1

Anxiety in practice

Diagnosis and management

2

What is ‘anxiety’?

A normal feeling: transient, disagreeable emotional state, may be adaptive, signals anticipated threat, initiates action.

A symptom: seen in wide variety of disorders,

A disorder: in which anxiety symptoms form a dominant element.

3

How do the patients describe their feelings of anxiety?As an intense negative emotion, patients will use

words as –tense, panicky, terrified, jittery, nervous, wound-up, apprehensive, worried etc.

Different symptoms of anxiety:

Somatic – subjective like twitching, tremors, hot and cold flashes, sweating, palpitations, chest tightness, difficulty swallowing, nausea, diarrhoea, dry mouth, decreased libido etc.

Cognitive- hyper vigilance, poor concentration, subjective confusion, fears of loosing control, or going crazy, catastrophic thinking etc.

4

Behavioural symptoms-fearful expressions, withdrawal, irritability, immobility, hyperventilation etc.

Perceptual disturbance- depersonalization, derealisation, hyperesthesia especially hyperacusis.

5

A few terms:

Trait anxiety: lifelong pattern of anxiety as a feature of temperament.

Free floating anxiety: persistently anxious mood in which cause is unknown, and in which large number of diverse thoughts and events trigger and compound the anxiety.

Situational anxiety: only in relation to specific occasions or external stimuli as in phobias.

Existential:being aware of its possible non-being

Ontic(fate and death),moral(guilt and condemnation) and spiritual(emptiness and meaninglessness)

6

Physical conditions presenting as anxiety stateMedical diseases: brain tumours in temporal lobe

or 3rd ventricle region, stroke, migraine, encephalitis, MS, epilepsy, Alzheimer's, Parkinson's, Huntington's and Wilsons’ disease

Hypoxia, hypoglycemia, hyperthyroidism, cushing’s syndrome, mitral valve prolapse.

Medications/drugs- cocaine, sympathomimetics eg. Amphetamines, caffeine, lidocaine, alcohol & sedative withdrawal.

7

Primary vs Secondary anxiety

Secondary anxiety as a response to an underlying condition- a psychotic disorder, depressions, substance related disorders.

Anxiety and depression: coexistence is substantial,

Anxiety symptoms such as anxious mood and irritability seen in majority of depressed patients,

2/3 rd patients with Panic disorders will become depressed in their life time.

8

Difference bt clinical anxiety and depression.

Clinical anxiety depression

Hypervigilance

Severe tension & panic

Perceived danger,

Phobic avoidance,

Doubt & uncertainty

Insecurity

Performance anxiety

Psychomotor retardation*Severe sadness,Perceived lossLoss of interest- anhedoniaHopelessness- suicidal*Self depreciation* Loss of libidoEarly morning awakening*Weight loss.* strongest clinical markers of depression.

9

Neurobiological mechanism of anxiety Amygdala: ‘fear reaction’ in animal models,

nerve projections from amygdala activates central autonomic nervous system of brain– behavioural and physiological manifestation of acute anxiety.

Hypothalamus-pituitary- adrenal axis: following early separation distress.

‘GAD: abnormal GABA in central BDZ receptors.

10

‘Panicogens’: genetically predisposed and traumatised by early separation distress people respond with acute panic attack with sod. Lactate infusion, co2, doxapram.

Hippocampus: neuronal degeneration Glucocoticoid effects- explains memory problems in PTSD.

11

Different anxiety disorders:

PANIC DISORDER AND AGORAPHOBIA: recurrent panic attacks.

The panic attack : an episode of abrupt intense fear that is accompanied by autonomic or cognitive symptoms: palpitations, sweating, trembling or shaking, sensations of shortness of breath or smothering, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling dizzy, unsteady, lightheaded, or faint, derealization (feelings of unreality) or depersonalization (being detached from oneself), fear of losing control or going crazy,fear of dying, paresthesias (numbness or tingling sensations), chills or hot flushes

12

Phobic Anxiety Disorders

Agoraphobia

A. There is marked and consistently manifest fear in, or avoidance of, at least two of the following situations:

(1) crowds;

(2) public places;

(3) traveling alone;

(4) traveling away from home.

13

Phobic Anxiety DisordersAgoraphobiaThere is marked and consistently manifest fear in, or avoidance of, at least two of the following situations:(1) crowds;(2) public places;3) traveling alone;(4) traveling away from home.B. At least two symptoms of anxiety in the feared situation Autonomic arousal symptoms(1) palpitations or pounding heart, or accelerated heart rate;(2) sweating; (3) trembling or shaking;(4) dry mouth (not due to medication or dehydration);

Symptoms involving chest and abdomen(5) difficulty in breathing;(6) feeling of choking;(7) chest pain or discomfort;(8) nausea or abdominal distress (e.g., churning in stomach);

Symptoms involving mental state(9) feeling dizzy, unsteady, faint, or light-headed;(10) feelings that objects are unreal (derealization), or that the self is distant or "not really here" (depersonalization);(11) fear of losing control, "going crazy," or passing out;(12) fear of dying;General symptoms(13) hot flushes or cold chills;(14) numbness or tingling sensations.

14

SPECIFIC AND SOCIAL PHOBIAS:"phobia" refers to an excessive fear of a specific object, circumstance, or situation.

Both require the development of intense anxiety, to the point of even situationally bound panic, upon exposure to the feared object or situation.

Also require that fear either interferes with functioning or causes marked distress.

Finally, both conditions require that an individual recognizes the fear as excessive or irrational and that the feared object or situation is either avoided or endured with great difficulty.

15

Obsessive-Compulsive Disorder:

Obsessions as defined by recurrent and persistent thoughts, impulses, or images that are experienced, at some time during the disturbance, as intrusive and inappropriate and that cause marked anxiety or distress,

Compulsions as defined by repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly.

16

PTSD

17

SUBSTANCE-INDUCED ANXIETY AND ANXIETY DUE TO A GENERAL MEDICAL CONDITION

prominent anxiety that arises as the direct result of some underlying physiological perturbation.

clinically significant symptoms of panic, worry, phobia, or obsessions emerge in the context of prescribed or illicit substance use.

For example, panic attacks have been tied to various medical conditions, including endocrinologic, cardiac, and respiratory illnesses.

18

Anxiety Disorder Not Otherwise Specified

This category includes disorders with prominent anxiety or phobic avoidance that do not meet criteria for any specific anxiety, disorder, adjustment disorder with anxiety, or adjustment disorder with mixed anxiety and depressed mood.

Examples include

1. Mixed anxiety-depressive disorder:

2. Clinically significant social phobic symptoms that are related to the social impact of having a general medical condition or mental disorder (e.g., Parkinson's disease, dermatological conditions, stuttering, anorexia nervosa, body dysmorphic disorder).

3. Situations in which the clinician has concluded that an anxiety disorder is present but is unable to determine whether it is primary, due to a general medical condition, or substance induced.

19

GENERALIZED ANXIETY DISORDER: a pattern of frequent, persistent worry and anxiety that is out of proportion to the impact of the event or circumstance that is the focus of the worry .

For example, while college students often worry about examinations, a student who persistently worries about failure despite consistently outstanding grades displays the pattern of worry typical of generalized anxiety disorder.

Patients with generalized anxiety disorder may not acknowledge the excessive nature of their worry, but they must be bothered by their degree of worry.

This pattern must occur "more days than not" for at least 6 months.

20

Case studies: 1

Ms. S. was a 25-year-old student who was referred for a psychiatric evaluation from the medical emergency room at a larger university-based medical center.

Ms. S. had been evaluated three times over the preceding 3 weeks in this emergency room.

Her first visit was prompted by a paroxysm of extreme dyspnea and terror that occurred while she was working on a term paper. The dyspnea was accompanied by palpitations, choking sensations, sweating, shakiness, and a strong urge to flee. Ms. S. thought that she was having a heart attack, and she immediately went to the emergency room.

She received a full medical evaluation, including an electrocardiogram (ECG) and routine blood work, which revealed no sign of cardiovascular, pulmonary, or other illness.

Although Ms. S. was given the number of a local psychiatrist, she did not make a follow-up appointment, since she did not think that her episode would recur.

She developed two other similar episodes, one while she was on her way to visit a friend and a second that woke her up from sleep. She immediately went to the emergency room after experiencing both paroxysms, receiving full medical workups that showed no sign of illness.-

21

Diagnosis:

Panic disorder:

22

Case study: 2

Mr. A. was a successful businessman who presented for treatment following a change in his business schedule. While he had formerly worked largely from an office near his home, a promotion led to a schedule of frequent out-of-town meetings, requiring weekly flights.

Mr. A. reported being "deathly afraid" of flying. Even the thought of getting on an airplane led to thoughts of impending doom as he envisioned his airplane crashing to the ground.

These thoughts were associated with intense fear, palpitations, sweating, clammy feelings, and stomach upset. While the thought of flying was terrifying enough, Mr. A. became nearly incapacitated when he went to the airport. Immediately before boarding, Mr. A. often had to turn back from the plane and run to the bathroom to vomit.

23

Diagnosis:

Specific phobia.

24

Case study:3Ms. B. presented for psychiatric admission after being transferred from a medical

floor where she had been treated for malnutrition.

Ms. B. had been found unconscious in her apartment by a neighbor. When brought to the emergency room by ambulance, she was found to be hypotensive and hypokalemic.

At psychiatric admission, Ms. B. described a long history of excessive cleanliness, particularly related to food items.

She reported that it was difficult for her to eat any food unless it had been washed by her three to four times, since she often thought that a food item was dirty. She reported that washing her food decreased the anxiety she felt about the dirtiness of food.

While Ms. B. reported that she occasionally tried to eat food that she did not wash (e.g., in a restaurant), she became so worried about contracting an illness from eating such food that she could no longer dine in restaurants. Ms. B. reported that her obsessions about the cleanliness of food had become so extreme over the past 3 months that she could eat very few foods, even if she washed them excessively.

She recognized the irrational nature of these obsessive concerns, but either could not bring herself to eat or became extremely nervous and nauseous after eating.

25

Diagnosis

OCD:

26

Case study:4

Mr. F. sought treatment for symptoms that he developed in the wake of an automobile accident that had occurred about 6 weeks prior to his psychiatric evaluation.

While driving to work on a mid-January morning, Mr. F. lost control of his car on an icy road. His car swerved out of control into oncoming traffic in another lane, collided with another car, and then hit a nearby pedestrian. Mr. F. was trapped in his car for 3 hours while rescue workers cut the door of his car.

Upon referral, Mr. F. reported frequent intrusive thoughts about the accident, including nightmares of the event and recurrent intrusive visions of his car slamming into the pedestrian.

He reported that he had altered his driving route to work to avoid the scene of the accident, and he found himself switching the television channel whenever a commercial for snow tires appeared. Mr. F. described frequent difficulty falling asleep, poor concentration, and an increased focus on his environment, particularly when he was driving.

27

Diagnosis:

PTSD

28

Case study: 5Ms. X. was a successful, married, 30-year-old attorney who

presented for a psychiatric evaluation to treat growing symptoms of worry and anxiety.

For the preceding 8 months, Ms. X. had noted increased worry about her job performance. For example, while she had always been a superb litigator, she increasingly found herself worrying about her ability to win each new case she was presented. Similarly, while she had always been in outstanding physical condition, she increasingly worried that her health had begun to deteriorate.

Ms. X. noted frequent somatic symptoms that accompanied her worries. For example, she often felt restless while she worked and while she commuted to her office, thinking about the upcoming challenges of the day.

She reported feeling increasingly fatigued, irritable, and tense.

She noted that she had increasing difficulty falling asleep at night as she worried about her job performance and impending trials.-

29

Diagnosis:

GAD:

30

Generalized Anxiety Disorder

31

GAD: Content Overview• GAD Background

— Epidemiology— Burden of illness— Treatment— Diagnosis

• Pregabalin Pharmacokinetics

• Pregabalin in GAD— Overview of clinical program— Efficacy— Tolerability and safety

32

GAD Epidemiology

General Population, Primary Care Setting, and Comorbidities

33

GAD Symptoms: Prevalence Estimates in the General Population

Prevalence (n=9282)

Duration of anxiety symptoms (minimum) Point (current) 1-year Lifetime

1 month* 2.6% 5.5% 12.7%

3 months* 2.1% 3.9% 8.0%

6 months (DSM-IV GAD)

1.8% 2.9% 6.1%

12 months(DSM-IV GAD)

1.6% 2.2% 4.2%

*Anxiety symptoms fulfilling DSM-IV criteria for GAD, except for durationData from NCS-R (DSM-IV criteria), USA Kessler et al. Psychological Med. 2005;35:1073-1082.

34

GAD: Lifetime Prevalence in the General Population

0

1

2

3

4

5

6

7

8

9

10

Brazil (n=1464)

Canada (n=6261)

The Netherlands(n=7076)

USA (n=5388)

All 4 samples(n=20189)

% o

f p

op

ula

tio

n

All Men Women

Data from surveys in 4 countries (DSM-III-R criteria)Kessler et al. Psychol Med. 2002;32:1213-1225

35

Lifetime Prevalence of GAD in the General Population by Age and Gender

0

5

10

15

15–24 25–34 35–44 > 45

Age (years)

Lif

eti

me

pre

va

len

ce

(%

)

Women

All

Men

Data from NCS (DSM-III-R criteria), USAWittchen et al. Arch Gen Psychiatry 1994;51:355-364

36

Anxiety Disorders in Primary Care: Point Prevalence Estimates

3.7

1.52.6

2

8.5

3.1

7

11.8

0

5

10

15

20

GAD Panic disorder Social anxietydisorder

PTSD

Po

int

pre

va

len

ce

(%

)

Lowest estimate Highest estimate

Stein. J Clin Psychiatry. 2003;64(suppl 15):35-39

37

Prevalence of GAD Symptoms in the Primary Care Setting

0

5

10

15

20

25

30

35

40

% o

f p

ati

en

ts

All (n=17,739) Men (n=7,274) Women (n=10,465)

GAD symptoms 1-4 weeks

GAD symptoms >6 months

(DSM-IV GAD)

Anxiety symptoms fulfilling DSM-IV for GAD criteriaWittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

38

GAD Symptoms Present Across the Age Spectrum in Primary Care Setting

20.3 21.123.3 23.2 23.3

19.8 19.3 19.5

5.66.6

6.8 7 6.6

2.7 2.4 3.1

0

5

10

15

20

25

30

35

40

16-19 20-29 30-39 40-49 50-59 60-69 70-79 80+

Age (years)

% o

f p

ati

en

ts

GAD DSM-IV diagnosis

*Anxiety symptoms

*Anxiety symptoms fulfilling DSM-IV GAD criteria, except for duration Based on sample of n=17,739Wittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

39

High Incidence of Comorbid Conditions in GAD

0

10

20

30

40

50

60

GI Disorders

GUdisorders

CV disease

Chronicpain (all)

Neuropathicpain only

MajorDepressive

Disorder

Dysthymia

Condition

% o

f s

ub

jec

ts

GAD population (n=13,386) Controls (n=89,971)

GI=gastrointestinal; GU=genitourinary, CV=cardiovascularData from medical claims databases 1999-2002 Data on file, Pfizer Inc. Brandenburg et al. ADAA 2005

***

***

***

***

***

******

***P<0.01 vs. controls

40

Lifetime Prevalence of Comorbid Psychiatric Disorders in Patients with GAD

34

38

61

72

22

34

58

0 10 20 30 40 50 60 70 80 90 100

Substance abuse/dependence

Dysthymia

Major depression

Any mood disorder

Panic disorder

Social phobia

Any other anxietydisorder

% of population with GAD

Data from international surveys in 4 countries (DSM-III-R criteria)Subset of population with GADKessler et al. Psychol Med. 2002;32:1213-1225

41

GAD Often Precedes the Development of Other Psychiatric Disorders

52

25

21

29

16

22

25

0 10 20 30 40 50 60 70 80 90 100

Substance abuse/dependence

Dysthymia

Major depression

Any mood disorder

Panic disorder

Social phobia

Any other anxietydisorder

% of population with GAD

Data from international surveys in 4 countries (DSM-III R criteria)Kessler et al. Psychol Med. 2002;32:1213-1225

Subset of those with GAD + comorbid disorder: GAD occurred first

42

GAD: Comorbidity, Presentation and Course of Illness

43

GAD: A Common Comorbid Condition

— Major depression1-4

— Panic disorder1-3

— Social phobia1

— Specific phobia1

— Post-traumatic stress disorder2

— Chronic pain conditions4

— Chronic fatigue syndrome2

— Gastrointestinal disease5

— Irritable bowel syndrome2,5

— Hypertension2

— Heart disease2

• GAD is one of the most common conditions that occurs comorbidly with other disorders

— 91% of patients with GAD have ≥1 additional diagnosis1

• GAD occurs comorbidly with many medical and psychiatric conditions, including:

1. Sanderson. J Nerve Ment Dis. 1990;178:588-591 2. Stein. J Clin Psychiatry 2001;62(suppl 11):29-34; 3. Keller. J Clin Psychiatry 2002;63(suppl 8):11-16 4. Data on file Pfizer Inc; 5. Sareen et al. Depress Anxiety 2005;21:193-202

44

Physical Symptoms May Predominate in GAD• Aches, pains, soreness

• Insomnia (difficulty falling asleep)

• Symptoms of autonomic arousal— Tachycardia, palpitations, sweating, tremor

• Gastrointestinal symptoms— Nausea, diarrhea

• Other— Dizziness, light-headedness— Breathing difficulties— Numbness, tingling— Hot or cold flushes

Starcevic. Anxiety Disorder in Adults. Oxford University Press. 2005:102-140Gorman. Clin Cornerstone. 2001;3(3):37-43

45

Most Patients with GAD do NOT Present with Anxiety as the Primary Complaint

0

10

20

30

40

50

60

Anxiety Somaticillness/

complaints

Pain Sleepdisturbance

Depression

% o

f p

ati

en

ts w

ith

GA

D

Based on sample of n=17,739; 5.3% with GAD (DSM-IV)Wittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

Only 13% had anxiety as primary complaint

46

GAD: Often Not Recognized in Primary Care

Mental disorder not recognized

Specific GAD diagnosis

Mental disorder

recognized but GAD not diagnosed

34%38%

28%

Based on sample of n=17,739; 5.3% with GAD (DSM-IV)Wittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

47

GAD Course of Illness

• Chronic — Waxing and waning of symptoms1

— Low rates of remission over long term1,2

• Intermittent exacerbations — Exaggerated response to stress1,3

• Symptom overlap with medical and psychiatric disorders3

— Many are undiagnosed4

• Episodes may be more persistent with age5

• Poorer outcomes in patients with psychiatric comorbidities6

1. Starcevic. Anxiety Disorder in Adults. Oxford University Press. 2005:102-1402. Yonkers et al. Depress Anxiety. 2003;17:173-9; 3. Stein. J Clin Psychiatry 2003.64(suppl 15):35-39; 4. Wittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34; 5. Wittchen et al. Arch Gen Psychiatry 1994;51:355-364; 6. Bruce et al. Am J Psychiatry. 2005;162:1179-87

48

Low Probability of Remission in GAD

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 (n=167) 2 (n=133) 3 (n=111) 4 (n=91) 5 (n=73)

Years since index episode

Pro

bab

ilit

yProbability of full remission

Full remission: PSR <3 for 8 weeks following index episode HARP 5-year prospective studyYonkers et al. Br J Psychiatry. 2000;176:544-549

49

Low Probability of Remission in GAD in Men and Women

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5 6 7 8

Years since index episode

Pro

ba

bili

ty o

f re

mis

sio

n

Men (n=48)

Women (n=119)

P=0.24 test for gender difference

Full remission: PSR <3 for 8 weeks following index episodeHARP 8-year prospective studyYonkers et al. Depress Anxiety. 2003;17(3):173-179

50

GAD: Burden of Illness

51

GAD Patients in Primary Care: Difficulty with Usual Activities in Past 4 Weeks

A little difficulty26%

No difficulty16%

Much difficulty26%

Some difficulty30%

Incapacitated2%

Data from PCAP (n=142), USAMaki et al. 2003. APA Presentation

Over 50% of patients had at least some difficulty

52

Disability/Impairment* in GAD and/or Major Depressive Episodes

0

10

20

30

40

50

60

70

80

90

100

No GAD orMDE

(n=16,023)

Pure GAD(n=666)

ComorbidGAD/MDE

(n=278)

Pure MDE(n=772)

No GAD orMDE

(n=16,023)

Pure GAD(n=666)

ComorbidGAD/MDE

(n=278)

Pure MDE(n=772)

% w

ith

dis

ab

ility

/imp

air

me

nt

MDE: major depressive episodeBased on primary care sample of n=17,739Wittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

Due to somatic problems Due to psychiatric problems

*Missing ≥ 1 day of work in previous month

53

Work Impairment in GAD and Other Chronic Conditions

0

2

4

6

8

10

12

14

GAD MDD Hypertension Arthritis Asthma Diabetes

Me

an

da

ys

Days work impairment in past month

Data from Midlife Development in the US survey (MIDUS)Work impairment based on work-loss days and work-cutback daysKessler et al. 2001. In: Rossi AS, editor. Chicago: University of Chicago Press. pp403-426

54

Patients with GAD Report Greater Work Impairment than Patients with MDD

0

10

20

30

40

50

60

70

No GAD orMDD (n=3764)

Pure GAD(n=33)

ComorbidGAD/MDD

(n=40)

Pure MDD(n=344)

% o

f re

spo

nd

ents

% with work days lost/impaired in past month

0

2

4

6

8

No GAD orMDD (n=3764)

Pure GAD(n=33)

ComorbidGAD/MDD

(n=40)

Pure MDD(n=344)

Wo

rk d

ays

lost

Average work days lost in past month

Wittchen et al. Int Clin Psychopharmacol. 2000;15:319-328

55

0

10

20

30

40

50

60

70

80

90

100

Generalhealth

Physicalfunction

Physicalrole

Bodily pain Mentalhealth

Socialfunction

Emotionalrole

Vitality

Me

an

SF

-36

sc

ore

No GAD or MDD

Pure MDD

Comorbid GAD/MDD

Pure GAD

GAD is Associated with Quality of Life Impairment: Mean SF-36 Scores in People with GAD and/or MDD

P<0.05: GAD vs. no GAD or MDD for all domains.P<0.05: GAD vs. MDD for general health, mental health, emotional role, vitalityWittchen et al. Int Clin Psychopharmacol. 2000;15:319-328

56

Increased Healthcare Utilization in GAD

7

1415

23

4

0

4

8

12

16

20

24

No GAD or MDE Pure GAD GAD + MDE

Av

era

ge

nu

mb

er

of

vis

its

/ye

ar

Primary care Specialist (outpatient)

Average number of visits in past year

MDE: major depressive episodeBased on primary care sample of n=17,739Wittchen. Depress Anxiety. 2002;16(4):162-171

(n=16,023) (n=666) (n=278)

57

Patients with GAD Have as Many Doctor Visits as Patients with Depression

0

10

20

30

40

50

60

70

80

4+ to PCPs 2+ to other specialists Psychiatrist

Doctors visited in the past year

% o

f re

sp

on

de

nts

No GAD or MDE (n=16,023)

Pure GAD (N=666)

GAD + MDE (n=278)

Pure MDE (n=772)

MDE: Major Depressive EpisodeWittchen et al. J Clin Psychiatry. 2002;63(suppl 8):24-34

58

Number of Concurrent Psychiatric Disorders† in GAD Patients

34

27

23

9.7

2

1.6

1.2

0 10 20 30 40 50 60

Other anxiety and/ordepressive disorders

Depressive disorders

Other anxietydisorders

% of patients

One

Two

Three ormore

†Excluding GAD itselfN=3,340 GAD patients. Psychiatric disorder in the same yearIMS Mediplus Database German GP Analysis. Data on file, Pfizer Inc

GAD in German GP database

# of concurrent disorders24%

29%

45%

59

Direct and Indirect Costs in GAD With and Without Comorbidity

35

21

25

42

34 33

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

GAD WITH comorbidity(n=604)

GAD without comorbidity(n=395)

% o

f p

ati

en

ts Work absenteeism

Outpatient services

HospitalizationMedications

Diagnostic tests

$2050/3 months $1250/3 months

Costs calculated as $(USA) in 1994 and expressed as equivalent value in 2007 $(USA)Souêtre et al. J Psychosom Res. 1994;38:151-160

60

GP Visits and Referrals in 1 Year: GAD Patients vs. Comparison Group

0

10

20

30

40

50

60

70

80

90

100

GAD patients Comparisongroup

% o

f p

ati

en

ts

>6

5 or 6

3 or 4

2

1

0

10

20

30

40

50

60

70

80

90

100

GAD patients Comparisongroup

% o

f p

ati

en

ts

4+

3

2

167%

39%

GP visits Referrals by GP# of referrals

**

**P<0.001 GAD vs. comparison group

N=3,340 in each group. Frequency in the yearIMS Mediplus Database German GP Analysis. Data on file, Pfizer Inc

GAD in German GP database

# of visits

61

GAD: Diagnosis

"Normal" worry vs. Generalized Anxiety Disorder (GAD)

“Normal” Worry: Generalized Anxiety Disorder:

Your worrying doesn’t get in the way of your daily activities and responsibilities.

You’re able to control your worrying. Your worries, while unpleasant, don’t

cause significant distress. Your worries are limited to a specific,

small number of realistic concerns. Your bouts of worrying last for only a

short time period.

Your worrying significantly disrupts your job, activities, or social life.

Your worrying is uncontrollable. Your worries are extremely upsetting

and stressful. You worry about all sorts of things,

and tend to expect the worst. You’ve been worrying almost every

day for at least six months.

62

Another GAD- Carrie’s story:

Carrie has always been a worrier, but it never interfered with her life before. Lately, however, she’s been feeling keyed up all the time. She’s paralyzed by an omnipresent sense of dread, and worries constantly about the future. Her worries make it difficult to concentrate at work, and when she gets home she can’t relax. Carrie is also having sleep difficulties, tossing and turning for hours before she falls asleep. She also gets frequent stomach cramps and diarrhea, and has a chronic stiff neck from muscle tension. Carrie feels like she’s on the verge of a nervous breakdown.

63

Sound Familiar?

“I can’t get my mind to stop…it’s driving me crazy!" 

“He’s late - he was supposed to be here 20 minutes ago! Oh my God, he must have been in an accident!”

“I can’t sleep — I just feel such dread … and I don’t know why!”

64

Background: GAD Evolution as a Distinct Diagnostic Entity is Relatively Recent

DSM-I (1952) Anxiety reaction

DSM-II (1968) Anxiety neurosis

DSM-III (1980) GAD(1-month duration) Panic disorder

DSM-IV (1994)

GAD(6-month duration)

Includes overanxious disorder of childhood

Anxiety disorders NOS

Rickels & Rynn. J Clin Psychiatry. 2001;62(suppl 11):4-12

65

Generalized Anxiety Disorder: DSM-IV Diagnostic Criteria

• Excessive anxiety and worry present most of the time for > 6 months• Difficult to control worry• Associated with (at least 3 items):

─ Restlessness ─ Being easily fatigued ─ Concentration difficulties─ Irritability─ Muscle tension─ Sleep disturbance

• Focus of anxiety and worry not confined to features of an Axis I disorder• Causes clincially significant distress or functional impairment• Not due to medication, illness, or substance abuse

DSM-IV-TR. APA 2000

66

Generalized Anxiety Disorder: ICD-10 Summary

• Anxiety is generalized and persistent and not associated with a particular environmental circumstance (i.e. it is free-floating)

• Anxiety present most days for at least several weeks at a time and usually for several months

• Symptoms should involve elements of:─ Apprehension

• E.g. Worry about future, feeling “on edge”, difficulty concentrating─ Motor tension

• E.g. Restlessness, fidgeting, tension headaches, trembling─ Autonomic overactivity

• E.g. Light-headedness, sweating, tachycardia, epigastric discomfort• Must not meet full criteria for depressive episode, phobic anxiety disorder,

panic disorder, or obsessive-compulsive disorder

ICD-10, WHO 1992

67

DSM-IV and ICD-10 GAD Diagnostic Criteria: Some Differences

DSM-IV ICD-10

Diagnostic classificationIndependent

categoryResidual category

Worry/anxiety symptomExcessive anxiety

and worryPersistent free-floating anxiety

Duration ≥6 months Several months

Autonomic hyper-activity and physical symptoms

Not essential Must be present

Functional impairment Must be present Not specified

Rickels & Rynn. J Clin Psychiatry. 2001;62(suppl 11):4-12Starcevic. Anxiety Disorder in Adults. Oxford University Press. 2005:102-140

68

Use of Published GAD Diagnostic Guidelines

66

49

4340

28 27

0

10

20

30

40

50

60

70

80

90

100

Germany Italy Spain UK

% u

sin

g g

uid

eln

es

Psychiatrist

PCP

Data on file, Pfizer Inc

n=44 n=43 n=40 n=40 n=30n=36

• DSM-III and IV guidelines most commonly used

69

Guidance for Exploring a Suspected Anxiety Disorder

Baldwin et al. J Psychopharmacol. 2005;19(6):567-596British Association for Psychopharmacology

Predominant symptom focus

Trauma history &

flashbacks

Obsessions

compulsions

Uncontrollable worry in several

areas

Intermittent panic/anxiety attacks and avoidance

Fear of social

scrutiny

Discrete/object

situation

Some uncued/ spontaneous

Check for PTSD

Check for OCD

Check for GAD

Check for Social

Anxiety Disorder

Check for specific phobia

Check for Panic

Disorder

Specific anxiety-related symptoms & impaired function

Also moderate/severe depression?Treat

depressionYes

No

70

GAD: Disease and Management Issues

• GAD lifetime prevalence ~5%• Comorbid disorders common

─ Common comorbidity of medical and psychiatric disorders• Usually chronic, relapsing-remitting course

─ Low probability of remission─ Long-term treatment often needed

• Sub-optimal recognition and diagnosis is common─ Often presents as somatic complaint

• Substantial quality of life and economic burden• Current treatments may have limitations

71

GAD Treatment

Cognitive therapy (CBT): probably the most effective treatment.

Counseling : 

Anxiety management courses : learning how to relax, problem solving skills, coping strategies, and group support.

Self helpYou can get leaflets, books, tapes, videos, etc, on relaxation and combating stress. They teach simple deep breathing techniques and other measures to relieve stress, help you to relax.

72

Drug treatment for GAD:

73

Rx Treatments For GAD

Benzodiazepines 43%

Antidepressants38%

European data. IMS 4Q07

Sedatives11%

AEDs 3%

Antipsychotics 5%

74

Evidence That Treating GAD Reduces the Risk of Developing MDD

0

5

10

15

20

25

30

GAD untreated (n=99) GAD treated (n=120)

% d

evel

op

ing

dep

ress

ion

Data from NCS, USA. MDD: Major Depressive Disorder (DSM-III-R) Hazard ratio =0.52 in patients who had taken psychotropic medication ≥4 times. Goodwin et al. Am J Psychiatry. 2002; 159(11):1935-1937

48% reduction: P<0.001

75

Current GAD Treatments: Benzodiazepines

Advantages

• Effective, mainly in somatic symptoms1

• Fast onset of action1

• Reproducible response1

Disadvantages

• Less effective for psychic symptoms1

• Dependence issues with long-term use2,3

• Withdrawal symptoms and rebound anxiety2,3

• Cognitive and psychomotor impairment2

• Drug-drug interactions (CYP 3A4)2

1. Gorman. J Clin Psychiatry. 2002;63(suppl 8):17-232. Nemeroff. J Clin Psychiatry. 2003;63(suppl 3):3-63. Chouinard. J Clin Psychiatry. 2004; 65(suppl 5):7-12

76

Current GAD Treatments: SSRIs/SNRIs

Advantages

• Effective, mainly in psychic symptoms1

• Reduce comorbid depressive symptoms1

• Low potential for abuse

Disadvantages

• Less effective for somatic symptoms1

• Variable patient response2

• Delayed onset of action2

• Sexual dysfunction2

• Weight gain1

• Discontinuation symptoms2

• Drug-drug interactions (CYP 2D6)1

1. Raj & Sheehan. Generalized Anxiety Disorder. Martin Dunitz Ltd. 2002:137-1522. Nemeroff. J Clin Psychiatry. 2003;63(suppl 3):3-6

77

Efficacy in Key Symptoms of GAD Across Drug Classes

Benzo TCAs SSRIs & SNRIs

Azapirones α2δ ligand

Speed of onset <7 days ~3 weeks ~3 weeks ~3 weeks <7 days

Psychic symptoms ++ +++ +++ +++ +++

Somatic symptoms +++ + + + +++

Associated insomnia +++ + + + +++

Secondary depressive symptoms

+ +++ +++ ++ ++

Benzo: benzodiazepine, SSRI: Selective serotonin re-uptake inhibitor, SNRI: Serotonin-noradrenaline re-uptake inhibitor; TCA: Tricyclic antidepressant. Not all classes approved for use in GAD in Europe. Montgomery. Expert Opin. Pharmacother. 2006;7(15):2139-54

+ Some efficacy, ++ Moderate efficacy, +++ Marked efficacy

78

Tolerability and Safety Profiles Across Drug Classes used in GAD

Benzo TCAs SSRIs & SNRIs

Azapirones α2δ ligand

Sedation/ psychomotor impairment

+++ ++ +/++ + ++

Weight gain + ++ + + ++

Sexual dysfunction 0/+ + ++ + 0/+

GI side-effects 0 + + + 0

Withdrawal syndrome +++ ++ 0/+/++ + +

Risk of drug interactions ++ ++ 0/+/++ + 0/+

Benzo: benzodiazepine, SSRI: Selective serotonin re-uptake inhibitor, SNRI: Serotonin-noradrenaline re-uptake inhibitor; TCA: Tricyclic antidepressant. Not all classes approved for use in GAD in Europe. Montgomery. Expert Opin. Pharmacother. 2006;7(15):2139-54

0: minimum-to-none; + Some, ++ Moderate, +++ Marked

79

Pregabalin: A new Approach

Advantages

Effective in somatic and psychic symptoms1

Fast onset of action2

Effective in refractory patients3

Low abuse potential

Familiar molecule through other indications

NO known PCK drug interactions – easy to use

Disadvantages

Less familiar with use in GAD

Potential rebound Anxiety on withdrawal

Dizziness and somnolence main AEs

1. Montgomery . Expert Opin. Pharmacother. 2006; 7(15):2139-2154 (6 studies combined)2. Herman et al. CINP 20083. Miceli et al. 2008

80

Thank you.