Panic Disorder with Agoraphobia from a Behavioral Neuroscience

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Psychophysiology, 53 (2016), 312–322. Wiley Periodicals, Inc. Printed in the USA. Copyright VC 2016 Society for Psychophysiological Research DOI: 10.1111/psyp.12553 Panic disorder with agoraphobia from a behavioral neuroscience perspective: Applying the research principles formulated by the Research Domain Criteria (RDoC) initiative

ALFONS O. HAMM,a* JAN RICHTER,a* CHRISTIANE PANE-FARR E, a DORTE WESTPHAL,b HANS-ULRICH WITTCHEN,b ANNA N. VOSSBECK-ELSEBUSCH,c ALEXANDER L. GERLACH,d ANDREW T. GLOSTER,e ANDREAS STROHLE,€ f THOMAS LANG,g TILO KIRCHER,h ANTJE B. M. GERDES,i GEORG W. ALPERS,i ANDREAS REIF,j AND JURGEN€ DECKERTk aDepartment of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany bInstitute of Clinical Psychology and Psychotherapy, Technische Universit€at Dresden, Dresden, Germany cDepartment of Clinical Psychology and Psychotherapy, University of M€unster, M€unster, Germany dDepartment of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany eDepartment of Psychology, University of Basel, Basel, Switzerland fDepartment of Psychiatry and Psychotherapy, Charite-Universit€atsmedizin, Berlin, Germany gChristoph-Dornier Foundation for Clinical Psychology, Bremen, Germany hDepartment of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany iDepartment Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany jDepartment of Psychiatry, Psychosomatics, and Psychotherapy, University of Frankfurt, Frankfurt, Germany kDepartment of Psychiatry, Psychosomatics, and Psychotherapy, University of W€urzburg, W€urzburg, Germany

Abstract In the current review, we reconceptualize a categorical diagnosis—panic disorder and agoraphobia—in terms of two constructs within the domain “negative valence systems” suggested by the Research Domain Criteria initiative. Panic attacks are considered as abrupt and intense fear responses to acute threat arising from inside the body, while anxious apprehension refers to anxiety responses to potential harm and more distant or uncertain threat. Taking a dimensional view, panic disorder with agoraphobia is defined with the threat-imminence model stating that defensive responses are dynamically organized along the dimension of the proximity of the threat. We tested this model within a large group of patients with panic disorder and agoraphobia (N 5 369 and N 5 124 in a replication sample) and found evidence that panic attacks are indeed instances of circa strike defense. This component of the defensive reactivity was related to genetic modulators within the serotonergic system. In contrast, anxious apprehension—characterized by attentive freezing during postencounter defense—was related to general distress and depressive mood, as well as to genetic modulations within the hypothalamic-pituitary-adrenal (HPA) axis. Patients with a strong behavioral tendency for active and passive avoidance responded better to exposure treatment if the therapist guides the patient through the exposure exercises. Descriptors: Anxiety, Startle Blink, Genetics, Psychopathological, Psychopathology, Autonomic

First clinical trial Funding/Support: This work is part of the German multicenter trial “Mechanisms of Action in CBT (MAC).” The MAC study is funded by the Ger- man Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. Centers: Principal investigators (PIs) with respective areas of responsibility in the MAC study are V. Arolt (M€unster: Overall MAC Program Coordi- nation), H. U. Wittchen (Dresden: PI for the Randomized Clinical Trial [RCT] and Manual Development), A. Hamm (Greifswald: PI for Psychophysi- ology), A. L. Gerlach (M€unster: PI for Psychophysiology and Panic subtypes), A. Str€ohle (Berlin: PI for Experimental Pharmacology), T. Kircher (Marburg: PI for functional neuroimaging), and J. Deckert (W€urzburg: PI for Genetics). Additional site directors in the RTC component of the program are G. W. Alpers (W€urzburg), T. Fydrich and L. Fehm (Berlin-Adlershof), and T. Lang (Bremen). Data Access and Responsibility: All PIs take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data. Data analysis and manuscript preparation were completed by the authors and coauthors of this article, who take responsibility for its accuracy and content. 312 Panic disorder with agoraphobia 313

Introduction defensive reactivity as well as to dimensional trait-like fear measures and genetic markers using multiple units of analysis. The National Institute of Mental Health (NIMH) has recently Finally, based on the data obtained from a multicenter random- introduced its Research Domain Criteria (RDoC) program with ized clinical trial (Gloster et al., 2011, 2013) investigating the the aim to “develop for research purposes new ways of classify- mechanisms of action of cognitive behavior therapy for panic ing mental disorders based upon dimensions of observable disorder with agoraphobia, we test whether defensive reactivity behavior and neurobiological measures” (Cuthbert & Insel, is related to clinical outcome and whether it can predict differen- 2013; Kozak & Cuthbert, 2016). Similar calls for action have tial effects. been recently proposed within the European Roadmap for Mental Health Research (ROAMER; Schumann et al., 2014; Wittchen et al., 2014), emphasizing the need for developing synergistic Diagnostic Criteria Defining Panic Disorder and approaches for linking traditional and novel diagnostic Agoraphobia approaches. In the present article, we first describe the diagnostic criteria for panic disorder and agoraphobia as currently used in According to DSM-5 (APA, 2013) recurrent (more than one) unex- the Diagnostic and Statistical Manual of Mental Disorders,5th pected panic attacks (Criterion A) are one essential diagnostic fea- ed. (DSM-5; APA, 2013), and then redefine these diagnostic fea- ture of panic disorder. A panic attack is defined by “an abrupt tures in terms of the research domains and constructs proposed in surge of intense fear or intense discomfort that reaches a peak the RDoC framework. By applying the defense cascade model within minutes” (crescendo criterion) “and during which time four derived from animal research in behavioral neuroscience, we (or more) of a list of 13 physical and cognitive symptoms have then describe defensive behaviors in a large group of patients occurred,” as reported by the patient. The term unexpected means with the principal diagnosis of panic disorder with agoraphobia that the individual does not perceive any obvious cue or trigger at assessed during a standardized behavioral avoidance test. We the time the panic attack occurs. The judgment, whether the panic then link these defensive behaviors to physiological measures of attack is unexpected or not, is made by the clinician.

Acknowledgments and Staff Members by Site: Greifswald (coordinating site for psychophysiology): Christiane Pane-Farre, Jan Richter, Susan Richter, Matthias von Rad; Berlin-Charite (coordinating center for experimental pharmacology): Harald Bruhn, Anja Siegmund, Meline Stoy, Andre Wittmann; Berlin-Adlershof: Irene Schulz; Munster€ (overall MAC Program Coordination, Genetics and Functional Neuroimaging): Andreas Behnken, Katharina Domschke, Adrianna Ewert, Carsten Konrad, Bettina Pfleiderer, Peter Zwanzger; Munster€ (coordinating site for psychophysiology and subtyping): Judith Eidecker, Swantje Koller, Fred Rist, Anna Vossbeck-Elsebusch; Marburg/Aachen (coordinating center for functional neuroimaging): Barbara Dr€uke, Sonja Eskens, Thomas Forkmann, Siegfried Gauggel, Susan Gruber, Andreas Jansen, Thilo Kellermann, Isabelle Reinhardt, Nina Vercamer- Fabri; Dresden (coordinating site for data collection, analysis, and the RCT): Franziska Einsle, Christine Fr€ohlich, Andrew T. Gloster, Christina Hauke, Simone Heinze, Michael H€ofler, Ulrike Lueken, Peter Neudeck, Stephanie Preiß, Dorte Westphal; Wurzburg€ Psychiatry Department (coordinating center for genetics): Andreas Reif; Wurzburg€ Psychology Department: Julia D€urner, Hedwig Eisenbarth, Antje B. M. Gerdes, Harald Krebs, Paul Pauli, Silvia Schad, Nina Steinh€auser; Bremen: Veronika Bamann, Sylvia Helbig-Lang, Anne Kordt, Pia Ley, Franz Petermann, Eva-Maria Schr€oder. Additional support was provided by the coordinating center for clinical studies in Dresden (KKS Dresden): Xina Gr€ahlert and Marko K€appler. The RTC project was approved by the Ethics Committee of the Medical Faculty of the Technical University of Dresden (EK 164082006). The neuroimaging components were approved by the Ethics Committee of the Medical Faculty of the Rheinisch-Westf€alischeHochschule University Aachen (EK 073/07). The experimental pharmacology study was approved by the Ethics Committee of the state of Berlin (EudraCT: 2006-00-4860-29). The study was registered with the ISRCTN: ISRCTN80046034. Second clinical trial Funding/Support: This work is part of the German multicenter trial: Mechanisms of CBT-treatment effects in patients with panic disorder and panic disorder with agoraphobia: The role of interoceptive exposure and fear augmentation (MCBT-PDAS). The study is funded by the German Federal Ministry of Education and Research (BMBF, 01GV0614) as part of the larger BMBF Psychotherapy Research Funding Initiative Improving the Treat- ment of Panic Disorder. Centers of the Multicenter Trial: Principal investigators (PIs) with respective areas of concentration of the MCBT-PDAS are Alfons Hamm (Greifs- wald: PI Psychophysiology); Thomas Lang (Bremen: Study Director for the Randomized Clinical Trial [RCT] and Manual Development); Alexander L. Gerlach (M€unster: PI Panic subtypes); Georg W. Alpers (Mannheim: PI Ambulatory assessment); Christiane Pane-Farre (Greifswald: PI Psycho- physiology and Panic Disorder); Tilo Kircher (Marburg: PI for functional neuroimaging); and J€urgen Deckert (W€urzburg: PI for Genetics). Additional site directors in the RCT component of the program are Winfried Rief (Marburg) and Paul Pauli (W€urzburg). Centers of the Research Network: Volker Arolt (M€unster: Overall Network Coordination), Hans-Ulrich Wittchen (Dresden), Andreas Str€ohle (Berlin). Data Access and Responsibility: All PIs take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data. Data analysis and manuscript preparation were completed by the authors and coauthors of this article, who take responsibility for its accuracy and content. Acknowledgments and Staff Members by Site: Bremen (coordinating center for the multicenter trial): Veronika Bamann, Sandra Cammin, Sarah Czil- wik, Kira Geisler, Sylvia Helbig-Lang, Kirsten Helmes, Anne Kordt, Tanja Leonhard, Mila Plett-Perelshteyn, Christian Soltau, Juliane S€ulz, Maxie von Auer; Greifswald (coordinating site for psychophysiology): Anett Hoffmann, Jan Richter; Mannheim (coordinating center for ambulatory assessment): Christoph Biwer, Elisabeth Borgmann, Antje Gerdes, Otto Martin, Kristina Steinbach, Bettina Stemmler, Andrew White; Marburg (coordinating center for functional neuroimaging): Tobias Fehlinger, Andreas Jansen, Nikita Jegan, Carsten Konrad, Marion Mickeler, Silke Rusch, Katrin Schl€otterer, Benjamin Straube, Mareike Stumpenhorst, Katrin Wambach, Yunbo Yang; Munster€ (coordinating site for panic subtypes): Susanne Ket- tler, Anna Vossbeck-Elsebusch; Wurzburg€ Psychiatry Department (coordinating center for genetics): Carola Gagel, Andreas Reif, Heike Weber; Wurzburg€ Psychology Department: Almut Friedl-Huber, Harald Krebs, Caroline Ott, Nina Steinh€auser. Additional support was provided by the coordinating center for clinical studies in Dresden (KKS Dresden): Marko K€appler. The RCT was approved by the Ethics Committee of the German Psychological Society (DGPs, AH11.2009). The study was registered with the NCT01323556. Role of Funding Source: The funding organizations had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. *Both authors contributed equally and should be considered as first authors. Address correspondence to: Prof. Dr. Alfons Hamm, Department of Psychology, University of Greifswald, Franz-Mehring-Straße 47, 17487 Greifs- wald, Germany. E-mail: [email protected] 314 A.O. Hamm et al.

In addition to such recurrent unexpected panic attacks, the indi- A. B. vidual has to acknowledge the experience of “persistent (for one month or more) concern or worry about additional panic attacks Pre-Encounter Defense Potentially Dangerous Context and their consequences” (Criterion B1), which could be physical -Hypervigilance to potential threat - Being alone in the shopping mall concerns, such as the worry that panic attacks reflect the presence of life-threatening illnesses (e.g., cardiac disease, seizure disorder), social concerns (fear of being judged negatively by others because Post-Encounter Defense Concern/Worry of visible panic symptoms), and concerns about mental functioning -Threat detected: Body symptoms detected -Increased selective attention, -Increased selective attention, (“going crazy”) or individuals have to show a significant maladap- -Freezing -Freezing, Startle Potentiation tive change in behavior related to the attacks (Criterion B2). “Examples of such changes in behavior include avoiding physical exertion, reorganizing daily life to ensure that help is available in Increasing Proximity Circa-Strike Defense Acute Panic the event of a panic attack, restricting usual daily activities and - Active defensive behavior - Active defensive behavior -Active Avoidance, Escape - Active Avoidance, Escape avoiding agoraphobia-type situations, such as leaving home, using public transportation, or shopping” (APA, 2013). The association between panic disorder and agoraphobic avoid- Figure 1. A: The Threat Imminence Model suggesting that defensive ance has been the focus of a long-standing controversy. Beginning reactivity is organized as a cascade of three different stages depending on the distance (proximity) of the threat. B: Application of the Threat with the DSM-III-R (APA, 1987), agoraphobia was considered to Imminence Model to describe the psychopathology of panic disorder. be a consequence or complication of a panic disorder and could not be coded as unique disorder in the DSM-IV-TR (APA, 2000). Epi- demiological evidence, however, suggests that agoraphobia— Anxiety about potential harm is more ambiguous, activated by although being frequently associated with panic disorder (in approx- physically or psychologically more distant or uncertain threat. In imately 50% of all cases)—can exist independently, that is, without patients with panic disorder, such anxious apprehension involves any history of panic disorder or even panic-like symptoms (Pane- increased vigilance to cues from the body and enhanced risk assess- Farre et al. 2014; Wittchen, Gloster, Beesdo-Baum, Fava, & Craske, ment, and is qualitatively distinct from responses to acute threat. 2011). Moreover, agoraphobia just as frequently precedes reports of Animal data suggest that these different defensive behaviors might panic attacks as panic attacks precede agoraphobia (Pane-Farre be dynamically organized along a dimension switching from one to et al. 2013). As a consequence, agoraphobia and panic disorder are the other depending upon the perceived proximity or imminence of now codable as separate disorders in DSM-5 (APA, 2015). Here, the threat, as outlined in the threat imminence model by Fanselow agoraphobia is defined as marked fear or anxiety about two (or (1994; see also Blanchard, 1997; Lang, Bradley, & Cuthbert, 1997). more) of five clusters of situations (Criterion A). These include sit- If an organism is in a context where threat has been encountered uations that are either characterized by entrapment (public transpor- previously but has not yet been detected (pre-encounter defense), tation, enclosed places, standing in line, or being in a crowd) or preemptive behavior is engaged including threat-nonspecific vigi- situations in which in case of emergencies no immediate help is lance. As soon as a threat is detected (postencounter defense), atten- available such as being in open spaces or outside of the home alone. tion is selectively allocated to the threat cue and defensive response As in the case of specific phobias, these clusters of situations are output is characterized by fear bradycardia (Campbell, Wood, & avoided when possible (Criterion B). In the current article, we will McBride, 1997), potentiation of the startle reflex gated through the € address some of these diagnostic controversies taking into account central nucleus of the amygdala (Lang, Davis, & Ohman, 2000), the research domains and constructs proposed by the RDoC. and motor “freezing,” depending on projections from amygdala to the ventral periaqueductal gray (vPAG) in the midbrain (Fanselow, 1994; Maren, 2001; Morgan & Carrive, 2001). Active defensive Defining Panic Disorder With Agoraphobia in Terms of the behavior (active avoidance, flight or fight) is initiated during circa Negative Valence Systems Domain strike defense, mediated by the dorsal periaqueductal gray (dlPAG) The phenomenology of panic disorder and agoraphobia can best be that directs the expression of escape behavior (Kim et al., 2013, conceptualized within the domain negative valence systems com- LeDoux, 2012) accompanied by a general discharge of the sympa- prising five different constructs. A panic attack is a prototypical thetic nervous system (Cannon, 1932). The left panel of Figure 1 example of an abrupt and intense fear response to an acute threat. depicts a schematic chart of the threat imminence model. Threat stimuli are species specific and can comprise external stim- As outlined above, panic attacks are abrupt surges of intense uli such as other animals (e.g., predators), nociceptive events (e.g., fear characterized by rapid increase in heart rate and skin conduct- painful stimuli), or harmful conspecifics (e.g., rivals). Note that ance (Cohen, Barlow, & Blanchard, 1985; Meuret et al., 2012) acute threat can also arise from inside the body. For example, often associated with overwhelming behavioral action tendencies hypoxia or hypercapnia result in the perception of acute air hunger for active avoidance/escape (Bouton, Mineka, & Barlow, 2001), or dyspnea, one of the central symptoms panic attacks (see Preter suggesting that panic attacks might be instances of a circa strike & Klein, 2008; Schimitel et al., 2012). Moreover, other interocep- defense state—an idea first proposed by Craske (1999) and elabo- tive signals like visceral pain (e.g., ischemia of the heart which is rated by Bouton, Mineka, and Barlow (2001). Recent animal data perceived as acute chest pain overlying the sternum) are potent also support this view. Infusion of low doses of potassium cyanide acute internal threat stimuli that can cause panic attacks. (KCN) produces hypoxia in the dlPAG and facilitates active avoid- In contrast to panic attacks as prototypical expressions of fear ance and escape behavior elicited by electrical stimulation of the responses to acute internal threat stimuli, concerns and worries dlPAG. In contrast, lesions of the dlPAG abolish KCN-evoked about the potential harm or consequences of these panic attacks escape behavior (Schimitel et al., 2012). Hypoxia can be consid- (Criterion B1 of panic disorder) can be conceptualized as responses ered as an acute internal threat triggering a panic attack as circa to potential threats (anxiety) within the negative valence system. strike defense (Canteras & Graeff, 2014). The second component Panic disorder with agoraphobia 315 of panic disorder—anxious apprehension—can be conceptualized of 369 patients all of whom were diagnosed with a principal diag- as postencounter defense within the threat-imminence model. Indi- nosis of panic disorder with agoraphobia (PD/AG) and enrolled for viduals with panic disorder perceive future panic attacks as uncon- a multicenter randomized controlled clinical trial study, Mecha- trollable and unpredictable and are extremely vigilant for somatic nisms of Action in Cognitive Behavioral Therapy (MAC; Gloster symptoms that might signal the beginning of a new panic attack. If et al., 2009). Patient recruitment, inclusion and exclusion criteria of such mild somatic symptoms are detected, attentive freezing is the multicenter RCT study, diagnostic tools and procedures, as engaged. well as patients’ sociodemographic characteristics are described There is evidence that the detection of mild body symptoms elsewhere (Gloster et al., 2009, 2011). indeed leads to anticipatory anxiety and attentive freezing in Guided by the observation emphasized in the RDoC initiative patients with panic disorder. Melzig, Holtz, Michalowski, and that individuals with different characteristics can fall into the same Hamm (2011) used the startle probe methodology to study anxious diagnostic category, the current article focuses on different patterns apprehension during perception of mild body symptoms during of defensive reactivity of this large patient group assessed in a early recovery from a guided hyperventilation task. Because imme- standardized behavioral avoidance task that was part of the diag- diately after the hyperventilation task the blood partial pressure of nostic procedure prior to therapy. We measured self-reported carbon dioxide (pCO2) is still below 30 mmHg for approximately 2 anxiety, defensive behavior, protective reflex modulation, and minutes mild body symptoms are still present without interference autonomic responses during anticipation of (patients were sitting in from the guided hyperventilation procedure itself. Startle probes front of the test chamber with its door open for 10 minutes) and were presented during recovery from the hyperventilation task (20 exposure to a small (75 cm wide, 120 cm long, and 190 cm high) cycles per minute; increased tidal volume until target pCO2 level dark and closed test chamber (for a maximum of 10 minutes), con- of 20 mmHg was reached) as well as after “recovery” from normo- structed according to descriptions by Ost,€ Johansson, and Jerre- ventilation (spontaneous breathing). As predicted, patients with malm (1982). Rachman and colleagues (Rachman, Levitt, & panic disorder showed a clear potentiation of their startle responses Lopatka, 1988; Rachman & Taylor, 1993) have successfully used during recovery from hyperventilation compared to the control this test as an experimental model to investigate physiological and condition (see Hamm, Richter, & Pane-Farre, 2014). Healthy con- cognitive symptoms of panic attacks in patients with claustropho- trols did not show any startle potentiation after recovery from bia. Because marked fear of entrapment and avoidance of being in hyperventilation although they had a comparable course of pCO2 enclosed places is also a prominent symptom in patients with panic during this phase (Melzig et al., 2011). These data suggest that the disorder and agoraphobia (Arrindell, Cox, Van der Ende, & Kwee, perception of mild body symptoms activates postencounter defense 1995; Cox, Swinson, Kuch, & Reichman, 1993; Kwon, Evans, & in these patients that parallels the defensive response pattern Oei, 1990; Rodriguez, Pagano, & Keller, 2007), we expected to evoked by conditioned external stimuli in fear conditioning experi- evoke defensive responses during this test in a large proportion of ments both in animals (see Davis & Whalen, 2001) and humans the PD/AG patient group. (Hamm & Weike, 2005). During exposure to the behavioral avoidance test (BAT), Pre-encounter defense is activated when the individual enters patients were sitting in the chamber with the door locked from the the context in which a previous panic attack has been experienced outside by the experimenter. Patients were instructed to remain in but body symptoms have not been detected yet. During this stage, the chamber for as long as possible and to knock on the wooden preemptive behavior is engaged including safety behavior but also door if they wanted to end the exposure before the maximum expo- threat-nonspecific hypervigilance. Increased sensitization of the sure time elapsed (which was unknown to the patients). They were attention system—as indexed by greater P1/N1 amplitudes of the instructed to press a button whenever they experienced a panic event-related potentials to fear-relevant but also neutral stimuli— attack in the chamber. The output of the button press was digitized was found when individuals with specific phobia were in a context and recorded as a separate channel in order to synchronize the where visual phobic stimuli might occur (see Michalowski, Melzig, onset of self-reported panic attacks with physiological recordings. Stockburger, Schupp, & Hamm, 2009; Michalowski, Pane-Farre, Applying this standardized behavioral avoidance test, we found L€ow, & Hamm, 2015). Passive agoraphobic avoidance occurs very that 236 patients (68.4%) reported medium to high levels of anxiety early in the defense cascade and in case of passive avoidance even associated with physiological and behavioral indices of increased prior to pre-encounter defense and is motivated by anxious appre- defensive response engagement (Richter et al., 2012). These data hension of the expected potential threat (e.g., a panic attack) in a suggest that two thirds of all PD/AG patients show symptoms of specific context. Supporting this view, Craske, Rapee, and Barlow fear when enclosed in this situation. Defensive reactivity, however, (1988) demonstrated that perceived probability of panicking in a differed substantially among patients, although the same principal specific situation was the strongest predictor (r 5 .49) for active diagnosis based on the categorical classification of indicative and passive avoidance of a variety of behavioral avoidance tests. symptom reports was assigned to all patients. Thirty-nine patients These data are particularly important, because changing probability (11.3%) refused to enter the chamber after the anticipation period estimates of an aversive outcome are important ingredients of (“passive avoiders”); 72 patients (20.9%) entered the test chamber extinction learning. Violations of such expectations would induce a after the anticipation period but terminated exposure prematurely prediction error (Rescorla & Wagner, 1972) initiating extinction (“active avoiders/escapers”; duration of exposure varied between 3 learning, which is considered to be one of the central mechanisms and 580 seconds, M 5 225.6; SD 5 171.0). One hundred twenty- of exposure therapy. five patients (36.2%) remained in the chamber despite medium to high levels of reported anxiety (“anxious completers”). These Empirical Evaluation: Defensive Behaviors in Patients With patients also showed a significant potentiation of the startle Panic Disorder and Agoraphobia response, and physiological indices of fears, that is, significantly elevated heart rate and skin conductance levels during the entire We tested defensive reactivity using multiple units of analysis in a duration of exposure (10 min) relative to the patients with panic subgroup of 345 (259 female patients) patients from a total sample disorder with agoraphobia (N 5 109; 31.6%) who did not report 316 A.O. Hamm et al.

Table 1. Mean Scores (and Standard Deviations) of the Reported Intensity of Agoraphobic Avoidance During All-Day Life Assessed With the Mobility Inventory (MI; Subscale: Alone; Range 1-5) for Patients With Panic Disorder With Agoraphobia (PD/AG) who Showed Active/Passive Avoidance During the BAT Compared to Those PD/AG Patients who Completed the Test Without Showing Any Passive or Active Avoidance Behavior. Situations Listed in the MI Were Clustered Into the Five Categories Listed in the Diag- nostic Criteria for Agoraphobia in the DSM-5 With MI Items in Brackets. Statistical Results of the Between-Group Comparisons (t test) Are Presented in the Last Column

PD/AG patients with PD/AG patients with Results of the statistical active/passive avoidance no active/passive avoidance between-group comparisons Clusters of situations during the BAT (N 5 130) during the BAT (N 5 304) (p value) 1. Using public transportation 3.60 (1.09) 3.16 (1.05) < .001 (cars [at any time and on expressways], buses, trains, subways, ships, planes) 2. Being in open spaces 2.36 (0.93) 2.21 (0.91) .11 (open spaces [outside and inside], high places, bridges, walking on the street) 3. Being in enclosed spaces 3.09 (0.92) 2.69 (0.89) < .001 (theaters, supermarkets, shopping malls, classrooms, restaurants, museums, elevators, stadiums, garages, enclosed spaces, staying home alone) 4. Standing in line or being in a crowd 3.27 (1.02) 3.05 (1.06) < .05 (standing in lines, parties or social gatherings, being in a crowd) 5. Being outside of the home alone 3.69 (1.35) 3.16 (1.40) < .001 (being far away from home) MI total score 3.11 (0.84) 2.78 (0.82) < .001 any anxiety during entrapment (“nonanxious completers”) (see uations. Thus, avoidance behavior observed in this specific Richter et al., 2012). behavioral task might be used to examine associations to genetic These differences in defensive reactivity during exposure to the risk markers of such avoidance disposition on a behavioral level. same standardized BAT were replicated in a second sample of 154 Although all patients (N 5 464) were diagnosed with PD/AG patients enrolled for a second randomized multicenter treatment as the principal diagnosis, the majority of patients (82%) were trial in the MAC study. Inclusion and exclusion criteria were iden- diagnosed with additional comorbid disorders. The most frequent tical to those employed in the first RCT, except that 30 patients comorbid disorder was Specific phobia. Of all PD/AG patients, were included with a principal diagnosis of panic disorder without 65.5% were diagnosed with this additional disorder. Two hundred agoraphobia. The remaining 124 patients were diagnosed with the twenty-seven patients (48.9%) were diagnosed with a Specific principal diagnosis of panic disorder with agoraphobia. In the Phobia—situational type comprising claustrophobic fears. Indeed, group of patients with PD/AG defensive reactivity in the standar- this group of patients did show significantly more active and pas- dized BAT was assessed 119 patients. As in the previous sample, sive avoidance behavior in the BAT. Moreover, these patients two thirds of the patients (N 5 77; 64.7% of the 119 PD/AG reported more fear and also showed stronger initial heart accelera- patients) showed clear evidence of defensive reactivity during tion compared to PD/AG patients without this comorbid diagnosis, exposure to this test as indexed by increased reported anxiety, suggesting that claustrophobic fears moderate defensive respond- potentiation of startle and increase in autonomic arousal, while ing during this task. However, number of comorbid diagnoses also 35.3% of the sample completed the test without significant symp- influenced avoidance behavior observed in the BAT (number of toms of anxiety. Again, replicating the results of the first study, comorbid diagnoses varied between patients from 1–2 [44%], over 8.4% (N 5 10) of this patient group refused to enter the chamber 3–4 [27%], up to 51 [11%]). Patients with five or more comorbid (“passive avoiders”) and 16.8% (N 5 20) terminated the task pre- diagnoses showed significantly more avoidance behavior than all maturely (active avoiders/escapers”). As expected, defensive other patients (p < .05). Moreover, number of comorbid diagnoses behavior in the standardized BAT was related to reported agora- was also related to severity of agoraphobic avoidance as assessed phobic avoidance as assessed with the Mobility Inventory (MI). by self-report (MI) or by the therapist (Clinical Global Impression; In Table 1 the situations were clustered according to the five cat- Agoraphobic Avoidance). Frequency of comorbid diagnoses was egories of situations that are listed in the DSM-5. Patients showing also associated with increased overall symptom severity (assessed passive and active avoidance in the standardized BAT also reported with the Brief Symptom Inventory [BSI]]) and reported depressive stronger avoidance in all clusters of agoraphobic situations except symptoms (assessed with the Beck Depression Inventory-II [BDI- for being in open spaces. Avoidance tendencies of being in open II]) replicating previous findings (McTeague, Lang, Laplante, & spaces were overall rated as less severe compared to all other clus- Bradley, 2011). ters of situations in our sample, suggesting that these situations are not as typical for agoraphobic avoidance as was originally thought Defensive Reactivity During Escape and Acute Panic (Westphal, 1871). Interestingly, patients showing behavioral avoidance in the BAT were more likely to also avoid situations like being The analysis of defensive reactivity in patients who showed active far away from home or being in crowds. This suggests that observed avoidance revealed that heart rate and skin conductance increased avoidance behavior during the BAT might not only be restricted to linearly during the last 60 seconds just prior to escape from the enclosed situations but might rather reflect a more generalized dis- chamber which was initiated at the peak of the autonomic surges position for avoidance that is also evident in other agoraphobic sit- (see upper panel of Figure 2). Interestingly, startle response Panic disorder with agoraphobia 317

actively avoid the aversive threat, reflecting focused preparation A Heart Rate Startle Blink Magnitude 94 50 for effective escape with reduced attention allocated to the task- Initial Responses Responses irrelevant probe stimulus. During Exposure During Last 60 Seconds 92 Before Escape 45 Blink Magnitude (µV) This pattern of defensive reactivity observed during active avoidance and preparation for escape from an aversive electrical 90 stimulus or from the BAT resembled the response pattern found 40 during acute panic attacks experienced by PD/AG patients during 88 exposure in the small, narrow chamber. Twenty-six patients (7.5% 35 of the patients) reported 34 panic attacks during exposure by press- 86

Heart Rate (bpm) Rate Heart ing the “panic button.” Startle blink magnitudes are presented in

30 mVolts averaged across two probe stimuli presented prior to the 84 button press and three probes presented after the button press. The lower panel of Figure 2 depicts startle magnitudes and heart rate 82 25 Initial -60 -50 -40 -30 -20 -10 0 changes averaged in 5-second bins starting 30 seconds prior to button press and 60 seconds during and after the button press for those Time (Seconds) 11 reported panic attacks for which both physiological measures were available (see Richter et al., 2012 for a more detailed analysis B Heart Rate Startle Blink Magnitude 90 60 of these data). In line with findings from an ambulatory monitoring study (Meuret et al., 2011), heart rate increased prior to the button 88 press, suggesting that increase in autonomic arousal indeed trig- 55 Blink Magnitude (µV) gered the experience of the panic attack. As during preparation for 86 active avoidance, startle magnitudes were also inhibited during 50 acute panic attacks, suggesting that acute panic attacks might be 84 instances of circa-strike defense possibly associated with the per-

45 ception of acute threat signals from inside the body (e.g., dyspnea). 82 Interestingly, there are early reports by Nashold, Wilson, and Heart Rate (bpm) Rate Heart Slaughter (1974) that electrical stimulations of the periaqueductal 40 80 gray evoked acute panic attacks in humans (see Schenberg et al., 2014 for review), supporting the view that panic attacks might be Panic Button Press 78 35 instances of circa-strike defense modulated by dlPAG. -30 -20 -10 0 10 20 30 40 50 60 Time (Seconds) Relating Defensive Reactivity to Dimensional Risk Factors: Figure 2. A: Mean heart rate and startle response magnitudes of 55 PD/ Psychological Traits and Genetic Markers AG patients during the initial 60 seconds of the exposure period in the dark room and the 60 seconds prior to escape from the dark room Using a standardized behavioral avoidance test, we found a large (active avoidance). bpm, beats per minute. B: Heart rate changes and heterogeneity in defensive responding of patients, all diagnosed blink magnitudes (mean magnitudes of the last two startle responses with the same principal diagnosis—PD/AG. We also found that prior to the button vs. mean response magnitudes after the button press) defensive responses were dynamically organized depending upon during 11 reported panic attacks in 11 PD/AG patients for which both the dominant action disposition that is activated during approach- variables could reliably recorded. ing threat. In the next step, we started to investigate whether we would find meaningful associations between individual patterns of magnitudes that were potentiated during the first 60 seconds of defensive reactivity, dimensional trait like risk factors and genetic exposure to the chamber (i.e., during attentive freezing) decreased dispositions (Domschke et al., 2011; Hohoff et al., 2015; Reif just prior to escape. This decrease was even stronger in patients et al., 2014; Straube et al., 2014). who escaped from the chamber during a self-reported panic attack Stimulated by cognitive models of panic disorder (Beck & (Richter et al., 2012), suggesting that this response pattern was Emery, 1985) Reiss (1991) and McNally (1994) suggested that even more pronounced for higher intensity of active avoidance/ individuals can be characterized by a trait like cognitive predisposi- escape. These data are in line with results by L€ow, Lang, Smith, tion—labeled anxiety sensitivity (AS)—to misinterpret ambiguous and Bradley (2008) who showed that startle responses switched cues and somatic symptoms as being predictive for deleterious from potentiation during attentive freezing to inhibition during the physical, psychological, and social consequences. AS is defined as stage of active response preparation. Following up on this research, a set of trait-like beliefs that the fear- or anxiety-related somatic L€ow, Weymar, and Hamm (in press) more recently demonstrated sensations indicate danger-associated harmful consequences. As that startle potentiation linearly increased with increasing proximity measured with the Anxiety Sensitivity Index (ASI; Reiss, Peterson, of the threat accompanied by fear bradycardia when individuals Gursky, & McNally, 1986), high AS is considered to be predictive had no option for active avoidance (which is typically the case in for the occurrence of panic attacks and the development of PD classical fear conditioning designs). In contrast, startle response (Schmidt, Zvolensky, & Maner, 2006; see meta-analysis by magnitudes were strongly inhibited and heart rate accelerated dur- Naragon-Gainey, 2010). Supporting this hypothesis, we found that ing circa strike when individuals were given the opportunity to panic disorder patients with agoraphobia (N 5 491) but also a sub- actively avoid the upcoming threat (an aversive electrical stimulus group of patients with panic disorder without agoraphobia from a in this experiment). Interestingly, the P3-component of the event- second multicenter clinical study (N 5 30) reported significantly related brain potential to the startle-eliciting acoustic probe stimu- elevated levels of AS compared to a student control group lus was also strongly attenuated when individuals had the option to (N 5 279) (patient with PD/AG: M 5 31.4, SD 5 11.6; patients 318 A.O. Hamm et al. with PD without AG: M 5 29.6, SD 5 10.6; healthy controls: cantly predicted active (OR: 1.07, p <.001) and passive avoidance M 5 18.6, SD 5 8.9). behavior in the BAT (OR: 1.08, p < .001), no other self-report A second trait like dimension derived from biological models measure was significant. Moreover, only reported suffocation fear suggesting breathing-related symptoms to be the main source of but no other self-report measure significantly predicted self- fear initiating panic attacks and therefore a central component for reported avoidance as assessed by the MI total score (b 5 0.44, the etiology of PD is fear of suffocation (Klein, 1993; Ley, 1985, p < .001), supporting the specific association between suffocation 2005). Fear of suffocation has also been suggested to predict the fear and avoidance behavior. number of reported panic symptoms, particularly during experimen- Different patterns of defensive reactivity were not only associated tally provoked panic attacks (Alius, Panne-Farre, Von Leupoldt, & with different dimensional trait–related self-report measures, but also Hamm, 2013; Taylor & Rachman, 1994). Interestingly, individuals with different genetic risk factors. In the MAC study, genetic data with high levels of suffocation fear not only report more anxiety from 269 patients who participated in the BAT and for whom blood and show elevated autonomic arousal during a dyspneic challenge, samples were available were analyzed. We investigated the influence but they also show “maladaptive” compensatory ventilatory behav- of two candidate genes that are involved in serotonergic neurotrans- ior while breathing through increased resistive loads (Alius et al., mission on patterns of defensive reactivity in the BAT. In a first step, 2013). Fear of suffocation was assessed using the suffocation sub- we analyzed a common variant in the promoter region of the gene scale of the Claustrophobic Questionnaire (CLQ; see Radomsky, encoding monoamine oxidase A (MAOA)—an enzyme that metabo- Rachman, Thordarson, McIsaac, & Teachman, 2001 for an updated lizes serotonin and norepinephrine. This polymorphism is a 30-bp version of this scale) in these studies. Supporting the hypothesis that variable number of tandem repeat (MAOA-uVNTR) affecting gene fear of suffocation might also be a risk factor for developing a PD/ expression (Deckert et al., 1999). Long alleles (3.5, 4, and 5 repeats AG, we found significantly elevated levels of suffocation fear in of the 30 base pairs) are associated with panic disorder in females panic disorder patients with agoraphobia but not in a subgroup of (Deckert et al., 1999; Maron et al.,2005;Samochowiecetal.,2004). patients from the second multicenter RCT study who were diag- Patients with the high-risk variant gene showed stronger fear nosed with panic disorder without meeting the criteria for agorapho- responses in the BAT, as indicated bysignificantlyelevatedheart bia (patients with panic disorder with agoraphobia: M 5 25.8, SD rate and reports of higher anxiety during exposure (Reif et al., 2014). 511.0; patients with panic disorder without agoraphobia: M 5 10.5, In addition, all but one patients reporting a panic attack in the cham- SD 5 7.6; healthy controls: M 5 8.4, SD 5 5.9). These data suggest ber (33 out of 34) were high-risk genotype carriers leading to the that both dimensional constructs might be associated with different overall assumption that patients carrying the MAOA-uVNTR risk aspects of the disorder and possibly with different patterns of defen- variant were more prone to show strong acute fear reactivity when sive reactivity. being confronted with a typical agoraphobic situation (in this case, Suffocation fear predicted actual passive and active avoidance/ being entrapped in a small dark chamber). Interestingly, Miller, Dea- escape in the BAT. Patients reporting clinically significant levels kin, and Anderson (2000) found enhanced panic responses to breath- of suffocation fear (2 SDs above the mean of the control group) ing 5% CO2 but lessened anxiety ratings during anticipation of this significantly more often avoided to enter the chamber or left it task when 5-HT functioning was reduced by acute tryptophan deple- before exposure time had elapsed (84% of the passive avoiders and tion (ATD). In a similar way, serotonin reduction increases acquisi- 77% of the active avoiders had suffocation fear levels that were 2 tion of active avoidance in rodents while elevated levels have the SDs above the mean). Moreover, suffocation fear was significantly opposite effect (Beninger, 1989). Stimulated by this research, we related to the duration patients remained in the chamber. Suffoca- investigated a serotonin receptor 1a gene (HTR1A)polymorphismin tion fear was also significantly correlated (r 5 .51; p < .001) with the group of 245 patients from the MAC-study who participated in the severity of avoidance as assessed at baseline with the MI. In the BAT. The G-allele in the transcriptional control region of the addition, suffocation fear was significantly related to reported anxi- HTR1A increases the expression of the gene at the presynapse where ety and panic symptoms during exposure suggesting that this trait the gene product functions as an autoreceptor and thus reducing sero- measure was related to the intensity of fear and avoidance in this tonergic neurotransmission due to enhanced auto-inhibitory feed- specific situation of entrapment. In contrast to suffocation fear, back. In line with previous animal data, we found significantly reported anxiety sensitivity was not related to active and passive increased active avoidance/escape behavior in GG-genome carriers avoidance in the BAT (the distribution of patients with clinically compared to CC carriers with GC carriers falling in between (see significant levels of AS (2 SDs above the mean of the healthy con- upper panel of Figure 3). This genetic modulation of active avoid- trol group) was 38%, 31.9%, and 35.9% of passive avoiders, active ance/escape behavior was also evident during exposure sessions of avoiders/escapers, and anxious completers, respectively). More- the standardized CBT. Duration of self-guided exposure was signifi- over, while ASI scores were not related to self-reported avoidance cantly shorter (particularly duringthetwomostfearedsituations)in behavior according to the MI (r 5 .07; n.s.), it was associated with the GG carriers compared to the CC carriers (see Straube et al., reports of catastrophic thoughts (assessed with the agoraphobic 2014). These data strongly suggest that the serotonergic system is cognitions questionnaire: r 5 .45; p < .001), reported fear of bodily involved in circa-strike defense. Reduction of 5 HT functioning sensations (assessed with the body sensations questionnaire: seems to increase acute fear/panic during exposure and to facilitate r 5 .43; p < .001), health worries (assessed with the Panic and escape behavior possibly mediated by the dlPAG. Agoraphobia Scale: r5 .47; p < .001), general distress (assessed In contrast to the serotonergic system, the corticotropin- with the BSI; r 5 .44; p <. 001), and depressive mood (assessed releasing hormone (CRH) does not modulate acute fear and avoid- with the Beck Depression Inventory: r 5 .30; p < .001), suggesting ance in the BAT but rather seems to be involved in the modulation that elevated anxiety sensitivity is more related to anxious appre- of general distress and chronic anxious apprehension. We investi- hension and negative affect, rather than to avoidance. These find- gated allelic variation of the CRH receptor 1 (CRHR1) in a sample ings were supported by the results of a logistic model of BAT of 267 patients with PD/AG from the MAC study. We found that avoidance behavior with multiple self-report measures (CLQ-SF, against other a single nucleotide polymorphism (SNP) of the CRH ASI, BDI, and BSI): only self-reported suffocation fear signifi- receptor 1 gene influences gene expression and was significantly Panic disorder with agoraphobia 319

A step linking different components of defensive reactivity to therapy 40 outcome measures, trying to identify how different components of the disorder might respond in a specific way to circumscribed ele- 35 ments of the intervention. 30

25 Relating Defensive Reactivity to Treatment Outcome

20 In a first multicenter randomized controlled trial, 369 patients with

Rate of 15 PD/AG were treated and followed up for 6 and 24 months (see Gloster et al., 2011, 2014). Patients were randomized to two 10 manual-based variants of CBT or a wait list control (WL; N 5 68)

active avoidance (%) 5 and were treated twice weekly for 12 sessions. CBT variants were N=9 of 60 N=27 of 120 N=21 of 65 identical in content, structure, and length except for implementation 0 CC CG GG of exposure in situ. In one variant (T1; N 5 163), exposure in situ rs6295 (-1019C/G HTR1A) exercises were accompanied by the therapist outside the therapy Genotype room; in the other variant (T–; N 5 138), exposure exercises were B planned and discussed with the patient, but exercises outside the Personality Trait Risk Factors Genetic Risk Factors therapy room were not accompanied by the therapist. Overall, this treatment was very effective in both treatment conditions (effect Suffocation Anxiety MAOA gene CRHR1 gene Fear Sensitivity 5HT1A gene sizes varied from 20.5 to 22.5 in all primary outcome variables from pre to post and further improved from post to 6 months + + follow-up; Gloster et al., 2011).Asecondmulticenter randomized controlled trial followed up on this study. In this study, 124 patients

Defensive responding Defensive responding with PD/AG were treated using two manual-based variants of CBT during cued threat + during potential harm for 12 sessions. Again, variants wereidenticalincontent,structure,

(acute panic) (anxious apprehension) and length except with regard to the implementation of exposure in - vivo. In one variant (T1; N 5 61), exposure treatment was compa- Figure 3. A: Rate of active avoidance/escape from the dark room accord- rable to the T1 variant from the first clinical trial. In the other vari- ing to the genotype of the serotonin receptor 1 a gene (HRTR1A). The G- ant (T11I; N 5 63), exposure in vivo exercises were also allele increases receptor expression at the presynapse and thereby reduces accompanied by the therapist, but in addition, patients were serotonergic neurotransmission. B: A descriptive model of the associations instructed to provoke bodily symptoms during exposure exercises between different components of defensive reactivity and trait-like dimen- (e.g., by doing a hyperventilationexercise).NoWLcontrolgroup sions of reported fear and genetic risk markers for fear and anxiety. was included in this study. Again,bothtreatmentconditionswere overall effective in this second treatment study. Treatment effects, associated with the categorical diagnosis of panic disorder and however, were systematically modulated by avoidance behavior defensive reactivity during the BAT (Weber et al., 2015). The risk assessed prior to therapy. We collected behavioral data from the allele carriers showed a reduced acute fear response and less active BAT for 397 patients with PD/AG who were allocated to the active avoidance in the BAT task but reported more general distress and treatment conditions in both clinical trials. We found significantly expressed more negative evaluations of their body symptoms, thus larger attrition rates in those 116 PD/AG patients who showed active showing more chronic and generalized anxious apprehension than or passive avoidance behavior (i.e., either did not enter the chamber acute fear or panic. Indeed, animal and human data suggest that or escaped prematurely) in the standardized BAT prior to therapy CRH is critical for expression of sustained anxiety but not phasic with nearly twice as many dropouts (N 5 35; 30.2%) as compared fear (Davis, Walker, Miles, & Grillon, 2010). to the 281 patients who did not show any avoidance behavior Summarizing our observations so far, we found evidence that (N 5 50; 17.8%; v2 5 7.48, p < .01). Interestingly, patients who dimensional trait-like measures as well as genetic markers that are showed active or passive avoidancebehaviorduringtheinitialBAT associated with PD/AG might be related to different components had better therapy outcome in case they completed the treatment. (i.e., acute fear/panic as an instance of circa-strike defense and anx- This effect was evident in both clinical trials. The left panel of Fig- ious apprehension reflecting postencounter defense) that define the ure 4 presents changes in one outcome measure (Panic and Agora- categorical diagnosis of the disorder (see lower panel of Figure 3 phobia Scale [PAS]; Bandelow, 1995—a 13-item questionnaire that for a summary). In the next step, we explore whether this dimen- measures self-reported severity of panic attacks, avoidance, anticipa- sional approach using the dynamics of defensive reactivity as a tory anxiety, disability, and worries about health) separately for new tool for describing patients who all received the same categori- patients who showed active or passive avoidance in the BAT prior cal diagnosis—PD/AG—might be useful for tailoring exposure to treatment or not. Larger improvements were found for patients therapy in a way to improve outcome. Numerous variants of showing high avoidance tendencies compared to patients with no cognitive-behavioral therapy (CBT) for panic disorder with and avoidance in the BAT but only if the therapist accompanied the without agoraphobia have been shown to be efficacious and are patients during exposure exercise outside the therapy room (avoid- therefore regarded as a first-line treatment (for a meta-analyses, see ance x treatment variant F(1, 222) 5 4.68, p < .05). This pattern of Sanchez-Meca, Rosa-Alcazar, Marin-Martinez, & Gomez-Conesa, results was replicated in the second clinical trial (see right panel of 2010). Despite the documented efficacy of CBT for PD/AG (Otto, Figure 4). Patients showing avoidance behavior prior to treatment Pollack, & Maki, 2000), several core questions remain, particularly profited more from exposure exercises. In the second trial, there about the mechanisms of action and essential contents and ingre- were no differences between the two variants because the therapist dients of the therapy. In the next section, we therefore take the first accompanied the patient during exposure exercise in both variants 320 A.O. Hamm et al.

Clinical Trial 1 Clinical Trial 2

with without with therapist-guidance therapist-guidance therapist-guidance 0 N=31 N=91 N=31 N=73 N=19 N=67

-5

-10 PAS

-15 (Difference Scores)

-20 BAT Avoiders BAT Non-Avoiders

Figure 4. Mean scores and standard deviations of the reduction in reported panic symptom and agoraphobia severity assessed with the Panic and Ago- raphobia Scale (PAS) from baseline to postassessment in treatment completers. Treatment outcome for patients showing active or passive avoidance in the BAT prior to therapy compared to those patients who completed the task from the first multicenter randomized trial (left: separated by the two treatment variants) and the second clinical trial (right).

(avoidance F(1, 82) 5 6.24; p < .05; avoidance x treatment variant dimensional construct defensive reactivity to approaching threat. F(1, 82) 5 0.46; p 5 .50). Comparable results were also obtained Using the defense cascade model derived from behavioral neuro- after controlling for baseline differences in the PAS scores. The cur- science research with animals and humans, we proposed a dynamic rent data provide first evidence that behavioral avoidance measured view stating that defensive responses vary on a dimension of threat in a standardized situation, as one component of defensive reactiv- imminence. Moreover, we presented evidence that these different ity, is related to the outcome of CBT. Even more important, there is defensive behaviors are related to different neural circuits in the an interaction between avoidance behavior prior to therapy and the brain. In the next step, we linked this model about behavior–brain effect of active ingredients of CBT. Exposure exercises outside the relationships to clinical problems. We report evidence showing that therapy room seem to be particularly effective for patients with high panic attacks can be considered as fear responses to acute threat avoidance disposition when the therapist actively accompanies with the urge for active avoidance/escape when threat stimuli from them. This variant of active exposure is not as relevant if patients do inside the body are imminent. We found that this component of not show very strong tendencies for active or passive avoidance defensive reactivity is related to the serotonergic system and prior to therapy. For those patients, it is equally effective to plan and responds better to exposure treatment if the therapist guides the discuss exposure exercises with them and then instruct them to do patient throughout the exposure exercises in vivo. A different com- the exposure exercises by themselves. ponent of the clinical problem, anxious apprehension to potential threat—characterized by attentive freezing during postencounter Conclusions defense—seems to be related to general distress and depressive mood, as well as to genetic modulations within the HPA axis and is Consistent with the goals of the RDoC initiative, we tried to activated to more proximal threat. Whether increased attentive develop an interdisciplinary approach conceptualizing the psycho- freezing can also be related to therapy outcome or specific compo- pathology of the categorical diagnosis—PD/AG—in terms of the nents of CBT (e.g., cognitive strategies) is still an open question.

References

Alius, M. G., Pane-Farre, C. A., Von Leupoldt, A., & Hamm, A. O. (2013). American Psychiatric Association. (2013). Diagnostic and statistical man- Induction of dyspnea evokes increased anxiety and maladaptive breath- ual of mental disorders, 5th ed., DSM-5. Arlington, VA: Author. ing in individuals with high anxiety sensitivity and suffocation fear. Arrindell, W. A., Cox, B. J., Van der Ende, J., & Kwee, M. G. (1995). Phobic Psychophysiology, 50, 488–497. doi: 10.1111/psyp.12028 dimensions—II. Cross-national confirmation of the multidimensional American Psychiatric Association. (1987). Diagnostic and statistical man- structure underlying the Mobility Inventory (MI). Behaviour Research ual of mental disorders, 3th ed., rev., DSM-III-R. Arlington, VA: and Therapy, 33, 711–724. doi: 10.1016/0005-7967(95)00002-F Author. Beck, A. T., & Emery, G. (1985). Anxiety disorders and phobias: A cogni- American Psychiatric Association. (2000). Diagnostic and statistical man- tive perspective. New York: Basic Books. ual of mental disorders, 4th ed., text rev., DSM-IV-TR. Arlington, VA: Beninger, R. J. (1989). The role of serotonin and dopamine in learning to Author. avoid aversive stimuli. In T. Archer & L.-G. Nilsson (Eds.), Aversion, Panic disorder with agoraphobia 321

avoidance, and anxiety: Perspectives on aversively motivated behavior of the etiology of panic disorder. Restorative Neurology and Neuro- (pp. 265–288). Hillsdale, NJ: Erlbaum. science, 32, 79–93. doi: 10.3233/RNN-139011 Blanchard, D. C. (1997). Stimulus, environmental, and pharmacological Hamm, A. O., & Weike, A. I. (2005). The neuropsychology of fear learn- control of defensive behaviors. In M. E. Bouton & M. S. Fanselow ing and fear regulation. International Journal of Psychophysiology, 57, (Eds.), Learning, motivation, and cognition: The functional behavior- 5–14. doi: 10.1016/j.ijpsycho.2005.01.006 ism of Robert C. Bolles (pp. 283–303). Washington, DC: American Hohoff, C., Weber, H., Richter, J., Domschke, K., Zwanzger, P. M., Psychological Association. Ohrmann, P., ...& Deckert, J. (2015). RGS2 genetic variation: Associ- Bouton, M. E., Mineka, S., & Barlow, D. H. (2001). A modern learning ation analysis with panic disorder and dimensional as well as intermedi- theory perspective on the etiology of panic disorder. Psychological ate phenotypes of anxiety. American Journal of Medical Genetics Part Review, 108, 4–32. doi: 10.1037/0033-295x.108.1.4 B: Neuropsychiatric Genetics, 168, 211–222. doi: 10.1002/ Campbell, B. A., Wood, G., & McBride, T. (1997). Origins of orienting ajmg.b.32299 and defensive responses: An evolutionary perspective. In P. J. Lang, R. Kim, E. J., Horovitz, O., Pellman, B. A., Tan, L. M., Li, Q., Richter-Levin, F. Simons, & M. T. Balaban (Eds.), Attention and orienting: Sensory G., & Kim, J. J. (2013). Dorsal periaqueductal gray-amygdala pathway and motivational processes (pp. 41–67). Hillsdale, NJ: Erlbaum. conveys both innate and learned fear responses in rats. Proceedings of Cannon, W. B. (1932). The wisdom of the body. New York: Norton. the National Academy of Sciences, 110, 14795–14800. doi: 10.1073/ Canteras, N. S., & Graeff, F. G. (2014). Executive and modulatory circuits pnas.1310845110 of defensive reactions: Implications for panic disorder. Neuroscience Klein, D. F. (1993). False suffocation alarms, spontaneous panics, and and Biobehavioral Reviews, 46, 352–364. doi: 10.1016/ related conditions: An integrative hypothesis. Archives of General Psy- j.neubiorev.2014.03.020 chiatry, 50, 306–317. doi: 10.1001/archpsyc.1993.01820160076009 Cohen, A. S., Barlow, D. H., & Blanchard, E. B. (1985). The psychophysi- Kozak, M. J., & Cuthbert, B. N. (2016). The NIMH Research ology of relaxation-associated panic attacks. Journal of Abnormal Psy- Domain Criteria initiative: Background, issues, and pragmatics. Psy- chology, 94, 96–101. doi: 10.1037/0021-843x.94.1.96 chophysiology, 53, 286–297. Cox, B. J., Swinson, R. P., Kuch, K., & Reichman, J. T. (1993). Dimen- Kwon, S. M., Evans, L., & Oei, T. P. (1990). Factor structure of the Mobil- sions of agoraphobia assessed by the Mobility Inventory. Behaviour ity Inventory for agoraphobia: A validational study with Australian Research and Therapy, 31, 427–431. doi: 10.1016/0005- samples of agoraphobic patients. Journal of Psychopathology and 7967(93)90102-z Behavioral Assessment, 12, 365–374. doi: 10.1007/bf00965990 Craske, M. G. (1999). Anxiety disorders: Psychological approaches to Lang, P. J., Bradley, M. M., & Cuthbert, B. N. (1997). Motivated attention: theory and treatment. New York: Basic Books. Affect, activation, and action. In P. J. Lang, R. F. Simons, & M. T. Craske, M. G., Rapee, R. M., & Barlow, D. H. (1988). The significance of Balaban (Eds.), Attention and orienting: Sensory and motivational panic-expectancy for individual patterns of avoidance. Behavior Ther- processes (pp. 97–135). Hillsdale NJ: Erlbaum. apy, 19, 577–592. doi: 10.1016/s0005-7894(88)80025-x Lang, P. J., Davis, M., & Ohman,€ A. (2000). Fear and anxiety: Animal Cuthbert, B. N., & Insel, T. R. (2013). Toward the future of psychiatric models and human cognitive psychophysiology. Journal of Affective diagnosis: The seven pillars of RDoC. BMC Medicine, 11, 126. doi: Disorders, 61, 137–159. doi: 10.1016/s0165-0327(00)00343-8 10.1186/1741-7015-11-126 LeDoux, J. (2012). Rethinking the emotional brain. Neuron, 73, 653–676. Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010). Phasic vs sus- doi: 10.1016/j.neuron.2012.02.018 tained fear in rats and humans: Role of the extended amygdala in fear Ley, R. (1985). Blood, breath, and fears: A hyperventilation theory of vs anxiety. Neuropsychopharmacology, 35, 105–135. doi: 10.1038/ panic attacks and agoraphobia. Clinical Psychology Review, 5, 271– npp.2009.109 285. doi: 10.1016/0272-7358(85)90008-x Davis, M., & Whalen, P. J. (2001). The amygdala: Vigilance and emotion. L€ow, A., Lang, P. J., Smith, J. C., & Bradley, M. M. (2008). Both predator Molecular Psychiatry, 6, 13–34. doi: 10.1038/sj.mp.4000812 and prey emotional arousal in threat and reward. Psychological Science, Deckert, J., Catalano, M., Syagailo, Y. V., Bosi, M., Okladnova, O., Di 19, 865–873. doi: 10.1111/j.1467-9280.2008.02170.x Bella, D., ... & Lesch, K. P. (1999). Excess of high activity monoa- L€ow, A., Weymar, M., & Hamm, A. O. (in press). When threat is near get mine oxidase A gene promoter alleles in female patients with panic dis- out of here: Dynamic of defensive behavior during freezing and escape. order. Human Molecular Genetics, 8, 621–624. doi: 10.1093/hmg/ Psychological Science. 8.4.621 Maren, S. (2001). Neurobiology of Pavlovian fear conditioning. Domschke, K., Reif, A., Weber, H., Richter, J., Hohoff, C., Ohrmann, P., Annual Review of Neuroscience, 24, 897–931. doi: 10.1146/ ... & Deckert, J. (2010). Neuropeptide S receptor gene—Converging annurev.neuro.24.1.897 evidence for a role in panic disorder. Molecular Psychiatry, 16, 938– Maron, E., Lang, A., Tasa, G., Liivlaid, L., Toru, I., Must, A., ...& Shlik, 948. doi: 10.1038/mp.2010.81 J. (2005). Associations between serotonin-related gene polymorphisms Fanselow, M. S. (1994). Neural organization of the defensive behavior sys- and panic disorder. The International Journal of Neuropsychopharma- tem responsible for fear. Psychonomic Bulletin & Review, 1, 429–438. cology, 8, 261–266. doi: 10.1017/s1461145704004985 doi: 10.3758/bf03210947 McNally, R. J. (1994). Panic disorder: A critical analysis. New York: Gloster, A. T., Hauke, C., H€ofler, M., Einsle, F. Fydrich, T., Hamm, A., Guilford. Str€ohle, A., & Wittchen, H.-U. (2013). Long-term stability of cognitive McTeague, L. M., Lang, P. J., Laplante, M.-C., & Bradley, M. M. (2011). behavioral therapy effects of panic disorder with agoraphobia: A two- Aversive imagery in panic disorder: Agoraphobia, severity, comorbid- year follow-up study. Behaviour Research and Therapy, 51, 830–839. ity, and defensive physiology. Biological Psychiatry, 70, 415–424. doi: doi: 10.1016/j.brat.2013.09.009 10.1016/j.biopsych.2011.03.005 Gloster, A. T., Klotsche, J., Gerlach, A. L., Hamm, A., Str€ohle, A., Melzig, C. A., Holtz, K., Michalowski, J. M., & Hamm, A. O. (2011). Gauggel, S., ... &Wittchen, H.-U. (2014). Timing matters: change Interoceptive threat leads to defensive mobilization in highly anxiety depends on the stage of treatment in cognitive behavioral therapy for sensitive persons. Psychophysiology, 48, 745–754. doi: 10.1111/j.1469- panic disorder with agoraphobia. Journal of Consulting and Clinical 8986.2010.01150.x Psychology. 82, 141–153. doi: 10.1037/a0034555 Meuret, A. E., Rosenfield, B., Wilhelm, F. H., Zhou, E., Conrad, A., Gloster, A. T., Wittchen, H.-U., Einsle, F., H€ofler, M., Lang, T., Helbig- Ritz, T., & Roth, W. T. (2012). Do unexpected panic attacks occur Lang, S., ...& Arolt, V. (2009). Mechanisms of action in CBT (MAC): spontaneously? Biological Psychiatry, 70, 985–991. doi: 10.1016/ Methods of a multi-center randomized controlled trial in 369 patients j.biopsych.2011.05.027 with panic disorder and agoraphobia. European Archives of Psychiatry Michalowski, J. M., Melzig, C. A., Stockburger, J., Schupp, H. T., & and Clinical Neuroscience, 259, 155–166. doi: 10.1007/s00406-009- Hamm, A. O. (2009). Brain dynamics of spider-phobic individuals 0065-6 exposed to phobia-relevant and other emotional stimuli. Emotion, 9, Gloster, A. T., Wittchen, H.-U., Einsle, F., Lang, T., Helbig-Lang, S., 306–315. doi: 10.1037/a0015550 Fydrich, T., ... & Arolt, V. (2011). Psychological treatment for panic Michalowski, J. M., Pane-Farre, C. A., L€ow, A., & Hamm, A. O. (2015). disorder with agoraphobia: A randomized controlled trial to examine Brain dynamics of visual attention during anticipation and encoding of the role of therapist-guided exposure in-situ in CBT. Journal of Con- threat- and safe cues in spider phobic individuals. Social Cognitive and sulting and Clinical Psychology, 79, 406–420. doi: 10.1037/a0023584 Affective Neuroscience, 10, 1177–1186. doi: 10.1092/scan/nsv002 Hamm, A. O., Richter, J., & Pane-Farre, C. A. (2014). When the threat Miller, H. E. J., Deakin, J. F. W., & Anderson, I. M. (2000). Effect of acute comes from inside the body: A neuroscience based learning perspective tryptophan depletion on CO2-induced anxiety in patients with panic 322 A.O. Hamm et al.

disorder and normal volunteers. The British Journal of Psychiatry, 176, Rodriguez, B. F., Pagano, M. E., & Keller, M. B. (2007). Psychometric 182–188. doi: 10.1192/bjp.176.2.182 characteristics of the Mobility Inventory in a longitudinal study of anxi- Morgan, M. M., & Carrive, P. (2001). Activation of the ventrolateral peria- ety disorders: Replicating and exploring a three-component solution. queductal gray reduces locomotion but not mean arterial pressure in Journal of Anxiety Disorders, 21, 752–761. doi: 10.1016/ awake, freely moving rats. Neuroscience, 102, 905–910. doi: 10.1016/ j.janxdis.2006.08.008 s0306-4522(00)00513-3 Samochowiec, J., Hajduk, A., Samochowiec, A., Horodnicki, J., Stepien, Naragon-Gainey, K. (2010). Meta-analysis of the relations of anxiety sensi- G., Grzywacz, A., & Kucharska-Mazur, J. (2004). Association studies tivity to the depressive and anxiety disorders. Psychological Bulletin, of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with 136, 128–150. doi: 10.1037/a0018055 anxiety disorders of the phobic spectrum. Psychiatry Research, 128, Nashold, B. S. Jr., Wilson, W. P., & Slaughter, G. S. (1974). The midbrain 21–26. doi: 10.1016/j.psychres.2004.05.012 and pain. In J. J. Bonica (Ed.), Advances in neurology, Vol 4 (pp. 191– Sanchez-Meca, J., Rosa-Alcazar, A. I., Marin-Martinez, F., & Gomez- 196). New York: Raven Press. Conesa, A. (2010). Psychological treatment of panic disorder with or Ost,€ L. G., Johansson, J., & Jerremalm, A. (1982). Individual response pat- without agoraphobia: A meta-analysis. Clinical Psychology Review, 30, terns and the effects of different behavioral methods in the treatment of 37–50. doi: 10.1016/j.cpr.2009.08.011 claustrophobia. Behaviour Research and Therapy, 20, 445–460. doi: Schenberg, L. C., Schimitel, F. G., de Souza Armini, R., Bernabe, C. S., 10.1016/0005-7967(82)90066-3 Rosa, C. A., Tufik, S., ...& Quintino-dos-Santos, J. W. (2014). Trans- Otto, M. W., Pollack, M. H., & Maki, K. M. (2000). Empirically supported lational approach to studying panic disorder in rats: Hits and misses. treatments for panic disorder: Costs, benefits, and stepped care. Journal Neuroscience & Biobehavioral Reviews, 46, 472–496. doi: 10.1016/ of Consulting and Clinical Psychology, 68, 556–563. doi: 10.1037/ j.neubiorev.2014.10.002 0022-006x.68.4.556 Schimitel, F. G., De Almeida, G. M., Pitol, D. N., Armini, R. S., Tufik, S., Pane-Farre, C. A., Fenske, K., Stender, J. P., Meyer, C., John, U., Rumpf, & Schenberg, L. C. (2012). Evidence of a suffocation alarm system H. J., ... Hamm, A. O. (2013). Sub-threshold panic attacks and agora- within the periaqueductal gray matter of the rat. Neuroscience, 200, phobic avoidance increase comorbidity of mental disorders: Results 59–73. doi: 10.1016/j.neuroscience.2011.10.032 from an adult general population sample. Journal of Anxiety Disorders, Schmidt, N. B., Zvolensky, M. J., & Maner, J. K. (2006). Anxiety sensitiv- 27, 485–493. doi: 10.1016/j.janxdis.2013.06.008 ity: Prospective prediction of panic attacks and Axis I pathology. Jour- Pane-Farre, C. A., Stender, J. P., Fenske, K., Deckert, J., Reif, A. John, U., nal of Psychiatric Research, 40, 691–699. doi: 10.1016/ ... & Hamm, A. O. (2014). The phenomenology of the first panic j.jpsychires.2006.07.009 attack in clinical and community based samples. Journal of Anxiety Schumann, G., Binder, E. B., Holte, A., de Kloet, E. R., Oedegaard, K. J., Disorders, 28, 5222528. doi: 10.1016/j.janxdis.2014.05.009 Robbins, T. W., Wittchen, H.-U. (2014). Stratified medicine for mental Preter, M., & Klein, D. F. (2008). Panic, suffocation false alarms, separa- disorders. European Neuropsychpharmacology, 24, 5–50. doi: 10.1016/ tion anxiety and endogenous opioids. Progress in Neuro- j.euroneuro.2013.09.010 Psychopharmacology and Biological Psychiatry, 32, 603–612. Straube, B., Reif, A., Richter, J., Lueken, U., Weber, H., Arolt, V., ... & Rachman, S., Levitt, K., & Lopatka, C. (1988). Experimental analyses of Kircher, T. (2014). The functional21019C/G HTR1A polymorphism panic—III–claustrophobic subjects. Behaviour Research and Therapy, and mechanisms of fear. Translational Psychiatry, 4, e490. doi: 26, 41–52. doi: 10.1016/0005-7967(88)90032-0 10.1038/tp.2014.130 Rachman, S., & Taylor, S. (1993). Analyses of claustrophobia. Journal of Taylor, S., & Rachman, S. (1994). Klein’s suffocation theory of panic. Anxiety Disorders, 7, 281–291. doi: 10.1016/0887-6185(93)90025-g Archives of General Psychiatry, 51, 505–506. doi: 10.1001/ Radomsky, A. S., Rachman, S., Thordarson, D. S., McIsaac, H. K., & archpsyc.1994.03950060069011 Teachman, B. A. (2001). The claustrophobia questionnaire. Journal of Weber, H., Richter, J., Straube, B., Lueken, U., Domschke, K., Schartner, Anxiety Disorders, 15, 287–297. doi: 10.1016/j.pnpbp.2007.07.029 C., ... & Reif, A. (2015). Allelic variation in CRHR1 predisposes to Reif, A., Richter, J., Straube, B., H€ofler, M., Lueken, U., Gloster, A. T., ... panic disorder by biasing towards fear. Molecular Psychiatry advance & Deckert, J. (2014). MAOA and mechanisms of panic disorder revis- online publication. doi: 10.1038/mp.2015.125 ited: From bench to molecular psychotherapy. Molecular Psychiatry, Westphal, C. (1871). Die Agoraphobie: Eine neuropathische Erscheinung 19, 122–128. doi: 10.1038/mp.2012.172 (The agoraphobia: A neuropathic phenomenon). Archiv fuer Psychia- Reiss, S. (1991). Expectancy model of fear, anxiety, and panic. Clinical trie und Nervenkrankheiten, 3, 13–171. Psychology Review, 11, 141–153. doi: 10.1016/0272-7358(91)90092-9 Wittchen, H.-U., Gloster, A. T., Beesdo-Baum, K., Fava, G. A., & Craske, Reiss, S., Peterson, R. A., Gursky, D. M., & McNally, R. J. (1986). Anxiety M. G. (2010). Agoraphobia: A review of the diagnostic classificatory sensitivity, anxiety frequency and the prediction of fearfulness. Behav- position and criteria. Depression and Anxiety, 27, 113–133. doi: iour Research and Therapy, 24, 1–8. doi: 10.1016/0005- 10.1002/da.20646 7967(86)90143-9 Wittchen, H.-U., Knappe, S., Andersson, G., Araya, R., Rivera, R. M. B., Rescorla, R. A., & Wagner, A. (1972). A theory of Pavlovian conditioning: Barkham, M., ... & Schumann, G. (2014). The need for a behavioural Variations in the effectiveness of reinforcement and nonreinforcement. science focus in research on mental health and mental disorders. Inter- In A. H. Black & W. F. Prokasy (Eds.), Classical conditioning II: Cur- national Journal of Methods in Psychiatric Research, 23, 28–40. doi: rent research and theory (pp. 64–99). New York: Appleton-Century- 10.1002/mpr.1409 Crofts. World Health Organization. (1992). The ICD-10 classification of mental Richter, J., Hamm, A. O., Pane-Farre, C. A., Gerlach, A. L., Gloster, A. T., and behavioural disorders: Clinical descriptions and diagnostic guide- Wittchen, H. U., ...& Arolt, V. (2012). Dynamics of defensive reactiv- lines. Geneva, Switzerland: Author. ity in patients with panic disorder and agoraphobia: Implications for the etiology of panic disorder. Biological Psychiatry, 72, 512–520. doi: 10.1016/j.biopsych.2012.03.035 (RECEIVED February 9, 2015; ACCEPTED August 1, 2015)