiome assessment of medical marijuana. Clin Microbiol Infect 23(4):269–270, 2017 27956269

Trotter JF, Hill-Callahan MM, Gillespie BW, et al; A2ALL Study Group: Severe psychiatric problems in right hepatic lobe donors for living donor liver transplantation. Transplantation 83(11):1506–1508, 2007 17565325

Trzepacz PT, DiMartini AF, Gupta B: Psychopharmacologic issues in transplantation, in The Transplant Patient. Edited by Trzepacz P, DiMartini A. Cambridge, UK, Cambridge University Press, 2000, pp 187–213

Twillman RK, Manetto C, Wellisch DK, et al: The Transplant Evaluation Rating Scale. A revision of the psychosocial levels system for evaluating organ transplant candidates. Psychosomatics 34(2):144–153, 1993 8456157

U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation: Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR) 2011 Annual Data Report. Rockville, MD, U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, 2012. Available at: https://srtr.transplant.hrsa.gov/annual_reports/2011/Default.aspx. Accessed September 26, 2017.

U.S. Renal Data System: USRDS 2008 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, 2008. Available at: https://www.usrds.org/atlas08.aspx. Accessed September 26, 2017.

Vaillant GE: The natural history of alcoholism and its relationship to liver transplantation. Liver Transpl Surg 3(3):304–310, 1997 9346756

Van Laecke S, Nagler EV, Peeters P, et al: Former smoking and early and long-term graft outcome in renal transplant recipients: a retrospective cohort study. Transpl Int 30(2):187–195, 2017 27896857

Waterman AD, Robbins ML, Paiva AL, et al: Your Path to Transplant: a randomized controlled trial of a tailored computer education intervention to increase living donor kidney transplant. BMC Nephrol 15:166, 2014 25315644

Watson CJ, Friend PJ, Jamieson NV, et al: Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67(4):505–509, 1999 10071017

Webzell I, Ball D, Bell J, et al: Substance use by liver transplant candidates: an anonymous urinalysis study. Liver Transpl 17(10):1200–1204, 2011 21744466

Weinrieb RM, Van Horn DH, McLellan AT, et al: Interpreting the significance of drinking by alcohol-dependent liver transplant patients: fostering candor is the key to recovery. Liver Transpl 6(6):769–776, 2000 11084066

Weinrieb RM, Van Horn DH, McLellan AT, et al: Alcoholism treatment after liver transplantation: lessons learned from a clinical trial that failed. Psychosomatics 42(2):110–116, 2001 11239123

Weinrieb RM, Barnett R, Lynch KG, et al: A matched comparison study of medical and psychiatric complications and anesthesia and analgesia requirements in methadone-maintained liver transplant recipients. Liver Transpl 10(1):97–106, 2004 14755785

Weinrieb RM, Van Horn DH, Lynch KG, Lucey MR: A randomized, controlled study of treatment for alcohol dependence in patients awaiting liver transplantation. Liver Transpl 17(5):539–547, 2011 21506242

Weitzner MA, Lehninger F, Sullivan D, et al: Borderline personality disorder and bone marrow transplantation: ethical considerations and review. Psychooncology 8(1):46–54, 1999 10202782

Weng FL, Israni AK, Joffe MM, et al: Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol 16(6):1839–1848, 2005 15800121

Wijdicks EF, Wiesner RH, Krom RA: Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 45(11):1962–1964, 1995 7501141

Wijdicks EF, Plevak DJ, Wiesner RH, et al: Causes and outcome of seizures in liver transplant recipients. Neurology 47(6):1523–1525, 1996 8960738

Wijdicks EF, Dahlke LJ, Wiesner RH: Oral cyclosporine decreases severity of neurotoxicity in liver transplant recipients. Neurology 52(8):1708–1710, 1999 10331708

Wilkinson ST, D’Souza DC: Problems with the medicalization of marijuana. JAMA 311(23):2377–2378, 2014 24845238

Wilson SE, de Groen PC, Aksamit AJ, et al: Cyclosporin A-induced reversible cortical blindness. J Clin Neuroophthalmol 8(4):215–220, 1988 2977135

Wirken L, van Middendorp H, Hooghof CW, et al: Pre-donation cognitions of potential living organ donors: the development of the Donation Cognition Instrument in potential kidney donors. Nephrol Dial Transplant 32(3):573–580, 2017 28160472

Wright DH, Lake KD, Bruhn PS, Emery RW Jr: Nefazodone and cyclosporine drug-drug interaction. J Heart Lung Transplant 18(9):913–915, 1999 10528754

Wright L, Pennington JJ, Abbey S, et al: Evaluation of a mentorship program for heart transplant patients. J Heart Lung Transplant 20(9):1030–1033, 2001 11557200

Yates WR, Booth BM, Reed DA, et al: Descriptive and predictive validity of a high-risk alcoholism relapse model. J Stud Alcohol 54(6):645–651, 1993 8271799

Yates WR, LaBrecque DR, Pfab D: Personality disorder as a contraindication for liver transplantation in alcoholic cirrhosis. Psychosomatics 39(6):501–511, 1998 9819950

Zelikovsky N, Schast AP, Palmer J, et al: Perceived barriers to adherence among adolescent renal transplant candidates. Pediatr Transplant 12(3):300–308, 2008 18194352

Zimbrean P, Emre S: Patients with psychotic disorders in solid-organ transplant. Prog Transplant 25(4):289–296, 2015 26645920

Zitt N, Kollerits B, Neyer U, et al: Cigarette smoking and chronic allograft nephropathy. Nephrol Dial Transplant 22(10):3034–3039, 2007 17517794