Psychology & Neuroscience ISSN: 1984-3054 [email protected] Pontifícia Universidade Católica do Rio de Janeiro Brasil Schenberg, Luiz Carlos Towards a translational model of panic attack Psychology & Neuroscience, vol. 3, núm. 1, enero-junio, 2010, pp. 9-37 Pontifícia Universidade Católica do Rio de Janeiro Rio de Janeiro, Brasil Available in: http://www.redalyc.org/articulo.oa?id=207014856003 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative PSYCHOLOGY Psychology & Neuroscience, 2010, 3, 1, 9 - 37 NEUROSCIENCE DOI: 10.3922/j.psns.2010.1.003 Towards a translational model of panic attack Luiz Carlos Schenberg Universidade Federal do Espirito Santo, Brazil Abstract About 20 years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia. Besides, they suggested that the decrease in 5-HT1A neurotransmission in the hippocampus results in learned helplessness and depression. Accordingly, the Deakin Graeff hypothesis provided a unified frame to the widespread use of 5-HT selective reuptake inhibitors in generalized anxiety, panic disorder and depression. Competitor hypotheses implicate panic attacks with the abnormal functioning of locus coeruleus, basolateral amygdala, dorsomedial hypothalamus or an as-yet-unknown suffocation alarm system. Conversely, cognitive psychologists suggest that panic attacks result from the catastrophic (cortical) interpretation of bodily symptoms. In any event, translational models of panic attack are expected to reproduce the main features of clinical panic, namely, the patient’s higher sensitivity to both lactate and CO2, the drug specific sensitivity, the lack of stress hormone responses during panic attacks, the higher vulnerability of women and the high comorbidity with agoraphobia, major depression and childhood separation anxiety. Therefore, here we review the main steps in the experimental approach to anxiety disorders which are paving the route towards a translational model of panic attack. Keywords: Panic, Anxiety, Stress, Suffocation, Serotonin, Periaqueductal Gray Matter Received 3 May 2010; received in revised form 26 June 2010; accepted 26 June 2010. Available on line 26 June 2010 A short story of panic disorder this feeling with ‘the nearest interpretation of the termination of life, such as the idea of sudden death or The foundations of the modern nosology of anxiety threatening insanity’. As well, anxiety attacks could be disorders were laid down by Sigmund Freud’s original associated to ‘some paresthesia ... [or] a disturbance classification of ‘anxiety neuroses’ (Angstneuroses) of one or many somatic functions, such as respiration, (Freud, 1896). In this early study, Freud attempted cardiac activity, vasomotor innervation, and glandular to distinguish anxiety disorders from ‘melancholia’ activity’. Remarkably, Freud pointed out that patients (major depression, MD) and a number of ill-defined suffering from anxiety attacks ‘put the feeling of anxiety psychiatric conditions which were at time subsumed to the background or [describe it] rather vaguely … under the label of ‘neurasthenias’. Remarkably, Freud as feeling badly, uncomfortably, etc’, an observation discerned two major syndromes of anxiety, i.e., the corroborated by present-day psychiatrists. Freud was ‘anxious expectation’ or ‘apprehension’, which he also aware about the high comorbidity of panic attacks considered the most essential form of anxiety disorder, and agoraphobia and linked the latter condition to a and the less frequent ‘attack of anxiety’. According to ‘locomotion disorder’ caused by the presence of dizziness Freud, whereas the anxious expectation was ‘a quantum during panic attacks. (pp. 87-89) Freud’s descriptions of freely floating anxiety which controls the choice of of ‘anxious expectation’ and ‘anxiety attack’ were very ideas by expectation’, anxiety attacks consisted in much the same of nowadays respective diagnoses of the sudden irruption of anxiety ‘into consciousness generalized anxiety disorder (GAD) and panic disorder without being aroused by the issue of any idea’. Freud (PD). However, it would take almost a century before emphasized that anxiety attacks could manifest either the inclusion of PD as a definite psychiatric illness in as ‘the anxious feeling alone’ or the combination of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-III, APA, 1980). Luiz Carlos Schenberg, Associate Professor, Department of Presumably, Freud’s clinical heritage was in Physiological Sciences, Federal University of Espírito Santo, some measure lost following the profound divorce Vitória, ES; Brazil. Correspondence regarding this article should be directed to: Dr. L. C. Schenberg, Departamento de Ciências of psychoanalysis from medicine. Consequently, Fisiológicas, CCS – UFES, Av. Marechal Campos 1468 (Maruípe), anxiety disorders continued to be vaguely diagnosed 29043-125, Vitória-ES, Brazil. Phone: +55-27-3335-7332. Fax: as ‘neurasthenias’ up to the middle of the last century. +55-27-3335-7340. E-mail: [email protected] Moreover, PD received a bewildering wealth of names 10 Schenberg including neurocirculatory asthenia, vasomotor neurosis, relaxation and sleep, of the increased frequency of nervous tachycardia, effort syndrome, Da Costa’s panic attacks in the late luteal phase dysphoric disorder syndrome, irritable heart, soldier heart and others (Pitts (LLPDD) and, conversely, its reduction in pregnancy, & McClure, 1967). This scenario begun to undergo a delivery and lactation. As a matter of fact, CO2 and profound change following the publication of Donald lactate-induced panic attacks remains the best model of Klein’s influential study showing that GAD and PD clinical panic insofar that they are not precipitated in were treated by different classes of drugs (Klein, 1964). healthy subjects (Klein, 1993; Pitts & McClure, 1967) Klein observed that whereas the ‘anxious expectation’ or patients suffering from obsessive-compulsive disorder responded to the current time anxiolytics (barbiturates, (as cited by Griez & Schruers, 1998) and social phobia meprobamate, chlordiazepoxide and low doses of (Liebowitz et al., 1985b). Also, whereas the panic attacks phenothiazines), panic attacks were only treated by the produced by infusion of lactate or inhalation of CO2 are chronic administration of the tricyclic antidepressant blocked by chronic treatment with TCA (Liebowitz et (TCA), imipramine. al., 1985a; Rifkin, Klein, Dillon, & Levitt, 1981; Woods, Around the same time, Pitts and McClure (1967) Charney, Delgado, & Heninger, 1990; Yeragani et al., showed that panic attacks had ‘physiological markers’ 1988), panics induced by β-carboline (Dorow, Horowski, insofar that they could be precipitated by intravenous Paschelke, & Amin, 1983) and yohimbine are not (Klein, infusions of .5 M sodium lactate in patients prone to 1993). The SFA hypothesis is also consistent with the spontaneous panic but not in normal volunteers. Further high comorbidity of panic and respiratory diseases studies provided ample evidence of the panicogenic (Preter & Klein, 2008; Shavitt, Gentil, & Mandetta, properties of sodium lactate, but also of CO2 and brain 1992). However, patients with GAD and, more markedly, acting drugs such as yohimbine, cholecystokinin (CCK), LLPDD are also highly sensitive to CO2 (Kent et al., flumazenil, β-carboline, caffeine, etc (for review, see 2001; Lapierre, Knott, & Gray, 1984). Graeff, Garcia-Leal, Del-Ben, & Guimarães, 2005). The Following the advent of DSM-III (APA, 1980), demonstration of the existence of physiological markers experimental researchers became gradually aware and drug-specific treatments of PD suggested that panic about the similarity of panic attacks with the defensive attacks were the outcome of a defective brain circuit behaviors and aversive emotions long known to be discharging maladaptively. produced by electrical stimulation of the dorsal half The next breakthrough came a few years after the of periaqueductal gray matter (DPAG) of animals inclusion of PD in the DSM-III (APA, 1980). Indeed, (Fernandez de Molina & Hunsperger, 1962) and humans the demonstration that clinical and lactate-induced (Nashold, Wilson, & Slaughter, 1969), respectively. At panics do not activate the hypothalamus-pituitary- the same time, the serotonin (5-HT) selective reuptake adrenal (HPA) axis was a remarkable finding inasmuch inhibitors (SSRI) begun to be widely prescribed for as it differentiated clinical panic from stress-like MD, GAD and PD. Therefore, Deakin and Graeff reactions and common fear (Hollander et al., 1989a, (1991) put forward a daring hypothesis according to 1989b, 1989c; Levin et al., 1987; Liebowitz et al., which the 5-HT ascending systems of the brain evolved 1985; Woods, Charney, Goodman, & Heninger, 1988; as a mechanism concerned with adaptive responses to Woods, Charney, McPherson, Gradman, & Heninger, aversive events. Briefly, the Deakin-Graeff hypothesis