Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects

doi:10.1016/S0006-3223(03)00571-7

Biological Psychiatry

Volume 54, Issue 12, 15 December 2003, Pages 1382-1388

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Abstract

Background

Recent studies have reported a high comorbidity between posttraumatic stress disorder (PTSD) and psychotic symptoms, and it has been hypothesized that PTSD with comorbid psychosis is a severe form of PTSD. Few studies have examined the neurobiology of PTSD with comorbid psychosis. If PTSD with secondary psychotic symptoms (PTSD-SP) is a severe form of PTSD, then it might be expected to show more extreme perturbations in the neuroendocrine patterns that characterize PTSD.

Methods

Patients with PTSD with secondary psychotic symptoms (PTSD-SP), PTSD without psychosis, and healthy comparison subjects were compared for differences in cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF) and somatotropin-release-inhibiting hormone (SRIF).

Results

The PTSD-SP subjects had significantly higher mean levels of CRF than either the PTSD or control subjects (p < .01). The three groups showed similar SRIF levels.

Conclusions

These data implicate abnormalities in the secretion of CRF with the production of secondary psychotic symptoms in PTSD. This finding supports the validity of PTSD-SP as a PTSD subtype and as a severe form of PTSD.

Introduction

Posttraumatic stress disorder (PTSD) is a disorder that develops in response to a traumatically stressful life event. Symptoms of PTSD include reexperiencing of the trauma, hyperarousal, and avoidance of stimuli associated with the trauma and numbing of general responsiveness (American Psychiatric Association 1994). The disorder is associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis, including increased concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), low baseline urinary cortisol, and alterations in the secretion and metabolism of norepinephrine and dopamine Charney et al 1993, Yehuda et al 1995b.

Recent studies have reported a high comorbidity between PTSD and psychotic symptoms, primarily in clinical samples. An epidemiologic study (Davidson et al 1991) and a large number of clinical studies Butler et al 1996, David et al 1997, Hamner, 1997, Hamner and Fossey, 1993, Hammer et al 1999, Hamner et al 2000, McFarlane et al 2001, Mueser and Butler, 1987, Mueser et al 1998, Sautter et al 1999, Wilcox et al 1991 have shown this association. One explanation for this comorbidity is that PTSD with psychotic symptoms is a severe form of PTSD (Hamner et al 2000). This is based on the finding that in psychotic PTSD the intensity of PTSD symptoms and psychotic symptoms are significantly correlated (Hamner et al 1999). An alternative hypothesis for the overlap of PTSD phenomena and psychotic symptoms is that the primary psychopathology in these patients may be schizophrenia.

To reduce the heterogeneity of PTSD with psychotic symptoms, Sautter and colleagues Cerbone et al., Sautter et al 2002 have defined a psychotic PTSD subtype termed PTSD with secondary psychotic symptoms (PTSD-SP), in which the onset of PTSD predates the onset of psychosis and patients with evidence of thought disorder and bizarre behavior are excluded. Studies have shown that PTSD-SP is more strongly associated with characteristics of PTSD than with the characteristics of the psychoses. Sautter et al (2002) reported high rates of familial depression and a paucity of familial psychosis, suggesting PTSD-SP is familially different from the psychotic disorders. This is consistent with psychophysiologic data reported by Cerbone et al (in press) showing that PTSD-SP patients do not have the type of deficits in smooth pursuit eye movements that are observed in patients with schizophrenia (Iacono et al 1992). These data suggest that the psychosis in PTSD-SP is most likely distinct from schizophrenia, and they support the validity of PTSD-SP as a PTSD subtype and not as a schizophrenia-related condition with comorbid PTSD.

If PTSD-SP is a severe form of PTSD, one might expect more extreme perturbations in the neuroendocrine patterns that characterize PTSD (Yehuda et al 2001). In particular, increased secretion of corticotropin-releasing factor might be expected. Corticotropin-releasing factor (CRF) is released throughout the brain during stress and plays an important role in mediating endocrine and behavioral responses to stress; CRF released from the hypothalamus increases the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which subsequently stimulates the release of cortisol from the adrenal gland (reviewed by Nemeroff et al 1991). In PTSD, CRF is elevated, as demonstrated by high basal cerebrospinal fluid CRF concentrations obtained via a single lumbar puncture (Bremner et al 1997) and from serial lumbar puncture sampling (Baker et al 1999).

It is possible that PTSD-SP is associated with increased somatotropin-release-inhibiting hormone (SRIF), an inhibitory peptide that has a wide cortical and limbic distribution. It is released from the anterior pituitary and serves to regulate negatively the secretion of growth hormone-releasing factor, ACTH, and other pituitary hormones. High levels of SRIF have been reported in PTSD (Bremner et al 1997), and SRIF has been shown to covary with CRF (Deutch et al 1987). Should SRIF approximate alterations in CRF, it may reflect generalized activation of the hypothalamic neuroendocrine axis.

In this study, we define a psychotic PTSD subtype consisting of cases with primary PTSD and secondary psychotic symptoms (PTSD-SP), in which the onset of PTSD preceded the onset of psychosis, and patients do not evidence thought disorder or bizarre behavior. We compared cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF) and somatotropin-release-inhibiting hormone (SRIF) in PTSD-SP, PTSD without psychosis, and healthy comparison subjects. We hypothesized that PTSD-SP would be associated with significantly higher levels of CRF and SRIF, supporting the theory that PTSD with secondary psychosis is a severe subtype of PTSD.

Section snippets

Methods and materials

All PTSD veterans were recruited from the PTSD Treatment Programs at the New Orleans VA Medical Center, and healthy comparison subjects were recruited from hospital housekeeping staff. Only male subjects were recruited for this study. The PTSD patients were recruited by distributing flyers through treatment staff, and control subjects were recruited by displaying flyers in the housekeeping staff room. All volunteers who met study criteria over a 2-month period were recruited. Patients were

Results

Refer to Table 1 for a list of the demographic variables among the three diagnostic groups. No significant differences were detected between the three diagnostic groups on the demographic variables. The subjects from the two patient groups did not show significant differences in lifetime depression or lifetime substance abuse or dependence. Table 2 summarizes the group levels of CRF and SRIF. The overall ANOVA showed significant CRF differences between the three groups (F = 5.46, df = 2,24, p =

Discussion

The results of this study show that PTSD with secondary psychotic symptoms is associated with significantly higher concentrations of CSF CRF compared with those of both nonpsychotic PTSD or healthy control subjects. The finding of high concentrations of CSF CRF in PTSP-SP supports the hypothesis that PTSD-SP is a severe form of PTSD (Hamner et al 1999) and supports the validity of PTSD-SP as a PTSD subtype. This reasoning is based on the premise that if PTSD-SP is a more severe form of PTSD,

Acknowledgements

We thank National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Department of Veterans Affairs South Mental Illness Research, Education, and Clinical Center for project funding and Julie H. Aguilar for assistance with manuscript preparation.

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Original article Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods and materials

Results

Discussion

Acknowledgements

Biol Psychiatry

Brain Res

Neurosci Lett

Schizophr Res

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Neuropsychopharmacology

Eur J Pharmacol

Brain Res

Biol Psychiatry

Life Sci

J Psychiatr Res

Psychiatry Res

J Psychiatry Res

Schizophr Res

Biol Psychiatry

Compr Psychiatry

Psychiatry Res

Eur J Pharmacol

Diagnostic and Statistical Manual of Mental Disorders

Structured Clinical Interview for DSM-IV-PTSD Module

Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress

Am J Psychiatry

Original article
Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects