Long-lasting behavioral effects of juvenile trauma in an animal model of PTSD associated with a failure of the autonomic nervous system to recover.

BACKGROUND: Early life exposure to potentially traumatic experiences (PTEs) significantly increases the risk of responding more severely to stressful events experienced in adulthood. The aim of this study was to assess the autonomic nervous system (ANS) response to exposure to two PTEs in youth and again in adulthood, in terms of heart rate and heart rate variability in animals that responded to the PTE dramatically as compared to those that displayed virtually no behavioral response and to control animals. METHODS: The prevalence of individuals displaying extreme anxiety-like behavioral responses to the PTE (predator urine or elevated platform) was assessed in the elevated plus-maze and startle response paradigms. Behavioral paradigms were complemented by assessment of the involvement of the ANS in relation to changes in behavior. RESULTS: Juvenile trauma increases the vulnerability for developing long-term behavioral disruptions, taken to represent post-traumatic stress symptoms, after a second exposure to the same stressor in adulthood. PTSD-like behaviors and persisting physiological abnormalities resulted from disturbed recovery from the initial stress response. CONCLUSIONS: Exposure to a PTE during youth can have significant and long-lasting effects in adulthood and predispose the individual to PTSD upon subsequent re-exposure. Monitoring of ANS parameters confirms that development of extreme long-term (PTSD-like) behavioral changes is associated with a failure of recovery from the initial ANS responses to stress exposure.

Decreased circulatory levels of neuroactive steroids in behaviourally more extremely affected rats subsequent to exposure to a potentially traumatic experience.

This study examined the effects of stress exposure on plasma levels of corticosterone, dehydroepiandrosterone (DHEA) and its sulphate derivative DHEA-S in relation to behavioural responses. The magnitude of anxiety-like behaviours on the elevated plus-maze and of non-habituated exaggerated startle reactions were assessed in rats exposed to stress compared to controls. Individuals displaying extreme behavioural changes were termed extreme behavioural response (EBR), as opposed to minimal behavioural response (MBR) in both paradigms performed consecutively. Significantly increased circulating corticosterone levels and decreased DHEA levels were found 7 d post-exposure only in EBR individuals, not in their MBR counterparts. DHEA-S levels were reduced in both EBR and MBR stress-exposed rats compared to controls. This suggests that concomitantly decreased circulatory levels of DHEA and elevated corticosterone levels may be associated with an extreme (pathological) response to stress, whilst maintenance of normal levels of both steroids may be associated with minimal response, denoting resilience.

Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates posttraumatic stress response in rats.

BACKGROUND: Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. RESULTS: Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. CONCLUSIONS: Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.

Characteristics of schizophrenia residents and staff rejection in community mental health hostels.

BACKGROUND: In the era of deinstitutionalization, increasing numbers of schizophrenia patients reside and receive rehabilitational treatment within the framework of community hostels. The quality of staff-patient relationships is a crucial determinant of the rehabilitational process outcome. METHOD: This study examined the characteristics of 56 schizophrenia hostel residents, measured the degree of staff criticism and rejection expressed towards these patients and assessed the contribution of residents and staff characteristics to the induction of staff rejection. Measures included assessments of patients' symptoms using the Positive and Negative Syndrome Scale (PANSS), staff attitudes using the Patient Rejection Scale (PRS), and patients' living skills using the Independent Living Skills Survey (ILSS). RESULTS: Young, relatively inexperienced instructors represented 60% of the hostels staff. Residents' symptoms and staff rejection levels were overall low. However, significantly increased rejection was expressed towards patients who were more symptomatic, as measured by PANSS total and positive symptoms scores and had diminished job-related and health care living skills. Staff older age and longer professional experience were correlated with higher rejection scores. LIMITATIONS: Relatively small sample size and catchment area. CONCLUSIONS: These findings highlight the need for a better definition and understanding of schizophrenia residents selection criteria and treatment goals in community hostels. Moreover, they suggest that improvements in this area should be coupled with the provision of specialized staff training aiming at the achievement of more flexible staff attitudes. Within this framework, the PRS may serve as a practical, cost-effective tool for monitoring crucial aspects of staff-patients relationships.

Effects of the cortisol synthesis inhibitor metyrapone on the response to carbon dioxide challenge in panic disorder.

Despite the well-known association between the hypothalamic-pituitary-adrenal (HPA) axis and normal fear, it is still unclear (a) to what extent corticotropin releasing hormone (CRH) or cortisol itself mediates fear responses, and (b) to what extent the HPA axis also affects panic disorder. The carbon-dioxide (CO2) challenge has been proposed as a model for panic. Participants received the cortisol synthesis inhibitor metyrapone 30 mg/kg of body weight once and placebo once, with 1 week between challenges, at 2300 h. The following morning, blood was taken for cortisol and ACTH levels, and then participants inhaled a single vital capacity inhalation of 35% CO2 and 65% oxygen. Before and after the inhalation, participants completed an inventory of the 13 DSM-IV symptoms of panic and the NIMH questionnaire of psychological and physical symptoms. Eight healthy controls and 14 patients with panic disorder completed the protocol. As expected, CO2 increased measures of anxiety, and metyrapone lowered cortisol and increased ACTH levels. Prechallenge anxiety was modestly lowered by metyrapone, but response to CO2 was not affected. Cortisol and ACTH levels before challenge partly predicted the response to CO2. The results support an anxiogenic role for cortisol in stress, and suggest that the pathophysiological mechanism that mediates CO2-induced panic differs from those underlying other kinds of anxiety.

Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy.

Despite the effectiveness of antipsychotic medications in treatment of schizophrenia, about 30% of patients who receive an adequate treatment have significant persisting symptoms. The problem of treatment-resistant psychosis is an important and difficult one. The aim of this study was to retrospectively evaluate the efficacy and safety of amisulpride augmentation in treatment-resistant schizophrenic patients. To the best of our knowledge, this is the first report about resistant schizophrenic and schizoaffective patients treated with the combinations of risperidone and amisulpride and ziprasidone and amisulpride. Data were collected from patient records. A total of 15 resistant schizophrenic patients (7 men, 8 women, 54.0 +/- 16.9 years old) were included in the study. Before addition of amisulpride, the patients were treated with monotherapy by atypical neuroleptics (clozapine, olanzapine, risperidone, or ziprasidone). The mean amisulpride dose was 693.3 +/- 279.6 mg/d. The mental state of 12 (80%) patients treated with combination was improved. Three (20%) patients showed no change in their mental state. Only 2 patients treated with a combination of risperidone and amisulpride had mild side effects. The results are preliminary and require confirmation in a randomized controlled trial. The authors suggest that amisulpride may be a promising option as an augmentation strategy in treatment-resistant schizophrenic patients.

Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder.

Post-traumatic stress disorder (PTSD) affects about 20-30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteria-CBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.

Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study.

BACKGROUND: Vitamin B6, or pyridoxine, plays an intrinsic role in the synthesis of certain neurotransmitters that take part in development of psychotic states. Several reports indicate that vitamin B6 may be a factor in a number of psychiatric disorders and related conditions, such as autism, Alzheimer's disease, hyperactivity, learning disability, anxiety disorder, and depression. Moreover, there are anecdotal reports of a reduction in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment of patients suffering from schizophrenia or organic mental disorder. The aim of this study was to examine whether vitamin B6 therapy influences psychotic symptoms in patients suffering from schizophrenia and schizoaffective disorder. METHOD: The effects of the supplementation of vitamin B6 to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic and schizoaffective patients (DSM-IV criteria) were examined in a double-blind, placebo-controlled, crossover study spanning 9 weeks. All patients had stable psychopathology for at least 1 month before entry into the study and were maintained on treatment with their prestudy psychoactive and antiparkinsonian medications throughout the study. All patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia on a weekly basis. Patients randomly received placebo or vitamin B6, starting at 100 mg/day in the first week and increasing to 400 mg/day in the fourth week by 100-mg increments each week. RESULTS: PANSS scores revealed no differences between vitamin B6- and placebo-treated patients in amelioration of their mental state. CONCLUSION: Further studies with larger populations and shorter duration of illness are needed to clarify the question of the possible efficacy of vitamin B6 in treatment of psychotic symptoms in schizophrenia.