Neuropsychiatric Disorders in Cushings Syndrome

Glucocorticoids are crucial in the initiation and consolidation of the stress response. Patients with active Cushing’s syndrome (CS) are exposed to excessive endogenous glucocorticoid levels. In these patients, psychopathology is often being observed. The most common co-morbid disorder is major depression, but to a lesser extent mania and anxiety disorders have also been reported. A severe clinical presentation of CS often also includes depression. Reduction of glucocorticoid synthesis or action, either with metyrapone, ketoconazole, or mifepristone, rather than treatment with antidepressant drugs, is generally successful in relieving depressive symptoms, as well as other disabling symptoms. Following successful surgical treatment of hypercortisolism, both physical and psychiatric signs and symptoms improve substantially. However, it appears that patients do not completely return to their premorbid level of functioning and persistent impairment of quality of life and cognitive function has been reported despite long-term cure. At present, it is not clear whether, and to which extent, psychopathology still affects general well-being after long-term cure of CS. Copyright © 2010 S. Karger AG, Basel Published online: September 10, 2010 Alberto M. Pereira Department of Endocrinology and Metabolism Leiden University Medical Center NL–2333 ZA Leiden (The Netherlands) Tel. +31 71 526 3738, Fax +31 71 524 6017, E-Mail a.m.pereira @ lumc.nl © 2010 S. Karger AG, Basel 0028–3835/10/0925–0065$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 30 :5 1 A M Pereira/Tiemensma/Romijn Neuroendocrinology 2010;92(suppl 1):65–70 66 exposed to a stressor, rapid changes occur within seconds to minutes through stimulation of the sympathetic nervous system via catecholamines (CRH, AVP) and via nongenomic actions of cortisol. These mediators increase excitability, resulting in behavioral changes characterized by increased vigilance, alertness, arousal, and attention. In addition, the stress response is characterized by slower changes that occur within minutes to hours via stimulation of both the mineralocorticoid (MR) and glucocorticoid (GR) receptor. All these changes, in the end, occur only with the purpose to induce the required behavioral adaptations for the individual to be able to adequately cope with the stressor. However, when the stressor becomes chronic, a so-called vulnerable phenotype develops, characterized by neurodegenerative changes within the central nervous system and cognitive impairment [1] . Thus, it is not surprising that CS, that can be considered the clinical human equivalent for severe chronic stress, is associated with behavioral abnormalities. Psychopathology in Active Cushing’s Syndrome Active, untreated CS is associated with a high prevalence of psychopathology. The frequencies of psychiatric symptoms have been evaluated since the late 1970s using different criteria in a total of approximately 500 patients with CS, mostly comprising small patient groups. A subset of these studies that evaluated psychopathology and personality traits are summarized in table 1 . An early study on personality traits in 53 patients with CS reported that 60% of these subjects had personality changes [2] . However, it is not clear from the data in that study whether these patients still had active Cushing’s disease. Another study in 9 patients with active Cushing’s disease concluded that patients had a higher tendency for anxiety than controls [3] . In contrast, Kelly et al. [4] concluded that patients with active CS and control patients scored equally on personality traits (neuroticism and extraversion). Starkman and Schteingart [5] evaluated the prevalence of psychiatric symptoms in 35 patients with active CS and found that irritability, depressed mood, and anxiety were present in the majority of the patients. Intriguingly, an increased overall psychiatric disability, measured by and indicated by a specific score, was associated with increased cortisol secretion. Among another consecutive unselected series of 29 patients with untreated CS, 25 (86%) were significantly depressed. In this study, the severity of the depression was not related to circulating cortisol levels, but the depression was rapidly relieved when the tumor or adrenal glands were removed [6] . Kelly et al. [7] compared in another study 15 patients with active CS both with 15 other patients who had been treated successfully for CS and with 13 patients with other pituitary tumors. Depression was the main psychiatric diagnosis using the CATEGO program after Present State Examinations. Patients with active CS were significantly more depressed (Hamilton Rating Scores) than were the other patients. Another study [8] compared 20 patients with Cushing’s disease with 20 patients with major depressive disorder using the Structured Clinical Interview for DSM-III-R (SCID) and Research Diagnostic Criteria. A diagnosis of generalized anxiety disorder, major depressive disorder, or panic disorder, either alone or in combination, was present in approximately two thirds of the patients with Cushing’s disease. Interestingly, behavioral symptoms usually first occurred at or after the onset of the first physical symptoms. However, the onset of panic disorder was associated with more chronic stages of active Cushing’s disease. In agreement with the studies that involved small patient numbers, psychopathology was highly prevalent in a large cohort of 162 patients with Cushing’s disease reported by Sonino et al. [9] . Major depression, according to DSM-IV criteria, was present in more than 50% of the patients. Interestingly, the presence of psychopathology was significantly associated with older age, female gender, higher pretreatment 24-hour urinary cortisol levels, a more severe clinical condition, and absence of pituitary adenoma ( table 2 ). This has led to the inclusion of mood disorders in a clinical index for rating the severity of CS [10] . Effects of Reduction of Corticosteroid Synthesis or Action on Psychopathology in Cushing’s Syndrome Only a few studies with a limited number of patients have reported the effects of successful reduction of corticosteroid excess on psychopathology. These studies demonstrate that both reduction of corticosteroid synthesis with ketoconazole or metyrapone and blockade of the glucocorticoid receptor with mifepristone positively affect psychopathology. The first study that reported the effects of medical treatment of patients with CS was published in 1979 [11] . In this study, in 38 patients with CS, 65% were diagnosed with depression of different clinical severity. The majority of the patients were treated with metyrapone which resulted in remission of psychiatric symptoms in virtually all of them [11] . This impressive D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 30 :5 1 A M Neuropsychiatric Disorders in Cushing’s Syndrome Neuroendocrinology 2010;92(suppl 1):65–70 67 Table 1. Overview of studies on psychopathology and personality traits in patients with Cushing’s disease and Cushing’s syndrome Author, year Number of subjects Gender (M/F) Age years (SD) Active/treated Methods Outcomes Starr, 1951 [2] 53 Cushing’s syndrome NA NA NA NA Of all patients, 35% had marked personality alterations, and 25% showed frank psychosis which resulted in institutionalization. Cohen, 1980 [6] 29 Cushing’s syndrome 7/22 Almost all were seen during admission for diagnosis. A few were first seen immediately after surgery Interviews. Detailed clinical history and an examination of mental state Of all patients, 86% had distinct affective disorders. Twenty-five patients suffered from depression, and one had manic and depressive episodes. Sablowski et al., 1986 [3] 9 Cushing’s disease 9 acromegaly 6 prolactinoma 24 controls Not given NA Before and after surgery Freiburger Personality Inventory, Giessen test, StateTrait-Anxiety Inventory Pre-operatively, there is a tendency to higher scores of trait-anxiety in pituitary patients compared to controls. This did not change after surgery. Furthermore, Cushing’s disease patients seemed more nervous and restrained than acromegaly patients. Kelly et al., 1996 [4] 43 Cushing’s syndrome 24 acromegaly and prolactinoma 10/33 NA Prospective study. Before and after treatment Present state examination, Hamilton rating scale CrownCrisp experiential index, Eysenck personality inventory Present state examination: only 19% of the active Cushing’s syndrome patients were normal, whereas 87% of the controls were normal. Depression and all scales of the CrownCrisp improved after treatment. When patients were re-assessed after appropriate treatment, there was a significant decrease in neuroticism score but no change in extraversion. Dorn et al., 1995 [20] 33 Cushing’s syndrome 17 matched hospitalized controls 5/28 3689 Hypercortisolemic during interview Interviews, atypical depression diagnostic scale, Hamilton rating scale, self-report instruments, medical records information Anytime during the active phase, 67% of the patients had at least one diagnosis. Atypical depression was the most frequent finding (52%). The duration of CS was an important factor in predicting whether patients sought psychological intervention. Dorn et al., 1997 [15] 33 Cushing’s syndrome 5/28 3689 Before and 3, 6 and 12 months after correction for hypercortisolism Interviews, atypical depression diagnostic scale, Hamilton rating scale, self-report instruments, medical records information Before cure, 67% had significant psychopathology. After cure, overall psychopathology decreased to 54% at 3 months, 36% at 6 months, and 24% at 12 months. There was an inverse correlation between psychological recovery and baseline morning cortisol. Atypical depression remained the most frequent finding. Flitsch et al., 2000 [21] 19 Cushing’s disease 18 acromegaly 11 NFMA 7/12 34812 Before and after (6 months) transsphenoidal microsurgery Semi-structured interview, Freiburger Persönlichkeitsinventar, State-trait-anxietyinventory, Rosenzweig picture frustration test, Befindlichkeitsskala, Giessener Beschwerdebogen Most common psychopathological signs were excitability and depression. At least one of these signs was found in 12 out of 19 Cushing’s disease patients. 6–8 months after surgery, the majority of the Cushing’s disease patients (10 of 19) noticed an increase in physical well-being. Sonino, 2006 [19] 24 Cushing’s syndrome 24 healthy matched controls 5/19 35811 1–3 years in remission Tridimensional personality questionnaire, Symptom Rating Test No significant differences in personality dimensions between patients and controls. On the Symptom Rating Test, patients scored higher on anxiety, depression and psychotic symptoms compared to controls. D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 30 :5 1 A M Pereira/Tiemensma/Romijn Neuroendocrinology 2010;92(suppl 1):65–70 68 treatment efficacy was later confirmed in another study with 53 patients with Cushing’s disease pretreated with metyrapone and 24 patients who had been given pituitary irradiation for a median duration of 27 months [12] . In contrast to metyrapone, a total of only 20 patients with CS have been reported that were treated with the GR antagonist mifepristone. The clinical applicability and effectivity of mifepristone in these CS patients was reviewed recently [13] . Treatment with mifepristone resulted in a dramatic improvement of clinical signs in 15/20 patients. In parallel, in 3 of the 4 patients with psychopathology a significant improvement was reported. It is important to note that the beneficial effects of mifepristone on psychopathology already occur within a few days after the initiation of treatment. Reversibility of Psychopathology after Remission of