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Cited by 278Stress Responses and CortisolSchizophrenia research and treatmentAdrenal Hormones and Disorders

Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment

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Mondelli, Valeria, Dazzan, Paola, Hepgul, Nilay, Di Forti, Marta, Aas, Monica, D'Albenzio, Alessandro, Di Nicola, Marco, Fisher, Helen +9 more·2010·Schizophrenia Research
DOI 10.1016/j.schres.2009.08.013PMC PMC3513410
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Abstract

First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

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Crossref · 10.1016/j.schres.2009.08.013

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    First-episode psychosis patients showed a trend toward higher diurnal cortisol levels than healthy controls (p=0.055).

    “Patients had a trend for higher diurnal cortisol levels (p=0.055)”
    • Also stated in: § 3.2. Cortisol levels · hedged
      “Patients showed a trend for higher levels of cortisol levels during the day compared with healthy controls, but this did not reach the statistical significance (AUC, t=−2.0, df=1, 82, p=0.055, see Table 2 and Fig. 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In controls, daytime cortisol levels correlated positively with the number of stressful events.

    “Of note also is that the relationship between cortisol levels during the day and stress measures was different in patients and controls, since cortisol levels in controls correlated positively with the number of stressful events, and showed not-significant positive correlations with perceived stress and childhood trauma.”
    Quote in the paperSubstantial claim
  • Findingown data

    In first-episode psychosis patients, the correlation between frequency of cannabis use and cortisol awakening response was not significant after covarying for childhood sexual abuse (r=0.27, p=0.1).

    “the correlation between frequency of cannabis use and cortisol awakening response was not significant after covarying for childhood sexual abuse (r=0.27, p=0.1).”
    Quote in the paperSubstantial claim
  • Findingown data

    In first-episode psychosis patients, the number of stressful life events in the last six months correlated negatively with diurnal cortisol levels (r=-0.36, p=0.014).

    “diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014)”
    • Also stated in: § 3.3. Correlation analyses · plain
      “in patients with first-episode psychosis, the number of stressful life events in the last 6 months correlated negatively with the cortisol levels during the day”
    Quote in the paperSubstantial claim
  • Findingown data

    In healthy controls, frequency of current cannabis use did not correlate with the cortisol awakening response.

    “frequency of current cannabis use was positively correlated with the cortisol awakening response in patients, but not in controls.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    Perceived stress was not significantly correlated with either diurnal cortisol levels or the cortisol awakening response in first-episode psychosis patients.

    “No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    An excess of stressful life events precedes the onset of psychosis and psychotic relapse in patients with schizophrenia.

    “an excess of stressful life events has been shown to precede the onset of psychosis and psychotic relapse in patients with schizophrenia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bebbington et al., 1993 source

      Not checked in the free run.

    • cites Walker et al., 2008 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Childhood adversities are linked to an increased risk of psychiatric disorders and are reported more frequently in patients with psychosis than in the general population.

    “childhood adversities have also been linked to an increased risk for development of psychiatric disorders, and have been reported to be more frequent in patients with psychosis than in the general population”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Read et al., 2005 source

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    Study design and conductown data

    Inter-rater reliability between researchers for the OPCRIT was very good (Cronbach's alpha=0.91).

    “Inter-rater reliability between researchers for the OPCRIT was very good (Cronbach’s alpha=0.91).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The rate of current tobacco smokers was significantly higher in patients than in controls.

    “The rate of current tobacco smokers was significantly higher in the patients than in controls (see Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Ethnicity was included as a covariate in confirmatory analyses.

    “Ethnicity was therefore included as a covariate in confirmatory analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The modified plasma cortisol assay was validated for salivary cortisol measurement, with reproducible calibration, good correlation with a published TR-FIA, analytical sensitivity of 0.2 nmol/l, and inter/intra assay precision below 10%.

    “The plasma cortisol assay of the analyzer was suitably modified and then validated for these measurements. A set of 10 cortisol standards in saline were used in each assay to plot a calibration graph. This was highly reproducible with slope of (mean± SEM) 0.197 ± 0.004. The method correlated well with a previously published TR-FIA (Juruena et al., 2006). It had analytical sensitivity of 0.2 nmol/l”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Juruena et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The rate of current cannabis users was double in patients compared with controls, but this difference did not reach statistical significance.

    “the rate of current cannabis users in the patients’ group was double than the one in controls, however this difference did not reach statistical significance (see Table 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The number of days of antipsychotic treatment was included as a covariate in all analyses of diurnal cortisol.

    “the number of days of antipsychotic treatment was included as covariate in all the analyses looking at cortisol during the day”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    First-episode psychosis patients did not differ from healthy controls in age, gender, or relationship status.

    “First-episode psychosis patients did not differ in age, gender, and relationship status from healthy controls”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The severity of symptoms was measured in the first month after contact with psychiatric services, which did not always correspond to the time of cortisol collection.

    “However, we measured the severity of symptoms in the first month after contact with psychiatric services, and this time-frame did not always correspond to the time when the cortisol was collected and thus reflect the severity of psychotic symptoms at the time of cortisol collection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An association between anxiety and predexamethasone cortisolemia before starting antipsychotic treatment in patients with first-episode psychosis was found.

    “Another possible factor, explaining the high cortisol levels in first-episode psychosis could be the anxiety associated with experiencing psychotic symptoms for the first time; indeed, Ceskova et al. (2006) found an association between anxiety and predexamethasone cortisolemia before starting antipsychotic treatment in patients with first-episode psychosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ceskova et al., 2006

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depressed patients with PTSD show lower cortisol levels than depressed patients without PTSD.

    “Interestingly, these results are consistent with a previous study by Oquendo et al. (2003) reporting that depressed patients with PTSD show lower cortisol levels than depressed patients without PTSD, again suggesting that the presence of extremely stressful and traumatic experience can determine a decrease in the activation of the HPA axis also in depression, another condition characterized by HPA”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oquendo et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subjects with chronic fatigue syndrome and post-traumatic stress disorder tend to show decreased cortisol awakening responses.

    “In contrast, subjects with chronic fatigue syndrome (Roberts et al., 2004), and post-traumatic stress disorder (Rohleder et al., 2004; Wessa et al., 2006), conditions usually characterized by lower cortisol levels during the day (Cleare, 2003; Yehuda, 2001), also tend to show decreased cortisol awakening responses (Roberts et al., 2004).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Roberts et al., 2004 source

      Not checked in the free run.

    • cites Rohleder et al., 2004 source

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    • cites Wessa et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lower levels of DHEA have been described late in the course of chronic illness.

    “Interestingly, one previous study has shown high serum levels of dehydroepiandrosterone-sulphate (DHEA-S), a hormone with anti-glucocorticoid action, in patients with first-episode psychosis (Strous et al., 2004), while lower levels of DHEA have been described late in the course of chronic illness (Maninger et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Maninger et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Patients and controls differed in ethnicity, but statistical analyses repeated with ethnicity as a covariate confirmed the significance of the results.

    “Second, patients and controls differed in ethnicity; however, all the statistical analyses were repeated using ethnicity as a covariate and confirmed the significance of the results obtained.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A larger pituitary volume has been described in healthy first degree relatives of patients with schizophrenia.

    “Furthermore, we have also recently described a larger pituitary volume in healthy first degree relatives of patients with schizophrenia (Mondelli et al., 2008), and proposed that the HPA axis hyperactivity may be related to a genetic predisposition to over-activate the axis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mondelli et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Stress measures were derived from self-reported questionnaires and not corroborated by external evidence, and may be less reliable.

    “Fourth, our measures of stress were derived from self-reported questionnaires and not corroborated by external evidence, and may represent a less reliable measure of stress.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Women with first-episode psychosis have a higher rate of childhood sexual abuse than men.

    “These authors did not explain this gender difference, but it is of note that women with first-episode psychosis have been described to have a higher rate of childhood sexual abuse than men (Fisher et al., 2009), and that our data show that childhood sexual abuse increases cortisol awakening response, thus potentially normalizing the blunted response in women.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fisher et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The association between schizophrenia and heavy smoking or nicotine dependence is widely recognized.

    “Indeed, the association between schizophrenia and heavy smoking or nicotine dependence is widely recognized (De Leon and Diaz, 2005) and previous studies have reported nicotine as a strong activator of the HPA axis (Rohleder and Kirschbaum, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites De Leon and Diaz, 2005

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    No specific mood evaluations were performed in the sample.

    “Last, depression is widely recognized to affect HPA axis activity, but we did not perform specific mood evaluations in our sample.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The DHEA-to-cortisol ratio is more informative than either DHEA or cortisol absolute concentrations.

    “The DHEA-to-cortisol ratio has been described as more informative than either DHEA or cortisol absolute concentrations in particular regarding the possible effect of these hormones on cognitive function (Maninger et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Maninger et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Only four patients had a family history of psychosis, preventing meaningful comparisons.

    “Family history for psychosis was recorded in this sample, but unfortunately only four patients had family history of psychosis, not allowing for any meaningful comparisons.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High serum levels of DHEA-S have been shown in patients with first-episode psychosis.

    “Interestingly, one previous study has shown high serum levels of dehydroepiandrosterone-sulphate (DHEA-S), a hormone with anti-glucocorticoid action, in patients with first-episode psychosis (Strous et al., 2004), while lower levels of DHEA have been described late in the course of chronic illness (Maninger et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Strous et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Saliva collection was not directly supervised.

    “Third, although the subjects completed information sheets during the saliva collection, we did not supervise directly the saliva collection in our subjects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A larger pituitary volume has been demonstrated weeks before the clinical onset of psychosis.

    “Indeed, the severity of the non-psychotic, prodromal symptoms preceding the onset may be important, as suggested by our work demonstrating a larger pituitary volume weeks before the clinical onset of the psychosis (Garner et al., 2005) — but unfortunately this measure was not available.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Garner et al., 2005 source

      Not checked in the free run.

26 of 26

  • The paper relies on this without support.

    The putative mechanisms listed (recent stressful events, perceived stress, childhood trauma, symptom severity, tobacco smoking, and cannabis use) had not previously been studied together with HPA axis activity in first-episode psychosis.

    “Surprisingly, however, these factors have not been yet studied together with HPA axis activity in first-episode psychosis.”

  • The paper relies on this without support.

    The set of factors examined in the study comprises the main putative mechanisms that could explain HPA axis hyperactivity at the onset of psychosis.

    “we investigate HPA axis activity (salivary cortisol during the day and in response to awakening) together with all of the putative mechanisms described above as well as the effects of antipsychotic treatment”

  • The paper relies on this without support.

    Dividing patients by less than two weeks versus more than two weeks of antipsychotic treatment indexes the effect of antipsychotics on cortisol rather than differences in illness severity or stage.

    “Patients were further divided into those with less than two weeks (n=17) and those with more than two weeks (n=33) of antipsychotic treatment, based on recent studies providing evidence that the greater “psychotic” improvement is seen within the first two weeks of treatment (Agid et al., 2006).”
3 of 3

Claims other papers make about this one

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  • Significant associations have been reported between the cortisol awakening response and both inadequate early-life paternal parenting and childhood sexual abuse in first-episode psychosis, and severity of positive symptoms of 'schizophrenia'.

    “Significant associations have been reported between the cortisol awakening response and both inadequate early-life paternal parenting and childhood sexual abuse in first-episode psychosis [60,64] and severity of positive symptoms of 'schizophrenia' [65] .”

    From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [60]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Changes in baseline diurnal levels of cortisol, often elevations, have been reported in psychosis, which may precede psychosis onset.

    “Changes in baseline diurnal levels of cortisol, often elevations, have been reported in psychosis [59,60] , which may precede psychosis onset [61] .”

    From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [60]

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Authors
Mondelli, V., Dazzan, P., Hepgul, N., Di Forti, M., Aas, M., D'Albenzio, A., Di Nicola, M., Fisher, H., Handley, R., Marques, T. R., Morgan, C., Navari, S., Taylor, H., Papadopoulos, A., Aitchison, K. J., Murray, R. M., & Pariante, C. M.
Affiliations
King's College London (GB)
Corresponding author
Mondelli, Valeria
ORCID
Venue
Schizophrenia Research
Publisher
Elsevier BV
Published
2010-02
Volume
116
Issue
2-3
Pages
234-242
ISSN
0920-9964 (ISSN-L)
DOI
10.1016/j.schres.2009.08.013
PMC
PMC3513410
OpenAlex
W2084285609
Semantic Scholar
4754ed061ac8070c47fc3f8ec12ba7e133f8fdfc
Cited by
278
References
76
Citations by year
2026: 1 · 2025: 8 · 2024: 10 · 2023: 14 · 2022: 10 · 2021: 16 · 2020: 22 · 2019: 17 · 2018: 23 · 2017: 25 · 2016: 31 · 2015: 20 · 2014: 23 · 2013: 21 · 2012: 17
FWCI
4.60
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Schizophrenia Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
National Institute for Health and Care Research (CL-2008-17-005)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
first-episode psychosis, cortisol awakening response
MeSH terms
Adolescent, Adult, Aged, Circadian Rhythm, Female, Humans, Hydrocortisone, Male, Middle Aged, Psychotic Disorders, Surveys and Questionnaires, Saliva, Statistics as Topic, Stress, Psychological, Time Factors, Antipsychotic Agents, Wakefulness, Area Under Curve, Young Adult

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