Panic Disorder Biology and Management

Prof. Hani Hamed Dessoki, M.D.PsychiatryProf. Hani Hamed Dessoki, M.D.PsychiatryProf. PsychiatryProf. Psychiatry

Chairman of Psychiatry DepartmentChairman of Psychiatry Department

Beni Suef UniversityBeni Suef University

Supervisor of Psychiatry DepartmentSupervisor of Psychiatry Department

El-Fayoum UniversityEl-Fayoum University

APA memberAPA member

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. 

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.

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.

• 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.

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/pub lica t/anxie ty.cfm

Comer, Fundamentals of Abnormal Psychology, 3e

9

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

• 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.

Biological Considerations

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

Panic Neurotransmitters

Norepinephrine Serotonin

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

GABA GABA

Biological Basis

Neurotransmitter dysregulation:

•NE

NE

• 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.

• 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.

• 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.

• 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.

Intrinsic Activity at D2 Receptors

Intrinsic Activity Describes the AbilityIntrinsic Activity Describes the Abilityof a Compound to Stimulate Receptorsof a Compound to Stimulate Receptors

No receptor activityNo receptor activityAntagonist (haloperidol, etc)Antagonist (haloperidol, etc)

Partial receptor activityPartial receptor activityPartial agonist (aripiprazole)Partial agonist (aripiprazole)

Full receptor activityFull receptor activityDD22 receptor receptor

Full agonist (dopamine)Full agonist (dopamine)

full agonist تنشط المقلدات هذه كاملة مقلدات � كامًال البيولوجي األثر وتعطي الخلية

Partial agonists تنشط ال وهي جزئية مقلداتبيولوجي أثر تعطي ولكن تماما�� المستقبًالت

جزئي .

antagonist بمستقبل ترتبط التي الليجند هيالمستقبل إغًالق إلى يؤدي وهذا تنشطه وال

هذه ) أخرى مادة بأي اإلرتباط من تمنعه بالتاليلبعض بيولوجي أثر حدوث تمنع من هي الليجندداخل تفرز التي الكيميائية والمواد الهرمونات

المستقبل مع ارتباطها بمنع الجسم

أو العكسي من Inverse agonistsالمقلد يقللالمستقبًالت نشاط

• Antagonists are silent and don’t have an action Antagonists are silent and don’t have an action of their own, they only block the action of of their own, they only block the action of agonist. agonist.

• Inverse agonist can block the action of agonist or Inverse agonist can block the action of agonist or they can reduce baseline activity in the absence they can reduce baseline activity in the absence of an agonist. of an agonist.

CHOLECYSTOKININ (CCK(:

• 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.

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.

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.

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.

LOCUS CERULEUS

Over Stimulation

• Youhinbin.

• Buspiron.

• Co2.

Inadequate inhibition

•Alpha, adreno agonist (clonidine(.

•GABA

•B. endorphines.

•Block of NE reuptake

Inadequate inhibition

•Alpha, adreno agonist (clonidine(.

•GABA

•B. endorphines.

•Block of NE reuptake

SensoryThalamus

Hippocampus

HypothalamusParaventricular Lateral Nucleus Nucleus

LocusCeruleus

PeriaquaductalGray Region

ParabrachialNucleus

Nucleus of theSolitary Tract

Neuroanatomical Pathways of Viscerosensory Information in the Brain

Association BundleMedial Prefrontal Cortex, Cingulate Insula

AmygdalaLateral Nucleus

Basal

CentralNucleus of

theAmygdala

Pituitary Autonomic Pathways

AdrenalPathways Visceral PathwaysAdapted from: Gorman J, et al. AJP 2000;157:493-505

AmygdalaAmygdala

Rahpe Nucleus

5HT

Rahpe Nucleus

5HT

Ventral

Tegmenteum

DA

Ventral

Tegmenteum

DA

Locus Ceruleus

NE

Locus Ceruleus

NE

CRFCRF

Facilitate,

Activate

Facilitate,

Activate

Symp. Activ.Symp. Activ.

GI distress GI distress

CognitiveCognitive

Hypervent.Hypervent.

StartleStartle

Endocrine activ.Endocrine activ.

(HPA axis)(HPA axis)

Motor activ.Motor activ.

Escape behaviorEscape behavior

(Pain modulation)(Pain modulation)

Symp. Activ.Symp. Activ.

GI distress GI distress

CognitiveCognitive

Hypervent.Hypervent.

StartleStartle

Endocrine activ.Endocrine activ.

(HPA axis)(HPA axis)

Motor activ.Motor activ.

Escape behaviorEscape behavior

(Pain modulation)(Pain modulation)

Lateral hypothalamusLateral hypothalamus

Vagus Dorsal M. N. Vagus Dorsal M. N.

Cortical AreasCortical Areas

Parabrachial N.Parabrachial N.

Nucelus Caudalis PontisNucelus Caudalis Pontis

PVNPVN

StriatumStriatum

Periaqueductal areaPeriaqueductal area

Lateral hypothalamusLateral hypothalamus

Vagus Dorsal M. N. Vagus Dorsal M. N.

Cortical AreasCortical Areas

Parabrachial N.Parabrachial N.

Nucelus Caudalis PontisNucelus Caudalis Pontis

PVNPVN

StriatumStriatum

Periaqueductal areaPeriaqueductal area

Medial prefrontal cortexMedial prefrontal cortex

Hippocampus

• 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.

• 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.

3 Phases = 3 brain regions3 Phases = 3 brain regions

Acute panicAcute panic Anticipatory anxiety

Anticipatory anxiety

Phobic avoidance

Phobic avoidance

The neurobiological underpeining of PD might be located in distinct neuroanatomical regions and circuits

The neurobiological underpeining of PD might be located in distinct neuroanatomical regions and circuits

Brain stemBrain stem

Limbic system

Amygdala

Hypothalamus

Hippocampus

Limbic system

Amygdala

Hypothalamus

Hippocampus

Medial PFCMedial PFC

Cognitive avoidance

Cognitive avoidance

Mediation of panic, unconditional fearMediation of panic, unconditional fear

Medulla

Respiratory C.Co2PH

chemosensitivity

Medulla

Respiratory C.Co2PH

chemosensitivity

Conditional fear

Conditional fear

PonsLC

Over stim.Less inhib

NE

PonsLC

Over stim.Less inhib

NE

Mid brainRaphe N

5HT

Mid brainRaphe N

5HT

1. Neuro-anatomical Background1. Neuro-anatomical Background

Limbic SystemLimbic System

ACC-FCACC-FC

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

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 %

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

Treatments

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.

• 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.

Treatment with SSRIs

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.

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.

DuloxitineAtomoxetine

ReboxetineDapoxetine

SNRIselective norepinephrine reuptake inhibitor

Selective norepinephrine uptake inhibitor

Not FDA approved yet

30,60, = Joypox tab

ultrshort acting SSRI for treatment of premature ejaculation.

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.

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.

• 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.

- 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.

• 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.

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.

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.

ConclusionConclusion

• 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

Future therapeutic Approaches

ApproachExampleMechanism

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 agonistFlesinoxonEptapirone

5HT1A activity

5. 5HT2a/cDeramciclane 5HT 2a/c

6. GABA receptors modulators

SuricloneAct near GABA and have properties similar to BZ

7. Glutaminergic agents?Act via glutamate in dorsal raphe nuclei (for treatment resistant cases)