Christine C. Gispen-de Wied

Selective impairments in the stress response in schizophrenic patients

Abstract Objective: In the vulnerability-stress concept of schizophrenia, schizophrenic patients are thought to display increased sensitivity to stress. Little is known about the biological mechanisms that are involved in stress processing in schizophrenic patients. In this study, hypothalamic-pituitary-adrenal (HPA) function in schizophrenic patients was studied for its essential role in stress processing and adaptation to the environment. Methods: Eighteen schizophrenic patients were compared to 21 healthy controls in their salivary cortisol response to a physical (bicycle ergometry) and a psychosocial (public speaking) stressor. Coping questionnaires were included as a measure of stress processing at the psychological level. Basal HPA function was assessed by measuring cortisol day profiles and feedback activity by using dexamethasone and hydrocortisone. Results: Schizophrenic patients showed blunted cortisol responses to the psychosocial stressor, but not to the physical stressor, in spite of similar increases in heart rate. The cortisol response to the psychosocial stressor tended to be negatively correlated to the use of passive and avoidant coping strategies. Basal HPA function appeared intact in the schizophrenic patients. Conclusions: The findings show a selective impairment in the response to psychosocial stress in schizophrenic patients. This suggests the involvement of brain systems that play a role in the activation of the HPA system to psychosocial stress, like arginin-vasopressin (AVP), and cognitive processes, like coping.

Blunted cortisol response to a psychosocial stressor in schizophrenia

Schizophrenia is considered a neurodevelopmental disorder in which vulnerability to stress may be a contributing factor. Coping is an important psychological component of stress processing, and the hypothalamic-pituitary-adrenal system (HPA system) is one of the biological components of stress adaptation. Disturbances of either of these components may make schizophrenic patients more vulnerable to develop a psychosis under stressful circumstances. In this study, 10 schizophrenic men were compared with 10 healthy male controls in their response to a psychosocial stressor, consisting of a public-speaking task. Heart rate was monitored as a measure of autonomic arousal. HPA responses were assessed by measuring salivary cortisol. Coping skills were measured by using the Utrecht Coping List and the Ways of Coping Checklist. The stress of speaking in public increased the heart rate in both patients and controls; however, a significant cortisol response was found in the controls, but not in the schizophrenic patients. The patients used more passive and avoidant coping strategies than controls. The findings provide support for the notion that schizophrenic patients have an impaired ability to adapt, both psychologically and biologically, to their environment.

The Effect of Clozapine on Caudate Nucleus Volume in Schizophrenic Patients Previously Treated with Typical Antipsychotics

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.

Differentiation between autism and Multiple Complex Developmental Disorder in response to psychosocial stress

Multiple Complex Developmental Disorder (MCDD) represents a distinct group within the autistic spectrum based on symptomatology. Unlike autistic children, part of MCDD children develop schizophrenia in adult life. Despite the differences, patients of both disorders are mainly characterized by abnormal reactions to their social environment. At the biological level, we showed in a previous study that MCDD children have a reduced cortisol response to psychosocial stress. Given the fact that autistic children clinically show more social impairments, it was hypothesized that they may have even further decreased cortisol responses to psychosocial stress than MCDD patients. Therefore, 10 autistic children were compared to 10 MCDD children and 12 healthy control children in their response to a psychosocial stressor, consisting of a public speaking task. In order to test whether any impairments in the biological stress response are specific for psychosocial stress, the autistic children were compared with 11 MCDD children and 15 control children in their response to a physical stressor, consisting of 10 min of bicycle exercise. Heart rate and salivary cortisol levels were used as indicators of response to the stress tests. Autistic children showed a relatively elevated cortisol response to psychosocial stress, in contrast to MCDD children who showed a reduced cortisol response. No differences in heart rate or cortisol responses to the physical stress test were found. The specific difference between autistic and MCDD children in their cortisol response to psychosocial stress indicates that the disturbed reactions to the social environment observed in these disorders may have different biological backgrounds.

Stress in schizophrenia : an integrative view

Stress and the development of a (schizophrenic) psychosis are inextricably related. The process by which stress actually affects psychosis is far less clear. The hypothalamic-pituitary-adrenal system, and in particular the release of corticosteroids, has been attributed an essential role. However, schizophrenia is a disorder in which many functions are distorted. Dysfunctions can be found in behavior, cognition, coping, physiology, pituitary-adrenal and immune functioning. In this short paper, these functions are discussed as to how they contribute to the way stress is appraised and processed. Schizophrenic patients are impaired in their biological response to stress by showing a blunted cortisol response to psychosocial stress. It is hypothesized that this reflects rather cognitive dysfunction, based on biological dysfunctions in those brain structures that are responsible for these processes, i.e. the prefrontal cortex and the limbic system. Considering the blunted cortisol response as a maladaptive stress response, its consequences are commented on with an emphasis on the immune system. Finally, the role of neuroleptics, and in particular the atypical ones, is discussed for their beneficial effect, beyond their fear-and anxiety-reducing properties, in restoring some of the cognitive dysfunctions schizophrenic patients display. By doing so, they may improve perception of the environment, enhance adjustment and thus a proper stress response. Integration of these processes in stress research described, may provide new vistas of the stress concept in schizophrenia.

HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study.

In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Programs Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1−142948(GT)n, rs3813929 (−759 C/T), and rs518147 (−697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1−142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone.

Modulating sensory gating in healthy volunteers: the effects of ketamine and haloperidol.

Abstract Background Antagonists of the N-methyl-D-aspartate (NMDA) receptors induce a broad range of psychophysiologic symptoms in healthy subjects that are similar to those of schizophrenia, such as disturbances in the sensory gating of stimuli. Because antipsychotics reduce symptoms in schizophrenia, they may also reduce the effects of NMDA antagonists. Methods In our study, a group of 18 healthy male volunteers was tested in prepulse inhibition (PPI) and P50 evoked potential paradigms during placebo–placebo, placebo–ketamine (.3 mg/kg; intravenous), and 2-mg haloperidol/.3 mg/kg intravenous ketamine conditions. Results Suppression of PPI and P50 in the ketamine condition did not differ from either the placebo–placebo or the haloperidol–ketamine condition; however, a significant reduction in percentage PPI to the lowest prepulse intensity and a reduction of P50 suppression were found in the haloperidol–ketamine condition. Conclusions The combination of haloperidol and ketamine was found to disrupt P50 suppression and PPI in healthy male volunteers, whereas ketamine alone did not affect either measure. This may imply that the disrupted P50 suppression and PPI found in schizophrenia is related to reduced dopaminergic activity, most likely in the prefrontal cortex.

Impaired Neuroendocrine and Immune Response to Acute Stress in Medication-Naive Patients With a First Episode of Psychosis

Little is known about how the biological stress response systems--the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system--function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.

Pituitary–adrenal reactivity in a child psychiatric population: salivary cortisol response to stressors

The aim of this explorative study was to investigate whether physical and psychological challenges are effective in inducing a cortisol response in psychiatric and control children, and if so whether the cortisol response can discriminate between diagnostic groups and is related to psychiatric symptoms. Fifty-two patients, including children with dysthymia, oppositional defiant disorder/conduct disorder, pervasive developmental disorder, not otherwise specified (PDDNOS) and attention deficit hyperactivity disorder, were compared to 15 healthy control children. Symptomatology was scored using the Child Behaviour Checklist. The response to both psychological and physical challenges was assessed by measuring salivary cortisol and heart rate. Physical challenge, but not psychological challenge, resulted in an overall increase in heart rate and saliva cortisol. Dysthymic and PDDNOS patients showed a diminished cortisol response, in spite of a significant increase in heart rate. These groups scored highest on the symptom factor withdrawal. Withdrawal was negatively correlated with the cortisol response. Thus, physical exercise is effective in inducing a salivary cortisol response in children. Dysthymic and PDDNOS patients have a disturbed pituitary-adrenal function in relation to physical stress, that may be associated with withdrawal.

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.