2. Panic Disorder Biology
and Management
Prof. Hani Hamed DDeessssookkii,, MM..DD..PPssyycchhiiaattrryy
PPrrooff.. PPssyycchhiiaattrryy
CChhaaiirrmmaann ooff PPssyycchhiiaattrryy DDeeppaarrttmmeenntt
BBeennii SSuueeff UUnniivveerrssiittyy
SSuuppeerrvviissoorr ooff PPssyycchhiiaattrryy DDeeppaarrttmmeenntt
EEll--FFaayyoouumm UUnniivveerrssiittyy
AAPPAA mmeemmbbeerr

3. History
• Panic has not always been recognized as
an exclusively psychiatric condition.
Research in this area continued along
separate medical and psychological axes
until 1980, when the development of
Diagnostic and Statistical Manual (DSM)-
III criteria established the overall concept
of panic disorder.

4. History cont”d
• The history of the word panic, of the concepts of Panic
attack and of Panic Disorder is a complex one.
• The adjective word panic, derived from the Greek,
stressed initially the intensity of a feeling of unjustified,
individual or collective, fear.
• In their present meanings, the concepts belong to the
group of anxiety states, the Panic attack being a
symptom characterized by a paroxysmal anxiety which
may appear in various psychopathological states,
whereas the Panic Disorder is a nosological category
whose diagnostic criterium is the appearance, with a
definite frequency, of Panic attacks.
• The disorder is frequently associated to agoraphobia
considered, when it exists, as a complication.

5. Panic Attacks & Panic Disorder
• It is common to confuse panic attacks with panic disorder.
• To qualify for the diagnosis of panic disorder itself, patients
must have some panic attacks that are entirely
unexpected.
• Panic attacks can also be reproducibly triggered by certain
specific situations for various individuals & therefore can
be expected.
• Situations that frequently act as triggers for panic attacks
e.g. driving or riding in a vehicle, esp over bridges,
shopping in crowded stores.
• The perception of lack of control or feeling "trapped" is a
common theme in situational triggers.

6. • Panic disorder affects up to 2 % of the population,
but < 1/3 receive treatment.
• It typically begins in late adolescence or early
adulthood but can present in childhood.
• Onset is rare after age 45.
• It is more prevalent in women (2:1).
• Genetic studies demonstrate a 15 to 20% rate of
panic disorder in relatives of patients with panic
disorder, including a 40% concordance rate for
panic disorder in monozygotic twins.

8. Panic Attack Facts
• Panic attacks can occur at any time, even during sleep.
• An attack usually peaks within 10 minutes, but some symptoms may
last much longer.
• Panic disorder affects about 6 million American adults
• Panic disorder is twice as common in women as men.
• Panic attacks often begin in late adolescence or early adulthood,
• Not everyone who experiences panic attacks will develop panic
disorder. Many people have just one attack and never have another.
• The tendency to develop panic attacks appears to be inherited.
• Panic disorder is often accompanied by other serious problems, such
as depression, drug abuse, or alcoholism.
http://www.nimh.nih.gov/publicat/anxiety.cfm

9. Comer, Fundamentals of Abnormal Psychology, 3e 9

10. DSM 5
 This chapter no longer includes OCD and
PTSD
 DSM 5 creates new chapters for OCD and
PTSD
 Panic Attacks and Agoraphobia are “unlinked”
in DSM- 5
 DSM- IV terminology describing different
types of panic attacks replaced in DSM-5 with
the terms “expected” or “unexpected” panic
attack

11. • Although not generally recognized, panic
disorder patients have a suicide rate
comparable with that of patients with MD.
• 20 to 40% of panic disorder patients report
having made suicide attempts & about 1/2
admit to having had suicidal ideation.
• This high rate of suicide attempts does not
appear to be caused by the presence of
depression.

12. Biological Considerations

13. Panic Disorder:
The Biological Perspective
• It is also unclear why some people have
such abnormalities in norepinephrine
activity
– Inherited biological predisposition is one
possibility
• Prevalence should be (and is) greater among close
relatives
– Among monozygotic (MZ, or identical) twins = 24%
– Among dizygotic (DZ, or fraternal) twins = 11%
• Issue is still open to debate

14. Panic Neurotransmitters
Norepinephrine Serotonin
GABA GABA
1. Brain stem: fires off systemically to create autonomic symptoms
2. Amygdala and Limbic System: generates anticipatory anxiety
3. Pre-frontal cortex: generates phobic avoidance

15. Biological Basis
Neurotransmitter : dysregulation
NE •
NE

16. • The theory of initial excess of NE is
supported by evidence that panic disorder
patients are hypersensitive to alpha-2
antagonists & hyposensitive to alpha-2
agonists.
• Thus, yohimbine, an alpha-2 antagonist,
acts as a promoter of NE release by
"cutting the brake cable" of the
presynaptic NE autoreceptor → an
exaggerated response in panic disorder
patients, including the precipitation of
overt panic attacks.

17. • Caffeine is also panicogenic (4-6 cups of coffee →
panic attack).
• It is an adenosine antagonist & can be synergistic
with NE.
• On the other hand, panic patients have a blunted
physiological response to postsynaptic adrenergic
agonists, perhaps as a consequence of an
overactive noradrenergic system.
• Thus, there may be a dysregulation in the
noradrenergic system, with changes in the
sensitivity of noradrenergic neurons & their
receptors altering their physiological functioning.

18. • GABA & its allosteric modulation by bz have also
been implicated in the biological basis of panic
disorder i.e. the ability of bz to modulate GABA is
out of balance.
• This may be due to changes in the amounts of
endogenous bz (i.e., "the brain's Xanax"), or to
alterations in the sensitivity of the bz receptor itself.
• Alternatively, it is possible that the brain is
producing an excess in anxiogenic inverse
agonists, causing the panic disorder patient to
have more anxiety & panic attacks.

19. • Some data suggest an abnormality in the bz receptor in
which the "set point" is shifted toward the inverse agonist
conformation.
• Thus, Cl channel conductance is already too diminished.
• Evidence comes from the fact that such patients require
administration of exogenous bz ligands (i.e. Xanax) to reset
the receptor complex's set point back to normal.
• Also, flumazenil, which is neutral & without behavioral
effects in normal subjects because it acts as a relatively
pure antagonist, can act differently in panic disorder
patients.
• It acts as an inverse agonist, perhaps via an abnormal shift
of the set point to the right, toward an inverse agonist
conformation → provokes panic attacks.

22. Intrinsic Activity at D2 Receptors
Intrinsic Activity DDeessccrriibbeess tthhee AAbbiilliittyy
ooff aa CCoommppoouunndd ttoo SSttiimmuullaattee RReecceeppttoorrss
NNoo rreecceeppttoorr aaccttiivviittyy
AAnnttaaggoonniisstt ((hhaallooppeerriiddooll,, eettcc))
PPaarrttiiaall rreecceeppttoorr aaccttiivviittyy
PPaarrttiiaall aaggoonniisstt ((aarriippiipprraazzoollee))
FFuullll rreecceeppttoorr aaccttiivviittyy
DD22 rreecceeppttoorr
FFuullll aaggoonniisstt ((ddooppaammiinnee))

23. مقلدات كاملة هذه المقلدات تنشط الخلية وتعطي full agonist
الثرر البيولوجي كاملاً
مقلدات جزئية وهي ل تنشط المستقبلات تماماً Partial agonists
. ولكن تعطي أثرر بيولوجي جزئي
هي الليجند التي ترتبط بمستقبل ول تنشطه وهذا antagonist
يؤدي إلى إغلاق المستقبل بالتالي تمنعه من الإرتباط بأي مادة أخرى ؤدي إلى إغلاق المستقبل بالتالي تمنعه من الرتتباط بأي مادة أخرى
( هذه الليجند هي من تمنع حدوث أثر بيولوجي لبعض الهرمونات هذه الليجند هي من تمنع حدوث أثرر بيولوجي لبعض الهرمونات
والمواد الكيميائية التي تفرز داخل الجسم بمنع ارتتباطها مع المستقبل
يؤدي إلى إغلاق المستقبل بالتالي تمنعه من الإرتباط بأي مادة أخرىقلل من نشاط المستقبلات Inverse agonists المقلد العكسي أو

24. • Antagonists are silent aanndd ddoonn’’tt hhaavvee aann aaccttiioonn
ooff tthheeiirr oowwnn,, tthheeyy oonnllyy bblloocckk tthhee aaccttiioonn ooff
aaggoonniisstt..
• IInnvveerrssee aaggoonniisstt ccaann bblloocckk tthhee aaccttiioonn ooff aaggoonniisstt oorr
tthheeyy ccaann rreedduuccee bbaasseelliinnee aaccttiivviittyy iinn tthhee aabbsseennccee
ooff aann aaggoonniisstt..

25. CHOLECYSTOKININ (CCK) هذه الليجند هي من تمنع حدوث أثر بيولوجي لبعض الهرمونات:
• It is a tetrapeptide that causes more panic
attacks when infused into patients with panic
disorder than it does in normal volunteers.
• This suggests increased sensitivity of the
brain type of CCK receptor, known as CCK-B.
• Unfortunately, in early investigations CCK-B
antagonists did not appear to be effective
for panic disorder.

26. Respiratory hypotheses
CARBON DIOXIDE LACTATE HYPERSENSITIVITY:
• Another biological theory proposes that panic attacks are a
result of abnormalities in respiratory function.
• This is based on observations that panic disorder patients
experience panic attacks more readily than normal control
subjects after exercising, when breathing carbon dioxide, or
when given lactate. These pts are chronic hyperventilators.
• Lactate may induce panic because it is a potent respiratory
stimulant panic disorder patients may be more sensitive to
agents that promote respiratory drive.

27. FALSE SUFFOCATION ALARM THEORY :
• It proposes that patients have a suffocation monitor in the brainstem,
which misinterprets signals misfires, triggering a false suffocation
alarm (panic attack).
• This theory is supported by:
- the chronic hyperventilation carbon dioxide hypersensitivity.
- the disorder of Ondine's curse (congenital central hypoventilation
syndrome) appears to be the opposite of panic disorder is
characterized by a diminished sensitivity of the suffocation alarm,
causing sufferers from this disorder to lack adequate breathing,
especially when asleep.
• The suffocation monitor is overly sensitive in panic disorder not
sensitive enough in Ondine's curse.
• According to this theory, spontaneous (i.e., unexpected) panic attacks
are thought to be mediated by this mechanism whereas chronic anxiety
or fear is not.

28. Neuroanatomic findings
• PET scans suggest abnormalities of neuronal
activity projections to the hippocampus, possibly
causing asymmetry of metabolic activity.
• Animal studies suggest that the locus coeruleus
appears central to modulation of vigilance,
attention anxiety or fear.
• Thus, hypersensitivity of the limbic system has
been considered a possible etiology or mechanism
mediating panic disorder.

29. LOCUS CERULEUS
Over Stimulation
• Youhinbin.
• Buspiron.
• Co2.
Inadequate inhibition
•Alpha, adreno agonist
(clonidine) هذه الليجند هي من تمنع حدوث أثر بيولوجي لبعض الهرمونات.
•GABA
•B. endorphines.
•Block of NE reuptake

30. Sensory
Thalamus
Hippocampus
Hypothalamus
Paraventricular Lateral
Nucleus Nucleus
Locus
Ceruleus
Periaquaductal
Gray Region
Parabrachial
Nucleus
Nucleus of the
Solitary Tract
Neuroanatomical Pathways of
Viscerosensory Information in the Brain
Medial Prefrontal Cortex, Cingulate Association Bundle Insula
Amygdala
Lateral Nucleus
Basal
Central
Nucleus of
the
Amygdala
Pituitary Autonomic
Pathways
Adrenal
Pathways Adapted from: Gorman J, et al. AJP 2000;157:493-505 Visceral Pathways

31. Locus Ceruleus
Amygdala
Ventral
Tegmenteum
Rahpe Nucleus
5HT
DA
NE
CRF
Facilitate,
Activate
SSyymmpp.. AAccttiivv..
GGII ddiissttrreessss
CCooggnniittiivvee
HHyyppeerrvveenntt..
SSttaarrttllee
EEnnddooccrriinnee aaccttiivv..
((HHPPAA aaxxiiss))
MMoottoorr aaccttiivv..
EEssccaappee bbeehhaavviioorr
((PPaaiinn mmoodduullaattiioonn))
LLaatteerraall hhyyppootthhaallaammuuss
VVaagguuss DDoorrssaall MM.. NN..
CCoorrttiiccaall AArreeaass
PPaarraabbrraacchhiiaall NN..
NNuucceelluuss CCaauuddaalliiss PPoonnttiiss
PPVVNN
SSttrriiaattuumm
PPeerriiaaqquueedduuccttaall aarreeaa
Medial prefrontal cortex
Hippocampus

32. • Few human studies found that lactate-sensitive
patients with panic disorder had
abnormal hemispheric asymmetry of
parahippocampal blood flow on PET scans.
• Also, patients with TLE foci frequently
experience panic-like symptoms; however,
only a small minority of panic disorder
patients were found to have abnormal
EEG.

33. • The ictal seizure-like analogy may be useful, for
panic may be tantamount to seizure-like neuronal
activation in parts of the brain that mediate emotions,
whereas true epilepsy may involve locations in the
brain mediating movement consciousness.
• Since there are both noradrenergic projections to the
hippocampus from the locus coeruleus
serotonergic projections to the hippocampus from
the raphe, it is possible that dysregulation of these
projections may account for neurophysiological
abnormalities hypothesized to occur in panic attacks.

34. 11.. NNeeuurroo--aannaattoommiiccaall BBaacckkggrroouunndd
PPhhaasseess == 33 bbrraainin rreeggioionnss 33
AAccuutete p paannicic Anticipatory
Anticipatory
anxiety
anxiety
Phobic
avoidance
Phobic
avoidance
BBrraainin s stetemm
Limbic system
Amygdala
Hypothalamus
Hippocampus
Limbic system
Amygdala
Hypothalamus
Hippocampus
Cognitive
avoidance
Medulla
Medulla

Respiratory C.
Respiratory C.
Co2
PH
chemosensitivity
chemosensitivity
Conditional
fear
Pons
LC
Over stim.
Less inhib
NE
Mid brain
Raphe N
5HT
The neurobiological underpeining of PD might be located in distinct
The neurobiological underpeining of PD might be located in distinct
neuroanatomical regions and circuits
neuroanatomical regions and circuits
MMeeddiaial lP PFFCC
Cognitive
avoidance

Co2
PH
MMeeddiaiatitoionn o of fp paannicic, ,u unnccoonndditiitoionnaal lf efeaarr
Conditional
fear
Pons
LC
Over stim.
Less inhib
NE
Mid brain
Raphe N
5HT
LLimimbbicic S Syysstetemm
AACCCC-F-FCC

35. Differential Diagnosis
• Cardiovascular Disease
– Angina
– CHF
– Hypertension
– Mitral valve prolapse
– Myocardial Infarction
– Paradoxical atrial
tachycardia
• Pulmonary Disease
– Asthma
– Pulmonary embolism
• Drug intoxication or
withdrawal
• Neurological Disease
– CVA / TIA
– Epilepsy
– Meniere’s disease
– Migraine
– Tumor
• Endocrine Disease
– Carcinoid syndrome
– Hyperthyroidism
– Perimenopausal
– Pheochromocytoma
• Other
– SLE
– Systemic infection
– Heavy metal poisoning

36. Course of Illness
• 30 – 40 % become symptom free
• 50 % with mild symptoms with little
impairment of function
• 10 – 20 % continue with significant
impairment
• Depression: 40 – 80 %
• Substance abuse: 20 – 40 %

37. Panic-Depression
Comorbidity
• 30-40% MDD have recurrent panic attacks
• 10-20% MDD have panic disorder
• 50-55% PD (or panic attacks) have MDD
• Patients with MDD and PD
– Earlier onset MDD
– More severe MDD

38. Treatments

39. SSRIs
• Now considered 1st-line treatments for panic
disorder.
• SSRIs can also treat coexisting depression
in the same patient at the same time.
• All SSRIs have been shown to be about
equally effective to take on average 3 to 8
weeks before benefit may be noticed.

40. • Patients with panic disorder tend to be more
sensitive to SSRIs than are depressed
patients, since they can easily develop
jitteriness or even short-term worsening of
their panic when treatment is initiated.
• Thus, panic patients usually start at a lower
dose than depressed patients.
• Doses must generally be increased to the
same or greater levels as antidepressants
over time as tolerated.

41. Treatment with SSRIs

42. SSRI profile for panic/social
phobia PTSD
• Maintenance doses starting doses may need
to be higher than usual antidepressant doses,
particularly for paroxetine.
• Onset of action is usually 2 to 8 weeks.
• Usual response is 50% reduction of symptoms,
especially in combination with other treatments
such as bz, trazodone, or CBT.

43. Newer antidepressants
• Used as 2nd-line therapy after SSRIs fail to
improve panic or in patients who cannot
tolerate them.
• These include:
nefazodone, venlafaxine XR, mirtazapine
reboxetine.
• Bupropion doesn’t seem to have apparent
antipanic actions.

44. Duloxitine Atomoxeti
ne
Reboxetine Dapoxetine
SNRI selective
Selective
norepineph
rine uptake
inhibitor
Not FDA
approved
yet
norepinephrine
reuptake inhibitor
30,60, =
Joypox tab
ultrshort
acting SSRI
for treatment
of premature
ejaculation.

45. Tricyclic antidepressants
• Imipramine clomipramine have been the most extensively
studied of the TCAs both have shown efficacy in treating
panic disorder.
• Others that have shown some efficacy include desipramine,
doxepin, amitriptyline nortriptyline.
• They have few or no overall advantages compared with
SSRIs, although occasionally a patient will respond to a
tricyclic not to an SSRI.
• They have disadvantages that make them 2nd- or 3rd-line
treatments for panic disorder, including anticholinergic side
effects, orthostatic hypotension weight gain.

46. Benzodiazepines
• Become adjunctive treatment to antidepressants
(particularly SSRIs), especially for long-term
treatment.
• 1ry advantage is rapid relief from anxiety panic
attacks as antidepressants have a delayed
therapeutic onset.
• The disadvantages include sedation, cognitive
clouding, interaction with alcohol, physiological
dependence the potential for a withdrawal
syndrome.

47. • Currently, many physicians adopt a
benzodiazepine-sparing strategy
i.e. use bz when necessary but conservatively.
i.e. use them:
- when treatment is initiated or a rapid-onset
therapeutic effect is desired.
- to improve the short-term tolerability of SSRIs by
blocking the jitteriness exacerbation of panic.

48. - if a patient is not fully responsive to an
antidepressant or combinations of
antidepressants.
• Once symptoms are suppressed for several
months to a year, they can be slowly
discontinued the patient maintained long-term
on the antidepressant alone.

49. • Alprazolam was researched more extensively
than any other bz in panic disorder is very
effective.
• Because of its short duration of action, it must be
administered in 3-5 daily doses.
• Clonazepam, which has a longer duration of
action has also been investigated in panic disorder.
• It can be administered twice a day.
• It is reported to have less abuse potential than
alprazolam to be easier to taper during
discontinuation owing to its longer half-life.

50. Cognitive behavioral
psychotherapies
• Cognitive therapy focuses on identifying the cognitive distortions
modifying them.
• Behavioral therapy specifically attempts to modify a patient's
responses, often through exposure to situations or physiologic stimuli
that are associated with panic attacks.
• Behavioral therapy appears to be most effective in treating the phobic
avoidance aspect of panic disorder agoraphobia does not appear as
effective in treating the panic attacks.
• These treatments had as high rate of effectiveness as antipanic drugs.
• Furthermore, for those who are able to complete an adequate period of
behavioral treatment, their improvements are perhaps more likely to be
sustained after discontinuing treatment than are drug induced
improvements after discontinuation of antipanic drugs.

53. Relapse after medication
discontinuation
• Although panic disorder can frequently be in remission within
6 months of beginning treatment, the relapse rate is
apparently very high once treatment is stopped, even for
patients who have had complete resolution of symptoms.
• When a patient has been asymptomatic on medication for 6
to 12 months, it may be reasonable to have a trial off
medication.
• If medication is discontinued, this should be done slowly
bzs in particular should be tapered over a period of at least 2
months possibly as long as 6 months.
• More commonly now, panic disorder is considered a chronic
illness, which requires maintenance therapy.

54. CCoonncclluussiioonn
• Drug therapies
– Both antidepressants and benzodiazepines
are also helpful in treating panic disorder with
agoraphobia
• Break the cycle of attack, anticipation, and fear
• Combination treatment (medications +
behavioral exposure therapy) may be
more effective than either treatment alone

55. Future therapeutic
Approaches
Approach Example Mechanism
1. CRF ? Antagonize effects of CRF in amygdala
2. Sub. P antagonist ? Antagonize effects of sub. P on raphe
nucli
3. Neuro active peptide
antagonists
?? CCK and NK antagonism
4. 5HT1A agonist Flesinoxon
Eptapirone
 5HT1A activity
5. 5HT2a/c Deramciclane  5HT 2a/c
6. GABA receptors
modulators
Suriclone Act near GABA and have properties
similar to BZ
7. Glutaminergic agents ? Act via glutamate in dorsal raphe nuclei
(for treatment resistant cases)