The risk of affective disorders in patients with adrenocortical insufficiency

Psychoneuroendocrinology (2006) 31, 614–622

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The risk of affective disorders in patients with adrenocortical insufficiency Anders F. Thomsena,*, Tine K. Kvistb, Per K. Andersenb, Lars V. Kessinga a

Psychiatric Research Unit, Department of Psychiatry, O 6233, Neuroscience Centre, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark b Department of Biostatistics, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark Received 8 August 2005; received in revised form 11 January 2006; accepted 13 January 2006

KEYWORDS Adrenocortical insufficiency; Adrenal insufficiency; Addison’s disease; Affective disorders; Depressive disorder; Bipolar disorder

Summary Objective: To investigate the risk of affective disorders among patients hospitalised with adrenocortical insufficiency in the study period: 1977–1999. Method: Using data from Danish registers, two study cohorts were identified by their ICD diagnoses at discharge from hospital: one comprising all patients with a first hospital admission with an index diagnosis of adrenocortical insufficiency; the other a control cohort comprising all patients with a first hospital admission with an index diagnosis of osteoarthritis. Subsequent admissions to psychiatric hospital wards with discharge ICD diagnoses of affective disorders were used as events of interest. Rates of readmission were estimated using Poisson regression models in survival analyses. Age, sex, duration of time after index discharge, and calendar time were included as co-variables. The primary analysis included all patients with adrenocortical insufficiency. Thereafter, the subgroup of patients with primary adrenocortical insufficiency (Addison’s disease) was investigated separately in a secondary analysis. Results: A study sample of 989 patients with adrenocortical insufficiency and 124,854 patients with osteoarthritis was identified. Eight hundred and fifty-two patients were subsequently readmitted with a diagnosis of affective disorder. Patients with adrenocortical insufficiency had a 2.68 (95% CI: 1.62–4.42) times greater rate of affective disorders and a 2.12 (95% CI: 1.16–3.86) times greater rate of depressive disorder when compared with the rate for patients with osteoarthritis. Patients with Addison’s disease had a 2.14 (95% CI: 1.14–4.03) times greater rate of affective disorders, and a 1.71 (95% CI: 0.81–3.63) times greater rate of depressive disorder compared with the rate of patients with osteoarthritis. Conclusion: Patients with adrenocortical insufficiency may be at increased risk of developing severe affective disorders. Conventional replacement therapy with hydrocortisone may not be sufficient to ensure the psychiatric well-being of these patients. Q 2006 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: C45 20764884; fax: C45 35456218. E-mail address: [email protected] (A.F. Thomsen).

0306-4530/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2006.01.003

Adrenocortical insufficiency and affective disorders

1. Introduction There are relatively many investigations of Cushing’s disease and the effect of hypercortisolemia on brain function and mood regulation, but few on the neuropsychiatric consequences of adrenocortical insufficiency and the resulting hormone deficiencies. Most existing studies of the neuropsychiatric symptoms of Addison’s disease are retrospective case series predating contemporary criteria for description and diagnosis of psychiatric disorders (Starkman, 2003). Formerly, it was believed that glucocorticoid replacement is an effective treatment for the psychiatric symptoms that patients with Addison’s disease exhibit on presentation, and that continuous replacement therapy ensures normal physical and psychological functioning (Money and Jobaris, 1977; Leigh and Kramer, 1984; Johnstone et al., 1990); however, recent epidemiological studies and studies of hydrocortisone and dehydroepiandrosterone (DHEA) replacement strategies suggest that patients may have persistent mental health reduction, lack of energy, and reduced quality of life (Arlt and Allolio, 2003). The physiological role of DHEA is unclear, but abnormal levels of DHEA are seemingly associated with chronic conditions where mood and well-being are often affected (Finset et al., 2004; Cleare et al., 2004; Boscarino, 2004). DHEA may have a significant antidepressant effect in patients with major depression (Wolkowitz et al., 1999; Schmidt et al., 2005). Patients with adrenocortical insufficiency have decreased production of DHEA, and although results are divergent, studies of the effects of DHEA supplementation suggest that patients with adrenocortical insufficiency have increased fatigue, and a decreased sense of wellbeing, general health and vitality (Arlt et al., 1999; Hunt et al., 2000; Lovas et al., 2003). It may be that mood is also negatively affected. Whether these impairments are associated with long-term mood changes of clinical severity is unknown. Adrenocortical insufficiency is a rare condition, and no prospective study of mental status during replacement therapy with different doses of hydrocortisone, or during supplementation with DHEA, included more than 40 patients or used a follow-up time of more than 1 year. Some of the studies investigated mood symptoms in patients with both primary- and secondary adrenocortical insufficiency. Patients with these syndromes may exhibit different disturbances in hypothalamic– pituitary–adrenal (HPA) axis regulation, and those with secondary adrenocortical insufficiency often

615 have additional deficiencies in other hormone systems, which may put them at greater risk of mood disorders than patients with primary adrenocortical insufficiency (Addison’s disease). In view of the lack of controlled, long-term studies, we found it relevant to investigate the risk of developing mood disorders in a cohort of patients with adrenocortical insufficiency with an approach that enabled us to follow many patients over a lengthy period. Using data available in the Danish patient registers, we conducted a cohort study with delayed entry into cohorts. We compared the risks for patients with hospital diagnoses of adrenocortical insufficiency or of osteoarthritis of receiving diagnoses of affective disorders on readmission to hospital. We investigated all patients with adrenocortical insufficiency diagnoses in a primary analysis. Thereafter, a subgroup of these patients with diagnoses of Addison’s disease was investigated in a secondary analysis. We hypothesised that patients hospitalised with adrenocortical insufficiency would have a higher incidence of negative mood disturbances, and hence a higher risk of hospitalisation with diagnoses of depressive disorder than control patients with osteoarthritis, and that this risk would be increased both for all patients with adrenocortical insufficiency and for the subgroup of patients with Addison’s disease. Because patients with adrenocortical insufficiency are treated with exogenous glucocorticoids, we also expected to find a higher relative risk of mania/bipolar disorder diagnoses among these patients. We used hospitalised control patients in order to reduce the impact of Berksons bias on the estimated rates of affective disorder hospitalisations (Berkson, 1946).

2. Methods 2.1. Danish register data We obtained data from three Danish registers after approval from the Danish Data Protection Agency. In Denmark, hospital admissions to psychiatric wards have been recorded in a nationwide register, the Danish Psychiatric Central Research Register (DPCRR) (Munk-Jorgensen and Mortensen, 1997) since 1 April 1970. From 1 April 1970 to 31 December 1993, the Danish edition of the International Classification of Diseases 8 (ICD-8) was used for registration (WHO, 1971). Since 1 January 1994, the updated International Classification of Diseases 10, ICD-10, has been in use (WHO, 1993).

616 Admissions to somatic hospital wards have been registered in the Danish National Hospital Register (DNHR) since 1 January 1977 (Andersen et al., 1999), where the ICD-8 and ICD-10 systems have been used in the same manner as in the DPCRR. These public registers are comprehensive for all Danish hospital admissions, as hospitals report of admission data is mandatory. All deaths in Denmark, in hospitals or elsewhere, are registered in the Danish Register of Causes of Death (DRCD) (Juel and Helweg-Larsen, 1999). Danish citizens have a unique personal identification number (the CPR number) that can be logically checked for errors, and this number is used to identify the individual citizen in the various registers. Therefore, data on hospital admissions and deaths can be registered precisely irrespective of changes in name or address. The rate of migration from Denmark is low, and citizens’ use of foreign hospitals is negligible. Thus, the full pattern of hospital admissions in Denmark can be established with confidence. When register data is used for research, the CPR numbers are encrypted so that researchers are blind to the identities of the individual patients. Therefore, Danish legislation permits use of the data for research without the registered citizens’ specific consent if the studies are approved and supervised by the Danish data protection agency. The hospital registers contain information about the diagnoses of patients, the admission and discharge dates, and the hospital wards where the patients were admitted. Information about the specific causes of the diseases, laboratory parameters, treatment, and prior illness treated in outpatient settings is not available for analysis.

2.2. The study sample The two study cohorts identified were: all inpatients with a main diagnosis of adrenocortical insufficiency, and all inpatients with a main diagnosis of osteoarthritis; the diagnoses were received on discharge after a first hospital admission (index discharge) between 1 January 1977 and 31 December 1999. In the initial analysis, adrenocortical insufficiency was defined by the ICD-8 diagnoses 255.10– 255.19, and the ICD-10 diagnoses E27.1–E27.4. Thus, the cohort comprised both patients with primary and secondary adrenocortical insufficiency. Patients with the register diagnoses 255.10 and E27.1, indicating Addison’s disease, were

A.F. Thomsen et al. investigated separately in a secondary analysis. As only first-time hospital admissions were included, patients who were hospitalised with diagnoses indicating Cushing’s disease prior to adrenocortical insufficiency were not included in the cohort. Osteoarthritis was defined by the ICD-8 diagnoses 713.00–713.09, and the ICD-10 diagnoses M15.0– M19.9. The events of interest were admissions to psychiatric hospitals with main discharge diagnoses of affective disorders as registered in the DPCRR. Affective disorders was defined as either depressive disorder, ICD-8 codes 296.09, 296.29, 286.89, 296.99, and ICD-10 codes F32.0–F33.31, F34.0– F34.9, F38.1–F39.9, or bipolar disorder, ICD-8 codes 296.19, 296.39 and ICD-10 codes F30.0– F31.6, F38.0. Data in Danish registers are collected systematically mainly for administrative purposes. Therefore, the diagnoses in the study were not standardised for research purposes, but were based on reliance on the diagnostic practice of Danish clinicians. The diagnostic validity of the DPCRR—diagnoses has been compared with ICD-10 research criteria for affective disorders and found correct in 84% of cases (Kessing, 1998). The validity of the diagnoses in the DHNR ranges from 75 to 90% (Mosbech et al., 1995). As validity decreases with the number of digits used, diagnoses were grouped into main categories such as ‘adrenocortical insufficiency’ or ‘depressive disorder’ as these could be defined using the first three digits of the ICD diagnoses. The diagnostic validity of the registers diagnoses for Addison’s disease has not been specifically investigated. Only main diagnoses for index- or event-diagnoses were used as indicating events, as these diagnoses were posted or supervised by consultants at the various wards discharging the patients. A main diagnosis denotes that investigating or treating this condition was the primary cause of hospitalisation. Only incident patients were included in the analyses. Patients admitted to hospital at an age younger than 15 years and patients registered with a diagnosis of affective disorder or of schizophrenia prior to the index admission were excluded. Patients with a first-discharge auxiliary diagnosis of affective disorder, schizophrenia, or with a diagnosis of the other cohort were excluded. Patients registered in the DPCRR with main diagnoses of affective disorder or of schizophrenia (ICD-8 code 295.xx and ICD-10 code F20–F29) between 1 April 1970 and 31 December 1976 were excluded.

Adrenocortical insufficiency and affective disorders

2.3. Statistical analysis The cohort of adrenocortical insufficiency patients was compared with that of patients with osteoarthritis using Poisson regression analysis. As death was expected to be a major hazard for patients entering the study, affective disorders and death were both treated as outcomes in a competing risks model. Using estimated incidence rates of affective disorders and death, the probability of receiving a subsequent diagnosis of affective disorder was calculated for individuals who were alive and without affective disorders at a given age. When estimating the rate of affective disorders, patients were censored (i.e. excluded from further participation in the study from this point of time) at the time of admission with schizophrenia, at the time of admission with a control-cohort diagnosis, or at time of death. All remaining patients were censored on 31 December 1999. When estimating the rate of death, patients were censored at the time of admission with an affective disorder, schizophrenia, a diagnosis from the comparison cohort, or on 31 December 1999. Sex was included in the model as a fixed covariate. Age (divided in four groups: 15–40; 40– 60; 60–75; 75C years), duration of time after index discharge (0–0.5; 0.5–1; 1C years), and calendar period (1977–1993; 1994–1999) were all included as time-dependent covariates. After the initial analysis where affective disorders (depressive disordersCbipolar disorders) were used as outcome events, a secondary analysis of the rates of depressive disorder in the two cohorts was performed. Because of the small number of bipolar disorder hospitalisations the rates of bipolar disorder were not estimated separately.

617 Table 1 Age and sex characteristics of the cohorts at first discharge, events and censorings, and causes of censorings during the follow-up. Adrenocortical insufficiency N 989 Women 632 (64%) Median age 51.4 (years) Number of patients age 15–40 302 40–60 323 60–75 262 75C 102 Affective dis16 (1.6%) orders (% of N) Censorings 973 Schizophrenia 0 Other index 32 disease End of study 623 Death (% of N) 318 (32%)

Osteoarthritis 124,854 74,068 (59%) 68.0

6439 31,873 51,479 35,063 820 (0.7%) 124,034 41 38 79,958 43,997 (35%)

minimal systemic side effects (Cole and Schumacher Jr., 2005), standard pharmacological treatment of osteoarthritis is not a confounding factor. Patients hospitalised with osteoarthritis are, on average, older than patients hospitalised with adrenocortical insufficiency, but the cohort of patients with osteoarthritis is large enough to comprise ample patients in every age group above 15 years of age to allow for comparison (Table 1). In the Poisson regression analysis, patients with adrenocortical insufficiency of sexZx and ageZy are compared to patients with osteoarthritis of similar sex and age, and thus, the age dependent increased rate of affective disorders is corrected for in the Poisson regression analysis.

2.4. Osteoarthritis as the control diagnosis

3. Results In previous published research on other diseases (Nilsson et al., 2002), it has been argued that patients admitted with osteoarthritis are suitable control persons if the aim is to compare rates of affective disorders. Osteoarthritis, like adrenocortical insufficiency, is a chronic condition that may require long-term medication and may pose longterm psychological concerns for patients (Wells et al., 1988). No influence of mood regulation or other major brain functions have been associated with osteoarthritis (Creamer et al., 1999; Gabriel et al., 1999). Patients with osteoarthritis in the knee have widely been treated with intra-articular glucocorticoid injections but as this therapy has

The study sample included 125,843 patients: 989 (0.8%) with adrenocortical insufficiency and 124,854 (99.2%) with osteoarthritis. Table 1 shows the distribution of patients, sex, median age at first discharge, number of patients in each age group, number of events, and number of patients censored. Of the 989 patients with adrenocortical insufficiency, 742 were hospitalised with diagnoses indicating Addison’s disease (Table 2). In the Poisson regression analyses, three interactions were included in the model: sex and index diagnosis; sex and age group; and index diagnosis and duration of time after index discharge. These

618

A.F. Thomsen et al.

Table 2 Distribution of diagnoses of adrenocortical insufficiency. ICD code

Diagnosis

Number of patients

Percent

25510

Addison’s disease, adrenocortical insufficiency Addison crisis Hypoaldosteronism Hypofunctio adrenocorticalis, no specification Hypofunctio adrenocorticalis Adrenocortical insufficiency, primary Adrenocortical insufficiency, acute Adrenocortical insufficiency, pharmacological Adrenocortical insufficiency, no specification

557

56.3

59 3 15

6.0 0.3 1.5

61 185

6.2 18.7

33

3.3

6

0.6

70

7.1

25511 25512 25518 25519 DE271 DE272 DE273 DE274

interactions were insignificant (p-values of 0.98, 0.08, and 0.51, respectively). Thereafter, the covariates: index diagnosis, sex, duration of time after index discharge, age group, and calendar time were included as main effects. The main effects were all highly significant (Table 3). The rate of readmissions with affective disorders was greatest in the first 6 months after index discharge. Women had a greater rate of hospitalisation with affective disorders than men. The rate of affective disorder was greatest in the age groups over 60 years. The incidence of affective disorder hospitalisations was greatest in the calendar period from 1994 to 1999 (these results are not shown in detail as they were primarily generated by the patients with osteoarthritis, who comprise the vast majority of the study population).

Patients with an index diagnosis of adrenocortical insufficiency had an increased rate of affective disorder hospitalisations compared with patients with an index diagnosis of osteoarthritis. Sixteen patients with adrenocortical insufficiency were later hospitalised with affective disorders compared to 820 events among patients with osteoarthritis. The rate ratio of affective disorders was 2.68 (95% CI: 1.62–4.42). Depressive disorder was the cause of 11 events in the adrenocortical insufficiency cohort and of 718 events in the osteoarthritis cohort. The rate ratio of depressive disorder was 2.12 (95% CI: 1.16–3.86). Among patients with adrenocortical insufficiency who developed affective disorder leading to readmission, 31% (NZ5) had a diagnosis of bipolar disorder, compared to 13% (NZ102) of patients with affective disorder following an index diagnosis of osteoarthritis. This number of hospitalisations with bipolar disorder in the cohort of patients with adrenocortical insufficiency was too low to make a separate Poisson regression analysis of these events meaningful. Among the 742 patients who had diagnoses of Addison’s disease, 11 patients were later hospitalised with affective disorders: four with diagnoses of bipolar disorder and seven with diagnoses of depressive disorder. Patients with Addison’s disease had a 2.14 (95% CI: 1.14–4.03), pZ0.03, times greater rate of affective disorders and a 1.71 (95% CI: 0.81–3.63), pZ0.2, times greater rates among depressive disorder when compared with the rate of patients with osteoarthritis. Figs. 1 and 2 show the estimated probabilities of a subsequent admission with a discharge diagnosis of affective disorder for patients hospitalised with either adrenocortical insufficiency or osteoarthritis

Table 3 Rate ratios with confidence intervals of affective disorders for three main effects in the Poisson analyses, and the p-value for each main effect as a predictor of affective disorders. Covariate Index diagnosis Adrenocortical insufficiency Addison’s disease Osteoarthritis Sex Women Men

RR

95% CI

2.68

1.62–4.42

0.0008

2.14 1.00

1.14–4.03

0.0340

1.61 1.00

1.39–1.88

!0.0001

1.37–2.17 0.96–1.65

!0.0001

Time after index discharge 0–0.5 years 1.72 0.5–1.0 years 1.26 1.0Cyears 1.00

p-Value

Figure 1 Estimated probability of hospitalisations with affective disorders for women from each of the study cohorts, hospitalised with an index episode at age 60. The estimated probabilities relate to the calendar period 1 January 1994 to 31 December 1999.

Adrenocortical insufficiency and affective disorders

Figure 2 Estimated probability of hospitalisations with affective disorders for men from each of the study cohorts, hospitalised with an index episode at age 60. The estimated probabilities relate to the calendar period 1 January 1994 to 31 December 1999.

at age 60 years, for women and men, respectively. The probabilities are adjusted for the competing risk of death. Patients discharged with a diagnosis of adrenocortical insufficiency had an increased risk of psychiatric hospitalisation due to affective disorders throughout their lifetime. Women had a greater risk than men, with an estimated risk of 4% over a 20-year period.

4. Discussion We identified 989 incident patients with a main diagnosis indicating adrenocortical hypofunction, with Addison’s disease as the principal cause of hospitalisation. Approximating a mean incidence, 742 cases of Addison’s disease during 23 years in a population of roughly five million inhabitants equals 6.5 new cases per million per year. This incidence rate is in agreement with previous incidence estimates of Addison’s disease (Kong and Jeffcoate, 1994; Lovas and Husebye, 2002). To contrast the risk of hospitalisation with affective disorders of the study patients with that of the general population, 1.6% of patients with adrenocortical insufficiency and 0.7% of the patients with osteoarthritis were later hospitalised with an affective disorder diagnosis, while a rough estimate suggests that 0.6% of the general population was hospitalised with affective disorders. This estimate is based on the assumptions that approximately four million Danes were constantly over 15 years of age, and that about 25,000 firsttime affective disorder hospitalisations occurred (Thomsen and Kessing, 2005), within the study period.

619 The incidence of the outcome events—hospital admissions with a main diagnosis of affective disorder—was relatively low: 16 patients with a history of adrenocortical insufficiency were admitted with an affective disorder diagnosis compared to 836 patients with a history of osteoarthritis. These raw rates of affective disorders may at first glance seem trivial, but an increased risk relative to control patients indicates more clinically severe episodes of affective disorders in the cohort of patients with adrenocortical insufficiency. This tendency is likely to reflect a greater incidence of affective disorder episodes that did not lead to hospital admission and probably also a greater prevalence of sub-clinical mood disturbances among these patients. Both for the group of all patients with adrenocortical insufficiency, and for the subsample of patients with Addison’s disease, the relative risk of affective disorders (i.e. bipolar disorderCdepressive disorder) was significant and tended to be greater than the relative risk of depressive disorder. The risk of depressive disorder was significant when all patients with adrenocortical insufficiency were included in the analysis, but was insignificant when only patients with Addison’s disease were included (1.71 (95% CI: 0.81–3.63), pZ 0.2). These results should be interpreted with caution because they are based on very few events among the patients with adrenocortical insufficiency, which is reflected in the wide confidence intervals. For example, the risk of depressive disorder among patients with Addison’s disease was generated by only seven hospitalisations, and was thus highly vulnerable to chance events happening in the Addison’s disease cohort. However, it seems fair to conclude that that there was an excess risk of both depressive and bipolar disorder in the heterogeneous group comprising all patients with adrenocortical insufficiency, whereas the patients with Addison’s disease were at increased risk of affective disorders and only tended to be at increased risk of depressive disorder. The greater risk of affective disorders in the group comprising all patients with adrenocortical insufficiency than in the subgroup of patients with Addison’s disease probably reflects that many patients with diagnoses other than 255.10 or E27.1 had secondary adrenocortical insufficiency due to pituitary disease. These patients may have been more prone to developing affective disorders because of additional endocrine disturbances, such as hypothyroidism, hypogonadism, or growth hormone deficiency (Deijen et al., 1996; Burman and Deijen, 1998).

620 As a result of the low number of events, the Poisson regression analyses had to be conducted with a minimum of covariates. The analyses showed no significant interaction between index diagnosis and duration of time after index discharge. The risk of affective disorders was greatest in the first 6 months after index discharge for patients with adrenocortical insufficiency and osteoarthritis alike, and the risks for patients with adrenocortical insufficiency were constant in the three time intervals after index discharge. No patients moved directly from hospitalisation with adrenocortical insufficiency to psychiatric hospitalisation with affective disorder. Therefore, it would seem that neither the psychological stress of being diagnosed with a chronic disorder nor the psychiatric symptoms directly associated with the index disease episode accentuated the increased risk of affective disorders among the patients with adrenocortical insufficiency in the first 6 months after index discharge. Thus, the constant increased rate ratio of affective disorder hospitalisations in the three time intervals after index discharge suggests that other factors contribute to an increased longterm risk. By comparing patients discharged from hospital with diagnoses of adrenocortical insufficiency with those who have passed the threshold of hospital admission with another chronic disease, we avoided biases that often affect epidemiological studies. Thus, recall bias, Berksons bias, and selection bias due to non-participation, or to geographic or socioeconomic factors, are minimized in this study design. We doubt that the pattern of prior admissions to somatic hospital wards has systematically influenced the subsequent distribution of affective diagnoses. Misclassifications or flawed diagnoses are probably randomly distributed between the two cohorts, without causing differential bias. However, detection bias cannot be excluded as a cause of the higher rate of hospitalisations, as patients with adrenocortical insufficiency were, most likely, followed with more outpatient visits than were patients with osteoarthritis. Patients with adrenocortical insufficiency may have co-morbid diseases, such as other autoimmune endocrine syndromes or tuberculosis, associated with both adrenocortical insufficiency and mood disorders. Thus, other diseases may act as confounders in the study (Kong and Jeffcoate, 1994; Trenton and Currier, 2001). The data did not allow for a full picture of co-morbidity because outpatient visits and visits to general practitioners are not included in the registers. Therefore, we did not attempt to correct for other diagnoses that the

A.F. Thomsen et al. patients may have received after index hospitalisation. While recognizing that bias and confounding may have influenced the results, we find that several other causes could contribute to an increased risk of affective disorders in patients with adrenocortical insufficiency. Five small studies have shown psychological and mood impairment in patients with primary (Riedel et al., 1993; Hunt et al., 2000) and secondary adrenocortical insufficiency (Arlt et al., 1999; Johannsson et al., 2002) and in patients adrenalectomized for Cushing’s disease (Nagesser et al., 2000). Contrary to these findings, the largest epidemiological study of patients with Addison’s disease showed increased fatigue and reduced vitality perception, but not a subjective perception of reduced mental health or of reduced social functioning (Lovas et al., 2002). However, Løva ˚s (2002) found that a high proportion of the patients received work disablement benefit, indicating that replacement therapy was not sufficient to render all patients’ lives normal. We find it plausible that subjectively reduced vitality perception, or the social consequences of disablement, could result in an increased long-term risk of depressive disorder in some patients with adrenocortical insufficiency. The adrenal cortex is a major source of DHEA in women, and women with adrenocortical insufficiency have very low serum concentrations of active androgens derived from DHEA (Oelkers, 1999). Supplementing DHEA results in beneficial androgen effects and positive behavioural changes in women with secondary adrenocortical insufficiency (Johannsson et al., 2002). In our analyses, the interaction between sex and index diagnosis was not significant. This means that women in general had a greater risk of affective disorders than men, regardless of the index diagnosis, and that the effect of sex was the same among patients with adrenocortical insufficiency and among patients with osteoarthritis. Seemingly, lack of adrenal androgens in the women with adrenocortical insufficiency did not increase their risk of affective disorders. However, deficiency of the neurosteroid effects of DHEA itself may explain the increased risk of severe affective disorders in adrenocortical insufficiency patients of both sexes. This supposition is supported by some (Arlt et al., 1999; Hunt et al., 2000), but not all (Lovas et al., 2003), studies of the effects of DHEA supplementation to patients with adrenocortical insufficiency. Another explanation that applies to both sexes is that patients with adrenocortical insufficiency may have imbalances in HPA regulation that are not reversed by hormone substitution, making these

Adrenocortical insufficiency and affective disorders

621

patients prone to developing affective disorder. Exogenous glucocorticoids may affect hippocampal volume (Ohl et al., 2000), cause dysregulation of the serotonin neurotransmitter system (Schacke et al., 2002), and have effects on a wide range of mechanisms in brain functioning such as peptide receptors, second messengers, ion transport and membrane integrity (Reus and Wolkowitz, 2003). The standard treatment of adrenocortical insufficiency in Denmark has been 15–30 mg of hydrocortisone daily, clinically adjusted to optimise patient well-being. However, replacement regimens may have been excessive (Peacey et al., 1997), and long-term exogenous glucocorticoid treatment with similar or lower doses may have caused impaired cognition (Keenan et al., 1995), which may ultimately increase the risk of developing affective disorders. Because of the small number of bipolar disorder hospitalisations, we did not analyse these events separately, but among the patients with adrenocortical disease who were hospitalised with an event, 31% were hospitalised with bipolar disorder, and the relative risk of affective disorder was greater than the relative risk of depressive disorder alone. This was also true for the subgroup of patients with Addison’s disease. Seemingly, these results reflect an increased tendency to develop bipolar disorder among patients with adrenocortical insufficiency, and a probable explanation of this is that standard glucocorticoid treatment may have induced steroid psychoses (Hall et al., 1979; Brown et al., 2004). Also, the failure of pharmacological therapy to emulate the natural circadian rhythm of plasma cortisol may have made patients prone to developing affective disorders (Jeffcoate, 1999). Causality cannot be determined by the present study, and further clinical studies should determine which mechanism is most likely to contribute to severe mood disorder in patients with adrenocortical insufficiency. It would be interesting to contrast the present study with similar data about Cushing’s disease. However, investigating Cushing’s disease diagnoses with the same methods as described above, we identified only 490 patients within the study period. Among these, there were five hospitalisations due to affective disorders, a number that is too low to perform further analyses (unpublished data).

disorders. Such a risk could arise from several causes, most notably a continuous dysregulation of the HPA axis, insufficient DHEA production, chronic co-morbid diseases, or side effects of glucocorticoid treatment. Physicians managing patients with adrenocortical insufficiency should be aware that conventional replacement therapy may not be sufficient to ensure the psychiatric well-being of these patients.

5. Conclusion Patients with adrenocortical insufficiency may be at an increased risk of developing severe affective

Acknowledgements Lars V. Kessing is employed in a professorship funded by the Lundbeck Foundation. The study was supported by the Lundbeck Foundation and by the ‘Slagtermester Max Woerzner og hustru Inge Woerzners Mindelegat’.

References Andersen, T.F., Madsen, M., Jorgensen, J., Mellemkjoer, L., Olsen, J.H., 1999. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan. Med. Bull. 46, 263–268. Arlt, W., Allolio, B., 2003. Adrenal insufficiency. Lancet 361, 1881–1893. Arlt, W., Callies, F., van Vlijmen, J.C., Koehler, I., Reincke, M., Bidlingmaier, M., Huebler, D., Oettel, M., Ernst, M., Schulte, H.M., Allolio, B., 1999. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N. Engl. J. Med. 341, 1013–1020. Berkson, J., 1946. Limitations of the application of fourfold table analysis to hospital data. Biometric Bull. 2, 126–135. Boscarino, J.A., 2004. Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann. NY Acad. Sci. 1032, 141–153. Brown, E.S., Varghese, F.P., McEwen, B.S., 2004. Association of depression with medical illness: does cortisol play a role? Biol. Psychiatry 55, 1–9. Burman, P., Deijen, J.B., 1998. Quality of life and cognitive function in patients with pituitary insufficiency. Psychother. Psychosom. 67, 154–167. Cleare, A.J., O’Keane, V., Miell, J.P., 2004. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology 29, 724–732. Cole, B.J., Schumacher Jr., H.R., 2005. Injectable corticosteroids in modern practice. J. Am. Acad. Orthop. Surg. 13, 37– 46. Creamer, P., Lethbridge-Cejku, M., Costa, P., Tobin, J.D., Herbst, J.H., Hochberg, M.C., 1999. The relationship of anxiety and depression with self-reported knee pain in the community: data from the baltimore longitudinal study of aging. Arthritis Care Res. 12, 3–7. Deijen, J.B., de Boer, H., Blok, G.J., van der Veen, E.A., 1996. Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21, 313– 322.

622 Finset, A., Overlie, I., Holte, A., 2004. Musculo-skeletal pain, psychological distress, and hormones during the menopausal transition. Psychoneuroendocrinology 29, 49–64. Gabriel, S.E., Crowson, C.S., O’Fallon, W.M., 1999. Comorbidity in arthritis. J. Rheumatol. 26, 2475–2479. Hall, R.C., Popkin, M.K., Stickney, S.K., Gardner, E.R., 1979. Presentation of the steroid psychoses. J. Nerv. Ment. Dis. 167, 229–236. Hunt, P.J., Gurnell, E.M., Huppert, F.A., Richards, C., Prevost, A.T., Wass, J.A., Herbert, J., Chatterjee, V.K., 2000. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J. Clin. Endocrinol. Metab. 85, 4650–4656. Jeffcoate, W., 1999. Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency. Ann. Clin. Biochem. 36 (Pt 2), 151–157. Johannsson, G., Burman, P., Wiren, L., Engstrom, B.E., Nilsson, A.G., Ottosson, M., Jonsson, B., Bengtsson, B.A., Karlsson, F.A., 2002. Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial. J. Clin. Endocrinol. Metab. 87, 2046–2052. Johnstone, P.A., Rundell, J.R., Esposito, M., 1990. Mental status changes of Addison’s disease. Psychosomatics 31, 103–107. Juel, K., Helweg-Larsen, K., 1999. The Danish registers of causes of death. Dan. Med. Bull. 46, 354–357. Keenan, P.A., Jacobson, M.W., Soleymani, R.M., Newcomer, J.W., 1995. Commonly used therapeutic doses of glucocorticoids impair explicit memory. Ann. NY Acad. Sci. 761, 400–402. Kessing, L.V., 1998. Validity of diagnoses and other clinical register data in patients with affective disorder. Eur. Psychiat. 13, 392–398. Kong, M.F., Jeffcoate, W., 1994. Eighty-six cases of Addison’s disease. Clin. Endocrinol. (Oxf) 41, 757–761. Leigh, H., Kramer, S.I., 1984. The psychiatric manifestations of endocrine disease. Adv. Intern. Med. 29, 413–445. Lovas, K., Husebye, E.S., 2002. High prevalence and increasing incidence of Addison’s disease in western Norway. Clin. Endocrinol. (Oxf) 56, 787–791. Lovas, K., Loge, J.H., Husebye, E.S., 2002. Subjective health status in Norwegian patients with Addison’s disease. Clin. Endocrinol. (Oxf) 56, 581–588. Lovas, K., Gebre-Medhin, G., Trovik, T.S., Fougner, K.J., Uhlving, S., Nedrebo, B.G., Myking, O.L., Kampe, O., Husebye, E.S., 2003. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J. Clin. Endocrinol. Metab. 88, 1112–1118. Money, J., Jobaris, R., 1977. Juvenile Addison’s disease: followup behavioral studies in seven cases. Psychoneuroendocrinology 2, 149–157. Mosbech, J., Jorgensen, J., Madsen, M., Rostgaard, K., Thornberg, K., Poulsen, T.D., 1995. The national patient registry. Evaluation of data quality. Ugeskr. Laeger 157, 3741– 3745. Munk-Jorgensen, P., Mortensen, P.B., 1997. The Danish Psychiatric Central Register. Dan. Med. Bull. 44, 82–84. Nagesser, S.K., van Seters, A.P., Kievit, J., Hermans, J., Krans, H.M., van de Velde, C.J., 2000. Long-term results of

A.F. Thomsen et al. total adrenalectomy for Cushing’s disease. World J. Surg. 24, 108–113. Nilsson, F.M., Kessing, L.V., Sorensen, T.M., Andersen, P.K., Bolwig, T.G., 2002. Major depressive disorder in Parkinson’s disease: a register-based study. Acta Psychiatr. Scand. 106, 202–211. Oelkers, W., 1999. Dehydroepiandrosterone for adrenal insufficiency. N. Engl. J. Med. 341, 1073–1074. Ohl, F., Michaelis, T., Vollmann-Honsdorf, G.K., Kirschbaum, C., Fuchs, E., 2000. Effect of chronic psychosocial stress and long-term cortisol treatment on hippocampus-mediated memory and hippocampal volume: a pilot-study in tree shrews. Psychoneuroendocrinology 25, 357–363. Peacey, S.R., Guo, C.Y., Robinson, A.M., Price, A., Giles, M.A., Eastell, R., Weetman, A.P., 1997. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin. Endocrinol. (Oxf) 46, 255–261. Reus, V.I., Wolkowitz, O.M., 2003. Psychiatric effects of glucocorticoid hormone medications. In: Wolkowitz, O.M., Rothschild, A.J. (Eds.), Psychoneuroendocrinology. American Psychiatric Publishing, Inc., Washington, DC, pp. 189–205. Riedel, M., Wiese, A., Schurmeyer, T.H., Brabant, G., 1993. Quality of life in patients with Addison’s disease: effects of different cortisol replacement modes. Exp. Clin. Endocrinol. 101, 106–111. Schacke, H., Docke, W.D., Asadullah, K., 2002. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Ther. 96, 23–43. Schmidt, P.J., Daly, R.C., Bloch, M., Smith, M.J., Danaceau, M.A., St Clair, L.S., Murphy, J.H., Haq, N., Rubinow, D.R., 2005. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychiatry 62, 154–162. Starkman, M.N., 2003. Psychiatric manifestations of hyperadrenocorticism and hypoadrenocorticism (Cushing’s and Addison’s Diseases). In: Wolkowitz, O.M., Rothschild, A.J. (Eds.), Psychoneuroendocrinology. American Psychiatric Publishing, Inc., Washington, DC, pp. 165–188. Thomsen, A.F., Kessing, L.V., 2005. Increased risk of hyperthyroidism among patients hospitalized with bipolar disorder. Bipolar. Disord. 7, 351–357. Trenton, A.J., Currier, G.W., 2001. Treatment of comorbid tuberculosis and depression. Prim. Care Companion. J. Clin. Psychiatry 3, 236–243. Wells, K.B., Golding, J.M., Burnam, M.A., 1988. Psychiatric disorder in a sample of the general population with and without chronic medical conditions. Am. J. Psychiatry 145, 976–981. WHO, 1971. Klassifikation af sygdomme. Systematisk del. International Classification of Diseases. Eigth revison, Danish edition. Sundhedsstyrelsen. WHO, 1993. Klassifikation af sygdomme. Systematisk del. International Statistical Classification of Diseases and Health Related Problems. Tenth revision, Danish edition. Sundhedsstyrelsen og Munksgaard. Wolkowitz, O.M., Reus, V.I., Keebler, A., Nelson, N., Friedland, M., Brizendine, L., Roberts, E., 1999. Doubleblind treatment of major depression with dehydroepiandrosterone. Am. J. Psychiatry 156, 646–649.