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     

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.     

Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects

RATIONALE: Several clinical studies suggest antidepressive and anxiolytic effects of regular aerobic exercise. OBJECTIVES: The present study examines the effects of a 10-week protocol of moderate aerobic exercise (3-4 miles jogging 3 times per week) on central serotonergic receptor sensitivity. METHODS: Neuroendocrine challenges using oral doses of meta-chlorophenylpiperazine (m-CPP; 0.4 mg/kg), ipsapirone (0.3 mg/kg), and placebo were performed in 12 untrained healthy volunteers before and after 10 weeks of moderate aerobic exercise. RESULTS: Before training, administration of the non-selective serotonergic agonist m-CPP, which exerts a number of well-reproducible effects mainly via its action on 5-HT2C receptors, was associated with a significant increase of cortisol and prolactin (but not adrenaline or noradrenaline) in comparison with the placebo condition. After the 10-week training period, administration of m-CPP was followed by a blunted cortisol response which was not significantly increased in comparison to the placebo challenge. In contrast, the increases of cortisol observed after administration of the 5-HT1A agonist ipsapirone were of the same magnitude during the pre- and post-training challenge sessions. The behavioral response to ipsapirone and the mean maximal increases of plasma adrenaline and noradrenaline did not change during the training period. CONCLUSIONS: Regular aerobic exercise is associated with a blunted cortisol response to m-CPP, which might reflect a downregulation of central 5-HT2C receptors.     

Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood.

Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.     

Serotonergic responsiveness in human cocaine users

BACKGROUND: Animal experiments show that repeated cocaine injections induce changes in brain serotonin (5-hydroxytryptamine, or 5-HT) function which can be detected by altered neuroendocrine responsiveness to serotonergic drug challenge. Studies of human cocaine users given a serotonergic challenge have produced inconsistent results. METHODS: Hormone responses evoked by the 5-HT releaser D,L-fenfluramine (FEN) were examined in eight human cocaine users who resided on a closed research ward. FEN (60 mg oral) was given after a 7-day cocaine-free period and 3 days after a 5-day period of daily double-blind administration of intranasal cocaine (96 mg) and active placebo (4 mg cocaine). Plasma cortisol and prolactin levels were measured after FEN challenges, and after cocaine and placebo administration. RESULTS: Cocaine significantly elevated plasma cortisol levels to a similar degree on the first and fifth days of administration, but did not alter prolactin levels on either day. The first FEN challenge significantly increased plasma prolactin and cortisol, whereas the second challenge increased only prolactin. CONCLUSIONS: Intranasal cocaine increases plasma cortisol without affecting prolactin, with no evidence for tolerance. The reduction in FEN-induced cortisol secretion after cocaine exposure suggests that deficits in 5-HT transmission during early cocaine abstinence might contribute to the maintenance of drug dependence.     

Cigarette smoking and psychophysiological stress responsiveness: effects of recent smoking and temporary abstinence

Studies comparing the cardiovascular function and stress responsiveness of regular smokers and non-smokers have produced mixed results, possibly because of variable intervals between stress tests and recency of smoking. This experiment compared the cardiovascular, cortisol and affective responses to a problem solving task of non-smoking young men (n=16) and regular smokers randomised to overnight abstinence (n=14) and smoking 30 min prior to testing (n=19). Smoking status was validated biochemically. Overnight abstinence was associated with reduced diastolic blood pressure at rest and with enhanced diastolic pressure and emotional responses to the task compared with other conditions. Recent smokers showed elevated heart rates, suppressed cardiac baroreceptor reflex sensitivity and reduced cortisol responsiveness, but did not differ from nonsmokers in blood pressure responses. The behavioral performance of the abstinent group was impaired, and their craving was greater than that of recent smokers. Both groups of smokers reported more dysphoric mood than non-smokers, and showed only limited recovery of emotional equilibrium following tests. The results are discussed in relation to mechanisms linking smoking, stress responsiveness and cardiovascular disease risk. The methodological implications for including regular smokers in psychophysiological studies are also considered.     

Temperature regulation in depression: functional 5HT1A receptor adaptation differentiates antidepressant response.

Observations in humans and animals have indicated that chronic, but not acute, antidepressant treatment (ADT) can desensitize 5-HT1A receptor-mediated responses, such as hypothermia. We hypothesized that 5-HT1A desensitization would be necessary for an antidepressant response (ADR) to occur. To test this hypothesis, we examined 5HT1A-agonist ipsapirone (IPS)-induced hypothermia in 28 depressed patients being treated with fixed doses of nortriptyline (75 mg) at 3-day and 3-week treatment points. Decreases in 24-item Hamilton scores (>12) were used to dichotomize the response data into ADR groups of 13 responders (ADR+) and 15 nonresponders (ADR-). A two-way repeated measures analysis of variance indicated significant temperature differences in the area under the curve between response groups across time from 3-day to 3-week intervals (df=1, 26, F=6.6, p<0.02). In comparison to 3 days treatment, at 3 weeks, the ADR+ patients showed blunted hypothermic responses to IPS. ADR- did not show this effect, implicating ADR+ patients to be less responsive to 5HT1A-receptor stimulation after 3 weeks treatment. Similar effects were not found for 5HT1A postsynaptically mediated ACTH and cortisol responses. These results indicate that to achieve ADR, serotonergic neurotransmission needs to be altered as reflected by the change in 5-HT1a receptor responsiveness documented herein.     

Complex effects of age and gender on hypothermic,adrenocorticotrophic hormone and cortisol responses to ipsapirone challenge in normal subjects

The effects of a challenge dose of the 5-HT_1A agonist, ipsapirone (0.3 mg per kg body weight), or placebo on body temperature and on adrenocorticotrophic hormone (ACTH) and cortisol release, were examined in 30 normal subjects (14 males, 19–74 years and 16 females, 22–69 years) using a randomized, double blind design. Irrespective of age or gender, ipsapirone induced a significant reduction in body temperature relative to placebo and a significant increase in ACTH and cortisol release. Maximal temperature reduction by ipsapirone was significantly blunted in older subjects and was inversely related to age. There was no gender difference in the hypothermic response to ipsapirone. ACTH and cortisol responses showed an opposite impact of aging in males and females. Whereas both responses diminished with age in male subjects, they increased with age in females. The cortisol response of older females was significantly larger than that of all the other subjects. Adverse effects of ipsapirone were also more marked in elderly females and were correlated with ACTH and cortisol responses. These findings should be taken into consideration in the use of ipsapirone and other 5-HT_1A agonists as challenge procedures for studying central serotonergic function in depression and other disorders. Careful matching of control and experimental subjects is indicated so as to avoid spurious results which reflect the effects of age and gender rather than the pathophysiology of the disorders being investigated.     

5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.     

Hormonal, cardiovascular, and subjective responses to acute stress in smokers

Rationale  There are complex relationships between stress and smoking; smoking may reduce the emotional discomfort of stress, yet nicotine activates stress systems and may alter responses to acute stress. It is important to understand how smoking affects physiological and psychological outcomes after stress and how these may interact to motivate smoking. Objectives  This study aimed to examine the magnitude and time course of hormonal, cardiovascular, and psychological responses to acute psychosocial stress in smokers and non-smokers to investigate whether responses to acute stress are altered in smokers. Materials and methods  Healthy male non-smokers (n = 20) and smokers (n = 15) participated in two experimental sessions involving a standardized public speaking stress procedure and a control non-stressful task. The outcome measures included self-reported mood, cardiovascular measures (heart rate and blood pressure), and plasma hormone levels (noradrenaline, cortisol, progesterone, and allopregnanolone). Results  Smokers exhibited blunted increases in cortisol after the Trier Social Stress Test, and they reported greater and more prolonged subjective agitation than non-smokers. Stress-induced changes in progesterone were similar between smokers and non-smokers, although responses overall were smaller among smokers. Stress did not significantly alter levels of allopregnanolone, but smokers exhibited lower plasma concentrations of this neurosteroid. Conclusions  These findings suggest that smoking dampens hormonal responses to stress and prolongs subjective discomfort. Dysregulated stress responses may represent a breakdown in the body’s ability to cope efficiently and effectively with stress and may contribute to smokers’ susceptibility to acute stress, especially during abstinence.     

长期吸烟者血浆皮质醇及β-内啡肽的变化

目的·· :探讨长期吸烟者在戒烟前后血浆皮质醇和 β-内啡肽水平的变化及形成机制。方法·· :于戒烟前后采集长期吸烟者静脉血 ,用放射免疫方法检测血浆皮质醇及血浆 β-内啡肽的含量。结果·· :长期吸烟者的血浆皮质醇(227.82ng·ml-1±s40.03ng·ml-1)及血浆 β-内啡肽(14.68ng·ml-1±s4.48ng·ml-1)明显高于正常组 ;戒断后长期吸烟组的血浆皮质醇(271.92ng·ml-1±s32.19ng·ml-1)明显升高 ,而血浆 β-内啡肽(8.16ng·ml-1±s4.97ng·ml-1)明显降低。结论·· :血浆皮质醇及 β-内啡肽可作为判断戒烟治疗效果的指标之一 ,而改善内源性阿片肽系统及下丘脑 -垂体 -肾上腺轴的功能可能对戒烟有助。     

The Relationship Between Tobacco Smoking,Cortisol Secretion,and Sleep Continuity

Background: Existing theories hold that chronic tobacco smoking leads to the development of adverse psychological symptoms, thus producing a compulsive urge to smoke in order to alleviate these sensations. Sleep disturbances are often considered among the negative consequences of chronic smoking. Objectives: The current study aimed at examining whether dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis may be involved in this disruption of sleep quality among smokers. Methods: Smokers and non-smokers provided saliva samples following awakening for assessment of cortisol concentrations as a measure of HPA activity. Subsequently the participants completed the State-Trait Anxiety Inventory, Brief Questionnaire on Smoking Urges, the Fagerstrom Test for Nicotine Dependence, and the Pittsburgh Sleep Quality Index. Next, their sleep was monitored objectively for one week using an actigraph. Results: While smokers' self-reported sleep quality was similar to that of non-smokers, their sleep recording data pointed to diminished sleep continuity (increased wake time after sleep onset; WASO), while total sleep time and sleep onset latency were similar to that of non-smokers. Cortisol secretion was higher among smokers. However, among smokers only, cortisol was negatively correlated with WASO, suggesting that the direct enhancing effect of smoking on WASO is somewhat balanced by an indirect process related to higher cortisol levels. Possible interpretations for this inconsistent mediation are discussed. Conclusions/Importance: Smoking is associated with reduced sleep continuity and the relationship between smoking and sleep continuity may involve the HPA axis.     

Nicotine and smoker status moderate brain electric and mood activation induced by ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist

As the increased smoking prevalence in schizophrenics may be interpreted as an adaptive response to an underlying biological defect, investigations into nicotine's actions within N-methyl-d-aspartate (NMDA) antagonist drug models of schizophrenia may improve our understanding of the role of glutamatergic neurotransmission in initiating and maintaining nicotine dependence in this disorder. In this double-blind, placebo-controlled, randomized study, the electroencephalographic (EEG) and subjective response to a sub-psychotomimetic intravenous dose of the NMDA antagonist ketamine was examined in 20 regular smokers and 20 non-smokers pretreated with placebo or nicotine gum. Although nicotine increased EEG arousal, ketamine produced electrocerebral signs of brain activation (decreased slow wave power) and sedation (decreased fast wave power and frequency), which were not affected by nicotine pretreatment and were evident only in non-smokers. Ketamine increased a number of self-report indices of subjective arousal, some of which were attenuated and potentiated by nicotine in smokers and non-smokers, respectively. These findings suggest that long-term (evidenced by smoker vs. non-smoker comparisons) and short-term (acute) nicotine exposure may alter NMDA receptor-mediated arousal and mood systems in a way that promotes nicotine dependence in smokers, and addresses neurobiological deficiencies in smokers with schizophrenia.     

5-HT1A receptor-effector system responsivity in panic disorder

To explore 5-HT_1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT_1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT_1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT_1A receptor-effector system, thus supporting the hypothesis that a 5-HT_1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT_1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT₂, 5-HT₃) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.Part of this work was presented at the VIII. World Congress of Psychiatry, Athens, Greece, October 12–19, 1989, and at the Annual ACNP Meeting, San Juan, Puerto Rico, December 10–14, 1990     

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.     

Efficacy and safety of a putative anxiolytic agent: ipsapirone

Ipsapirone is an azopirone derivative that selectively interacts with serotonin-1A (5-HT1A) receptors and fails to affect other neurotransmitter receptors. In this study, ipsapirone at 15 mg or 30 mg was compared with diazepam at 15 mg and placebo in a double-blind, random assignment study design in patients with generalized anxiety disorder (GAD). During 4 weeks of treatment, both active drugs were therapeutically superior to placebo, without significant drug vs. drug therapeutic differences. The side-effect profile of ipsapirone at 15 mg was favorable compared to diazepam, but at 30 mg ipsapirone produced significant gastrointestinal disturbances.     

Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers

Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25–35% following a year of treatment. Although the in vivo binding properties are well known, varenicline''s neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent ~17 days of order-balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine''s ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non-smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline''s downregulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline''s efficacy as a pharmacotherapy for smoking cessation.     

Ipsapirone challenge in aggressive men shows an inverse correlation between 5-HT1A receptor function and aggression

Previous studies have suggested that 5-HT_1A receptor function is linked to aggression. We studied 12 healthy men selected to have high trait levels of aggression. They filled in various self-rating measures of aggression, and underwent a double blind, crossover challenge with ipsapirone (20 mg orally) and a placebo. On both occasions, we measured the endocrine (ACTH, cortisol, growth hormone and prolactin), hypothermic and bodily symptom responses every 30 min for 180 min. We found that subjects with blunted neuroendocrine responses to the ipsapirone challenge had significantly higher self-ratings of aggression on a number of measures. The same relationship held using the bodily symptom response to ipsapirone: blunted responses were associated with higher ratings of aggression. We conclude that impaired 5-HT_1A receptor function is associated with increased aggressiveness. Received: 19 January 1999 / Final version: 11 October 1999     

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.     

Citalopram challenge in social anxiety disorder

The aim of the present study was to evaluate neuroendocrine and behavioural responses to a challenge with the selective serotonin (5-HT) reuptake inhibitor citalopram (Cit) in patients with social anxiety disorder (SAD). Cit was given intravenously (20 mg over 30 min) to 18 patients with SAD and 18 matched healthy subjects in a double-blind, placebo-controlled cross-over design. Cit challenge resulted in the increased plasma concentrations of cortisol and prolactin relatively to placebo without significant differences between the patients and controls. The patients had higher ratings of anxiety that were not affected by Cit, and more headaches than controls after Cit. Thus, the neuroendocrine sensitivity to 5-HT stimulation with Cit in patients with SAD was not different from the response in controls indicating lack of major alterations in the function of 5-HT receptors. The increased headache in patients may suggest hypersensitivity of some subtypes of 5-HT receptors in SAD.