Panic Disorder and Agoraphobia
James C. Ballenger
Introduction
Panic disorder draws its name from the Greek god Pan, god of flocks. Pan was known for suddenly frightening animals and humans ‘out of the blue’. The spontaneous ‘out of the blue’ character of panic attacks is the principal identifying characteristic of panic disorder and central to its recognition and diagnosis.
We know the syndrome that we currently call panic disorder with and without agoraphobia has probably existed since the beginning of recorded history. Hippocrates presented cases of obvious phobic avoidance around 400 BC.(1) One of the first modern descriptions was by Benedikt around 1870, describing individuals who developed sudden anxiety and dizziness in public places.(2)
Certainly, our current modern ideas of panic disorder evolved essentially simultaneously in the United States and Europe in the early to mid-1960s. Donald Klein in the United States described in 1964 the panic syndrome and reported that it was responsive to imipramine.(3) Isaac Marks in the United Kingdom also described panic attacks and agoraphobic avoidance, and treating the syndrome effectively with behaviour therapy.(4)
Until the last several decades, panic disorder and agoraphobia were actually thought to be rare syndromes. It is now clear that individuals with these difficulties are anything but rare. In fact, panic disorder is one of the most common presenting problems in individuals seeking mental health treatment and the fifth most common problem seen in primary care settings.(5) It was thought to be a mild problem, but we now know that it is associated with significant dysfunction. The disability in social, occupational, and family life is in fact comparable to major depression.
Although there are differences in the understandings of panic disorder and its treatments across the world, this chapter will review the current understanding about panic disorder, its characteristics, diagnosis, aetiology, and treatments.
Clinical features
One of the earliest and most accurate descriptions of panic attacks was provided by Charles Darwin in 1872 as he described his own episodes:
The heartbeats quickly and violently so that it palpitates and knocks against the ribs … the skin instantly becomes pale as during incipient faintness … under a sense of great fear … in connection with the disturbed action of the heart, the breathing is hurried … one of the best marked symptoms is the trembling of all the muscles of the body.(6)
The most characteristic type of panic attack is the spontaneous ‘out of the blue’ episode of extreme anxiety. Other ‘situational panic attacks’ occur immediately upon exposure, or in anticipation of exposure to particular situations, usually where panic attacks have occurred previously. Some individuals have panic attacks in certain situations some of the time, but not always, and these are labelled ‘situationally predisposed panic attacks’.
Panic attacks also occur in other anxiety syndromes and are more or less the same in whatever syndrome where they occur. However, spontaneous panic attacks in panic disorder tend to have more dizziness, paraesthesia, shaking, chest pain, and fears of going mad. Shortness of breath is more common in panic attacks in agoraphobia. Certainly blushing is particularly characteristic of panic attacks in social phobia.
The symptoms of panic attacks in order of their frequency include palpitations, pounding heart, tachycardia, sweating, trembling or shaking, shortness of breath or smothering, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling dizzy, unsteady, lightheaded or faint, derealization or depersonalization, fear of losing control or going mad, fear of dying, paraesthesia, and chills or hot flushes.
Panic attacks by definition generally involve four or more of the above symptoms to meet diagnostic criteria for panic disorder in the DSM-IV. The anxiety is crescendo in nature, building to a peak in 10 min in most cases. Panic attacks usually last for several minutes, but in some patients they can last for hours. The frequency and severity of panic attacks varies greatly between individuals and, at times, in individuals. Some have only one to three panic attacks per year, whereas others may have multiple panic attacks each day. Some individuals have bursts of panic attacks and then an absence of all attacks for a period of time. Across a large panic disorder clinical trial, the typical patient described one to two panic attacks per week.(7)
Panic attacks with fewer than four symptoms have been labelled ‘limited-symptom attacks’ or ‘little panic attacks’, and most individuals with panic disorder have these, as well as panic attacks with four or more symptoms. The threshold of four symptoms was chosen for DSM-IV because individuals with panic attacks with four symptoms or more had more disability than patients with one- to three-symptom attacks. This threshold is clearly arbitrary, and patients having panic attacks with fewer symptoms do have significant morbidity.
Panic attacks are extremely frightening and patients develop an essentially logical fear of having more panic attacks. Patients develop worry and anxiety about the possibility of panic attacks recurring. This anxiety between attacks has been called ‘anticipatory anxiety’ and can be almost constant, and characteristically increases prior to exposure to situations previously associated with panic attacks (e.g. having to shop in the supermarket where a panic attack has occurred).
A significant number of people with panic attacks go on to develop fear and avoidance of situations associated with previous panic attacks. They also fear situations where escape would be difficult or embarrassing, or where help might not be available. Most patients mistakenly believe they become incapacitated and incapable of taking care of themselves during a panic attack and therefore, many go on to develop avoidance of a variety of situations where they could not easily get help. Factor analytical studies demonstrate that there are clusters of situations associated with avoidance. These typically include public transportation (e.g. buses, trains, planes), riding in or driving a car, especially on heavily travelled roads, crowds (e.g. the cinema, a football match, large shopping centres), shopping (especially in supermarkets), particularly where one must stand in queues, and bridges, tunnels, elevators, and other enclosed spaces.(8) In the event of a panic attack, people often have an overwhelming need to escape or return to a place of safety such as home. Therefore they fear situations where escape is difficult or impossible, e.g. airplanes, traffic jams on a bridge, dental appointments, etc. On closer examination, it is clear that patients do not actually fear the situation itself but rather reason ‘what if’ the panic feelings occur while in that situation. This has led to the syndrome being called the ‘what if’ syndrome, emphasizing that there is actually a ‘fear of the fear’.(9)
Patients tend to avoid such situations or force themselves to endure them in distress or take a companion along ‘to help’. Others limit their travel to short distances from home or take longer routes where they perceive help would be available (e.g. police, doctors’ offices, fire stations, etc).
Some patients develop agoraphobic avoidance following their first attack, some only after frequent and severe attacks, and some never develop agoraphobic avoidance. In community samples, one-third to half of patients who meet criteria for panic disorder also has significant agoraphobic avoidance. The rate is higher (75 per cent) in most clinical samples. A minority (5 per cent) ultimately become unable to leave their homes and are housebound.
Many patients have panic attacks that awaken them from sleep (nocturnal panic attacks), as well as during the day. These are in fact quite common and the majority of panic disorder patients experience them. These occur during slow wave sleep early in sleep. These panic attacks are essentially identical to traditional panic attacks that occur during the day. There is a group of patients who have what are called non-fearful panic attacks. These involve the sudden onset of physiological symptoms without the cognitive components of fear or anxiety. These primarily are medical patients, usually cardiac, who might have episodes of sudden tachycardia and palpitations but no fear.(10)
Classification
The earliest modern accounts of what is almost certainly the panic disorder syndrome began appearing in the mid-1900s. There were accounts beginning in 1866 of paroxysmal anxiety episodes that did not use the term ‘panic attack’. During the American Civil War, patients were diagnosed with ‘irritable heart syndrome’ or ‘Da Costa syndrome’ (1871) with clear descriptions of what we now know as panic disorder. Westphal in Germany in 1872 clearly described patients having panic attacks and agoraphobic avoidance of wide open spaces.(11) Again, in the First World War (1918) the syndrome ‘neurocirculatory asthenia’ was described which had most of the features of panic disorder.
It was, in fact, Freud in Case IV of Katharina, published in 1895, who set the background for the modern classification of panic disorder. However, it was the Feighner criteria published in the United States in 1972 that give the first formal diagnostic recognition to the syndrome.(12) The Research Diagnostic Criteria (RDC) which followed in 1978 first split panic disorder away from what we now call generalized anxiety disorder (GAD). In the RDC, panic disorder had panic attacks while GAD did not. These diagnoses were made part of the DSM-III diagnostic scheme in 1980.
It was the conceptualization of panic disorder by Donald Klein in 1964 in the United States that led to the predominant view of the syndrome, certainly in the United States.(13) Klein argued that panic attacks were the core of the syndrome, and the remaining clinical phenomena were consequences of the panic attacks. He conceptualized that anticipatory anxiety was the fear of the possible recurrence of panic attacks, and similarly that agoraphobia was the subsequent fear and avoidance of situations where panic attacks had occurred. The bringing together of these three phenomena into one concept was accepted in the DSM-IIIR, and more recently in the DSM-IV in the United States.(14)
The biological findings that typical panic attacks could be elicited in panic disorder patients with infusions of lactate, doses of caffeine, or breathing 35 per cent CO2 supported this conceptualization of the syndrome as primarily centered around panic attacks. This hypothesis was further supported by epidemiological findings of essentially the same illness around the world.
However, this idea remains controversial across the different sides of the Atlantic. The American DSM-IIIR and DSM-IV diagnostic schema continue to utilize the idea that panic attacks are pre-eminent and created two diagnoses: panic disorder and panic disorder with agoraphobia. In Europe and in the ICD-10, agoraphobia is conceptualized as dominant over panic attacks. Therefore, when agoraphobia and panic attacks are both present, the diagnosis is conceptualized as a phobia and that condition is diagnosed as agoraphobia with panic attacks. Beyond this theoretical debate is the clinical question whether the treatment should be aimed first at panic attacks (in the United States concept) or at agoraphobic avoidance, for example with exposure therapy (in the European schema).
(a) Diagnosis
The most recently revised diagnostic schema for this syndrome is the DSM-IV. Changes from the DSM-IIIR were made based on two principles:
1 any new empirical data that required changes be made;
2 an attempt to make the DSM-IV and ICD-10 more compatible.
For the diagnoses of panic disorder and agoraphobia, an attempt was also made to more nearly describe the prototypic patient and to move away from the pseudoquantification of using number of panic attacks per week.(14)
The DSM-IV clarified that panic attacks occurred in multiple syndromes including social phobia, obsessive-compulsive disorder, depression, and others. However, DSM-IV utilized the distinction that only in panic disorder were there recurrent spontaneous panic attacks not bound to any particular situation. The diagnosis of panic disorder has several requirements including the following:
Recurrent, unexpected panic attacks (situational panic attacks could also occur but there would need to be at least two unexpected panic attacks by history).
Panic attacks needed to be followed by at least 1 month of persistent anxiety about potential recurrence of further panic attacks, implications of these attacks (e.g. going mad, something wrong medically), or a significant behavioural change because of these attacks. This was necessary because some patients had panic attacks and completely changed their lives but denied that they were worried about experiencing more panic attacks or the implications of the panic attacks.(14)
The agoraphobia criteria remained largely unchanged, but it was made more clear that the diagnosis was based on persistent fear and avoidance of certain clusters of situations and listed the most common.
The controversial diagnosis of agoraphobia without a history of panic disorder was retained until further clarification is obtained through research. Our current understanding is that these patients generally have never fully met criteria for panic disorder because their panic-like symptoms have not met the diagnostic criterion requiring four full symptoms for a panic attack. Available research suggests that these patients are otherwise very much like typical patients with panic disorder and agoraphobia. Some patients actually have only one or two symptoms (e.g. fear of loss of bladder or bowel control or only tachycardia).
Perhaps the most difficult diagnostic issue is the frequent comorbidity. The Epidemiologic Catchment Area study documented that approximately 50 per cent of panic disorder patients over their lifetime have another anxiety disorder.(15)
In actuality, depression is more commonly comorbid with panic disorder than even agoraphobia and suggests a close relationship between these syndromes. Comorbid depression ranged from 22.5 to 68.2 per cent in various samples. Lifetime rates vary from 35 to 91 per cent.(16) Although approximately half the patients developed panic disorder and depression at essentially the same time, one-quarter develop depression before panic disorder and one-quarter panic disorder before depression.(17) Surprisingly, bipolar illness has been reported to be as high as 20.8 per cent.
Easily one-third of panic disorder patients abuse alcohol. The percentage in clinical samples is much higher with 13 to 43 per cent of panic disorder patients also meeting criteria for alcoholism.(18)
(b) Differential diagnosis
It is particularly important to determine whether agoraphobic avoidance is present, because its treatment usually requires some sort of exposure therapy. Patients will often not volunteer that they are avoiding certain situations out of embarrassment. As mentioned earlier, depression and panic disorder often occur together and again patients often do not describe the other syndrome, but rather describe the syndrome which is most painful to them at that time. However, proper recognition of comorbid depression is especially important because of the marked increase (four-fold) in suicide attempts in patients with panic disorder and depression.
The difference between panic disorder and GAD depends on whether patients have panic attacks and whether they have multiple, unrealistic, and excessive worries about most aspects of life, not just panic attacks. These worries in GAD often concern money, health, children, work problems, etc. The differential with social phobia centres on whether the anxiety is confined entirely towards social situations where the individual fears embarrassment and humiliation. Specific phobias involve panic attacks, but they occur in very specific situations (e.g. high places, thunderstorms) or in the presence of specific objects (e.g. animals, snakes). The posttraumatic stress disorder patient may have many panic-like symptoms, but their illness begins quite specifically after a traumatic experience and anxiety is associated with reminders of that trauma. Finally, obsessive-compulsive disorder can involve panic attacks but only in the specific context of obsessional concerns (e.g. contamination, etc.). In these patients, panic attacks are also dwarfed in importance by typical obsessions and compulsions/rituals concerning contamination, symmetry, bad events, etc.
(c) Medical conditions
Panic-like symptoms do occur in various medical conditions (hyperthyroidism, phaeochromocytoma, hyperparathyroidism, seizures, cardiac arrhythmias, especially supraventricular tachycardia, inner ear difficulties, chronic obstructive pulmonary disease, use of marijuana, withdrawal from drugs of abuse, and over the counter drugs containing caffeine or pseudoephedrine) (Table 4.7.3.1). Also, the typical panic disorder patient does report a large number of physical symptoms and usually to a non-psychiatric physician.
As mentioned, there are medical conditions that can mimic panic disorder (Table 4.7.3.1). There is also evidence that there are slightly increased rates of certain illnesses, for example hyperthyroidism (11-13 per cent) and perhaps mitral valve prolapse. However, these are uncommon in panic disorder patients. Most experts recommend a relatively conservative diagnostic medical work-up. Generally, the most valuable part of a medical examination is a careful history with follow-up of any strongly suggested possibilities, supplemented by a few laboratory tests (complete blood count, thyroid function tests, metabolic screen, and ECG, especially if the patient is over 40 years of age).
(d) Panic disorder in the general medical setting
Conservative estimates of panic disorder in primary care have ranged from 3 to 8 per cent with at least 50 per cent going unrecognized.(19) The average panic disorder patient in general medicine
takes 10 years or more for a correct diagnosis to be made with an escalation of the use of health care services over this period. In general, the presence of panic disorder leads to a three-fold increase in utilization of general medical services.
takes 10 years or more for a correct diagnosis to be made with an escalation of the use of health care services over this period. In general, the presence of panic disorder leads to a three-fold increase in utilization of general medical services.
Table 4.7.3.1 Medical conditions that produce panic-like symptoms | ||||||||||||||||||||||||||
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The percentage of panic disorder patients is also markedly higher in certain medical groups. These include the very prevalent but most difficult to diagnose patients with vague symptoms such as fatigue, back pain, headache, dizziness, chest pain, etc.(20) or multiple symptoms (more than five).(21)
In a classic study of unrecognized panic disorder patients who were referred for a psychiatric consultation from primary care, 39 per cent had cardiovascular symptoms, 33 per cent gastrointestinal symptoms, and 44 per cent neurological.(22) It is now clear that 16 to 25 per cent of patients presenting to the emergency room with chest pain have panic disorder. Fully 25 per cent of cardiology practice involves panic disorder, usually unrecognized with 80 per cent of patients with chest pain and normal angiograms ultimately diagnosed with panic disorder. We could also increase our yield of recognizing panic disorder patients in certain procedure-oriented situations. For instance, 28 per cent of patients referred for Holter monitoring for palpitations have panic disorder, as do 66 per cent of patients undergoing a work-up to rule out phaeochromocytoma.(23) Also, 44 per cent of irritable bowel syndrome and 15 per cent of patients with headache symptoms seeing a physician have panic disorder, and these are both very prevalent disorders.
Recent studies document that treatment of panic disorder in the medical setting when diagnosed there is most cost-effective.
(e) Comment
A recent large study sponsored by the World Health Organization (WHO) studied primary care patients in 14 different countries.(19) Of patients in that study who had a single panic attack in the previous month, 99 per cent had an anxiety disorder or depression, or a subthreshold anxiety disorder or depressive disorder. The occurrence of a single panic attack also predicted the onset of panic disorder in two-thirds of the patients studied in the next year, a four-fold increase in depression (51 per cent) in the next year, and marked increases in alcoholism, social phobia, and obsessive-compulsive disorder. It would appear that the occurrence of even a single panic attack may well represent the ‘tip of the iceberg’ and should serve as a signal for increased scrutiny for anxiety and depressive syndromes. This has been recently replicated in a large (N = 3021) European sample.(24)
Epidemiology
Surveys largely utilizing DSM diagnoses have found wide agreement and generally equal prevalence’s of panic disorder across many countries.(16,25) Utilizing specific criteria for panic attacks, prevalence for panic attacks has generally averaged 7 to 9 per cent of the population (range 1.8-22.7 per cent). However, if criteria for panic attacks are liberalized somewhat (‘fearful spells’) in terms of the number of times and severity, the prevalence doubles.
There is a striking uniformity worldwide for the observed prevalence of panic disorder. In 10 community studies involving over 40 000 subjects, the majority of studies found lifetime prevalence rates for panic disorder averaging 1.5 to 3.7 per cent, with a yearly prevalence of around 1 and 1.1 per cent of panic disorder with agoraphobia (lifetime).(25) In clinical samples there is greater variability. In the previously mentioned WHO survey of 14 countries, the prevalence for panic disorder in primary care ranged from a low of 1.4 per cent to a high of 16.5 per cent for panic attacks and 0 to 3.5 per cent for panic disorder itself.(19) The average was 1.1 per cent (currently) and 3.5 per cent (lifetime), which is surprisingly similar to the community samples. As mentioned, rates are much higher in specialized medical clinics and range from 15 per cent in dizziness clinics, to 16 to 65 per cent in cardiology practices, to 35 per cent in hyperventilation clinics, etc.
Risk factors
Panic disorder has been uniformly observed to be at least two times more prevalent in females than males.(25) The Epidemiologic Catchment Area study demonstrated a prevalence of 3:2. In clinical samples it is generally 3:1. The onset of panic disorder appears to fall into two peaks. The first occurs in the early to mid-twenties (15-24 years old) with a second peak at 45-54 years of age. The onset of panic disorder after the age of 65 is rare (0.1 per cent).
The highest rates of panic disorder and agoraphobia occur in widowed, divorced, or separated individuals living in cities. Limited education, early parental loss, and physical or sexual abuse are also risk factors. Agoraphobia is clearly more prevalent in females, and females make up three-quarters of the sample with extensive avoidance. Males tend to have longer duration of illness but less agoraphobia and depression, and less frequent help seeking. Perhaps the greater necessity to perform in the workplace retards avoidance in males.
Aetiology
Genetic predisposition
Certainly the preponderance of evidence suggests there is a genetic contribution to the predisposition to develop panic attacks and agoraphobia. There are increased rates of panic disorder in first-degree relatives ranging from 2- to 20-fold with the median
seven- to eight-fold. Overall, studies suggest that another affected relative can be found 25 to 50 per cent of the time, two times as often in female relatives. The increased familial aggregation is specific for panic disorder. These findings are certainly consistent with a modest genetic transmission with relatively high specificity.
seven- to eight-fold. Overall, studies suggest that another affected relative can be found 25 to 50 per cent of the time, two times as often in female relatives. The increased familial aggregation is specific for panic disorder. These findings are certainly consistent with a modest genetic transmission with relatively high specificity.
Although twin studies are limited, Torgersen(26) did find increased concordance in monozygotic twins (31 versus 0 per cent). In the largest sample of interviewed female twins, a several-fold increase was again found (23.9 versus 10.9 per cent).(27) Skre et al.(28) found a two-fold increase of panic disorder in monozygotic twins, while other studies fail to find an increased incidence.
Overall, evidence from family and twin studies suggests that panic disorder involves modest inheritability of around 30 to 40 per cent. The best model suggests 50 per cent genetic and 50 per cent environmental influences. Recent linkage studies to confirm these hypotheses have been contradictory (e.g. with angiotensin, brain-derived neurotropic factor) but do suggest that single-gene transmission is unlikely. However, research is active in this area with positive replicated linkages with chromosomes 13q, 22q, 7p, and 9q31. Identified candidate genes include the ADOR2A, 10832/T, CCK genes, and genes coding for the 5HT1A, 5HT2A, and COMT genes and there is evidence of a link to the corticotrophin releasing hormone gene.(29) This leaves the possibilities of either heterogeneity across families and/or a polygenic inheritance.(30)
Several converging lines do link childhood anxiety with adult anxiety, consistent with a genetic predisposition. This is particularly true for separation anxiety in children. Kagan et al.(31) have prescribed that 10 per cent of Caucasian children are born with heightened anxiety which they call behavioural inhibition. Behavioural inhibition is higher in children of anxiety-disordered parents, and there are high rates of anxiety disorders in children of adults with panic disorder. As behaviourally inhibited children have matured, they have been found to show higher rates of anxiety and phobic disorders.(32) Currently, this is probably the best model of an inherited anxiety predisposition. A variant of this type model proposes that there is an aethological factor involving an evolutionarily determined vulnerability to unfamiliar territory. This might explain why the seemingly inherited anxiety is to specific situations. This is also consistent with the high rate of precipitating events prior to the onset of clinical difficulties. In this model an evolutionarily/genetically determined vulnerability would be clinically ‘activated’ by critical stressors.
Precipitating events have been reported in 60 to 96 per cent of cases. These have often centred on separation or loss, relationship difficulties, taking on new responsibility, and physiological stressors (e.g. childbirth, surgery, hyperthyroidism).(33) This is certainly consistent with a diathesis/vulnerability model with the illness being precipitated in a predisposed individual in adulthood.
There are also many studies suggesting that traumatic early events may figure in the vulnerability leading to panic disorder. The majority of children in some studies have experienced early parental separation. A traumatic event in childhood has been retrospectively reported in at least two-thirds of individuals, a three-fold increase.(34) The most common adult disorder following sexual abuse before the age of five is in fact a 44 per cent incidence of agoraphobia.(35)
There is some evidence in a prospective study involving over 3000 individuals that dependent personality traits were later associated with the development of anxiety disorders. There are also retrospective data that adult panic disorder patients describe their parents as being overly protective and less caring. It is difficult to separate the effects on individuals of the anxiety disorders themselves which create dependent behaviour, or overprotectiveness in the parents producing dependent personality traits.
Biological models
(a) Noradrenaline
There is considerable evidence implicating the brain noradrenaline (norepinephrine) brain systems and panic disorder. The noradrenergic agents yohimbine and isoproterenol stimulate panic attacks in panic disorder patients, suggesting a possible subsensitivity of pre-synaptic alpha 2 inhibitory adrenoreceptors. Both these drugs increase the firing rate of the locus ceruleus, generally thought to be part of the brain anxiety circuit. It is also true that most effective medications in the treatment of panic disorder in fact decrease locus ceruleus firing rate and most panicogenic stimuli increase the locus ceruleus firing rate.
(b) Serotonin (5HT)
Findings with 5HT brain systems in panic disorder are contradictory, probably because of the different 5HT circuits and receptors in different areas of the brain. Most investigators believe, however, that an increase in 5HT transmission decreases panic disorder perhaps because 5HT neurones in ventrolateral periaqueductal grey appear to inhibit sympathoexcitation and the fight or flight response in the rat.(36) The principal human evidence for 5HT being central in panic is that the selective serotonin reuptake inhibitors are effective and that they increase 5HT transmission after long-term use. Also, rapid depletion of 5HT has been shown to result in an increase in panic responses to flumazenil. Whether this increased neurotramsmission in fact leads to downregulation of a supersensitive post-synaptic receptor is one logical possibility, but is as yet unproven. These theories received recent support from PET scan studies demonstrating reductions in brain 5HT1A receptors(37) and 5HT transporter binding.(38)
(c) γ-Aminobutyric acid
The γ-aminobutyric acid (GABA) system is almost certainly involved in panic disorder with perhaps the strongest evidence being that benzodiazepine agonists such as alprazolam and clonazepam are clearly effective treatments for panic disorder. Also GABA antagonists such as flumezanil have panicogenic effects in panic disorder patients, and reverse benzodiazepine agonists such as β-carbolines can cause panic attacks. There is an impaired GABA neuronal response to benzodiazepines (BZs) on brain magnetic spectroscopy and decreased GABA levels in the cingulate and basal ganglia, also on magnetic spectroscopy. Also, positron emission tomography data have demonstrated decreased benzodiazepine binding in the inferior brain areas, including the inferior parietotemporo-occipital areas.
(d) Cholecystokinin-pentagastrin
Cholecystokinin is clearly involved in anxiety in animals. Also, panic disorder patients develop panic attacks in a dose-dependent fashion with administration of pentagastrin. However, cholecystokinin antagonists have not yet been shown to be effective in humans.
Recent genetic studies implicate CCK gene polymorphisms in panic disorder.
(e) Brain imaging
The explosion of brain imaging data demonstrating a brain circuit for fear and anxiety involving the extended amygdala circuit (amygdala, hippocampus, periaqueductal grey, locus coeruleus, thalamus, cingulate, and orbitofrontal areas) has lead to the hypotheses that it is this circuit which is abnormally active in panic disorder.(39)
(f) Psychological factors
Many critics disagree with the importance of biological findings in panic disorder, principally, various European workers and the cognitive theorists. They argue that panic attacks are not ‘biological’ and that a phobic attitude is required, and/or certain temperamental factors. Others attempt an integrated model utilizing both findings of biological differences and psychological factors of temperament and child-rearing practices.
Course and prognosis
There is limited evidence with appropriate population-based samples to clearly delineate the course of panic disorder. Available evidence suggests that panic disorder is a stable but chronic condition once criteria for the disorder are met. Most patients seeking treatment have experienced chronic, frequently chronically worsening, illness generally for 10 to 15 years prior to diagnosis.(7) However, other evidence does suggest that there is heterogeneity in terms of course.
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