On balance, is panic a biological or a physiological phenomenon? Or is this a silly question?

Introduction
To the patient the question of whether the panic episodes are biological or psychological in origin is extraneous. Biological explanations suggest there is something wrong with their body, while psychological explanations suggest there is something wrong with their minds. This question, however, is great importance when devising models to explain behavior and therapies to alleviate panic episodes.

The DSM-IV classifies panic disorder as recurrent, unpredictable attacks of severe anxiety. The dominant symptoms vary from person to person, but sudden onset of palpitations, chest pain, choking sensations, dizziness, and feelings of unreality (depersonalization or derealization) are common. There is also, almost invariably, a secondary fear of dying, losing control, or going mad. Individual attacks usually last from 5-20 minutes on average. The subject often responds to the symptoms by making a hasty exit from whatever situation they have occurred in. These specific situations may be subsequently avoided. Fear of having another attack whilst in public or while alone leads to the avoidance of even more places and situations. Hence panic disorder may appear with or without agoraphobia. Panic attacks that occur secondary to being in a phobic situation are regarded as an expression of the severity of the phobia, which is given diagnostic precedence.

A great debate has developed between the biological and psychological camps as to which perspective best explains panic disorder. Seligman encapsulates this argument as being between the 'disorder of the body' and 'disorder of the mind' factions. This essay will show that these to approaches are not necessarily antithesis. Furthermore, meager neurological knowledge and techniques are the greatest hindrance to current understanding.

The biological perspective
D. Klein championed the argument that panic disorder is distinct from other anxiety disorders and is essentially biological in nature. Klein bases his biological argument on two main pillars. Firstly, he observed that patients with anxiety disorders responded more favorably to imipramine and than to drugs used in other anxiety disorders. Secondly, it is well documented that panic episodes can be induced in the lab using lactate infusions. Lactate infusions are more effective panicogenics for patients with a history of panic disorder than for other patient and control groups. These two pillars are reinforced by evidence that induction of panic through lactate infusion can be blocked by prior administration of imipramine.
Initially Klein did not propose a biological mechanism for panic induction. However his revised theory, schematized below, introduces a likely suspect: the suffocation alarm system.

Klein proposed that psychological cues for example being in a crowded, stuffy environment with no apparent exit might trigger the alarm system. He suggests that these cues may lower the threshold at which the alarm is activated. Further, people with congenitally low thresholds might be more hypersensitive to both biological and psychological cues. Hence Klein's revised approach is psycho-biological.

Klein attaches much significance to the medical condition known as hyperventilation syndrome or" Ondines Curse". This condition is seen in a small percentage of infants and children. These children are born with a low sensitivity to hypoxia. In normal subjects oxygen and bicarbonate are optimized through respiratory center neurons that drive ventilation in response to metabolite levels (e.g. lactate, potassium ions etc). In sleep, when conscious ventilation cannot take place and the autonomic control of ventilation becomes most important. Ondine's curse suffers can become very hypoxic without this triggering compensatory mechanisms. The subsequent changes in blood pH lead to a cascade of pathological effects. For Klein, this disease is an illustration that there is a specific mechanism geared to prevent hypoxia, a suffocation alarm.

Rachman and Taylor devised a study to find out if fear of suffocation is important in the etiology of panic. They subjected a mixed group of students to a suffocation challenge test after eliciting their fears and experiences of suffocation through a questionnaire and an interview. It was found that the subjects with the highest fear of suffocation were seven times more likely to report unexpected panics than subjects with low fear.

There is widespread evidence for the prevalence of suffocation fears in many populations. Further investigation of what triggers these fears may elucidate further the proposition that psychological cues can trigger the suffocation alarm. Klein's theory has drawn some valid criticism.
Klein fails to offer any solid detail as to where this alarm is and how it may function physiologically. Also, people do die from carbon monoxide asphyxiation. Why doesn't the suffocation alarm trigger panic and escape reactions and hence save these people? Klein suggests that carbon monoxide and similar agents may disable the suffocation alarm. Physiological investigations are much needed to identify and characterize the postulated suffocation alarm.

That imipramine has anti-panic effects and lactate induces panic has been confirmed. However, more drugs have been identified that alleviate the rate of panic episodes. Both classes of antidepressants and certain benzodiazepines do seem to be effective.

Chemical agents other than lactate can also induce panic. Often these other agents (e.g. cocaine) do not share common chemical properties with lactate. Patients with panic are not as distinct as Klein first postulated. Barlow and Craske have shown that panics are commonly reported by all categories of anxiety disorder patients

One study found that lactate-induced panic rate among patients with depression, generalized anxiety disorder and panic did not differ much. Would that mean that these groups have the same malfunctioning suffocation alarm? Or is the physical disorder more widespread? The likelihood of lactate-induced panics decreases with every repeated induction. This is not consistent with a biological dysfunction, unless this dysfunction has the curious characteristic of showing adaptation to negative stimuli.

Though Klein two pillars- imipramine and lactate - appear to crumble when closely scrutinized, Klein's work led to fruitful developments in the biological approach which shall be discussed later.

The cognitive perspective
The presence of maladaptive cognitions is not necessary for the DSM diagnostic. However, cognitive models are based on the idea that it is the misinterpretation of benign bodily sensations that induces panic. The scheme below is based on D.M. Clarke's cognitive theory of panic, which has much in common with Barlow's approach.

Both Hibbert and Ley independently found that patients often report experiencing unusual sensations before the fearful thoughts or panic episode begins. Furthermore, patients do report a sense of impairment of ordinary thought processes during a panic episode. Confusion and 'blankness' is accompanied by cognitions like "I feel I am in great danger." or "I feel that I am about to completely lose control."

Thoughts seem to correspond with the bodily sensations felt. In one study, cardiac-concerned patients commonly held the belief in an imminent heart attack, or a fainting episode was more than a comparable group of cancer-concerned patients.

Seligman poses a pertinent question. Why does a person, after experiencing hundreds of episodes of panic, fail to learn that his heart it not failing? Cognitive theory predicts that avoidance behaviors reinforce maladaptive cognitions. The subject perceives that they have escaped the catastrophe due to their actions. The belief in the catastrophe need not be compromised by the non-appearance of it.
On balance, the cognitive approach to panic boasts more evidence than the biological approach. There is coherence between the theory and its clinical application i.e. cognitive therapy. Its broad parameters even explain phenomena that have remained unexplainable by the biological theories. However this theory has attracted criticisms from biological, conditioning and cognitive theorists.

Like the biological theory, it is criticized for being loosely specified. Moreover, the effectiveness of anxiolytic medication seems inconsistent with the theory.

There is evidence that some panics occur in the absence of fearful cognitions. It remains unclear whether this is due to a lack of recognition and articulation of present thoughts, or proof that cognitions are unnecessary for the induction of panic episodes. This is confounded by the observation that patients reporting 'non-cognitive panics' also report occasions where panic is accompanied with fearful thoughts.

The criticism that episodes of panic that arise when the patient is relaxed cannot be accounted for by the cognitive model is weak. The patient's experiences, even that of relaxation, and can be misinterpreted as a signal of imminent catastrophe. Rachman describes a patient who responded with anxiety and panic when she felt her body relax and her breathing slow. She paralleled these sensations with the relaxation, unreality and depersonalization she had felt after taking a street drug. Hence the relaxation signals were interpreted as a sign of catastrophe i.e. going insane.

Supporting clinical evidence is often criticized for ambiguities of causality. Ideally one would wish to clearly track decline in panic against changes in cognition to clarify causality. However cognitive changes take place over weeks and often in a context quite removed from the panic episode. Also, panic decline often occurs quite slowly and may be out of step with cognitive changes. Hence the ambiguity as to whether panic causes fearful cognitions or vice versa may be resolved by improvements in long-term clinical measurement of panic episodes and cognition changes.

A study by Salkovskis et al (1999) showed the role of safety-seeking behaviors in the maintenance of panic disorder with agoraphobia. Of the patients randomized into two groups, those who received exposure treatment accompanied by cognitive therapy to facilitate disconfirmation reported less anxiety after both exposure sessions. However this finding was based on only eighteen patients. Furthermore, due to the short-term nature of this trial (the first exposure was 5 minutes and the second 15 minutes) it bears less weight than retrospective meta-analysis of treatment efficacy for thousands of patients.

Clarke acknowledges that biological factors do play a role. He proposes that perhaps patients have more intense internal sensations than others do. New research suggests that there is evidence that some people have a higher sympathetic drive than others do. It is thought that this may give them a higher state of arousal, demonstrated by the fact that they would startle easier than others may. Higher sympathetic drive would mean higher levels of dopaminergic firing, which has been implicated as a vulnerability factor for depression and anxiety disorders.

The demographic distribution of panic remains largely unexplained. Panic disorder most commonly appears in early adulthood. The elderly, who have more reason to pay close attention to bodily sensations, rarely develop panic disorder. Women are 2-4 times more likely to develop this disorder.

The method of treatment that is most effective may be so because it is based on the soundest explanation of the etiology and maintenance of panic disorder. Currently psychological techniques, medication, or a combination of both are used to treat panic.

Traditionally, behavior therapy was the main treatment. Graded exposure was combined with relaxation techniques and anxiety management programs. Recently this has been expanded into cognitive behavioral therapy (CBT), the most powerful treatment at present. This combines graded exposure with talking therapy to identify maladaptive cognitions. Reported success rates vary from 75-90% panic-free patients after therapy.

It is unclear whether a decline in cognitions and/or bodily sensations arises from a decline in panic or vice versa, during the course of treatment. A study by Magraf et al (1993) showed that exposure therapy was as efficacious and enduring as cognitive behavioral therapy. Cognitions declined to the same extent in both groups. Hence cognitions may be mere epiphenomena. An alternate explanation is that a direct attack on cognitions guided by the therapist is as effective as an indirect attack where the patent accumulates personal, discomfirmatory evidence. What then is the role of the cognitive therapist? And why are disconfirmatory experiences from exposure therapy more efficacious than disconfirmatory experiences in real life?

However, a seemingly contradictory outcome study by Clark et al (1984) found that panic patients who received indirect treatment as well as cognitive therapy had a superior therapeutic outcome to those who received indirect treatment.

Some studies show that behavioral therapy alone is equally effective as cognitive therapy and vice versa. Arntz and van den Hout found that cognitive therapy only was more effective than relaxation treatment or no treatment at all (for waiting-list patients) for patients with panic disorder. Post-therapy panic-free status was 77.8-83.3%, 50% and 27.7% respectively. Hence short-term studies offer often contradictory evidence of therapeutic success.

The most reliable evidence comes from Van Balkom et al (1997) who conducted a meta-analysis of treatment of panic disorder to determine which treatment method was most useful. The study compared the short-term efficacy of benzodiazepines, antidepressants, psychological panic management, exposure in vivo, pill-placebo combined with exposure and psychological panic management combined with exposure in vivo. These treatments were also compared against control groups, pill-placebo, attention placebo and a waiting list. All interventions were superior to the controls. However, the combination of anti-depressants with exposure in vivo proved the most potent short-term treatment of panic with agoraphobia. This does not prove conclusively that the biological and behavioral approaches are the most accurate models. Yet, it does raise the need for a reassessment of the effectiveness of CBT. Not only may anti-depressants and exposure prove more useful, but they are also more cost-effective methods of treatment.
Majorities of patients receive medication as treatment and not CBT due to practical and financial limitations. Lader states that though anti-anxiety drugs suppress the symptoms of anxiety to some extent, sometimes quite effectively, they do not deal with the root causes of the disorder.

One might expect that the combination of psychological therapy and medication might have additive effects on the therapy's success. Suprisingly, it has been found that combination treatment is not superior to either psychotherapy-only or medication-only treatments. Despite this, combination therapies continue to be treatment of choice in many clinical facilities, though there is evidence that medication increases likelihood of relapse.

Biological arguments re-emerge
There is increasing genetic evidence for the biological approach. Hettema et al (20001) conducted a meta-analysis of data from family and twin studies of panic disorder, GAD, phobias and OCD to explore the role of genetic and environmental factors in their etiology. They found that there was familial aggregation in all these disorders. For panic disorder the risk of inheritance was 0.43. They concluded that genetic factors largely determine the development of panic disorder. Environmental factors are responsible for the rest of the risk. Though this provides support for a more biological approach to panic disorder, it also points at the importance of investigating what environmental factors might make a person vulnerable to developing this disorder.

Familial studies have found comorbidity risk for relatives to lie between 10-20%. These findings are confounded by the overlap of panic disorder, major depression and alcohol abuse. While there is clearly a genetic component governing vulnerability to anxiety, differences in family are seen in severity (penetrance) and heterogeneity (development of related disorders).

Twin studies further support genetic predisposition to panic disorder. Panic disorder shows increased concordance for monozygotic rather than dizygotic twins. However heterogeneity is an issue here as well. Rarely do monozygotic twins both have panic disorder. However combinations of panic for one with either alcohol abuse or depression for the other are common enough to be significant. Hence, though genetic factors play a major role, environmental factors may swing the balance either way. Further twin studies may elucidate the influences that determine individual's psychological morbidity.

Ley's panic subtype theory posited that panic disorders could be differentiated into respiratory and psychological subtypes through testing sensitivity to carbon dioxide levels. Moynihan and Gevirtz (2001) have recently found that this is indeed the case. Respiratory panickers showed lower resting levels of end-tidal carbon dioxide. This suggests that they are chronic (compensated ) hyperventilators. Psychological panickers did not differ in end-tidal carbon dioxide from controls. Hence the respiratory panickers are likely to be more sensitive to carbon dioxide inhalations or lactate infusion. How this translates into vulnerability in vivo is yet to be uncovered.

It is likely that when more is understood about the biological origins of panic, a new generation of drugs will be emerge to combat it. Current therapies involve the use of beta-blockers, tricyclic antidepressants, selective serotonin uptake inhibitors, monaoamine oxidase inhibitors and benzodiazepines. But medications only give short-term benefits, with a high relapse rate. Cognitive theorists claim that this is because they suppress the symptoms of panic while ignoring the real causes of panic- maladaptive cognitions.

There continues to be increasing research into the physiological dysfunction that may cause panic. The success of anxiolytic drugs has spurred interest into the role of serotonin, noradrenergic, dopaminergic, and GABA-ergic neural systems in the control of arousal and generation of emotion. There is also interest in the role the limbic system might play. LeDoux focuses on the amygdala as the area where negative memories and emotional inputs from the hippocampus and neocortex may coincide with autonomic inputs from brainstem centers. The conditioning event that would imprint the 'feelings of catastrophe' would be a prior event where panic was generated either through hyperventilation or panicogens e.g. LSD and cocaine. When the autonomic symptoms are re-experienced, even in a benign situation, the now neurally associated with negative beliefs about imminent threat and panic ensues. Though conditioning approaches have yet to offer a widely accepted model for panic, it is probable that the more we learn about the neurological basis for arousal, emotion and ultimately consciousness, the closer we shall come to effective drugs that target groups of brain nuclei like the amygdala.

Psychological explanations for panic have and continue to dominate both theory and treatment of panic. In my estimation, this is due to the relative poorness of neurophysiological research and techniques. It must be remembered that ultimately all psychological debates based upon the 'mind' may be fossilized in one fell sweep when neurophysiology finally reduces the mind phenomenon to the firing of neurons. At that time, when psychological models are fully explainable in biological terms, the question answered by the essayist will become silly. In the meantime, the development of succesful treatments for panic disorder hinges upon the complete description of panic disorder in biological and psychological terms. Hence the advance the panic debate is both a theoretical and clinical priority.

COMMENTS
I like the way you have tackled this question, and the conclusions you draw are sound. And I will not punish you for the Methusalean length. As long as you felt that you penetrated into the matter and took away some insights - that is all that matters.

Regarding brain and biochemical abnormalities: One line of evidence that is not mentioned always suggests that panic disorder may be associated with increased activity in the hippocampus and locus coeruleus, portions of the brain that monitor external and internal stimuli and control the brain's responses to them. Also, it has been shown that panic disorder patients have increased activity in a portion of the nervous system called the adrenergic system, which regulates such physiological functions as heart rate and body temperature. However, it is not clear whether these increases reflect the anxiety symptoms or whether they cause them.

There are also several different techniques to provoke panic attacks in people who have panic disorder. The best known method is intravenous administration of sodium lactate. Other substances that can trigger panic attacks in susceptible people include caffeine (generally 5 or more cups of coffee are required).

Hyperventilation and breathing air with a higher-than-usual level of carbon dioxide can also trigger panic attacks in people with panic disorder (you mention this). All this however does not make the question any more intelligible - but you made that clear in your synthesis bit.

Seeing as you may be interested in the clinical perspective (not intended to be covered bu the essay question at all - but important nonetheless), here are some notes (not mine) on the psychopharmacology of panic disorder:

The three groups of medications most commonly used are the tricyclic antidepressants, the high-potency benzodiazepines, and the monoamine oxidase inhibitors (MAOIs).

The tricyclic antidepressants were the first medications shown to have a beneficial effect against panic disorder. Imipramine is the tricyclic most commonly used. When imipramine is prescribed, the patient usually starts with small daily doses that are increased every few days until an effective dosage is reached. The slow introduction of imipramine helps minimize side effects such as dry mouth, constipation, and blurred vision. People with panic disorder, who are inclined to be hypervigilant about physical sensations, often find these side effects disturbing at the outset. Side effects usually fade after the patient has been on the medication a few weeks.

It usually takes several weeks for imipramine to have a beneficial effect on panic disorder. Most patients treated with imipramine will be panic-free within a few weeks or months. Treatment generally lasts from 6 to 12 months. Treatment for a shorter period of time is possible, but there is substantial risk that when imipramine is stopped, panic attacks will recur. Extending the period of treatment to 6 months to a year may reduce this risk of a relapse. When the treatment period is complete, the dosage of imipramine is tapered over a period of several weeks.

The high-potency benzodiazepines are a class of medications that effectively reduce anxiety. Alprazolam, clonazepam, and lorazepam are medications that belong to this class. They take effect rapidly, have few bothersome side effects, and are well tolerated by the majority of patients. However, some patients, especially those who have had problems with alcohol or drug dependency, may become dependent on benzodiazepines.

Treatment with high-potency benzodiazepines is usually continued for 6 months to a year. One drawback of these medications is that patients may experience withdrawal symptoms - malaise, weakness, and other unpleasant effects - when the treatment is discontinued. Reducing the dose gradually generally minimizes these problems. There may also be a recurrence of panic attacks after the medication is withdrawn.

Of the MAOIs, a class of antidepressants which have been shown to be effective against panic disorder, phenelzine is the most commonly used. Treatment with phenelzine usually starts with a relatively low daily dosage that is increased gradually until panic attacks cease or the patient reaches a maximum dosage of about 100 milligrams a day.

Use of phenelzine or any other MAOI requires the patient to observe exacting dietary restrictions, because there are foods and prescription drugs and certain substances of abuse that can interact with the MAOI to cause a sudden, dangerous rise in blood pressure. All patients who are taking MAOIs should obtain their physician's guidance concerning dietary restrictions and should consult with their physician before using any over-the-counter or prescription medications.

As in the case of the high-potency benzodiazepines and imipramine, treatment with phenelzine or another MAOI generally lasts 6 months to a year. At the conclusion of the treatment period, the medication is gradually tapered.

Newly available antidepressants such as fluoxetine (one of a class of new agents called serotonin reuptake inhibitors) appear to be effective in selected cases of panic disorder.

Causes of Panic Disorders

The National Institute of Mental Health supports a sizable and multifaceted research program on panic disorder - its causes, diagnosis, treatment, and prevention. This research involves studies of panic disorder in human subjects and investigations of the biological basis for anxiety and related phenomena in animals. It is part of a massive effort to overcome the major mental disorders, an effort that started during the 1990s - the Decade of the Brain. Here is a description of some of the most important new research on panic disorder and its causes.

Genetics. Panic disorder runs in families. One study has shown that if one twin in a genetically identical pair has panic disorder, it is likely that the other twin will also. Fraternal, or non-identical twin pairs do not show this high degree of "concordance" with respect to panic disorder. Thus, it appears that some genetic factor, in combination with environment, may be responsible for vulnerability to this condition.
NIMH-supported scientists are studying families in which several individuals have panic disorder. The aim of these studies is to identify the specific gene or genes involved in the condition. Identification of these genes may lead to new approaches for diagnosing and treating panic disorder.

Brain and Biochemical Abnormalities. One line of evidence suggests that panic disorder may be associated with increased activity in the hippocampus and locus coeruleus, portions of the brain that monitor external and internal stimuli and control the brain's responses to them. Also, it has been shown that panic disorder patients have increased activity in a portion of the nervous system called the adrenergic system, which regulates such physiological functions as heart rate and body temperature. However, it is not clear whether these increases reflect the anxiety symptoms or whether they cause them.

Another group of studies suggests that people with panic disorder may have abnormalities in their benzodiazepine receptors, brain components that react with anxiety-reducing substances within the brain.
In conducting their research, scientists can use several different techniques to provoke panic attacks in people who have panic disorder. The best known method is intravenous administration of sodium lactate, the same chemical that normally builds up in the muscles during heavy exercise. Other substances that can trigger panic attacks in susceptible people include caffeine (generally 5 or more cups of coffee are required). Hyperventilation and breathing air with a higher-than-usual level of carbon dioxide can also trigger panic attacks in people with panic disorder.

Because these provocations generally do not trigger panic attacks in people who do not have panic disorder, scientists have inferred that individuals who have panic disorder are biologically different in some way from people who do not. However, it is also true that when the people prone to panic attacks are told in advance about the sensations these provocations will cause, they are much less likely to panic. This suggests that there is a strong psychological component, as well as a biological one, to panic disorder.
NIMH-supported investigators are examining specific parts of the brain and central nervous system to learn which ones play a role in panic disorder, and how they may interact to give rise to this condition. Other studies funded by the Institute are under way to determine what happens during "provoked" panic attacks, and to investigate the role of breathing irregularities in anxiety and panic attacks.

Animal Studies. Studies of anxiety in animals are providing NIMH-sponsored researchers with clues to the underlying causes of this phenomenon. One series of studies involves an inbred line of pointer dogs that exhibit extreme, abnormal fearfulness when approached by humans or startled by loud noises. In contrast with normal pointers, these nervous dogs have been found to react more strongly to caffeine and to have brain tissue that is richer in receptors for adenosine, a naturally occurring sedative that normally exerts a calming effect within the brain. Further study of these animals is expected to reveal how a genetic predisposition toward anxiety is expressed in the brain.

Other animal studies involve macaque monkeys. Some of these animals exhibit anxiety when challenged with an infusion of lactate, much like people with panic disorder. Other macaques do not exhibit this response. NIMH-supported scientists are attempting to determine how the brains of the responsive and non-responsive monkeys differ. This research should provide additional information on the causes of panic disorder.

In addition, research with rats is exploring the effect of various medications on the parts of the brain involved in anxiety. The aim is to develop a clearer picture of which components of the brain are responsible for anxiety, and to learn how their actions can be brought under better control.

Cognitive Factors. Scientists funded by NIMH are investigating the basic thought processes and emotions that come into play during a panic attack and those that contribute to the development and persistence of agoraphobia. The Institute also supports research evaluating the impact of various versions of cognitive-behavioral therapy to determine which variants of the procedure are effective for which people. The NIMH panic disorder research program will also explore the effects of interpersonal stress such as marital conflict on panic disorder with agoraphobia and determine if including spouses in the cognitive-behavioral treatment of the condition improves outcome.