Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder

Michelle Nigri Levitan Marcos H. Chagas Ila M. Linares José A. Crippa Mauro B. Terra Alcir T. Giglio Joana L.C. Cordeiro Giovana J. Garcia Rosa Hasan Nathalia C. Andrada Antonio E. Nardi About the authors

Abstract

Objective:

To present the most relevant findings regarding the Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder.

Methods:

We used the methodology proposed by the Brazilian Medical Association for the Diretrizes Project. The MEDLINE (PubMed), Scopus, Web of Science, and LILACS online databases were queried for articles published from 1980 to 2012. Searchable questions were structured using the PICO format (acronym for “patient” [or population], “intervention” [or exposure], “comparison” [or control], and “outcome”).

Results:

We present data on clinical manifestations and implications of panic disorder and its association with depression, drug abuse, dependence and anxiety disorders. In addition, discussions were held on the main psychiatric and clinical differential diagnoses.

Conclusions:

The guidelines are proposed to serve as a reference for the general practitioner and specialist to assist in and facilitate the diagnosis of panic disorder.

Panic disorder; anxiety; guidelines; diagnosis; differential diagnosis


Introduction

Panic disorder (PD) is characterized by the presence of sudden anxiety attacks accompanied by somatic symptoms (panic attacks) and development of a persistent concern about their recurrence and possible implications.11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. PD a disabling condition associated with long-term negative consequences such as decreases in productivity, welfare, social relations and self-realization, and may lead to high utilization of medical resources.22. Marciniak M, Lage MJ, Landbloom RP, Dunayevich E, Bowman L. Medical and productivity costs of anxiety disorders: case control study. Depress Anxiety. 2004;19:112-20. The lifetime prevalence of PD is estimated to range from 1.5 to 5%.33. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2006;63:415-24.

Many patients begin to avoid situations or places where they previously experienced a panic attack or believe one may occur, developing an avoidance known as agoraphobia. People with PD are often not recognized as having the disorder. It is common for patients to seek several experts depending on their predominant somatic complaints (e.g., heart, stomach, respiratory symptoms) and undergo a variety of tests before being diagnosed with PD. Without a correct diagnosis, the appropriate treatment cannot be provided and the disorder tends to become chronic.44. Liebowitz MR. Panic disorder as a chronic illness. J Clin Psychiatry. 1997;58:5-8. PD often occurs alongside other psychiatric comorbidities. Community surveys have showed a high frequency of substance abuse, depression, and suicide attempts in these patients.55. Markowitz JS, Weissman MM, Ouellette R, Lish JD, Klerman GL. Quality of life in panic disorder. Arch Gen Psychiatry.1989;46:984-92. The difficulty in establishing the diagnosis of PD or the distinction between PD and other diseases prevents early treatment and a better quality of life for these patients.

Based on this evidence, the Brazilian Medical Association (BMA) and the Brazilian Psychiatric Association (BPA) have developed guidelines to help medical professionals through the general diagnosis and differential diagnosis of PD.

Methods

We reviewed articles written between 1980 and 2012 and indexed in the following databases: MEDLINE (PubMed), Scopus, Web of Science, and LILACS. Relevant publications and diagnostic manuals, such as the DSM-IV and the ICD-10, were also included. The search strategy was based on structured questions formulated according to the PICO format, which stands for “patient” (or population”), “intervention” (or exposure), “comparison” (or control), and “outcome,” as recommended by the BMA. The use of objective and structured clinical questions enables the development of strategies for finding the best evidence. For example, the search strategy we used for the question: “Is there current evidence of the role of genetic factors in the etiology of PD?” was as follows: P - patients with PD (panic disorder OR panic agoraphobia), I - indicators of genetic influence (genetic predisposition to disease genetics OR* models, genetic linkage OR chromosome mapping genetic markers, OR family twin studies OR dizygotic twins, monozygotic twins), C - no control group, O - no outcome. This strategy led to articles that were chosen according to the following steps: selection of evidence, critical evidence, extraction, and translation of the results according to the grade of recommendation and strength of evidence. These criteria were arranged as follows: a) experimental or observational studies with better consistency; b) less consistent experimental and observational studies; c) case reports; and d) opinions devoid of critical evaluation, based on physiological studies or animal models.

For intersections in accordance with the proposed question, we used the following keywords: panic disorder, agoraphobia, diagnosis, questionnaires, sensitivity and specificity, classification, epidemiology, prevalence, prevention and control, life change events, Severity of Illness Index, prognosis, recurrence, age factors, age distribution, risk factors, comorbidity, phobic disorders, generalized anxiety disorder, depression, post-traumatic, sleep, sleep disorders, polysomnography, genetic predisposition to disease, genetics, genetic markers, social environment, phenotype, differential, lactates/diagnostic use, carbon dioxide/diagnostic use, respiration/drug effects, heart/pathophysiology, heart diseases, cardiovascular diseases, arrhythmias, hypertension, blood pressure, heart rate, electrocardiography, thyroiditis, autoimmune, cerebral cortex/abnormalities, image processing, magnetic resonance imaging, antidepressive agents, cognitive therapy, and combined modality therapy.

After analyzing this material, we selected articles that had higher recommendation grades and greater strength of evidence to support these guidelines. The following sections list the most important findings of the BMA and BPA guidelines that relate to both the diagnosis and differential diagnosis of PD.

Results and discussion

What is the significance of scales in the identification and evaluation of patients with PD?

Scales for assessment of panic attacks are widely used in clinical trials, ensuring that information collected regarding specific symptoms is standardized and compared with other studies for later application in clinical practice. The goal of initial evaluation is to characterize the clinical picture systematically and quickly and cover a wide range of symptoms. The collected data are transformed into a numerical score that reflects the total frequency and severity of symptoms. Assessment may be repeated throughout treatment to investigate the clinical improvement and therapeutic effects of the administered treatment and to provide objective data on the clinical progress of the patient66. Ito LM, Ramos RT. Escalas de avaliação clínica do transtorno de pânico. In: Gorenstein C, Andrade LH, Zuardi AW. Escalas de avaliação clínica em psiquiatria e psicofarmacologia. São Paulo: Lemos; 2000. p. 145-55. (D).

Diagnostic identification has been determined through semi-structured clinical interviews, such as the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)77. First MB, Spitzer RL, Gibson M, Williams JB. Structured clinical interview diagnostic (SCID) for DSM-IV Axis I Disorders (Clinical Version) SCID-CV. Washington DC: American Psychiatric Association; 1997. (D) and the Mini International Neuropsychiatry Interview (MINI) - Brazilian version88. Amorim P. Mini International Neuropsychiatric Interview (MINI): validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr. 2000;22:106-15. (B), which are both based on the DSM-IV1 (D). Administered to a Brazilian population suspected of suffering from PD with agoraphobia, MINI showed a sensitivity of 44% and specificity of 97%, yielding a likelihood of disease (LR+) of 14.67 (95%CI 4.71-45.69), increasing the LR+ from 5 to 44%88. Amorim P. Mini International Neuropsychiatric Interview (MINI): validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr. 2000;22:106-15. (B).

Scales that assess symptoms of PD may be divided into global scales of anxiety, scales of the frequency and intensity of panic attacks, scales of phobic avoidance, and scales of distorted cognition regarding physical reactions of anxiety66. Ito LM, Ramos RT. Escalas de avaliação clínica do transtorno de pânico. In: Gorenstein C, Andrade LH, Zuardi AW. Escalas de avaliação clínica em psiquiatria e psicofarmacologia. São Paulo: Lemos; 2000. p. 145-55. (D). Several scales have been translated into Portuguese, but no specific scale for clinical features or identification of patients with PD has been validated in a Brazilian sample. The scales most commonly used in Brazilian practice are described below.

The Clinical Global Impression (CGI), which provides an overall assessment of the severity of PD on a scale of 1 to 7 according to the frequency and intensity of panic attacks, anticipatory anxiety levels, levels of phobic avoidance, and family/occupational dysfunction, has been used to evaluate the severity of panic after pharmacological treatment99. Bandelow B. Defining response and remission in anxiety disorders: toward an integrated approach. CNS Spectr. 2006;11:21-8. (D). The Hamilton Anxiety Scale (HAM-A) measures overall anxiety and consists of 14 items divided into two groups: seven mood symptoms related to anxiety and seven physical symptoms of anxiety. This scale exhibits better diagnostic capacity when studying depression in relation to anxiety1010. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50-5. (B).

The Panic Disorder Severity Scale (PDSS) measures the severity of core symptoms of PD. The PDSS is a five-point Likert scale that includes the frequency of panic attacks and limited symptom episodes, the anguish caused by these attacks, anticipatory anxiety, fear, agoraphobic avoidance, social impairment, and loss of productivity in work activities caused by panic attacks1111. Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, et al. Multicenter collaborative panic disorder severity scale. Am J Psychiatry. 1997;154:1571-5. (A). This scale has better diagnostic capacity for patients with agoraphobia, a sensitivity of 99%, and a specificity of 98%, yielding a LR+ of 49.50 (95%CI 12.55-195.2), increasing the diagnostic certainty from 5% (prevalence/pretest probability) to 72%.1212. Monkul ES, Tural U, Onur E, Fidaner H, Alkin T, Shear MK. Panic Disorder Severity Scale: reliability and validity of the Turkish version. Depress Anxiety. 2004;20:8-16. For patients without agoraphobia, the PDSS has low diagnostic power, with a sensitivity of 83.3% and a specificity of 64%, yielding a LR+ of 2.31 (95%CI 1.75-3.04) and increasing the diagnostic probability to only 11%1313. Shear MK, Rucci P, Williams J, Frank E, Grochocinski V, Vander Bilt J, et al. Reliability and validity of the Panic Disorder Severity Scale: replication and extension. J Psychiatr Res. 2001;35:293-6. (A).

The Panic Associated Symptoms Scale (PASS) measures the severity of the following core symptoms of PD: panic attacks, anticipatory anxiety, and agoraphobia. Using a cutoff point of 7.6, it has a sensitivity of 99% and specificity of 98%, providing a LR+ of 49.50 (95%CI 12.55-195.22), increasing the diagnostic certainty from 5% (prevalence) to 72%1414. Argyle N, Deltito J, Allerup P, Maier W, Albus M, Nutzinger D, et al. The panic-associated symptom scale: measuring the severity of panic disorder. Acta Psychiatr Scand. 1991;83:20-6. (B). The HAM-A shows good correlation with the PASS1414. Argyle N, Deltito J, Allerup P, Maier W, Albus M, Nutzinger D, et al. The panic-associated symptom scale: measuring the severity of panic disorder. Acta Psychiatr Scand. 1991;83:20-6. (B), with r = 0.78.

Patients seen in primary care and at risk of psychiatric disorders may be evaluated using the Patient Health Questionnaire (PHQ-PD)1515. Wittkampf KA, Baas KD, van Weert HC, Lucassen P, Schene AH. The psychometric properties of the panic disorder module of the Patient Health Questionnaire (PHQ-PD) in high-risk groups in primary care. J Affect Disord. 2011;130:260-7. (B). The PHQ-PD found that 4.8% of patients suffer from PD, with a higher rate of 7.6% in patients who already had psychiatric comorbidities and 9.8% of patients before they presented inexplicable physical complaints. This questionnaire has a sensitivity of 71% and a specificity of 83%, providing a LR+ of 4.18 (95%CI 2.66-6.56), which increases the pretest probability (prevalence of disease) from 5 to 18% for the general population and 10 to 32% for patients with inexplicable somatic complaints1515. Wittkampf KA, Baas KD, van Weert HC, Lucassen P, Schene AH. The psychometric properties of the panic disorder module of the Patient Health Questionnaire (PHQ-PD) in high-risk groups in primary care. J Affect Disord. 2011;130:260-7. (B).

For screening, the Panic Disorder Self-Report (PSR) is a self-enforcement questionnaire, based on the DSM-IV11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D), which showed 100% specificity and 89% sensitivity as compared with a structured diagnostic interview. This instrument also features test-retest reliability, discriminant validity, and clinical validity, but has not yet been validated in Portuguese1616. Newman MG, Holmes M, Zuellig AR, Kachin KE, Behar E. The reliability and validity of the Panic Disorder Self-report: a new diagnostic screening measure of panic disorder. Psychol Assess. 2006;18:49-61. (B). The PSR provides a LR+ of 89 (95%CI 12.64-626.42), which increases the pretest probability of disease from 5 to 82%.

What are the clinical manifestations of PD in adults?

Individuals with PD have recurrent, unexpected anxiety attacks. A panic attack is defined as a brief period of intense fear or discomfort, during which somatic symptoms develop abruptly11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D). For the diagnosis of PD, the patient must present spontaneous panic attacks which occur “out of the blue.” Often, the attacks become situational, associated to previous places or situations where the patient had a spontaneous panic attack, such as crowds or traffic11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D).

The other feature of PD is anticipatory anxiety. The patient develops a concern about the recurrence of panic attacks, maintaining heightened awareness of bodily sensations. Once the anxiogenic situations associated with panic attacks are avoided, agoraphobia soon develops1717. Roy-Byrne PP, Craske MG, Stein MB. Panic disorder. Lancet. 2006;16:1023-32. (D). In this phase, there is avoidance of places or situations in which it is difficult or embarrassing to obtain help in the case of a panic attack. In general, the agoraphobic patient tends to avoid being alone and in crowded places. Thus, safety behaviors are developed, such as the use of anxiolytic drugs and ensuring that one is in the company of others, which greatly restrict functionality1717. Roy-Byrne PP, Craske MG, Stein MB. Panic disorder. Lancet. 2006;16:1023-32. (D).

According to the DSM-IV11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D), panic disorder is a period of intense fear and discomfort in which four or more of the following symptoms are present: 1) shortness of breath (dyspnea) or choking sensation; 2) dizziness, unsteadiness, lightheadedness, or feeling faint; 3) palpitations or accelerated heart rate (tachycardia); 4) trembling or shaking; 5) sweating; 6) smothering; 7) nausea or abdominal distress; 8) depersonalization or derealization; 9) paresthesias (numbness or tingling); 10) chills or hot flushes; 11) chest pain; 12) fear of dying; and 13) fear of going crazy or losing control. Furthermore, there must be at least 1 month of persistent concern about having another panic attack, worry about possible implications or consequences of panic attacks, or a significant behavioral change related to the attacks.

The ICD-10 criteria for the diagnosis of PD1818. World Health Organization (WHO). Classificação de transtornos mentais e de comportamento da CID-10: Descrições clínicas e diretrizes diagnósticas. Geneva: WHO; 1993. (D) include: 1) recurrent attacks of severe anxiety (panic attacks) that are not consistently associated with a certain situation or circumstance, i.e., are unpredictable; 2) symptoms include sudden onset of palpitations, chest pain, choking sensations, dizziness, and feelings of unreality (depersonalization or derealization). Moreover, there is often a secondary fear of dying, losing control, or going mad.

What are the clinical manifestations of PD in children and adolescents?

Symptoms of PD in children and adolescents are similar to those experienced by adults, such as palpitations, tremors, restlessness, dizziness, shortness of breath, weakness, sweating, chest pain, abdominal discomfort, nausea, numbness, and fear of losing control1919. Masi G, Favilla L, Mucci M, Millepiedi S. Panic disorder in clinically referred children and adolescents. Child Psychiatry Hum Dev. 2000;31:139-51.

20. Ehlers A. Somatic symptoms and panic attacks: a retrospective study of learning experiences. Behav Res Ther. 1993;31:269-78.
-2121. Diler RS, Birmaher B, Brent DA, Axelson DA, Firinciogullari S, Chiapetta L, et al. Phenomenology of panic disorder in youth. Depress Anxiety. 2004;20:39-43. (B). Although PD is considered rare in young individuals, the frequency of the disorder may range from 0.52222. Essau CA, Conradt J, Petermann F. Frequency of panic attacks and panic disorder in adolescents. Depress Anxiety. 1999;9:19-26. (B) to 2%2121. Diler RS, Birmaher B, Brent DA, Axelson DA, Firinciogullari S, Chiapetta L, et al. Phenomenology of panic disorder in youth. Depress Anxiety. 2004;20:39-43. (B); rates as high as 6% have been reported. No epidemiological data are available for agoraphobia, except from patients referred to pediatric clinical services, with rates between 152323. Biederman J, Faraone SV, Marrs A, Moore P, Garcia J, Ablon S, et al. Panic disorder and agoraphobia in consecutively referred children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36:214-23. (B) and 18%2222. Essau CA, Conradt J, Petermann F. Frequency of panic attacks and panic disorder in adolescents. Depress Anxiety. 1999;9:19-26. (B).

As has been reported in several studies and is often noted in clinical practice, many adults with PD report that their symptoms began in childhood or adolescence. When comparing demographic and clinical characteristics of children and adolescents with and without PD, there were no gender differences in expressing symptoms of the disorder; however, there was a higher occurrence of PD in girls.

Regarding differences in the manifestations of PD in each age group, several authors argue that cognitive symptoms (e.g., fear of losing control) would be more present during adolescence and adulthood than in childhood2323. Biederman J, Faraone SV, Marrs A, Moore P, Garcia J, Ablon S, et al. Panic disorder and agoraphobia in consecutively referred children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36:214-23. (B). Contrary to this finding, other studies argue that there are no differences in the symptoms presented by children and adults or children and adolescents1919. Masi G, Favilla L, Mucci M, Millepiedi S. Panic disorder in clinically referred children and adolescents. Child Psychiatry Hum Dev. 2000;31:139-51.,2121. Diler RS, Birmaher B, Brent DA, Axelson DA, Firinciogullari S, Chiapetta L, et al. Phenomenology of panic disorder in youth. Depress Anxiety. 2004;20:39-43. (B).

Is there evidence of the role of genetic factors in the etiology of PD?

Among biological factors, the role of genetics in the onset and maintenance of PD has been investigated2424. Kendler KS, Karkowski LM, Prescott CA. 1999. Fears and phobias: reliability and heritability. Psychol Med.1999;29:539-53. (D). Family studies show a higher incidence of PD among first-degree relatives of patients2525. Judd FK, Burrows GD, Norman TR. The biological basis of anxiety. An overview. J Affect Disord. 1985;9:271-84. (D), with heritability being estimated at 43-48% for PD and 61% for agoraphobia2626. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158:1568-78. (B).

A number of chromosomal regions have been associated with susceptibility to PD, specifically 2q2727. Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R, et al. A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry. 2006;60:388-401. and 15q2727. Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R, et al. A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry. 2006;60:388-401. (B), chromosome 72828. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr. Genomewide survey of panic disorder. Am J Med Genet. 2001;105:105-9. (B), chromosome 1q2929. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S, et al. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet. 2001;105:548-57. (B), chromosome 9q3030. Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, et al. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet. 2003;72:1221-30. (B), 12q3131. Smoller JW, Block SR, Young MM. Genetics of anxiety disorders: the complex road from DSM to DNA. Depress Anxiety. 2009;26:965-75. (D), 22q,3232. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de Leon A, Hodge SE, et al. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA. 2003;100:2550-5. and 13q3232. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de Leon A, Hodge SE, et al. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA. 2003;100:2550-5. (B). Several studies also suggest that anxiety disorders, including phobias and PD, are complex traits that share at least one susceptibility locus in relation to chromosome 4q3333. Kaabi B, Gelernter J, Woods SW, Goddard A, Page GP, Elston RC. Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. Am J Hum Genet. 2006;78:543-53. (B).

It is important to note that, despite genetic factors, phenotypic expression is established through the interaction between genes and the environment3434. Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, et al. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet. 2001;105:195-206. (D). Twin studies have indicated moderate heritability in PD and suggest that environmental and genetic contributions are equally important2424. Kendler KS, Karkowski LM, Prescott CA. 1999. Fears and phobias: reliability and heritability. Psychol Med.1999;29:539-53.,3535. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Panic disorder in women: a population-based twin study. Psychol Med. 1993;23:397-406. (B).

Is there evidence of the role of environmental stressors in the etiology of PD?

A number of studies note the high prevalence of stressful life events, such as serious illness or an accident involving a family member or close friend, personal physical illness, worsening relations with one's spouse, trouble with one's boss, and worsening conditions in the workplace, prior to development of PD3636. Faravelli C, Pallanti S. Recent life events and panic disorder. Am J Psychiatry. 1989;146:622-6.,3737. Roy-Byrne PP, Geraci M, Uhde TW. Life events and the onset of panic disorder. Am J Psychiatry. 1986;143:1424-7. (B).

In a study of 187 patients with PD, the average number of significant life events was 7.8, with a mean value of 3.6 for positive events and 5.3 for negative events. Twenty-five percent of events were considered highly undesirable, while 22% were considered very desirable. In addition, adverse life events were associated with worse psychopathology3838. Lteif GN, Mavissakalian MR. Life events and panic disorder/agoraphobia. Compr Psychiatry. 1995;36:118-22. (B).

A 5-year longitudinal study assessed the factors involved in the onset of panic attacks in 2,000 office workers in a factory. Recent stressful events had a direct effect on the first episode of panic (standardized path coefficient of 0.06), with the strongest predictive value among other variables that were evaluated3939. Watanabe A, Nakao K, Tokuyama M, Takeda M. Prediction of first episode of panic attack among white-collar workers. Psychiatry Clin Neurosci. 2005;59:119-26. (A).

What is the importance of agoraphobia in the diagnosis of PD?

In recent years, agoraphobia has been viewed as directly related to recurrent panic attacks, and in most cases, it appears as a consequence or complication of PD4040. Perugi G, Frare F, Toni C. Diagnosis and treatment of agoraphobia with panic disorder. CNS Drugs. 2007;21:741-64. (D). Other authors believe agoraphobia may be conceptualized as an independent disorder, with more specific criteria that are residual and subordinate to PD4141. Wittchen HU, Gloster AT, Beesdo-Baum K, Fava GA, Craske MG. Agoraphobia: a review of the diagnostic classificatory position and criteria. Depress Anxiety. 2010;27:113-33. (D).

In patients with different subtypes of PD, it was observed that situational panic attacks were more related to the presence of agoraphobia and anticipatory anxiety was higher when agoraphobia was accompanied by PD4242. Uhlenhuth EH, Leon AC, Matuzas W. Psychopathology of panic attacks in panic disorder. J Affect Disord. 2006;92:55-62. (B). Results from the National Comorbidity Survey Replication found that lifetime prevalences of 22.7% for panic attack as an isolated event, 3.7% for PD without agoraphobia, and 1.1% for PD with agoraphobia, the latter being associated with a greater number of panic attacks and a greater persistence of the disorder. The presence of agoraphobia was associated with increased severity and a greater number of comorbidities33. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2006;63:415-24. (A). Despite the high prevalence of agoraphobia in PD, this condition is often underdiagnosed and undertreated4040. Perugi G, Frare F, Toni C. Diagnosis and treatment of agoraphobia with panic disorder. CNS Drugs. 2007;21:741-64. (D).

PD patients with agoraphobia tend to have a more chronic disorder than do those without agoraphobia. In a 3-year cohort study of PD patients with and without agoraphobia, those who had only PD recovered more often than did patients with PD with agoraphobia. Nevertheless, there were no between-group differences in disease recurrence rates at the end of the follow-up period4343. Francis JL, Weisberg RB, Dyck IR, Culpepper L, Smith K, Orlando Edelen M, et al. Characteristics and course of panic disorder and panic disorder with agoraphobia in primary care patients. J Clin Psychiatry. 2007;9:173-9. (A). Recovery rates tended to be lower, estimated at 18-64%, in individuals diagnosed with PD and agoraphobia4444. Roy-Byrne PP, Cowley DS. Course and outcome in panic disorder: a review of recent follow-up studies. Anxiety. 1994-1995;1:151-60. (D).

Likewise, a longitudinal study and a naturalistic observation, the Harvard/Brown Anxiety Research Project, found that the probability of remission for patients with PD at 1-year follow-up was 39%. When agoraphobia was present, this rate fell to 17%4545. Keller MB, Yonkers KA, Warshaw MG, Pratt LA, Gollan JK, Massion AO, et al. Remission and relapse in subjects with panic disorder and panic with agoraphobia: a prospective short-interval naturalistic follow-up. J Nerv Ment Dis. 1994;182:290-6. (A). In patients who were studied for 8 years, the percentage of remission was higher (38%) among those initially diagnosed as having PD without agoraphobia than for those diagnosed with agoraphobia (20.6%)4646. Carpiniello B, Baita A, Carta MG, Sitzia R, Macciardi AM, Murgia S, et al. Clinical and psychosocial outcome of patients affected by panic disorder with or without agoraphobia: results from a naturalistic follow-up study. Eur Psychiatry. 2002;17:394-8. (B).

Are there differences between PD patients with or without agoraphobia?

PD may exist either with or without agoraphobia, but cases of agoraphobia without a history of PD are more uncommon4747. Bienvenu OJ, Onyike CU, Stein MB, Chen LS, Samuels J, Nestadt G, et al. Agoraphobia in adults: incidence and longitudinal relationship with panic. Br J Psychiatry. 2006;188:432-8. (B) and this diagnostic categorization is still controversial.

Comparisons between outcomes in PD with agoraphobia and in PD without agoraphobia are inconclusive. People with PD and agoraphobia interpret stimuli with a catastrophic way of thinking; yet, research has suggested that the consequences of catastrophizing events were not sufficient to differentiate between the two groups4848. Berle D, Starcevic V, Hannan A, Milicevic D, Lamplugh C, Fenech P. Cognitive factors in panic disorder, agoraphobic avoidance and agoraphobia. Behav Res Ther. 2008;46:282-91. (B). Moreover, it has been observed that, in patients with PD and agoraphobia who were treated with exposure to panicogenic situations, the presence of residual agoraphobia was a strong predictor of relapse4949. Fava GA, Rafanelli C, Grandi S, Conti S, Ruini C, Mangelli L, et al. Long-term outcome of panic disorder with agoraphobia treated by exposure. Psychol Med. 2001;31:891-8. (B).

Comparison of the treatments administered to patients with PD with or without agoraphobia showed that, in both groups, a combination of psychotherapy and drug therapy was more effective than monotherapy during the acute phase (first 8-12 weeks of treatment), while patients in the chronic phase (after 12 weeks) should be treated with combined therapy or psychotherapy alone5050. Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry. 2006;188:305-12. (A). In the acute phase, there is a relative risk reduction associated with combination therapy vs. pharmacotherapy alone, with RR = 1.24 (95%CI 1.02-1.52), and combination therapy vs. psychotherapy alone, with RR = 1.16 (95%CI 1.03-1.30). For treatment during the chronic phase, combination therapy is more effective than pharmacotherapy alone, which reduces the relative risk to RR = 1.61 (95%CI 1.23-2.11), whereas no significant differences between combination therapy and psychotherapy were found (RR = 0.96, 95%CI 0.79-1.16)5050. Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry. 2006;188:305-12. (A). Additionally, there were no significant differences between the types of pharmacological treatment for PD with and without agoraphobia5151. Bruce SE, Vasile RG, Goisman RM, Salzman C, Spencer M, Machan JT, et al. Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Am J Psychiatry. 2003;160:1432-8. (B).

What is the impact of depression on the diagnosis and prognosis of patients with PD?

Anxiety disorders and depression co-occur with great frequency, and most cases of depression are secondary to an anxiety disorder (67.9%)5252. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE, et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med. 2005;352:2515-23. (A). Studies show that, because depression is the most common mood found in PD, it must be addressed during PD treatment, especially due to its association with worse severity of PD5353. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry. 2000;176:229-35. (A). In a WHO study involving 25,916 patients who were treated in the primary health care setting, the likelihood of depressed patients presenting comorbid PD were 12 times greater than expected5454. Sartorius N, Ustün TB, Lecrubier Y, Wittchen HU. Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl. 1996;38-43. (A).

In a population survey, the lifelong prevalence of depression in patients with PD was significantly higher (55.6%, OR = 6.8) than that of PD in people with depression (11.2%, OR = 6.2). In addition, people with PD and depression reported significant more physiological symptoms during attacks (9.1%) than those without depression (p ≤ 0.001). Patients were also more likely to use psychiatric services when suffering comorbid conditions as opposed to one condition5353. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry. 2000;176:229-35. (A).

In general, studies have shown that depression in PD is associated with a more severe psychopathology5454. Sartorius N, Ustün TB, Lecrubier Y, Wittchen HU. Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl. 1996;38-43. (A), worse prognosis5555. Noyes R Jr, Reich J, Christiansen J, Suelzer M, Pfohl B, Coryell WA. Outcome of panic disorder. Relationship to diagnostic subtypes and comorbidity. Arch Gen Psychiatry. 1990;47:809-18. (B), poor response to treatment5656. Keller MB, Lavori PW, Goldenberg IM, Baker LA, Pollack MH, Sachs GS, et al. Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. J Affect Disord. 1993;28:27-38. (B), an increased number of suicide attempts5757. Johnson J, Weissman MM, Klerman GL. Panic disorder, comorbidity, and suicide attempts. Arch Gen Psychiatry. 1990;47:805-8. (B), and limited functioning5858. Van Valkenburg C, Akiskal HS, Puzantian V, Rosenthal T. Anxious depressions. Clinical, family history, and naturalistic outcome comparisons with panic and major depressive disorders. J Affect Disord. 1984;6:67-82. (B) than PD or depression alone. Patients should also be evaluated for presence of the demoralization syndrome, which is characterized by low self-esteem and feelings of inadequacy and guilt arising from the limitations of PD5959. Klein DF. Mixed anxiety depression. For and against. Encephale. 1993;19:493-5. (D) and is sometimes confused with depression. In this syndrome, symptoms improve after successful treatment of PD, often with no need for specific mood-directed treatments. Early diagnosis of PD can reduce the risk of developing depression5252. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE, et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med. 2005;352:2515-23. (A).

What is the impact of alcohol and illicit drug abuse and dependence on the diagnosis and prognosis of patients with PD?

Patients with PD may engage in alcohol abuse. There are several explanations for this co-occurrence: a) PD leads to alcohol abuse, which is often used as self- medication for the improvement of anxiety symptoms; b) chronic alcohol use and withdrawal induce neurochemical changes that lead to panic attacks; and c) a third factor, such as familial transmission, leads to the development of the two conditions6060. Cosci F, Schruers KR, Abrams K, Griez EJ. Alcohol use disorders and panic disorder: a review of the evidence of a direct relationship. J Clin Psychiatry. 2007;68:874-80. (D). In a 3-year prospective epidemiological study of women, occasional intake of large amounts of alcohol (binge drinking) was associated with an increased risk of PD, with OR = 2.23 (95%CI 1.01-4.91)6161. Chou KL, Liang K, Mackenzie CS. Binge drinking and Axis I psychiatric disorders in community-dwelling middle-aged and older adults: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 2011;72:640-7. (A).

In 73.1% of PD patients, the onset of alcohol use preceded the onset of PD. It has been observed that patients with PD and alcoholism may experience a more severe disorder, with an increased number of panic attacks and increased anticipatory anxiety6262. Márquez M, Segui J, Canet J, Garcia L, Ortiz M. Alcoholism in 274 patients with panic disorder in Spain, one of the main producers of wine worldwide. J Affect Disord. 2003;75:237-45. (B). Other psychoactive substances, such as cocaine, cannabis, and nicotine, also appear to be able to trigger panic attacks or increase the frequency and intensity of these attacks6363. Roy-Byrne PP, Uhde YW. Exogenous factors in panic disorder: clinical and research implications. J Clin Psychiatry. 1988;49:56-61. (D).

Moreover, patients with both PD and alcohol abuse or dependence tend to frequently report a history of depression and use of other psychoactive substances. Alcoholic patients with comorbid PD often have other comorbidities as well, such as depression, dysthymia, and a history of more suicide attempts6464. Segui J, Márquez M, Canet J, Cascio A, Garcia L, Ortiz M. Panic disorder in a Spanish sample of 89 patients with pure alcohol dependence. Drug Alcohol Depend. 2001;63:117-21. (B). Individuals who experience panic attacks attempt suicide more often, especially if they abuse alcohol5757. Johnson J, Weissman MM, Klerman GL. Panic disorder, comorbidity, and suicide attempts. Arch Gen Psychiatry. 1990;47:805-8. (B).

What are nocturnal panic attacks? What is the significance of nocturnal panic attacks in the diagnosis of PD?

Nocturnal panic attacks are characterized by a sudden awakening from sleep in a state of panic, which is defined as an abrupt and rapid period of intense fear or discomfort, accompanied by physical or cognitive symptoms. These panic attacks occur without an obvious trigger6565. Lopes FL, Nardi AE, Nascimento I, Valença AM, Mezzasalma MA, Freire RC, et al. Diurnal panic attacks with and without nocturnal panic attacks: are there some phenomenological differences? Rev Bras Psiquiatr. 2005;27:216-21. (B). They are distinguished from night terrors, sleep apnea, and nightmares6666. Craske MG, Tsao JC. Assessment and treatment of nocturnal panic attacks. Sleep Med Rev. 2005;9:173-84. (D), and their prevalence ranges from 44 to 71% of patients with PD6666. Craske MG, Tsao JC. Assessment and treatment of nocturnal panic attacks. Sleep Med Rev. 2005;9:173-84. (D). On the other hand, diurnal panic attacks occur when the subject is awake and can be spontaneous or situational.

A polysomnographic study of PD patients showed respiratory irregularities in the subgroup of patients with panic attacks, which suggests that nocturnal panic attacks could be a variant of PD6767. Stein MB, Millar TW, Larsen DK, Kryger MH. Irregular breathing during sleep in patients with panic disorder. Am J Psychiatry. 1995;152:1168-73. (C). Similarly, another study indicated that patients with prominent respiratory symptoms are more sensitive to CO2 inhalation and have higher rates of nocturnal panic attacks, which is related to a more severe subtype of panic, a longer duration of the disease, and more intense phobic symptoms6868. Biber B, Alkin T. Panic disorder subtypes: differential responses to CO2 challenge. Am J Psychiatry. 1999;156:739-44. (B). Patients with nocturnal panic attacks are more often depressed or have other psychiatric symptoms6969. Sarísoy G, Böke O, Arík A, Sahin AR. Panic disorder with nocturnal panic attacks: symptoms and comorbidities. Eur Psychiatry. 2008;23:195-200. (B) and tend to be more prone to developing anorexia nervosa and somatization disorder7070. Albert U, Maina G, Bergesio C, Bogetto F. Axis I and II comorbidities in subjects with and without nocturnal panic. Depress Anxiety. 2006;23:422-8. (B).

Thus, diurnal and nocturnal panic attacks seem to develop in different ways. In nocturnal panic attacks, biological factors such as dysfunction of the autonomic nervous system can be a crucial aspect, whereas cognitive and psychological factors may act as an initial stimulus for diurnal panic attacks7171. Levitan MN, Nardi AE. Nocturnal panic attacks: clinical features and respiratory connections. Expert Rev Neurother. 2009;9:245-54. (D).

Several pharmacological agents are more effective in patients with nocturnal panic attacks, while cognitive and behavioral strategies may be more suitable for daytime panic attacks7272. Shapiro CM, Sloan EP. Nocturnal panic - an underrecognized entity. J Psychosom Res. 1998;44:21-3. (D). It is also possible that patients with diurnal and nocturnal panic attacks are similar with respect to comorbidities, symptoms of negative affect, and impact in interpersonal functioning. Patients with nocturnal attacks tend to have more sleep disturbances and less agoraphobic avoidance, because the association between panic situational factors is less frequent,7373. Craske MG, Lang AJ, Mystkowski JL, Zucker BG, Bystritsky A, Yan-Go F. Does nocturnal panic represent a more severe form of panic disorder? J Nerv Dis. 2002;190:611-8. (B) but do not differ from patients with diurnal panic attacks in sleep architecture, sleep physiology, sleep quality, or self-reported severity of PD6666. Craske MG, Tsao JC. Assessment and treatment of nocturnal panic attacks. Sleep Med Rev. 2005;9:173-84. (D). Likewise, in a short-term prospective study of 57 patients taking nortriptyline, both groups showed similar features in terms of phenomenological results6565. Lopes FL, Nardi AE, Nascimento I, Valença AM, Mezzasalma MA, Freire RC, et al. Diurnal panic attacks with and without nocturnal panic attacks: are there some phenomenological differences? Rev Bras Psiquiatr. 2005;27:216-21. (B).

Should psychiatrists screen PD patients for sleep disorders?

Subjective reports have shown high rates of sleep complaints in PD patients as compared with control groups7474. Babson KA, Feldner MT, Trainor CD, Smith RC. An experimental investigation of the effects of acute sleep deprivation on panic-relevant biological challenge responding. Behav Ther. 2009;40:239-50. (A). Although the findings of polysomnographic studies of PD patients are still inconsistent7575. DeZee KJ, Jackson JL, Hatzigeorgiou C, Kristo D. The Epworth sleepiness scale: relationship to sleep and mental disorders in a sleep clinic. Sleep Med. 2006;7:327-32. (B), decreases in the efficiency and duration of sleep have been reported7676. Stein MB, Enns MW, Kryger MH. Sleep in nondepressed patients with panic disorder: II. Polysomnographic assessment of sleep architecture and sleep continuity. J Affect Disord. 1993;28:1-6.,7777. Arriaga F, Paiva T, Matos-Pires A, Cavaglia F, Lara E, Bastos L. The sleep of non-depressed patients with panic disorder: a comparison with normal controls. Acta Psychiatr Scand. 1996;93:191-4. (B). In general, lack of sleep has been strongly associated with comorbid depression, with a prevalence rate of 30-40%7878. Lepine JP. Epidemiology, burden and disability in depression and anxiety. J Clin Psychiatry. 2001;62:4-10. (A).

Chronic complaints about sleep occur in up to 53% of PD patients without comorbidities. When there is a comorbid mood disorder, this rate reaches 86%7979. Overbeek T, van Diest R, Schruers K, Kruizinga F, Griez E. Sleep complaints in panic disorders patients. J Nerv Ment Dis. 2005;193:488-93. (B). The most common complaints are often confused with depression and are related to initiating and maintaining sleep, early awakening, difficulty awaking, oversleeping, lethargy, and daytime sleepiness7979. Overbeek T, van Diest R, Schruers K, Kruizinga F, Griez E. Sleep complaints in panic disorders patients. J Nerv Ment Dis. 2005;193:488-93. (B).

In general, a high percentage of patients (77%) with nocturnal panic attacks reported sleeping problems7979. Overbeek T, van Diest R, Schruers K, Kruizinga F, Griez E. Sleep complaints in panic disorders patients. J Nerv Ment Dis. 2005;193:488-93. (B). Nocturnal panic attacks may disturb sleep, buth by interrupting it and because of subsequent anticipatory anxiety, which is characterized by fear of sleeping and having a panic attack. This fear leads to the avoidance of sleep and then to sleep deprivation, which further aggravates anxiety. Polysomnography is of particular importance in the clinical diagnosis because it allows for the differential diagnosis of panic attack, night terrors, nightmares, and sleep apnea6666. Craske MG, Tsao JC. Assessment and treatment of nocturnal panic attacks. Sleep Med Rev. 2005;9:173-84. (D).

In the case of panic attacks in a social situation, how does one make the differential diagnosis between social anxiety disorder (SAD) and PD?

Symptoms related to social anxiety and PD may be confused, especially when the patient's only avoidance is social situations8080. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry. 2000;176:229-35. (A). Identifying the focus of fear is essential to establishing a diagnosis. In cases of social anxiety, fear and somatic symptoms are triggered by situational activators, such as exposure and social performance. In PD, these symptoms are sudden and often do not result from a trigger.

Beliefs related to fear are also different. In the context of SAD, fears are related to the fear of being humiliated in a social situation or displaying excessive anxiety. In PD, beliefs are associated with fear of having a panic attack in public and the inability to receive help in a social environment.

What are the differences between the most common concerns of patients with generalized anxiety disorder (GAD) and patients with PD?

In GAD, patient concerns are focused on situations of everyday life, and are accompanied by stress, worry, and fear of the worst, e.g., family violence or health problems. There is no focus on bodily sensations or fear of having a panic attack, but rather an excess of continued anxiety symptoms11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D).

In the event of an extremely anxiogenic situation, how does one differentiate between PD and post-traumatic stress disorder (PTSD)?

In PTSD, the patient must have experienced or witnessed a situation posing real danger to their life or to others. After the traumatic experience, a person with PTSD usually has distressing memories of the event and intrusive dreams. Because the memories are painful, the person tends to avoid thoughts, activities, and places related to the trauma. Other symptoms such as insomnia, irritability, and difficulty concentrating tend to occur11. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Press; 2000. (D).

Conversely, in PD, there is no history of direct or indirect exposure to the types of situations that typically cause PTSD. Instead, the panic attack is spontaneous, sudden, with no apparent cause, and may even occur during sleep.

Which clinical diseases should be considered in the differential diagnosis of PD?

The set of symptoms that characterize panic attacks or PD may be confused with a series of clinical medical conditions8181. Muller JE, Koen L, Stein DJ. Anxiety and medical disorders. Curr Psychiatry Rep. 2005;7:245-51. (D). In the differential diagnosis of PD and clinical entities of an organic nature, late onset (after the age of 45 years) and the presence of atypical symptoms, such as dizziness, unconsciousness, and loss of sphincter control, suggest that an organic cause may be associated with the attacks8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. (D). It is also important to note that clinical diseases may co-occur with PD, in which case both conditions must be treated.

The differential diagnosis should include the following clinical diseases, stratified by organ system involved: 1) cardiovascular system - acute myocardial infarction may be the clinical situation that most often resembles PD, because its symptoms - such as chest tightness, shortness of breath, palpitations, sweating, and feeling of impending death - may also occur in anxiety attacks and coexist in both situations (thus, the patient should undergo tests such as ECG and serum cardiac markers to rule out an organic etiology; normal ECG and cardiac markers confirm the diagnosis of PD8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. [D]); other cardiovascular diseases from which PD must be differentiated include congestive heart failure, hypertension, mitral valve prolapse, angina pectoris, and atrial tachycardia8383. Morris A, Baker B, Devins GM, Shapiro CM. Prevalence of panic disorder in cardiac outpatients. Can J Psychiatry. 1997;42:185-90. (B); 2) neurological system - neurological conditions such as temporal lobe epilepsy, space-occupying lesions, multiple sclerosis8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. (D), and Parkinson disease8484. Factor SA, Molho ES. Emergency department presentation of patients with Parkinson's disease. Am J Emergency Med. 2000;18:209-15. (C) can mimic a panic attack; 3) endocrine system - Addison's disease, Cushing's syndrome, diabetes, hypoglycemia, hyperthyroidism, hypoparathyroidism, self-immune thyroiditis8585. Stein MB, Uhde TW. Autoimmune thyroiditis and panic disorders. Am J Psychiatry. 1989;146:259-60. (C), and pheochromocytoma can mimic a panic attack8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. (D); in addition to these conditions, premenstrual syndrome and menopausal disorders can also exhibit characteristics that may warrant inclusion into the differential diagnosis of PD8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. (D); 4) acute lung diseases - asthma, pulmonary embolism, and chronic obstructive pulmonary disease or acute anxiety can trigger situations with clinical manifestations similar to those found in PD8787. Valença AM, Nardi AE, Nascimento I, Zin WA, Lopes FL, Mezzasalma MA, et al. Early carbon dioxide challenge test may predict clinical response in panic disorder. Psychiatry Res. 2002;112:269-72. (D); 5) other medical conditions - drug use (hallucinogens, marijuana, cocaine, amphetamines, and nicotine) and withdrawal syndromes (alcohol, benzodiazepines, opiates, and cocaine) can also mimic the symptomatology of PD8282. Sadock BJ, Sadock VA. Compêndio de Psiquiatria: ciências do comportamento e psiquiatria clínica. 9th ed. Porto Alegre: Artmed; 2007. (D).

What are the results of laboratory studies of PD?

Pharmacological induction of panic attacks in the laboratory has been one of the strategies used in PD research. This technique enables study of panic attacks under controlled conditions and evaluation of the efficacy of pharmacotherapy for PD.

In one study, unmedicated patients with PD (n=31) were subjected to inhalation of 35% CO2 and compressed atmospheric air. Overall, 71% of the patients (n=22) had panic attacks with CO2, whereas none of the subjects reacted to the compressed air8686. Valença AM, Nardi AE, Nascimento I, Mezzasalma MA, Lopes FL, Zin WA. Ataques de pânico provocados pelo dióxido de carbono: estudo clínico-fenomenológico. Rev Bras Psiquiatr. 2001;23:15-20. (B). In another study by the same group, panic attacks were blocked by clonazepam (2 mg/day) but not by placebo, and patients who took clonazepam did not present any panic attacks at the end of the study (p ≤ 0.001)8787. Valença AM, Nardi AE, Nascimento I, Zin WA, Lopes FL, Mezzasalma MA, et al. Early carbon dioxide challenge test may predict clinical response in panic disorder. Psychiatry Res. 2002;112:269-72. (B).

In a trial of antidepressant treatment of PD, after the 7th day, responses to CO2 diminished significantly in groups receiving imipramine (20 mg/day, p = 0.004), paroxetine (10 mg/day, p = 0.001), and sertraline (25 mg/day, p = 0.004)8888. Bertani A, Perna G, Arancio C, Caldirola D, Bellodi L. Pharmacologic effect of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in panic patients: a double-blind, random, placebo-controlled study. J Clin Psychopharmacol. 1997;17:97-101. (A).

In general, hyperventilation or breath-holding maneuvers, despite inducing respiratory alkalosis with transient breathlessness, dizziness, and anxiety, have not been proven to cause panic attacks in most patients who undergo this experiment, except in patients who are more susceptible8989. Vickers K, Jafarpour S, Mofidi A, Rafat B, Woznica A. The 35% carbon dioxide test in stress and panic research: Overview of effects and integration of findings. Clin Psychol Rev. 2012;32:153-64. (D).

What are the results of neuroimaging studies in PD?

With the advent of functional imaging studies, cerebral regions are being mapped and correlated with behavioral disorders, including anxiety disorders9090. Ferrari MCF, Busatto GF, McGuire PK, Crippa JA. Structural magnetic imaging in anxiety disorders: an update of research findings. Rev Bras Psiquiatr. 2008;30:251-64. (B).

In a study with 12 PD patients and 12 controls, the volume of the right and left amygdala was decreased in PD patients, while controls showed no change in their sizes9191. Massana G, Serra-Grabulosa JM, Salgado-Pineda P, Gastó C, Junqué C, Massana J, et al. Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging. Neuroimage. 2003;19:80-90. (B). Following this line of research, other authors found that the left temporal lobe of 11 PD patients exhibited a reduction in volume compared to 11 healthy controls9292. Uchida RR, Del-Ben CM, Santos AC, Araújo D, Crippa JA, Guimarães FS, et al. Decreased left temporal lobe volume of panic patients measured by magnetic resonance imaging. Braz J Med Biol Res. 2003;36:925-9. (B).

The hippocampal region of the septum seems to play an important role in controlling anxiety9393. Gray JA, McNaughton N. The neuropsychology of anxiety. An enquiry into the functions of the septo-hippocampal system. 2nd ed. Oxford: Oxford University; 2000. (D). Thus, there is suspicion that the septo-hippocampal system plays a role in the occurrence of PD. In one study, researchers detected a high frequency of cavum septi pellucidi with electroencephalographic abnormalities in patients with PD9494. Dantendorfer K, Prayer D, Kramer J, Amering M, Baischer W, Berger P, et al. High frequency of EEG and MRI brain abnormalities in panic disorder. Psychiatry Res. 1996;68:41-53. (B). Another study, however, did not confirm the previous observations in 21 patients with PD compared with 21 controls9595. Crippa JA, Uchida R, Busatto GF, Guimarães FS, Del-Ben CM, Zuardi AW, et al. The size and prevalence of the cavum septum pellucidum are normal in subjects with panic disorders. Braz J Med Biol Res. 2004;37:371-4. (B).

When comparing the gray matter of 19 PD patients to 20 healthy volunteers, researchers found an increase in the left insula of this area in PD patients compared to healthy controls and an increase in the superior temporal gyrus, midbrain and bridge. Relative gray matter deficits were observed in the right anterior cingulate cortex. The authors concluded that abnormalities in the brain stem are involved in the generation of panic attacks9696. Uchida RR, Del-Ben CM, Busatto GF, Duran FL, Guimarães FS, Crippa JA, et al. Regional gray matter abnormalities in panic disorder: a voxel based morphometry study. Psychiatry Res. 2008;163:21-9. (B).

Is there any benefit to performing heart tests after a diagnosis of PD has been established?

A study of 5,187 patients showed that the presence of any anxiety disorder diagnosis was significantly associated with the presence of various diseases. PD was associated with vascular conditions (OR = 2.28), bone or joint diseases (OR = 2), and neurological conditions (OR = 1.75). Other anxiety disorders such as GAD, SAD, and simple phobias had less of an association with physical illness than did PD9797. Sareen J, Cox BJ, Clara I, Asmundson GJ. The relationship between anxiety disorders and physical disorders in the U.S. National Comorbidity Survey. Depress Anxiety. 2005;21:193-202. (A). A population-based study in Norway evaluated 64,871 patients to explore the correlation between PD and systolic blood pressure. GAD was associated with the presence of low systolic blood pressure, while patients with PD had a mean systolic blood pressure of 140 mmHg9898. Davies SJ, Bjerkeset O, Nutt DJ, Lewis G. A U-shaped relationship between systolic blood pressure and panic symptoms: the HUNT study. Psychol Med. 2012;42:1969-76. (A).

Decreased heart rate variability was identified as a potential risk factor for sudden death in patients recovering from myocardial infarction9999. Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256-62.,100100. Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85:164-71. (B). Evidence suggests that patients diagnosed with PD exhibit reduced heart rate variability compared with controls. These findings suggest that individuals with PD show changes in cardiac autonomic control, and these changes could place them at an increased risk of ventricular arrhythmia101101. Yeragani VK, Balon R, Pohl R, Ramesh C, Glitz D, Weinberg P, et al. Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand. 1990;81:554-9. (B) and sudden cardiac death102102. Yeragani VK, Pohl R, Berger R, Balon R, Ramesh C, Glitz D, et al. Decreased heart rate variability in panic disorder patients: a study of power-spectral analysis of heart rate. Psychiatry Res. 1993;46:89-103. (C).

A study of 3,369 postmenopausal women showed that those who experienced at least one full-blown panic attack in the preceding 6-month period were more likely to have the cardiovascular risk factors smoking, hypertension, and diabetes mellitus, as well as a history of cardiovascular morbidity (A).103103. Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, et al. Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study. Arch Gen Psychiatry. 2007;64:1153-60.

A 32-year study of 402 cases of coronary heart disease (137 cases of nonfatal myocardial infarction, 134 cases of angina, 131 cases of fatal coronary heart disease, 26 cases of sudden cardiac death, and 105 cases of non-sudden death) and 1,869 individuals without coronary artery disease showed that subjects with coronary disease who reported symptoms of anxiety had a higher risk of fatal outcome, with an OR of 3.20 (95%CI 1.27-8.09) for fatal coronary disease and an OR of 5.73 for sudden death (95%CI 1.26-26.1). An increased risk of myocardial infarction or nonfatal angina was not found104104. Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study. Circulation. 1994;90:2225-9. (A) These data suggest an association between anxiety and fatal coronary heart disease, particularly sudden cardiac death, in patients with coronary heart disease and symptoms of anxiety, which indicates the need for careful study of this population.

Conclusions

These guidelines, which were designed by the BMA in partnership with the BPA, serve to facilitate and assist in the decisions of physicians and to provide clarity, clinical applicability, and practical relevance for the diagnosis and differential diagnosis of PD.

Due to the close association between PD and autonomic activation, PD is often mistaken for clinical conditions such as stroke and high blood pressure, which can delay treatment. This confusion can also occur with other psychiatric disorders that have symptoms similar to those of PD. In addition to prolonging patient suffering, unsuitable treatment of the patients leads to unnecessary financial costs.

Research on PD has intensified during the last decade, particularly regarding neuroimaging, which reflects the interest of the scientific community in gaining a better understanding of this disorder. Laboratory studies using panicogenic agents are also important for exploring the mechanisms underlying the development of PD.

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Publication Dates

  • Publication in this collection
    Dec 2013

History

  • Received
    2 Apr 2012
  • Accepted
    30 Jan 2013
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