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The paper here presented was motivated by a case study involving high-dimensional and high-frequency tidal volume traces measured during induced panic attacks. The focus was to develop a procedure to determine the significance of whether a mean curve dominates another one. The key idea of the suggested method relies on preserving the order in mean while reducing the dimension of the data. The observed data matrix is projected onto a set of lower rank matrices with a positive constraint. A multivariate testing procedure is then applied in the lower dimension. We use simulated data to illustrate the statistical properties of the proposed testing procedure. Results on the case study confirm the preliminary hypothesis of the investigators and provide critical support to their overall goal of creating an experimental model of the clinical panic attack in normal subjects.

Panic patients are vulnerable to induction of panic attacks by sub-threshold interoceptive stimuli such as intravenous (i.v.) sodium lactate infusions. Facilitation of serotonergic signaling with selective serotonin reuptake inhibitors can suppress anxiety and panic-like responses, but the mechanisms involved are not clearly defined. We investigated the effects of i.v. 0.5 M sodium lactate or saline, in control and panic-prone rats on c-Fos expression in serotonergic neurons within subdivisions of the midbrain/pontine raphe nuclei. Rats were chronically infused with either the GABA synthesis inhibitor l-allylglycine into the dorsomedial hypo thalamus to make them panic-prone, or the enantiomer d-allylglycine (d-AG) in controls. Lactate increased c-Fos expression in serotonergic neurons located in the ventrolateral part of the dorsal raphe nucleus (DRVL) and ventrolateral periaqueductal gray (VLPAG) of control, but not panic-prone, rats. The distribution of lactate-sensitive serotonergic neurons in d-AG-treated rats is virtually identical to previously defined pre-sympathomotor serotonergic neurons with multisynaptic projections to peripheral organs mediating 'fight-or-flight'-related autonomic and motor responses. We hypothesized that serotonergic neurons within the DRVL/VLPAG region represent a 'sympathomotor control system' that normally limits autonomic/behavioral responses to innocuous interoceptive and exteroceptive stimuli, and that dysfunction of this serotonergic system contributes to an anxiety-like state and increases vulnerability to panic in animals and humans.

In order to elucidate the impact of psychological factors on panic severity the correlation between baseline anxiety and panic response to cholecystokinin-tetrapeptide (CCK-4), an established model of human anxiety, was investigated in 33 healthy volunteers. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI). Trait and state anxiety did not differ between panickers and nonpanickers nor were they correlated with panic severity. In conclusion, psychological factors are not major determinants for the subjective panic response to CCK-4 thus emphasising the importance of neurobiological factors.

Background: Chronic exercise has been shown to have therapeutic effects in panic disorder (PD). The mechanism of these effects is unknown. Acute exercise reduces the effect of a panic challenge in healthy volunteers. Such an effect has not yet been demonstrated in PD patients. The present study aimed at exploring the antipanic effects of acute exercise on a 35% CO2 panic provocation in treatment-naïve PD patients to further elucidate the mechanisms of the beneficial effects of exercise on panic., Methods: Eighteen PD patients performed either moderate/hard exercise or very-light exercise before a 35% CO2 challenge in a randomized, between-group design. The reactivity to CO2 was assessed with the Visual Analogue Anxiety Scale and the DSM-IV Panic Symptom List., Results: Panic reactions to CO2 were smaller in patients that performed moderate/hard exercise in contrast to those that performed very-light exercise. Increments in both measurements and panic rates were consistently reduced by intense exercise., Limitations: Since this study focuses on the acute effects of exercise on CO2 sensitivity in patients with PD, the results of repetitive exercise sessions on the rate of spontaneous panic attacks and overall symptoms are warranted. The small sample size and other limitations are addressed., Conclusions: Exercise reduced the panicogenic effects of a CO2 challenge. In addition to its therapeutic potential, exercise may also be useful as a laboratory maneuver with heuristic value in experimental research into the mechanisms of antipanic treatment.

Pentagastrin is a cholecystokinin (CCK)-B agonist and laboratory panicogenic agent that produces endocrine (ACTH and cortisol), symptom (anxiety, panic) and cardiovascular (heart rate) responses. Although in vitro data have supported its chemical stability, preliminary data suggested that increasing time between drug preparation and drug infusion could reduce the magnitude of endocrine and symptom responses. The current study examined this possibility. Twenty-one healthy subjects presented at the University of Michigan General Clinical Research Center (GCRC) and had an intravenous catheter inserted. Heart rate, cortisol levels and subjective anxiety were measured before and after pentagastrin and placebo injections. Pentagastrin was prepared either within 60 min of IV infusion (Normal Preparation group) or at least 3.5 h prior to infusion (Early Preparation group). Relative to the Normal Preparation group, Early Preparation subjects had similar heart rate responses but significantly smaller cortisol and subjective anxiety responses. Early preparation of pentagastrin thus appears to weaken endocrine and subjective anxiety responses, highlighting the importance of attending to often overlooked procedural variables (e.g., time between preparation and administration) in studies of this type. The sensitivity of cortisol and anxiety responses to preparation time, but insensitivity of heart rate, is consistent with previous studies suggesting different thresholds of activation for the three response modalities. These differential sensitivities may suggest different and separable CCK-B stimulated pathways for each response, which combine to produce panic, rather than a single, unified CCK-B mediated panicogenic response.

Objective: Psychoimmunological research in panic disorder (PD) so far focussed on single time point evaluation in resting conditions. No robust evidence for changes in the immune system was found using this method. However, PD is characterized by the occurrence of unexpected panic attacks (PAs). The current research focuses on cytokine and acute phase protein (APP) levels and mitogen-induced cytokine secretion following 35% CO(2) inhalation-induced panic., Methods: Eighteen PD patients and 18 matched healthy control subjects underwent both a placebo and a 35% CO(2) inhalation on separate days. Blood samples for cytokine and APP determination were taken before and after the inhalation. In addition to serum determination, whole blood samples were cultured and stimulated with mitogens for assessment of the functional capacity of the immune system., Results: The 35% CO(2) inhalation induced significantly higher levels of anxiety in PD patients as compared to the control subjects, but no differences in immune parameters were found, either in basal conditions or after experimental panic induction., Conclusion: In our sample we do not find any changes in serum levels or functional capacity of several immunological parameters in the experimentally provoked PAs. Similar results have been found in social phobia, whereas in other affective disorders such as depression and posttraumatic stress disorder, immune changes are evident. Changes seem to coincide with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, the bidirectional communication pathway between the immune system and the HPA axis might play a role in some affective disorders, but it does not specifically seem to be involved in the etiology of PD.

Pharmacological magnetic resonance imaging (phMRI) is a method to study effects of psychopharmacological agents on neural activation. Changes of the blood oxygen level dependent (BOLD), the basis of functional MRI (fMRI), are typically obtained at relatively high sampling frequencies. This has more recently been exploited in the field of fMRI by applying independent component analysis (ICA), an explorative data analysis method decomposing activation into distinct neural networks. While already successfully used to investigate resting network and task-induced activity, its use in phMRI is new. Further extension of this method to tensorial probabilistic ICA (tensor PICA) allows to group similar brain activation across the anatomical, temporal, subject or session domain. This approach is useful for pharmacological experiments when no pharmacokinetic model exists. We exemplify this method using data from a placebo-controlled cholecystokinine-4 (CCK-4) injection experiment performed on 16 neuropsychiatrically and medically healthy males (age 25.6 +/- 4.2 years). Tensor PICA identified strong increases in activity in 12 networks. Comparison with results gained from the standard approach (voxelwise regression analysis) revealed good reproduction of areas previously associated with CCK-4 action, such as the anterior cingulate, orbitofrontal cortex, cerebellum, temporolateral, left parietal and insular areas, striatum, and precuneus. Several other components such as the dorsal anterior cingulate and medial prefrontal cortex were identified, suggesting higher sensitivity of the method. Exploration of the time courses of each activated network revealed differences, that might be lost when a fixed time course is modeled, e. g. neuronal responses to an acoustic warning signal prior to injection. Comparison of placebo and CCK-4 runs further showed that a proportion of networks are newly elicited by CCK-4 whereas other components are significantly active in the placebo conditions but further enhanced by CCK-4. In conclusion, group ICA is a promising tool for phMRI studies that allows quantifying and visualizing the modulation of neural networks by pharmacological interventions.

A proportion of patients with panic disorder (PD) display an increased sensitivity to the anxiogenic/panicogenic properties of caffeine. The aim of this study is to identify probable baseline differences between PD patients who panic and those who do not, after caffeine administration. In a randomized, double-blind, cross-over experiment performed in two occasions 3-7 days apart, 200 and 400 mg of caffeine, respectively, were administered in a coffee form to 23 patients with PD with or without Agoraphobia. Evaluations included the State-Trait Anxiety Inventory, the DSM-IV 'panic attack' symptoms (visual analogue scale form), the Symptom Checklist-90-Revised (SCL-90-R), as well as breath-holding (BH) duration, heartbeat perception accuracy and heart rate. Only those patients who did not present a panic attack after both challenges ('no panic group', N=14, 66.7%), and those who presented a panic attack after at least one challenge ('panic group', n=7, 33.3%) were included in the analysis. The panickers, compared to the non-panickers, presented at baseline: significantly higher total score of the SCL-90-R; significantly higher scores on all the SCL-90-R clusters of symptoms, except that of 'paranoid ideation'; significantly lower BH duration. The present preliminary findings indicate that PD patients who panic after a 200 mg or a 400 mg caffeine challenge, compared to the PD patients who do not panic after both of these challenges, may present at baseline significantly higher non-specific general psychopathology--as reflected in the SCL-90-R--and significantly shorter BH duration., ((c) 2007 Wiley-Liss, Inc.)

It was suspected that the delusional convictions of bewitchment and devil persecution of two female patients (41 and 40-years-old) could be the consequence of an erroneous interpretation of the sensations induced by panic attacks, as several authors have previously suggested. The interest of this case report stems from the manner in which we tested our clinical hypothesis. The patients agreed to the use of a lactate provocation test in double-blind, placebo-controlled conditions during four randomized sessions on consecutive days (two with lactate and two with placebo). The results for patient A strongly supported our hypothesis: patient A developed two full-blown panic attacks during the active lactate sessions, whereas patient B developed one subthreshold and one moderate panic attack during the active lactate sessions. The results of these investigations led to a more specific psychotherapeutic approach for patient A.

Objective: Evaluate the incidence of mental disorders using pegylated interferon plus ribavirin retreatment in nonresponder hepatitis C virus-infected patients., Method: The Mini-International Neuropsychiatric Interview (MINI) was used to evaluate 30 hepatitis C virus-infected interferon-nonresponder patients at baseline and following 4, 12 and 24 weeks of pegylated interferon retreatment., Results: During the pegylated interferon/ribavirin retreatment, 5(16.6%) patients developed psychiatric side effects: 3(10%) were diagnosed with major depressive disorder, 1(3.3%) had a brief psychotic disorder and 1(3.3%) presented with panic attacks., Conclusion: This is the first prospective study evaluating the incidence of neuropsychiatric side effects during interferon retreatment of hepatitis C virus-infected patients, suggesting that the risk of acquiring serious psychiatric symptoms during retreatment with interferon-alpha (IFN-alpha) may not be higher than during the first antiviral therapy. This finding challenges the hypothesis that during a second treatment with IFN-alpha, patients with hepatitis C may be at greater risk for neuropsychiatric side effects than naïve patients.

Objective: Panic disorder (PD) has been associated with an increased risk for cardiovascular (CV) morbidity and mortality. There are inconsistent reports of increased low-density lipoprotein cholesterol (LDL-C) in patients with PD. Studies have reported a correlation between cholesterol levels and the intensity and frequency of panic attacks (PAs), suggesting that an elevation in cholesterol could be due to physiological and neurochemical changes that occur during and after a PA. The objective of our study was to show that the occurrence of a PA is associated with an increase in LDL-C., Materials and Methods: We used a double-blind, placebo-controlled crossover design with randomized injections of placebo and pentagastrin in 18 patients with PD (11 men, 7 women) and 33 healthy-control subjects (24 men, 9 women)., Results: Pentagastrin-induced PAs were associated with a statistically significant 10.4% delayed (24 h) increase in LDL-C levels in male subjects. Such an effect was not observed in female subjects., Conclusion: LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.

Rationale: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules., Objectives: To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection., Methods: We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly., Results: The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers., Conclusions: The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.

Our aim was to observe if patients with panic disorder (PD) and patients with major depression with panic attacks (MDP) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) respond in a similar way to the induction of panic attacks by an oral caffeine challenge test. We randomly selected 29 patients with PD, 27 with MDP, 25 with major depression without panic attacks (MD), and 28 healthy volunteers. The patients had no psychotropic drug for at least a 4-week period. In a randomized double-blind experiment performed in 2 occasions 7 days apart, 480 mg caffeine and a caffeine-free (placebo) solution were administered in a coffee form and anxiety scales were applied before and after each test. A total of 58.6% (n = 17) of patients with PD, 44.4% (n = 12) of patients with MDP, 12.0% (n = 3) of patients with MD, and 7.1% (n= 2) of control subjects had a panic attack after the 480-mg caffeine challenge test (chi(2)(3) = 16.22, P = .001). The patients with PD and MDP were more sensitive to caffeine than were patients with MD and healthy volunteers. No panic attack was observed after the caffeine-free solution intake. The patients with MD had a lower heart rate response to the test than all the other groups (2-way analysis of variance, group by time interaction with Greenhouse-Geisser correction: F(3,762) = 2.85, P = .026). Our data suggest that there is an association between panic attacks, no matter if associated with PD or MDP, and hyperreactivity to an oral caffeine challenge test.

Animal models of diseases are widely used in the preclinical phase of drug development. They have a place in early human clinical psychopharmacology as well, in order to get early clues that contribute to establish the proof of concept (POC) already in healthy volunteers (HV). Different types of models are available (pharmacological or non-pharmacological provocation, models based on age-related characteristics). This review is focused on pharmacological models in HV, with the aim to identify the main issues raised by their use in pharmaceutical trials. The available models unevenly fulfil the requirements of face validity, sufficient response rate, test-retest consistence and responsiveness to reference drugs. Most of them have been developed in the purpose of pathophysiology studies, using rating instruments validated for clinical practice. Substantial progress could be made by adapting models to the specific requirements of pharmaceutical trials, including wider use of biomarkers. Characteristics that make models, as well as biomarkers, suitabLe for use in drug development are proposed. Despite obvious limitations, human models can significantly enhance the way phase I studies contribute to establish the POC, provided they are integrated into adapted phase I development plans. Their use as industrial tools for drug evaluation requires specific, dedicated development.

Low-frequency (LF) rTMS shows beneficial effects in patients with depression and anxiety disorders. To explore its anxiolytic properties we investigated the effects of rTMS on experimentally induced panic attacks. Eleven healthy subjects underwent 1 Hz rTMS or sham rTMS over the right dorsolateral prefrontal cortex in a randomized cross-over protocol. Panic induction with 50 mug CCK-4 was carried out immediately after rTMS. Response to CCK-4 was assessed using the Acute Panic Inventory and the Panic Symptom Scale and measurements of heart rate, plasma ACTH and cortisol. All subjects reported a marked panic response following CCK-4 administration after both real and sham rTMS. Moreover, injection of CCK-4 induced a marked increase in heart rate, cortisol and ACTH concentrations. However, ANOVA showed no significant differences in any of the measures between both conditions. In contrast to the effects of pretreatment with alprazolam on CCK-4-induced panic in healthy subjects LF rTMS does not affect CCK-4-induced panic and cortisol or ACTH release.

The authors describe a 31-year-old woman who developed persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Independently of that, she had experienced a panic attack followed by dystonias, shortly after a single dose of that drug, 17 years before. Both temporal association and recurrence of anxiety symptoms after re-challenge with metoclopramide suggest a causal relationship. The case might provide an initial piece of evidence that dopaminergic neurotransmission can be involved in the pathogenesis of generalized anxiety disorder.

This study investigates whether naloxone, an opioid receptor antagonist, could render normal controls, normally nonresponsive to panic inducing stimuli, sensitive to the physiological and behavioral effects of sodium lactate, a robust panicogen in panic disorder patients. Twelve normal controls received intravenous naloxone followed by sodium lactate. Four of these subjects underwent a separate infusion with naloxone followed by saline. Respiratory physiological symptoms were measured throughout. Clinical symptoms, assessed by the Acute Panic Inventory (API), an Anxiety Scale, and the Borg Breathlessness Scale, were recorded. Eight of the twelve subjects experienced strong physiological reactivity to naloxone-lactate manifested by significantly increased tidal volume. Concomitant increases in the API and Borg scales were demonstrated; however, fear or anxiety was not affected. The four subjects retested with naloxone followed by saline did not experience significant increases on any measure. These results provide preliminary evidence that endogenous opioid system function may be a key modulator of responsivity to sodium lactate. Dysregulation of the opioid system may potentially underlie critical aspects of panic disorder neurobiology, including respiratory abnormalities and suffocation sensitivity.

Extracellular recordings were made from output neurons in the dorsal half of the periaqueductal gray matter (dPAG) in urethane-anesthetized female Wistar rats. All the neurons were quiescent. A basal level of firing was therefore induced by continuous iontophoretic application of D,L-homocysteic acid (DLH). In the presence of the GABA(A) receptor antagonist bicuculline methiodide (BIC 0-30 nA) the DLH-induced firing increased further, revealing the presence of ongoing GABAergic inhibitory tone on the recorded neurons. The BIC-induced increase in firing rate was significantly greater in neurons recorded during estrus (Est) and late diestrus (LD) compared with proestrus (Pro) and early diestrus (ED) suggesting that GABAergic tone was lower in Est and LD. I.v. injection of the panicogenic cholecystokinin (CCK)(B) receptor agonist pentagastrin (PG, 40 microg kg(-1)) produced an increase in firing rate in 12/17 (70%) of neurons tested in the dPAG. Iontophoretic application of PG (10-30 nA) also produced a current-related increase in firing rate in 73.6% of the neurons tested. The excitatory response was reduced during application of the selective CCK(B) receptor antagonist beta-[2-([2-(8-azaspiro[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino)-2-oxoethyl]-(R)-napthalenepropanoic acid (CR2945) (60 nA, n=6). The PG-evoked increase in firing rate was significantly greater in neurons recorded during Est and LD compared with during Pro and ED. Juxtacellular labeling with neurobiotin in eight neurons revealed multipolar cells 12-44 microm diameter with up to six primary dendrites. In three of eight neurons, a filled axon was present and coursed without branching toward the perimeter of the periaqueductal gray matter (PAG). The estrous cycle-related change in responsiveness to BIC and PG suggests that the panic circuitry in the PAG may become more responsive to panicogenic agents during estrus and late diestrus as a consequence of a decrease in the intrinsic level of inhibitory GABAergic tone. The findings may have implications for understanding the neural processes that underlie the development of premenstrual dysphorias in women.

The present investigation evaluated the associations between lifetime psychedelic use, abuse, and dependence and panic attacks. The study consisted of a representative epidemiological sample from a state wide survey of the Colorado general adult population (n=4745; 52% female). Consistent with prediction, after controlling for theoretically relevant variables, psychedelic abuse and dependence, but not use, were significantly related to an increased lifetime risk of panic attacks. The results are discussed in terms of better understanding the role of psychedelic use in relation to the occurrence of panic attacks.

Recent concerns have been raised regarding whether antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) might increase suicidal tendencies and intense debate-rages over the pros and cons of their use. Although systematic reviews and population-based studies have been conducted, a consensus on this association remains to be established. Subsequently, the concept of so-called 'activation syndrome' associated with antidepressants has been accepted without its adequate verification. In the present report, we present our experience of seven cases considered of having 'activation syndrome' brought on by antidepressants, and examine its clinical relevance to bipolar spectrum disorder (Ghaemi, et al., 2001) both symptomatologically and diagnostically. Five patients, diagnosed as having major depressive disorder according to the diagnostic manual (DSM-IV), met the criteria of bipolar spectrum disorder and suffered from activation syndrome following the administration of SSRIs, mainly paroxetine. Similarly, hypomania developed in all five cases with depression; the diagnostic criteria of a hypomanic episode were not met. In the remaining two patients, who were both diagnosed with bipolar disorder, one showed irritability and insomnia through imipramine use, and the another developed a hypomanic and/or a mixed state after the co-administration of fluvoxamine and trazodone. From the results of our examination, 'bipolarity', which is the pivotal factor of bipolar spectrum, might exist behind the phenomenon recognized as activation syndrome, and be revealed by antidepressant treatment, just like manic switching. Moreover, the various problems encountered in the current practice of treating mood disorders, including unipolar-bipolar dichotomy, manic switching by antidepressants, and narrow criteria for a mixed episode, were pointed out a new through this concept of activation syndrome. Actually, the understanding of activation syndrome clinically leads to the prevention of suicidal behavior and the careful use of antidepressants for bipolar (spectrum) disorder, but we must be prudent when applying this concept, since it has not yet been established.

The use of isotretinoin as a treatment for acne is related to psychiatric syndromes such as psychosis and depression. On the other hand, several drugs have been identified as causing panic attacks. A relationship between dermatologic and psychiatric disease has also been established. We report a 20 year-old male who started to suffer panic attacks after using isotretinoin for acne.

Patients with postural tachycardia syndrome (POTS) might be misdiagnosed with panic disorder due to shared clinical features. The first aim of our study was to investigate the relationship between symptoms of POTS and panic disorder. The second aim was to delineate clinical features distinguishing symptoms of POTS from panic disorder. A total of 11 patients with POTS and 11 control subjects participated in an IRB-approved, prospective, placebo-controlled study. The experimentally induced panic-like symptoms of POTS were systematically studied using the Acute Panic Inventory (API) questionnaire. The participants answered the questionnaire after each placebo infusion and after each of the three provoking stimuli: head-up tilt test (HUT), isoproterenol infusion (ISI), and sodium lactate infusion (SLI). API responses were summed for each subject at each time point of administration. Individual API symptoms and summed responses were analyzed for statistical significance. All patients with POTS developed symptoms of orthostatic intolerance during HUT. Pharmacologically induced symptoms subjectively mimicked spontaneous symptoms in 5 of 11 patients during ISI and in none of 11 patients during SLI. In contrast, API scores in these patients reached panic threshold in 0 of 11 following HUT, in 4 of 11 following ISI and in 4 of 11 following SLI. Individual symptoms analysis revealed that significant increase in scores was limited to the somatic symptoms of palpitations, dyspnea, and twitching or trembling. In conclusion, the symptoms of POTS are phenomenologically different and clinically distinguishable from panic disorder symptoms.

Objective: To describe tardive rebound anxiety phenomena (panic, anxiety and insomnia) following abrupt paroxetine discontinuation., Method: Case report, with comprehensive literature review on rebound and withdrawal phenomena associated with psychotropic medications., Results: Three different discontinuation syndromes with psychotropics are described: (1) new-onset CNS-depressant type withdrawal symptoms (minor and major); (2) rebound syndromes; and (3) supersensitivity symptoms. Abrupt paroxetine discontinuation has been well described and fits the first category. Tardive rebound panic disorder-phenomena with paroxetine has some features of the supersensitivity category., Conclusion: Chronic paroxetine treatment may lead to 5-HT2-receptor down regulation, with desensitization of 5-HT1A and 5-HT2 receptors, which may contribute to tardive rebound symptoms upon abrupt withdrawal. Early reports suggest that genetic factors may also contribute to withdrawal symptoms in susceptible individuals. Cholinergic rebound may also occur and could explain tardive insomnia and anxiety in paroxetine withdrawal.

Exercise has an anxiolytic activity and it increases the concentrations of atrial natriuretic peptide (ANP). Because ANP has an anxiolytic activity, this hormone might contribute to the anxiolytic effects of aerobic exercise. Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks were studied in 10 healthy subjects after "quiet rest" or 30 min of aerobic exercise. Plasma ANP concentrations were measured before and after exercise or quiet rest using a commercial IRMA kit. Compared to quiet rest, CCK-4-induced anxiety was reduced and plasma ANP concentrations were increased by prior exercise. This anxiolytic activity of exercise was correlated with the increase in plasma ANP concentrations. Our results suggest that besides other mechanisms, ANP might be a physiologically relevant humoral link between the heart and anxiety-related behavior contributing to the acute anxiolytic effects of exercise.

Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.

Objective: Earlier analyses have shown that, among currently well individuals with no history of panic attacks, a family history of panic disorder is associated with a greater likelihood of panic symptoms after exposure to 35% CO2 and of ventilatory-response abnormalities during inhalation of 5% CO2. An association of those features with a subsequent onset of panic attacks would compose additional evidence that they are trait markers for panic disorder., Methods: Subjects who were free of current Axis I disorders other than simple or social phobia and who had a first-degree relative with panic disorder (high risk) and subjects who had no first-degree relatives with panic disorder or major depressive disorder (low-risk) underwent two challenge procedures. The first measured anxiety responses to a single breath of 35% CO2, and the second measured ventilatory responses to a 3-minute exposure to 5% CO2. After a mean interval of 4 years, 66 high-risk (48 female; mean age = 23.0 years) and 24 low-risk subjects (15 female; mean age = 23.1 years) were questioned by telephone about the occurrence of any spontaneous panic attack in the interval., Results: Sixteen (23.9%) of the high-risk and one (4.2%) of low-risk subjects had experienced at least one spontaneous panic attack; Cox regression analyses revealed a significant relationship between abnormal ventilatory responses to 5% CO2 and the later onset of panic attacks. Subjective responses to 35% CO2 were not predictive. Neuroticism scores were not associated with abnormal ventilatory responses to CO2 but were also predictive of later panic attacks., Conclusions: High neuroticism scores and abnormal ventilatory responses to 5% CO2 appear to be additive trait markers for panic disorder.

Panic disorder and cigarette smoking co-occur at a rate that exceeds what would be expected by chance. Theoretically, cigarette smoking may (a) attenuate panicky symptoms via cognitive factors or pharmacological action, (b) contribute to the development of panic disorder, or (c) share an etiological vulnerability with panic. The present study was aimed at testing whether nicotine has a direct influence on laboratory-elicited panic. In a placebo-controlled, double-blind, randomized, cross-over study, 33 healthy nonsmokers underwent a 35% CO2 challenge after transdermal administration of a nicotine patch on one test day and a placebo patch on another test day. Physiological measures (blood pressure, heart rate) and rating scale scores (Panic Symptom List [PSL], Visual Analog Scale of Anxiety, State-Trait Anxiety Inventory) were assessed. Compared with the placebo condition, nicotine increased diastolic blood pressure (p < .1), heart rate (p < .001), and PSL scores (p < .005) prior to the CO2 challenge but did not affect responding to the CO2 challenge itself. Results are consistent with the notion that nicotine promotes autonomic activation. However, the present study did not provide direct evidence that nicotine elicits panic in healthy volunteers. Replication in a clinical sample is warranted.

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.

Rationale: Data by [Bell et al. J Psychopharmacol (2002) 16:5-14] suggest that a decrease in 5-HT neurotransmission predisposes to panic attacks and that the antipanic effect of SSRIs depends upon the availability of 5-HT in the brain., Objectives: Our aim was to assess the effect of acute tryptophan depletion (TD) on cholecystokinin-tetrapeptide (CCK-4)- induced symptoms in patients with panic disorder (PD) who had responded to a 10-week treatment with a selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram., Materials and Methods: A total of 18 patients (6 males and 12 females, mean age 34.5 years) received a tryptophan-free amino acid drink and a control drink, each followed by a CCK-4 challenge (25 microg), 1 week apart in a double-blind crossover design., Results: The results showed no significant differences in response to the CCK-4 challenge between the TD and the control conditions. Panic rate after the CCK-4 challenge was 27.8% after depletion and 33.3% after control drink (chi2=0.13, p=0.72). No significant effects of TD were observed in panic intensity scores, subjective anxiety, or cardiovascular indices., Conclusions: This study demonstrates that an acute lowering of brain 5-HT availability with TD does not affect response to a CCK-4 challenge in PD patients successfully treated with citalopram. Thus, the reduction of CCK-4 sensitivity following SSRI-treatment in patients with PD may be related to mechanisms other than 5-HT availability in the brain, possibly to a reduction in brain cholecystokinin receptor sensitivity.

Our aim was to describe the clinical features of 35% CO2-induced panic attacks in patients with panic disorder (PD) (Diagnostic and Statistical Manual and Mental Disorders, Fourth Edition) and compare them with the last spontaneous panic attack in patients with PD who had not had a panic attack after the 35% CO2 challenge test. We examined 91 patients with PD submitted to the CO2 challenge test. The test consisted of exhaling as fully as possible, took a fast vital capacity breath, held their breath for 8 seconds, exhaled, and then repeated the fast vital capacity breath, again holding for 8 seconds. The patients inhaled the 35% CO2/65% O2 mixture or atmospheric compressed air, randomly selected in a double-blind design. Scales were applied before and after the test. A total of 68.1% (n = 62) patients with PD had a panic attack (responders) after the CO2 test (chi2(1) = 25.87, P = .031). The last spontaneous panic attack and the symptom profile from the patients with PD who had not had a panic attack after the test (n = 29, 31.9%) were described to compare. The responders had more respiratory symptoms (chi2(1) = 19.21, P < .001), fulfilling the criteria for respiratory PD subtype (80.6%); the disorder started earlier (Mann-Whitney, P < .001), had a higher familial prevalence of PD (chi2(1) = 20.45, P = .028), and had more previous depressive episodes (chi2(1) = 27.98, P < .001). Our data suggest that there is an association between respiratory PD subtype and hyperreactivity to a CO2 respiratory challenge test. The responders may be a subgroup of respiratory PD subtype with future diagnostic and therapeutic implications.

Objective: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO(2)-induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO(2) are associated with elevated cortisol levels in juvenile offspring., Method: A total of 131 offspring (ages 9-19) of parents with panic disorder, major depression, and no mental disorder underwent CO(2) inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO(2) inhalation., Results: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO(2) predicted elevated cortisol levels in offspring., Conclusions: As in adults, anxiety response to CO(2) in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses.

Anxiety-related responding to, and recovery from, a 5-min 10% carbon dioxide-enriched air presentation among 80 participants with no history of psychopathology was examined. Half of participants were instructed to suppress challenge-induced emotional responses, whereas their matched counterparts were instructed to observe such responses. Responding from immediately post-challenge through a 10-min recovery period was analyzed as a function of Anxiety Sensitivity-Physical Concerns and experimental condition using individual growth curve modeling. Anxiety Sensitivity-Physical Concerns moderated the effect of suppression only on emotion valence during recovery. In terms of main effects, suppression resulted in increased heart rate during recovery and Anxiety Sensitivity-Physical Concerns was positively associated with post-challenge self-reported anxiety. Results are discussed in terms of the potential role of inhibition-oriented affect regulation processes in the etiology of panic disorder.

Among ethical concerns associated with biological challenge procedures is the risk of potentiating panic attacks in otherwise healthy persons who have no history of panic. The aim of the present study was to determine if repeated exposure to 20% CO2 challenge increases the risk of developing panic attacks in a nonclinical sample. One hundred and fifty-five (39.5%) of 392 participants who underwent a 20% CO2 challenge procedure and 51 (63.0%) of 81 controls who breathed only room air were evaluated for panic attacks using the Panic Attack Questionnaire-Revised both at 6 and 12 months after the experiment. The percentage of participants who developed subsequent panic attacks did not differ significantly between the CO2 challenge group and the room air controls. High dose CO2 challenge does not increase the risk of subsequent panic attacks in nonclinical populations; it is a safe paradigm for use in psychopathology research with healthy individuals.

Objective: Regular physical activity is anxiolytic for both healthy subjects and patients with panic disorder. However, the acute antipanic activity of exercise has not yet been studied systematically., Method: The effects of quiet rest or aerobic treadmill exercise (30 minutes at 70% of maximum oxygen consumption) on cholecystokinin tetrapeptide (CCK-4)-induced panic attacks were studied in a crossover design in 15 healthy subjects. The effects were measured with the Acute Panic Inventory., Results: Panic attacks occurred in 12 subjects after rest but in only six subjects after exercise. In both conditions, CCK-4 administration was followed by a significant increase in Acute Panic Inventory scores; however, prior exercise resulted in significantly lower scores than quiet rest., Conclusions: Aerobic exercise has an acute antipanic activity in healthy subjects. If the authors' results are confirmed in patients, the optimum intensity and duration of acute exercise for achieving antipanic effects will have to be characterized.

Doxapram causes panic anxiety in humans. To determine whether doxapram alters corticotropin-releasing factor (CRF) expression in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), or bed nucleus of the stria terminalis (BNST), we used immunohistochemistry to measure CRF peptide in these brain areas after doxapram injection. Doxapram injection significantly increased CRF-like immunoreactivity (CRF-IR) within the CeA, but not in the BNST or PVN, and this increase was significant 2h after injection. In addition, doxapram significantly increased CRF mRNA expression within the CeA, and this was most prominent 30min after injection. These results suggest that doxapram selectively increases CRF expression within the CeA, and that this is mediated by increased CRF gene transcription. This increase in CRF-IR within the CeA might explain the doxapram-induced anxiety reaction.

Panic disorder (PD) and panic-like anxiety have been associated with an increased risk of cardiovascular death. No study has specifically examined the association between panic attacks and ischemia in patients who have coronary artery disease (CAD). We hypothesized that panic attacks would induce myocardial perfusion defects in patients who have CAD and PD. Sixty-five patients who had CAD and positive results with nuclear exercise stress testing (35 with PD and 30 without PD served as controls) underwent a well-established panic challenge test (1 vital capacity inhalation of a gas mixture containing 35% carbon dioxide and 65% oxygen) and were injected with technetium-99m sestamibi at inhalation. Single-photon emission computed tomography was used to assess per-panic challenge perfusion defects, and heart rate, blood pressure, and 12-lead electrocardiogram were continuously measured during the procedure. Patients were not withdrawn from their cardiac medications. Patients who had PD were significantly younger than the controls; otherwise groups did not differ with respect to gender, cardiac medications, nuclear exercise test results, and baseline heart rate and blood pressure. Seventy-four percent of patients (26 of 35) who had PD had a panic attack at inhalation versus 6.7% of controls (2 of 30, p <0.001). As hypothesized, patients who had PD and demonstrated a panic attack were more likely to develop a reversible myocardial perfusion defect than were controls who did not have an attack (80.9% vs 46.4% p = 0.009). Thus, despite being on their cardiac medications, panic attacks preferentially induced significant perfusion defects in patients who had CAD and PD. In conclusion, panic attacks in patients who have CAD appear to be bad for the heart.

Cholecystokinin (CCK) has been implicated in anxiety disorders. The midbrain periaqueductal gray (PAG), which modulates anxiety and panic reactions, contains CCK-immunoreactive fibers and CCK(2) receptors. The present study investigated the involvement of CCK(2) receptors of the PAG dorsolateral subdivision (dlPAG) in the regulation of inhibitory avoidance and escape, two defensive behaviors that have been related in terms of psychopathology to generalized-anxiety and panic disorders, respectively. Male Wistar rats were microinjected in the dlPAG with the CCK(2) receptor agonist cholecystokinin-tetrapeptide (CCK-4; 0.08-0.32 nmol/0.2 microL), the CCK(2) receptor antagonist LY-225910 (0.05-0.20 nmol/0.2 microL) or LY-225910 prior to CCK-4. Inhibitory avoidance and escape behaviors were evaluated in the elevated T-maze. Whereas CCK-4 facilitated escape, indicating a panic-like action, LY-225910 had the opposite effect. Pretreatment with a non-effective dose of LY-225910 prevented the panic-eliciting action of CCK-4. Neither CCK-4 nor LY-225910 affected inhibitory avoidance acquisition. The present results substantiate the view that dlPAG CCK(2) receptors modulate panic-related behaviors.

A bibliographic search has been performed in MEDLINE using cortisol and panic as key-words, occurring in the title and/or in the abstract. Human studies were selected, with no time limit. The following publications were excluded: review articles, case reports, panic attacks in disorders other than panic disorder, and studies on changes that occurred in-between panic attacks. The results showed that real-life panic attacks as well as those induced by selective panicogenic agents such as lactate and carbon dioxide do not activate the hypothalamic-pituitary-adrenal (HPA) axis. Agonists of the colecystokinin receptor B, such as the colecystokinin-4 peptide and pentagastrin, increase stress hormones regardless of the occurrence of a panic attack and thus, seem to activate the HPA axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increased anxiety in both normal subjects and panic patients raised stress hormone levels; among them are the alpha2-adrenergic antagonist yohimbine, the serotonergic agents 1-(m-chlorophenyl) piperazine (mCPP) and fenfluramine, as well as the psychostimulant agent caffeine. Therefore, the panic attack does not seem to activate the HPAaxis, in contrast to anticipatory anxiety.

This case conference presents a patient with von Willebrand disease, receiving year-long interferon treatment for hepatitis C. She was referred to C-L Psychiatry following a severe exacerbation of panic disorder. Our guest interviewer is Dr. Craig White, a Scottish cognitive therapist. The subsequent discussion outlines the treatment challenges of panic disorder that occurs when a patient is receiving interferon. A literature review evaluates psychological effects of interferon and biological mechanisms by which interferon may exacerbate anxiety and depression. A cognitive therapy conceptualization of interferon-induced exacerbation of panic disorder is proposed.

The present study is aimed at characterizing the carbon dioxide (CO2) procedure in healthy subjects to achieve reliable provocation of anxiety symptoms. Thirty healthy subjects inhaled in single-blind both compressed air and 7% CO2 mixture. Panic Symptom List (PSLIII-R), Visual Analogue Scale-Anxiety (VAS-A), State Anxiety Inventory (STAI-Y/1), respiratory parameters and skin conductance were measured. 'Responders' were classified depending on PSLIII-R scores after CO2. Twelve out of the 21 'responders' performed a second test to assess test-retest repeatability. In 21 subjects Delta%VAS-A (45.4 +/- 32.1) and PSLIII-R (pre-test 2.3 +/-2.1, post-test 17.5 +/- 8.2) but not STAI-Y/1, significantly increased during CO2 inhalation. Respiratory Rate, Minute Volume, end-Tidal CO2 and skin conductance rose in 'responders'. Repeatability was studied with Bland-Altman plots, revealing mean difference between tests close to 0 for both Delta%VAS-A and PSLIII-R. Among physiologic parameters, end-Tidal CO2 and Respiratory Rate showed good repeatability, with a within-subject CV of 9.2% and 6%, respectively. The challenge produced measurable response in healthy subjects. Good test-retest repeatability was observed in 'responders'. These data indicate that the test can be suitable for testing putative anti-panic or anxiolytic drugs in clinical studies using a within subject, crossover design.

Objective: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects., Method: Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant., Results: Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge., Conclusions: The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.