Panic Disorder (panic disorder with or without agoraphobia, DSM-IV ...

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Panic Disorder (panic disorder with or without
agoraphobia, DSM-IV-TR #300.01, 300.21)

Panic disorder is characterized by the repeated occurrence of
must assume that in rare instances a patient may experience a
discrete panic attacks. Between attacks these patients are
panic attack without undue anxiety at all.
often well, although most, after repeated attacks, develop
some persistent apprehension, or anticipatory anxiety,
regarding the possibility of another attack; in turn, about one
Tremor may or may not be a complaint; some patients
complain more of a sense of internal shakiness.
half of these patients eventually develop agoraphobia.
This is a relatively common disorder and has a lifetime
The palpitations and chest discomfort often prove most
alarming to patients. The discomfort itself may be quite
prevalence of from 1 to 2%. It is several times more common
in women than in men. In the past these patients might have
severe and sometimes radiates to the left shoulder or the left
received many different diagnoses including the following:
side of the neck. Such complaints, of course, also cause
DaCosta’s syndrome, “effort heart,” neurocirculatory
discomfort in the emergency room physician. The
palpitations are often described as “racing,” and less often as
asthenia, neurasthenia, and acute anxiety neurosis. However,
in reading old reports keep in mind that these are not actual
“skipped beats.”
synonyms for panic disorder but rather loosely defined terms
that include not only patients who today would be diagnosed
The other symptoms require little discussion. Patients
as having panic disorder but also many other patients
describe them in the most varied terms, and one may inquire
suffering sometimes from quite disparate disorders.
specifically after each term to become familiar with the range
of descriptions possible.
In most patients the attacks are without precipitating factors,
and this is perhaps one of the most striking features of panic
Although some patients, in retrospect, report feeling vaguely
unwell in the weeks or months before their first panic attack,
attacks. They seem to “come out of the blue” and strike
most experience no prodrome, and the onset of the illness is
without warning. Although patients may recall with vivid
clarity the exact circumstances surrounding the first attack,
heralded by the occurrence of the first attack. This experience
is often recalled in vivid detail, and patients may be able to
they are generally unable to identify anything that could
describe precisely the circumstances in which the attack
conceivably have caused the attack. Many patients, after
repeated attacks, may come to fear being in situations where
occurred. This first attack generally occurs in late
adolescence or the early twenties; however, later onsets, up to
help might not be readily available should another attack
the thirties, are not uncommon. Rarely, onset may occur in
occur. Thus they may have anxiety about driving on limited
access freeways, or bridges, or in tunnels. Flying or boating
childhood or over the age of 40.
may likewise be avoided. In describing their fear of these
situations, patients may give the impression that they are
afraid that the situation itself might cause a panic attack.
However, on closer questioning one can see that what they
are afraid of is not so much that the situation will cause the
The panic attack itself usually comes on acutely, often within
attack but that they might have an attack in that situation and
a minute, and crescendos rapidly. Symptoms generally last
be unable to get to help
only 5 to 15 minutes, or sometimes less, and very rarely up to
an hour, and then recede over minutes. After the attack most
patients feel “shaken,” and may feel drained and

apprehensive for a long time, sometimes hours. During the
attack itself, patients may experience any of the symptoms
listed in the box (this page). These symptoms may appear in
Panic Attack Symptoms
any combination, and a patient rarely experiences all of these
symptoms during any one attack.

Hot and cold
The anxiety may take any of several forms. Some patients
experience the classic “sense of impending doom,” as if
something terrible were about to happen. Some fear they are
Tremor Dyspnea
having a heart attack or a stroke, and this may occasion
Palpitations Dizziness
multiple visits to the emergency room. Some fear they will
“go crazy.” For others the anxiety may be only a minor part
of the symptomatology of the attack; rarely, patients do not
Nausea or
have any anxiety at all during the attack, only a sense of
discomfort. The existence of these cases, dubbed “panic
attacks without panic,” was initially controversial. However,
in every other respect they are typical attacks, and as no other
Diaphoresis Acral
etiology than panic disorder can be established for them, one


The discovery of panicogens has been one of the major fruits

of research in panic disorder. These are substances that,
immediately. In some patients, as noted below, agoraphobia
though innocuous to normal controls, reliably produce panic
may develop.
attacks in patients with panic disorder. These induced panic
attacks are essentially identical to the naturally occurring
ones. Furthermore, these induced attacks may be prevented
Nocturnal panic attacks are not uncommon; however, as
by the same medications that are effective in preventing the
patients may not report them, one should inquire after them
naturally occurring attacks.
specifically. Polysomnography has revealed that these
nocturnal attacks tend to arise from non-REM sleep.
Several substances have been shown to be panicogenic. They
include sodium lactate, inhalation of 5% or 35% carbon
dioxide, cholecystokinin tetrapeptide, caffeine, yohimbine,
isoproterenol, and the benzodiazepine antagonist, flumazenil.
The frequency with which panic attacks occur varies widely,
Of these the best studied is sodium lactate infusion. In light
and it appears that the long-term course falls more or less into
of the family studies noted above, it is of interest that the
one of two patterns. In one pattern, the frequency gradually
inhalation of 35% carbon dioxide by the asymptomatic and
waxes and wanes (anywhere from once daily to once every
not-ill relatives of probands induces panic attacks, an effect
few months), over many years or decades, without the patient
not seen in normal controls.
ever experiencing any prolonged attack-free intervals. In the
other pattern one does see prolonged attack-free intervals,
Various neurotransmitters have also been investigated. The
and in this pattern it may be appropriate to speak of an
noradrenergic system is strongly implicated by the
“episodic” course, wherein episodes, characterized by panic
panicogenic efficacy of adrenergic agents such as yohimbine
attacks occurring with varying frequency, are separated by
and isoproterenol, and this is further supported by studies
intervals free of attacks.
demonstrating a blunted GH response to clonidine
administration. The serotoninergic system is implicated not
only by the undoubted efficacy of serotoninergic
antidepressants in the treatment of panic disorder, but also by
studies involving manipulation of brain serotonin levels. For
The most common complication of panic disorder is
example, depletion of tryptophan, the dietary precursor of
agoraphobia, and this is seen in anywhere from one-third to
serotonin, increases the effectiveness of a panicogen such as
one-half of all patients, generally within the first year. Here
flumazenil, whereas the administration of 5-
the anticipatory anxiety becomes so severe and attached to so
hydroxytryptophan, which increases serotonin levels, will
many different situations that patients begin to more or less
blunt the effectiveness of CO
severely restrict their travels. Truck drivers may give up their
2 inhalation as a panicogen. The
GABA-ergic system is strongly implicated by the
long-distance routes and restrict themselves to local
effectiveness of flumazenil as a panicogen and by the
deliveries; traveling salespersons may quit their routes
effectiveness of benzodiazepines in the treatment of panic
altogether. At its worst these patients may become
disorder, and is supported by a recent finding of reduced
GABA levels in the occipital cortex of panic disorder
Abuse of alcohol, benzodiazepines, or other tranquilizers or
sedatives is a serious risk. Patients may use these to quell
Functional MRI studies, although not entirely in agreement,
anticipatory anxiety; others may take them during the panic
suggest strongly that the hippocampus and parahippocampal
attack itself in the mistaken belief that blood levels sufficient
gyrus are abnormally activated in panic disorder.
to have an effect will occur before the attack remits
spontaneously. This complication may compound itself if
tolerance and withdrawal occur. During withdrawal, panic
Integrating these findings into a coherent etiologic theory is
attacks are more likely to occur, which in turn could spur
problematic and requires some speculation. However, it
further use of a tranquilizer, thus setting up a vicious cycle.
appears plausible to say that panic disorder represents an
inherited disturbance in the overall function of noradrenergic,
serotoninergic or GABAergic systems in one or more of
Patients who suffer from both panic disorder and major
those central nervous system structures responsible for
depression may be at higher risk for suicide than those with
anxiety. Candidate structures include the locus ceruleus,
major depression alone. However, contrary to earlier reports,
dorsal raphe nucleus, parahippocampus, hippocampus and
those with panic disorder alone do not appear to be at higher
amygdala. The locus ceruleus is noradrenergic, the dorsal
risk for a suicide attempt.
raphe nucleus serotoninergic, and both send fibers to a large
number of structures, including the parahippocampus,
hippocampus and amygdala, structures rich in GABA
receptors. Stimulation of these limbic structures, in turn, is
well known to produce fear and anxiety. If one assumes that
Panic disorder appears to run in families. As the degree of
overactivity of the amygdala is the “final common pathway,”
consanguinity increases from general population to first-
then disturbance in any one of the other structures, or the
degree relatives, or from dizygotic to monozygotic twins, so
amygdala itself, could cause a panic attack.
too does the risk of having panic disorder. Although this is
consistent with a hereditary basis, the effects of a shared
environment cannot be ruled out, and until adoption studies
It has been proposed that one possible “trigger” for the
are done, the basis for the familial occurrence of panic
activation of this neuronal circuit is an abnormal sensitivity
disorder remains uncertain. Genetic and linkage studies, to
to disturbances of acid-base balance in the brainstem. Such a
date, have not yielded robust findings.
sensitivity, if it did exist, could explain the efficacy of
panicogens such as lactate infusion and CO2 inhalation,

maneuvers which both induce changes in acid-base balance.
might be inclined toward a diagnosis of panic disorder,
This “false suffocation alarm” could then lead to
especially with a history of numerous prior identical attacks.
overactivation of either the locus ceruleus or dorsal raphe
At the moment of lodgment of a relatively large pulmonary
embolus, patients may have a sudden onset of chest
Before leaving this discussion of the etiology of panic
discomfort, dyspnea, nausea, diaphoresis, and significant
disorder a word is in order regarding the association of panic
anxiety, thus presenting a clinical picture quite similar to a
disorder with mitral valve prolapse. Although this association
panic attack. The disproportionate emphasis on dyspnea
has not been consistently replicated, most studies do support
relative to other symptoms is a helpful diagnostic point for
it. It appears unlikely, however, that mitral valve prolapse
pulmonary embolus. Likewise, hemoptysis or wheezing point
causes panic or that, vice versa, panic causes prolapse; rather
immediately to the correct diagnosis; however, these latter
the association is probably secondary to some commonly
two symptoms are often not present. As is the case with
shared abnormality, the nature of which is unclear.
myocardial ischemia, the setting of the illness may be a
helpful point. Prolonged immobilization, thrombophlebitis or
cardiac failure would make one’s index of suspicion higher
for pulmonary embolus, especially if this were a first episode.
Panic attacks may be seen in simple phobia, social phobia,
Paroxysmal supraventricular tachycardia (SVT), also known
posttraumatic stress disorder, and obsessive-compulsive
as paroxysmal atrial tachycardia, occasionally may cause
disorder. In these disorders, however, the panic attacks are
diagnostic problems because the patient may become quite
precipitated. For example, if the simple phobic has to
anxious during an attack of tachycardia. Two diagnostic
approach a snake, the social phobic public speaking, the
points strongly suggest SVT: first, a hyperacute onset (often
posttraumatic patient a situation reminiscent of the original
less than a second) and, second, the ability of the patient to
trauma, or the obsessive-compulsive patient a contaminated
terminate the attack by a Valsalva maneuver. Holter
object, a severe panic attack may indeed occur. If, however,
monitoring will help establish the diagnosis; however, it is
these patients can avoid the stimuli, there are no panic
important to utilize “event monitoring” so that the episode is
attacks. In such cases a separate diagnosis of panic disorder is
not missed.
not made.
Simple partial seizures may occasionally be characterized by
Occasionally an otherwise normal individual experiences a
a panic attack. Clues to this diagnosis include not only the
spontaneous panic attack; to qualify, however, for a diagnosis
occurrence, at other times, of other seizure types (e.g., grand
of panic disorder, the attacks must be either severe enough to
mal or complex partial) but also the exquisitely paroxysmal
cause marked distress or be frequent, occurring generally
nature of the ictal panic attack: whereas panic attacks in
once a month or more.
panic disorder take minutes to crescendo, the ictal anxiety
peaks within seconds. An EEG may or may not be helpful in
Panic attacks are also seen with some frequency in patients
such cases, as it may be normal even while the patient is
suffering from a depressive episode either as part of major
having the seizure.
depression or bipolar disorder. In some cases the panic
attacks may actually predate the onset of the depressive
Episodic hypoglycemia may be very difficult to distinguish
symptoms, and when they are concurrent with depressive
from a panic attack. Symptomatic episodes of hypoglycemia,
symptoms, no relationship between them and the severity of
however, tend to have a slower onset than a panic attack and
the depressive symptoms is evident. In such cases a separate
tend to last longer. Relief of symptoms with orange juice or
panic disorder is occurring in addition to the depressive
some other sugar is a helpful diagnostic point. The setting is
disorder, and consequently, two diagnoses are given.
also helpful; the suspicion for hypoglycemia is higher in a
patient taking insulin or an oral hypoglycemic and in those in
A number of conditions may produce symptomatic episodes
whom the attacks tend to occur postprandially.
that may very closely resemble panic attacks, thus
engendering some diagnostic confusion (see the box on this
A minority of patients with pheochromocytoma have
page). Usually, however, certain differential points allow a
paroxysmal attacks that very closely resemble panic attacks.
correct diagnosis.
Typically, though, in contrast to patients with panic attacks,
these patients have a prominent headache. Furthermore,
Parkinson’s disease is associated with panic attacks when
hypertension is always present during the attack and is often
patients are treated with levodopa and have a prominent “on-
also present between the attacks. Furthermore, although
off” effect. Here, as the preceding dose of levodopa wears off
paroxysms in pheochromocytoma may occur spontaneously,
and the parkinsonism worsens, patients may have a panic
at times they are precipitated by abdominal compression or
attack very similar to those seen in panic disorder.
micturition, factors that clearly distinguish them from panic
Patients suffering a myocardial infarction or an attack of
angina pectoris may complain of chest pain, dyspnea, nausea,
Mastocytosis may present with episodes of light-headedness,
diaphoresis, and often a sense of impending doom. Radiation
palpitations, headaches, dyspnea, chest pain, and nausea.
of pain to the neck or arm is not an infallibly reliable
Though these episodes, in these respects, are similar to panic
diagnostic point, since this may also occur during a panic
attacks, certain points suggest the correct diagnosis. Patients
attack. The general medical setting of the illness is often
with mastocytosis almost always experience intense flushing
diagnostically helpful. Clearly, if the patient is elderly, with
during the episode. Interestingly, though this can be
known cardiac disease or multiple coronary risk factors, one
profound, they rarely complain of it and must be questioned
might lean toward a diagnosis of myocardial insufficiency.
directly about the presence or absence of flushing.
Conversely, if the patient is young, with no risk factors, one
Furthermore, after the attack most patients experience

profound lethargy to the point of prostration, which may last
metabolites) should be used only as indicated by one’s
for days or longer. Such post-attack prostration is not seen
diagnostic suspicions.
after a panic attack. Finally, physical examination generally
Conditions that may Produce
The goal of treatment in panic disorder is twofold: to prevent
Symptomatic Episodes that Resemble
future attacks and to relieve anticipatory anxiety and enable
Panic Attacks
patients to overcome any avoidance behavior they may have
developed. Both cognitive-behavioral treatment and

medication have a role; medications are discussed first.
Simple partial
When initiating pharmacologic treatment one must impress
on the patient the fact that, short of intravenous medication,
probably nothing is available that reliably aborts an attack
once it has begun, and that therefore the thrust of drug
Angina pectoris Pheochromocytoma
treatment is to prevent future attacks.
Supraventricular Mastocytosis
Once the patient has decided on prophylactic treatment, the
next step is to select the prophylactic agent best suited for the
patient. Two groups of medicines provide effective
prophylaxis: certain benzodiazepines and most of the

currently available antidepressants. Which group to choose
has been the subject of intense debate. Buspirone is not

urticaria pigmentosa, although not all patients with
Four benzodiazepines are clearly effective: alprazolam,
mastocytosis have this.
clonazepam, lorazepam and diazepam. The benzodiazepines
offer certain advantages. They have a rapid onset of action,
generally few side effects, and often serve to reduce the
Carcinoid syndrome is often included in the differential
anticipatory anxiety that most patients with panic disorder
diagnosis of panic attacks, but it would appear difficult to
experience. The total daily dose is gradually titrated up until
confuse the two. The flushing and diarrhea that are hallmarks
symptoms are controlled: alprazolam may be started at from
of the carcinoid syndrome are relatively minor in a panic
0.75 to 1.5 mg, with most patients responding to doses of
from 1.5 to 6 mg; comparable figures for clonazepam are 0.5
to 1.5 mg to start, titrating to from 1.0 to 4.0 mg, for
lorazepam 1 to 2 mg to start, titrating to from 2 to 6 mg, and
Certain other disorders are often included on the differential
for diazepam 4 to 10 mg to start, titrating to from 10 to 60
diagnosis for panic disorder, including hyperthyroidism,
mg. Alprazolam, if given in the extended-release
certain drug intoxications, and certain drug withdrawals;
formulation, may be given once daily; otherwise the total
however, the anxiety seen in these disorders is generally not
daily dose must be divided into three or more
paroxysmal. The anxiety of hyperthyroidism may wax and
administrations; clonazepam and diazepam are generally
wane, but is not episodic. Drugs such as caffeine, cocaine,
given in two divided doses.
amphetamines and various over-the-counter
sympathomimetics may produce an episode of anxiety, but,
unless the durg is injected intravenously or taken by
Given the risk of neuroadaptation with benzodiazepines,
inhalation, the onset is usually gradual. Withdrawal from
many clinicians prefer to start with an antidepressant,
alcohol, benzodiazepines or other sedative-hypnotics is often
choosing an SSRI, tricyclic or MAOI. The SSRIs are
accompanied by anxiety which may at times undergo an
generally better tolerated than the tricyclics, and the MAOIs,
episodic surge similar to a panic attack. In such cases, these
though undoubtedly effective, are generally held in reserve
“attacks” subside with abstinence.
given their side-effect profile and dietary requirements.
Regardless of which antidepressant is chosen it is generally
prudent to start with a low dose: although in most cases a full
As may be gathered from the foregoing discussion, the
“antidepressant” dose is required, starting at or near such a
differential diagnosis in patients suspected of panic disorder
dose often precipitates either agitation or a “flurry” of panic
is rather extensive. The task of differential diagnosis here,
attacks, and consequently one should begin with a dose from
however, is not as formidable as it may seem. A careful
one-tenth to one-third of the “full” dose, followed by an
history generally points in the right direction. If one is lucky
upward titration, in similar increments, every week or so.
enough to have the patient under observation during an
Importantly, although most patients do indeed both tolerate
attack, one should, in addition to a careful description of
and require a titration to a “full dose” there is a small
symptoms and cutaneous signs, note blood pressure, pulse,
minority of patients who do not tolerate more than a small
and if possible obtain an ECG, blood for a glucose level, and,
amount but yet do get a good anti-panic effect from it.
if suspicious of mastocytosis, a histamine level.
Unfortunately, one cannot as yet tell prospectively which
Determination of CBC and cardiac enzymes depends on the
patients will have this sort of response. Once an optimum
level of suspicion of cardiac or pulmonary disease. Other
dose has been reached, a response may not be seen for weeks,
tests (such as a pulmonary scan, arteriography, Holter
and a full response may be delayed for up to 3 months. Given
monitor, electroencephalogram, glucose tolerance test,
this potentially long delayed response, many clinicians will
plasma norepinephrine and epinephrine, and 24-hour urine
begin treatment with a combination of a benzodiazepine and
for 5-hydroxyindoleacetic acid or histamine and its
an SSRI (e.g., clonazepam and sertraline) and then taper off

the benzodiazepine once the SSRI has had a chance to
Finn CT, Smoller JW. The genetics of panic disorder.
become effective.
Current Psychiatry Reports 2001;3:131–137.

Fleet RP, Martel JP, Lavoie KL, et al. Non-fearful panic
Among the SSRIs, the following (with their average doses)
disorder: a variant of panic in medical patients?
have been shown to be effective in double-blinded studies:
Psychosomatics 2000;41:311–320.
paroxetine (40 mg), fluoxetine (20 mg), fluvoxamine (150

mg), citalopram (20 mg), escitalopram (10 mg) and
Goddard AW, Mason GF, Almai A, et al. Reductions in
sertraline. In the case of sertraline, it appears that any dose
occipital cortex GABA levels in panic disorder detected with
between 50 and 200 mg is effective.
1h-magnetic resonance spectroscopy. Archives of General
Of the tricyclics, imipramine, in doses of 150 to 200 mg,

although effective, and indeed the “gold standard,” is
Gorman JM, Kent JM, Sullivan GM, et al. Neuroanatomical
generally poorly tolerated over the long haul. Nortriptyline,
hypothesis of panic disorder, revised. The American Journal
in doses of from 50 to 150 mg, desipramine, in doses of from
of Psychiatry 2000;157: 493–505.
150 to 200 mg, and clomipramine, in doses of from 50 to 150

mg, are alternatives.
Kampman M, Keijsers GP, Hoogduin CA, et al. A
randomized, double-blind, placebo-controlled study of the
effects of adjunctive paroxetine in panic disorder patients
Of the MAOIs, phenelzine, in doses of 30 to 90 mg, is
unsuccessfully treated with cognitivebehavioral therapy
effective. Two other reversible MAOIs, not yet available in
alone. The Journal of Clinical Psychiatry 2002;63: 772–777.
the United States, are also effective, namely brofaromine and

Katerndahl DA. Panic and prolapse: meta-analysis. The
Journal of Nervous and Mental Disease
Other medications that may be considered include

propranolol and inositol. Propranolol, in total daily doses of
Lessmeier TJ, Gamperling D, Johnson-Liddon V, et al.
roughly 180 mg, may be effective, but the clinical impression
Unrecognized paroxysmal supraventricular tachycardia.
is that it is less reliably so than a benzodiazepine or an
Potential for misdiagnosis as panic disorder. Archives of
antidepressant. Inositol is an isomer of glucose which serves
Internal Medicine 1997;157:537–543.
as a precursor for inositol, an intracellular “second

messenger”: remarkably, in a double-blinded comparison,
Mellman TA, Uhde TW. Patients with frequent sleep panic:
with doses of roughly 6000 mg bid, it was more effective
clinical findings and response to medication treatment. The
than fluvoxamine. Clearly, this is very promising, and bears
Journal of Clinical Psychiatry 1990;51:513–516.
watching for replication.

Palatnik A, Frolov K, Fux M, et al. Double-blind, controlled,
crossover trial of inositol versus fluvoxamine for the
Response to medical treatment is usually quite good. Many
treatment of panic disorder. Journal of Clinical
patients become completely free of panic attacks. However, a
Psychopharmacology 2001;21:335–339.
large percentage continue to have attacks, albeit much less

frequently and of much less severity.
Russell JL, Kushner MG, Beitman BD, et al. Non-fearful
panic disorder in neurology patients validated by lactate
Cognitive-behavior therapy, used either independently or in
challenge. The American Journal of Psychiatry
conjunction with medical treatment, should also be
considered, especially in light of the fact that in addition to

reducing the frequency of panic attacks, it is also an effective
Schruers K, van Diest R, Overbeek T, et al. Acute L-5-
treatment for agoraphobia.
hydroxytryptophan administration inhibits carbon dioxide-
induced panic in panic disorder patients. Psychiatry Research

Sheehan DV. The management of panic disorder. The
Journal of Clinical Psychiatry 2002;63(Suppl 14):17–21.

Bakker A, van Dyck R, Spinhoven P, et al. Paroxetine,
clomipramine, and cognitive therapy in the treatment of panic
disorder. The Journal of Clinical Psychiatry 1999;60:831–

Bakker A, van Balkom AJ, Spinhoven P. SSRIs vs. TCAs in
the treatment of panic disorder: a meta-analysis. Acta
Psychiatrica Scandinavica
2002;106: 163–167.

Bell C, Forshall S, Andover M, et al. Does 5-HT restrain
panic? A tryptophan depletion study in panic disorder
patients recovered on paroxetine. Journal of

Bisaga A, Katz JL, Antonini A, et al. Cerebral glucose
metabolism in women with panic disorder. The American
Journal of Psychiatry
1998;155: 1178–1183.