HPA-axis hyperactivity and mortality in psychotic depressive disorder: Preliminary findings

https://doi.org/10.1016/j.psyneuen.2008.02.005Get rights and content

Summary

Background

The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder.

Methods

The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1 mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m.

Results

Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to CV causes (t=4.01, p<0.001 and t=3.03, p=0.004, respectively). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0) μg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6) μg/dl (t=3.03, df=53, p=0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t=2.05, p=0.048).

Conclusions

Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.

Section snippets

Background

Previous research into the effects of hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity on mortality has focused on its relationship to risks for suicide and there are now at least six reports of a significant association between HPA-axis hyperactivity and completed suicide in groups with mood disorder (Carroll et al., 1980; Coryell and Schlesser, 2001, Coryell and Schlesser, 1981; Norman et al., 1990; Targum et al., 1983; Yerevanian et al., 2004). Another two found the relationship to be

Participants

Between 1982 and 1984 consecutive admissions to the adult psychiatric units at the University of Iowa were screened to select those who (1) had delusions and/or hallucinations, (2) were 18 years of age or older, (3) did not have a manic syndrome or a mixed state, (4) were not taking lithium, (5) were not mentally retarded, delirious or demented and (6) were not in medical or pharmacological circumstances that would invalidate either a DST or a thyroid-releasing-hormone stimulation test.

The

Cardiovascular deaths

Table 1 displays the baseline demographics, RDC diagnostic composition and DST results for the 54 individuals with psychotic depressive disorder. There were 13 deaths during a mean (SD) follow-up period of 17.1 (4.6) years, of which 4 (30.8%) were from CV causes. All four of these cases, and 22 (44.0%) of the remaining subjects, had post-dexamethasone cortisol concentrations exceeding 5 μg/dl (p=0.047, Fisher's exact test). Three of the 4 CV deaths also had values exceeding 10 μg/dl in contrast

Conclusions

If HPA-axis hyperactivity accounts, at least in part, for the association between depressive disorder and an increased likelihood for CV death, and if a cortisolemia dose-effect operates in this mediation, then the association should be more apparent among patients who have depressive disorder with psychotic features. Not all patients with psychotic depressive disorder manifest HPA-axis hyperactivity but they are more likely to do so than depressed patients without psychotic features (Nelson

Role of the funding source

Funding for this study was provided by NIMH Grants MH 38777 and MH 64834. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Conflict of interest

Each of the authors reported that he or she had no conflict of interest regarding this manuscript.

References (45)

  • B. Weber-Hamann et al.

    Metabolic changes in elderly patients with major depression: evidence for increased accumulation of visceral fat at follow-up

    Psychoneuroendocrinology

    (2006)
  • B.I. Yerevanian et al.

    The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression

    J. Affect. Disord.

    (2004)
  • E.A. Young et al.

    Similarity in saliva cortisol measures in monozygotic twins and the influence of past major depression

    Biol. Psychiatry

    (2000)
  • C. Allgulander

    Suicide and mortality patterns in anxiety neurosis and depressive neurosis

    Arch. Gen. Psychiatry

    (1994)
  • A. Aromaa et al.

    Depression and cardiovascular diseases

    Acta. Psychiatr. Scand. Suppl.

    (1994)
  • J.C. Barefoot et al.

    Symptoms of depression, acute myocardial infarction, and total mortality in a community sample

    Circulation

    (1996)
  • D.W. Black et al.

    The relationship between DST results and suicidal behavior

    Ann. Clin. Psychiatry

    (2002)
  • B.J. Carroll et al.

    Suicide, neuroendocrine dysfunction and CSF 5-HIAA concentrations in depression

  • W. Coryell et al.

    Suicide and the dexamethasone suppression test in unipolar depression

    Am. J. Psychiatry

    (1981)
  • W. Coryell et al.

    The dexamethasone suppression test and suicide prediction

    Am. J. Psychiatry

    (2001)
  • W.H. Coryell et al.

    HPA axis hyperactivity and recovery from functional psychoses

    Am. J. Psychiatry

    (1989)
  • W. Coryell et al.

    The clinical and neuroendocrine features of psychotic depression

    J. Nerv. Ment. Dis.

    (1984)
  • Cited by (16)

    • Social change and access to a palatable diet produces differences in reward neurochemistry and appetite in female monkeys

      2016, Physiology and Behavior
      Citation Excerpt :

      Lower ranking, or more subordinate animals, are thereby exposed continuously to an adverse social environment, similar to that experienced by people [31]. Critically, the experience of social subordination in female macaques results in diminished glucocorticoid negative feedback inhibition of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis [32,33], a physiological phenotype similar to what has been describe in humans suffering from psychopathology such as depression [34,35]. Furthermore, subordinate macaques show reduced D2R binding potential (D2R-BP) in striatal regions as assessed by positron emission tomography (PET) [27,36].

    • Is the Psychotic Depression Assessment Scale a useful diagnostic tool?: The CRESCEND study

      2014, Journal of Affective Disorders
      Citation Excerpt :

      It is consistent with a previous finding that suicidal ideation and a history of suicide attempts were more common in patients with PD than with non-PD (Schaffer et al., 2008). Coryell et al. (2008) reported that blood cortisol concentration after a dexamethasone suppression test was a predictor of suicide in patients with PD, while Vythilingam et al. (2003) demonstrated that patients with PD had higher mortality rates than patients with non-PD. Although the cause of death in these patients was mostly illness rather than suicide, it is possible that cortisol concentration mediates the relationship between PD, suicide, and mortality.

    • Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling

      2013, Psychoneuroendocrinology
      Citation Excerpt :

      Both human and rodent studies demonstrate that repeated administration of SSRIs attenuate 5-HT1A receptor agonist-induced increase in oxytocin and adrenocorticotropic hormone (ACTH) secretion, suggesting a desensitization of 5-HT1A receptors in the paraventricular nucleus of the hypothalamus (PVN) (Gomez-Gil et al., 2010; Lerer et al., 1999; Lesch et al., 1991; Li et al., 1996). Since these hormones are related to the pathogenesis of depression, desensitization of 5-HT1A receptors in the PVN may contribute to the therapeutic effects of SSRIs (Coryell et al., 2008; Wasserman et al., 2010). Seven to 14 days of treatment with either the SSRI fluoxetine or paroxetine resulted in desensitization of 5-HT1A receptor signaling in the PVN (Li et al., 1997b, 1996; Raap et al., 1999).

    • Association between functional polymorphism of the AVPR1b gene and polymorphism rs1293651 of the CRHR1 gene and bipolar disorder with psychotic features

      2012, Journal of Affective Disorders
      Citation Excerpt :

      This is reflected in high levels of the 24-hour urinary free cortisol, high rates of dexamethasone nonsuppression, and high post dexamethasone cortisol levels (Schatzberg et al., 2000). Not all of the patients with psychotic features in the course of depressive disorder manifest hyperactivity of HPA-axis but they are more likely to do so than depressed patients without psychotic features (Coryell et al., 2008). The combined dexamethasone–corticotrophin-releasing hormone (dex-CRH) test is also abnormal in bipolar patients during relapse and recovery (Watson et al., 2004).

    • A multisite trial of mifepristone for the treatment of psychotic depression: A site-by-treatment interaction

      2009, Contemporary Clinical Trials
      Citation Excerpt :

      The proposed etiology includes dysregulation and overactivity of the hypothalamic–pituatary–adrenal axis. Aberrations in cortisol have been observed in many previous studies [5–10]. Previous research suggests that mifepristone, a cortisol receptor (GRII) antagonist, can reduce the psychotic symptoms associated with psychotic depression.

    View all citing articles on Scopus
    View full text