Panic Disorder 1

Description

The DSM-IV (American Psychiatric Association, 1994) defines panic disorder as the spontaneous, unexpected occurrence of panic attacks followed by persistent concern, worry, and anxiety about having additional panic attacks. Panic attacks are defined as a discrete period of intense fear or discomfort in which at least 4 of 13 symptom criteria are met that develop abruptly and reach a peak within 10 minutes. Some of these criteria include cardiac palpitations, sweating, feelings of choking, fear of losing control, and fear of dying. Panic disorder is divided into panic disorder with or without accompanying agoraphobia. However, agoraphobia can also occur without panic disorder, and panic attacks can occur in the absence of panic disorder. Comorbidity with depressive and addictive disorders is frequent.

Barlow et al. (1994) and Smoller and Tsuang (1998) noted that because the diagnostic criteria remain purely clinical, the nosology of anxiety disorders, such as panic disorder, is controversial and evolving. Therefore, it is difficult to do genetic studies because of the difficulty in delineating overlapping phenotypes within the broader context of anxiety disorders. For example, there may be overlap of panic with specific phobias, variable expressivity of panic and anxiety or depression, or phenocopies within a family. The terms 'anxiety neurosis' and 'phobic neurosis' were used in the past (before the DSM-III in 1980) to encompass all of these disorders. Smoller and Tsuang (1998) suggested that dimensional personality traits, such as shyness, behavioral inhibition, and neuroticism (see 607834), could be used to define an anxiety phenotype.

Schumacher et al. (2011) provided a review of the genetics of panic disorder. They noted that there is high (80%) comorbidity with other psychiatric disorders, including agoraphobia, mood disorders, substance abuse, and other anxiety disorders. Associated personality traits include anxiety sensitivity, behavioral inhibition, neuroticism, and harm avoidance. Women are more susceptible to development of the disorder, which has an average age of onset at 23.6 years.

Genetic Heterogeneity of Susceptibility to Panic Disorder

Susceptibility to panic disorder-1 (PAND1) has been mapped to chromosome 13q. See also PAND2 (607853), mapped to chromosome 9, and PAND3 (609985), mapped to chromosome 4.

Inheritance

Like many other complex behavioral traits, panic disorder is likely caused by an interaction of multiple loci, rather than a single locus.

There is considerable evidence for a familial component to anxiety disorders in general and panic attacks in particular. Cohen et al. (1951) reported a pioneer study of a disorder that they referred to as neurocirculatory asthenia (NCA; also anxiety neurosis, effort syndrome). The families of 139 patients with neurocirculatory asthenia and of 80 control subjects were investigated. Detailed information was provided on the criteria of diagnosis as well as the findings in these cases. The prevalence of the disorder was high in relatives of the patients with chronic neurocirculatory asthenia but there was little, if any, increase in patients with acute NCA. Only 1 case of NCA was found in first-degree relatives of control subjects lacking the disorder. In families of chronic NCA patients, when neither parent was affected, 27.5% of the offspring were affected; when 1 parent was affected, 37.7% were affected; and when both parents were affected, 61.9% were affected by NCA. In families with NCA patients, more mothers (54.8%) had NCA than fathers (17.5%). A high prevalence of alcoholism was observed in the fathers of patients with NCA as compared with the fathers of controls. Cohen et al. (1951) suggested that alcoholic fathers may represent cases of NCA. They thought that simple imitation, i.e., copying, could not explain the high familial prevalence of the disorder. The data appeared to fit best with dominant inheritance.

Noyes et al. (1978) reported that the risk for 'anxiety neurosis' among first-degree relatives of patients with the disorder was 18% compared to 3% for controls. Pauls et al. (1980) analyzed 19 kindreds with panic disorder and concluded that the segregation suggested autosomal dominant inheritance. Seven of the 19 kindreds were ascertained through a proband who had mitral valve prolapse in addition to panic disorder. Autosomal dominant inheritance was equally supported by the other 12 pedigrees.

In a study of 32 monozygotic (MZ) and 53 dizygotic (DZ) adult same-sex twin pairs, Torgersen (1983) found that the frequency of anxiety disorders was twice as high in the MZ as in the DZ pairs. Panic disorder and agoraphobia with panic attacks were more than 5 times more frequent in the MZ twins. Genetic factors were not apparent for generalized anxiety disorder. In a family study of 40 patients with agoraphobia and 40 patients with panic disorder, Noyes et al. (1986) showed that the risk for panic disorder was increased among the relatives of patients with agoraphobia (8.3%) and the relatives of patients with panic disorder (17.3%). The risk for agoraphobia was also increased among the relatives of patients with agoraphobia (11.6%), but not the relatives of patients with panic disorder (1.9%). No greater risk for affective disorders was found among the relatives. The authors suggested that agoraphobia may be a more severe variant of panic disorder.

In a study of 117 probands with panic disorder, Hopper et al. (1987) found that the presence of an affected parent or sib incurred an approximately 5 times increased risk of developing panic disorder. Although they noted that the familial aggregation was consistent with a genetic hypothesis, they suggested that it could also be explained by common family environmental factors.

Skre et al. (1993) suggested a genetic contribution in the etiology of panic disorder, generalized anxiety disorder, and posttraumatic stress disorder (PTSD) among 20 MZ and 29 DZ twins. Among 120 twin pairs, Perna et al. (1997) found a significantly higher concordance among MZ than DZ twins for panic disorder (73% vs 0%), but not for spontaneous panic attacks (57% vs 43%), confirming a role for genetic factors in panic disorder. In a study of 152 probands with panic disorder, Goldstein et al. (1997) found that the risk of panic disorder in adult first-degree relatives of probands with onset before 20 years or after 20 years of age was increased 17-fold and 6-fold, respectively. The authors concluded that age at onset may be useful in differentiating familial subtypes of panic disorder.

In a study of 2,287 Australian and 1,185 Dutch twins and sibs, Middeldorp et al. (2005) found a correlation of 0.20 for generalized anxiety disorder and 0.25 for social phobia, yielding an upper heritability estimate of 40% and 50%, respectively. The correlation for panic disorder with or without agoraphobia was 0.23, yielding a heritability estimate of 46% for same-sex sibs only, suggesting different familial factors for men and women.

In a review, Schumacher et al. (2011) noted that the estimated heritability of panic disorder is 48%, and that most cases show complex genetic inheritance.

Panic Disorder Syndrome Associated with Bladder/Kidney Conditions

In a study of 34 families with panic disorder, Weissman et al. (2000) identified a subgroup of 19 families with a 'syndrome' consisting of bladder or kidney conditions, thyroid problems, migraines and other serious headaches, and mitral valve prolapse. Not all of the individuals with the 'syndrome' had panic disorder. Bladder and kidney problems included frequent infections, enuresis after age 5 years, urinary frequency or retention, and rare structural abnormalities. In addition, the authors completed a case-control study of patients with interstitial cystitis and found an elevated rate of panic disorder. Family members of those with interstitial cystitis, both with and without panic disorder, had elevated rates of the 'syndrome' compared to controls.

Panic Disorder with Joint Laxity

Gratacos et al. (2001) studied 7 pedigrees in which multiple members were affected by panic/phobic disorders and joint laxity. Twenty patients had panic disorder (10 without agoraphobia and 10 with agoraphobia), 8 had agoraphobia, 32 had social phobia, 50 had simple phobia, and 65 had joint laxity; several patients had more than 1 phenotype. Cytogenetic study in 10 patients revealed an interstitial duplication at 15q24-q26, termed DUP25, in all samples. FISH analysis of all 93 available samples detected DUP25 in 67 patients (72%). Three different forms of DUP25 were identified: a 'telomeric' duplication in a direct and in an inverted form (79% of individuals), a 'centromeric' duplication (direct), with the probe signals at 15q22 (16%), and both duplications (5%). DUP25 was detected in approximately 7% of control groups. Ninety percent of patients diagnosed with 1 or several anxiety disorders in the pedigrees had DUP25. All patients with panic disorder with or without agoraphobia and all patients with social phobia carried DUP25. DUP25 was found in 87% of subjects with joint laxity. Conversely, the penetrance of DUP25 was not complete, being 37% for panic disorder (with or without agoraphobia), 40% for social phobia, 48% for simple phobia, and 63% for joint laxity. Overall, 20% of subjects with DUP25 did not have any anxiety phenotypes. Gratacos et al. (2001) replicated their findings by detecting DUP25 in 68 of 70 unrelated patients with panic disorder/agoraphobia, in contrast to the 14 of 189 control samples with the duplication. Mosaicism, different forms of DUP25 within the same family, and absence of segregation of 15q24-q26 markers with DUP25 and the psychiatric phenotypes suggested a nonmendelian mechanism of disease-causing mutation. Gratacos et al. (2001) proposed that DUP25 is a susceptibility factor for a clinical phenotype that includes panic and phobic disorders and joint laxity. Tabiner et al. (2003) used the experimental approach of Gratacos et al. (2001) in a study of 16 patients with panic/anxiety disorders and control subjects in a southern region of the United Kingdom. DUP25 was not observed in any of the patients or controls.

Schumacher et al. (2003) tested for the presence of DUP25 in a sample of 50 patients with panic disorder and 50 controls using a quantitative real-time PCR approach. Contrary to the findings of Gratacos et al. (2001), their results were compatible with the absence of DUP25, and no significant difference could be detected between patients and controls.

Using molecular gene dosage analysis and FISH to study lymphoblastoid cells from 26 unrelated patients with panic disorder, Zhu et al. (2004) found no association of DUP25 with panic disorder. The authors noted that many factors can influence FISH analysis, including chromosome preparation, probe size, and content of repetitive DNA sequences within the probe, and suggested that the findings of Gratacos et al. (2001) may have been in error.

Mapping

Panic Disorder 1 (PAND1) on Chromosome 13q

Weissman et al. (2000) suggested that panic disorder associated with bladder conditions may possibly represent a subtype of panic disorder. Linkage analysis performed on affected families with that specific phenotype yielded a maximum lod score of 3.6 at marker D13S779 on chromosome 13q when panic was considered as the affected phenotype. A score of 4.2 was obtained when individuals with 1 or more of the 'syndrome' conditions were considered as affected. The 15 families with panic disorder alone provided negative lod scores at the same locus.

The same group (Hamilton et al., 2003) identified 41 additional families with members having the panic disorder/bladder syndrome. Using both single-locus and multipoint analytic methods, they found significant linkage on chromosome 22 (hlod score = 4.11 at D22S445) and on chromosome 13q (hlod score = 3.57 at D13S793) under a dominant genetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extended the previous findings from the 19 families. The results suggested that there are genes on 13q, and possibly on chromosome 22 as well, that influence susceptibility to this pleiotropic syndrome.

Genomewide Mapping Studies

In a genomewide scan of families with panic disorder, Knowles et al. (1998) identified a locus on chromosome 7p15 that yielded a lod score of 1.71 at marker D7S435 under an autosomal recessive mode of inheritance. Crowe et al. (2001) also found a potential susceptibility locus for panic disorder at 7p15 in a genomewide scan of 23 families (lod score = 2.23 at D7S2846). Using a Bayesian alternative approach to linkage analysis based on direct measurement of the posterior probability of linkage (PPL), Logue et al. (2003) reanalyzed the data collected by Crowe et al. (2001). They reported 'much clearer evidence' for a locus for panic disorder on chromosome 7p (80% probability of linkage to marker D7S521). There was also suggestion of a second locus on chromosome 16 near marker D16S749.

Hamilton et al. (2002) presented evidence suggesting a susceptibility locus for panic disorder near the COMT gene on chromosome 22 (lod score = 2.93 at marker D22S944).

Molecular Genetics

Association with the COMT Gene on Chromosome 22q11

Woo et al. (2002) studied 51 patients meeting DSM-IV criteria for panic disorder and 45 healthy comparison subjects for the val158-to-met (V158M) polymorphism in the COMT gene (116790.0001) on chromosome 22q11. The frequency of the met/met genotype (associated with lower activity of the enzyme) was significantly higher in patients with panic disorder than in healthy subjects (19.6% vs 2.2%, p less than 0.04 with Yates correction). Furthermore, panic disorder was significantly associated with the met allele (38.2% vs 18.9%, p less than 0.005 with Yates correction). Patients with panic disorder who had the met/met genotype had a poorer treatment response than those with other genotypes. Woo et al. (2002) concluded that COMT activity might be related to susceptibility to panic disorder and treatment response to medications.

Among 108 Japanese patients with anxiety disorders, including 29 with panic disorder, Ohara et al. (1998) found no association with the COMT V158M polymorphism.

Animal Model

Johnson et al. (2010) showed that orexin (HCRT; 602358) may be involved in panic disorder and anxiety (see 607834), both of which are disorders associated with increased arousal, hypervigilance, and stimulation of the autonomic nervous system. A rat model of panic disorder showed increased activation of Hcrt-positive cells in the dorsomedial-perifornical hypothalamus after sodium lactate administration that correlated with anxious behavior compared to nonpanic rats. This response was attenuated with siRNA against the Hcrt gene, as well as by antagonists to the Hcrt receptor (HCRTR1; 602392) injected directly into the stria terminalis. These attenuating effects mimicked treatment with benzodiazepines, which result in increased GABAergic activity. Finally, cerebrospinal fluid levels of orexin were increased among 53 individuals with panic anxiety compared to controls, suggesting that the orexin system may be involved in the pathophysiology of panic anxiety.