Neuropsychoanalysis, 2010, 12 (1) 67 An Integrated Model of Panic 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 panic disorder benefits from such an integrative analysis. We review genetic, neurochemical, and neuroimaging 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 vulnerability, 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 feelings and fantasies, often unconscious, further intensify fears 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 affect 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 neurosis,” 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 Psychiatry, 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 Society • 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 norepinephrine 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 fear 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 anxiety 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 amygdala, hippocampus, thalamus, 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, Rush, 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