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.     

Attenuated adrenocorticotropic responses to psychological stress are associated with early smoking relapse

Rationale Research has demonstrated that psychosocial stressors increase smoking and risk for smoking relapse. Alterations in biological systems involved in the stress response caused by chronic smoking may contribute to early relapse. Objectives We examined the extent to which pituitary–adrenocortical and cardiovascular responses to stress following the first 24 h of a quit attempt predict early relapse. Methods Seventy-two smokers interested in cessation attended a laboratory stress session 24 h after the beginning of their cessation attempt. Adrenocorticotropin (ACTH), plasma and salivary cortisol concentrations, systolic and diastolic blood pressure (BP), and heart rate (HR) responses to acute psychological stressors (public speaking and cognitive challenges) were used to predict relapse over a 4-week follow-up period. Results Those who relapsed within 4 weeks showed attenuated hormonal and cardiovascular responses to stress and exaggerated withdrawal symptoms. Cox proportional hazards survival analysis showed that attenuated ACTH, plasma cortisol, systolic and diastolic BP, positive affect, and exaggerated withdrawal symptoms and smoking urges during acute stress predicted early relapse. Stepwise model showed that ACTH, diastolic BP, and exaggerated withdrawal symptoms remain as significant predictors. When baseline smoking and psychological measures were included in the model, changes in ACTH, diastolic BP, and both factors of smoking urges remained significant predictors of relapse. Conclusions These results demonstrate that altered stress response predicts increased vulnerability for smoking relapse.     

CO2 challenge results in hypothalamic-pituitary-adrenal activation in healthy volunteers

The 35% CO(2) challenge is known to induce symptoms of a panic attack both in panic disorder (PD) patients and healthy volunteers. Although the challenge applies more to PD patients, studies in healthy volunteers provide the opportunity to isolate the physical symptoms from the disorder and to focus on the direct effect from the challenge on stress responsive systems. One of the main stress responsive systems is the hypothalamic-pituitary-adrenal (HPA) axis. It remains unclear whether panic symptoms are accompanied by HPA axis activation. Differences in design have hampered any comparison between studies. For example, both serum and salivary cortisol have been used to provide an index of HPA axis activation. Furthermore, indications for central HPA axis disturbance have been suggested. The current study aimed to study the HPA axis response following the induction of panic symptoms in healthy volunteers, both at the pituitary level and at the adrenal level. Furthermore, both serum and salivary cortisol levels were determined. Subjective feelings of anxiety and, correspondingly, cortisol and ACTH levels, were found to be significantly increased following the 35% CO(2) challenge. Cortisol and ACTH responses to CO(2) were also associated. A significant cortisol increase was observed in both serum and saliva samples, although these were more pronounced when considering the free fraction serum values. We conclude that the induction of panic symptoms results in HPA axis activation, both at the pituitary and adrenal level. The question remains as to whether positive responders to the 35% CO(2) inhalation (more specifically PD patients) show a more pronounced HPA axis response.     

Smoking modulates neuroendocrine responses to ipsapirone in patients with panic disorder.

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients.In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22).Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers.In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.     

Selective impairments in the stress response in schizophrenic patients

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. Received: 21 October 1999 / Final version: 12 January 2000     

5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo.

Blunted neuroendocrine and physiological responses to the selective 5-HT(1A) receptor agonist, ipsapirone, have been observed in patients with panic disorder and/or agoraphobia (PDA). In order to examine whether this hyporesponsiveness to ipsapirone is modified by pharmacological or non-pharmacological therapeutic interventions, challenges with an oral dose of ipsapirone (0.3 mg/kg) and placebo were performed in patients with PDA before and after 10 weeks of treatment with clomipramine, aerobic exercise and placebo. Before treatment, administration of ipsapirone was followed by significant increases of cortisol, anxiety and other psychopathological symptoms in comparison to the placebo challenge. In addition, a significant decrease of body temperature was observed. After the 10-week treatment period, the psychological responses to ipsapirone were significantly reduced in the clomipramine and the exercise group. In contrast, there was a non-significant trend towards higher cortisol responses after clomipramine and exercise treatment. The hypothermic response to ipsapirone was significantly reduced by clomipramine treatment. In conclusion, our results demonstrate that effective treatment of panic disorder has divergent effects on the psychological, neuroendocrine and temperature responses to ipsapirone.     

Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers

We tested the hypothesis that psychophysiological responses to behavioral challenges are enhanced by short-term abstinence from smoking. Blood pressure (BP), salivary cortisol levels, and withdrawal symptoms were measured after a period of smoking abstinence (18 h) or ad libitum smoking, during rest, and in response to acute behavioral challenges. Thirty habitual smokers (15 women and 15 men) participated in two laboratory sessions conducted on two separate days (after abstinence or ad libitum smoking). Cotinine concentrations in saliva and expired carbon monoxide were measured in both conditions. Abstinence produced significant withdrawal symptoms in all participants, with women reporting greater desire to smoke than men. Participants showed greater systolic BP responses to the behavioral challenges in the abstinence condition than the control condition. They also showed worse cognitive performance on the challenges in the abstinence than in the ad libitum condition. Men had greater salivary cortisol levels than women, and both men and women showed the expected decline in cortisol levels across time, but showed no difference between the abstinence and ad libitum smoking conditions in the laboratory or during ambulatory measurements. These results indicate that abstinence alters mood, performance, and BP responses to acute challenges but not adrenocortical responses. It is possible that these changes mediate stress-related vulnerability to smoking relapse.     

Salivary cortisol concentrations are associated with acute nicotine withdrawal

Research has shown that smoking commercial cigarettes results in slight elevations in cortisol levels relative to smoking nicotine-free cigarettes. It is not clear however, whether cortisol concentrations are associated with nicotine withdrawal symptoms among regular cigarette smokers. Nicotine withdrawal symptoms resemble a stress response, and may therefore contribute to cortisol production. This preliminary study focuses on assessing the association between salivary cortisol levels and subsequent levels of self-reported withdrawal and craving symptoms. Twenty male smokers were studied during a 4-h deprivation period. All participants smoked an initial cigarette shortly after arrival and were informed that they would be unable to smoke for the remainder of the session. The session consisted of each participant watching a movie, and then waiting in the laboratory for two consecutive 30-min intervals. Self-reported nicotine withdrawal and craving were assessed four times and salivary cortisol, five times, during the session. Results show that baseline cortisol concentrations predicted subsequent withdrawal symptoms and craving measured using the Tobacco Withdrawal Symptom Checklist (WSC). This suggests that salivary cortisol may contribute to, or be a marker of, nicotine withdrawal symptoms.     

Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder

In patients with panic disorder and /or agoraphobia (PDA) an increased sensitivity of central 5-HT2C receptors and a decreased responsiveness of 5-HT1A receptors has been postulated. In the present study, neuroendocrine challenges were performed using oral doses of the non-selective 5-HT2C agonist m-chlorophenylpiperazine (m-CPP) (0.4 mg/kg), the selective 5-HT1A antagonist ipsapirone (0.3 mg/kg), and placebo in 40 patients with PDA and 12 healthy controls in order to compare 5-HT2C and 5-HT1A-specific psychobehavioural and neuroendocrine response patterns. At baseline, all psychobehavioural variables and the plasma concentration of noradrenaline (NE) were significantly increased in the patient group compared to the controls. The administration of m-CPP or ipsapirone was followed by comparable psychological symptoms and, in 55% of all patients, panic attacks. In comparison to the control subjects, patients were characterized by significantly higher psychological reactions to both challenge agents and a significantly higher NE response to m-CPP. In the patient group, there was also a trend towards an increased cortisol response after administration of m-CPP and a decreased cortisol and hypothermia response after administration of ipsapirone compared to the control group. The neuroendocrine findings of our study support earlier reports of opposite changes in the responsiveness of 5-HT2C and 5-HT1A-related receptors in PDA patients. The behavioural hypersensitivity to both, m-CPP and ipsapiron, shows that the provocation of anxiety and other psychological symptoms might be influenced by     

Attenuated adrenocortical and blood pressure responses to psychological stress in ad libitum and abstinent smokers

Chronic smoking may alter physiological systems involved in the stress response. This study was designed to examine the effects of ad libitum smoking and abstinence on adrenocortical and cardiovascular responses to acute psychological stress in dependent cigarette smokers. We evaluated differences among abstinent smokers, smokers who continued to smoke at their normal rate, and nonsmokers in salivary cortisol concentrations, systolic and diastolic blood pressure (BP), heart rate (HR), and mood reports. Measurements were obtained during rest and in response to acute psychological stress (public speaking) in one session (stress session) and during continuous rest in a control session. Thirty-eight smokers (21 women) and 32 nonsmokers (18 women) participated. Smokers were assigned to either abstain from smoking the night prior to and the day of each session, or to continue smoking at their normal rate before each session. All groups showed significant stress-induced changes in BP and HR. Smokers, regardless of their assigned condition, showed attenuated systolic BP responses to the public-speaking stressor when compared to nonsmokers. While resting cortisol levels were greater among smokers than nonsmokers, no cortisol response to the acute stressor was demonstrated in either ad libitum or abstinent smokers. These results indicate that chronic smoking diminishes adrenocortical and cardiovascular responses to stress, and that short-term abstinence does not correct these alterations.     

A placebo-controlled study of sertraline’s effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults

Rationale  

The dexamethasone/corticotropin-releasing hormone (Dex/CRH) test is a neuroendocrine probe involving serial blood sampling of cortisol during a standardized pharmacological challenge without inducing psychological distress in humans. Some past studies in depressed patients have shown a “normalization” or decrease in cortisol response to the Dex/CRH test following successful treatment with an antidepressant. Studies in nondepressed healthy adult samples have also shown aberrant cortisol reactivity to be associated with depression risk factors. These findings prompted research into the use of the Dex/CRH test as a tool for developing antidepressant drugs.     

Neuroendocrine and behavioural responses to opioid receptor-antagonist during heroin detoxification: relationship with personality traits

The present study investigated clinical, cardiovascular and neuroendocrine consequences of rapid opioid detoxification (ROD) in heroin-dependent individuals, affected, or not, by comorbid antisocial personality disorder (ASPD). Thirty-two patients underwent ROD and subsequent treatment with daily naltrexone: 3 days detoxification procedures were performed utilizing clonidine, baclofen, oxazepam and ketoprofene, without anaesthesia. Withdrawal symptoms, mood changes, cardiovascular indexes (heart rate, blood pressure), norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH) and cortisol (CORT) were evaluated during naloxone-naltrexone administration on the second day of detoxification treatment. The patients were divided into two groups following DSM-IV criteria for ASPD. Group A comprised 14 ASPD patients and group B comprised 18 patients without ASPD. Slight and transient withdrawal symptoms and mood changes were demonstrated on the second day in the whole sample of patients, in association with a significant, but moderate, elevation of heart rate, blood pressure, NE (two-fold), EPI (five-fold), ACTH (two-fold) and CORT (two-fold) plasma levels, in response to opioid receptor-antagonist administration. When evaluated separately in ASPD (group A) and non-ASPD patients (group B), significantly higher withdrawal symptoms and mood changes, heart rate, blood pressure, NE, ACTH and cortisol levels were observed in ASPD subjects. By contrast, no differences were found in EPI responses to naloxone-naltrexone administration between group A and B patients. The significant differences demonstrated in clinical and neuroendocrine responses to opioid receptor-antagonist administration, in relation to personality traits, could be due to reduced alpha-adrenergic receptor sensitivity, which was previously reported in ASPD, with a possible impairment of clonidine action. Our study suggests that a detailed diagnostic assessment before detoxification procedure may help to predict treatment outcome.     

<Emphasis Type="SmallCaps">L</Emphasis>-5-Hydroxytryptophan induced increase in salivary cortisol in panic disorder patients and healthy volunteers

BACKGROUND: Hypersensitivity of brain serotonin receptors has been proposed as a causal mechanism in the pathophysiology of panic disorder. This theory can be tested, using serotonergic stimulation of the HPA axis. Up to now, plasma cortisol has generally been used as the outcome measure in such studies. Assessment of salivary cortisol is a non-invasive alternative to measure HPA axis activity.METHOD: Salivary cortisol levels were measured in 24 panic disorder patients and 24 healthy volunteers, following ingestion of 200 mg L-5-hydroxytryptophan or placebo.RESULTS: A significant rise in cortisol was observed in both patients and controls following ingestion of L-5-hydroxytryptophan. No such effects were seen in the placebo condition.CONCLUSION: The results show that L-5-hydroxytryptophan stimulated salivary cortisol is a useful probe of serotonin function in healthy volunteers as well as panic disorder patients, and provide some evidence against a serotonin receptor hypersensitivity in panic disorder.     

Hormonal evidence for altered responsiveness to social stress in major depression.

In patients with major depression, abnormalities in baseline cortisol secretion and resistance to negative feedback are well established. However, it is unclear if patients with major depression have alterations in the hypothalamic-pituitary-adrenal (HPA) response to stressors. While other challenges to the HPA axis have used endocrine stimuli such as insulin-induced hypoglycemia, we now report of the response to a social stressor in patients with major depression and matched control subjects. We used the Trier Social Stress Test (TSST), a public speaking task followed by mental arithmetic challenge in front of a panel of judges. The results suggest that depressed patients manifest normal cortisol response to a social stressor, despite increased pre-stressor plasma cortisol. However, the beta-endorphin response to the TSST was significantly smaller in the depressed patients compared to matched controls. These data are similar to data found with exogenous corticotropin-releasing-hormone challenge studies and suggest that elevated baseline cortisol can modulate the pituitary corticotroph response to a stressor, but that changes in adrenal sensitivity to ACTH result in a robust cortisol response to this stressor.     

Multimodal assessment of the effect of chewing gum on nicotine withdrawal

The present study was designed to evaluate the usefulness of chewing gum to reduce nicotine withdrawal, craving, and salivary cortisol concentrations during temporary nicotine deprivation. A total of 20 male smokers were studied under conditions when gum was and was not accessible during a 4-hour deprivation period. All subjects smoked an initial cigarette shortly after arrival for the two experimental sessions and were informed that they would be unable to smoke for the remainder of each session. The sessions consisted of each subject watching a movie, then waiting in the lab for two consecutive 30-min intervals. Self-reported nicotine withdrawal and craving were assessed four times and salivary cortisol five times during each experimental session. Results from this study indicate that chewing gum helps with self-reported withdrawal but not craving when a smoker is prevented from smoking. This study also provides preliminary data on the use of salivary cortisol as a physiological marker that may map these self-reports of nicotine withdrawal and craving.     

Cortisol Response to Stress in Adults with Attention Deficit Hyperactivity Disorder

Background:

Differences in the cortisol response have been reported between children exhibiting the inattentive and hyperactive/impulsive subtypes of attention deficit hyperactivity disorder. However, there is no such information about adults. The aim of the present study was to determine the possible differences between the combined and inattentive subtypes in the cortisol response to stress.

Methods:

Ninety-six adults with attention deficit hyperactivity disorder, 38 inattentive and 58 combined, without any medical or psychiatric comorbidities and 25 healthy controls were included. The Trier Social Stress Test was used to assess physiological stress responses. Clinical data and subjective stress levels, including the Perceived Stress Scale, were also recorded.

Results:

No significant differences in the cortisol response to the Trier Social Stress Test were found between patients and controls. However, albeit there were no basal differences, lower cortisol levels at 15 (P=.015), 30 (P=.015), and 45 minutes (P=.045) were observed in the combined compared with the inattentive subtype after the stress induction; these differences disappeared 60 minutes after the stress. In contrast, the subjective stress responses showed significant differences between attention deficit hyperactivity disorder patients and controls (P<.001), but no differences were seen between attention deficit hyperactivity disorder subtypes. In turn, subjective stress measures, such as the Perceived Stress Scale, positively correlated with the whole cortisol stress response (P<.027).

Conclusions:

Both the combined and inattentive attention deficit hyperactivity disorder adults exhibited a normal cortisol response to stress when challenged. Nevertheless, the inattentive patients displayed a higher level of cortisol after stress compared with the combined patients. Despite the differences in the cortisol response, adults with attention deficit hyperactivity disorder reported high levels of subjective stress in their every-day life.     

Atomoxetine increases salivary cortisol in healthy volunteers

It has been proposed that acute hypothalamo-pituitary-adrenal (HPA) axis challenge using noradrenergic drugs may be of utility in assessing the functional integrity of central noradrenaline pathways. Atomoxetine (formerly tomoxetine) is a highly selective noradrenaline reuptake inhibitor, which has recently been licensed for the treatment of attention deficit hyperactivity disorder (ADHD).The aim of this study was to assess the effects of acute atomoxetine on salivary cortisol levels for the first time.A total of 60 healthy male volunteers received 60 mg atomoxetine, 30 mg citalopram, or placebo per os in a double-blind parallel groups design (n = 20 per group). Salivary cortisol, blood pressure and pulse rates were recorded at baseline and at +1.0, +1.5, +2.5 and +3.5 hours after capsule administration.60 mg atomoxetine led to highly significant increases in salivary cortisol and a moderate increase in pulse rate, in the absence of significant effects on blood pressure. 30 mg citalopram had no significant effects on cortisol or cardiovascular parameters.These data support the utility of atomoxetine neuroendocrine challenge for evaluating central noradrenaline pathways, which may be of future use in neuropsychiatric patient studies. Furthermore, the effects of atomoxetine on HPA axis function may have clinical implications given the use of this agent in the treatment of ADHD.     

Physiological and affective reactivity to a 35% CO(2) inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism

The inhalation of 35% carbon dioxide (CO(2)) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO(2) reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO(2) reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO(2) challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age±SD: 20.6±2years) were selected and underwent a 35% CO(2) inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO(2) was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO(2) reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO(2) inhalation procedure.