amany haroun 2 - ASUIP · 2019. 11. 3. · Kessler RC, Berglund P, DemlerO, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication

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OPTIMIZING MANAGEMENT OF DEPRESSION WITH COMORBID ANXIETY DISORDER

PROF. AMANY HAROUN EL RASHEEDM.N.P., D.P.P., M.D.

MASTER IN MENTAL HYGIENE (JOHNS HOPKINS UNIV.)

FELLOWSHIP IN SUBSTANCE ABUSE TREATMENT & PREVENTION (JOHNS HOPKINS UNIV.)

APA INTERNATIONAL MEMBERSHIP AMBASSADOR

FRC PSYCH

WPA FELLOWSHIP

ISAM FELLOWSHIP

ASAM MEMBERSHIP

OBJECTIVES

• How common is Depression with comorbid anxiety?

• Depression with comorbid anxiety in the differentclassifications

• Why is this comorbidity important?

• How to optimize the management of comorbid anxietyand depression

HOW COMMON IS DEPRESSION WITH COMORBID ANXIETY?

COMORBIDITY AND DEPRESSION

• 72.1% of those with lifetime MDD and 64% ofthose with 12-month MDD have at least oneadditional psychiatric disorder.

• Primarily anxiety disorder, substance abusedisorder, or impulse control disorder.

Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

HOW COMMON IS ANXIOUS DEPRESSION?

•Among outpatients with MDD, lifetime comorbidity foranxiety disorders is 40% (1,2) to 60% (3,4)

• In STAR*D 52% of participants had anxious depression

(defined by a HRSD17 Anxiety/Somatization Factor score>7) (5)

1. Sanderson et al, AJP. 1990; 2. Hasin et al, AGP, 20053. Fava et al, Comp Psychiatry, 2000; 4. Kessler et al, JAMA, 20085. Fava et al, AJP, 2008

MIXED ANXIETY DEPRESSION

•It is COMMON for people to suffer fromdepression and anxiety at the same time

•Depression and anxiety frequently coexist in thesame individual, either concurrently or at different

times, and numerous studies show that the presence ofan anxiety disorder is the single strongest risk factor

for development of depression.

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NATURE OF THE RELATIONSHIP BETWEEN DEPRESSION AND ANXIETY

•Controversy continues over the nature of the relationship

between depression and anxiety, some believing they are

distinct, separate entities while others now the majority view

them as overlapping syndromes that present at different

points on a phenomenological and/or chronological continuum, and

share a common neurobiology, the degree of overlapdepending on whether each is described at the level of symptoms,syndrome or diagnosis.

NATURE OF THE RELATIONSHIP BETWEEN DEPRESSION AND ANXIETY

•Pure disorders are relatively rare

•Comorbidity patterns differ by type of anxiety

•Anxiety disorders are usually primary disorders

•Anxiety disorders are important risk factors fordepression

ANXIETY AS A RISK FACTOR FOR DEPRESSION

•Depending on the type of primary anxiety disorder, the risk

for onset of secondary depression is increased 2-4 times

above the risk expected for subjects with no previoushistory of anxiety disorders.

•The number of anxiety disorders present, the persistence

of anxious avoidance behavior, and the degree of

psychosocial impairment are strongest factors associatedwith depression onset.

Wittchen et. Al, Acta Psychiatrica Scandinavica, 102(406), 2000

ANXIETY IN MAJOR DEPRESSION

•59% have an anxiety disorder

•70% and more, have anxiety symptoms

Kessler et al. BJP. 1996

MDD AND ANXIETY DISORDERS

AnxietyDisorders59%59%Major

DepressionMajor

Depression

1. Kessler et al. Arch Gen Psychiatry, 1995 2. DSM-IV 3. Rasmussen. Psychopharmacol Bull, 1988 4. Van Ameringen et al. J Affect Disord, 1991 5. Brawman-Mintzer, Lydiard RB. J Clin Psychiatry,

1996 6. Stein et al, Am J Psychiatry, 2000

MajorDepression

MajorDepression

Posttraumatic Stress DisorderPosttraumatic Stress Disorder

Social Phobia (Social Anxiety Disorder)

Social Phobia (Social Anxiety Disorder)

OCDOCD

Panic DisorderPanic Disorder

GADGAD

8%-39% of5Patients with GAD

67% of Patients3with OCD

34-70% of Patients with4,6Social Phobia

1of Patients with PTSD% 48 50% to 65% of Patients2with Panic Disorder

COMORBID MOOD AND ANXIETY DISORDERSLifetime Comorbidity

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0

20

30

40

50

60

70

PanicDisorder

PTSD SimplePhobia

SocialPhobia

GAD AnyAnxietyDisorder

% C

omor

bid

With

MD

D

1010%

20%24%

27%

17%

58%

MDD = major depressive disorder.

Kessler RC, et al. Br J Psychiatry Suppl. 1996;30:17-30.

COMORBIDITY OF ANXIETY DISORDERS WITH MOOD DISORDERS IN THE COMMUNITY MIXED ANXIETY DEPRESSION

•Community data likely underestimate true

prevalence, since affected individuals frequentlypresent in primary care with somatic, rather thanpsychological, complaints.

•>50% of episodes of depression andanxiety are unrecognised in primary care (Kessler et

al.,1999)


• It may present initially with physical symptomssuch as fatigue and pain from 2 - 4 weeks

•Further inquiry will reveal depressed moodand feeling of fear, apprehension or stateof gloom

WORLD HEALTH ORGANIZATION [WHO] STUDY ON PSYCHOLOGICAL DISORDERS IN PRIMARY CARE

•25 000 consecutive adults were screened at 15 sites

in 14 countries. Over 5 000 were further assessedwith detailed psychiatric interviews.

• A quarter had a recognizable mental disorder.Arch Gen Psychiatry. 1993;50(10):819-824. doi:10.1001/archpsyc.1993.01820220075008

•

WORLD HEALTH ORGANIZATION [WHO] STUDY ON PSYCHOLOGICAL DISORDERS IN PRIMARY CARE

•The commonest being a depressive disorder (11.7%) or ananxiety disorder (10.5%), with 4.6% having both.

•Only half of the mental disorders were recognised by theprimary care physician; among those patients with arecognised mental disorder, half were offered drugtreatment.

Arch Gen Psychiatry. 1993;50(10):819-824. doi:10.1001/archpsyc.1993.01820220075008

WHO IS AT RISK FOR MIXED ANXIETY-DEPRESSIVE DISORDER?

•Family history of mental health

disorders and/or substance

addictions.

•Poverty.

•Female.

•Lack social or familial support.

•Serious and/or chronic illness.

•Dependent personality.

•Low self-esteem.

•Experienced a childhood trauma.

•Under a lot of stress.

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DEPRESSION WITH COMORBID ANXIETY IN THE DIFFERENT CLASSIFICATIONS


•Greater awareness of these important mood

states in combination would automatically act as a

spur to improving a part of psychiatricclassification that remains in some disarray.

ICD-10•Mixed anxiety and depression (MAD) was first introduced as

a diagnostic category in the ICD-10 classification forpatients seen mainly in primary care settings.

•These patients are defined as those suffering from symptomsof anxiety and depression of limited and equal intensity

accompanied by at least some autonomic features, who donot qualify for specific diagnosis of anxiety or depressivedisorders and are independent of stressful life events.

DSM-5Added a specifier for Depressive Disorder “with anxious distress”:

• Anxious distress is defined as the presence of at least two of thefollowing symptoms during the majority of days of major depressiveepisode or persistent depressive disorder (dysthymia):

1. Feeling keyed up or tensed.

2. Feeling unusually restless.

3. Difficulty concentrating because of worry.

4. Fear that something awful may happen.

5. Feeling that the individual might lose control of himself or herself.

Major depressive disorder

w/ anxious distress

w/ mixed features

w/ atypical features w/ melancholic features

w/ mood-[congruent, incongruent]psychotic features

w/ catatoniaw/ peripartum onset

w/ seasonal pattern

≥2 of the following:• keyed-up/tense• unusually restless• can’t concentrate b/c of worry• fear something awful may happen• might lose control

DEPRESSIVE DISORDER “WITH ANXIOUS DISTRESS”

Specify current severity

•Mild: Two symptoms

•Moderate: Three symptoms

•Moderate-severe: Four or five symptoms

•Severe: Four or five symptoms and with motor agitation

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DEPRESSIVE DISORDER “WITH ANXIOUS DISTRESS”

• Anxious distress has been added noted as a prominent feature ofboth bipolar and major depressive disorder in both primary careand specialty mental health settings.

• High levels of anxiety have been associated with higher suicide risk,longer duration of illness, and greater likelihood of treatment non-response.

• As a result, it is clinically useful to specify accurately the presenceand severity levels of anxious distress for treatment planning andmonitoring of response to treatment.

ADJUSTMENT DISORDERSA. The development of emotional or behavioral symptoms in response

to an identifiable stressor(s) occurring within 3 months of theonset of the stressor(s).

B. These symptoms or behaviors are clinically significant, as evidenced by oneor both of the following:

1- Marked distress that is out of proportion to the severity orintensity of the stressor taking into account the external context andcultural factors that might influence symptom severity and presentation.

2- Significant impairment in social, occupational, or other important areasof functioning.

ADJUSTMENT DISORDERS

C. The stress-related disturbance does not meet the criteria for

another mental disorder and is not merely an exacerbation of the

pre-existing mental disorder.

D. The symptoms do not represent normal bereavement.

E. Once the stressor or its consequences have terminated, the symptomsdo not persist for more than an additional 6 months.

ADJUSTMENT DISORDERS

Specify whether:

• With depressed mood: Low mood, tearfulness, or feeling of hopelessness are predominant

• With anxiety: Nervousness, worry, jitteriness, or separation anxiety is predominant

• With mixed anxiety and depressed mood: A combination of depression and

anxiety is predominant.

• With disturbance of conduct: Disturbance of conduct is predominant

• With mixed disturbance of emotions and conduct: Both emotional symptoms

(e.g., depression, anxiety) and a disturbance of conduct are predominant.

• Unspecified

Major depression Anxiety disorder

Low moodAnhedoniaWeight gain/lossLoss of interestSuicidal ideation

HypervigilanceAgoraphobia

Compulsive rituals

FearApprehensionChronic painGI symptoms

WorryAgitation

Difficulty concentratingSleep disturbances

FatigueLow energy

SYMPTOMS COMMON TO DEPRESSION AND ANXIETY

OVERLAP SYMPTOMS OF DEPRESSION ORANXIETY

• Dysphoria

• Sleep disturbance

• Appetite disturbance

• Impaired concentration

• Fatigue

• Irritability

• Non-specific somatic complaints

Clayton, J of Clinical Psychiatry, (Suppl.11),1990

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SOMATIC SYMPTOMS SUGGESTIVE OF UNDERLYING “ANXIOUS” DEPRESSION

• Chronic pain• Headache• Dizziness• Palpitation• Intestinal grips• Epigastric pain• Diarrhea• Restlessness

DIFFERENCES IN SOMATIC SYMPTOMATOLOGY

•Depressed patients have more conspicuous vegetative

symptoms, such as anorexia, weight loss and diminishedlibido

•Anxious patients have symptoms more closelyassociated with sympathetic nervous overactivity, suchas tachycardia, sweating, and symptoms induced byhyperventilation.

Maser et al., in Handbook of Depression, 1995


•It is sometimes difficult to know whether anxiety hasled into depression or vice versa

•When the two coexist simultaneously, either as diagnoseddisorders or subsyndromal states, they may be viewed asmixed anxiety depression or as comorbid syndromes,i.e. separate disorders occurring concurrently.

WHEN THE ANXIETY DISORDER IS PRIMARY

•Anxious mood

•Initial insomnia

•No psychomotor change

•No significant therapeutic response to exercise


WHEN THE DEPRESSIVE DISORDER IS PRIMARY

•Depressed mood

•Terminal insomnia

•Psychomotor agitation or retardation

•Positive response to exercise


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WHY IS MIXED ANXIETY DEPRESSION IMPORTANT?

COMORBIDITY IS ASSOCIATED WITH INCREASED IMPAIRMENT

0%

10%

20%

30%

40%

50%

Impaired SocialFunctioning

ImpairedOccupationalFunctioning

Fair/PoorPerceived

Mental Health

Controls (n=5,217)

Pure GAD (n=92)

Pure MDD (n=489)

Comorbid GAD + MDD(n=99)

*Kessler RC, et al. AM J Psychiatry. 1999;156:1915-1923

PD = panic disorder, MDD = major depression per PRIME-MD.*Adjusted for sociodemographics and substance abuse.

Goodwin R, et al. Depress Anxiety. 2001;14:244-246.

SUICIDAL IDEATION AND PANIC DISORDER (PD) WITH COMORBID DEPRESSION (MDD) IN PRIMARY CARE

1

3.3

5.3

15.4

0

2

4

6

8

10

12

14

16

18

No PD or MDD(n = 758)

PD/No MDD(n = 44)

MDD/No PD(n = 83)

PD + MDD(n = 40)

Adju

sted

Odd

s R

atio

2-W

eek

Prev

alen

ce S

uici

dal I

deat

ion*

MANAGEMENT OF MIXED ANXIETY DEPRESSION

MANAGEMENT OF MIXED ANXIETY DEPRESSION

•Various classes of antidepressant drugs offer symptomrelief for these patients, the most selective of the SSRIsholding the greatest promise for sustained clinical

improvement.

•As both depression and anxiety disorders tend to bechronic and recurring, treatment should be effective in the

long term and should prevent relapse of the condition.

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TREATMENT STRATEGY•Yet, the crucial parameter of successful

pharmacotherapy seems to be the length of treatment,ensuring enhancement of the compromisedneuroprotective and neuroplastic mechanisms.

•Current recommendations suggest that depression and

anxiety should be treated for similar lengths of time;

for at least 6 months, and possibly up to a year afterthe initial episode.

Nutt D. Treatment of depression and concomitant anxiety. European Neuropsychopharmacology 10 (Suppl. 4) (2000) S433–S437

TREATMENT STRATEGY• When depression is accompanied by symptoms of anxiety, the

first priority should usually be to treat the depression.

NICE guideline recommendation:

• When the person has an anxiety disorder and comorbiddepression or depressive symptoms, treating the anxiety disorderfirst (since effective treatment of the anxiety disorder will oftenimprove the depression or the depressive symptoms).

The NICE guideline on the treatment & management of depression in adults. 2010

TREATMENT GUIDELINES FOR PATIENTS WITH MDD AND ANXIETY DISORDER

Select a medication indicated for both disorders• SSRIs indicated for MDD, GAD, OCD, PD, PTSD and SAD (SNRI for GAD and

SP)• Dosing Adjustments

• Start low – esp. for PD• Go slow• But don’t stop too soon – esp. for OCD

• Role of benzodiazepines unclear• Acutely may aid antidepressant tolerability and speed onset• Avoid as monotherapy

• Be gentle and patient, but persistent

Don’t forget psychosocial interventions• Cognitive behavioral therapy can target both depressive and anxiety symptoms

Pollack MH, Marzol PC. CNS Spectrums. 2000;5:23.

PREDICTORS OF TREATMENT CONCORDANCE PROBLEMS : PATIENT ( INTENTIONAL )

Intentional

Side Effects

Few Benefits

Dependency.

AvailabilityCost

Adjustment To suit

Daily routine

Stigma

Mitchell & Selmes.Advances in Psychiatric Treatment 2007 .vol 13,336-346

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FDA-APPROVED USES FOR SSRI AND SNRI DRUGS

DRUG MDD OCD PD GAD SP PTSD PMDDCitalopram √Escitalopram √ P √Fluoxetine √ √ √Fluvoxamine √Paroxetine √ √ √ √ √ √Sertraline √ √ √ √ √ √Venlafaxine √ √ √

PAROXTEINE CR IN TREATMENT OF

MIXED ANXIETY & DEPRESSION

Weekly mean depressed mood and psychic anxiety sub-item in the HAMD-17 item score over the 8 week the paroxetine CR treatment (statistically significant at each visit compared to baseline ( ps<0.0001). intent-to-treat population (ITT) with the LOCF. The last available post-baseline measurement was assigned as an endpoint.

Pae CU, Bahk WM, Jon DI, et al. Effectiveness and tolerability of paroxetine controlled release (CR) in the treatment of major depressive disorder: an open-label, prospective, multi-center trial in Korea. Hum Psychopharmacol. 2007 Aug;22(6):351-9.

PAROXTEINE CR SIGNIFICANTLY IMPROVES THE SUB-ITEMS OF THEDEPRESSED MOOD AND PSYCHIC ANXIETY IN HAMD-17

PAROXTEINE CR SIGNIFICANTLY IMPROVES PATIENTS WITH DEPRESSED MOOD AND PSYCHIC ANXIETY

•At the endpoint, there was a 62.5% improvement in the

depressed mood and a 54.2% improvement in psychic anxiety.

Pae CU, Bahk WM, Jon DI, et al. Effectiveness and tolerability of paroxetine controlled release (CR) in the treatment of major depressive disorder: an open-label, prospective, multi-center trial in Korea. Hum Psychopharmacol. 2007 Aug;22(6):351-9.

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ADVERSE EVENTS—A SIGNIFICANT CAUSE OF TREATMENT DISCONTINUATION

- A MAJOR OBSTACLE TO EFFECTIVE TREATMENT

ADVERSE EVENTS—A SIGNIFICANT CAUSE OF TREATMENT DISCONTINUATION

- A MAJOR OBSTACLE TO EFFECTIVE TREATMENT

Poor tolerability in early therapy

Drop out of therapy

1. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician in patients' adherence to antidepressant therapy. Med Care. 1995 Jan;33(1):67-74.2. Maddox JC, Levi M, Thompson C. The compliance with antidepressants in general practice. J Psychopharmacol. 1994 Jan;8(1):48-52.

LOWER ADVERSE EVENTS E.G.(NAUSEA)

PAROXTEINE CR USE IS ASSOCIATED WITH

Golden RN, Nemeroff CB, McSorley P, et al. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry. 2002 Jul;63(7):577-84.

NAUSEA IS ONE OF THE MOST COMMON SIDE EFFECTSNAUSEA IS ONE OF THE MOST COMMON SIDE EFFECTS

• Nausea is a leading cause of prematuretreatment discontinuation for the SSRIs andserotonin norepinephrine reuptake inhibitors1

• Clinical trials in major depression with Paroxetine IR (n = 6145)

• -most common adverse event associated with withdrawal from Paroxetine IR was nausea (3.2% vs. 1.1% on placebo)

RATIONALERATIONALE

• Enterochromaffin cells in the gut mucosa secrete 5-HT

• Paroxetine (like all SSRIs) inhibits 5-HT reuptake, and rapid dissolution andabsorption leads to high localised mucosal Paroxetine concentrations in theupper GI tract

• Results in nausea due to stimulation of 5-HT3 receptors in peripheral duodenalsynapses

• Optimising the rate and site of absorption should reduce upper GI mucosalconcentrations of Paroxetine (and 5-HT), reducing the incidence and severity ofnausea

• Paroxetine CR is a controlled release formulation of paroxetine, in which thestart of absorption is delayed and the rate of absorption is reduced.

The acid-resistant enteric coat on Paroxetine CR means that drug release is delayed until the tablet has passed through the stomach shifts absorption further down in small intestine

The polymeric matrix of Paroxetine CR controls the dissolution rate, and 80% of the drug is released in ~ 4-5 hours

Golden RN, NemeroffCB, McSorley P, et al. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry. 2002 Jul;63(7):577-84.

Paroxetine CR (25–62.5 mg/day; N = 212) and paroxetine immediate-release (IR; 20–50 mg/day; N = 217) were compared with placebo (N = 211) in the pooled dataset from 2 identical, double-blind, 12-week clinical trials.

Paroxteine showed low dropouts rate due to AEs

CR = controlled-release,IR = immediate-release.

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Sheehan DV, Eaddy MT, Shah MB, et al. Differences in total medical costs across the SSRIs for the treatment of depression and anxiety. Am J Manag Care. 2005 Oct;11(12 Suppl):S354-61.

Medical and pharmacy administrative claims data were abstracted from the Integrated Healthcare Information Services National Managed Care Benchmark database. The database is nationally representative and includes data from 30 health plans covering more than 25 million lives.

PAROXTEINE CR SHOWED THE LOWEST MEDICAL COST COMPARED TO OTHER MEDICATIONS IN AN AVERAGE UNADJUSTED 6-MONTH MEDICAL

COSTS STRATIFIED BY DIAGNOSIS

Sheehan DV, Eaddy MT, Shah MB, et al. Differences in total medical costs across the SSRIs for the treatment of depression and anxiety. Am J ManagCare. 2005 Oct;11(12 Suppl):S354-61.

ParoxteineCR were associated with an 8.7% lower 6-month medical cost compared with patients

receiving IR SSRIs.1

COMMON COGNITIVE ERRORS ASSOCIATED WITH NON-COMPLIANCE WITH DRUG TREATMENT

Not comfortable with diagnosis

PATIENT MIGHT SAY:• “I don’t really feel depressed and/or anxious”• “I don’t think that I am that depressed and/or anxious”• “I am really just stressed out.”

EXPLORE BY ASKING:

“What do you think is going on?

The MacArthur Initiative on Depression & Primary Care: Care Manager Training Manual



INTERVENE BY:• Explaining to the patient that their primary care clinician believed

they are suffering mixed anxiety depressed and that treatmentwould be helpful.

• Explore what is uncomfortable about the diagnosis (do they knowsomeone who is depressed or seriously mentally ill and perhaps this isfrightening to them).

• Explore what they believe having “mixed anxiety depression”means and dispel some of the myths.




INTERVENE BY:• If a patient continues to be adamant that they do not have

depression and/or anxiety, acknowledge their stance and focusmore on what symptoms they have.

• For example, suggest that the medication they have beenprescribed will help relieve their difficulty sleeping.


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INTERVENE BY:

• If after talking further with the patient, you think that he or sheis relaxing more about the “diagnosis” – you might mentionthat “anxiety depression” is a combination of the varioussymptoms that they are experiencing – difficulty sleeping,feeling hopeless, etc.



Concerned about addiction

PATIENT MIGHT SAY:• “I don’t want to be on the medicine forever.”• “I don’t want to become addicted to it.”

EXPLORE BY ASKING:“Have you heard or known about someone who had trouble with the medication being addictive?”



Concerned about addiction

INTERVENE BY:• Informing the patient that the medications are not

addictive.

•Explain that it is common for people to be on themedication for six months to a year and in some caseslonger.

•Be sure to say that the decision about how long to stay onthe medication should be made with their psychiatrist orprimary care clinician.


Concerned about addictionINTERVENE BY

• Emphasize that they should not stop or change theirmedication dose without talking to their primary careclinician first.

• Mention that often people go off of their medication too soonbecause they are feeling better.

• By stopping medication too soon, they are running the risk ofa relapse.


CONCLUSIONS

CONCLUSIONS•Depressive and anxiety disorders are common inprimary care settings, yet up to half the patientswho present with these disorders may not bediagnosed and others may not be treated.

•The cornerstone of detection is an understanding ofthe common presenting symptoms andsyndromes.

•

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CONCLUSIONS•Patients with depression or anxiety frequently presentcomplaining of physical symptoms, which mayobscure the psychiatric diagnosis.

•Once a depressive or anxiety disorder is detected,possible causes to be explored include underlyingmedical conditions, psychiatric conditions, and drug oralcohol use.

•

CONCLUSIONS

•Anxiety comorbidity with MDD results in increasedseverity, increased risk of suicidality, as well aspoorer outcomes mood disorders

•Treatment must involve attention to bothdisorders

CONCLUSIONS•In general, the SSRIs and the SNRI are used first-linein the treatment of both anxiety and depression due totheir broad spectrum of efficacy with respect to anxiety anddepressive disorders and their relative safety in overdose.

•However, because these agents are often associated with aninitial exacerbation of anxiety among anxious patients, it isrecommended that clinicians start patients at lowerdoses and then titrate up over the first few weeksof treatment.

“The good physiciantreats the disease,but the great physiciantreats the person.”

William Osler

THANK YOU

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Documents

amany haroun 2 - ASUIP · 2019. 11. 3. · Kessler RC, Berglund P, DemlerO, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication