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1.  An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus 
Physiology & behavior  2012;107(5):686-698.
Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/ perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and “flight” associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15 years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypics features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO2, or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, Patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model’s predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.
PMCID: PMC3574569  PMID: 22484112
hypothalamus; perifornical; orexin; GABA; glutamate; panic; anxiety; fear; serotonin; norepinephrine; locus coeruleus; raphe; animal model; l-allylglycine; dorsomedial hypothalamus; DMH; PeF; sodium lactate; hypercapnia; yohimbine; cholecystokinin; CCK; CRF; BNST; amygdala; lateral septum
2.  Asthma and Panic in Young Adults 
Rationale: Psychologic factors are increasingly recognized to influence the onset and course of asthma. Previous cross-sectional community-based studies have provided evidence for a relatively specific association between asthma and panic. Objectives: To examine concurrent and longitudinal associations between asthma and panic in young adults. Measurements and Main Results: Prospective community-based cohort study of young adults (n = 591) followed between ages 19 and 40. Information was derived from six subsequent semistructured diagnostic interviews conducted by professionals. Cross-sectionally (over the whole study period), asthma was more strongly associated with panic disorder (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7, 9.3) than with any panic, which included panic disorder and panic attacks (OR = 2.1; 95% CI, 1.1, 4.5). Longitudinally, after adjusting for potentially confounding variables, active asthma predicted subsequent panic disorder (OR = 4.5; 95% CI, 1.1, 20.1), and the presence of panic disorder predicted subsequent asthma activity (OR = 6.3; 95% CI, 2.8, 14.0). Asthma predicted any panic (OR = 2.7; 95% CI, 1.1, 7.1), whereas any panic did not predict subsequent asthma activity. Associations were stronger in smokers than in nonsmokers, and stronger in women than in men. Smoking, early-childhood anxiety, and a family history of allergy were important confounders of the asthma–panic association. Conclusions: This is the first long-term follow-up study on asthma and panic. It showed dose–response-type relationships between panic and asthma, and bidirectional longitudinal associations between the two conditions. It provided evidence for familial factors and smoking as possible shared etiologic explanations.
PMCID: PMC2718460  PMID: 15764721
anxiety; child development; respiratory tract disease; sex; smoking
3.  Smoking Behavior and Alcohol Consumption in Individuals With Panic Attacks 
Individuals with anxiety often report greater smoking and drinking behaviors relative to those without a history of anxiety. In particular, smoking and alcohol use have been directly implicated among individuals experiencing panic attacks, diagnosed with panic disorder, or high on panic-relevant risk factors such as anxiety sensitivity. Less is known, however, about specific features of panic that may differentiate among those who do or do not use cigarettes or alcohol. The purpose of the current study was to replicate previous research findings of an association between panic symptomatology, cigarette smoking, and alcohol consumption, as well as extend findings by examining whether specific symptoms of panic attacks differentiated among those who do or do not use cigarettes or alcohol. Participants (n = 489) completed the Panic Attack Questionnaire-IV, a highly detailed assessment of panic attacks and symptoms, as well as self-report measures of smoking history and alcohol use. Consistent with previous research, participants who reported a history of panic attacks (n = 107) were significantly more likely to report current daily or lifetime daily cigarette smoking, and significantly greater hazardous or harmful alcohol use than participants with no panic history (n = 382). Although smoking and hazardous alcohol use were highly associated regardless of panic status, participants with panic attacks showed elevated hazardous alcohol use after controlling for daily or lifetime smoking. Surprisingly, although participants who reported having had at least one panic attack were more likely to smoke, panic attack symptoms, intensity, or frequency did not differentiate panickers who did or did not smoke. Furthermore, panic-related variables were not shown to differentially relate to problematic drinking among panickers. Implications for understanding the complex relationship between panic attacks and smoking and drinking behaviors are discussed.
PMCID: PMC3170754  PMID: 21915160
smoking; alcohol; panic attacks; comorbidity
4.  A comparison of low-dose risperidone to paroxetine in the treatment of panic attacks: a randomized, single-blind study 
BMC Psychiatry  2009;9:25.
Because a large proportion of patients with panic attacks receiving approved pharmacotherapy do not respond or respond poorly to medication, it is important to identify additional therapeutic strategies for the management of panic symptoms. This article describes a randomized, rater-blind study comparing low-dose risperidone to standard-of-care paroxetine for the treatment of panic attacks.
Fifty six subjects with a history of panic attacks were randomized to receive either risperidone or paroxetine. The subjects were then followed for eight weeks. Outcome measures included the Panic Disorder Severity Scale (PDSS), the Hamilton Anxiety Scale (Ham-A), the Hamilton Depression Rating Scale (Ham-D), the Sheehan Panic Anxiety Scale-Patient (SPAS-P), and the Clinical Global Impression scale (CGI).
All subjects demonstrated a reduction in both the frequency and severity of panic attacks regardless of treatment received. Statistically significant improvements in rating scale scores for both groups were identified for the PDSS, the Ham-A, the Ham-D, and the CGI. There was no difference between treatment groups in the improvement in scores on the measures PDSS, Ham-A, Ham-D, and CGI. Post hoc tests suggest that subjects receiving risperidone may have a quicker clinical response than subjects receiving paroxetine.
We can identify no difference in the efficacy of paroxetine and low-dose risperidone in the treatment of panic attacks. Low-dose risperidone appears to be tolerated equally well as paroxetine. Low-dose risperidone may be an effective treatment for anxiety disorders in which panic attacks are a significant component.
Trial Registration Identifier: NCT100457106
PMCID: PMC2696444  PMID: 19470174
5.  Panic disorder and incident coronary heart disease: a systematic review and meta-analysis protocol 
Systematic Reviews  2015;4:33.
The clinical presentation of panic disorder and panic attack overlaps many symptoms typically experienced in coronary heart disease (CHD). Etiological links between panic disorder and CHD are controversial and remain largely tenuous. This systematic review aims to pool together data regarding panic disorder with respect to incident CHD or myocardial infarction.
Electronic databases (MEDLINE, EMBASE, PsycINFO and SCOPUS) will be searched using a search strategy exploding the topics for CHD and panic disorder. Authors and reference lists of included studies will also be contacted to identify additional published and unpublished studies. Eligibility criteria are as follows: Population: persons without CHD who meet criteria for panic disorder, panic attack, anxiety neurosis or elevated panic disorder symptoms; Comparison: persons without CHD who do not meet criteria for panic disorder, panic attack, anxiety neurosis or elevated panic disorder symptoms; Outcome: verified fatal and non-fatal CHD at follow-up; including coronary revascularization procedure, coronary artery disease, and myocardial infarction. Studies adopting self-report CHD will be ineligible. Screening will be undertaken by two independent reviewers with disagreements resolved through discussion. Data extraction will include original data specified as hazard ratios, risk ratios, and original cell data if available. Risk of bias assessment will be undertaken by two independent reviewers. Meta-analytic methods will be used to synthesize the data collected relating to the CHD outcomes with Cochrane Review Manager 5.3.
This systematic review aims to clarify whether panic disorder is associated with elevated risk for subsequent CHD. An evaluation of the etiological links between panic disorder with incident CHD might inform evidence-based clinical practice and policy concerning triaging chest pain patients, diagnostic assessment, and psychiatric intervention with panic disorder patients.
Systematic review registration
PROSPERO CRD42014014891.
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0026-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4376084  PMID: 25875199
Panic disorder; Panic attack; Anxiety disorder; Anxiety neurosis; Coronary heart disease; Myocardial infarction; Systematic review; Meta-analysis; Protocol; Etiology
6.  Childhood Internalizing and Externalizing Problems Predict the Onset of Clinical Panic Attacks over Adolescence: The TRAILS Study 
PLoS ONE  2012;7(12):e51564.
Panic attacks are a source of individual suffering and are an independent risk factor for later psychopathology. However, much less is known about risk factors for the development of panic attacks, particularly during adolescence when the incidence of panic attacks increases dramatically. We examined whether internalizing and externalizing problems in childhood predict the onset of panic attacks in adolescence.
This study is part of the TRacking Adolescents’ Individual Lives Survey (TRAILS), a Dutch longitudinal population cohort study (N = 1,584). Internalizing and Externalizing Problems were collected using the Youth Self-Report (YSR) and the parent-report Child Behavior Checklist (CBCL) at baseline (age 10–12). At age 18–20, DSM-IV defined panic attacks since baseline were assessed with the Composite International Diagnostic Interview (CIDI). We investigated whether early adolescent Internalizing and Externalizing Problems predicted panic attacks between ages 10–20 years, using survival analysis in univariate and multivariate models.
There were N = 314 (19.8%) cases who experienced at least one DSM-IV defined panic attack during adolescence and N = 18 (1.2%) who developed panic disorder during adolescence. In univariate analyses, CBCL Total Problems, Internalizing Problems and three of the eight syndrome scales predicted panic attack onset, while on the YSR all broad-band problem scales and each narrow-band syndrome scale predicted panic attack onset. In multivariate analyses, CBCL Social Problems (HR 1.19, p<.05), and YSR Thought Problems (HR 1.15, p<.05) and Social Problems (HR 1.26, p<.01) predicted panic attack onset.
Risk indicators of panic attack include the wide range of internalizing and externalizing problems. Yet, when adjusted for co-occurring problem behaviors, Social Problems were the most consistent risk factor for panic attack onsets in adolescence.
PMCID: PMC3520948  PMID: 23251576
7.  Panic, Suffocation False Alarms, Separation Anxiety and Endogenous Opioids 
This review paper presents an amplification of the suffocation false alarm theory (SFA) of spontaneous panic (Klein, 1993). SFA postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. That panic is distinct from Cannon’s emergency fear response and Selye’s General Alarm Syndrome is shown by the prominence of intense air hunger during these attacks. Further, panic sufferers have chronic sighing abnormalities outside of the acute attack. Another basic physiologic distinction between fear and panic is the counter-intuitive lack of hypothalamic-pituitary-adrenal (HPA) activation in panic. Understanding panic as provoked by indicators of potential suffocation, such as fluctuations in pCO2 and brain lactate, as well as environmental circumstances fits the observed respiratory abnormalities. However, that sudden loss, bereavement and childhood separation anxiety are also antecedents of “spontaneous” panic requires an integrative explanation. Because of the opioid system’s central regulatory role in both disordered breathing and separation distress, we detail the role of opioidergic dysfunction in decreasing the suffocation alarm threshold. We present results from our laboratory where the naloxone-lactate challenge in normals produces supportive evidence for the endorphinergic defect hypothesis in the form of a distress episode of specific tidal volume hyperventilation paralleling challenge-produced and clinical panic.
PMCID: PMC2325919  PMID: 17765379
Affective neuroscience; Endogenous opioids; Panic disorder; Respiratory physiology; Separation Anxiety
8.  The Role of Panic-fear in Comorbid Asthma and Panic Disorder 
Journal of anxiety disorders  2008;23(2):178-184.
We examined mediational models of panic-fear, panic disorder (PD), and asthma outcomes among adult asthma patients. PD was assessed by the Anxiety Disorders Interview Schedule. Twenty-one asthma-PD patients and 27 asthma-only patients completed spirometry and questionnaires. Asthma-PD patients reported greater illness-specific and generalized panic-fear than asthma-only patients, despite no differences in asthma severity or physical symptoms during asthma attacks. Illness-specific panic-fear mediated the relationship between PD and poorer health-related quality of life, including emotional disturbance due to asthma. Illness-specific panic-fear was associated with more primary care office visits for asthma. Asthma-PD patients reported greater irritability during asthma attacks than asthma-only patients. Generalized panic-fear was directly associated with restriction of activities due to asthma and use of rescue medication for asthma. Neither measure of panic-fear was associated with asthma severity. Panic-fear experienced during asthma attacks may be an important area to target for improving health-related quality of life among asthma-PD patients.
PMCID: PMC2661851  PMID: 18667290
asthma; generalized panic-fear; illness-specific panic-fear; panic disorder; quality of life
Nature medicine  2009;16(1):111-115.
Introductory paragraph
Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In subjects with panic disorder there is evidence of decreased central GABAergic activity as well as marked increases in autonomic and respiratory responses following intravenous infusions of 0.5M sodium lactate1–3. In an animal model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial/perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses4–9. The dorsomedial/perifornical hypothalamus is enriched in orexin (ORX, also known as hypocretin)-containing neurons10 that play a critical role in arousal10,11, vigilance10 and central autonomic mobilization12, all of which are key components of panic. Here, we demonstrate that activation of the ORX neurons is necessary for developing a panic-prone state in the animal model, and either silencing the hypothalamic ORX gene (Hcrt) product with RNA interference or systemic ORX1 antagonists blocks the panic responses. Moreover, we show that subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety, and that ORX antagonists constitute a potential novel treatment strategy for panic disorder.
PMCID: PMC2832844  PMID: 20037593
10.  Aversive imagery in panic disorder: Agoraphobia severity, comorbidity and defensive physiology 
Biological psychiatry  2011;70(5):415-424.
Panic is characterized as a disorder of interoceptive physiological hyperarousal, secondary to persistent anticipation of panic attacks. The novel aim of the present research was to investigate whether severity of agoraphobia within panic disorder covaries with the intensity of physiological reactions to imagery of panic attacks and other aversive scenarios.
A community sample of principal panic disorder (n=112; 41 without agoraphobia, 71 with agoraphobia) and control (n=76) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis oculi) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also measured.
Overall panic disorder patients exceeded controls in startle reflex and heart rate during imagery of standard panic attack scenarios, concordant with more extreme ratings of aversion and emotional arousal. Accounting for the presence of agoraphobia revealed that both panic disorder with and without situational apprehension showed the pronounced heart rate increases during standard panic attack imagery observed for the sample as a whole. In contrast, startle potentiation to aversive imagery was more robust in those without versus with agoraphobia. Reflex diminution was most dramatic in those with the most pervasive agoraphobia, coincident with the most extreme levels of comorbid broad negative affectivity, disorder chronicity, and functional impairment.
Principal panic disorder may represent initial, heightened interoceptive fearfulness and concomitant defensive hyperactivity, which through progressive generalization of anticipatory anxiety, ultimately transitions to a disorder of pervasive agoraphobic apprehension and avoidance, broad dysphoria and compromised mobilization for defensive action.
PMCID: PMC3152659  PMID: 21550590
imagery; anxiety; panic; agoraphobia; comorbidity; depression; anhedonia; anxiety sensitivity; chronicity; emotional reactivity; narrative imagery; diagnostic subtypes; psychophysiology; startle; heart rate; facial expressivity; skin conductance; corrugator; EMG; SCL
11.  Panic disorder in primary care: Comorbid psychiatric disorders and their persistence 
Although 70–80% of panic disorder patients use primary care to obtain mental health services, relatively few studies have examined panic patients in this setting. This study aimed to examine both the lifetime and current comorbid psychiatric disorders associated with panic disorder in primary care, the duration and severity of the disorder, and the sociodemographic factors associated with it.
Patients were screened for panic disorder. Panic disorder and the comorbid disorders were determined using the Structured Clinical Interview for DSM-IV Axis I and II.
Eight different health care centers in primary care in the city of Espoo.
Finnish-speaking, between 18 and 65 years of age.
Main outcome measures
Comorbid psychiatric disorders, the duration and severity of the disorder, and the sociodemographic factors.
A sample of 49 panic disorder patients and 44 patients with no current psychiatric diagnosis were identified; 98% of panic disorder patients had at least one comorbid lifetime DSM-IV Axis I disorder. Major depressive disorder and other anxiety disorders were most common comorbid disorders. Lifetime alcohol use disorders also showed marked frequency. Interestingly, the remission rates of alcohol use disorders were notable. The panic symptoms appeared to persist for years. Panic disorder was associated with low education and relatively low probability of working full time.
Also in primary care panic disorder is comorbid, chronic, and disabling. It is important to recognize the comorbid disorders. High remission rates of comorbid alcohol use disorders encourage active treatment of patients also suffering from these disorders.
PMCID: PMC3520420  PMID: 23113695
Comorbid disorders; Finland; general practice; panic disorder; primary care
12.  Recent Trends in the Incidence of Anxiety Diagnoses and Symptoms in Primary Care 
PLoS ONE  2012;7(8):e41670.
Anxiety is common, with significant morbidity, but little is known about presentations and recording of anxiety diagnoses and symptoms in primary care. This study aimed to determine trends in incidence and socio-demographic variation in General Practitioner (GP) recorded diagnoses of anxiety, mixed anxiety/depression, panic and anxiety symptoms.
Methodology/Principal Findings
Annual incidence rates of anxiety diagnoses and symptoms were calculated from 361 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2008, adjusted for year of diagnosis, gender, age, and deprivation. Incidence of GP recorded anxiety diagnosis fell from 7.9 to 4.9/1000PYAR from 1998 to 2008, while incidence of anxiety symptoms rose from 3.9 to 5.8/1000PYAR. Incidence of mixed anxiety/depression fell from 4.0 to 2.2/1000PYAR, and incidence of panic disorder fell from 0.9/1000PYAR in 1998 to 0.5/1000PYAR in 2008. All these entries were approximately twice as common in women and more common in deprived areas. GP-recorded anxiety diagnoses, symptoms and mixed anxiety/depression were commonest aged 45–64 years, whilst panic disorder/attacks were more common in those 16–44 years. GPs predominately use broad non-specific codes to record anxiety problems in the UK.
GP recording of anxiety diagnoses has fallen whilst recording of anxiety symptoms has increased over time. The incidence of GP recorded diagnoses of anxiety diagnoses was lower than in screened populations in primary care. The reasons for this apparent under-recording and whether it represents under-detection in those being seen, a reluctance to report anxiety to their GP, or a reluctance amongst GPs to label people with anxiety requires investigation.
PMCID: PMC3411689  PMID: 22870242
13.  Reducing the Symptomatology of Panic Disorder: The Effects of a Yoga Program Alone and in Combination with Cognitive-Behavioral Therapy 
Introduction: Yoga is a holistic system of different mind–body practices that can be used to improve mental and physical health. It has been shown to reduce perceived stress and anxiety as well as improve mood and quality of life. Research documenting the therapeutic benefits of yoga has grown progressively for the past decades and now includes controlled trials on a variety of mental health conditions such as depression, anxiety, and panic disorder.
Objectives: The primary goal of this study was to investigate the effects of yoga in patients suffering from panic disorder. We aimed at observing the efficacy of yoga techniques on reducing the symptomatology of panic disorder (anxiety and agoraphobia), compared to a combined intervention of yoga and psychotherapy.
Method: Twenty subjects previously diagnosed with panic disorder were selected. Subjects were randomly assigned to both experimental groups: Group 1 (G1-Yoga: 10 subjects) attended yoga classes and Group 2 (G2-CBT + Yoga: 10 subjects) participated in a combined intervention of yoga practice followed by a cognitive-behavioral therapy (CBT) session. Both interventions occurred weekly for 100 min and lasted 2 months. Subjects were evaluated two times during the study: pre-test and post-test. Psychometric tools included the Beck Anxiety Inventory (BAI), Hamilton Anxiety Rating Scale (HAM-A), The Panic Beliefs Inventory (PBI), and Body Sensations Questionnaire (BSQ).
Results: Statistical analysis showed significant reductions in anxiety levels associated with panic disorder (G1: BAI – p = 0.035, HAM-A – p = 0.000; G2: BAI – p = 0.002, HAM-A – p = 0.000), panic-related beliefs (G1: PBI – p = 0.000; G2: PBI – p = 0.000) and panic-related body sensations (G1: BSQ – p = 0.000; G2: BSQ – p = 0.000) both in G1 and G2. However, the combination of yoga and CBT (G2) showed even further reductions in all observed parameters (mean values).
Conclusion: This study observed significant improvement in panic symptomatology following both the practice of yoga and the combination of yoga and psychotherapy. While contemplative techniques such as yoga promote a general change in dealing with private events, CBT teaches how to modify irrational beliefs and specific cognitive distortions. The results observed in G2 might indicate that the techniques complemented each other, increasing the intervention efficacy. These findings are in agreement with many investigations found in the literature which observed improvements in different mental health parameters after the practice of contemplative techniques alone or combined to psychotherapy. Future research joining psychological and physiological variables could help better elucidate the mechanisms through which mind-body practices work to improve mental health.
PMCID: PMC4259001  PMID: 25538634
anxiety; cognitive-behavioral therapy; contemplative practice; panic disorder; yoga
14.  Fatigue and Circadian Activity Rhythms in Breast Cancer Patients Before and After Chemotherapy: A Controlled Study 
Fatigue (Abingdon, Eng. Print)  2013;1(1-2):12-26.
Breast cancer (BC) patients often experience cancer-related fatigue (CRF) before, during, and after their chemotherapy. Circadian rhythms are 24-hour cycles of behavior and physiology that are generated by internal pacemakers and entrained by zeitgebers (e.g., light). A few studies have suggested a relationship between fatigue and circadian rhythms in some clinical populations.
One hundred and forty-eight women diagnosed with stage I-III breast cancer and scheduled to receive at least four cycles of adjuvant or neoadjuvant chemotherapy, and 61 controls (cancer-free healthy women) participated in this study. Data were collected before (Baseline) and after four cycles of chemotherapy (Cycle-4). Fatigue was assessed with the Short Form of Multidimensional Fatigue Symptom Inventory (MFSI-SF); circadian activity rhythm (CAR) was recorded with wrist actigraphy (six parameters included: amplitude, acrophase, mesor, up-mesor, down-mesor and F-statistic). A mixed model analysis was used to examine changes in fatigue and CAR parameters compared to controls, and to examine the longitudinal relationship between fatigue and CAR parameters in BC patients.
More severe CRF (total and subscale scores) and disrupted CAR (amplitude, mesor and F-statistic) were observed in BC patients compared to controls at both Baseline and Cycle-4 (all p's<0.05); BC patients also experienced more fatigue and decreased amplitude and mesor, as well as delayed up-mesor time at Cycle-4 compared to Baseline (all p's<0.05). The increased total MFSI-SF scores were significantly associated with decreased amplitude, mesor and F-statistic (all p's<0.006).
CRF exists and CAR is disrupted even before the start of chemotherapy. The significant relationship between CRF and CAR indicate possible underlying connections. Re-entraining the disturbed CAR using effective interventions such as bright light therapy might also improve CRF.
PMCID: PMC3568994  PMID: 23412418
breast cancer; fatigue; circadian activity rhythm; chemotherapy
15.  Clinical Characteristics of the Respiratory Subtype in Panic Disorder Patients 
Psychiatry Investigation  2014;11(4):412-418.
Panic disorder has been suggested to be divided into the respiratory and non-respiratory subtypes in terms of its clinical presentations. The present study aimed to investigate whether there are any differences in treatment response and clinical characteristics between the respiratory and non-respiratory subtypes of panic disorder patients.
Among the 48 patients those who completed the study, 25 panic disorder patients were classified as the respiratory subtype, whereas 23 panic disorder patients were classified as the non-respiratory subtype. All patients were treated with escitalopram or paroxetine for 12 weeks. We measured clinical and psychological characteristics before and after pharmacotherapy using the Panic Disorder Severity Scale (PDSS), Albany Panic and Phobic Questionnaire (APPQ), Anxiety Sensitivity Index-Revised (ASI-R), State-Trait Anxiety Inventory (STAI-T, STAI-S), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D).
The prevalence of the agoraphobia was significantly higher in the respiratory group than the non-respiratory group although there were no differences in gender and medication between the two groups. The respiratory group showed higher scores on the fear of respiratory symptoms of the ASI-R. In addition, after pharmacotherapy, the respiratory group showed more improvement in panic symptoms than the non-respiratory group.
Panic disorder patients with the respiratory subtype showed more severe clinical presentations, but a greater treatment response to SSRIs than those with non-respiratory subtype. Thus, classification of panic disorder patients as respiratory and non-respiratory subtypes may be useful to predict clinical course and treatment response to SSRIs.
PMCID: PMC4225205  PMID: 25395972
Panic disorder; Selective Serotonin Reuptake Inhibitors; Clinical subtypes; Treatment outcome
16.  Autonomic Activation During Sleep in PTSD and Panic: A Mattress Actigraphic Study 
Biological psychiatry  2009;66(1):41-46.
While it has been reported that persons with posttraumatic stress disorder manifest tonic autonomic activation, the literature contains numerous counter-examples. In revisiting the question, this study employed a novel method of mattress actigraphy to unobtrusively estimate heart rate and respiratory sinus arrhythmia over multiple nights of sleep in the home.
Sleep cardiac autonomic status was estimated in four diagnostic groups, posttraumatic stress disorder, panic disorder, persons comorbid for both conditions, and controls. All 59 participants were community-residing non-veterans screened for sleep apnea and period leg movement disorder with polysomnography. Heart rate and respiratory sinus arrhythmia were calculated from the kinetocardiogram signal measured via accelerometers embedded in a mattress topper. Times in bed and asleep were also estimated. Per participant data were obtained from a median of 12 nights.
Both posttraumatic stress disorder and posttraumatic stress disorder/panic disorder comorbid groups exhibited significantly higher heart rates and lower respiratory sinus arrhythmia magnitudes than panic disorder participants and controls. Panic disorder participants were indistinguishable from controls. The PTSD-only group exhibited longer times in bed and longer times presumably asleep than the other three groups.
In this study, posttraumatic stress disorder but not panic disorder was associated with altered cardiac autonomic status during sleep. Among participants meeting criteria for PTSD alone, autonomic activation co-occurred with prolongation of actigraphic sleep.
PMCID: PMC2734329  PMID: 19232575
17.  Association Study between 5-HT1A Receptor Gene C(-1019)G Polymorphism and Panic Disorder in a Korean Population 
Psychiatry Investigation  2010;7(2):141-146.
Serotonergic dysfunction is quite evident in panic disorder. We investigated whether the C(-1019)G polymorphism of 5-HT1A receptor gene may play a role in the pathogenesis of panic disorder in a Korean population.
The 5-HT1A receptor genotype for the single nucleotide polymorphism (SNP) C(-1019)G was analyzed in 94 patients and 111 healthy controls. The severity of the patients' symptoms was examined using the Spielberger State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale (PDSS), Anxiety sensitivity index (ASI), Acute Panic Inventory (API) and Hamilton's Rating Scale for Anxiety (HAM-A).
The distribution of the genotypes of the C/G polymorphism did not differ significantly from those predicted by Hardy-Weinberg equilibrium in patients as well as the controls. No association between the C(-1019)G polymorphism and panic disorder was detected in either the allele frequency or genotype distribution. There was no significant association with genotype distribution in the panic disorder with agoraphobia. However, there was a significant difference of symptom severity between C/C, C/G, and G/G genotype or between C and G allele in panic disorder patients without agoraphobia. PDSS scores were significantly higher in subjects with the G/G genotype or with G allele in patients without agoraphobia, not in total patients or patients with agoraphobia.
Although there were no significant differences in the genotype and allele distributions, we found a significant association between panic symptom severity and the serotonin 1A receptor gene. This result suggests that the serotonin 1A receptor and serotonin may play a role in the pathogenesis of panic disorder.
PMCID: PMC2890869  PMID: 20577624
Panic disorder; Agoraphobia; Association; Polymorphism; 5-HT1A gene
18.  A prospective cohort study to refine and validate the Panic Screening Score for identifying panic attacks associated with unexplained chest pain in the emergency department 
BMJ Open  2013;3(10):e003877.
Panic-like anxiety (panic attacks with or without panic disorder), a highly treatable condition, is the most prevalent condition associated with unexplained chest pain in the emergency department. Panic-like anxiety may be responsible for a significant portion of the negative consequences of unexplained chest pain, such as functional limitations and chronicity. However, more than 92% of panic-like anxiety cases remain undiagnosed at the time of discharge from the emergency department. The 4-item Panic Screening Score (PSS) questionnaire was derived in order to increase the identification of panic-like anxiety in emergency department patients with unexplained chest pain.
Methods and analysis
The goals of this prospective cohort study were to (1) refine the PSS; (2) validate the revised version of the PSS; (3) measure the reliability of the revised version of the PSS and (4) assess the acceptability of the instrument among emergency physicians. Eligible and consenting patients will be administered the PSS in a large emergency department. Patients will be contacted by phone for administration of the criterion standard for panic attacks as well as by a standardised interview to collect information for other predictors of panic attacks. Multivariate analysis will be used to refine the PSS. The new version will be prospectively validated in an independent sample and inter-rater agreement will be assessed in 10% of cases. The screening instrument acceptability will be assessed with the Ottawa Acceptability of Decision Rules Instrument.
Ethics and dissemination
This study protocol has been reviewed and approved by the Alphonse-Desjardins research ethics committee. The results of the study will be presented in scientific conferences and published in peer-reviewed scientific journals. Further dissemination via workshops and a dedicated website is planned.
PMCID: PMC3808760  PMID: 24163208
Unexplained chest pain; Non-cardiac chest pain; Panic attacks; Panic disorder; Emergency medicine
Panic disorder is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as 0.5 M sodium lactate infusions. Although studied for four decades, the mechanism of lactate sensitivity in panic disorder has not been understood. The dorsomedial hypothalamus/perifornical region (DMH/PeF) coordinates rapid mobilization of behavioral, autonomic, respiratory and endocrine responses to stress, and rats with disrupted GABA inhibition in the DMH/PeF exhibit panic-like responses to lactate, similar to panic disorder patients. Utilizing a variety of anatomical and pharmacological methods, we provide evidence that lactate, via osmosensitive periventricular pathways, activates neurons in the compromised DMH/PeF, which relays this signal to forebrain limbic structures such as the bed nucleus of the stria terminalis to mediate anxiety responses, and specific brainstem sympathetic and parasympathetic pathways to mediate the respiratory and cardiovascular components of the panic-like response. Acutely restoring local GABAergic tone in the DMH/PeF blocked lactate induced panic-like responses. Autonomic panic-like responses appear to be a result of DMH/PeF-mediated mobilization of sympathetic responses (verified with atenolol) and resetting of the parasympathetically-mediated baroreflex. Based on our findings, DMH/PeF efferent targets such as the C1 adrenergic neurons, paraventricular hypothalamus and the central amygdala are implicated in sympathetic mobilization; the nucleus of the solitary tract is implicated in baroreflex resetting; and the parabrachial nucleus is implicated in respiratory responses. These results elucidate neural circuits underlying lactate induced panic-like responses and the involvement of both sympathetic and parasympathetic systems.
PMCID: PMC3065200  PMID: 18059441
panic; c-Fos; hypothalamus; GABA; anxiety; lactate; l-allylglycine
20.  New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray 
Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction.
PMCID: PMC3854168  PMID: 22437485
Panic; Animal model; Periaqueductal gray; Serotonin; Opioids
21.  Development of mental health first aid guidelines for panic attacks: a Delphi study 
BMC Psychiatry  2009;9:49.
Panic attacks are common, and while they are not life-threatening events, they can lead to the development of panic disorder and agoraphobia. Appropriate help at the time that a panic attack occurs may decrease the fear associated with the attack and reduce the risk of developing an anxiety disorder. However, few people have the knowledge and skills required to assist. Simple first aid guidelines may help members of the public to offer help to people who experience panic attacks.
The Delphi method was used to reach consensus in a panel of experts. Experts included 50 professionals and 6 people who had experience of panic attacks and were active in mental health advocacy. Statements about how to assist someone who is having a panic attack were sourced through a systematic search of both professional and lay literature. These statements were rated for importance as first aid guidelines by the expert and consumer panels and guidelines were written using the items most consistently endorsed.
Of 144 statements presented to the panels, 27 were accepted. These statements were used to develop the guidelines appended to this paper.
There are a number of actions which are considered to be useful for members of the public to do if they encounter someone who is having a panic attack. These guidelines will be useful in revision of curricula of mental health first aid programs. They can also be used by members of the public who want immediate information about how to assist someone who is experiencing panic attacks.
PMCID: PMC2739201  PMID: 19664244
22.  Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network 
Physiology & behavior  2012;107(5):733-742.
Although the hypothalamic orexin system is known to regulate appetitive behaviors and promote wakefulness and arousal (Sakurai, 2007), this system may also be important in adaptive and pathological anxiety/stress responses (Suzuki et al., 2005). In a recent study, we demonstrated that CSF orexin levels were significantly higher in patients experiencing panic attacks compared to non-panicking depressed subjects (Johnson et al., 2010). Furthermore, genetically silencing orexin synthesis or blocking orexin 1 receptors attenuated lactate-induced panic in an animal model of panic disorder. Therefore, in the present study, we tested if orexin (ORX) modulates the panic responses and brain pathways activated by two different panicogenic drugs.
We conducted a series of pharmacological, behavioral, physiological and immunohistochemical experiments to study the modulation by the orexinergic inputs of anxiety behaviors, autonomic responses, and activation of brain pathways elicited by systemic injections of anxiogenic/panicogenic drugs in rats.
We show that systemic injections of two different anxiogenic/panicogenic drugs (FG-7142, an inverse agonist at the benzodiazepine site of the GABAA receptor, and caffeine, a nonselective competitive adenosine receptor antagonist) increased c-Fos induction in a specific subset of orexin neurons located in the dorsomedial/ perifornical (DMH/PeF) but not the lateral hypothalamus. Pre-treating rats with an orexin 1 receptor antagonist attenuated the FG-7142-induced anxiety-like behaviors, increased heart rate, and neuronal activation in key panic pathways, including subregions of the central nucleus of the amygdala, bed nucleus of the stria terminalis, periaqueductal gray and in the rostroventrolateral medulla.
Overall, the data here suggest that the ORX neurons in the DMH/PeF region are critical to eliciting a coordinated panic responses and that ORX1 receptor antagonists constitute a potential novel treatment strategy for panic and related anxiety disorders. The neural pathways through which ORX1 receptor antagonists attenuate panic responses involve the extended amygdala, periaqueductal gray, and medullary autonomic centers.
PMCID: PMC3472124  PMID: 22554617
23.  Impact of Stressful Life Events on the Course of Panic Disorder in Adults a 
Journal of affective disorders  2011;134(1-3):373-376.
Panic Disorder with/without Agoraphobia (PD/PDA) is a prevalent anxiety disorder, associated with impairment in quality of life and functionality, as well as increased healthcare utilization. Extant research shows a relationship between stressful life events (SLEs) and the onset of panic attacks in adults who ultimately develop PD/PDA. However, limited attention has been paid to how SLEs might affect the severity of panic symptoms in individuals with PD/PDA. In this study, we examined the relationship between SLEs and panic symptom severity in adults with PD/PDA.
Four hundred-eighteen adults with PD/PDA from the Harvard/Brown Anxiety Research Program (HARP), a long-term prospective longitudinal observational multicenter study of adults with a current or past history of anxiety disorders were included in this study. We examined occurrence of SLEs and their impact on panic symptom severity 12-weeks pre- and post-SLE.
A time-slope effect showed that participants had worsened panic symptoms over the course of the 12-weeks after family/friends/household and work SLEs. That is, their symptoms worsened progressively after the event, rather than immediately thereafter (i.e., significant symptom change within the same week of the event).
The sample may not be representative of the general population.
These findings provide new insights into how SLEs affect panic symptoms in adults with PD/PDA in that household-related SLEs, such as serious family arguments, and work-related SLEs, such as being fired, put some adults at risk for worsened panic symptoms within 12-weeks of the event.
PMCID: PMC3170458  PMID: 21658775
Panic Disorder; Panic Disorder with Agoraphobia; Stressful Life Events
24.  Changes in cerebral blood flow after cognitive behavior therapy in patients with panic disorder: a SPECT study 
Inconsistent results continue to be reported in studies that examine the neural correlates of cognitive behavioral therapy (CBT) in patients with panic disorder. We examined the changes in regional cerebral blood flow (rCBF) associated with the alleviation of anxiety by CBT in panic patients.
The change in rCBF and clinical symptoms before and after CBT were assessed using single photon emission computed tomography and various clinical measures were analyzed.
Fourteen subjects who completed CBT showed significant improvements in symptoms on clinical measures, including the Panic and Agoraphobic Scale and the Anxiety Sensitivity Index-Revised. After CBT, increased rCBF was detected in the left postcentral gyrus (BA 43), left precentral gyrus (BA 4), and left inferior frontal gyrus (BA 9 and BA 47), whereas decreased rCBF was detected in the left pons. Correlation analysis of the association between the changes in rCBF and changes in each clinical measure did not show significant results.
We found changes in the rCBF associated with the successful completion of CBT. The present findings may help clarify the effects of CBT on changes in brain activity in panic disorder.
PMCID: PMC4000241  PMID: 24790449
single photon emission computed tomography (SPECT); anxiety; neural correlate; brain activity
25.  Co-Variation of Depressive Mood and Locomotor Dynamics Evaluated by Ecological Momentary Assessment in Healthy Humans 
PLoS ONE  2013;8(9):e74979.
Computerized ecological momentary assessment (EMA) is widely accepted as a “gold standard” method for capturing momentary symptoms repeatedly experienced in daily life. Although many studies have addressed the within-individual temporal variations in momentary symptoms compared with simultaneously measured external criteria, their concurrent associations, specifically with continuous physiological measures, have not been rigorously examined. Therefore, in the present study, we first examined the variations in momentary symptoms by validating the associations among self-reported symptoms measured simultaneously (depressive mood, anxious mood, and fatigue) and then investigated covariant properties between the symptoms (especially, depressive mood) and local statistics of locomotor activity as the external objective criteria obtained continuously. Healthy subjects (N = 85) from three different populations (adolescents, undergraduates, and office workers) wore a watch-type computer device equipped with EMA software for recording the momentary symptoms experienced by the subjects. Locomotor activity data were also continuously obtained by using an actigraph built into the device. Multilevel modeling analysis confirmed convergent associations by showing positive correlations among momentary symptoms. The increased intermittency of locomotor activity, characterized by a combination of reduced activity with occasional bursts, appeared concurrently with the worsening of depressive mood. Further, this association remained statistically unchanged across groups regardless of group differences in age, lifestyle, and occupation. These results indicate that the temporal variations in the momentary symptoms are not random but reflect the underlying changes in psychophysiological variables in daily life. In addition, our findings on the concurrent changes in depressive mood and locomotor activity may contribute to the continuous estimation of changes in depressive mood and early detection of depressive disorders.
PMCID: PMC3773004  PMID: 24058642

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