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Schumacher, M.M.; Santambrogio, J. Dexamethasone Suppression Test in Psychiatry. Encyclopedia. Available online: https://encyclopedia.pub/entry/44717 (accessed on 18 May 2024).
Schumacher MM, Santambrogio J. Dexamethasone Suppression Test in Psychiatry. Encyclopedia. Available at: https://encyclopedia.pub/entry/44717. Accessed May 18, 2024.
Schumacher, Martin M., Jacopo Santambrogio. "Dexamethasone Suppression Test in Psychiatry" Encyclopedia, https://encyclopedia.pub/entry/44717 (accessed May 18, 2024).
Schumacher, M.M., & Santambrogio, J. (2023, May 23). Dexamethasone Suppression Test in Psychiatry. In Encyclopedia. https://encyclopedia.pub/entry/44717
Schumacher, Martin M. and Jacopo Santambrogio. "Dexamethasone Suppression Test in Psychiatry." Encyclopedia. Web. 23 May, 2023.
Dexamethasone Suppression Test in Psychiatry
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The dexamethasone suppression test (DST) assesses the functionality of the HPA axis and can be regarded as the first potential biomarker in psychiatry. In 1981, a group of researchers at the University of Michigan published a groundbreaking paper regarding its use for diagnosing melancholic depression, reporting a diagnostic sensitivity of 67% and a specificity of 95%.

dexamethasone suppression test Cushing’s syndrome HPA-axis depression

1. Introduction

With the advent of modern psychotropic medications, starting in the early 1950s, psychiatry became more biology-oriented, with high expectations for identifying the somatic etiologies of the endogenous psychoses and corresponding biomarkers. The neurotransmitter-based hypotheses of the etiologies/pathophysiologies of depression and schizophrenia further fueled this development. Of the nervous, immune, and endocrine systems, the nervous system has received much attention and importance in biopsychiatry, but no robust biomarkers associated with neurotransmitters have yet been found. More recently, the important role of the immune system in mental disorders has been acknowledged, with autoimmune encephalitides being identified as causes of different neurological and psychiatric disorders in some patients. This is currently a very active field and many autoantibodies can be considered as promising biomarkers.
Disorders of the endocrine system, however, were the first to be recognized as strongly related to mental disorders. Psychiatrists Maxime Laignel-Lavastine (1875–1953), Manfred Bleuler (1903–1994), and Edward Sachar (1933–1984), and neurosurgeon Harvey Cushing (1869–1939) were among the early leaders in the area where endocrinology and psychiatry intersect. Although all endocrine systems have an impact on mental wellbeing, the hypothalamic–pituitary–adrenal (HPA) axis, in particular, has received much attention in psychiatry [1]. Early research in this field started in the 1960s, headed by Edward Sachar and Bernard Carroll (1940–2018). The dexamethasone suppression test (DST) was introduced in endocrinology for the diagnosis of Cushing’s syndrome in 1960 [2]. Its importance for psychiatry was recognized by Carroll; in 1968, he started studying cortisol in plasma, urine, and cerebrospinal fluid; varying the times and dosages of glucocorticoid administration; examining different sampling schedules; optimizing the statistical handling of these complex measures; and exploring the differences between psychiatric patients with melancholic depression, patients with other psychiatric disorders, and normal subjects. It is important to distinguish melancholic depression (melancholia, endogenous depression) from exogenous forms of depression (i.e., neurotic, reactive). Melancholia is considered to be a biological disease characterized by a recurrent course, familial aggregation, and a pronounced component of psychomotor disturbances (i.e., retardation and/or agitation of mental and physical activities). Carroll observed that in the majority of patients with melancholic depression, the application of dexamethasone, a synthetic high-potency glucocorticoid with a long biological half-life, approximately 25 times more active than endogenous cortisol, did not suppress the secretion of 11-hydroxycorticosteroids (e.g., cortisol) [3]. He led further research that, in 1981, culminated in the seminal article, A Specific Laboratory Test for the Diagnosis of Melancholia, published in the Archives of General Psychiatry [4], in which the authors proposed the DST for a laboratory-based diagnosis of melancholia, so the DST can be considered as the first biomarker in psychiatry. This research was met with great interest and enthusiasm by the psychiatric community and triggered many studies by other researchers using the DST as a diagnostic tool in psychiatry. Unfortunately, the results of these studies were inconsistent and, for the most part, did not confirm Carroll’s findings and claims. The reasons for this are various and include the use of divergent versions of the DST (according to Helena Kraemer there were “almost as many DSTs as there are DST studies[5] and significantly different patient populations. In 1980, the American Psychiatric Association (APA) published DSM-III, introducing the very broad major depressive disorder (MDD) construct. As many researchers subsequently applied the DSM-III criteria for patient selection, the DST lost much of its sensitivity. As explained by Shorter and Fink [1] and Lutz [6], there were various factors that contributed to DST’s ultimate fall from grace including personal agendas, psychiatric community dynamics, political factors, the prevailing zeitgeist, and the unfavorable judgement of the APA. An improved, standardized, and validated version of the DST would be a useful tool in clinical psychiatry and also for drug development.

2. Hypercortisolism, the HPA Axis, Cushing’s Syndrome, and Depression

Hypercortisolism is common in patients with severe depression [7][8][9][10]; it manifests in elevated levels of cortisol in the serum, cerebrospinal fluid (CSF), saliva and/or 24 h urine and elevated levels of corticotropin-releasing hormone (CRH) in the CSF.
Research in this field started in the 1960s [3][11] and a comprehensive review was published recently [12]. On the other hand, depression and, to a lesser extent, mania and anxiety are also very common in patients suffering from Cushing’s syndrome (CS) [13][14]. In most CS patients, hypercortisolism is due either to hypersecretion of the adrenocorticotropic hormone (ACTH) by a pituitary tumor, to ectopic ACTH secretion from an extrapituitary neoplastic lesion, or to autonomous cortisol secretion by an adrenal tumor.
A detailed list of CS etiologies, which fall into two major categories, endogenous and exogenous, can be found in Kannan [15]. Distinguishing between endogenous and exogenous CS can be challenging for both the endocrinologist and psychiatrist, with the risk of a wrong diagnosis having negative consequences for the patient. This situation becomes even more complicated as some patients with physiological hypercortisolism exhibit only minimal physical CS features.
In certain subclinical forms of endogenous CS [16][17], psychiatric symptoms are their first and only manifestation [18]. A recurrent form of CS, cyclical Cushing’s syndrome, which can closely mimic recurrent mood disorders such as melancholia, has been reported for all CS etiologies. Irrespective of age, primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease are also often cyclic [18]. These are important observations, as melancholic depression (according to the definition of Kraepelin et al. [19]) is also a periodic disease.
Exogenous CS patients fall into two groups, iatrogenic and factitious. The former is due to prolonged treatment with corticosteroids or ACTH, while the latter, usually called pseudo-Cushing’s syndrome (i.e., physiologic or non-neoplastic CS), is mainly caused by neuropsychiatric disorders, polycystic ovary syndrome (PCOS), obesity, poorly controlled diabetes mellitus, alcoholism, or eating disorders [20].
All CS etiologies have an excessive secretion of cortisol as a common final pathway. The clinical pictures with regard to the physical and mental signs and symptoms are due to the underlying hypercortisolism. However, these do not allow for the identification of their specific etiology and call for further clinical investigations (e.g., imaging, biopsies, and hormone analyses).
The treatment of CS should target the underlying etiology. Iatrogenic CS and the mental symptoms caused by prolonged treatment with glucocorticoids [21] cease when the drug is withdrawn. Such treatment, which targets the reduction in glucocorticoid synthesis or action, either with metyrapone, ketoconazole, or mifepristone, as opposed to treatment with antidepressant drugs, is generally successful in relieving depressive symptoms as well as other disabling symptoms [22][23]. Following successful surgical treatment of hypercortisolism, both physical and psychiatric signs and symptoms substantially improve [24]. These findings suggest that hypercortisolism might be the cause of the observed psychopathology.
In healthy subjects, the release of CRH and ACTH is regulated by cortisol via a negative feedback mechanism, while in patients with Cushing’s disease (CD) and other subtypes of CS, this feedback is impaired, leading to the secretion of excess cortisol. In healthy subjects, dexamethasone (DEX) acts on the hypothalamus and pituitary, suppressing the secretion of cortisol, but this does not happen in patients with CS. Interestingly, nonsuppression was also observed in some patients with exogenous CS (pseudo-Cushing’s syndrome) subjected to the DST.
The psychiatric symptoms and their frequency observed in patients with endogenous CS and those with major depression were described by Murphy [22]. The prevalence of typical symptoms such as depressed mood, decreased energy, irritability, insomnia, and impaired memory are increased to a similar extent in both diseases.
Many organic illnesses have a recurrent or intermittent course. Organic illnesses can also cause recurrent mental symptoms, suggesting a “psychogenic” disorder and making the detection of the underlying disease more difficult. Gustave Newman lists the following related diseases: multiple sclerosis, acute intermittent porphyria, pheochromocytoma, systemic lupus erythematosus, pancreatitis, herpes simplex encephalitis and episodic dyscontrol syndrome [25]. Other autoimmune diseases, intermittent Cushing’s syndrome, and other diseases can be added to this list. This observation supports the possibility that even mental disorders, such as melancholia and bipolar disorder, which by definition have a recurrent course, can be mimicked by somatic diseases.

3. The DST and Psychiatric Nosology

Carroll, in his 1981 publication [4], proposed the DST as a tool for the diagnosis of melancholia. Obviously, the definition of melancholia and the reliability of this diagnosis are of utmost importance for the performance of the DST (i.e., its sensitivity and specificity).
What is melancholia? This question might be considered naïve, but it is nevertheless very relevant because there is still no consensus in the psychiatric community regarding melancholia as a mental disease sui generis or the characteristics uniquely describing it. Melancholia (also called endogenous, endogenomorphic, or vital depression) has been described as a clinical entity for millennia and was widely accepted by the physicians working in lunatic asylums of the past. Emil Kraepelin considered melancholia to be part of manic-depressive insanity (MDI) [19][26]. This definition of melancholia includes psychotic depression, bipolar depression, mixed bipolar depression, and probably also schizoaffective psychosis. In contrast to ordinary depression, which is mainly phenomenologically characterized by different mental symptoms, melancholia has a strong somatic component comprising a recurrent course, familial aggregation, and pronounced psychomotor disturbances. A melancholic episode often occurs without any external (psychosocial) triggers and is inert to psychotherapeutic interventions.
With the advent of DSM-III in 1980, melancholia was grouped together with other neurotic/reactive depressions under the label of major depressive disorder (MDD). This resulted in a very heterogeneous entity that continues to hinder progress in depression research and psychopharmacology and has been lamented by many experts [27][28][29]. Indeed, several experts have called for melancholia to be reinstated as a valid disease entity [30][31]. It is also described comprehensively in the literature [32][33].
Currently, the most reliable diagnostic tool for melancholia is probably the CORE measure [31][32] of psychomotor disturbance, which is based on 18 signs (not symptoms) assessed by an experienced clinician. These signs belong to the subscales of agitation (facial agitation, motor agitation, facial apprehension, stereotyped movement, and verbal stereotypy), retardation (slowed speed of movement, slowing of speech, delay in motor activity, bodily immobility, delay in verbal responses, facial immobility, and postural slumping) and noninteractiveness (nonreactivity, inattentiveness, poverty of associations, shortened verbal responses, and impaired spontaneity of speech). A value is attributed to each sign (zero if absent; one if present). These values are then added to obtain the total CORE score (range: 0 to 18). A score of eight or more is needed for the diagnosis of melancholia. There is also a more refined CORE measure, graded according to the severity of the signs (absent: 0, present: 1 to 3) available (range: 0 to 54). The reliability and validity of the CORE measure has been assessed in many international studies [32][34].
Carroll et al., investigating the performance of the DST, made a clinical diagnosis of melancholia as described in the article Diagnosis of Endogenous Depression published in the Journal of Affective Disorders [35]. In addition to the application of a structured psychiatric interview (Schedule for Affective Disorders and Schizophrenia (SADS)), the patient’s previous psychiatric history, family history, and past hospital records were taken into consideration. The major diagnostic features of endogenous depression (i.e., melancholia) were listed as: (i) history of mania, hypomania, or endogenous depression; (ii) definite family history; (iii) severe agitation or retardation; (iv) depressive psychosis; (v) pervasive anhedonia; (vi) definite pathological guilt. The severity of depression was quantified with the Hamilton rating scale and the Carroll self-rating scale [35].
Other researchers have mostly used only symptom-based tools such as the Research Diagnostic Criteria (RDC) or the DSM-III, though some have preferred the Newcastle scale [36][37][38][39]. It must be clearly stated that the vast majority of other researchers investigating the DST have not used the Carroll–Feinberg definition and diagnostic criteria of melancholia, applying broader (and less appropriate) definitions. The use of these different tools partially explains the inconsistent results across studies.
Mark Zimmerman et al. from the University of Iowa examined the relationship between the performance of the DST and four definitions of endogenous depression, namely DSM-III, Feinberg and Carroll, Newcastle, and RDC [39]. They found rather similar percentages (36–48%) of nonsuppressors in groups of patients diagnosed with “definite endogenous depression”.
Unfortunately, there is no gold standard for the tools used for the diagnosis of melancholia; Hui and Zhou of the Division of Biostatistics at the Indiana University School of Medicine reviewed the statistical methods developed to estimate the sensitivity and specificity of screening or diagnostic tests when the fallible tests are not evaluated against a gold standard [40].

References

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  3. Carroll, B.J.; Martin, F.I.; Davies, B. Resistance to suppression by dexamethasone of plasma 11-O.H.C.S. levels in severe depressive illness. Br. Med. J. 1968, 3, 285–287.
  4. Carroll, B.J.; Feinberg, M.; Greden, J.F.; Tarika, J.; Albala, A.A.; Haskett, R.F.; James, N.M.; Kronfol, Z.; Lohr, N.; Steiner, M.; et al. A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch. Gen. Psychiatry 1981, 38, 15–22.
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