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* Anxiety Disorders (General)
Psychosomatics 42:300-313, August 2001
© 2001 The Academy of Psychosomatic Medicine

Prevalence and Risk of Depression and Anxiety-Related Disorders During the First Three Years After Heart Transplantation

Mary Amanda Dew, Ph.D., Robert L. Kormos, M.D., Andrea F. DiMartini, M.D., Galen E. Switzer, Ph.D., Herbert C. Schulberg, Ph.D., Loren H. Roth, M.D., M.P.H., and Bartley P. Griffith, M.D.

Received August 25, 2000; revised December 28, 2000; accepted January 11, 2001. From the Departments of Psychiatry, Psychology, Epidemiology, Surgery (Artificial Heart and Cardiothoracic Transplantation Programs), and Medicine, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, PA; and the Department of Psychiatry, Weill Medical College of Cornell University, Ithaca, NY. Address reprint requests to Dr. Dew, Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA, 15213. E-mail: DewMA{at}msx.upmc.edu


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although poor psychological adjustment to organ transplantation appears to be a major contributor to reduced quality of life and increased physical morbidity, the prevalence and risk factors for psychiatric disorder have not been considered beyond the first 12–18 months after transplantation. The authors enrolled a representative sample of 191 heart transplant recipients in a prospective examination of the prevalence, clinical characteristics, and risk factors for DSM-III-R major depressive disorder (MDD), generalized anxiety disorder (GAD), associated adjustment disorders, and posttraumatic stress disorder related to transplant (PTSD-T) during the 3 years postsurgery. Survival analysis indicates that cumulative risks for disorder onset were MDD, 25.5%; adjustment disorders, 20.8% (17.7% with anxious mood); PTSD-T, 17.0%; and any assessed disorder, 38.3%. There was only one case of GAD. PTSD-T onset was limited almost exclusively to the first year posttransplant. Episodes of MDD (but not anxiety disorders) that occurred later posttransplant (8 to 36 months postsurgery) were more likely than early posttransplant episodes to be treated with psychotropic medications. For both MDD and anxiety disorders, later episodes were less likely to be precipitated by transplant-related stressors than other life stressors. Factors increasing cumulative risk for psychiatric disorder posttransplant included pretransplant psychiatric history, female gender, longer hospitalization, more impaired physical functional status, and lower social supports from caregiver and family in the perioperative period. Risk factors' effects were additive; the presence of an increasing number of risk factors bore a dose-response relationship to cumulative risk of disorder.

Key Words: Transplantation • Depression • Anxiety

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Poor psychological adjustment to the organ transplant experience appears to be a major contributor to reduced quality of life1–6 and increased physical morbidity in the years after transplantation.4,7–11 Elevations in self-reported distress levels and clinically significant, diagnosable episodes of psychiatric disorder have been observed in the aftermath of all types of solid organ transplantation, including kidney, heart, liver, pancreas, and lung transplantation.12–27 At least during the early years posttransplant (the period on which most work has focused to date), psychiatric morbidity is associated with poorer medical compliance4,9–11,28–33 and with the occurrence of infections and acute and chronic graft rejection.4,9,11

Although the frequency, risk factors for, and other correlates of psychiatric disorders after organ transplantation have been examined in a variety of cohorts, the interpretation of such data—and hence its use for the development of clinical interventions—is limited for several reasons (see Dew et al.3,4 for reviews). First, samples are typically cross-sectional and include persons who vary dramatically in how long they have had their transplants. Because rates obtained from these samples are rarely adjusted for length of time since transplant, it has not been possible to estimate the true prevalence or cumulative risk for disorders across time posttransplant. Moreover, whether prevalence rates of prominently observed conditions such as major depressive disorder (MDD) and posttraumatic stress disorder related to the transplant (PTSD-T) are stable over time posttransplant or change over the long-term years is unknown. Second, most reports have relied on relatively small samples of well fewer than 100 persons, resulting in estimates with wide margins of error and in lack of power to examine either clinical characteristics or psychosocial correlates of observed disorders. Finally, studies of cohorts followed longitudinally have focused almost exclusively on the first 1–2 years posttransplant,2–4,34 despite the fact that survival rates for major types of transplantation (heart, liver, kidney) are over 50% even 5–8 years after the transplant.35

We enrolled and followed a relatively large, representative sample of heart transplant recipients in the first prospective examination of the prevalence, clinical characteristics, and key risk factors for mental health outcomes through 3 years after heart transplantation. In the present report, we examine the cumulative risk of onset of depressive or anxiety-related disorders during the 3-year period, as well as clinical characteristics of the episodes. We also consider whether pre- and early posttransplant health-related and psychosocial factors affected heart recipients' risk of developing one or more of the targeted psychiatric disorders posttransplant. Potential risk factors were selected based on prior evidence of their importance in transplant populations and in other groups exposed to health-related and non–health-related life stressors.3,14,17,20,23,36–38


  METHODS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Respondents
One hundred ninety-one adults (age 18 or older) who received heart transplants between July 1989 and July 1995 in the Cardiothoracic Transplantation Program, University of Pittsburgh Medical Center, were enrolled in a prospective examination of health after transplantation.9,17 All adults surviving beyond the initial posttransplant recovery period (defined as the first 6 weeks after surgery) were eligible for the study (N=202) and were initially contacted at that time. (Four additional recipients were ineligible for miscellaneous reasons, e.g., not fluent in English.) The refusal rate for the present sample was 5.4% (n=11). Respondents were indistinguishable from the few nonrespondents on transplant-related and sociodemographic characteristics. During the 3-year study period, 24 respondents (12.6%) refused to continue their participation, 27 died (14.1%), and 4 were lost to follow-up for other reasons (e.g., transfer to a different transplant center for follow-up) (2.1%). Our analyses of prevalence rates of psychiatric disorders include data from all individuals until they were lost to follow-up.

Table 1 presents data on cardiac-related and sociodemographic characteristics for the entire sample of 191 persons, for the panel subgroup with complete follow-up, and for the two subgroups with incomplete follow-up. As detailed elsewhere,9 the Pittsburgh cohort is similar to the International Society for Heart and Lung Transplantation (ISHLT) Registry of adult heart recipients worldwide during the study enrollment period39,40 in indication for transplant, donor organ characteristics, and recipient demographic characteristics. Respondents with complete data through the follow-up period were similar to those lost to refusal and death during this period on the majority of characteristics in Table 1. However, trends noted on several variables and the one significant difference indicate that respondents who died—as would be expected—tended to have poorer health status in the early months posttransplant: they were hospitalized longer after surgery, had poorer Karnofsky Index41 scores (as rated by Transplant Team nurse practitioners at 2 months posttransplant), and were more likely to be offered medication "rescue" (i.e., switching from cyclosporine, the most established immunosuppressant, to tacrolimus, which was initially experimental in the Pittsburgh program).


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TABLE 1. Background characteristics of 191 heart recipients



Procedure
After obtaining informed consent, individual, 90- to 120-minute face-to-face interviews were conducted when respondents returned for outpatient Transplant Team evaluations at 2-, 7-, and 12-months posttransplant. A similar long-term follow-up assessment was conducted at the time of their 3-year anniversary posttransplant. The semistructured interviews were conducted by clinically trained interviewers. These clinicians had master's or doctoral degrees in mental health disciplines. They participated in an intensive, comprehensive training program and interrater reliability evaluation before conducting interviews, with periodic field checks of interrater reliability for study instruments during the data collection phase of the study. The interrater reliability evaluations and field checks were accomplished through comparison of clinicians' scoring of patient responses to each other and to those of the trainer. Comparison data were gathered both by having the clinicians rate audio tapes of interviews conducted by others and by having clinicians (or the trainer) sit in as observers during actual patient interviews conducted by other clinicians in the study. On semistructured instruments (e.g., the SCID), interrater reliability levels were maintained at levels exceeding an intraclass correlation of 0.90.

Instruments
Psychiatric status posttransplant. Because depression- and anxiety-related disorders appear to be the most common psychiatric complications in chronically physically ill populations,36,42,43 including transplant recipients,3 we examined specific DSM-III-R disorders,44 including major depressive disorder (MDD), generalized anxiety disorder (GAD), adjustment disorder with depressed and/or anxious mood (posttransplant only), and posttraumatic stress disorder related to the transplant experience (PTSD-T). With the exception of PTSD-T, discussed below, disorders were assessed with the Structured Clinical Interview for DSM-III-R (SCID).45 The 2-month interview assessed lifetime pretransplant and early posttransplant history; subsequent interviews covered the period since last assessment.

Early in the study, we noted that recipients frequently mentioned symptoms and experiences surrounding the transplant that resembled PTSD. Thus, we broadened our 12-month and 36-month posttransplant interviews to include an assessment of transplant-related PTSD (PTSD-T), adapted from the Michigan version of the WHO/ADAMHA Composite International Diagnostic Instrument (CIDI),46,47 and diagnosed according to the symptom and duration criteria of DSM-III-R. (PTSD was not included in the SCID at the time we assembled our interview.) The 12-month interview assessed whether PTSD-T-related symptoms occurred during the period 0–7 months posttransplant and/or 8–12 months posttransplant; the 36-month assessment covered the period since last assessment.

Given the challenge of assigning psychiatric diagnoses among persons with physical illnesses,36,42,48 we adopted a conservative approach to diagnosis. In individual case review, we followed Cavanaugh's49 recommendations such that psychiatric diagnoses were based primarily on affective/cognitive symptoms; somatic symptoms were used to support the diagnosis only when these somatic symptoms were judged by the interviewer and by us to have been severe, disproportionate to the medical illness, and temporally related to the affective/cognitive symptoms. Interviewers were trained to question respondents extensively concerning the nature and severity of any symptoms.

We assigned diagnoses only after thorough review of interview data and medical records data regarding medications taken during the period. It is important to note that doses of corticosteroids—which had the potential to influence mood—were kept quite low after the initial recovery period. The maintenance dose for the present sample averaged only 9 mg/day, with a range of 0–22.5 mg/day. Such levels are considerably lower than that typically found to influence mood.50 Steroid dose at the time of onset of the psychiatric disorders assessed in the present paper ranged from 0 to 22.5 mg/day, with a median of 10 mg (interquartile range, 7.5–15 mg). Approximately 16% of individuals who met psychiatric diagnostic criteria had been weaned from steroids completely. Furthermore, although the study was not designed to detect transient mood changes associated with steroid dose changes, we were able to examine cross-sectional correlations in this sample between prednisone dose and Symptom Checklist-9051 depression and anxiety symptom levels (as well as anger/hostility levels) at each interview timepoint.9,52 These correlations were uniformly small and nonsignificant.

Potential risk factors for psychiatric disorder posttransplant. We considered a selected series of pretransplant health-related and psychosocial characteristics and posttransplant stressors and social support-related variables based on previous evidence that these classes of variables influence individuals' likelihood of developing one or more of the targeted psychiatric disorders posttransplant.

Pretransplant characteristics. These measures included known demographic risk factors for psychiatric disorder (gender, age, and level of education)47 and whether or not respondents had a lifetime personal history of major depression and/or GAD, assessed as described above. With respect to the transplant, we considered the role of indication for transplant, length of time waiting for the transplant, and whether individuals had required circulatory support as a bridge to transplant. The latter two factors were included based on our own and others' previous work, indicating that they affect a variety of posttransplant physical and mental health outcomes.53,54

Posttransplant health stressors and supports. With respect to health-related stress, we ascertained whether or not individuals had required an extended period of hospitalization immediately posttransplant, defined as a hospital stay of greater than 1 month. [The average hospital stay at our center was 1 month (interquartile range, 3–5 weeks) during the years in which recipients were enrolled in the present study.] We also determined from medical records whether or not respondents had experienced significant acute graft rejection during the first 2 months posttransplant. Acute rejection was coded as present for any endomyocardial biopsy during this period graded as 3A or higher, using standard ISHLT criteria.55 Biopsies were performed during patients' routine outpatient clinical visits and/or during hospitalization; the standard biopsy schedule during the first 2 months posttransplant was weekly for the first month and once to twice during the second month posttransplant.

The second measure of health stress related to the transplant was the recipient's self-reported physical functional status at the initial interview, as measured by the physical health subscales of the Sickness Impact Profile (SIP).56 (We could not use the Karnofsky Index because it was not available for all respondents.) The physical health subscales (totaling 52 items) assess the areas of sleep and rest, body care and movement, mobility, and ambulation. The percentage of items endorsed was determined. Individuals were classified as showing impairment if 20% or more of the items were endorsed; one-third of the sample scored above this cutpoint. In the absence of any clinically defined cutpoint as to what constitutes serious impairment on the SIP subscales,57 we chose this cutpoint based on empirical evidence that a level of 20% or higher is relatively rare across the many chronic illness samples for which descriptive data are available: less than one-quarter to one-tenth of respondents in a variety of samples have endorsed 20% or more of the physical subscales' items.56,57

Three areas of social supports available to the recipient were assessed at the initial interview. The quality of a respondent's relationship with the individual they identified as their primary family caregiver (the spouse in 76% of the sample) was measured with a 20-item questionnaire adapted from measures developed by Spanier58 and Pearlin and Schooler59 and used in various community-based and patient populations.60–62 Principal components analysis indicated that all items loaded on a single underlying factor; we thus created a caregiver support index by averaging the items (Cronbach's {alpha}=0.88 for the present sample).

Support from family members in addition to the primary caregiver was assessed with the Cohesion subscale of the Family Environment Scale,63 a measure designed to assess respondents' perceptions of family members' friendliness and supportiveness of each other. Our principal components analysis yielded one underlying dimension, and items were averaged to form a support index ({alpha}=0.72 for the sample). Finally, friend support was assessed with 14 items developed by Moos64 concerning the degree to which respondents felt they could rely on friends for emotional and practical support. Based on a principal components analysis, the items were averaged to form a summary index ({alpha}=0.89 for the present sample). The three social support measures had skewed distributions; scores were dichotomized at each variable's median into lower and higher support groups.

Analysis
Survival analysis, using a life-table approach,65 was adopted as the key analytic strategy so that all available data were included from each individual until the end of the observation period or until their data were censored (due to either death or refusal). (We used a life-table approach rather than estimating Kaplan-Meier survival curves because, by the design of this clinical epidemiologic study, individuals were retrospectively reporting on episodes occurring at any time since their previous interview. This is unlike the situation in clinical trials in which individuals are monitored daily or weekly and the exact date of episode onset can be determined very precisely.)

With the exception of PTSD-T, the cumulative percentages of the sample of 191 who developed each of the assessed psychiatric disorders posttransplant were calculated across the four assessment intervals (0–2 months, 3–7 months, 8–12 months, and 13–36 months posttransplant). For PTSD-T, the cumulative percentages were calculated across the three intervals included in our interviews (0–7 months, 8–12 months, and 13–36 months; see Instruments description above). Clinical features of all episodes of disorders occurring posttransplant (incident as well as recurrent) are also described, and we tested whether these features differed depending on when the episodes occurred: relatively early (0–7 months) posttransplant vs. later (8–36 months).

The effects of potential risk factors on time to occurrence of three specific posttransplant psychiatric outcomes (first onset of any of the assessed disorders; first onset of MDD; first onset of any of the anxiety disorders) was evaluated in the context of survival analysis. Individual as well as combined effects of the risk factors were considered.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Cumulative prevalence rates posttransplant
Table 2 presents the cumulative risk for onset of the targeted DSM-III-R disorders in the cohort across the first 36 months posttransplant. By 36 months posttransplant, 25.5% of the cohort had experienced episodes of MDD. MDD was more likely to first occur during the first 12 months posttransplant than during the 13–36-month period. This was also the pattern for adjustment disorders.


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TABLE 2. Cumulative rates of onset of selected DSM-III-R disorders during 36 months posttransplant in 191 heart recipients



By contrast, Table 2 shows that PTSD-T had its onset almost exclusively during the first 12 months posttransplant, and PTSD-T was as prevalent as MDD by 12 months posttransplant. About one-third of the new onsets of this disorder during the first 12 months (i.e., the increase in cumulative percentage from 9.6% to 15.6% in the second half of the year) were, by DSM definition, cases with delayed onset. Beyond 12 months posttransplant, there was only a single new-onset case of PTSD-T.

There was only one case of GAD during the study period, and this occurred during the first year posttransplant. However, the adjustment disorders in the sample largely reflected anxiety-related conditions. Individuals with adjustment disorder with anxiety generally met symptom criteria for GAD (the presence of at least 6 of 18 symptoms) but did not have episodes lasting for the 6-month minimum required for GAD. Overall, the 12-month cumulative prevalence rate of any of the assessed disorders posttransplant was 28.7%; the cumulative prevalence rose to 38.3% by 36 months posttransplant.

Clinical characteristics of psychiatric episodes occurring early vs. later posttransplant. Table 3 summarizes clinical characteristics of two of the most prevalent classes of diagnoses, MDD and anxiety disorder (adjustment disorder with anxiety and GAD), classified according to whether the episodes occurred relatively early vs. later posttransplant. (PTSD could not be so classified, since all but one episode began during the first year posttransplant; however, we summarize clinical characteristics of these episodes below). The table includes clinical information on all episodes occurring during the 3-year study period, whether or not they represented the initial onset of the disorder posttransplant (see footnote c to Table 3).


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TABLE 3. Clinical characteristics of all posttransplant episodes of DSM-III-R major depression and anxiety disorders (adjustment disorder and generalized anxiety disorder).a



For MDD, although the total number of episodes occurring posttransplant (n=43) is limited and thus restricts our power to detect differences by time period posttransplant, it is noteworthy that a significantly greater percentage of episodes occurring later posttransplant were treated with psychotropic medications (primarily antidepressants and minor tranquilizers). Although the most common precipitants for MDD both early and later posttransplant pertained to transplant-related physical health (e.g., occurrence of rejection and exacerbation of physical difficulties), a greater proportion of the later episodes were reported to be triggered by events and circumstances not directly related to the transplant. There was a trend for later episodes to be longer but to include less suicidal ideation.

Regardless of the timing of MDD episodes relative to the transplant, for the majority of all episodes (see first column of Table 3), duration and number of clinically significant symptoms well exceeded the DSM-III-R minimum of 2 weeks' duration with five symptoms. In 72% of all episodes, the recipients described some form of functional (primarily social and role performance) impairment accompanying the depression.

For anxiety, while no differences were statistically reliable in the small sample, it is noteworthy that the distribution of precipitating factors for the disorder appeared to shift from transplant-related events to other events, as was noted for MDD across earlier vs. later episodes. For all episodes of anxiety, regardless of timing of onset relative to the transplant (first column of Table 3), about half were associated with functional impairment. Only about one-quarter of the cases sought treatment, and few received any medications, despite the facts that most episodes averaged well above six symptoms and over one-third of the episodes lasted for longer than 1 month.

PTSD-T occurred almost exclusively in the first year posttransplant, and we have extensively characterized this disorder during the first year posttransplant previously.17,26 We note here that among the most common symptoms in the current sample were persistent intrusive thoughts about the experience, including, for example, unbidden memories and flashbacks to the events surrounding the wait for a heart and the perioperative period. The average duration was 7.5 months (SD=7.3, median=4), indicating that the disorder frequently had a chronic course in the sample. (PTSD exceeding 3 months is designated as chronic in the DSM.) Recipients averaged 8.2 symptoms (SD=2.1) (a minimum of 6 is required for diagnosis). Only 12% of PTSD-T cases had sought professional mental health treatment, and 20% had received medications. The period of waiting for a donor heart was the most commonly cited aspect (31%) of the transplant experience that provoked posttransplant reactions, followed by the surgery and postoperative recovery (23%), and learning about/being evaluated for a transplant (19%).

Risk factors for psychiatric disorder posttransplant
To examine which factors before and shortly posttransplant increased recipients' risk of psychiatric disorder posttransplant, we focused on three outcomes: the occurrence of any of the assessed psychiatric disorders, the occurrence of MDD, and the occurrence of any anxiety disorder (adjustment disorder with anxiety, GAD, PTSD) across the 3-year posttransplant period.

The left side of Table 4 shows the categories of potential risk factors that were considered, including historical, pretransplant characteristics (demographic and psychiatric history variables; cardiac-related variables) and early posttransplant variables (health-related stressors and social supports). The first column of Table 4 displays the sample distribution on each of these risk factors [e.g., 47 persons in the cohort (24.6%) had a positive history of depressive or anxiety-related disorders prior to transplant, the remainder did not].


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TABLE 4. Tests of differences in time to onset of posttransplant psychiatric disorder and cumulative proportions of transplant recipients who experienced posttransplant psychiatric disorders according to pre- and early posttransplant risk factors



A series of separate survival analyses were conducted for each of the three psychiatric outcome variables, in which individuals with and without each risk factor were compared to determine whether they differed in time to posttransplant onset of disorder across the 36-month study period. Results are displayed in Table 4 and Figure 1A and Figure 1B. First, as shown in the second column of Table 4, persons with a prior psychiatric history had significantly shorter times to onset of psychiatric disorder posttransplant (test of difference in survival curves for those with vs. without a psychiatric history, D (df=1)=8.23, P<0.05). Table 4 also presents the cumulative proportions of each risk factor group who met criteria for any psychiatric disorder by the end of the 36-month follow-up period posttransplant: 51% of those with a positive history had had episodes of disorder posttransplant, compared with 34% of individuals without a pretransplant history. Among other risk factors, women were at significantly greater cumulative likelihood of disorder, as were persons with longer hospitalizations immediately posttransplant, more physical functional limitations early posttransplant, and low family support in the early aftermath of the transplant. Lower support from one's family caregiver also marginally increased risk of disorder.



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FIGURE 1A. Examples of additive effects of individual risk factors on time to onset of MDD posttransplant(Survival curves with identical superscripts indicate pairs of groups differing at P<0.05.)




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FIGURE 1B. Examples of additive effects of individual risk factors on time to onset of MDD posttransplant(Survival curves with identical superscripts indicate pairs of groups differing at P<0.05.)


Table 4 indicates that some risk factors were important not only for risk of any of the assessed psychiatric disorders posttransplant (vs. none). These risk factors were also important for risk of MDD and anxiety disorders specifically (e.g., past psychiatric history and female gender). However, other risk factors were unique to MDD (e.g., a longer wait for the transplant, requiring mechanical circulatory support prior to transplant, and experiencing a greater degree of physical functional limitations in the early recovery period posttransplant). Time to onset of anxiety disorders was also associated with a unique set of risk factors, including a longer period of hospitalization immediately posttransplant, and receiving low levels of family emotional support in the early aftermath of the transplant.

Given the importance of pretransplant psychiatric history and gender for all three categories of posttransplant outcome variables, additional survival analyses were performed to determine whether these two risk factors interacted with, or modified, each other and/or any of the other potential risk factors' effects. There was no statistically reliable evidence of any such effects (results available from M.A.D.). In other words, the impact of the factors appeared to be additive, and this is illustrated in Figure 1A, which shows the study sample grouped according psychiatric history and gender. Respondents with both risk factors were most likely to experience MDD, followed by individuals with just one of the risk factors. Recipients with neither factor were unlikely to develop MDD posttransplant (test of overall differences in survival curves, D(df=3)=18.08, P=0.0004). Figure 1B provides a second illustration of additive effects, displaying respondents according to psychiatric history and level of early posttransplant physical functional impairment (test of overall differences in survival curves, D(df=3)=21.52, P=0.0001).

Because risk factors' effects appeared additive, we performed a final survival analysis to examine whether the total number of risk factors that respondents possessed significantly increased their risk for onset of any psychiatric disorder posttransplant. We created a "dose" variable by determining how many of six risk factors each respondent possessed, and the risk factors were those found individually to be significantly associated with time to onset of psychiatric disorder posttransplant. These included a positive psychiatric history, female gender, more impaired physical functional status early posttransplant, longer hospitalization, low caregiver support, and low family support. Results of the analysis are shown in Figure 2. By 36 months posttransplant, the great majority (85%) of individuals who had only 0 or 1 risk factor had not yet experienced any episodes of psychiatric disorder posttransplant. As the number of risk factors increased to 2, then 3, then 4–5 (no respondent had all 6 risk factors), there was a similar increase in cumulative rates of disorder onset. Only 34% of individuals with a total of 4 or 5 risk factors had not experienced an episode of psychiatric disorder by 36 months posttransplant. The four survival curves plotted in Figure 2 differ significantly (D[df=3]=27.31, P<0.0001). In addition, significant pairwise differences between the curves were also obtained in most instances (see Figure 2).



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FIGURE 2. Effect of total number of risk factors on time to onset of any psychiatric disorder posttransplant(Test of overall differences between survival curves, D(3)=27.31, P<0.0001. Survival curves with identical superscripts indicate pairs of groups differing at P<0.05.



  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study is the first empirical examination of the cumulative rates and risk factors for psychiatric disorder through 3 years after heart transplantation. Although a variety of investigations have examined rates of psychiatric disorders among transplant candidates and among recipients relatively early posttransplant, little is known about the course of these disorders in the long-term years. Our findings, in concert with previous prevalence studies in this population, suggest the following conclusions.

First, concerning MDD, prior to transplant a median (across all available studies) of 19% of heart candidates have a lifetime history of one or more episodes of disorder, with a median point prevalence of 5.9% at the time of the evaluation for transplant candidacy.7,17,18,22,24,25,66–70 After the transplant, the occurrence of new episodes is 13%–14% by 12–18 months posttransplant.17,71 Then, as shown in the present report, the rate of MDD continues to climb to a cumulative prevalence of 25.5% by 3 years posttransplant. In short, about one in five patients will have experienced MDD in their entire lifetimes prior to heart transplant; about one in four will experience it in just the first 3 years after the transplant.

The elevated rate posttransplant is striking not only in comparison to lifetime rates prior to transplant but also compared to prevalence rates in community-based samples and chronic disease samples seen in specialty medical settings. For example, a recent national community-based investigation reported a 17% lifetime rate of MDD.47 In chronic disease samples, the lifetime prevalence of MDD has a median of 24% (interquartile range, 20%–29%).36 The fact that our cohort met or exceeded these lifetime rates in only the first 36 months after transplant attests to the impact of the transplant experience and its potential as a stressor. On the other hand, the somewhat greater clustering of MDD episodes in the first year posttransplant, combined with a slowing in new onsets in ensuing years suggests that individuals ultimately show some degree of accommodation to the experience, and it affirms the general psychosocial hardiness of many transplant recipients. Some of our other findings, discussed below, also suggest a profile of accommodation and hardiness among many heart recipients.

Anxiety disorders have been studied in less detail than MDD in transplant populations, and a shortcoming of many investigations, including the present one, is that the complete range of anxiety disorders is not evaluated. Thus, it is difficult to make any comparisons to other chronic disease populations or to community-based samples. Focusing on the few reports of heart transplant patients available to date, the median lifetime rate of anxiety disorder (all types but excluding adjustment disorders) is approximately 5.9% in heart transplant candidates.22,24,69 The rate of new episodes is approximately 22% by 2 years posttransplant.24 Our data suggest that PTSD-T is a prominent anxiety disorder in this population—especially during the first year posttransplant26—with a cumulative prevalence of 17% by 3 years posttransplant. In contrast, the rate of GAD appears to be quite low in heart recipients, occurring in less than 1% of patients by 1 year posttransplant,17 with no apparent increase by 3 years posttransplant. Instead, we have found that adjustment disorder with anxiety is considerably more prominent than GAD, both during the first year posttransplant17 and through 3 years of follow-up. It is noteworthy that respondents who experienced adjustment disorder with anxiety met the full symptom criteria for GAD, but their episodes were shorter than the 6 months required for the GAD diagnosis.

At least in heart recipients, anxiety disorders posttransplant appear to occur largely during the first year after surgery, in contrast to the somewhat more gradual pattern of continued increase noted for MDD over the 3 years of follow-up. Moreover, the cumulative rate of MDD appears to be greater than the rate of any of the anxiety disorders studied to date. An important issue concerns whether the greater prominence of MDD relative to anxiety disorders is specific to heart recipients or would generalize to other types of solid organ recipients. There is no strong evidence to date that rates of psychiatric disorders vary by type of organ transplant,2,3 although no large-scale prevalence rate comparisons have yet been performed. However, there are hints that depressive illness is more common in end-stage heart, kidney, and liver populations than in end-stage lung disease groups, while anxiety disorders appear more prevalent in lung patients (including transplant candidates).4,36,72,73 The relative importance of mood vs. anxiety disorders across transplant types is an important issue to address in order to design appropriately targeted clinical education and intervention strategies for primary and secondary prevention of these conditions in transplant populations.

The specific clinical characteristics of the disorders observed in the present sample indicate that respondents were experiencing marked distress at severity and duration levels well beyond the threshold for diagnosis of clinical disorder. The majority of episodes of disorder were associated with marked functional impairment. Yet, as has been found for psychiatric illness in other samples from community-based and nonpsychiatric medical settings,74 the majority of heart recipients did not seek professional help specifically for their distress, and only a minority received psychotropic medications. In the context of the transplant experience, patients with MDD were more likely to receive medications if their episodes occurred longer after the transplant. This may be related in part to the hesitancy of the transplant team to recommend the addition of antidepressant medications to the complex regimen during the earlier months posttransplant, despite 1) evidence that these medications do much to relieve suffering in depressed persons, 2) evidence of favorable side effects profiles and lack of significant interactions of many antidepressants (e.g., sertraline, paroxetine, venlafaxine, tricyclics) with other immunosuppressive and posttransplant-related medications,68,75–78 and 3) the availability at major transplant centers of psychiatric expertise specific to transplant populations, thereby helping to ensure that antidepressants that do interact with transplant-related medications (e.g., fluvoxamine, nefazodone, fluoxetine, via the cytochrome P450 pathway) will be avoided.

Although we had limited ability to detect many differences between earlier vs. later episodes of diagnosable disorder due to small total numbers of cases, we found some evidence suggesting that the psychological salience of the transplant experience decreased with time. Thus, the event triggering the depressive and anxiety-related episodes was less likely to be transplant-specific as time wore on posttransplant. Moreover, onset of PTSD-T (which was, by definition, triggered by transplant-related events) was almost exclusively limited to the first year posttransplant. As noted elsewhere,9,26 the occurrence of this disorder appears to indicate a failure of the patient to come to terms with the transplant experience. Yet the fact that onset of this disorder was rare after the first year suggests that even patients with PTSD-T eventually do incorporate the transplant experience into their lives. Unfortunately, although the PTSD-T appears to resolve, its occurrence during the first year posttransplant is a harbinger of physical morbidity in subsequent years.9 In sum, since psychological reactions during the first year posttransplant appear to be critical for long-term physical health and well-being,8–10 and since long-term morbidity is associated with exacerbations in long-term distress posttransplant,2,4 it will be important to continue to chart the course of psychiatric status beyond the 3-year focus of the present investigation. Extended follow-up is especially critical since many of the long-term health problems that eventually result in graft loss and/or patient death (e.g., cardiac allograft disease, malignancies) do not fully develop until well beyond 3 years posttransplant. These conditions may provoke steeper increases in rates of mental health difficulties in ensuing years.79

We identified a variety of pre- and early posttransplant characteristics that affected cumulative likelihood of experiencing any psychiatric disorder posttransplant, as well as MDD and anxiety disorders in particular. Although pretransplant variables such as psychiatric history and gender are not modifiable, some early posttransplant characteristics (e.g., those related to family supports) may be able to be bolstered in order to reduce patients' risk of significant psychiatric distress. However, the identification of even unmodifiable factors has important implications for the development of preventive education and intervention strategies in order to prepare at-risk patients and their families for life posttransplant. For example, we have previously found evidence suggesting that women and their families may have unreasonable expectations regarding their physical functional capacity and return to pre-illness activity levels in the first year posttransplant.80 This, in turn, appears to contribute to the relatively higher distress levels observed in women vs. men posttransplant. Such findings clearly point to the need for targeted interventions to address the unique risk factors that individuals bring to the transplant experience. Indeed, our "dose-response" analyses of the additive effects of multiple risk factors suggests that targeting even one or two factors out of a larger total number may bring about sizable decreases in likelihood of mood and anxiety disorders after heart transplantation.

In conclusion, our findings regarding prevalence and risk factors point to assessment-related and intervention-related activities that need greater attention in heart recipient and potentially other types of solid organ transplant recipient populations. With respect to assessment, just as psychosocial and psychiatric evaluations are a routine part of most pretransplant candidacy workups, routine evaluation of mental health status and outcomes in this population would seem to be a vital—but generally underutilized—element for achieving a key goal of transplantation, namely the maximizing of patient quality of life. Moreover, such assessments are needed and justified by data showing that psychiatric status posttransplant predicts longer-term physical health outcomes.4,9,10 Better understanding of the timing and risk factors for psychiatric disorders posttransplant will, in turn, allow interventions to be targeted to the transplant recipients with the greatest psychosocial needs.


  ACKNOWLEDGMENTS

 
An earlier version of this paper received the 1999 Dlin/Fischer Clinical Research Award from the Academy of Psychosomatic Medicine, November, 1999.

This research was funded by grants MH45020 and MH59229 from the National Institute of Mental Health and HL54326 from the National Heart, Lung and Blood Institute, Rockville, MD.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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