John Kasckow

Corticotropin-releasing hormone in depression and post-traumatic stress disorder

Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis.

Plasma and Cerebrospinal Fluid Interleukin-6 Concentrations in Posttraumatic Stress Disorder

Background: Interleukin-6 (IL-6) secretion is suppressed by glucocorticoids and stimulated by catecholamines. Patients with posttraumatic stress disorder (PTSD) have decreased cortisol and increased catecholamine secretion. The purpose of this study was to assess the relation of IL-6 levels and hypothalamic-pituitary-adrenal and noradrenergic activity in patients with well-characterized PTSD. Methods: Cerebrospinal fluid (CSF) was withdrawn via a lumbar subarachnoid catheter over 6 h from 11 combat veterans with PTSD and 8 age- and sex-matched healthy controls. Blood was withdrawn concurrently. We measured IL-6, CRH and norepinephrine concentrations in the CSF and IL-6, ACTH, cortisol and norepinephrine in plasma. Results: Mean and median CSF IL-6 concentrations were higher in PTSD than in controls (mean = 24.0 vs. 14.6, p = 0.05; median = 26.7 vs. 14.3, p < 0.03): plasma IL-6 concentrations, however, were not different between the two groups. Plasma IL-6 and norepinephrine were positively correlated in the PTSD group (r = +0.74, p < 0.04), but not in normals (r = –0.55, p = 0.20). Conclusions: PTSD patients have increased CSF concentrations of IL-6. Their plasma IL-6 is not elevated but is more tightly associated with noradrenergic output in these patients than in normals. Both findings might be explained by the low cortisol secretion previously reported in PTSD as a result of lowered glucocorticoid suppression of IL-6 secretion. High levels of CSF IL-6 may reflect neurodegeneration or compensatory neuroprotection.

Health-related quality of well-being in chronically hospitalized patients with schizophrenia: comparison with matched outpatients.

Quantifying the functional consequences of illness in terms of quality of life can enhance our understanding of both mental and physical disorders. However, little is known about the quality of life among older inpatients vs. outpatients with schizophrenia. We present the results of health-related quality of life assessments in 54 middle-aged and elderly long-term inpatients with schizophrenia and a demographically matched outpatient sample. Assessments were performed using the Quality of Well-Being (QWB) scale, along with standard measures of psychopathology and global cognitive impairment. Compared with outpatients, the inpatients had a significantly lower health-related quality of life, as measured by the QWB. In the inpatient and outpatient groups, higher levels of positive symptoms were associated with lower health-related quality of life. Health-related quality of life remained fairly stable among the inpatients who remained hospitalized over 6 months. In both inpatients and outpatients, baseline cognitive status and psychopathology predicted QWB scores at the 6-month follow-up. These findings further support the use of the QWB in severely mentally ill populations; implications for improving health-related quality of life among older patients with schizophrenia are discussed.

Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis

Central regulation of hypothalamo-pituitary-adrenocortical (HPA) axis stress responses is mediated by a relatively circumscribed group of projections to the paraventricular hypothalamus (PVN). The dorsomedial hypothalamus (DMH), medial preoptic area (mPOA), and bed nucleus of the stria terminalis (BST) provide direct, predominantly inhibitory, innervation of the PVN. These PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including the prefrontal cortex, amygdala, hippocampus, and septum. The neurochemical phenotype of limbic circuits targeting PVN relays has not been systematically analyzed. The current study combined retrograde tracing and immunohistochemistry/in situ hybridization to identify the specific sites of glutamatergic and GABAergic inputs to the DMH, mPOA, and BST. Following Fluoro-gold (FG) injections in the DMH, retrogradely labeled cells co-localized with vesicular glutamate transporter mRNA in the prefrontal cortex, ventral hippocampus, and paraventricular thalamus. Co-localization of FG and glutamic acid decarboxylase mRNA was present throughout the central and medial amygdaloid nuclei and septal area. In addition, the mPOA received predominantly GABAergic input from the septum, amygdala, and BST. The BST received glutamatergic projections from the hippocampus and basomedial amygdala, whereas, GABAergic inputs arose from central and medial amygdaloid nuclei. Thus, discrete sets of neurons in the hypothalamus and BST are positioned to summate limbic inputs into PVN regulation and may play a role in HPA dysfunction and stress-related illness.

Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder

BACKGROUND Although elevated concentrations of both corticotropin-releasing hormone (CRH) and norepinephrine are present in the cerebrospinal fluid (CSF) of patients with post-traumatic stress disorder (PTSD), the effects of exposure to traumatic stimuli on these stress-related hormones in CSF are unknown. METHODS A randomized, within-subject, controlled, cross-over design was used, in which patients with war-related PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6-9 weeks apart). During one session the patients watched a 1-h film containing combat footage (traumatic film) and in the other a 1-h film on how to oil paint (neutral film). At 10-min intervals, we quantified CRH and norepinephrine in CSF, and ACTH and cortisol in plasma, before, during, and after symptom provocation. Subjective anxiety and mood were monitored using 100-mm visual analog scales. Blood pressure and heart rate were obtained every 10min from a left leg monitor. RESULTS Eight of 10 patients completed two CSF withdrawal procedures each. A major drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral videotape. CSF norepinephrine rose during the traumatic film relative to the neutral videotape; this rise directly correlated with magnitude of mood drop. In contrast, CSF CRH concentrations declined during the trauma-related audiovisual stimulus, both absolutely and relative to the neutral stimulus; the magnitude of CRH decline correlated with degree of subjective worsening of anxiety level and mood. Plasma cortisol concentrations were lower and ACTH levels similar during the stress compared with the neutral videotape. CONCLUSIONS CSF concentrations of the stress hormones norepinephrine and CRH differentially change after exposure to 1h of trauma-related audiovisual stimulation in chronic, combat-related PTSD. While the CSF norepinephrine increase was postulated, the decline in CSF CRH levels is surprising and could be due to audiovisual stress-induced increased uptake of CSF CRH into brain tissue, increased CRH utilization, increased CRH degradation, or to an acute stress-related inhibition or suppression of CRH secretion.

Managing suicide risk in patients with schizophrenia.

The management of suicide risk in patients with schizophrenia poses many challenges for clinicians. Compared with the general population, these patients have an 8.5-fold greater risk of suicide. This article reviews the literature dealing with the treatment of at-risk patients with schizophrenia. An integrated psychosocial and pharmacological approach to managing this population of patients is recommended. Although there is at least modest evidence suggesting that antipsychotic medications protect against suicidal risk, the evidence appears to be most favourable for second-generation anti-psychotics, particularly clozapine, which is the only medication approved by the US FDA for preventing suicide in patients with schizophrenia. In addition, treating depressive symptoms in patients with schizophrenia is an important component of suicide risk reduction. While selective serotonin receptor inhibitors (SSRIs) ameliorate depressive symptoms in patients with schizophrenia, they also appear to attenuate suicidal thoughts. Further research is needed to more effectively personalize the treatment of suicidal thoughts and behaviours and the prevention of suicide in patients with schizophrenia.

Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors.

Vanilloid receptors (VR) are molecular integrators of painful chemical and physical stimuli. Olvanil is an agonist of the vanilloid receptor; capsazepine is a competitive VR antagonist. The authors were interested in investigated the effects of these compounds on anxiety-like behaviors in rats using the elevated plus maze. In addition, the authors examined the effects of olvanil on the Porsolt swim test. Doses of 0, 0.2, 1.0 and 5.0 mg/kg olvanil, respectively, yielded percent open arm entries at 5 min of 25+/-10.1, 19.3+/-7.1, 14.9+/-5.9 and 0+/-0. We demonstrated a drug effect by showing that the mean of the 0.2, 1 and 5 mg/kg doses was significantly lower than the 0 mg/kg dose at P<.05. In addition, the authors examined the effect of olvanil on the ability of rats to perform in the Porsolt swim test. Float time for rats was tested with 0.1 or 2 mg/kg olvanil and differences between the float times for the lower and higher doses were significant at P<.05. In addition, the effects of various doses of the vanilloid antagonist capsazepine was examined on elevated plus maze behavior. Doses of 0, 1, 5 and 10 mg/kg yielded percent time in the open arms at 5 min of 1.46+/-1.38, 15.05+/-10.42, 11.54+/-10.57, and 14.56+/-7.86. The mean of the 1, 5 and 10 mg/kg doses was significantly greater than the percent time in the open arms for the vehicle, consistent with a drug effect. The results suggest that the vanilloid agonists and antagonists may impact on behaviors involving anxiety and affect. However, it cannot be ruled that the findings could be due to nonspecific motor effect.

Corticotropin‐Releasing Hormone (CRH) Expression and Protein Kinase A Mediated CRH Receptor Signalling in an Immortalized Hypothalamic Cell Line

Corticotropin‐releasing hormone (CRH) is a 41 amino acid neuropeptide which plays an important role in the stress response in the hypothalamus. We describe the development of an immortalized hypothalamic cell line which expresses CRH. We hypothesized that this cell line would possess the relevant characteristics of parvocellular CRH‐expressing neurones such as glucocorticoid receptor (GR) expression and vasopressin (VP) coexpression. For production of hypothalamic cells, embryonic day 19 rat pup hypothalami were dissected and dissociated into tissue culture dishes. They were immortalized by retrovirus‐mediated transfer of the SV40 large T antigen gene at 3 days of culture and then screened for expression of CRH following dilution cloning. One cell line was chosen (IVB) which exhibited CRH‐like immunoreactivity (CRH‐LI) and expressed CRH, VP and CRH1 receptor RNA via the reverse transcriptase‐polymerase chain reaction. In addition, the cell line expressed the neuronal marker, microtubule‐associated protein‐2. We verified that the CRH‐LI from IVB cell lysates coeluted with CRH standard via reversed‐phase high‐performance liquid chromatography (HPLC). Furthermore, oxidation of the lysate converted its HPLC profile to that identical with oxidized CRH standard. In addition, IVB cells exhibited high affinity binding to CRH. Incubation of IVB cells with CRH lead to increases in cAMP levels and protein kinase A activity in a concentration‐dependent manner. Incubation of IVB cells with CRH also resulted in increases in phospho‐cyclic‐AMP response element binding protein (CREB) imunostaining as detected by immunocytochemical analysis. Finally, CRH treatment of IVB cell lines has been linked to CREB‐mediated gene expression as determined via the PathDetect CREB trans‐reporting system. The characteristics of IVB cells, such as CRH and VP coexpression, GR expression and a biologically active CRH‐R1‐mediated signalling pathway, suggest that this neuronal cell line may serve as model of parvocellular CRH neurones.

Suicidal ideation and suicide attempts among middle-aged and older patients with schizophrenia spectrum disorders and concurrent subsyndromal depression.

This study examines the prevalence and correlates of current suicidal ideation and past suicide attempts among patients aged 40 and older with schizophrenia spectrum disorders and concurrent depressive symptoms. Nearly half the sample (n = 132) reported having attempted suicide once or more in their lifetime; those who had attempted, exhibited greater depression and psychopathology. A regression analysis revealed that only past suicide attempts and hopelessness significantly accounted for the presence of current suicidal ideation. Surprisingly, current suicidal ideation did not differ by diagnosis, race/ethnicity, marital status, living situation, age, education, or severity of medical illness. Overall, suicidal ideation and the presence of past suicide attempts were remarkably prevalent, highlighting the need for continued clinical vigilance with this patient population. The impact of hopelessness and general psychopathology, as well as the insignificance of demographic characteristics and medical illness severity warrant further investigation.

Pituitary adenylate cyclase-activating polypeptide stimulates corticotropin-releasing factor, vasopressin and interleukin-6 gene transcription in hypothalamic 4B cells

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) are the two major regulatory peptides in the hypothalamic-pituitary-adrenal axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, is secreted into the pituitary portal circulation, resulting in the release of adrenocorticotropic hormone from the anterior pituitary. AVP is synthesized in the PVN and supraoptic nucleus by various stressors. Hypothalamic 4B cells coexpress CRF and AVP. In 4B cells transfected with either a CRF or an AVP promoter-luciferase construct, forskolin increased the transcriptional activity of CRF or AVP. In the present study, we tried to determine whether pituitary adenylate cyclase-activating polypeptide (PACAP) regulates both CRF and AVP genes in the hypothalamic cells, because receptors for PACAP were expressed in the hypothalamic cells. PACAP stimulated activity of both CRF and AVP promoter via protein kinase A pathway. PACAP stimulated interleukin (IL)-6 promoter activity and the levels of IL-6 mRNA and protein. IL-6 stimulated activity of both CRF and AVP promoter in a dose-dependent manner. Finally, we found that the stimulatory effects of PACAP on both activities were significantly inhibited by treatment with anti-IL-6 monoclonal antibody. These data suggest that PACAP is involved in regulating the synthesis of IL-6 mRNA and IL-6 protein, and that the increase in endogenous IL-6 also contributes to stimulate the expression of both CRF and AVP genes. Taken together, these findings indicate that PACAP stimulates the transcription of CRF, AVP, and IL-6 genes in hypothalamic 4B cells.