Correlations of plasma oxytocin with clinical and hormonal parameters in panic disorder.

AIMS: The potential association between oxytocin (OXT) plasma levels and clinical and hormonal parameters in panic disorder (PD) especially in its acute phase - has not been investigated as yet. This was the aim of this article. METHOD: Twenty-four consecutively-referred, acutely-ill, medication-free PD patients with (PDA, N = 21) or without agoraphobia, moreover without comorbidities, completed the following clinical measures: Hamilton Anxiety Rating Scale (HARS); Agoraphobic Cognitions Questionnaire (ACQ); Mobility Inventory-Alone subscale (MI-alone); and number of panic attacks during last 21 d (PA21d). Plasma levels of OXT, adrenocorticotropic hormone (ACTH) and cortisol were evaluated. RESULTS: OXT levels were significantly, negatively associated with the HARS scores (r= -0.59 p=.002) and weakly, negatively correlated with the ACQ scores (r = -0.403 p=.051). No significant correlations were traced between OXT levels and PA21d, MI-alone, ACTH, and cortisol. CONCLUSION: In acutely-ill, medication-free PD patients, OXT plasma levels may be relevant to the severity of their 'general' anxiety symptoms, but not to the 'specific' panic psychopathology.

Apathy associated with antidepressant drugs: a systematic review.

OBJECTIVES: Administration of antidepressant drugs - principally selective serotonin reuptake inhibitors (SSRIs) - may induce clinically significant 'apathy' which can affect treatment outcomes adversely. We aimed to review all relevant previous reports. METHODS: We performed a PUBMED search of English-language studies, combining terms concerning psychopathology (e.g. apathy) and classes of antidepressants (e.g. SSRI). RESULTS: According to certain inclusion (e.g. use of DSM/ICD diagnostic criteria) and exclusion (e.g. presence of a clinical condition that may induce apathy) criteria, 50 articles were eligible for review. Together, they suggest that administration of antidepressants - usually SSRIs - can induce an apathy syndrome or emotional blunting, i.e. a decrease in emotional responsiveness, to circumstances which would have triggered intense mood reactions prior to pharmacotherapy. The reported prevalence of antidepressant-induced apathy ranges between 5.8 and 50%, and for SSRIs ranges between 20 and 92%. Antidepressant-induced apathy emerges independently of diagnosis, age, and treatment outcome and appears dose-dependent and reversible. The main treatment strategy is dose reduction, though some data suggest the usefulness of treatment with olanzapine, bupropion, agomelatine or amisulpride, or the methylphenidate-modafinil-olanzapine combination. CONCLUSION: Antidepressant-induced apathy needs careful clinical attention. Further systematic research is needed to investigate the prevalence, course, aetiology, and treatment of this important clinical condition.

Cholesterol levels in plasma and cerebrospinal fluid in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis.

Cholesterol is essential for myelin formation, but may also modulate mechanisms involved in adaptive immune responses. It is unclear whether lack of remyelination in multiple sclerosis (MS) results from an insufficient capacity of oligodendrocyte precursor cells to differentiate or from cholesterol insufficiency. Several studies have assessed the potential association of lipid profile and its metabolism with demyelination, disability, and disease progression. The aim of the present study was to measure cholesterol levels in plasma and cerebrospinal fluid (CSF) of patients with relapsing remitting MS (RRMS) or with clinically isolated syndrome (CIS), and to investigate whether there is an association between cholesterol levels and disease characteristics. Sixty-two patients with CIS and 46 patients with RRMS were included in the study. All patients had low EDSS and were medication-free at assessment. Forty-eight subjects within the same age range served as controls. Cholesterol concentrations were measured in plasma and in CSF by the same enzymatic - colorimetric method, and were related to clinical status, disease activity in magnetic resonance imaging (MRI) and presence of oligoclonal bands in CSF (OBs). Significantly lower levels of plasma and CSF cholesterol were found in patients compared to controls. Patients with OBs showed significantly lower levels of CSF cholesterol but not plasma cholesterol compared to OBs-negative patients. A positive correlation of plasma cholesterol with age and of CSF cholesterol with EDSS was found. Our results suggest that low CSF cholesterol in MS patients with positive OBs might reflect extensive demyelination and a more aggressive disease course associated with an increased humoral immune response against membrane components.

Pituitary-adrenal axis hormones in early-onset versus late-onset panic disorder.

OBJECTIVE: It has been hypothesised that early-onset panic disorder (PD) may constitute a biologically distinct subtype of PD, but the few relevant data are inconclusive. We systematically explored for potential psychopathological and hormonal differences between early-onset (age at onset ≤ 27 years) versus late-onset PD, in consecutively-referred, medication-free, acutely-ill PD outpatients, moreover without comorbid mental disorders except agoraphobia (N = 54; age = 32.3 ± 7.5 years; early-onset = 27; females = 38). METHODS: Hormones assessed (plasma levels) included adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulphate (DHEAS). Psychopathological measures included panic attacks' number during last three weeks, the Agoraphobic Cognitions and the Body Sensations Questionnaires and the Hamilton Anxiety Rating Scale. RESULTS: Early-onset PD patients - compared to their late-onset counterparts - had longer duration of the disease. The two onset-groups demonstrated similar panic and anxiety symptoms and similar ratios of smokers/never-smokers. However, early-onset patients demonstrated significantly greater ACTH and DHEAS levels and higher (marginally significant) cortisol levels than the late-onset patients. Moreover, in the early-onset patients only, significant positive correlations emerged between ACTH levels and the severity of both panic and anxiety symptomatology. CONCLUSIONS: These findings suggest that the two onset-groups demonstrate significant differences in the hypothalamic-pituitary-adrenal axis functioning, at least when acutely-ill.Key pointsEarly-onset panic disorder (EOPD) may differ biologically from late-onset PD (LOPD).EOPD was correlated with greater adrenocorticotropic hormone (ACTH) plasma levels.EOPD was correlated with greater dehydroepiandrosterone sulphate plasma levels.In EOPD only, ACTH levels were positively correlated with panic and anxiety symptoms.

Stress Hormones as Predictors of Response to Cognitive Behavior Therapy in Panic Disorder.

OBJECTIVE: Data regarding the potential association between the outcome of psychotherapy of panic disorder (PD) and biological parameters are few. In 21 (16 females) consecutively referred, medication-free, acutely ill PD outpatients, without comorbidities, except agoraphobia, we systematically explored for potential neuroendocrine and clinical correlates of response to a brief cognitive behavior therapy (CBT). METHODS: Cortisol and adrenocorticotropic hormone (ACTH) basal plasma levels were measured. Measures of psychopathology: (a) Symptom Checklist-90-Revised (SCL-90-R), (b) Clinical Global Impressions-Improvement (CGI-I) Scale, (c) Agoraphobic Cognitions Questionnaire (ACQ), and (d) Mobility Inventory (MI)-alone subscale. RESULTS: Nonresponders to CBT (CGI-I >2; N = 6) - as compared to the responders (CGI-I ≤2; N = 15) - demonstrated significantly higher cortisol and ACTH basal plasma concentrations. These differences were much stronger when only female patients (nonresponders = 4; responders = 12) were taken into consideration. Regarding psychopathology, nonresponders to CBT suffered from more severe agoraphobia (MI-alone) at baseline. On the contrary, more intense manifestations of anger (SCL-90-R) at baseline were associated with a better treatment outcome. Response to CBT was associated with significant reductions in all SCL-90-R subscales, more pronounced for "phobic anxiety" and "anxiety" subscales. CONCLUSIONS: This study suggests that in acutely ill, medication-free PD patients, response to CBT may be associated with certain hormonal and clinical parameters at baseline.

Clinical and psychometric features of psychiatric patients after a suicide attempt in relation with menstrual cycle phases.

There is evidence that frequency of suicide attempts of fertile women is related to the menstrual cycle phases, while the influence of hormonal and psychiatric features has been hypothesized. This study aims to explore the distribution and possible differences in clinical characteristics of women who attempted suicide in relation to menstrual cycle. Seventy fertile female psychiatric patients, hospitalized in psychiatric department after a suicide attempt, were studied. Depression was assessed using Beck Depression Inventory, suicide intent with the Suicide Intent Scale, and aggression using the Buss-Perry Aggression Questionnaire. A profile of psychopathology was obtained by using Symptom Check List SCL-90-R. Attempts were more frequent during the last 4 days of luteal phase and during the 4 days of menses, with 59% of attempts to occur during these 8 days. Patterns of number of attempts and cycle phase were similar for subgroups regarding diagnosis, violent/non-violent mode of suicide attempt, and one or repeated attempts. Although attempts were unequally distributed during the cycle, none of the psychiatric features assessed in the present study were related to the higher frequency of attempts during premenstrual/menstrual days, indicating the need to include additional aspects of suicidal behavior in future studies.

Association of Plasma Cortisol Levels with Clinical Characteristics of Suicide Attempters.

OBJECTIVE: There is evidence that suicidal behavior, among others, is an abnormal response to stress caused by a dysfunction in the activity of hypothalamus-pituitary-adrenal axis, and that cortisol levels are low in a considerable number of people attempting suicide. In this study, we aimed to search for associations of plasma cortisol levels with the clinical characteristics of a group of psychiatric suicide attempters. METHOD: The cortisol was measured in the morning in 200 psychiatric patients hospitalized after a suicide attempt, with diagnoses of major depressive disorder, bipolar disorder, psychosis, and personality/adjustment disorder, and compared to the levels of 138 healthy controls. Comparisons were also made for diagnostic subgroups and across diagnoses, with regard to depressive symptomatology, mode of attempt, suicide intent, number of attempts, and age. RESULTS: Cortisol levels were significantly lower for the whole group of attempters compared to controls. Furthermore, low cortisol levels characterized attempters with personality/adjustment disorder, higher depressive symptomatology, low suicide intent, non-violent attempt mode, repeated attempts, and of younger age. CONCLUSIONS: Certain clinical characteristics were identified in attempters with low cortisol levels. In previous studies, low cortisol levels have been associated with impairments in cognitive control, decision-making, and emotional processing that may lead, in the presence of stressors, to suicidal behavior, frequently with non-fatal outcome. Adding plasma cortisol levels to demographic and psychopathological data may help in identifying a subpopulation of attempters with neurocognitive deficits linked to dysfunction of Hypothalamic-Pituitary-Adrenal-axis activity, with implications for treatment.

Body mass index and plasma leptin in psychiatric suicide attempters.

OBJECTIVES: To evaluate body mass index (BMI) and its correlate plasma leptin levels that have been associated with psychiatric morbidity and suicidal behaviour, in relation to clinical features in psychiatric patients after a suicide attempt. METHODS: BMI and plasma leptin were assessed in 198 patients (66 males, age range of 21 to 80 years) who were admitted to the hospital after a suicide attempt, 98 with major depressive disorder, 28 with bipolar disorder, 30 with psychosis, and 42 with personality or adjustment disorder, compared to data of 134 healthy subjects, and evaluated in relation to gender, diagnosis, mode of attempt, and pharmacological treatment before attempt. The ratio leptin/BMI was used as a measure of adipocyte leptin secreting activity. RESULTS: Drugs taken for treatment before attempt, among them atypical neuroleptics, were not associated either to BMI or to plasma leptin. The positive correlation between BMI and leptin was significant in all groups. Compared to same gender controls, significant differences were found only for female patients, namely higher BMI for patients with psychosis and patients with bipolar disorder, while leptin/BMI ratio was higher only in females with bipolar disorder. CONCLUSION: BMI and plasma leptin in psychiatric suicide attempters are elevated in certain diagnostic groups in females, not related to previous pharmacologic treatment. The lack of a control group without a history of suicide attempts does not allow the attribution of enhanced leptin secreting activity found in female bipolar attempters specifically to suicidal behavior or to the disorder as a diagnostic entity.

Psychoticism in patients with panic disorder with or without comorbid agoraphobia.

OBJECTIVE: A few case-reports have previously described transient psychotic-like symptoms in non-psychotic patients with panic disorder (PD). We aimed to systematically explore whether PD patients without any current or past psychosis can be differentiated according to the severity of 'psychoticism' as a dimension, comprising clinical features such as psychotic-like experiences, increased social alienation, hostility and suspiciousness. METHODS: Sample included 35 (female = 26) medication-free, non-psychotic patients consecutively referred from our Department's Outpatient Clinic for acute symptoms of DSM-5 PD with (PDA; N = 29) or without concurrent agoraphobia. Psychometric measures included the Symptom Checklist-90-Revised (SCL-90-R), Agoraphobic Cognitions Questionnaire (ACQ), Body Sensations Questionnaire (BSQ), and panic attacks during last 21 days PA-21d. RESULTS: Multiple regression analysis (forward stepwise) revealed that, among all SCL-90-R subscales, the psychoticism-subscale was most significantly associated with panic-related beliefs included in the ACQ, while significant associations emerged between the paranoid ideation-subscale and the ACQ and BSQ measures. Moreover, significant correlations emerged between the SCL-90-R psychoticism-subscale and all three measures of PD symptoms (ACQ, BSQ, PA-21d) and between the SCL-90-R paranoid ideation-subscale and both the ACQ and BSQ. CONCLUSIONS: This significant association between levels of psychoticism and severity of panic symptoms may reflect a more severe subtype of PD.

Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode.

AIMS: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS. METHODS: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol. RESULTS: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB. CONCLUSIONS: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc.

Testosterone and dehydroepiandrosterone sulfate in female anxious and non-anxious major depression.

OBJECTIVES: Major Depression with severe anxiety has been proposed as a distinct clinical variant of Major Depressive Disorder (MDD). This proposal invites the investigation of the differential biological correlates of the anxious versus non-anxious MDD. One such research area might be their possible differential associations with androgens. METHODS: Plasma total testosterone and dehydroepiandrosterone were assessed in adequately matched female inpatients with anxious MDD, non-anxious MDD and normal controls. RESULTS: Androgen levels were significantly lower in both patient groups compared to those of controls. Moreover, they were significantly lower in anxious MDD patients compared to those of their non-anxious MDD counterparts. The limitations of this study were cross-sectional design of the study, the small sample size of the study sample and the outpatient status of the control group. In addition, free testosterone levels were not measured. CONCLUSIONS: Our findings indicate that female major depression is associated with lower androgen levels, a deficiency aggravated by the severity of their concomitant anxiety.

On the differential diagnosis of anxious from nonanxious major depression by means of the Hamilton Scales.

OBJECTIVE: Anxious major depressive disorder (A-MDD) is differentially diagnosed from nonanxious MDD (NA-MDD) as MDD with a cut-off score ≥ 7 on the HAM-D anxiety-somatization factor (ASF). We investigated whether additional HAM-D items discriminate A-MDD from NA-MDD. Moreover, we tested the validity of ASF criterion against HAM-A, gold standard of anxiety severity assessment. METHODS: 164 consecutive female middle-aged inpatients, diagnosed as A-MDD (n = 92) or NA-MDD (n = 72) by the normative HAM-A score for moderate-to-severe anxiety (≥ 25), were compared regarding 17-item HAM-D scores. The validity of ASF ≥ 7 criterion was assessed by receiver-operating characteristics (ROC) analysis. RESULTS: We found medium and large effect size differences between A-MDD and NA-MDD patients in only four out of the six ASF items, as well as in three further HAM-D items, namely, those of agitation, middle insomnia, and delayed insomnia. Furthermore, the ASF cut-off score ≥ 9 provided the optimal trade-off between sensitivity and specificity for the differential diagnosis between A-MDD and NA-MDD. CONCLUSION: Additional HAM-D items, beyond those of ASF, discriminate A-MDD from NA-MDD. The ASF ≥ 7 criterion inflates false positives. A cut-off point ≥ 9 provides the best trade-off between sensitivity and specificity of the ASF criterion, at least in female middle-aged inpatients.

Evidence for involvement of central noradrenergic activity in crying proneness.

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

Neuroendocrine evidence of normal hypothalamus-pituitary dopaminergic function in Huntington's disease.

OBJECTIVES: In addition to neuronal loss in striatum and cerebral cortex that characterizes Huntington's disease (HD), hypothalamic atrophy has also been found only in certain areas, probably not including dopaminergic functions. METHODS: We assessed the reactivity of the hypothalamus-pituitary dopaminergic system by measuring the acute prolactin (PRL) responses to 5 mg i.m. haloperidol in male and female HD patients and in female subjects with expanded CAG repeats in the Huntington gene before disease onset, as well as in a group of healthy males. RESULTS: The responses of the male patients were similar to those of a group of male healthy volunteers. Females gave higher PRL responses, with no differences in the response patterns of female patients and females at risk for HD. PRL elevations were not related to severity of illness, or to presence of dementia, depression, or psychotic features. CONCLUSIONS: The results implicate a normal dopaminergic input from hypothalamus to pituitary and preserved pituitary dopamine receptors, indicating that hypothalamic atrophy in HD does not affect mechanisms involved in PRL secretion by haloperidol.

Psychiatric diagnosis, gender, aggression, and mode of attempt in patients with single versus repeated suicide attempts.

There is evidence that patients with multiple suicide attempts in their history are at greater risk to repeat attempt and eventually die by suicide compared to those with a single attempt. This cross-sectional study aimed to explore possible differences in clinical characteristics between patients with a single attempt and patients with repeated attempts. Two hundred thirty one patients hospitalised in psychiatric department after suicide attempt were studied. Comparisons were made in relation to age, gender, psychiatric diagnosis, aggression, depression severity, suicide intent and mode of attempt. Highest frequencies of patients with repeated attempts were found for bipolar disorder (69%) and lowest for adjustment/personality disorders (39%). In patients with repeated attempts, female gender was associated with non-violent attempt mode. Depressive symptomatology was higher in patients with repeated attempts among females. In patients with depression those with repeated attempts were younger than patients with single attempt. In patients with mood disorders, total aggression and hostility scores were higher in females with repeated attempts but not in males. Psychiatric diagnosis, gender and attempt mode are features that differentiate patients with single and repeated attempts and should be considered to identify patients at increased risk to repeat attempt and design effective prevention interventions.

Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis.

Axonal degeneration and brain tissue loss occur during disease progression in multiple sclerosis (MS) and are expected to influence neurotransmitter activities, with consequences on neurologic and psychiatric symptomatology. We searched for relationships of disease duration, disability, and severity of MS patients to CSF levels of the major metabolites of noradrenaline, dopamine, and serotonin, MHPG, methoxyhydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 39 patients with relapsing-remitting (RR) MS in remission, and 26 patients with progressive (PR) MS. Disability and Disease Severity were assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). Compared with the levels of 50 control subjects, MHPG levels were not different in either MS group, correlated negatively to duration of illness and number of relapses in the RRMS group, but not to EDSS score or to MSSS. Homovanillic acid levels were significantly lower only in the PRMS group, with a negative correlation to duration of illness, and a strong negative correlation to EDSS score, but not to MSSS. 5-HIAA was significantly lower in both RRMS and PRMS groups. In the RRMS group, 5-HIAA levels were negatively related to EDSS and to MSSS. Multiple regression analyses revealed a significant association of MHPG to duration of illness, and a strong negative association of 5-HIAA to MSSS rather than to EDSS. The strong negative correlation of MSSS to CSF 5-HIAA levels in RRMS group of patients indicates that deficits in central serotonergic activity are related to the rate of disability accumulation in RRMS, and could be linked to the reported reduction of disease activity by serotonergic drugs.

Plasma homovanillic acid and prolactin in Huntington's disease.

Dopaminergic activity is expected to be altered in patients with Huntington's disease (HD) and be related to factors like duration and severity of illness or patients' specific symptomatology like dementia, depression, or psychotic features. We assessed plasma homovanillic acid (pHVA) and plasma prolactin (pPRL), two correlates of dopaminergic activity, in 116 subjects with CAG repeats expansion in the HD gene, 26 presymptomatic (18 females) and 90 with overt symptomatology (43 females). Patients were evaluated using the Unified HD Rating Scale and the Total Functional Capacity Scale. Presence of dementia, depression, and psychotic features were also assessed. The age range of the patients was 22-83 years, duration of illness from 0.5 to 27 years, and CAG repeat number from 34 to 66. A group of 60 age and sex matched healthy subjects served as control group. Plasma PRL in subjects at risk and in neuroleptic-free patients, evaluated separately for males and females, did not differ from controls. Plasma HVA levels did not differ from controls in the group of presymptomatic subjects, but were significantly higher in the patients group. This increase was positively associated mainly with severity of illness and functional capacity of the patients, and not with presence of depression or dementia. Plasma HVA levels may be proven to be a peripheral index of disease progression. Reducing dopaminergic activity may have not only symptomatic, but also neuroprotective effects in HD.

Caffeine challenge and breath-holding duration in patients with panic disorder.

OBJECTIVE: Breath-holding (BH) has been used as a simple probe to increase endogenous carbon dioxide (CO2). In patients with Panic Disorder (PD), lower baseline BH duration is associated with caffeine-induced panic attacks. In this paper, we assessed BH duration in PD patients in relation to panic attacks induced by caffeine intake. METHODS: BH duration and state anxiety were assessed in 40 PD patients (12 males), both at baseline and after a 400-mg caffeine challenge test. RESULTS: Patients panicking after caffeine administration (14 patients, 4 males) exhibited a significant reduction of their post-challenge BH duration, while no change of the BH duration was observed in non-panicking patients (26 patients, 8 males). Reduction in post-challenge BH duration was not related to higher anxiety levels--as reflected in the State-Trait Anxiety Inventory-State Form scores--independently of the occurrence of a panic attack. Panickers exhibited significantly lower baseline BH duration, compared to non-panickers. CONCLUSIONS: Our findings indicate that in PD patients, caffeine-induced panic attacks are strongly associated with a significant reduction of BH duration at both pre- and post-challenge. Jointly, these findings suggest that in a subgroup of PD patients, sensitivity to endogenous CO2 accumulation may underlie both the lower BH durations and the caffeine-induced panic attacks. In this subgroup of PD patients, caffeine might exert its panicogenic properties through the exacerbation of patients' already pathological hypersensitivity to CO2 accumulation, as indicated by both the significant decrease of their BH duration at post-challenge and by their significantly lower baseline BH duration respectively.