Second edition

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1990); furthermore, a recent study demonstrated atrophy
of both amygdalae (Massana et al. 2003b). Finally, a single
photon emission computed tomography (SPECT) study
revealed a decrease in presynaptic serotonin reuptake
transporters within the midbrain, thalamus, and temporal
lobes (Maron et al. 2004).
Integrating all of these findings into a coherent theory
regarding the pathophysiology of panic disorder is problematic
and does require some speculation. With this caveat
in mind it appears plausible to say that panic disorder
results from an inherited disturbance in the metabolism of
norepinephrine, serotonin, and/or GABA in one or more of
the central nervous system structures that subserve the
experience of anxiety. Candidate structures include the
locus ceruleus, the dorsal raphe nucleus, the parahippocampal
gyrus, hippocampus, and amygdala. The locus
ceruleus is noradrenergic and the dorsal raphe nucleus is
serotoninergic, and both send fibres to a large number of
structures, including the parahippocampus, hippocampus,
and amygdala, structures that are rich in GABA receptors.
Stimulation of the parahippocampus, hippocampus, and,
especially, the amygdala is well-known to produce anxiety.
If one considers the amygdala as being the ‘final common
pathway’ in the development of anxiety, then dysfunction
of any one of these upstream structures, or of the amygdala
itself, could produce an attack. It has been proposed that
one possible ‘trigger’ for the activation of this circuitry is an
abnormal sensitivity of brainstem structures to disturbances
in the acid–base balance (Klein 1993). Such a sensitivity,
in turn, could explain the panicogenic effects of
lactate infusion and carbon dioxide inhalation.
Before leaving this section on etiology, some words are
in order regarding mitral valve prolapse. Although there is
a clear association between this disorder and panic disorder
(Katerndahl 1993), it is probably not etiologic in a
direct sense. In all likelihood the association is probably
secondary to some, as yet unidentified, common factor
that underlies both disorders.
Differential diagnosis
As noted earlier, the term ‘panic attack’ refers to an anxiety
attack that happens to occur secondary to panic disorder,
and, consequently, in pursuing the differential diagnosis of
panic disorder one must consider the various other causes
of anxiety attacks, as discussed in Section 6.5.
Occasionally, an otherwise normal individual will have
an anxiety attack, and, after thorough investigation, no
clear cause may be found. In such cases one is tempted to
make a diagnosis of panic disorder; however, by convention,
this diagnosis should probably be withheld until subsequent
attacks have occurred and one is able to
demonstrate that, at least at some point in the course, a frequency
of once monthly or more has been observed.
Anxiety attacks may also be seen as part of the depressive
episodes of either major depressive disorder or bipolar
20.10 Panic disorder 633
disorder; if their occurrence is confined solely within the
limits of the depressive episode, an additional diagnosis of
panic disorder is not warranted. However, if one can
demonstrate that the anxiety attacks preceded the onset of
the depressive episode, or persisted beyond the resolution
of the episode, then the additional diagnosis is appropriate.
Of the other causes of anxiety attacks noted in Section
6.5, some of the most common are simple phobia, social
phobia, post-traumatic stress disorder, and obsessive–
compulsive disorder. In all of these disorders, however, the
anxiety attacks are precipitated. For example, if the simple
phobic has to approach a snake, the social phobic public
speaking, the post-traumatic patient a situation reminiscent
of the original trauma, or the obsessive–compulsive a
contaminated object, a severe anxiety attack may indeed
occur. If however, these precipitating situations may be
avoided, these patients remain free of attacks.
Of the less common causes of anxiety attacks noted in
Section 6.5, special consideration should be given to myocardial
infarction or angina, paroxysmal atrial tachycardia,
hypoglycemia, hyperventilation, and simple partial seizures.
As noted earlier, panic attacks may be accompanied by chest
pain, which may radiate to the neck or shoulder, hence suggesting
a diagnosis of cardiac disease, and in these cases the
general medical setting is very helpful. Clearly, if the patient
is elderly and has known risk factors and no history of panic
attacks, then one would lean toward a diagnosis of coronary
artery disease; by contrast, if the patient is young and lacks
risk factors, one might be inclined to lean toward a diagnosis
of panic disorder. An episode of paroxysmal atrial tachycardia
may occasionally prompt considerable anxiety in the sufferer.
However, here one finds a hyperacute onset of the
tachycardia, over a second or so, in contrast to the build-up
of a panic attack, which occurs over a minute or so; furthermore,
in paroxysmal atrial tachycardia a valsalva manuever
may terminate the attack, whereas such a manuever has no
effect on a panic attack. Hypoglycemia should be suspected
in the case of a diabetic who has missed a meal, and in whom
the attack is associated with hunger; prompt relief with glucose
confirms the suspicion. Hyperventilation is suggested by
the prominent dyspnea and by relief with re-breathing
through a paper bag. Simple partial seizures are suggested by
an exquisitely paroxysmal onset, over seconds, and by a history
in most cases of other, more obvious seizure types, such
as complex partial seizures or grand mal seizures.
Treatment
Pharmacologic treatment of panic disorder has as its goal
the prevention of future panic attacks, and the first step
is to choose one of the various medications that are effective
in this regard, including antidepressants (SSRIs, tricyclics,
or MAOIs), benzodiazepines, and inositol. Cognitive–
behavioral therapy (Beck et al. 1992) also appears to be
effective; if this is tried first and is less than fully effective,
then one may simply proceed to pharmacologic treatment.