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Aims: It has been suggested that schizophrenic patients are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms. The biological system often studied in relation to stress is the hypothalamic–pituitary–adrenal (HPA) axis, which controls the release of cortisol. We investigated whether the diurnal basal activity of the HPA axis differed between young male patients with schizophrenia and healthy controls.
Methods: Twenty-seven male patients (mean age 22 ± 5 years) and 38 healthy male control subjects (mean age 22 ± 3 years) were included in the present study. Saliva was sampled at five time points during the day: directly after awakening, 30 min thereafter, and at 12.00 hours, 16.00 hours and 22.00 hours.
Results: The cortisol concentration decreased significantly more during the day in the patient group thanin the control group. Patients also showed a significantly decreased area under the curve with respect to the increase, again indicating that the cortisol concentrations decreased more during the day in patients than in controls. Both the morning increase and the area under the curve with respect to the increase were significantly negatively correlated with negative symptom severity.
Conclusions: Patients with schizophrenia showed a different daytime sensitivity of the HPA axis. Our findings further suggest that an increase in negative symptom severity is related to a decreased HPA axis sensitivity.
SEVERAL AUTHORS HAVE suggested that patients with schizophrenia are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms.1–3 According to the Neural Diathesis Stress Model proposed by Walker and Diforio,2 schizophrenia is the result of an interaction between the genetic vulnerability of a person and the (stressful) life events a person encounters. It has been found that persons with schizophrenia report greater subjective stress to both major as well as minor life events compared with healthy control subjects,4–6 possibly including the social difficulties these patients experience.7 The biological system often studied in relation to stress is the hypothalamic–pituitary–adrenal (HPA) axis, which controls the release of several hormones in response to stress, including cortisol.4
HPA axis functioning can be investigated by inducing physical, cognitive or psychosocial stress, or simply by measuring basal cortisol levels at several time points during the day. Most studies investigating baseline cortisol have found increased levels of cortisol in patients with schizophrenia (for a review, see Walker and Diforio2). However, the majority of these studies did not take the diurnal cortisol pattern into account, which may lead to measurement biases, as cortisol concentrations fluctuate during the day. Unfortunately, studies investigating the diurnal pattern of cortisol in schizophrenia are scarce, and some of these studies measured cortisol concentrations at predefined time points, such as 08.00 hours, 09.00 hours, etc.,8–10 whereas cortisol increase in the morning is related to time of awakening rather than to a predefined time point, introducing measurement bias due to the variations in time of awakening of the participants.11
Diurnal cortisol levels have been found to be related to a variety of trait characteristics, such as anxiety, depression and social impairments.4,12 Cortisol has also been found to be related to a person's current mood: positive affect was significantly associated with lower salivary cortisol levels13 and negative affect was significantly associated with higher salivary cortisol levels.12,13 Wüst et al.14 have found a relationship between morning cortisol increase and several aspects of perceived chronic stress: worries, social stress and lack of social recognition.
The aim of the present study was to investigate whether young adult male inpatients with schizophrenia demonstrated an increased basal activity of the HPA axis, assessed by means of free cortisol concentrations in saliva, based on multiple samples throughout the day, with measurements starting immediately after awakening. In addition, we investigated whether HPA axis functioning was related to symptom severity and social integration scores.
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The aim of the present study was to evaluate whether the functioning of the HPA axis in young male patients with schizophrenia differed from the functioning of the HPA axis in healthy control subjects. Overall, the patients and controls did not differ in their absolute levels of cortisol at any specific time point. However, as shown by the differences in AUCi, the patients with schizophrenia showed steeper decreases in cortisol concentration during the day relative to controls. The AUCi is an indicator of changes over time, i.e. the sensitivity of the HPA axis, whereas absolute cortisol levels are more indicative of the basal HPA axis functioning, i.e. total hormonal output.18 The steeper decrease in cortisol levels in the patient group suggests that the sensitivity of the HPA axis in patients is increased, resulting in a system that may be more reactive to stressors. This finding is in line with the neural diathesis stress model of Walker and Diforio,2 who assume that exposure to psychosocial stressors exacerbates the symptoms of schizophrenia and that vulnerability to schizophrenia is associated with heightened behavioral responsivity to stressors.
Additionally, we found that the PANSS subscale for negative symptoms correlated negatively with the Morning Increase and the AUCi in the patient group. As stated above, the AUCi and Morning Increase are indicators of the sensitivity of the HPA axis.18 As four of the seven items on the PANSS subscale for negative symptoms concern affective flattening and social and emotional withdrawal, it appears that the HPA axis of patients with more negative symptoms was less affected by the emotional and social symptoms (social stress) associated with the disease than patients with fewer negative symptoms. Most previous studies have linked increased morning cortisol responses with perceived stress and negative affect, but contradicting results have also been found (see for a review Clow et al.19). Our findings are consistent with the findings of Wüst et al.,14 who suggested that morning cortisol is related to aspects of social integration and behavior: they found a positive relationship between the Morning Increase and social stress. Studies investigating baseline cortisol failed to find significant relationships between HPA axis functioning and schizophrenia symptoms,23,24 whereas studies using the dexamethasone suppression test have found relationships between hypercortisolemia and the severity of negative and cognitive symptoms.25,26
We did not find overall higher cortisol concentrations during the day in patients with schizophrenia compared with controls, suggesting that the basal HPA axis functioning in patients with schizophrenia was not different. Some previous studies investigating cortisol concentrations at predefined time points in unmedicated, relatively young patients with schizophrenia have found overall increased cortisol concentrations during the day relative to controls,8,10,27,28 whereas others found normal diurnal cortisol concentrations in patients with schizophrenia.29,30 Most of our patients used antipsychotic medication. Studies investigating cortisol concentrations at predefined time points in medicated patients have found mixed results. Patients using first-generation antipsychotics showed increased cortisol levels relative to controls in one study,9 but not in another,31 and patients using second generation antipsychotics did not show significantly different cortisol day curves relative to healthy control subjects.9,32 Most of the medicated patients in our study used second-generation antipsychotics, and, consistent with the studies mentioned above,9,32 we did not find overall higher cortisol concentrations during the day in patients with schizophrenia compared with healthy subjects. Furthermore, antipsychotic medication use did not affect the diurnal cortisol levels significantly. We also controlled for smoking, time of awakening, use of benzodiazepines, and duration of illness, but none of these factors explained the variation in cortisol levels significantly.
Our results may be limited due to a few methodological issues. First, we did not ask the participants to refrain from smoking during the sampling day because patients would not cooperate if we did. It should be noted, however, that we did control for smoking behavior in our statistical analyses. Another limitation was the fact that the patients with schizophrenia were hospitalized, whereas the healthy controls were not. It is possible that the differences we found between groups were the result of hospitalization rather than of schizophrenia itself. We only included male participants in our study, which limits the potential to generalize the findings of the study. Also, some of the patients did not use antipsychotic medication, whereas others used either typical or atypical medication. It was not possible to investigate all patients under medication-free conditions due to their symptom severity. Another issue was participant adherence: it was unclear to what extent the participants were compliant to our saliva sampling instructions, which is an important factor when investigating saliva samples.33 However, we did stress the importance of correct sampling during the oral and written instructions, and we asked participants to write down the exact time at which each saliva sample was taken, thereby controlling for possible deviations from our instructions. The patients were assisted by the nursing staff during their saliva sampling. For future research, a solution to this issue would be the use of digital sampling devices that record the exact time of sampling.
Concluding, we found that patients with schizophrenia only differed from healthy control subjects regarding the sensitivity of their HPA axis, and not in their basal HPA axis functioning. The Morning Increase and AUCi were negatively associated with the severity of the negative symptoms in schizophrenia, possibly due to the lack of (social) stress these patients experience.