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Panic Disorder Name: Lina Tran 997481185 Group: Anxiety Disorders Turnitin ID: 240284346 Panic disorder (PD), one subtype of anxiety disorder, is characterized by the recurrent and spontaneous onset of panic attacks, or the psychosomatic symptoms of fear. This, accompanied by an intense anxiety towards a future episode, can be debilitating for those suffering from this illness and may result in the development of agoraphobia. Functional neuroimaging, as well as volumetric studies have implicated the abnormalities of multiple brain regions that are involved in the execution of fear response, internal sense of body states and anxiety including the periaqueductal gray, hypothalamus, amygdala, anterior cingulate cortex and insular cortex1. Abnormal activity within these structures and connections between them may be inappropriately activating fear circuits and eliciting the effects of the sympathetic division of the autonomic system observed in panic attacks2. Linkage studies have found heritability estimates of about 40%, but an encompassing common variant has yet to be found 3. The serotonergic 5-HT receptors have been known to be involved in PD, but more recent studies have been able to elucidate the nature of its role in inhibition of panic-attacks. Furthermore, gene variations in the neuropeptide cholecystokinin signaling, GABA dysfunction within the limbic system, and enhanced pH chemosensation in the brain may also underlie the neurobiology of panic disorder4. This indicates that there is also a strong environmental basis to the disorder, and research has shown factors such as childhood parental separation and life stress to be increasingly important components of the etiology of PD. The most effective treatment options available involve the coupling of cognitive behavioural therapy and pharmacological options such as SSRIs and benzodiazepines. A deeper understanding of the neurological causes of panic disorder can aid in the research and development of more effective agents with reduced sideeffect profiles and enhanced improvement times5. General Overview Symptoms and Diagnosis According to the DSM IV, panic disorder requires the presence of both repeated occurrence of spontaneous panic attacks where at least one of the attacks was followed by one month or more of one secondary symptoms of intense worry and anxiety, or a change in behaviour related to future attacks. The symptoms of a panic attack, show may be normal in isolation, but the occurrence of 4 or more in a progressive manner peaking within 10-20 minutes indicates a panic attack. These panic attacks must not be due directly to the use of drugs or medications. In many cases, individuals with panic disorder will go on to develop agoraphobia as they associate and avoid situations where they believe the potential exists for the onset of another panic attack, especially if they would not be able to escape (e.g. stores, public transportation, crowds etc.). Hence, panic disorder may be diagnosed as either with or without agoraphobia 6. Panic disorder patients exhibit a marked sensitivity to panic-provocation with chemical agents such as yohimbine, cholecystokinin, sodium lactate and carbon dioxide7,8. Epidemiology

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Panic disorders have a lifetime prevalence of 3-4% and every year, 7% of the population will experience a panic attack.9 The development of PD generally occurs between the age of 19-35yo, with an average onset of 25. Once it begins, symptoms and attacks will persist for at least one year in 92% of patients. Individuals with panic disorder are more likely to also suffer from other anxiety disorders such as generalized anxiety disorder or social phobia, depression and a particularly high cooccurrence of substance abuse. About 25% of panic cases also have alcohol abuse disorder, and this is believed to be in part due to patients attempting to self-medicate with the short-term anxiety reducing effects of alcohol10. A third of those diagnosed with panic disorder will also go on to develop agoraphobia.11 Etiology of Panic Disorder Genetics Linkage mapping and twin studies indicate a 40-50% heritable component to the variation observed developing panic disorder, which is higher than most other anxiety disorders12. it is not one common or rare variant polymorphism, but many that contribute to the heredity of PD. Genes implicated include 5-HT1 receptors, and CCK system genes. Recently, a transgenic mouse model of panic disorder has been established by overexpressing TrkC gene, a neurotrophin-3 receptor, presenting candidate genes for further study of the genetic elements of PD.13 Neuroanatomical Correlates It is believed that panic disorder arises from abnormal functioning of the fear network resulting in the maladaptive activation of the fear response which manifests as a panic attack. These fearful experiences may lead to a learned fear memory as demonstrated by avoidant behaviour following the onset of PD as well as the feelings of anxiety regarding future episodes. Research has also shown that panic disorder may involve deficits in the default-mode network, reduced activity of limbic structures including the right anterior cingulate cortex, amygdala, putamen, and parahippocampal gyrus and increased recruitment of the insula14. Amygdala The amygdala is a key structure of the limbic system with a role in the perception of fear, the fear response and learned fear memory and reduced activity of this region appears to contribute to panic disorder. Research finds individuals who report reduced panic attacks and symptoms following therapeutic intervention still demonstrate avoidant behaviour indicating that there is some artifact that remains as a learned fear memory which may provide an explanation for the effects of CBT15. Furthermore, volumetric MRI studies on individuals with panic disorder were found to have amygdalar atrophy16. It is hypothesized that the amygdala mediates the panic response through its output to the thalami, brainstem regions and activates the HPA axis, with observed changes in pituitary volume and levels of stress hormones following a panic attack1718. However, there is conflicting evidence regarding the involvement of the HPA axis and other regulatory pathways have been suggested, particularly through the PAG19.The amygdala may be activating panic circuits in response to rising levels in CO2 and changes in brain pH through pH sensitive ASIC1a ion channels that are required for contextual fear20. ASIC1a channels are numerous in the amygdala and knockout experiments demonstrated a resulting deficit in conditioned and unconditioned fear in mice, so the ability of this channel to detect local changes

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in pH and cause a response in the amygdala may be the basis for the fear conditioning of internal sensation that is believed to underlie the onset of panic attacks21. Periaqueductal Gray The periaqueductal gray (PAG) is a midbrain structure that has long been shown to be involved in approach and avoidance defense mechanisms22. Its role in the pathobiology of panic disorder has been described and may be the locus where panic attacks arise. Upon stimulation, either electrically or through chemical modulators, animal models have exhibited characteristics of a panic response.23 24 Local gray matter volume changes have also been observed in fMRI studies in individuals with panic disorder25. There is new evidence that the PAG may serve as the suffocation alarm system that has been believed to contribute to some of the features of panic disorder26. Over-activation of the PAG, and hence the putative alarm system, may explain the heightened sensitivity of pH, CO2 and lactate observed in panic patients27 (see CO2 and Anxiety Disorders for more information). Anterior Cingulate Cortex Panic disorder has been associated with a reduction in gray matter volume of the right ACC.28 The anterior cingulate cortex has a number of cognitive functions, playing roles in error detection, emotional modulation and interoceptive awareness and is activated during CCK-4 induced panic29 30. An enhanced awareness of somatic features of fear has believed to contribute to susceptibility to panic attacks31. These factors may provide an explanation for the seemingly sudden onset and the rapid crescendo of psychological stress involved in panic attacks. Individuals with damage to the anterior cingulate cortex, particularly the right dorsal ACC, have shown to subsequently acquire panic disorder or experience their first panic attack32. Cerebellum While it is well established that the cerebellum is responsible for balance, the integration of sensory inputs for co-ordinating fine movements and locomotion, evidence is accumulating that the cerebellum also has a role in cognitive functions such as impulsivity , and may contribute to mental disease333435. Inhibition of cerebellar nuclei was observed in a model of panic involving deep brain stimulation of the dorsolateral PAG that elicited panic-like symptoms36. It was shown that activation of deep cerebellar nuclei was significantly reduced after inducing a panic model of escape with the largest effect being in the vermis and fastigial nucleus . Moers-Hornikx et al. (2011) suggest that that deactivation results in dysfunction in selective attention, which in this case would be attention to physiological sensation, allowing for the misappropriated panic response. Neurotransmitters It is believed that dysregulation of various neurotransmitter systems in brain regions involving the emotional and physiological correlates of panic and acute anxiety are the basis of panic disorder. Neurotransmitters implicated include noradrenaline (especially in the locus coeruleus), endogenous opioids, serotonin, GABA, CCK and orexin. Inherited polymorphisms of genes encoding the regulation of these neurotransmitters are currently the basis of genetic studies attempting to parse out the various neurobiological systems that contribute to panic disorder37. Serotonin Serotonin has been implicated in panic disorder following research showing that drugs modulating the serotonin system were also able to reduce panic attacks 38. Serotonin in the brain

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stem and PAG reduce panic symptoms, but within the amygdala, it works to increase anticipatory anxiety, a critical component of panic disorder. There is an observed reduced functioning of serotonergic receptors within the raphe nucleus in panic patients.39 Gene length variation in the 5HT transporter seems to influence the intensity of the panic modeled response to dose-dependent CO2 inhalation40. While there is much evidence refuting a link between the previously implicated promoter region polymorphisms (5HTTLPR), recent research has shown an association between panic disorder and the serotonin transporter gene SLC6A4.4142 GABA Reduced GABAergic inhibitory activity in the PAG and brain regions projecting to the amygdala are believed to play a role in panic disorder. In rats with GABAergic dysfunction in loci related to panic-generation such as the amygdala, dorsomedial hypothalamus and PAG exhibited increased panic-like symptoms43. GABAa receptor activity may be a mediator of the panicolytic effect of the neurotrophin BDNF. Injection of BDNF into the dorsal PAG reduced the panic response and its mechanism of action appears to rely on an interaction of the BDNF-TrkB receptor and the GABAergic system. 44 CCK System Cholecystokinin-tetrapeptide (CCK-4) has been established in models of generating panic and genetic studies in CCK system genes, which identified new susceptibility alleles, indicate a role of the this molecule in panic disorder.45 Functional neuroimaging has demonstrated its effect on regions in the cerebral cortex, amygdala, hippocampus and brainstem, possibly as a neurotransmitter46. In general, various cytokine abnormalities have been implicated in panic disorder. It is hypothesized that the inflammatory state, indicated by an increase in proinflammatory cytokines in perhipheral blood, is associated with panic disorder to be due to the immense and repeated psychological and physiological stress that is caused by panic attacks.47 Orexin(Hypocretin) Recent findings suggest that the activation of the orexin (or hypocretin) system may be involved in the panic disorder including an increase of orexin in CSF of panic subjects 48. Orexin is a neurotransmitter deriving mainly from the lateral hypothalamic area and has roles in arousal, and respiration, two characteristic facets of the pathophysiology of panic disorder49,50. Johnson et al. (2010) demonstrate in rat panic models that silencing the orexin expressing neurons in the dorsomedial hypothalamus was able to supress the panic response to sodium lactate infusion. Furthermore, genetic studies have found an apparent relationship between the Val308lso polymorphism of the hypocretin receptor gene and increased vulnerability to developing anic disorder51. Environmental Factors Stressful psychological events such as early separation in childhood have been implicated in panic disorder. Childhood parental loss or seperation anxiety were antecedents to panic disorder development later on and often corresponded to an individual's first panic attack 52. Based on the diathesis-stress model, it is hypothesized that stressful environmental factors, such as stable maternal environment and early childhood separation interact with genetic predispositions and vulnerabilities, resulting in the development of panic disorder53. Treatment

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Psychotherapy Cognitive behavioural therapy has proven to be at least as effective as pharmaceutical methods of treatment and helps prevent a relapse following treatment significantly more so than patients only being treated with panicolytic drugs54. CBT may involve the learning of relaxation techniques, keeping a log of the thoughts and situations that arise concurrently with panic symptoms, and a gradual exposure to these situations that tend to cause anxiety or panic attacks in an attempt to extinguish the anxious behaviour (exposure therapy). The cognitive aspect of the therapy involves reducing the maladaptive cognitive patterns that exacerbate the anxiety experienced at the onset of a panic attack such as believing that they might die (thought restructuring). There is mounting evidence in favour of internet-based CBT for panic disorder, providing a more cost-effective route for treatment while maintaining the same rates of improvements55. Pharmacological Treatments Many biological treatments are available for panic disorder and among the widely used drugs, most are commonly classified as antidepressant medications. These include SSRIs, SNRis, tricyclics and benzodiazepines. The mechanism of their action is thought to improve the dysfunction of the neurotransmitter systems in brain regions involved in the manifestation of panic (see Neuroanatomical correlates above), but a deeper understanding of what physiological changes result has yet to be determined.56 SSRIs and SNRIs such as escitalopram, paroxetine and venlafaxine are generally the first treatment approach due to the reduced risk of addiction that is observed with use of benzodiazepines and more negative side-effects associated with tricyclics57. The combination of CBT and pharmacological agents, especially benzodiazepines, is more effective than either of the approaches alone, particularly in patients who do show little improvement with initial CBT treatment5859. New Lines of Treatment As a new approach to treatment, the role of exercise in improving mental health has been growing in recent years. Moderate/hard exercise improved levels of reduced BDNF as well as reducing panic symptoms during a CO2 challenge in panic patients though further research is necessary to determine the value of these findings in terms of treatment approach. 60 61. There is also evidence showing that breathing training aimed at raising and sustaining levels of pC02 results in reduced levels of panic symptoms related to interoceptive fear62.

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Neurowiki Final Summary and Assessment Panic Disorder from group Anxiety Disorders Name: Lina Tran Student # - 997481185 Initial Summary and Editing My neurowiki article was part of the Anxiety Disorders group and initially created on March 17th when I included my introduction, included a table of contents and played around with formatting options. During this time, the writing up of the various sections and reworking of content ensued, mostly offline. On March 26th I uploaded and worked with the formatting of the images I wanted to use in the neurowiki in order to break up what would otherwise be a wall of text. By April 1st, I had all my sections online. Alessia Dolcetti and Lisa Bilston provided feedback with regards to how I could interconnect my wiki to other wiki pages such as Default Mode Network, and the other anxiety disorder pages, as well as suggesting the referencing of my images which I promptly attended to and followed their suggestions. Following this, I continued to I also made sure to include links for each of my references to their respective PubMed page, and a full free article version was available, I linked directly to the pdf or html page and provided the PMC code in order to aid readers who had further interest in the studies that formed the basis of my wiki. And on the eve of April 5th, I attended to some last, but nonetheless helpful, comments and suggestions from Ho Wan, and Amy Chow to fix some technicalities, elaborate on AISC1a receptors, make clearer and some of the networks involved in panic disorder. Overall, many changes were made to improve the flow and succinctness of the academic content, as well as the aesthetic components of my neurowiki following my initial draft. Involvement in other Neurowikis During the course of the project, there was extensive messaging between my fellow Anxiety Disorder group members and I with regards to content suggestions, referencing, formatting of neurowikis and so forth for their respective pages. As the person charged with establishing the home page for Anxiety Disorders, I made sure that the page was up and running with our introduction, created pages for the other group members to start editing their own individual pages easily, provided a template for formatting their wikis and made sure they were tagged for easy access in the navigation bar. I was able to assist Soo Jung Lee with the formatting of her page, and tagging her groups pages, as well as fixing the tagging of some other groups pages such as Adult Neurogenesis/Neural Stemcells, and Default Mode Network who appeared to be having problems. I also initiated the use of the help pages that Professor Ju originally made available (which some very tech-savvy members were able to take advantage of and provided some very helpful articles for the class) by providing a link to a page with details for formatting and including some helpful tips. I created a tag in the navigation pane to bring together all the different help pages put them at the top so as to bring peoples attention to all the great help available that others were providing. I suggested an article on the significant role of primary cilia in adult neurogenesis in the dentate gyrus to the Adult Neural Stem Cells in Neurogenesis page as it appears to be an emerging field of research interest. I tried to provide academic input where I could alongside any technical help I could provide.

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Lim, L. W., Blokland, A., Visser-Vandewalle, V., Vlamings, R., Sesia, T., Steinbusch, H., Schruers, K., Griez, E., & Temel, Y. (2008). High-frequency stimulation of the dorsolateral periaqueductal gray and ventromedial hypothalamus fails to inhibit panic-like behaviour. Behav Brain Res. 193(2), 197203. 24 Schenberg, L.C., Pvoa, R.M., Costa, A.L., Caldellas, A.V., Tufik, S., Bittencourt, A.S. (2005). Functional specializations within the tectum defense systems of the rat. Neurosci Biobehav Rev, 29, 12791298. 25 see 26 Schimitel FG, de Almeida GM, Pitol DN, Armini RS, Tufik S, Schenberg LC. (2012). Evidence of a suffocation alarm system within the periaqueductal gray matter of the rat. Neuroscience, 200, 59-73. 27 Preter M, Lee SH, Petkova E, Vannucci M, Kim S, Klein DF. (2011). Controlled cross-over study in normal subjects of naloxone-preceding lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss. Psychol Med, 41, 385393. 28 Asami, T., Hayano, F., Nakamura, M., Yamasue, H., Uehara, K., Otsuka, T., Roppongi, T., Nihashi, N., Inoue, T., Hirayasu, Y. (2008). Anterior cingulate cortex volume reduction in patients with panic disorder. Psychiatry Clin Neurosci, 62(3), 322-30. 29 Ives-Deliperi, V. L., Solms, M., Meintjes, E. M. (2011). The neural substrates of mindfulness: an fMRI investigation. Soc Neurosci. 6(3), 231-42. 30 Eser, D., Leicht, G., Lutz, J., Wenninger, S., Kirsch, V., Schule, C., Karch, S., Baghai, T., Pogarell, O., Born, C., Rupprecht, R., Mulert, C. (2009). Functional neuroanatomy of CCK-4-induced panic attacks in healthy volunteers. Hum Brain Mapp, 30, 511522. 31 Acheson, D.T., Forsyth, J.P., Prenoveau, J.M., & Bouton, M.E. (2007). Interoceptive fear conditioning as a learning model of panic disorder: an experimental evaluation using 20% CO(2)-enriched air in a non-clinical sample. Behav Res Ther, 45(10), 2280-94. 32 Shinoura, N., Yamada, R., Tabei, Y., Otani, R., Itoi, C., Saito, S., & Midorikawa, A. (2011). Damage to the right dorsal anterior cingulate cortex induces panic disorder. J Affect Disord, 133(3), 569-72. 33 Moers-Hornikx, V.M., Sesia, T., Basar, K., Lim, L.W., Hoogland, G., Steinbusch, H.W., Gavilanes, D.A., Temel, Y., & Vles, J.S. (2009). Cerebellar nuclei are involved in impulsive behaviour. Behav Brain Res, 203(2), 256-63. 34 Filippi, R., Richardson, F.M., Dick, F., Leech, R., Green, D.W., Thomas, M.S., Price, & C.J. (2011). The right posterior paravermis and the control of language interference. J Neurosci, 31(29), 10732-40. 35 Baldacara, L., Borgio, J.G., Lacerda, A.L, & Jackowski, A.P. Cerebellum and psychiatric disorders . Rev Bras Psiquiatr 30(3), 2819. 36 Moers-Hornikx, V.M., Vles, J.S., Lim, L.W., Ayyildiz, M., Kaplan, S., Gavilanes, A.W., Hoogland, G., Steinbusch, H.W., & Temel, Y. (2011). Periaqueductal grey stimulation induced panic-like behaviour is accompanied by deactivation of the deep cerebellar nuclei. Cerebellum, 10(1), 61-9. PMC:3038216 37 See 9 38 Bell, C. J., & Nutt, D. J. (1998) Serotonin and panic. Br J Psychiatry, 172, 465-471. 39 Broocks, A., Meyer, T., Opitz, M., Bartmann, U., Hillmer-Vogel, U., George, A., Pekrun, G., Wedekind, D., Rther, E., Bandelow, B. (2003). 5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo. Eur Neuropsychopharmacol, 13(3), 153-64. 40 Schruers, K., Esquivel, G., van Duinen, M., Wichers, M., Kenis, G., Colasanti, A., Knuts, I., Goossens, L., Jacobs, N., van Rozendaal, J., Smeets, H., van Os, J., Griez, E. (2011). Genetic moderation of CO2-induced fear by 5-HTTLPR genotype. J Psychopharmacol. 25(1), 37-42. 41 Wachleski, C., Blaya, C., Salum, G.A., Vargas, V., Leistner-Segal, S., & Manfro, G.G. (2008). Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder. Neurosci Lett, 431(2), 173-8. 42 Strug, L.J., Suresh, R., Fyer, A.J., Talati, A., Adams, P.B., Li, W., Hodge, S.E., Gilliam, T.C., & Weissman, M.M. (2010). Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5HTTLPR). Mol Psychiatry, 15(2), 166-76. 43 Johnson, P.L., & Shekhar, A. (2006). Panic-Prone State Induced in Rats with GABA Dysfunction in the Dorsomedial Hypothalamus Is Mediated by NMDA Receptors. J Neurosci. 26(26), 7093-104. 44 Casarotto, P.C., de Bortoli, V.C., Corra, F.M., Resstel, & L.B., Zangrossi, H.(2010). Panicolytic-like effect of BDNF in the rat dorsal periaqueductal grey matter: the role of 5-HT and GABA. Int J Neuropsychopharmacol, 13, 573-82.

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Koefoed P, Woldbye DP, Hansen TO, Hansen ES, Knudsen GM, Bolwig TG, Rehfeld JF. (2010). Gene variations in the cholecystokinin system in patients with panic disorder. Psychiatr Genet, 20(2), 59-64. 46 See 24 47 Hoge, E.A., Brandstetter, K., Moshier, S., Pollack, M.H., Wong, K. K., & Simon, N.M. (2009). Broad Spectrum of Cytokine Abnormalities in Panic Disorder and Posttraumatic Stress Disorder. Depress Anxiety, 26, 447-55. 48 Johnson, P., Truitt, W., Fitz, S., Minick, P., Dietrich, A., Sanghani, S., Traskman-Bendz, L., Goddar A. W., Brundin, L., & Shekhar, A. (2010). A Key Role of Orexin in Panic. Nature Medicine, 16(1), 111-6. 49 Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deisseroth, K., & de Lecea, L. (2007). Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature, 450(7168), 420-4. 50 Kuwaki, T., Zhang, W. (2010). Orexin neurons as arousal-associated modulators of central cardiorespiratory regulation. (2010). Respir Physiol Neurobiol, 174(1-2), 43-54. 51 Annerbrink, K., Westberg, L., Olsson, M., Andersch, S., Sjdin, I., Holm, G., Allgulander, C., Eriksson, E. (2011). Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene. Psychiatr Genet 21(2), 85-9. 52 Preter, M., & Klein, D. F. (2008) Panic, Suffocation False Alarms, Separation Anxiety and Endogenous Opioids. Prog Neuropsychopharmacol Biol Psychiatry, 32(3), 603-12. 53 D'Amato, F.R., Zanettini, C., Lampis, V., Coccurello, R., Pascucci, T., Ventura, R., Puglisi-Allegra, S., Spatola, C.A., Pesenti-Gritti, P., Oddi, D., Moles, A., & Battaglia, M. (2011). Unstable maternal environment, separation anxiety, and heightened CO2 sensitivity induced by gene-by-environment interplay. PLoS One, 6(4), 18637. 54 Barlow, D.h., Gorman, J. M., Shear, M. K., & Woods, S. W. (2000). Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Journal of the American Medical Association, 283, 2529-36. 55 Bergstrm, J., Andersson, G., Ljtsson, B., Rck, C., Andrewitch, S., Karlsson, A., Carlbring, P., Andersson, E., & Lindefors, N. (2010). Internet-versus group-administered cognitive behaviour therapy for panic disorder in a psychiatric setting: a randomised trial. BMC Psychiatry. 10, 54. 56 Morilak, D.A., & Frazer, A. (2004). Antidepressants and brain monoaminergic systems:a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychopharmacol, 7, 193218. 57 See 4 58 Kampman, M.,Keijsers, G.P., Hoogduin, C.A., & Hendriks, G.J. (2002). A randomized, double-blind, placebocontrolled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. J Clin Psychiatry, 63(9):772-7. 59 Hofmann, S.G., Sawyer, A.T., Korte, K.J., & Smits, J.A. (2009 ). Is it Beneficial to Add Pharmacotherapy to Cognitive-Behavioral Therapy when Treating Anxiety Disorders? A Meta-Analytic Review. Int J Cogn Ther, 2(2):16075. 60 Strhle, A., Stoy, M., Graetz, B., Scheel, M., Wittmann, A., Gallinat, J., Lang, U.E., Dimeo, F., & Hellweg, R. (2010). Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder. Psychoneuroendocrinology, 35(3), 364-8. 61 Esquivel, G., Dandachi, A., Knuts, I., Goossens, L., Griez, E., & Schruers, K. (2011). Effects of acute exercise on CO(2) -induced fear. Depress Anxiety, 0, 1-4. 62 Meuret, A.E., Rosenfield, D., Hofmann, S.G., Suvak, M.K., & Roth, W.T. (2009). Changes in respiration mediate changes in fear of bodily sensations in panic disorder. J Psychiatr Res, 43(6), 63441.