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1.  Duloxetine in panic disorder with somatic gastric pain 
Panic disorder is the most common type of anxiety disorder, and its most common expression is panic attacks characterized with sudden attacks of anxiety with numerous symptoms, including palpitations, tachycardia, tachypnea, nausea, and vertigo: ie, cardiovascular, gastroenterologic, respiratory, and neuro-otologic symptoms. In clinical practice, panic disorder manifests with isolated gastroenteric or cardiovascular symptoms, requiring additional clinical visits after psychiatric intervention. The first-line treatment for anxiety disorders, and in particular for panic disorder, is the selective serotonin reuptake inhibitors. However, these drugs can have adverse effects, including sexual dysfunction, increased bodyweight, and abnormal bleeding, that may be problematic for some patients. Here we report the case of a 29-year-old Caucasian woman affected by panic disorder with agoraphobia who was referred to our clinic for recurrent gastroenteric panic symptoms. The patient reported improvement in her anxiety symptoms and panic attacks while on a selective serotonin reuptake inhibitor, but not in her gastric somatic problems, so the decision was taken to start her on duloxetine, a serotonin-norepinephrine reuptake inhibitor. After 6 months of treatment, the patient achieved complete remission of her gastric and panic-related symptoms, and was able to stop triple gastric therapy. Other authors have hypothesized and confirmed that duloxetine has greater initial noradrenergic effects than venlafaxine and is effective in patients with panic disorder. This case report underscores the possibility of tailoring therapeutic strategies for the gastroenteric expression of panic disorder.
doi:10.2147/NDT.S35922
PMCID: PMC3842215  PMID: 24294001
anxiety disorder; panic attacks; palpitations; tachycardia; tachypnea; nausea; vertigo
2.  THE PANIC ATTACK–PTSD MODEL: APPLICABILITY TO ORTHOSTATIC PANIC AMONG CAMBODIAN REFUGEES 
Cognitive behaviour therapy  2008;37(2):101-116.
This article examines the ability of the “Panic Attack–PTSD Model” to predict how panic attacks are generated and how panic attacks worsen posttraumatic stress disorder (PTSD). The article does so by determining the validity of the Panic Attack–PTSD Model in respect to one type of panic attacks among traumatized Cambodian refugees: orthostatic panic (OP) attacks, that is, panic attacks generated by moving from lying or sitting to standing. Among Cambodian refugees attending a psychiatric clinic, we conducted two studies to explore the validity of the Panic Attack–PTSD Model as applied to OP patients, meaning patients with at least one episode of OP in the previous month. In Study 1, the “Panic Attack–PTSD Model” accurately indicated how OP is seemingly generated: among OP patients (N = 58), orthostasis-associated flashbacks and catastrophic cognitions predicted OP severity beyond a measure of anxious–depressive distress (SCL subscales), and OP severity significantly mediated the effect of anxious–depressive distress on CAPS severity. In Study 2, as predicted by the Panic Attack–PTSD Model, OP had a mediational role in respect to the effect of treatment on PTSD severity: among Cambodian refugees with PTSD and comorbid OP who participated in a CBT study (N = 56), improvement in PTSD severity was partially mediated by improvement in OP severity.
doi:10.1080/16506070801969062
PMCID: PMC2755517  PMID: 18470741
stress disorder; posttraumatic; panic disorder; panic attack; flashbacks; catastrophic cognitions; Cambodian refugees; orthostatic intolerance
3.  Panic Disorder Among Cambodian Refugees Attending a Psychiatric Clinic 
General hospital psychiatry  2000;22(6):437-444.
This study surveys Khmer refugees attending two psychiatric clinics to determine both the prevalence of panic disorder as well as panic attack subtypes in those suffering panic disorder. A culturally valid adaptation of the SCID-panic module, the Cambodian Panic Disorder Survey (CPDS), was administered to 89 consecutive Cambodian refugees attending these psychiatric clinics. Utilizing culturally sensitive panic probes, the CPDS provides information regarding both the presence of panic disorder and panic-attack subtypes during the month prior to interview. Of 89 patients surveyed at two psychiatric clinics, 53 (60%) currently suffered panic disorder. Among the 53 patients suffering panic disorder, the most common panic attack subtypes during the previous month were the following: “sore neck” [51% of the 53 panic disorder patients (PDPs)], orthostatic dizziness (49% of PDPs), gastro-intestinal distress (26% of PDPs), effort induced (21% of PDPs), olfactory induced (21% of PDPs), and “while-sitting dizziness” (16% of PDPs).
PMCID: PMC2749726  PMID: 11072060
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.
Background
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.
Methods
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).
Results
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.
Conclusion
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
ClinicalTrials.gov Identifier: NCT100457106
doi:10.1186/1471-244X-9-25
PMCID: PMC2696444  PMID: 19470174
5.  Overgeneralization of Conditioned Fear as a Pathogenic Marker of Panic Disorder 
Objective
Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear.
Method
Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG).
Results
Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity.
Conclusions
The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.
doi:10.1176/appi.ajp.2009.09030410
PMCID: PMC2806514  PMID: 19917595
6.  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.
doi:10.1016/j.physbeh.2012.03.016
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
7.  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.
doi:10.1891/0889-8391.25.1.61
PMCID: PMC3170754  PMID: 21915160
smoking; alcohol; panic attacks; comorbidity
8.  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.
doi:10.1590/S0100-879X2012007500036
PMCID: PMC3854168  PMID: 22437485
Panic; Animal model; Periaqueductal gray; Serotonin; Opioids
9.  Panic disorder among Vietnamese refugees attending a psychiatric clinic: Prevalence and subtypes 
General hospital psychiatry  2001;23(6):337-344.
This study surveys Vietnamese refugees attending two psychiatric clinics to determine both the prevalence of panic disorder (PD) as well as panic attack subtypes in those suffering PD. A culturally valid adaptation of the SCID-panic module (the Vietnamese Panic Disorder Survey or VPDS) was administered to 100 Vietnamese refugees attending two psychiatric clinics. Utilizing culturally sensitive panic probes, the VPDS provides information regarding both the presence of PD and panic attack subtypes during the month prior to interview. Of 100 patients surveyed, 50 (50%) currently suffered PD. Among the 50 patients suffering PD, the most common panic attack subtypes during the previous month were the following: “orthostatic dizziness” (74% of the 50 panic disorder patients [PDPs]), headache (50% of PDPs), wind-induced/temperature-shift-induced (24% of PDPs), effort-induced (18% of PDPs), gastro-intestinal (16% of PDPs), micturition-induced (8% of PDPs), out-of-the-blue palpitations (24% of PDPs), and out-of-the-blue shortness of breath (16% of PDPs). Five mechanisms are adduced to account for this high PD prevalence as well as the specific profile of subtypes: 1) a trauma-caused panic attack diathesis; 2) trauma-event cues; 3) ethnic differences in physiology; 4) catastrophic cognitions generated by cultural syndromes; and 5) a modification of Clark’s spiral of panic.
PMCID: PMC2749719  PMID: 11738465
Vietnamese refugees; Panic disorder; Panic disorder subtypes; Trauma; Catastrophic cognitions
10.  NEURAL PATHWAYS UNDERLYING LACTATE INDUCED PANIC 
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.
doi:10.1038/sj.npp.1301621
PMCID: PMC3065200  PMID: 18059441
panic; c-Fos; hypothalamus; GABA; anxiety; lactate; l-allylglycine
11.  Cognitive behavior therapy in the treatment of panic disorder 
Indian Journal of Psychiatry  2009;51(2):108-116.
Background:
Comprehensive cognitive behavior therapies have been proved to be more effective than behavioral interventions. However, the efficacy of CBT is not studied in the Indian context and also, the amount of change brought about by CBT is not known. Aims: This study aims to examine the efficacy of cognitive behavioral intervention (CBI) in the treatment of panic disorder. Our specific objectives were to assess the effectiveness of CBI in reducing symptom severity as well as cognitions related to panic and panic-related behaviors. Design: The study adopted a two-group comparison with pre- and postassessments design.
Materials and Methods:
The sample consisted of 30 patients sequentially allotted to the CBI (n = 15) and behavioral intervention (BI, n = 15) groups. Assessment was done using a semistructured interview schedule, panic disorder severity scale, Texas panic attack record form, Anxiety Sensitivity Index, Agoraphobic cognitions questionnaire, Behavioral avoidance checklist, and Panic appraisal inventory. The CBI group was provided with comprehensive cognitive behavior therapy and the BI group with psycho-education and applied relaxation.
Results:
CBI was found to be superior to BI in the reduction of panic symptoms, behavioral avoidance, safety behaviors, and cognitions. A large percentage of the CBI group patients met the criteria for clinically significant change with a large magnitude of change.
Conclusion:
Multicomponent CBI is superior to BI in terms of the amount of change it brings about with respect to panic symptoms, avoidance, safety behaviors, and cognitions.
doi:10.4103/0019-5545.49450
PMCID: PMC2755166  PMID: 19823629
Clinically significant change; magnitude of change; multicomponent cognitive behavioral intervention
12.  Fear of memories: the nature of panic in posttraumatic stress disorder 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.19084.
Background
Although there is increasing evidence that panic attacks are common in posttraumatic stress disorder (PTSD), little is known if posttraumatic panic is comparable to panic attacks observed in panic disorder (PD).
Objective
This study examined the cognitive responses to panic attacks in participants with PD and PTSD.
Method
Participants with PD (n=22) and PTSD (n=18) were assessed on the Anxiety Disorder Interview Schedule for DSM-IV and subsequently administered the Agoraphobic Cognitions Questionnaire and a measure of fears related to trauma memories.
Results
Although participants did not differ in terms of catastrophic appraisals about somatic sensations, PTSD participants were more likely to experience fears about trauma memories and being harmed by trauma again during their panic attacks than PD participants.
Conclusions
These findings suggest that although PTSD participants fear somatic outcomes during panic attacks, their panic attacks are distinguished by a marked fear of trauma memories.
doi:10.3402/ejpt.v3i0.19084
PMCID: PMC3488113  PMID: 23130094
Panic attack; posttraumatic stress disorder; panic disorder; trauma memories
13.  The Genetic Basis of Panic Disorder 
Journal of Korean Medical Science  2011;26(6):701-710.
Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.
doi:10.3346/jkms.2011.26.6.701
PMCID: PMC3102861  PMID: 21655053
Panic Disorder; Genetics; Genome-Wide Association Study; Polymorphism
14.  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.
Introduction
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.
doi:10.1136/bmjopen-2013-003877
PMCID: PMC3808760  PMID: 24163208
Unexplained chest pain; Non-cardiac chest pain; Panic attacks; Panic disorder; Emergency medicine
15.  The Weight of Cognitions in Panic: The Link between Misinterpretations and Panic Attacks 
PLoS ONE  2013;8(8):e70315.
In cognitive theory it is hypothesized that panic attacks are provoked by catastrophic misinterpretations of bodily sensations. The aim of the present study was to investigate the ability of associated word pairs referring to catastrophic thinking (e.g. palpitations-heart attack) in producing panic attacks. Patients with PD (n = 20), patients with mixed anxiety disorders (n = 20), and a healthy control group (n = 30) participated in the present study. To enhance ecological validity we first conducted a stimulus validation experiment. Subsequently, nine suitable panic and neutral word pairs were presented in block to the participants. Anxiety levels were assessed before and after the presentation. PD patients were more anxious when reading these word pairs, compared to neutral word pairs. However, none of the participants experienced a panic attack upon reading the word pairs. From the present results it seems that catastrophic thinking is rather related to the anticipatory anxiety for panic attacks, but not necessarily with the occurrence of the panic attacks themselves.
doi:10.1371/journal.pone.0070315
PMCID: PMC3734098  PMID: 23940559
16.  Development of mental health first aid guidelines for panic attacks: a Delphi study 
BMC Psychiatry  2009;9:49.
Background
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.
Methods
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.
Results
Of 144 statements presented to the panels, 27 were accepted. These statements were used to develop the guidelines appended to this paper.
Conclusion
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.
doi:10.1186/1471-244X-9-49
PMCID: PMC2739201  PMID: 19664244
17.  A KEY ROLE FOR OREXIN IN PANIC ANXIETY 
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.
doi:10.1038/nm.2075
PMCID: PMC2832844  PMID: 20037593
18.  Somatic panic-attack equivalents in a community sample of Rwandan widows who survived the 1994 genocide 
Psychiatry research  2003;117(1):1-9.
The present study is the first to attempt to determine rates of panic attacks, especially ‘somatically focused’ panic attacks, panic disorder, symptoms of post-traumatic stress disorder (PTSD), and depression levels in a population of Rwandans traumatized by the 1994 genocide. The following measures were utilized: the Rwandan Panic-Disorder Survey (RPDS); the Beck Depression Inventory (BDI); the Harvard Trauma Questionnaire (HTQ); and the PTSD Checklist (PCL). Forty of 100 Rwandan widows suffered somatically focused panic attacks during the previous 4 weeks. Thirty-five (87%) of those having panic attacks suffered panic disorder, making the rate of panic disorder for the entire sample 35%. Rwandan widows with panic attacks had greater psychopathology on all measures. Somatically focused panic-attack subtypes seem to constitute a key response to trauma in the Rwandan population. Future studies of traumatized non-Western populations should carefully assess not only somatoform disorder but also somatically focused panic attacks.
PMCID: PMC2772881  PMID: 12581815
Panic disorder; Stress disorders; post-traumatic; Depression; Rwanda; Holocaust
19.  Panic following trauma: the etiology of acute posttraumatic arousal 
Journal of anxiety disorders  2004;18(2):193-210.
Two studies examined the contributing factors for panic symptoms following trauma. In Study 1, survivors of sexual and nonsexual assaults (N = 105) were assessed at 2 weeks postcrime. Prior trauma, psychiatric history, crime characteristics, and peritraumatic dissociation were assessed. Posttraumatic panic was modestly predicted by childhood sexual abuse (CSA) experiences, a history of Anxiety and Depression, and peritraumatic dissociation. Childhood physical abuse (CPA), Adult Victimization, crime variables, and a prior history of Substance Use disorders and posttraumatic stress disorder (PTSD) were not implicated. In Study 2, the role of peritraumatic panic in predicting later arousal was also examined in a similar sample who were assessed within 6 weeks of their trauma (N = 93). Presence of significant arousal during trauma predicted frequency of posttrauma panic attacks, but not its severity. In contrast to Study 1, prior history of PTSD, perception of life threat, and the index trauma being a sexual assault all predicted posttrauma panic, whereas prior trauma exposure and depression did not. These findings are discussed in terms of cognitive and arousal factors that may influence posttrauma panic.
doi:10.1016/S0887-6185(02)00290-6
PMCID: PMC2967764  PMID: 15033216
Trauma; Panic; PTSD; Assault; Physiological arousal
20.  Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network 
Physiology & behavior  2012;107(5):733-742.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.physbeh.2012.04.016
PMCID: PMC3472124  PMID: 22554617
21.  Familial Aggregation of Panic Disturbances in Parkinson’s Disease 
Panic disorder has an elevated prevalence in Parkinson’s disease (PD). To explore the basis for this co-occurrence, the familial aggregation of panic disorder was examined in patients with PD. Probands and relatives of patients with PD and panic disorder (PD-PANIC; N=20, N=115) and control probands with PD and no active psychiatric illness (PD-NA; N=17, N=108) were interviewed by phone, using a structured interview to determine panic status. Lifetime prevalence of panic and “panic-like” disorders was higher in PD-PANIC than in PD-NA relatives. Panic and “panic-like” disorders are familial disorders in PD.
doi:10.1176/appi.neuropsych.23.4.417
PMCID: PMC3547673  PMID: 22231313
22.  Controlled comparison of the characteristics of patients with panic disorder. 
BACKGROUND. Increased general practice attendance rates have been associated with the diagnosis of mental illness but panic disorder has not been specifically investigated in this respect. In addition, studies have failed adequately to assess type and frequency of secondary care referral and patterns of psychotropic prescription in patients with panic disorder in relation to matched controls. AIM. This study set out to compare subjects with panic disorder with age and sex matched controls on measures of general practice consultation rate; psychotropic and non-psychotropic drug use; referral to secondary care, laboratory and radiological tests and hospital admissions; history of illness and complaints; and psychiatric comorbidity. METHOD. The study was carried out in nine practices in the Forth Valley area. One hundred patients with panic disorder, previously diagnosed using DSM III-R criteria, were identified and matched by age and sex with controls. Data were collected by review of general practice case notes. RESULTS. Subjects with panic disorder had significantly higher rates of general practice consultation over the 10 year period prior to DSM III-R diagnosis of panic disorder than controls. Subjects with panic disorder had also been prescribed a significantly greater number of psychotropic and non-psychotropic medications over this period, had had more secondary care investigations and had higher rates of mainly minor illness and related complaints than controls. High comorbidity of panic disorder with depression which had been diagnosed over the 10 year period prior to DSM III-R diagnosis of panic disorder was found. CONCLUSION. The results of this study describe a population of subjects with panic disorder who are long-term heavy users of primary care services. The results also suggest an association between panic disorder and both minor illness and psychiatric comorbidity over the 10 year period prior to DSM III-R diagnosis of panic disorder.
PMCID: PMC1238951  PMID: 8068393
23.  The Experience of Panic Symptoms across Racial Groups in a Student Sample 
Journal of anxiety disorders  2010;24(8):873-878.
While there is general agreement that, across cultures, panic disorder appears to be characterized by sudden onset of bodily sensations, such as dizziness and heart palpitations, followed by catastrophic misinterpretations of these symptoms, there remains a need for research investigating ethnic/cultural differences in the experience of panic attacks. In addition to investigating ethnic differences in the experience of panic, it is important to assess whether increased endorsement of panic symptoms translates into increased dysfunction. The present study investigated differences in the experience of panic attacks and examined the relation between symptom endorsement and overall distress and impairment in a large multiracial/ethnic student population. Preliminary analyses indicated that although overall endorsement of panic symptoms was similar across groups, differences did emerge on specific symptoms. Participants identifying as Asian tended to endorse symptoms such as dizziness, unsteadiness, choking, and feeling terrified more frequently than those identifying as Caucasian, and individuals identifying as African American reported feeling less nervous than those identifying as Caucasian. Participants of Hispanic/Latino(a) descent showed no differences from any other group on symptom endorsement. Panic symptom severity was not found to differ across racial/ethnic groups; however, the correlation between panic symptoms and panic severity was stronger for Asian and Caucasian participants than for African Americans. These results suggest that symptoms of panic may be experienced differently across racial/ethnic groups, and highlight the need for clinicians and researchers to assess panic symptoms within the context of culture.
doi:10.1016/j.janxdis.2010.06.010
PMCID: PMC2956784  PMID: 20621442
24.  The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders 
Journal of Neural Transmission  2008;116(6):649-657.
Recent evidence suggests that the GABA transporter 1 (GAT-1; SLC6A1) plays a role in the pathophysiology and treatment of anxiety disorders. In order to understand the impact of genetic variation within SLC6A1 on pathological anxiety, we performed a case–control association study with anxiety disorder patients with and without syndromal panic attacks. Using the method of sequential addition of cases, we found that polymorphisms in the 5′ flanking region of SLC6A1 are highly associated with anxiety disorders when considering the severity of syndromal panic attacks as phenotype covariate. Analysing the effect size of the association, we observed a constant increase in the odds ratio for disease susceptibility with an increase in panic severity (OR ~ 2.5 in severely affected patients). Nominally significant association effects were observed considering the entire patient sample. These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety and highlight GAT-1 as a promising target for treatment of anxiety disorders with panic symptoms.
Electronic supplementary material
The online version of this article (doi:10.1007/s00702-008-0075-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00702-008-0075-y
PMCID: PMC2694916  PMID: 18607529
GAT-1; Single nucleotide polymorphisms; Anxiety disorders and panic; Sequential addition of cases; GABA system genetics
25.  Carbon Dioxide Provocation of Anxiety and Respiratory Response in Bipolar Disorder 
Journal of affective disorders  2006;99(1-3):45-49.
Background
Frequent bipolar/panic comorbidity implies bipolar individuals may experience CO2-provoked anxiety and changes in respiratory patterns similar to those experienced by individuals with panic disorder.
Methods
16 euthymic bipolar individuals breathed air and air combined with 5% CO2 for 15 minutes each. Respiratory and subjective anxiety measures were collected.
Results
On CO2 subjects were more anxious and breathed more deeply and rapidly than with air; the degree of increase in anxiety attributable to CO2 was directly correlated with the degree of increase in minute ventilation. Five individuals were assessed as having a panic attack. Panic response to CO2 was predicted by the degree of anxiety experienced with air alone.
Conclusions
Comparison with the results of similar panic studies shows bipolar disorder is associated with enhanced respiratory response to CO2. Hypersensitivity to CO2 among bipolar individuals suggests a possible pathological mechanism common to both bipolar and panic disorders. These preliminary data support the expanded application of CO2 challenges in bipolar subjects.
doi:10.1016/j.jad.2006.08.029
PMCID: PMC1850806  PMID: 17007935
Affective disorders; psychophysiology; panic disorder; hypercapnia; hyperventilation

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