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Neuropsychoanalysis, 2010, 12 (1) 67

An Integrated Model of Disorder

Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg (New York)

Clinicians are shifting away from dualistic conceptions of mind and brain toward a view of psychiatric illnesses as involving interac- tions between biology, mind, and environment. Our understanding of benefits from such an integrative analysis. We review genetic, neurochemical, and data on panic disorder, along with a series of biological and psychological models. We propose that separation and suffocation alarm systems cut across various models, and we suggest how biological, psychological, and environmental interactions can lead to panic onset and persistence. Separation and suffocation alarm systems may become sensitized due to environmental events, an inborn , or both. These oversensitized systems create a vulnerability to envi- ronmental experiences of loss and intrusion and to frightening psychological experiences of separation and suffocation. In individuals with this vulnerability, angry and fantasies, often unconscious, further intensify of loss of or intrusion by attachment figures, triggering separation and suffocation alarms and associated panic attacks. This model provides a basis for understanding how psychological and biological approaches different components of these interactive systems, leading to relief of panic symptoms. We discuss implications of this integrative model for current clinical practice and future research.

Keywords: panic disorder; integrated model; suffocation alarm; separation distress; intrapsychic conflict; clinical implications

Increasingly, clinicians are moving away from dual- as the interactions between genotype and environ- istic conceptions of mind and brain toward view- ment on behaviors and the impact of psychosocial fac- ing illnesses as both biological and mental (Kendler, tors and psychotherapy on the brain. For instance, in 2005). In addition, psychiatric disorders can develop males followed prospectively, the degree of antisocial from the interaction of mind and brain: subjective behavior was related to an interaction between child- experiences affect the brain and body, and brain pro- hood maltreatment and having the low MAO-A activ- cesses affect the mind. Complex interactions also oc- ity genotype (Caspi et al., 2002). Caspi et al. (2003) cur between genetic factors, mind, and environment. found that individuals with ss or ls versions of the se- Gabbard (2005), for example, focusing on personal- rotonin transporter promoter gene were found to have ity disorders, emphasized the need to understand and more depressive symptoms and disorders in relation to address both mind and brain. Efforts to delineate the stressful life events in comparison to ll individuals. In contributions of and interactions among these various a study (Fonagy et al., 1996) looking more specifically factors are important in developing etiological models at the interactions between psychology and the envi- and appropriate treatment interventions for specific ronment, the capacity for mentalization—the ability disorders. Such integrative models are consistent with to understand one’s own and others’ behavior in terms Freud’s (1916–17) notion of a “complemental series,” of mental states—was found to mediate the impact of in which biology, psychology, and environment make trauma in the development of borderline personality varying contributions to what he referred to as “choice disorder. of ,” and with Kendler’s (2005) concept of In panic disorder, as with other psychiatric illnesses, integrative pluralism. biological, psychological, and environment fac- Several studies have demonstrated the interaction tors probably interact in complex ways, and various between biology, psychology, and environment, such models have been suggested for its development and

Fredric N. Busch and Larry S. Sandberg: Weill Cornell Medical College, New York, U.S.A.; Maria A. Oquendo and Gregory M. Sullivan: Department of , Columbia University, New York, U.S.A. Correspondence to: Fredric N. Busch, 10 East 78th St., #5A, New York, NY 10075, U.S.A. (email: [email protected]).

© 2010 The International Neuropsychoanalysis • http://www.neuropsa.org 68 Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg persistence. However, most of these models have fo- (Lydiard et al., 1992; Schweizer, Patterson, Rickels, cused primarily on biological or psychological factors & Rosenthal, 1993), are effective in treating panic and have not addressed complex interactions between disorder. them. Building on these models and current evidence, Challenge studies have provided further informa- we propose to delineate potential links between brain, tion about the underlying chemistry. A series of agents mind, and environment in panic disorder. The inte- have been found to induce panic, particularly in panic- grated model suggests how separation and suffocation disorder patients. Inhalation of CO2-enriched air trig- alarm systems cut across various models of panic gers panic, to a greater degree in panic patients than disorder and account for many aspects of the biologi- in healthy controls (Gorman et al., 1994). Yohimbine cal, psychological, and environmental interactions. Im- (Charney, Heninger, & Breier, 1984) triggers panic, plications of an integrated model for current clinical possibly through agonism. Lactate (Li- practice and future research are examined. We briefly ebowitz et al., 1985), caffeine (Klein, Zohar, Geraci, review genetic, neurochemical, and neuroimaging data Murphy, & Uhde, 1991), and cholecystokinin-4 (Brad- on panic disorder, describe a series of models that have wejn & Koszycki, 1994) also induce panic, although been proposed for panic disorder, and then proceed the basis of this induction is unclear. These data have with a discussion of our proposed interactional model. been interpreted as supporting, variously, a false suf- focation alarm model of panic or the existence of an abnormally sensitive network (Klein, 1993; Gor- Genetic man et al., 2000). These data indicate that several neurotransmitters In brief, genetic studies have found increased preva- and homeostatic systems are central to modulation of lence of panic disorder among families of probands and panic, the disruption of which can lead to compared with families of controls, and twin studies panic onset and persistence. These neurotransmitters have demonstrated higher concordance rates among and other agents that affect brain chemistry directly monozygotic than dizygotic twins (Kendler, Neale, impact cortical and subcortical brain structures felt to Kessler, Heath, & Eaves, 1993; Skre, Onstad, Torg- be operative in anxiety and panic. As discussed further ersen, Lygren, & Kringlen, 1993; Torgersen, 1983; in models below, a neurophysiological vulnerability to Weissman et al., 1993). Efforts to identify specific anxiety and panic can have a broad effect on an indi- genes linked to panic have been inconclusive, although vidual’s psychology, creating an increased fearfulness a study by Fyer et al. (2006), using sex-specific recom- about the external world, interpersonal relationships, bination fractions, indicated that chromosomal regions and intrapsychic feelings and fantasies. 2q and 15q were involved in genetic susceptibility to panic disorder. Thus, evidence suggests that a suscep- tibility to panic disorder is inherited (Finn & Smoller, Neuroimaging studies 2001). The neuroimaging literature on panic disorder is com- plicated by the difficulties of studying panic patients Neurochemistry of panic disorder and panic attacks in a scanner and by inconsistencies in findings, as is typical in neuroimaging literature on For our purposes here, we provide a brief overview of psychiatric disorders (Gorman et al., 2000; Oquendo the neurochemistry of panic disorder, which has been & Parsey, 2007). Despite these limitations, functional covered in greater depth in articles focusing on this neuroimaging studies of panic disorder suggest abnor- area (Gorman, Kent, Sullivan, & Coplan, 2000; Stein, malities in subcortical fear-related neural circuitry, and 2005). Dysfunction in numerous neurotransmitter sys- in emotional regulation-related areas of the prefrontal tems has been associated with panic disorder, including cortex (PFC) (Kent & Rauch, 2003). Subcortical ab- serotonin (Targum & Marshall, 1989), norepinephrine normalities include an asymmetry in hippocampal and (Pyke & Greenberg, 1986), gamma-aminobutyric acid parahippocampal activity, typically with right greater (Hasler et al., 2008), and opioids (Preter & Klein, than left (Nordahl et al., 1990), and increased activity 2008). In addition, medications that affect some of in the , hippocampus, , brainstem, these neurotransmitters, such as selective serotonin and cerebellum (Sakai et al., 2005). Cortical abnormal- reuptake inhibitors (Coplan et al., 1997; Viana, Graeff, ities include a decrease or smaller increase in global & Loschmann, 1997), serotonin-norepinephrine reup- cerebral blood flow in panic patients in comparison to take inhibitors (Thase, 2006), and benzodiazepines controls (Ponto et al., 2002; Stewart, Devous, , An Integrated Model of Panic Disorder 69

Lane, & Bonte, 1988; Woods et al., 1988) and a spe- early or more recent experiences, can sensitize the fear cific decrease in the medial PFC regions (Javanmard system or that individuals prone to panic may be more et al., 1999). Notably, effective treatment of panic reactive to traumas due to an oversensitive system. disorder with cognitive-behavioral therapy (CBT) ap- They link phobic avoidance to hippocampus-depen- peared to reverse these abnormalities, with a reduction dent contextual learning and link sensitivity to separa- in activity in the hippocampus, anterior cingulate, cere- tion and overreaction to somatic cues to higher cortical bellum, and pons and increased activity in the medial centers. PFC (Sakai et al., 2006). In terms of treatment, Gorman et al. (2000) hy- Thus, functional imaging studies in panic disorder pothesize that panic symptoms can be diminished via suggest a deficient global cerebral and PFC response “top-down” impact on cortical pathways through psy- during panic, abnormal activity in the subcortical fear chotherapy that overrides automatic amygdala respons- network, and lateralized hippocampal abnormalities. es or “bottom-up” through affecting the brainstem and From these findings a model has been proposed sug- amygdala with medication. It is likely, however, that gesting that panic develops from either hyperactivity in psychological interventions also directly affect sub- the subcortical fear circuitry, deficient cortical control, cortical systems via aspects of the therapeutic relation- or PFC-mediated “braking” of subcortical activity, or a ship (neuroimaging studies, discussed above, suggest combination of these factors (Kent and Rauch, 2003). reduction in limbic and paralimbic activity following The findings are consistent with the models of LeDoux effective psychotherapeutic interventions—Sakai et al. and colleagues (LeDoux, Cicchetti, Xagoraris, & Ro- 2006); thus, psychotherapy may act through a “bot- manski, 1990; LeDoux, Iwata, Cicchetti, & Reis, 1988) tom-up” process. Additionally, medication may affect and of Gorman et al. (2000), described below, includ- cortical structures via the placebo effect. Zubieta et ing other data linking the amygdala and PFC to panic. al. (2005), for example, found significant placebo-in- duced activation of µ-opioid receptor-mediated neuro- transmission in both higher order and subcortical brain Models of panic disorder: biological models regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal An oversensitive fear network cortex, the , and the nucleus accumbens in PET scans of 14 men given a challenge. Al- Gorman et al. (2000) focus on a neuroanatomical basis though Gorman et al. (2000) state that psychodynamic for panic disorder, but they suggest ways in which the therapy may be helpful in dealing with the impact of mind and environment may interact with biology. They early disruptions in attachments, they do not further hypothesize that panic disorder involves dysfunction discuss how the psychodynamic model may inform of the brain’s fear network. This network is centered understanding or treatment of panic disorder. in the amygdala, with afferent neuronal projections from the prefrontal cortex and thalamus, and efferent output projections to the brainstem and hypothala- A separation-distress system mus that mediate particular physiological components of the fear response. The authors note the similarity Panksepp (1998) differentiates a PANIC system in the between the fear reaction of an animal to amygdala brain, associated with separation distress, from a FEAR and a panic attack. Based on the work of system associated with other types of anxiety, such as LeDoux et al. (1988, 1990) and others, they suggest anticipatory anxiety. The separation-distress system, panic may involve a rapid-response system reacting to shared by all mammals, is linked to distress vocaliza- danger-associated stimuli transmitted to the amygdala tions (DVs), which are primitive means of communica- through brainstem and thalamic pathways, unbridled tion by which infants signal the need for parental care. from the inhibitory influence of cortical structures in- Panksepp (1998, 2005) suggests that panic attacks volved in complex processing and evaluation of sen- stem from sudden of the separation-distress sory information. In this model, panic is caused by an system. Consistent with the separation-distress model, “oversensitive fear network” that is inappropriately the limited retrospective epidemiological/ litera- activated secondary to either a problem with the input ture in panic disorder suggests high rates of separation from thalamic and brainstem structures or by a neuro- and losses in panic patients’ developmental history and cognitive deficit that results in inappropriate cortical in the time period preceding panic onset (Faravelli & modulation of the amygdala. Gorman et al. (2000) also Pallanti, 1989; Kaunonen, Paivi, Paunonen, & Erjanti, suggest that environmental factors, such as traumatic 2000). Chemically, separation distress is modulated 70 Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg by opioids, oxytocin, and prolactin, although opioids results from an episodic functional endogenous opioid have the most robust impact. The link between panic deficit, associated with increased sensitivity of both and actual and symbolic separation is a core feature separation and suffocation systems. of the psychodynamic model, with patients having the internal belief or fantasy that they cannot function suc- cessfully on their own. Models of panic disorder: psychological models

The cognitive-behavioral model The false suffocation alarm model The cognitive-behavioral model views panic as devel- Klein (1993) posited a false suffocation alarm model, oping from a learned fearfulness of bodily sensations in which the brain is postulated to have an evolved and agoraphobia as a behavioral response to the an- suffocation alarm system that can be hypersensitive ticipation of those sensations. As described by Craske and can misfire in the absence of an actual suffocation (1988), the model also incorporates biological factors risk. He differentiates panic from a typical emergency as contributory. The initial panic attack develops from fear response in that it includes shortness of breath as a the misfiring of a fear system, often triggered by stress- symptom and does not activate the hypothalamic–pitu- ful life events, in psychologically and physiologically itary–adrenal axis. From the psychological standpoint, vulnerable individuals. The physiological vulnerability suffocation fears can represent the experience of a con- is viewed as hyperactivity or lability in the autonomic trolling or intrusive parent, a danger that can become nervous system. The psychological vulnerability is a internalized, or a of being trapped by conflicted set of danger-laden beliefs about physical sensations feelings (see the psychodynamic model below). or about the world in general. These beliefs can be generated by life experiences, such as traumatic losses, or by repeated warnings from overprotective parents The opioid-deficit model about the danger of the world or potential physical illnesses. Stressful life events can trigger panic by en- Evidence suggests that opioids are importantly in- hancing neurophysiological arousal or priming cogni- volved in separation and suffocation systems in the tive schema. brain that are believed to be related to panic (Preter The first panic attack is a traumatic event, and con- & Klein, 2008). Opioids trigger comfort feelings and ditioned cues from the first attack, such as specific reduce distress from loss and social . DVs are physical sensations, trigger recurrences of panic, per- reduced by opioids. Suffocation sensitivity is also di- haps outside the patient’s awareness. Patients develop minished by opioids, allowing, for example, increased heightened arousal, scanning for symptoms confirming tolerance of high CO2 levels in subjects. Sinha, their sense of danger, and the heightened arousal leads Goetz, and Klein (2007) found that the opioid antago- to an increase in the somatic sensations accompanying nist naloxone, given before a lactate infusion, led nor- anxiety. Thus, a vicious cycle—fear of fear—develops: mal subjects to show respiratory tidal volumes similar a physical sensation is misappraised, generating fear to those found in panic attacks. arousal and an increase in physical sensations, lead- In a more recent, expanded version of the false suf- ing to increased misappraisal and fear, and ultimately focation alarm model, Preter and Klein (2008) suggest a panic attack. Agoraphobia is one method of a link between separation and suffocation models from with the of having a panic attack, as it al- the biological standpoint. They acknowledge the im- lows the individual to avoid situations in which it is portance of separation sensitivity in panic, noting the feared that panic occur. frequency of sudden loss and bereavement as precipi- Despite its emphasis on learning models and be- tants of panic (Faravelli and Pallanti, 1989; Kaunonen havioral treatment, cognitive-behavioral theory posits et al., 2000) and panic patients’ frequent history of sep- a role for biologically sensitized fear systems in the aration-anxiety disorder. They agree with Panksepp’s development and persistence of panic. Although not- (1998) delineation of a separation-distress system in ing that developmental experiences may contribute the brain importantly linked to separation anxiety and to panic onset, and that panic triggers may be uncon- panic. Preter and Klein (2008) propose that the sepa- scious, cognitive-behavioral models do not view these ration-distress and the suffocation alarm system are factors as central in treatment and do not note a role for linked via the opioid system, which the evidence above intrapsychic conflict, as found in the psychodynamic suggests modulates both. They hypothesize that panic model discussed below. An Integrated Model of Panic Disorder 71

A psychodynamic model addition, other studies had found anger as an accom- paniment in some instances to panic attacks and the Busch et al. (1991) and Shear, Cooper, Klerman, existence of anger attacks with similar symptoms to Busch, and Shapiro (1993) proposed psychodynamic panic (Fava, Anderson, & Rosenbaum, 1990), except models of panic disorder, developed from psycho- with anger rather than anxiety as the primary affect. analytic theory, clinical experience, and psychological More recent systematic psychological studies of panic studies of patients with panic disorder. Based in part patients have found increased rates of suppressed or on the research of Kagan and colleagues (Biederman et expressed anger compared to controls (Baker, Hollo- al., 1990; Kagan et al., 1990; Rosenbaum, Biederman, way, Thomas, Thomas, & Owens, 2004). Hirshfeld, Bolduc, & Chaloff, 1991; Rosenbaum et al., Shear et al. (1993) also noted that “Some panic- 1988), these models posit that individuals vulnerable vulnerable individuals are sensitive to separation and to panic disorder have a temperamentally based fear overly reliant on others, but others are sensitive to of the unfamiliar, leading them to feel more dependent suffocation and overly reliant on a sense of indepen- on their parents to provide a sense of safety. Fearful dence” (p. 862). Thus panic patients are attempting dependency can also stem from developmental trau- to psychologically manage suffocation and separation mas, such as temperamental or controlling behavior or fears. Below we suggest that mental representations abandonment threats by the parents. Due to underlying of these fears can trigger neurophysiologically based insecurity or frightening parental behavior, the child separation and suffocation alarms. experiences parents as unreliable or rejecting, trig- This psychodynamic theory is consistent with and gering angry feelings. The dependency can become a in part derived from Bowlby’s theories of attachment narcissistic injury, as the child feels inadequate due to (1973) and subsequent applications of this theory in his need for the parents’ help. To ward off feelings of psychoanalytic theorizing, clinical work, and research. injury, the sense of incapability may be blamed on the Bowlby (1973) postulated that anxious attachment—a parents, causing further anger. concept related to fearful dependency, as described The anger at the parents becomes threatening due above—typically develops from disruptive experi- to its being experienced as a potential disruption to ences during childhood, including separation from or needed attachments. The ego attempts to manage an- loss of attachment figures, abandonment threats, or ger and separation fears unconsciously via defenses, parental conflicts. Individuals develop internal work- particularly , reaction formation, and undoing. ing models of attachment figures as unresponsive or As an adult, a stressor involving a perceived or actual inconsistent, creating a vulnerability to subsequent loss or attachment threat intensifies feelings of aban- psychopathology, particularly in the setting of loss or donment and anger. A vicious cycle develops of fearful separation. dependency, anxiety, , and anger, leading to more Several types of studies suggest that patients with fearful dependency. This cycle induces the failure of panic disorder and agoraphobia have been affected defenses and panic onset. This constellation of con- by disruptions in attachment, although these results flicted anger and fearful dependency exacerbates the may be affected by retrospective assessment (Peter, vulnerability to persistence and recurrence of panic. Brückner, Hand, & Rufer, 2005). Studies indicate that An inhibition of (due to assertiveness patients with panic disorder and agoraphobia perceive being connected to anger and autonomy, and therefore their parents as having provided low levels of care and dangerous) interferes with potential resolution of in- high levels of protection (referred to as “affectionless terpersonal problems that would reduce overall stress control”), compared to subjects without known psy- levels and relieve the intensity of the underlying anger. chiatric disorders (Faravelli et al., 1991; Leon & Leon, Consciously or unconsciously experienced anger and 1990; Pacchierotti et al., 2002; Silove, 1986; Wiborg abandonment fears remain a threat and can lead to & Dahl, 1997). Adults with panic disorder have been panic attacks through environmental or internal fantasy found to have experienced a higher rate of traumatic triggers. life events as children compared to control subjects These models give a prominent place to the threat (Faravelli, Webb, Ambonetti, Fonnesu, & Sessarego, of angry feelings—which are often unconscious—dis- 1985; Peter et al., 2005). Several studies (Faravelli & rupting needed attachments. Observations about the Pallanti, 1989; Kaunonen et al., 2000; Milrod, Leon, role of anger in panic stemmed from clinical evaluation & Shear, 2004) indicate that a significant loss or sepa- of a series of panic patients given semi-structured psy- ration frequently precedes the onset of panic disorder chodynamic interviews, as well as subsequent clinical in adults. In a study of attachment styles in adults, experience (Busch et al., 1991; Shear et al., 1993). In anxious attachment was found to be more related to 72 Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg separation anxiety than to panic disorder itself (Mani- psychodynamic and cognitive behavioral treatments, cavasagar, Silove, Marnane, & Wagner, 2009) as both work to help patients identify their symptoms Models regarding the development of panic disorder as derived from mental states rather than from realistic have been proposed in which problems in attachment dangers. are a central theme. For instance, Mattis and Ollen- dick (1997) suggest that children with certain tempera- mental , such as high distress reactivity, Impact of environmental factors which is not relieved by a caretaker, develop insecure attachment. Their inability to experience separation Many studies have demonstrated the presence of en- without significant distress will lead to an anxious vironmental stressors both pre-panic and in early life fear of the recurrence of separation and its associated (Faravelli & Pallanti, 1989; Faravelli et al., 1985; Kau- alarms. Davila, Ramsay, Stroud, and Steinberg (2005) nonen et al., 2000; Milrod, Leon, & Shear, 2004; Peter note how caretakers’ inability to respond effectively et al., 2005), particularly loss and separation experi- to the child can cause impairments in affect regula- ences. In reviewing the above models, the environment tion, creating a vulnerability to extreme affect, such can play a role in panic in several ways: (1) Stressors, as that found in panic disorder. Thus, in various ways, either early in life or pre-panic, could sensitize the insecure attachment increases the likelihood that the biologically based fear system, and/or they could set separation-distress system, which we associate with off a psychological fear of traumatic separation. (2) A panic disorder, will be triggered in the context of actual biological and/or psychological (temperamental) vul- or symbolic separation. nerability can increase the likelihood that a traumatic event will trigger panic or (3) a biological and/or psy- chological vulnerability can increase the likelihood A mentalization model that an event will be viewed or experienced as trau- matic. Bystritsky et al. (2001), after examining fMRI Fonagy, Gergely, Jurist, and Target (2005) have pro- in panic patients exposed to anxiety-provoking situa- posed that many psychiatric disorders involve a com- tions, speculated that the structures showing increased ponent of disruptions in mentalization—the capacity activity were part of a neural circuit related to retrieval to perceive and interpret the behavior in oneself and of strong emotional events, facilitating recapitulation others as deriving from intentional mental states. Such of traumatic experiences. disruptions can develop from problematic mirroring From the psychological standpoint, fearful depen- by the parent for the developing child. Fonagy et al. dency and negative self and object representations (2005) posit that such mirroring deficits interfere with that precede panic attacks likely interfere in managing the capacity to accurately identify anxiety and associ- stressors that contribute to panic onset. For instance, ated physiological changes, leading to catastrophic a patient’s unassertiveness can interfere with his cop- misinterpretation of these bodily experiences as being ing with a difficult problem with a boss or spouse, dangerous. Such individuals are prone to operating in intensifying frightening angry fantasies. Current life the mode of “psychic equivalence,” equating panic stressors, frequently losses or significant separations, symptoms to real dangers rather than the product of can trigger panic through direct traumatic impact or a mental state. Rudden, Milrod, Aronson, and Target through their meaningful link with earlier developmen- (2008) have furthered this concept of disrupted mental- tal traumas. For example, a patient’s conflict with a boss ization and panic disorder, focusing on panic patients’ can trigger fears of early-life abandonment threats by lack of awareness of mental states and environmen- parents. tal experiences contributing to their panic symptoms. Thus, panic patients view symptoms as appearing “out of the blue” rather than deriving from psychologically An integrative model threatening experiences (such as separation), which then trigger conflicted feelings (such as anger) and Alexander, Feigelson, and Gorman (2005) suggested an fantasies that are felt to be dangerous. Rudden et al. integrated model of panic disorder, based on Pavlovian (2008) developed a measure of panic-specific reflective models of the acquisition of conditioned fear and acti- functioning to assess whether improving mentalization vation of the amygdala. They proposed that classical for panic patients regarding their panic symptoms is conditioning and associated neural connections estab- associated with improvement in the disorder. Improved lished in early life are in part responsible for panic in mentalization may also be a bridging concept between adulthood. These connections derive from the danger An Integrated Model of Panic Disorder 73 situations described by Freud (1926 [1925]), includ- A proposed integrated model ing loss of the object, loss of , castration anxiety, and superego anxiety. They hypothesize that memories Despite the tendency to focus on psychological or of danger situations are synaptically connected to the biological contributions, there has been a striking con- lateral nucleus of the amygdala; thus, traumatic ex- vergence of various models of panic disorder as de- periences are stored in the amygdala. Stimulation of scribed in the major formulations above. The models these neurons in adulthood triggers the sympathetic typically include an oversensitized biological system nervous system and panic attacks. Seemingly harmless that “fires” inappropriately, and most of them include environmental and internal stimuli can trigger panic a psychologically based vulnerability. They involve an unconsciously through associations to prior danger imbalance between overactivated subcortical structures situations stored in the amygdala. An environmental or and inadequately inhibiting cortical structures. In addi- internal trigger may also be contextual, and it may be tion, disrupted attachment and separation are recurrent dependent on the hippocampus for providing a repre- themes in the biological and psychodynamic models of sentation of context to the amygdala. panic. In some biological models, panic disorder de- Alexander, Feigelson, and Gorman (2005) addition- velops from a neurophysiological defect, a pathologi- ally suggest that panic derives from a weak ego and cally low threshold for an inborn fear response, linked associated less effective ego defenses, interfering with to separation anxiety. This theory is echoed and devel- modulation of anxiety. Here, ego functions correspond oped further in Panksepp’s separation-distress model neuroanatomically to the ventromedial PFC, which is (1998) and Preter and Klein’s (2008) endogenous opi- involved in extinction of fear-conditioned responses oid-deficit model. Busch et al. (1991) and Shear et al. via neurons projecting to the amygdala and is associ- (1993) emphasize how a biologically based separation ated with relatively lower activity in anxious patients. sensitivity can broadly affect an individual’s tempera- Thus, in panic patients there is an inability to use logic ment and psychological functioning, increasing the to suppress more fear-inducing circuits of the brain. likelihood of psychological separation fears that can These psychological configurations echo the imbalance trigger panic. Klein’s biological models emphasize between cortical control and subcortical fear circuitry suffocation sensitivity (Klein, 1993; Preter & Klein, found in neuroimaging studies. The authors suggest 2008), and Shear et al.’s (1993) psychodynamic theory that there is an interaction between neurophysiological of panic notes the significance of suffocation sensitiv- reactivity and , as nurturing and sup- ity as a psychological experience. Most models include portive parents produce adults with a stronger ego and some form of learning in which various cues, including more resistant stress systems. intrapsychic and environmental cues, become panic Panksepp (2005), commenting on Alexander, Fei- triggers and/or experiences associated with panic be- gelson, and Gorman (2005), noted that the authors come frightening. focus on amygdala-based fear systems rather than on We suggest that biological, psychological, and en- the separation-distress system. Panksepp (2005) views vironmental factors interact in specific ways in the separation anxiety as primary, and he states that early triggering, persistence, and recurrence of panic dis- loss of social security sensitizes brain systems for fu- order (see Figure 1). An integrated model suggests a ture panic attacks. He believes that there is inhibitory series of potential interactions among brain, mind, and top-down failure for the separation-distress system as environment over the course of development. Panic- well as for the fear system. Aronson (2005) critiqued prone individuals may be genetically predisposed to the Alexander, Feigelson, and Gorman (2005) model the development of an oversensitized fear network, for being based on actual experiences of danger rather separation-distress system, and/or suffocation alarms than on the dynamic unconscious. In the psychody- beginning early in life. Traumatic developmental namic model, panic can be caused by a fantasized experiences can also create a biological sensitivity. danger, not necessarily based on early trauma or devel- Neurophysiological vulnerabilities and/or traumatic opmental events. developmental events can lead to psychological dis- In our view, the integrative model of Alexander, tress in unfamiliar or constricting situations and to Feigelson, and Gorman (2005) does not take adequate the experience of fantasies, intrapsychic conflicts, and account of the role of separation distress, suffoca- mental representations involving separation, suffoca- tion alarms, and intrapsychic conflict, particularly sur- tion, and anger as dangerous. An oversensitized fear rounding anger, in panic onset. The proposed model network can operate in tandem with an oversensitized below includes these factors in an integrated neurobio- psychological system, increasing the vulnerability to logic/psychoanalytic model. traumatizing separation or experiences and 74 Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg

BIOLOGY ENVIRONMENT PSYCHOLOGY

Genetics TRAUMA

Serotonin/ Opioid norepinephrine deficit abnormalities

Activated Weak ego/Strong id subcortical Inability to mentalize network/ Insufficient Vulnerability to cortical usual experiences control of separation intrusion

Oversensitized Psychological experiences fear network of anger, separation, Suffocation alarm suffocation are perceived Separation distress as dangerous, conflicted Interpersonal problems involving assertiveness, dependency

PANIC

Figure 1. An intergated model of panic disorder. the likelihood of perceiving events as threatening loss affects. Disruptions in neurochemical systems, such as or suffocation. Biological and psychological vulner- serotonin or opiates, can lead to overly sensitized sepa- abilities can lead to interpersonal problems and to ration and suffocation alarm systems. Some findings other difficulties coping with the environment stem- suggest that traumatic memories may be encoded in the ming from insecurity, unassertiveness, and conflicted amygdala and associated structures (Alexander, Feigel- dependency. Psychological vulnerabilities, including son, & Gorman, 2005; Bystritsky et al., 2001), which negative affect and intrapsychic conflict, probably ex- could be triggered by mental or biological events. acerbate an oversensitized biological fear system. Our model proposes a link between core physiologi- Neurochemical and neuroimaging studies are con- cal disturbances in suffocation alarm and separation- sistent with a model of biological and psychological distress systems and psychological conflicts involving vulnerabilities, with abnormalities demonstrated in the separation and suffocation themes. Oversensitized PFC, along with the amygdala and hippocampus. From separation and suffocation alarms predispose to envi- these findings a model has been proposed suggesting ronmental and psychological experiences of separation that panic disorder emerges from a combination of and suffocation becoming triggers of panic disorder. inappropriate activity in subcortical fear circuitry and Mental representations of separation and suffocation insufficient cortical control over the ensuing affective (the experience of controlling or intrusive others; feel- state. Psychodynamically, the limited cortical control ing stifled due to difficulty in assertively expressing can represent a weak ego unable to modulate intense needs; trapped between wishes to avoid con- An Integrated Model of Panic Disorder 75 trolling others and dependency wishes) can become patient had completed projects she was working frightening due to anticipated consequences of these on. In addition, Ms. B was angry at her boss for her experiences and a belief that they can become actual- intrusiveness and felt a sense of injustice, believing ized. We hypothesize that psychological experiences that she was smarter than her boss, who neverthe- meaningfully associated with separation and suffoca- less had more power. Ms. B was concerned that tion may trigger these chemical alarms or at least fear bringing up any of her about having too systems that suggest these dangerous experiences are much work was “being a bitch” and would say to happening. This could occur, for example, through in- herself: “Who do you think you are?” In the context creased activation of subcortical limbic systems and/or of these increasing pressures and her conflict about reduced cortical inhibition of subcortical systems, or addressing them, Ms. B had the onset of panic at- through triggering separation or suffocation alarms. tacks of increasing severity, until she had to take a In addition, we view anger, along with separation disability leave from work. Thus, the panic attacks and suffocation alarms, as part of an adaptive sys- occurred in the context of interacting suffocation tem, with evidence suggesting that the amygdala plays (the experience of her boss’s intrusiveness), separa- an important role in the expression of anger (Siever, tion, and anger fears. Ms. B’s panic diminished with 2008). Given the flight/fight response, anger may often panic-focused psychodynamic psychotherapy and be triggered alongside anxiety. However, particularly venlafaxine, increased to 300 mg/day. when experienced as psychic representations, anger, In therapy, the origins of her conflicts were ex- separation, and suffocation systems can be in conflict. plored. Although several determinants emerged, a For example, patients become fearful that the expres- highly relevant developmental experience occurred sion of anger will lead to loss of attachment figures with her mother when she was an adolescent. She or to further intrusion by them. Thus, the threats sur- was the youngest of four children and the only one rounding anger can trigger separation and suffocation alone with her mother, who was having increasingly alarms and associated panic attacks. severe alcohol problems. She felt constantly criti- Chemically based negative affects can also induce cized by her mother, particularly about being “fat,” particular self and object representations and fearful and feared her mother’s vicious temper. Ms. B, how- fantasies. When patients are anxious, they can view ever, was also frightened that her mother would get relationships as more easily threatened, themselves as severely injured or die, so that she felt she needed more needy and/or incompetent, and others as more to stay at home with her. She felt trapped by having rejecting, abandoning, or critical. These polarized to do this, and also very angry at her mother for her self and other representations then negatively affect behavior. However, she feared expressing her anger, the of current interpersonal experiences, out of concern that her mother would drink even heightening the threat to these attachments and the risk more or scream at her. She also felt guilty that she of panic onset. was so angry at her mother, whom she knew was in need of help but refused to get it. Clinical vignette When the patient returned to work, she became very anxious about addressing her concerns with her boss The following vignette demonstrates the use of our and concerned about recurrence of panic. The thera- integrated model in the clinical situation. pist explored links between her experience of her boss and her mother that were increasing her anxiety Ms. B described the onset of panic in the context of and disrupting her ability to manage the situation. stress at her , after being assigned an increasing The therapist and Ms. B identified that, like her number of tasks. She was having difficulty complet- mother, her boss was troubled, highly dramatic, and ing them in a timely fashion and felt under increas- prone to catastrophic thinking. She struggled with ing pressure. Ms. B feared criticism from her boss conflicted feelings toward her boss, including anger, but also saw her as someone who would react as guilt, and a fear the boss would “fall apart” or would if situations were in a crisis, even when the patient retaliate against her by firing her. Like her adoles- felt they were not. Her boss’s reaction would create cent experience, Ms. B felt trapped in her situation, significant anxiety for Ms. B, as she viewed her as both by her feelings and by her need to make money. a powerful, potentially damaging authority figure Her recognition of these factors helped to ease her and feared being fired. She experienced her boss as anger and anxiety and allowed her to communicate intrusive and demanding, constantly asking if the in an ongoing way with her boss about workload, 76 Fredric N. Busch, Maria A. Oquendo, Gregory M. Sullivan, & Larry S. Sandberg

which further reduced her stress. Ms. B had recon- are of value in the treatment of panic. It also explains ceptualized her boss as caught in her own struggles, why some patients may require psychotherapy, medi- rather than being a demanding, suffocating “strong” cation, or a combination approach at different points other, and was able to recognize that her guilt was in the treatment of their disorder. Studies focusing not inappropriate in the context of the work situation. only on determining whether a given treatment is ef- Both psychotherapy and medication appeared to ficacious, but also on identifying for which particular play a role in diminishing the dangers of anger, suf- patients it is most effective would be instructive. In focation, and separation. addition, studies regarding the utility and indications for combination treatments are needed. Comorbidity Using the model above, we suggest that Ms. B’s panic of panic disorder is highly relevant to this determina- resolved with the attenuation of overreactive subcorti- tion. For instance, Milrod, Leon, Barber, Markowitz, cally based suffocation alarm and separation-distress and Graf (2007) and Milrod, Leon, Busch, et al. (2007) systems. One mode of approach was through venla- found that panic patients who had comorbid cluster C faxine, acting on serotonergic and noradrenergic neu- personality disorders had a greater response to panic- rotransmitters to modulate these symptoms primarily focused psychodynamic psychotherapy than patients via the subcortical route. The second approach, psy- who did not. Short-term treatments may not prevent chotherapy, led to increased cortical inhibitory control in many patients, in part because they may not over these subcortical systems and possibly to a direct provide adequate impact on biological, psychological, impact on subcortical systems, via dampening of the and environmental factors. More studies could focus fear surrounding fantasies involving anger, separation, on determining what types of longer term interventions and suffocation. These psychological interventions re- may be needed to maintain remission, with efforts to duced the likelihood of separation or suffocation fears minimize side effects. sending signals that could trigger suffocation or sepa- Finally, an integrated model suggests that inter- ration alarms. ventions to reduce environmental stressors should be part of a panic-disorder treatment, including efforts to ease problematic interpersonal relationships, marital Clinical and research implications conflict, and job stresses. As noted above, unassertive- ness and separation anxiety in close relationships can Use of an interactive model provides a basis for un- lead patients to accept negative treatment from others. derstanding how both psychological and biological Interventions that can help to address these problems approaches can be effective in the treatment of panic include medication, psychodynamic therapy, and in- disorder. Neurophysiological studies indicate, as per terpersonal therapy (Blechner, 2007). It would be of Gorman et al. (2000), that psychotherapy may work value to track in studies how persistence or reduction through augmenting prefrontal cortical control via pro- of stresses affects long-term outcome. In addition to jections to the amygdala, whereas medication may directly affecting the environment, efforts to reduce act by attenuating activity in subcortical structures, vulnerability to stressors, including catastrophic mis- with both approaches able to modulate panic episodes. interpretations of them, should be a part of panic treat- However, psychological interventions may also affect ment. subcortical structures (Sakai et al. 2006), and medi- cation impacts cortical structures, including through the placebo effect (Zubieta et al., 2005). 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