For other related disorders, see Anxiety Disorders.

external image simpsons+as+art+homer+as+edward+munch+the+scream.bmp Panic disorder (PD), one subtype of anxiety disorders, is characterized by the recurrent and spontaneous onset of panic attacks, or the psychosomatic symptoms of fear. This, accompanied by an intense anxiety towards a future episode, can be debilitating for those suffering from this illness and may result in the development of agoraphobia. Functional neuroimaging, as well as volumetric studies have implicated the abnormalities of multiple brain regions that are involved in the execution of fear response, internal sense of body states and anxiety including the periaqueductal gray, hypothalamus, amygdala, anterior cingulate cortex and insular cortex[1]. Abnormal activity within these structures and connections between them may be inappropriately activating fear circuits and eliciting the effects of the sympathetic division of the autonomic system observed in panic attacks[2]. Linkage studies have found heritability estimates of about 40%, but an encompassing common variant has yet to be found. The serotonergic 5-HT receptors have been known to be involved in PD, but more recent studies have been able to elucidate the nature of its role in inhibition of panic-attacks. Furthermore, gene variations in the neuropeptide cholecystokinin signalling, GABA dysfunction within the limbic system, and enhanced pH chemosensation in the brain may also underlie the neurobiology of panic disorder[3]. This indicates that there is also a strong environmental basis to the disorder, and research has shown factors such as childhood parental separation and life stress to be increasingly important components of the etiology of PD[2]. The most effective treatment options available involve the coupling of cognitive behavioural therapy and pharmacological options such as SSRIs and benzodiazepines. A deeper understanding of the neurological causes of panic disorder can aid in the research and development of more effective agents with reduced side-effect profiles and enhanced improvement times[4].

General Overview


Symptoms and Diagnosis

Symptoms2.png
Table 1. Adapted from Torpy & Golub (2011).
According to the Diagnostic and Statistical Manual of Mental Disorders, panic disorder requires the presence of both repeated occurrence of spontaneous panic attacks where at least one of the attacks was followed by one month or more of the secondary symptoms of intense worry and anxiety (table 1), or a change in behaviour related to future attacks. The symptoms of a panic attack, show may be normal in isolation, but the occurrence of 4 or more in a progressive manner peaking within 10-20 minutes indicates a panic attack. These panic attacks must not be due directly to the use of drugs or medications. In many cases, individuals with panic disorder will go on to develop agoraphobia as they associate and avoid situations where they believe the potential exists for the onset of another panic attack, especially if they would not be able to escape (e.g. stores, public transportation, crowds etc.). Hence, panic disorder may be diagnosed as either with or without agoraphobia[5]. Panic disorder patients exhibit a marked sensitivity to panic-provocation with chemical agents such as yohimbine, cholecystokinin, sodium lactate and CO2[6] [7].

Epidemiology

Panic disorders have a lifetime prevalence of 3-4% and every year, 7% of the population will experience a panic attack[8]. The development of PD generally occurs between the age of 19-35yo, with an average onset of 25. Once it begins, symptoms and attacks will persist for at least one year in 92% of patients.
Individuals with panic disorder are more likely to also suffer from other anxiety disorders such as generalized anxiety disorder or social phobia , depression and a particularly high co-occurrence of substance abuse[9]. About 25% of panic cases also have alcohol abuse disorder, and this is believed to be in part due to patients attempting to self-medicate with the short-term anxiety reducing effects of alcohol. A third of those diagnosed with panic disorder will also have agoraphobia[8].

Etiology of Panic Disorder


Genetics

Linkage mapping in family history studies and twin studies indicate a 40-50% heritable component to the variation observed developing panic disorder, which is higher than most other anxiety disorders [10]. It is not one common or rare variant polymorphism, but many that contribute to the heredity of PD. Genes implicated include those encoding 5-HT1 receptors, and CCK system, further attributing to the belief that a disruption in the regulation of neurotransmitters underlies PD. Recently, a transgenic mouse model of panic disorder has been established by overexpressing TrkC gene, a neurotrophin-3 receptor, implicating neurotrophins in the etiology of panic and presenting candidate genes for further study of the genetic elements of PD[11].

Neuroanatomical Correlates

It is believed that panic disorder arises from abnormal functioning of the fear network resulting in the maladaptive activation of the fear response which manifests as a panic attack. These fearful experiences may lead to a learned fear memory as demonstrated by avoidant behaviour following the onset of PD as well as the feelings of anxiety regarding future episodes. Research has also shown that panic disorder may involve deficits in the default mode network , reduced activity of limbic structures including the right anterior cingulate cortex, amygdala, putamen, and parahippocampal gyrus and increased recruitment of the insula[12].

Amygdala

Fear_Network.png
Figure 1. The network by which normal fight-or-flight response to threatening or frightful stimuli, believed to be the pathways activated in panic attack, is shown above. It centres around the amygdala, which facilitates the somatic and psychological symptoms of panic, via connections to and from the hypothalamus, thalamus, other limbic structures and the brainstem. Irregular functioning of brain regions involved in this network, or the connections between them are believed to contribute to the etiology of panic disorder. Source: Gorman et al (2000)
The amygdala is a key structure of the limbic system with a role in the perception of fear, the fear response and learned fear memory and reduced activity of this region appears to contribute to panic disorder. Research finds individuals who report reduced panic attacks and symptoms following therapeutic intervention still demonstrate avoidant behaviour indicating that there is some artifact that remains as a learned fear memory which may provide an explanation for the effects of CBT[13]. Furthermore, volumetric MRI studies on individuals with panic disorder were found to have amygdalar atrophy[14]. It is hypothesized that the amygdala mediates the panic response through its output to the thalami, brainstem regions and activates the HPA axis , with observed changes in pituitary volume and levels of stress hormones following a panic attack[15] [16]. However, there is conflicting evidence regarding the involvement of the HPA axis and other regulatory pathways have been suggested, particularly through the PAG[17]. The amygdala may be activating panic circuits in response to rising levels in CO2 and changes in brain pH through pH sensitive ASIC1a ion channels that are required for contextual fear[18]. ASIC1a channels are numerous in the amygdala and knockout experiments demonstrated a resulting deficit in conditioned and unconditioned fear in mice, so the ability of this channel to detect local changes in pH and cause a response in the amygdala may be the basis for the fear conditioning of internal sensation that is believed to underlie the onset of panic attacks[19].This may be the basis for the fear conditioning of internal sensation that underlies the onset of panic attacks.

Periaqueductal Grey

The periaqueductal gray (PAG) is a midbrain structure that has long been shown to be involved in approach and avoidance defense mechanisms[20]. Its role in the pathobiology of panic disorder has been described and may be the locus where panic attacks arise. Upon stimulation, either electrically or through chemical modulators, animal models have exhibited characteristics of a panic response[21] [22]. Local gray matter volume changes in the midbrain have also been observed in fMRI studies in individuals with panic disorder[1].There is new evidence that the PAG may serve as one possible site for the suffocation alarm system that is theorized to be one of the causes of panic disorder[23]. Indeed, the inhalation of CO2 is able to reliably induce panic attacks and causes fear response in animal models. [24]. Over-activation of the PAG, and hence the putative alarm system, may explain the heightened sensitivity of pH, CO2 and lactate observed in panic patients (see CO2 and Anxiety Disorders for more information)[25].

Anterior Cingulate Cortex

Panic disorder has been associated with a reduction in gray matter volume of the right anterior cingulate cortex[26]. The anterior cingulate cortex has a number of cognitive functions, playing roles in error detection, and emotional modulation. [27] In particular, the rostral dorsal ACC is functionally activated during anticipation of negative interoceptive threat and body sensation such as hyperventilation, a common symptom of a panic attack [28] [29]. An enhanced awareness of somatic features of fear has believed to contribute to susceptibility to panic attacks[30]. These factors may provide an explanation for the seemingly ‘sudden’ onset of attacks and the preceding rapid crescendo of psychological stress. Individuals with damage to the anterior cingulate cortex, particularly the right dorsal ACC, have shown to acquire panic disorder or experience their first panic attack following[31].

Cerebellum

While it is well established that the cerebellum is responsible for balance, the integration of sensory inputs for co-ordinating fine movements and locomotion, evidence is accumulating that the cerebellum also has a role in cognitive functions such as impulsivity , and may contribute to mental disease [32] [33] [34]. Inhibition of cerebellar nuclei was observed in a model of panic involving deep brain stimulation of the dorsolateral PAG that elicited panic-like symptoms [35]. It was shown that activation of deep cerebellar nuclei was significantly reduced after inducing a panic model of escape with the largest effect being in the vermis and fastigial nucleus . Moers-Hornikx et al. (2011) suggest that that deactivation results in dysfunction in selective attention, which in this case would be attention to physiological sensation, allowing for the misappropriated panic response.

Neurotransmitters and PD

It is believed that dysregulation of various neurotransmitter systems in brain regions involving the emotional and physiological correlates of panic and acute anxiety are the basis of panic disorder. Neurotransmitters implicated include noradrenaline (especially in the locus coeruleus), endogenous opioids, serotonin, GABA, CCK and orexin. Inherited polymorphisms of genes encoding the regulation of these neurotransmitters are currently the basis of genetic studies attempting to parse out the various neurobiological systems that contribute to panic disorder[9].

Serotonergic System

5ht1Areceptorsreducedbythridinraphe.jpg
Decreased activity of 5ht1A receptors by a third in the dorsal raphe of PD patients. Source: NIMH http://infocenter.nimh.nih.gov/
Serotonin has been implicated in panic disorder following research showing that drugs modulating the serotonin system were also able to reduce panic attacks[36]. Serotonin in the brain stem and PAG reduce panic symptoms, but within the amygdala, it works to increase anticipatory anxiety, a critical component of panic disorder. There is an observed reduced functioning of serotonergic receptors within the raphe nuclei in panic patients[37]. Gene length variation in the 5HT transporter seems to influence the intensity of the panic modeled response to dose-dependent CO2 inhalation[38]. While there is much evidence refuting a link between the previously implicated promoter region polymorphisms (5HTTLPR), recent research has shown an association between panic disorder and the serotonin transporter gene SLC6A4[39] [40].

GABA

Reduced GABAergic inhibitory activity in the PAG and brain regions projecting to the amygdala are believed to play a role in panic disorder. In rats with GABAergic dysfunction in loci related to panic-generation such as the amygdala, dorsomedial hypothalamus and PAG exhibited increased panic-like symptoms[41]. GABAa receptor activity may be a mediator of the panicolytic effect of the neurotrophin BDNF. Injection of BDNF into the dorsal PAG reduced the panic response and its mechanism of action appears to rely on an interaction of the BDNF-TrkB receptor and the GABAergic system[42].

CCK

Cholecystokinin-tetrapeptide (CCK-4) has been established in models of generating panic and genetic studies in CCK system genes, which identified new susceptibility alleles, indicate a role of the this molecule in panic disorder[43]. Functional neuroimaging has demonstrated its effect on regions in the cerebral cortex, amygdala, hippocampus and brainstem, possibly as a neurotransmitter[24]. In general, various cytokine abnormalities have been implicated in panic disorder. It is hypothesized that the inflammatory state, indicated by an increase in proinflammatory cytokines in perhipheral blood, is associated with panic disorder to be due to the immense and repeated psychological and physiological stress that is caused by panic attacks[44].

Orexin

Recent findings suggest that the activation of the orexin (or hypocretin) system may be involved in the panic disorder including an increase of orexin in CSF of panic subjects[45]. Orexin is a neurotransmitter deriving mainly from the lateral hypothalamic area and has roles in arousal, and respiration, two characteristic facets of the pathophysiology of panic disorder.[46] [47] Johnson et al. (2010) demonstrate in rat panic models that silencing the orexin expressing neurons in the dorsomedial hypothalamus was able to supress the panic response to sodium lactate infusion. Furthermore, genetic studies have found an apparent relationship between the Val308lso polymorphism of the hypocretin receptor gene and increased vulnerability to developing anic disorder[48].

Environmental Factors

Stressful psychological events such as early separation in childhood have been implicated in panic disorder. Childhood parental loss or seperation anxiety were antecedents to panic disorder development later on and often corresponded to an individual's first panic attack.[49] Based on the diathesis-stress model, it is hypothesized that stressful environmental factors, such as stable maternal environment and early childhood separation interact with genetic predispositions and vulnerabilities, resulting in the development of panic disorder[50].

Treatment


Psychotherapy

Cognitive behavioural therapy has proven to be at least as effective as pharmaceutical methods of treatment and helps prevent a relapse following treatment significantly more so than patients only being treated with panicolytic drugs[51]. CBT may involve the learning of relaxation techniques, keeping a log of the thoughts and situations that arise concurrently with panic symptoms, and a gradual exposure to these situations that tend to cause anxiety or panic attacks in an attempt to extinguish the anxious behaviour (exposure therapy). The cognitive aspect of the therapy involves reducing the maladaptive cognitive patterns that exacerbate the anxiety experienced at the onset of a panic attack such as believing that they might die (thought restructuring). There is mounting evidence in favour of internet-based CBT for panic disorder, providing a more cost-effective route for treatment while maintaining the same rates of improvements[52].

Medication

The x-ray crystallography structure of paroxetine, a commonly prescribed selective serotonin reuptake inhibitor for the treatment of panic disorder. Source: Ibers, J. A. (1999). Acta Crys C55.
The x-ray crystallography structure of paroxetine, a commonly prescribed selective serotonin reuptake inhibitor for the treatment of panic disorder. Source: Ibers, J. A. (1999). Acta Crys C55.
Many biological treatments are available for panic disorder and among the widely used drugs, most are commonly classified as antidepressant medications. These include SSRIs, SNRIs, tricyclics and benzodiazepines. The mechanism of their action is thought to improve the dysfunction of the neurotransmitter systems in brain regions involved in the manifestation of panic (see Neuroanatomical Correlates above), but a deeper understanding of what physiological changes result has yet to be determined[53]. SSRIs and SNRIs such as escitalopram, paroxetine and venlafaxine are generally the first treatment approach due to the reduced risk of addiction that is observed with use of benzodiazepines and more negative side-effects associated with tricyclics[4]. The combination of CBT and pharmacological agents, especially benzodiazepines, is more effective than either of the approaches alone, particularly in patients who do show little improvement with initial CBT treatment[54] [55].

New Lines of Treatment

As a new approach to treatment, the role of exercise in improving mental health has been growing in recent years. Moderate/hard exercise improved levels of reduced BDNF as well as reducing panic symptoms during a CO2 challenge in panic patients though further research is necessary to determine the value of these findings in terms of treatment approach[56] [57]. There is also evidence showing that breathing training aimed at raising and sustaining levels of pC02 results in reduced levels of panic symptoms related to interoceptive fear[58].

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External Links


APA Panic Disorder Guide The Panic Centre: Treatment and Support