Uri Loewenthal

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.

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.

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.

Sexual Dysfunction in Male Posttraumatic Stress Disorder Patients

Background: Previous studies have suggested that sexual dysfunction may be associated with posttraumatic stress disorder (PTSD). Yet such studies have not examined a full range of sexual functioning and have not accounted for the possibility that medication used to treat PTSD may contribute to sexual dysfunction. Objective: The current study compares the various components of sexual functioning among three groups of males: (1) untreated PTSD patients (n = 15), (2) PTSD patients currently treated with selective serotonin reuptake inhibitor (SSRI) agents (n = 27) and (3) a group of normal controls (n = 49). Methods: All participants completed an 18-item questionnaire for assessment of sexual functioning. Those with PTSD also completed the Impact of Events Scale and the Symptom Check List-90 (SCL-90). Results: Untreated and treated PTSD patients had significantly poorer sexual functioning in all domains (desire, arousal, orgasm, activity and satisfaction) as compared to normal controls. Those treated with SSRI had greater impairment in desire, arousal and frequency of sexual activity with a partner. There was a high correlation between sexual dysfunction among the PTSD group and the anger-hostility subscale of the SCL-90. Conclusions: PTSD appears to be associated with pervasive sexual dysfunction that is exacerbated by treatment with SSRIs. PTSD may represent a heterogeneous syndrome. Patients with PTSD have a high rate of comorbid panic disorder, major depression and anxiety, and it could thus be argued that these comorbid disorders, rather than PTSD, accounted for the observed result. Future research aimed at understanding comorbidity and heterogeneity should help to illuminate the psychobiology of PTSD and eventually guide both medication and psychosocial treatments.

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.

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.

An association between stress-induced disruption of the hypothalamic-pituitary-adrenal axis and disordered glucose metabolism in an animal model of post-traumatic stress disorder.

Retrospective clinical reports suggesting that traumatic stress populations display an increased propensity for glucose metabolism disorders were examined in a controlled prospective animal model. Stress‐induced behavioural and hypothalamic‐pituitary‐adrenal (HPA) axis response patterns were correlated to central and peripheral parameters of glucose metabolism and signalling, and to body measurements in Sprague–Dawley rats exposed to predator scent stress. Forty days post‐exposure, fasting blood glucose and insulin levels, oral glucose tolerance test, body weight and white adipose tissue mass, systemic corticosterone levels and brain expression of insulin receptor (IR) and insulin‐sensitive glucose transporter 4 (GLUT4) protein levels were evaluated. In a second experiment inbred strains with hyper‐ (Fischer) and hypo‐ (Lewis) reactive HPA axes were employed to assess the association of metabolic data with behavioural phenomenology versus HPA axis response profile. For data analysis, animals were classified according to their individual behavioural response patterns (assessed at day 7) into extreme, partial and minimal response groups. The exposed Sprague–Dawley rats fulfilling criteria for extreme behavioural response (EBR) (20.55%) also exhibited significant increases in body weight, abdominal circumference and abdominal white adipose tissue mass; a hyperglycaemic oral glucose tolerance test; and fasting hyperglycaemia, hyperinsulinaemia and hypercorticosteronemia, whereas minimal responders (MBR) and control animals displayed no such disturbances. Hippocampal and hypothalamic expression of IR and GLUT4 protein were significantly lower in EBR than in MBR and control rats. The inbred strains showed no metabolic differences at baseline. Exposed Fischer rats displayed hyperglycaemia and hyperinsulinaemia, whereas Lewis rats did not. A significant protracted disorder of glucose metabolism was induced by exposure to a stress paradigm. This metabolic response was associated with the characteristic pattern of HPA axis (corticosterone) response, which underlies the behavioural response to stress.

Reversal of pathologic cardiac parameters after transition from clozapine to olanzapine treatment: a case report.

Antipsychotic medications have been associated with significant cardiovascular adverse effects and instances of sudden cardiac death. Recently, we started to evaluate cardiac parameters in medicated patients with schizophrenia using power spectrum analysis of heart rate variability. We present a case of a patient with long-standing schizophrenia who was treated with clozapine. His electrocardiogram revealed minor abnormalities, including a prolonged QT interval. Power spectrum analysis of heart rate variability demonstrated marked abnormalities in autonomic nervous system activity. Two years later, his treatment was switched to olanzapine. We reevaluated his cardiac parameters. Power spectrum analysis studies revealed that heart rate had significantly improved and that power spectrum cardiovascular parameters had returned to normal. Serial electrocardiograms revealed a minimally and asymptomatically prolonged QT interval. This case demonstrates the importance of screening electrocardiograms, even in healthy young patients. It also emphasizes how minor changes in electrocardiogram can be overlooked on standard electrocardiograms. Power spectrum analysis of heart rate variability is useful in this instance because it magnifies the trace and detects even minor disturbances. Care should be taken in prescribing antipsychotic drugs to patients who are prone to cardiovascular side effects, and alternatives to antipsychotics with prominent anticholinergic profile, in particular, should be sought.

506. Changes of autonomic heart rate parameters during treatment with clozapine, olanzapine, and haloperidol

Power spectral analysis (PSA) of heart rate variability (HRV) offers a reliable means of assessment of cardiovascular autonomic responses, providing a “window” onto the interaction of sympathetic and parasympathetic tone. Alterations in HRV are associated with various physiological and pathophysiological processes and may contribute to morbidity and mortality. Standardized heart rate analysis was carried out in twenty schizophrenic patients treated with 300–600 mg/day of clozapine as monotherapy, twenty schizophrenic patients treated with 5–10 mg/day haloperidol as monotherapy and twenty schizophrenic patients treated with 5–10 mg/day Olanzapine as monotherapy. Our preliminary results show that schizophrenic patients treated with clozapine had significantly lower HRV, lower high frequency (HF) and higher low frequency (LF) components compared to the patients treated with haloperidol. Prolonged QTc intervals were more common in the clozapine treated patient sample. Patients treated with 300 mg of clozapine per day showed significant change of HRV, fulfilling the criteria of cardiovascular autonomic neuropathy. Probably, the autonomic dysfunction is caused by the dose-dependent anticholinergic side effect of clozapine. The clinical application of these preliminary findings will be discussed.