Trastorno de pánico: Definiendo fenotipos.

Trastorno de pánico: Definiendo fenotipos.

(Panic disorder: Defining phenotypes. )

Giampaolo Perna; Michele Cucchi; Danila di Pasquale; Giovanni Migliarese; Laura Bellodi.

Anxiety Disorders Clinical and Research Unit, Department of Neuropsychiatric Sciences, Universita' Vita Salute San Raffaele, Milan, Italy
Tel. # 39-2-26433211 ; Fax # 39-2-26433265.

PALABRAS CLAVE: trastorno de angustia, trastorno de pánico, fenotipos, gold standard, vulnerabilidad genética, dióxido de carbono.

(KEYWORDS: Panic disorder, phenotypes, gold standard, genetic vulnerability, carbon dioxide. )

[otros artículos] [6/2/2002]


Resumen

Con el fin de conseguir una definición de los límites del trastorno de angustia (trastorno de pánico) es necesario considerar el espectro de las expresiones fenotípicas que pudieran compartir una susceptibilidad genética común, y excluir otras condiciones similares clínicamente pero no relacionadas desde el punto de vista genético.

Unos marcadores biológicos mensurables y específicos pueden ser una herramienta útil en la definición de los "fenotipos verdaderos" del trastorno. La hipersensibilidad al dióxido de carbono y el análisis de la complejidad de los trazados respiratorios apoyan la idea de que el estudio de la función respiratoria en el trastorno de angustia pudiera ser útil para encontrar un fenotipo "gold standard" "para esta entidad.

Las anormalidades respiratorias en el trastorno de angustia pueden derivarse de una alteración en el control de este sistema, constituir la expresión de alteraciones en otros sistemas (como el cardiovascular o el vestibular), o derivarse de una disfunción homeostática más general.

Abstract

To reach a definition of the boundaries of panic disorder it is necessary to consider the spectrum of phenotypical expressions that might share a common underlying genetic vulnerability and to exclude other conditions, clinically similar, that are genetically unrelated. Measurable and specific biological markers might be a valid tool for the definition of the "true" phenotypes.

Carbon dioxide hypersensitivity and the analysis of the complexity of the respiratory tracing support the idea that the study of respiration in panic disorder might help for a further step trying to find out a valid "gold standard" phenotype for the panic disease. Respiratory abnormalities in panic disorder patients might arise from intrinsic instability in the control of that system but might be also the expression of perturbations of other systems (i. e. cardiovascular, vestibular) or from a more general dysfunction of the homeostatic brain.

One of the main problem in the etiopathogenetic studies of panic disorder, as of the other psychiatric disorders in general, is the definition of the boundaries of the disease under study. To reach this aim it is necessary to consider the spectrum of phenotypical expressions that might share a common underlying genetic vulnerability and to exclude other conditions, clinically similar, that are genetically unrelated. From a etiopatogenetic point of view, the development of a disease comes from the interaction of a specific genetic predisposition and environmental factors, leading to three mean different phenotypical expressions: “Clinical phenotypes”, in which the clinical characteristic of a specific disease are completely expressed as in patients with panic disorder, “subclinical phenotypes”, in which the clinical expression is incomplete as in subjects with sporadic unexpected panic attacks, and “symptom-free phenotypes”, in which there is a genetic underlying vulnerability not expressed clinically.

In addition, “phenocopies” can mime the clinical or subclinical picture of a specific genetic disease without sharing any common genetic background. Many authors have tried to define the boundaries of the panic spectrum, including several clinical conditions that might share a common genetic vulnerability: The results, however, are often discordant. Some examples are represented by sporadic unexpected panic attacks and social phobia. Morbidity risk for panic disorder are higher in families of patients with sporadic panic attacks than in families of healthy controls and similar to that found in families of patients with panic disorder (Perna, Gabriele et al. 1995). Twin studies show contrasting results. The study by Torgersen (1983) supports the presence of a common genetic vulnerability for panic disorder and for sporadic unexpected panic attacks but our data (Perna, Caldirola et al. 1997), although limited by the small sample examined, do not support a significant genetic relationship between panic disorder and sporadic panic attacks in twin pairs, since there was not a significant concordance between panic disorder and sporadic panic attacks in monozygotic twins. These observations suggest that patients with sporadic panic attacks might be heterogeneous including a subgroup that might share a common genetic predisposition with panic disorder and thus might belong to the panic spectrum and another one related to different factors, perhaps environmental or cognitive.

Family studies in patients with social phobia did not show an higher familiar risk for DP but recent ones reported an higher risk for panic disorder and not for social phobia in families of patients with co-diagnosis of panic disorder and social phobia, the latter with an age of onset earlier than the former (Fyer, Mannuzza et al. 1996). These results support the existence of a genetic relationship between patients with panic disorder and a subgroup of patients with social phobia and, if it will be confirmed, early-onset social phobia should be considered a phenotypical expression of the panic spectrum vulnerability.

Measurable and specific biological marker might be a valid tool for the definition of the “true” phenotypes, sharing a common genetic vulnerability. Everybody might be enable to overcome diagnostic definitions based only on clinical and temporal characteristics and also to clarify the etiopathogenesis of the disease under study. Several experimental studies have identified hypersensitivity to CO2 as a putative valid marker in panic disorder.

Since genetic factors are important in the etiology of panic disorder and thus, given the validity of CO2 hypersensitivity as a biological marker of panic disorder, it was an obvious step to investigate the genetic relationships between panic and respiration. Studies from three different teams suggested that there is a familial association between panic disorder and CO2 hypersensitivity (Perna, Cocchi et al. 1995; Fyer, Mannuzza et al. 1996; Perna, Bertani et al. 1996; Coryell 1997; Coryell and Arndt 1999; van Beek and Griez 2000). We (Perna, Cocchi et al. 1995) tested the reactivity to the 35% CO2 test in a group of healthy first-degree relatives of patients with panic disorder, that never experienced panic attacks during their lifetime: healthy relatives reacted significantly more than healthy subjects without a familiar history of panic disorder, with rates of CO2 induced panic-attacks of 22% in the first group and of 2% in the second group.

These results, suggesting an association between hypersensitivity to hypercapnia and familial vulnerability to panic disorder, was confirmed by Coryell (Coryell 1997) who investigated reactivity to 35% CO2 in groups of healthy subjects with a familiar vulnerability to panic disorder, to depressive disorders and without a family history of panic or depressive disorders. Carbon dioxide-induced panic attacks were reported in 45. 5% of the subjects with positive family history for panic disorder but none in the other two groups. Finally, Van Beek and Griez (van Beek and Griez 2000) confirmed these data comparing an age-sex matched sample of 50 healthy first degree relatives and 50 healthy controls. The association between familiar vulnerability to panic disorder and respiration has been further confirmed by a study of our team investigating the relationships between CO2 hypersensitivity in patients with panic disorder and familial-genetic risk for panic disorder. Patients hyperreactive to the CO2 showed a morbidity risk for panic disorder (14. 4%) significantly higher than that found in patients with a normal reactivity to CO2 (3. 9%) suggesting that CO2 hyperreactivity might be associated with a subtype of panic disorder specifically related to a greater familial loading. (Perna, Bertani et al. 1996).

A familiar association between respiration and panic disorder has been also supported by a recent study of the Columbia team (Horwath, Adams et al. 1997). The results showed that relatives of patients with panic disorder with respiratory symptoms had an almost threefold higher risk for panic and an almost sixfold higher risk for panic with smothering symptoms than relatives of patients with panic disorder but without respiratory symptoms.

The authors concluded that panic disorder with smothering symptoms might be a subtype of panic disorder associated with an increased familiar risk, thus a group of interest for genetic studies.

If the etiology of panic disorder is strongly related to genetic factors and if CO2 hypersensitivity is related to the pathogenesis of panic disorder, it can be thought that CO2 hypersensitivity is modulated by genetic influences. This idea has been confirmed by a recent twin study (Bellodi, Perna et al. 1998) showing a wise probe of a significantly different concordance between rate for CO2-induced panic attacks in MZ pairs (55. 6%) than in DZ pairs (12. 5).

Taken together, these studies support the idea that the study of respiration in panic disorder might help for a further step trying to find out a valid "gold standard" phenotype for the panic disease. Carbon dioxide hypersensitivity has a relevant genetic component and seems to be significantly related to a familiar vulnerability to panic disorder. Carbon dioxide hypersensitivity might be a phenotypical expression of a genetic vulnerability to panic disorder even in the absence of panic disorder, thus, subjects hyperreactive to hypercapnia or with respiration abnormalities might considered "affected" members in formal and molecular genetic studies. Alternatively, hypersensitivity to CO2 might be considered the phenotypic expression of one of the genes involved in the "respiratory panic disease" and thus, only the presence of both clinical panics and CO2 hypersensitivity could define the "true" phenotype for genetic studies.

Beyond behavioral hyperreactivity to CO2 inhalation, the evidence of respiration physiology abnormalities could be a more direct way in the search of “true phenotypes”, however results from studies investigating respiratory parameters comparing mean scores between panic patients and healthy controls or patients with other anxiety disorders led to inconsistent results. Since respiration is a complex physiologic function with multiple central/peripheral inputs, abnormalities in its function could be more accurately investigated by the analysis of the complexity of the respiratory tracing rather than simply measuring the absolute values of the parameters. Consistent and specific respiratory abnormalities were found when the breathing pattern of PD patients was studied.

The presence of respiratory irregularities in patients with panic disorder appear to be confirmed by studies with respiratory challenges. Patients with panic disorder show a greater breath to breath variability during a rebreathing test than what is usually observed in controls (Papp, Martinez et al. 1995). Compared with healthy subjects, patient with panic disorder showed an increased irregularity in tidal volume and minute ventilation and an increased rate of pauses in breathing during sleep (Stein, Millar et al. 1995; Martinez, Papp et al. 1996). In awake PD patients, baseline respiratory frequency and tidal volume were more irregular than in healthy controls (Gorman, Fyer et al. 1988; Bystritsky and Shapiro 1992; Bystritsky, Craske et al. 2000). Patients with panic disorder showed excessive sighing and they also reported tidal volume’s irregularity significantly greater not only than in healthy controls (Abelson, Weg et al. 2001) but also in patients with Generalized Anxiety Disorder (Wilhelm, Trabert et al. 2001). The tidal volume’s irregularity persisted after both doxapram-induced hyperventilation and cognitive intervention, suggesting that it might be an intrinsic and stable feature of patients with panic disorder (Abelson, Weg et al. 2001). Finally preliminary data form our team (Caldirola et al, unpublished manuscript) suggest that patients with respiratory CO2 induced panic attacks showed a more irregular baseline respiratory pattern compared to subjects without respiratory symptoms during the CO2 challenge.

The importance of this finding for the understanding of panic etiopathogenesis is supported by the evidence of a higher variability in respiratory pattern in response to 5% CO2 inhalation in relatives of panic patients compared to relatives of healthy controls and of affective patients (Coryell, Fyer et al. 2001). Pine and co-workers (Pine, Coplan et al. 1998; Pine, Klein et al. 2000) reported more irregularities in respiratory rate in children with childhood anxiety disorders who developed panic symptoms after CO2 inhalation. Finally, preliminary data from Perna and co-workers (Perna, Bertani et al. in press) suggest that variability in respiration might be higher in children of patients with panic disorder than in children of healthy controls. Respiratory irregularities and pattern variability could be a physiological trait marker of panic vulnerability able to identify subjects at risk for panic and to promote formal and molecular genetic studies in PD.

Finally, since basic physiological functions in the organism are strictly interrelated in a neural network with reciprocal modulations, abnormal function of the respiratory system does not necessary imply an intrinsic instability in the control of that system but might be the expression of perturbations of other systems or from a more general dysfunction of the homeostatic brain. The latter possibility seems to be supported by studies reporting evidences for an abnormal regulation of the cardiovascular and the balance systems in PD patients. Cardiovascular and respiratory functions are highly interconnected and fluctuations in cardiac output or in cerebral blood flow could influence the entity and the time-course of the chemoreflex response by inducing variations in gas exchanges and in circulatory function.

PD patients show a decrease in cardiac vagal function and a relative increase in sympathetic activity, with a decreased global heart rate variability, leading to a reduced and abnormal flexibility and adaptability to external/internal inputs. The brainstem respiratory network is also highly interconnected with the vestibular nuclei to maintain blood gas homeostasis during movement and changes in posture (Balaban and Thayer 2001). Recently, we found that many PD patients have subclinical abnormalities in their balance system function and that symptomatological reactivity to CO2 is correlated to some static posturography parameters (Perna, Alpini et al. 2001). Therefore, respiratory abnormalities in PD patients might arise from a more global and complex abnormality in the integration of the brainstem neuronal circuits that regulate physiological homeostasis.

In conclusion, behavioral or physiological abnormalities in respiration might become significant biological markers able to help the identification of “true phenotypes” specifically related to the “Panic Disease” beyond the classical clinical definition of Panic Disorder, that have greatly limited studies focused on the etiopathogenetic factors of panic. Beyond respiration, we can think that a valid biological marker of the “Panic Disease” might be represented by the instability of brainstem homeostatic functions.

Bibliografía

Abelson, J. L. , J. G. Weg, et al. (2001). “Persistent respiratory irregularity in patients with panic disorder. ” Biol Psychiatry 49(7): 588-95.

Balaban, C. D. and J. F. Thayer (2001). “Neurological bases for balance-anxiety links. ” J Anxiety Disord 15(1-2): 53-79.

Bellodi, L. , G. Perna, et al. (1998). “CO2-induced panic attacks: a twin study. ” Am J Psychiatry 155(9): 1184-8.

Bystritsky, A. , M. Craske, et al. (2000). “Autonomic reactivity of panic patients during a CO2 inhalation procedure. ” Depress Anxiety 11(1): 15-26.

Bystritsky, A. and D. Shapiro (1992). “Continuous physiological changes and subjective reports in panic patients: a preliminary methodological report. ” Biol Psychiatry 32(9): 766-77.

Coryell, W. (1997). “Hypersensitivity to carbon dioxide as a disease-specific trait marker. ” Biol Psychiatry 41(3): 259-63.

Coryell, W. and S. Arndt (1999). “The 35% CO2 inhalation procedure: test-retest reliability. ” Biol Psychiatry 45(7): 923-7.

Coryell, W. , A. Fyer, et al. (2001). “Aberrant respiratory sensitivity to CO(2) as a trait of familial panic disorder. ” Biol Psychiatry 49(7): 582-7.

Fyer, A. J. , S. Mannuzza, et al. (1996). “Panic disorder and social phobia: effects of comorbidity on familial transmission. ” Anxiety 2(4): 173-8.

Gorman, J. M. , M. R. Fyer, et al. (1988). “Ventilatory physiology of patients with panic disorder [published erratum appears in Arch gen Psychiatry 1991 Feb; 48(2):181]. ” Arch gen Psychiatry 45(1): 31-9.

Horwath, E. , P. Adams, et al. (1997). “Panic disorder with smothering symptoms: evidence for increased risk in first-degree relatives. ” Depress Anxiety 6(4): 147-53.

Martinez, J. M. , L. A. Papp, et al. (1996). “Ambulatory monitoring of respiration in anxiety. ” Anxiety 2(6): 296-302.

Papp, L. A. , J. M. Martinez, et al. (1995). “Rebreathing tests in panic disorder. ” Biol Psychiatry 38(4): 240-5.

Perna, G. , A. Bertani, et al. (1996). “Family history of panic disorder and hypersensitivity to CO2 in patients with panic disorder. ” Am J Psychiatry 153(8): 1060-4.

Perna, G. , A. Bertani, et al. (in press). “Anti-panic drug modulation of 35% CO2 hyperreactivity and short -term treatment outcome. ” J Clin Psychopharmacol.

Perna, G. , D. Caldirola, et al. (1997). “Panic attacks: a twin study. ” Psychiatry Res 66(1): 69-71.

Perna, G. , S. Cocchi, et al. (1995). “Sensitivity to 35% CO2 in healthy first-degree relatives of patients with panic disorder. ” Am J Psychiatry 152(4): 623-5.

Perna, G. , A. Dario, et al. (2001). “Panic disorder: the role of the balance system. ” J Psychiatr Res 35(5): 279-86.

Perna, G. , A. Gabriele, et al. (1995). “Hypersensitivity to inhalation of carbon dioxide and panic attacks. ” Psychiatry Res 57(3): 267-73.

Pine, D. S. , J. D. Coplan, et al. (1998). “Ventilatory physiology of children and adolescents with anxiety disorders. ” Arch gen Psychiatry 55(2): 123-9.

Pine, D. S. , R. G. Klein, et al. (2000). “Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group. ” Arch gen Psychiatry 57(10): 960-7.

Stein, M. B. , T. W. Millar, et al. (1995). “Irregular breathing during sleep in patients with panic disorder. ” Am J Psychiatry 152(8): 1168-73.

Torgersen, S. (1983): Genetic factors in anxiety disorders. Arch gen Psychiatry 40, 1085-1089.

van Beek, N. and E. Griez (2000). “Reactivity to a 35% CO2 challenge in healthy first-degree relatives of patients with panic disorder. ” Biol Psychiatry 47(9): 830-5.

Wilhelm, F. H. , W. Trabert, et al. (2001). “Physiologic instability in panic disorder and generalized anxiety disorder. ” Biol Psychiatry 49(7): 596-605.