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Transcript of PATHOPHYSIOLOGY AND CLINICAL BIOCHEMISTRY (PAT 331H / PHM 330Y) FACULTY OF PHARMACY ANXIETY February...
PATHOPHYSIOLOGY AND CLINICAL PATHOPHYSIOLOGY AND CLINICAL BIOCHEMISTRY BIOCHEMISTRY
(PAT 331H / PHM 330Y)(PAT 331H / PHM 330Y)FACULTY OF PHARMACYFACULTY OF PHARMACY
ANXIETY ANXIETY February 4, 2008February 4, 2008
Dr. Peggy Richter, Dr. Peggy Richter, Anxiety Disorders Clinic, CAMH Anxiety Disorders Clinic, CAMH Associate Professor, University of Associate Professor, University of
Toronto Toronto
ANXIETYANXIETY
ObjectivesObjectives Review nature of anxietyReview nature of anxiety Description/clinical features of Description/clinical features of
major anxiety disordersmajor anxiety disorders Overview of etiology of anxiety Overview of etiology of anxiety
disordersdisorders
ANXIETY Term used to describe both Term used to describe both
symptoms and disorderssymptoms and disorders Occurs normally as signal of Occurs normally as signal of
impending danger or threatimpending danger or threat Very common, occurs in many Very common, occurs in many
disorders in addition to the anxiety disorders in addition to the anxiety disordersdisorders
Differentiated from Differentiated from fearfear on basis of on basis of whether there is a clear source of whether there is a clear source of danger danger i.e. “fight or flight” response i.e. “fight or flight” response
ANXIETY
Adaptive value : Adaptive value : helps to plan and prepare for threathelps to plan and prepare for threat moderate levels enhance learning and moderate levels enhance learning and
performance performance Maladaptive when chronic / severeMaladaptive when chronic / severe
ANXIETYANXIETY
Symptoms include : Symptoms include : physiologicalphysiological symptoms of activated symptoms of activated
sympathetic nervous system sympathetic nervous system (increased heart rate, increased (increased heart rate, increased respiration, sweating etc.)respiration, sweating etc.)
cognitivecognitive component (awareness of component (awareness of being frightened)being frightened)
behavioural behavioural components (urge to components (urge to escape) escape)
Anxiety Disorders (DSM-Anxiety Disorders (DSM-IV)IV)
Panic disorder with or without Panic disorder with or without agoraphobiaagoraphobia
Agoraphobia without panic disorderAgoraphobia without panic disorder Specific phobiasSpecific phobias Social phobiaSocial phobia Obsessive compulsive disorderObsessive compulsive disorder Posttraumatic stress disorderPosttraumatic stress disorder Acute stress disorderAcute stress disorder Generalized anxiety disorderGeneralized anxiety disorder Anxiety disorder due to a general medical Anxiety disorder due to a general medical
conditioncondition Substance-induced anxiety disorderSubstance-induced anxiety disorder Anxiety disorder not otherwise specifiedAnxiety disorder not otherwise specified
Anxiety Disorders: Anxiety Disorders: PrevalencePrevalence
Depression
Depression
Social Social
anxiety disorder
anxiety disorder
Posttraumatic
Posttraumatic
stress disorder
stress disorder
Generalized
Generalized
anxiety disorder
anxiety disorder
Panic disorder
Panic disorder
Obsessive-
Obsessive-
compulsive disorder
compulsive disorder
17%17%
13%13%
7.8%7.8%
5%5%
3.5%3.5%
2.5%2.5%
Kessler RC, et al. Arch Gen Psychiatry 1994;51:8-19Stein MB, et al. JAMA 1998;280:708-713
Kessler RC, et al. Arch Gen Psychiatry 1995;52:1048-1060
Lifetime Prevalence of Anxiety Lifetime Prevalence of Anxiety Disorders: 25%Disorders: 25%
Spectrum of Depression Spectrum of Depression and Anxiety Disordersand Anxiety Disorders
Generalized anxiety disorderGeneralized anxiety disorder
DepressionDepression
Social Social anxiety anxiety disorderdisorder
Panic disorderPanic disorder
Obsessive-compulsive disorderObsessive-compulsive disorder
Posttraumatic Posttraumatic stress disorderstress disorder
Panic AttacksPanic Attacks
Discrete episode of intense Discrete episode of intense anxiety, with abrupt onset of anxiety, with abrupt onset of symptoms such as palpitations, symptoms such as palpitations, sweating, trembling, shortness of sweating, trembling, shortness of breath, chest pain, nausea, breath, chest pain, nausea, dizziness or faintness, fear of dizziness or faintness, fear of losing control or going crazy, fear losing control or going crazy, fear of dyingof dying
Panic DisorderPanic Disorder Unexpected attacks followed by at least one Unexpected attacks followed by at least one
month of persistent concern about having month of persistent concern about having another attack, worry about the another attack, worry about the consequences of attacks, or change in consequences of attacks, or change in behaviourbehaviour
May or may not be accompanied by May or may not be accompanied by agoraphobia:agoraphobia: Fear about being in places or situations from Fear about being in places or situations from
which escape might be difficult or embarrassing, which escape might be difficult or embarrassing, or in which help may be unavailableor in which help may be unavailable
e.g., Discomfort / avoidance of being outside e.g., Discomfort / avoidance of being outside home alone, traveling, standing in a crowd or home alone, traveling, standing in a crowd or line, riding on buses or subwaysline, riding on buses or subways
Panic DisorderPanic Disorder
Life-time prevalence Life-time prevalence panic disorder is 2.5% panic disorder is 2.5%
agoraphobia 5%agoraphobia 5% 3F: 1M3F: 1M treatment: treatment:
cognitive behavioural therapy (CBT)cognitive behavioural therapy (CBT)
pharmacotherapy with pharmacotherapy with antidepressants antidepressants (SSRIs, SNRI)/ anxiolyticsanxiolytics
Specific PhobiasSpecific Phobias characterized by fear / avoidance of characterized by fear / avoidance of
specific situations or objectsspecific situations or objects four major types:four major types:
animalanimalnatural environment natural environment (e.g., heights, storms, (e.g., heights, storms,
water)water)blood, injection, injury typeblood, injection, injury typesituational type situational type (e.g., planes, elevators, (e.g., planes, elevators,
enclosed spaces)enclosed spaces) single most common mental disorders: single most common mental disorders:
life-time prevalence 14%life-time prevalence 14% treatment: cognitive behavioural treatment: cognitive behavioural
therapytherapy
Social PhobiaSocial Phobia(Social Anxiety Disorder)(Social Anxiety Disorder)
characterized by anxiety about public characterized by anxiety about public scrutiny, and excessive fear of acting scrutiny, and excessive fear of acting in a humiliating or embarrassing in a humiliating or embarrassing mannermanner
two types: two types: specific social phobiaspecific social phobia: fear of one or more : fear of one or more
discrete social situations, especially discrete social situations, especially performance anxietyperformance anxiety
generalized social phobiageneralized social phobia:: difficulty with difficulty with most social situationsmost social situations
Social PhobiaSocial Phobia (Social Anxiety Disorder)(Social Anxiety Disorder)
frequently comorbid with other anxiety frequently comorbid with other anxiety disorders, depression, alcohol abusedisorders, depression, alcohol abuse
life-time prevalence 13%life-time prevalence 13% F=MF=M Treatment: CBT, pharmacotherapy with Treatment: CBT, pharmacotherapy with
antidepressants antidepressants (SSRIs, SNRI)(SSRIs, SNRI), anxiolytics, anxiolytics Beta-blockers and anxiolytics frequently Beta-blockers and anxiolytics frequently
used p.r.n. in performance anxiety used p.r.n. in performance anxiety
Obsessive-Compulsive Obsessive-Compulsive DisorderDisorder
Characterized by: Characterized by:
ObsessionsObsessions:: intrusive, unwanted, intrusive, unwanted, disturbing thought, image or impulse (e.g., disturbing thought, image or impulse (e.g., contamination, doubting, somatic, contamination, doubting, somatic, aggressive, sexual)aggressive, sexual)
CompulsionsCompulsions: need to perform acts : need to perform acts (thoughts or behaviours) in response to (thoughts or behaviours) in response to obsessions (e.g., checking, washing, obsessions (e.g., checking, washing, counting, hoarding)counting, hoarding)
Obsessive-Compulsive Obsessive-Compulsive DisorderDisorder
May be extremely disabling, most May be extremely disabling, most frequently chronicfrequently chronic
Frequently comorbid with other Frequently comorbid with other anxiety disorders, depressionanxiety disorders, depression
Life-time prevalence 2.5%Life-time prevalence 2.5% Treatment: CBT and/or SSRI’s, Treatment: CBT and/or SSRI’s,
frequently necessary long-termfrequently necessary long-term
Posttraumatic Stress Posttraumatic Stress Disorder & Acute Stress Disorder & Acute Stress
DisorderDisorder Characterized by development of anxiety Characterized by development of anxiety
symptoms after exposure to a traumatic symptoms after exposure to a traumatic eventevent actual or threatened death or injury to actual or threatened death or injury to
themselves or othersthemselves or others associated with feelings of fear, helplessness, associated with feelings of fear, helplessness,
or horroror horror Most common traumas are combat (male), Most common traumas are combat (male),
assault/rape (female) assault/rape (female) (includes war, torture, (includes war, torture, natural catastrophes, serious accidents)natural catastrophes, serious accidents)
Posttraumatic Stress Posttraumatic Stress Disorder & Acute Stress Disorder & Acute Stress
DisorderDisorderAssociated with:Associated with: Persistent reexperience of the eventPersistent reexperience of the event
e.g. intrusive recollections or dreams, or “flashbacks”e.g. intrusive recollections or dreams, or “flashbacks” Avoidance of stimuli associated with Avoidance of stimuli associated with
the trauma / emotional numbingthe trauma / emotional numbing e.g. avoidance of thoughts, feelings, activities, places e.g. avoidance of thoughts, feelings, activities, places
or people associated with the event, emotional or people associated with the event, emotional detachment, reduced future expectationsdetachment, reduced future expectations
Symptoms of arousalSymptoms of arousal e.g. insomnia, irritability, impaired concentration, e.g. insomnia, irritability, impaired concentration,
hypervigilancehypervigilance
Posttraumatic Stress Posttraumatic Stress Disorder & Acute Stress Disorder & Acute Stress
DisorderDisorder symptoms last symptoms last 1 month in Acute Stress 1 month in Acute Stress
Disorder; Disorder; 1 month in PTSD, may have 1 month in PTSD, may have delayed onsetdelayed onset
current concept developed following Vietnam current concept developed following Vietnam war, but described historically as “soldier’s war, but described historically as “soldier’s heart”, shell shock, ? Persian Gulf Syndromeheart”, shell shock, ? Persian Gulf Syndrome
life-time prevalence 7% generally, 30% of life-time prevalence 7% generally, 30% of Vietnam veteransVietnam veterans
treatment: pharmacotherapy with treatment: pharmacotherapy with antidepressants, behaviour /cognitive therapy, antidepressants, behaviour /cognitive therapy, short-term dynamic therapy, EMDR (Eye short-term dynamic therapy, EMDR (Eye Movement Desensitization and Reprocessing)Movement Desensitization and Reprocessing)
Generalized Anxiety Generalized Anxiety Disorder Disorder (GAD)(GAD)
characterized by chronic excessive characterized by chronic excessive anxiety/worryanxiety/worry
associated with restlessness, fatigue, impaired associated with restlessness, fatigue, impaired concentration, irritability, muscle tension, concentration, irritability, muscle tension, insomniainsomnia
usually comorbid with other anxiety disorders usually comorbid with other anxiety disorders or depressionor depression
slow insidious onsetslow insidious onset 1-year prevalence of 5%1-year prevalence of 5% 2F:1M2F:1M treatment: pharmacotherapy (SSRIs, SNRI, treatment: pharmacotherapy (SSRIs, SNRI,
buspirone, benzodiazepines), CBT, relaxation buspirone, benzodiazepines), CBT, relaxation techniques, supportive psychotherapy techniques, supportive psychotherapy
Anxiety Disorder Due to a Anxiety Disorder Due to a General Medical ConditionGeneral Medical Condition
panic is most common presentation, but panic is most common presentation, but can be similar to any anxiety syndrome can be similar to any anxiety syndrome
particularly common in acute care particularly common in acute care settings, e.g. ICUsettings, e.g. ICU
may be due to wide range of medical may be due to wide range of medical conditions, e.g., thyroid and other conditions, e.g., thyroid and other endocrine abnormalities, cardiac endocrine abnormalities, cardiac conditions, hypoglycemia, brain lesionsconditions, hypoglycemia, brain lesions
treatment is best directed at underlying treatment is best directed at underlying conditioncondition
Substance-Induced Anxiety Substance-Induced Anxiety DisorderDisorder
may be due to recreational may be due to recreational drugs such as cocaine, drugs such as cocaine, caffeine, amphetamines, caffeine, amphetamines, serotonergic drugsserotonergic drugs
associated with withdrawal associated with withdrawal from benzodiazepines, alcoholfrom benzodiazepines, alcohol
treat underlying problemtreat underlying problem
ANXIETY - EtiologyANXIETY - EtiologyGenetic factorsGenetic factors Solid evidence for involvement in PD, GAD, Solid evidence for involvement in PD, GAD,
OCDOCD Primarily based on family studies, results from Primarily based on family studies, results from
direct genetic investigation just beginning to direct genetic investigation just beginning to emergeemerge
TemperamentTemperament Behavioural inhibition evident in infancyBehavioural inhibition evident in infancy predisposed to remain anxiouspredisposed to remain anxious
Life experiencesLife experiences poor parental bonding implicatedpoor parental bonding implicated traumatic conditioning experiences common traumatic conditioning experiences common
in social phobia, specific phobiasin social phobia, specific phobias
ANXIETY - EtiologyANXIETY - Etiology
EvolutionaryEvolutionary primates and humans share biological primates and humans share biological
preparedness to rapidly associate certain preparedness to rapidly associate certain stimuli with danger (e.g., snakes)stimuli with danger (e.g., snakes)
social fears may relate to dominance social fears may relate to dominance hierarchies hierarchies
Behavioural / learning theoriesBehavioural / learning theories have led to development of effective treatmentshave led to development of effective treatments conditioning important in specific and social conditioning important in specific and social
phobias, PDAphobias, PDA may be direct or vicarious may be direct or vicarious
ANXIETY - EtiologyANXIETY - Etiology
Cognitive theoryCognitive theory faulty or counterproductive thinking faulty or counterproductive thinking
patterns may underlie or perpetuate patterns may underlie or perpetuate disordersdisorders
tendency to overestimate danger/ tendency to overestimate danger/ probability of harmprobability of harm
information processing biasesinformation processing biases may catastrophically interpret bodily may catastrophically interpret bodily
sensations sensations perception of control, predictability perception of control, predictability
Etiology of AnxietyEtiology of Anxiety
predispositionpredisposition
temperamenttemperamentexperiencesexperiences
beliefsbeliefs
illness/biologyillness/biology
complicationscomplications
ANXIETY - ANXIETY - NeurobiologyNeurobiologyNeuroanatomical modelsNeuroanatomical models PanicPanic: :
panicpanic locus ceruleus locus ceruleus periaqueductal grey periaqueductal grey (uncondititioned fear)(uncondititioned fear) & & amygdala (amygdala (conditioned fear)conditioned fear)
anticipatory anxietyanticipatory anxiety limbic lobelimbic lobeavoidanceavoidance prefrontal cortexprefrontal cortex
OCDOCD::caudatecaudate inhibitory/gating functioninhibitory/gating functionprefrontal cortexprefrontal cortex lack of inhibition of lack of inhibition of unwanted unwanted thoughts/impulses provokes thoughts/impulses provokes ritualsrituals
Neurobiology of Neurobiology of PanicPanic
Norepinephrine:Norepinephrine: stimulation of LC stimulation of LC (locus ceruleus)(locus ceruleus) fear/ fear/
ablation of LC eliminates fear responseablation of LC eliminates fear response LC projects to multiple structures LC projects to multiple structures
involved in anxiety/fear involved in anxiety/fear (ie amygdala, (ie amygdala, periaqueductal grey, entorrhinal cortex, periaqueductal grey, entorrhinal cortex, hypothalamus)hypothalamus)
excitatory LC input mediated by excitatory LC input mediated by glutamate, Cortisol Releasing Factor, glutamate, Cortisol Releasing Factor, substance Psubstance P
inhibitory via GABA receptorsinhibitory via GABA receptors
Neurobiology of Neurobiology of PanicPanic
SerotoninSerotonin supported by efficacy of SSRIssupported by efficacy of SSRIs major nuclei: major nuclei:
MRNMRN limbic/ prefrontal cortex structures limbic/ prefrontal cortex structures Mediates fear/ anticipatory anxietyMediates fear/ anticipatory anxiety
DRNDRN prefrontal cortex, basal ganglia, prefrontal cortex, basal ganglia, thalamus, thalamus, LC, substantia nigra, LC, substantia nigra, periaqueductal grey periaqueductal grey Modulates cognitive/ behavioural componentsModulates cognitive/ behavioural components
strong feedback relationship with LCstrong feedback relationship with LC
MRN: medial raphe nucleus DRN: dorsal raphe nucleus
Neurobiology of Neurobiology of PanicPanic
GABA (GABA (-aminobutyric acid)-aminobutyric acid) anxiolytic/panicolytic effects of anxiolytic/panicolytic effects of
benzodiazepines benzodiazepines (BZDP)(BZDP) GABAGABAAA receptors have binding sites for receptors have binding sites for
BZDP, barbiturates, and BZDP, barbiturates, and chloride ion channelchloride ion channel
high density of GABA-high density of GABA-BZ receptors in BZ receptors in hippocampus, hippocampus, amygdala, occipital/amygdala, occipital/frontal cortexfrontal cortex
Neurobiology of PanicNeurobiology of Panic Amygdala key in conditioned fear Amygdala key in conditioned fear
aquisition/extinctionaquisition/extinction Hippocampus involved in explicit memory contextHippocampus involved in explicit memory context amygdala activation decreased prefrontal amygdala activation decreased prefrontal
activity/ inhibition of amygdalaactivity/ inhibition of amygdala ++GABA/BZDP receptors++GABA/BZDP receptors
LC: ++NE neuronsLC: ++NE neurons Implicated in animal studiesImplicated in animal studies Strong feedback relationship with raphe nuclei/5HTStrong feedback relationship with raphe nuclei/5HT
Increasing evidence re significance of NMDA Increasing evidence re significance of NMDA receptor in conditioningreceptor in conditioning
The Amygdala The Amygdala
Paraventricular Nucleus-Hypothalam
usActivates HPA
Axis
Lateral Hypothala
musActivates
Sympathetic NS
Adapted from Ninan & Dunlop, J Clin Psychiatry, 2005
Orbitofrontal-Subcortical Orbitofrontal-Subcortical Circuits in OCDCircuits in OCD
Orbitofrontal cortex
Medial dorsal
thalamus
(+)
Striatum(ventromedial caudate)
(+)
(-)
GPi &SNr
Indirectbasal
gangliacontrolsystem
(-) (-) (Direct Pathway)
(-)
(Indirect Pathway)(+)
Excess tone in the direct pathway activity in OFC, caudate, and medial dorsal thalamus
Adapted from Saxena & Rauch, 2000
ANXIETY – ANXIETY – NeurotransmittersNeurotransmitters
SUMMARYSUMMARY Norepinephrine (NE) hypothesis of panicNorepinephrine (NE) hypothesis of panic Gamma-aminobutyric acid (GABA) in panic, Gamma-aminobutyric acid (GABA) in panic,
GADGAD Serotonin system implicated in OCD, other Serotonin system implicated in OCD, other
anxiety disorders anxiety disorders NE in social phobiaNE in social phobia PTSD: adrenergic, sleep dysregulation, HPA PTSD: adrenergic, sleep dysregulation, HPA
axisaxis Dopamine system in OCD?Dopamine system in OCD?
ANXIETY – ANXIETY – Laboratory Laboratory InvestigationsInvestigations
Particularly important in panic disorderParticularly important in panic disorder Routine tests may include:Routine tests may include:
CBCCBC thyroid functionsthyroid functionselectrolyteselectrolytes liver functionsliver functionsglucoseglucose urinalysisurinalysiscalciumcalcium EKGEKGureaurea creatininecreatinine
Further testing depends on findings:Further testing depends on findings: chest pain: stress test, chest X-ray, cardiac chest pain: stress test, chest X-ray, cardiac
enzymesenzymes neurological abnormalities: EEG, CAT or MRI neurological abnormalities: EEG, CAT or MRI
Anxiety (PAT 331H / PHM 330Y)
Managing the Anxiety Managing the Anxiety DisordersDisorders
Cognitive Behavior Therapy…Cognitive Behavior Therapy…
is the is the first-linefirst-line treatment treatment for for
allall anxiety disorders anxiety disorders
Meta-analysis of GAD Meta-analysis of GAD TreatmentTreatment
Treatment N Mean ES % Drop-outs
CBT 8 0.91 9.8AnxietyManagementTraining
3 0.91 2.5
Relaxation 3 0.64 21.5BZDPs 23 0.70 13.1Buspirone 9 0.39 16.8Antidepressants 3 0.57 33.5
Gould et al, Behav Therapy; 28:1997
CBT is Protective in CBT is Protective in PanicPanic
0
10
20
30
40
50
60
70
CBT PBO CBT+PBO
AcuteMaintenanceFollow-Up
• Barlow et al (2000): N=312 in RCT for panic
• CBT confers lasting benefit (p=.001)
Imip CBT+Imip
CG
I R
esp
on
der
Rate
(%
)
Barlow et al, JAMA 2000; 283:2529-2536
Comparative Efficacy of Comparative Efficacy of SRIs SRIs
in OCDin OCD60
3843
39
0
10
20
30
40
50
60
Clomipramine Fluvoxamine
CGI: "much / verymuch improved"P
erce
nt
Greist et al, 1995
Compared results of 4 large controlled multicentre trials (N>320 for each)
Fluoxetine Sertraline
Choice of MedicationChoice of Medication
SSRIs are generally first-line SSRIs are generally first-line (PDA, (PDA,
SAD, OCD), or SAD, OCD), or SNRI for GAD, SADSNRI for GAD, SAD strong efficacy datastrong efficacy data well-tolerated, safewell-tolerated, safe effective for comorbid depression, anxietyeffective for comorbid depression, anxiety typical starting dosage:typical starting dosage:
paroxetine 10 mg. o.d.paroxetine 10 mg. o.d. citalopram 10 mg. o.d.citalopram 10 mg. o.d. fluoxetine 10 mg. o.d.fluoxetine 10 mg. o.d. venlafaxine 37.5 mg. o.d.venlafaxine 37.5 mg. o.d.
Choice of MedicationChoice of MedicationBenzodiazepines:Benzodiazepines: often added often added
initiallyinitially good efficacy for high-potency agents good efficacy for high-potency agents
(lorazepam, clonazepam, diazepam)(lorazepam, clonazepam, diazepam) rapid onset of actionrapid onset of actionBUTBUT risk of dependancerisk of dependance withdrawal potential/rebound problemswithdrawal potential/rebound problems side effects side effects (sedation, coordination, (sedation, coordination,
memory)memory)SO…SO… BZDPs are never 1BZDPs are never 1stst or 2 or 2ndnd line agents line agents
Do not PRN!Do not PRN!Continuous dosing is more effective and reduces risk of abuse
ANXIETY - SummaryANXIETY - Summary
Anxiety disorders are commonAnxiety disorders are common Generally treatable with Generally treatable with
pharmacotherapypharmacotherapy
(typically SSRIs, benzodiazepines)(typically SSRIs, benzodiazepines) Cognitive-behavioural therapy is an Cognitive-behavioural therapy is an
important component of any treatment important component of any treatment planplan
Etiology is complex and multifactorial, Etiology is complex and multifactorial, and varies with the disorderand varies with the disorder