DEPRESSION

Diagnosis and treatment

TYPES of DEPRESSION

TYPES of DEPRESSION

Major Depressive Disorder Minor Depressive Disorder Recurrent Brief Depressive Disorder Bipolar Disorder – Depressive Episode Depressive Disorder NOS Premenstrual Dysphoric Disorder Mixed Anxiety-Depressive Disorder Postpsychotic Depressive Disorder of Schizophrenia Atypical Depression Depressive Disorder Due to a GMC Substance-Induced Depressive disorder Dysthymia

1. Insomnia or hypersomnia

2. Depressed mood or loss of interest or pleasure

3. Feelings of worthlessness

4. Fatigue

5. Diminished ability to think or make decisions

6. Weight change

7. Psychomotor retardation or agitation

8. Preoccupation with death,hopelessness

DSM-IV Criteria for Major Depressive Episode

5 symptoms in the same 2-week period

DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.

Global burden of disease

Üstün and Sartorius (1995); Murray and Lopez (1996)

Prevalence – 10%.

Depression

Recognised – 5%.

Treated – 3%.

World Health Organisation’s guideline for length of treatment for depression is 12 months.

Actual length of treatment is 3-4 months.

Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19.

Epidemiology of Depression

Lifetime prevalence of a major depressive episode (MDE)1: 17%− Male: 13%

− Female: 21%

Trends− Age at onset: younger

− Incidence: increasing− Etiology: biologic vs psychologic

TREATMENT OF DEPRESSION

Why is it important

to be fast, effective and safe?

1. Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no. 93-0550. April 1993.

2. National Vital Statistics Reports. Vol 48, No. 11, July 24, 2000.

Depression and Suicide

Up to 15% of patients with MDD severe enough to require hospitalization eventually commit suicide1

Suicide is the 8th leading cause of death in the U.S.2

1. Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.

2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227.

3. Jiang W, et al. Arch Intern Med. 2001;161:1849-1856.

4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205.

5. Rovner BW, et al. JAMA. 1991;265:993-996.

6. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319.

Depression May Worsen Outcome of Many General Medical Conditions

Depression may worsen morbidity and mortality after myocardial infarction1,2

Depression increases morbidity and mortality in patients with CHF3,4

Depression increases risk of mortality in patients in nursing homes5

Depression worsens morbidity post-stroke6

Lost productivity—55%

Outpatient care—6%

Suicide—17%

Inpatient care—19%

Pharmaceuticals—3%

Greenberg PE, et al. J Clin Psychiatry. 1993;54:405-418.

Economics of Depression —U.S.A. Data - Total Annual Cost ~$44 Billion

U.S. data.

Depression in the old age

Lifetime prevalence of a major depressive episode (MDE)1: 17%

− Male: 13%− Female: 21%

Incidence of depression in ambulatory elderly patients (>65yrs) – 30%

Epidemiology of Depression

Depression and Suicide

70% of suicides follow a depressive illness Most common risk factors:

old age male gender

Increasing age also an important risk factor in women

Depression and physical co-morbidity in older people

Older patients diagnosed with major depression have a greater number of physical disorders

Shows a high correlation with physical illness

May worsen the course of physical illness

May itself be modified by chronic ill health

Causes of death in depressed older patients

The common causes of death in depressed older patients.

Zubenko et al (1997)

Disorders of digestive system 7%

Neoplasms 14%

Disorders of respiratory system 17%

Disorders of circulatory system 46%

Suicide 4%

Others 12%

Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11.

The goal of treatment in clinical practice should be remission of

symptoms

Treatment of Depression: Facing the Problem

Pharmacological treatment

Choosing Antidepressants

Choose drugs according to side effect profile− e.g., sedating drug for agitated depression− Consider possible drug-drug interactions, − P450 Iso enzymes

Treatment of depression in the elderly Pharmacological treatment

Tricyclic antidepressants - safety and tolerability

SSRIs – Comparable efficacy: Improved safety and tolerability

1. Rush AJ, et al. Psychiatric Ann. 1995;25:704-709.

2. Thase ME. J Clin Psychiatry. 1997;58:393-398.

3. Frank E, et al. Arch Gen Psychiatry. 1991;48:851-855.

Response Remission

50% decrease from baselinein HAM-D or MADRS scores

CGI score of 1 or 2

HAM-D score 7Minimally symptomatic or

asymptomaticPsychosocial/occupational

functioning restored

Goals of Treatment in Major Depressive Disorder1-3

Euthymia

Symptoms

Syndrome

Treatment phases

Progression

to disorder

Acute(6 to 12 wk)

Continuation(4 to 9 mo)

Maintenance(1 y)

Time

Incr

ea

sed

sev

eri

ty Relapse

Remission

RecurrenceRelapse

Response

Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

+

+

Remission Is the Goal of Treatment in Major Depression

• Up to 50% of “responders”

do not achieve remission

• Residual symptoms are nearly as common as non-response

Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11.

The goal of treatment in clinical practice should be remission of symptoms

Treatment of Depression:Facing the Problem

*P<0.001.Adapted from Paykel ES, et al. Psychol Med. 1995;25:1171-1180.

Remission (HAM-D17 7)Decreases Risk of Relapse

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Months between remission and relapse (or end of study)

Pati

en

ts r

ela

psin

g

(%)

Response without remission (n=19)

Remission (n=41)*

Longitudinal follow-up study of patients

treated with usual care by their physicians

0

2

4

6

8

10

12

14

16

18

Mea

n d

ays

of

wo

rk

mis

sed

per

yea

r

**

*P<0.001.†Clinical depression status at 12-month assessment. Persistent=still meeting diagnostic

criteria for MDD; response=HAM-D 8, but not meeting diagnostic criteria; remission=HAM-D 7.

Simon GE, et al. Gen Hosp Psychiatry. 2000;22:153-162.

Patients Treated to Remission HadFewer Missed Workdays

Persistent ResponseRemission†

depression† but not remission† (n=118)

(n=35) (n=137)

Treatment with Antidepressants

1950s 1960s 1970s 1980s 1990s

Phenelzine

Isocarboxazid

Tranylcypromine

Imipramine

Clomipramine

Nortriptyline

Amitriptyline

Desipramine

Fluoxetine

Sertraline

Paroxetine

Fluvoxamine

Citalopram

Nefazodone

Mirtazapine

Venlafaxine

Duloxetine

Milnacipran

Reboxetine

Moclobemide

Escitalopram

Maprotiline

Amoxapine

Mianserin

The evolution of antidepressants

More serotonin selectiveMore noradrenaline selective

100

venlafaxine

fluoxetine

paroxetineparoxetine

sertralinesertraline

fluvoxaminefluvoxamine

amitriptyline

imipramine

maprotilinemaprotiline

nortriptyline

protriptyline

desipraminedesipramine

amoxapine

Serotonin-noradrenaline spectrum of antidepressants

80 60 40 20 0 20 40 60 100 300 500

noradrenaline uptake Ki / serotonin Kiserotonin Ki / noradrenaline uptake Ki

Different classes of antidepressant

Class Examples

TCAs Clomipramine, imipramine, nortriptyline, desipramine, amitriptyline

MAOIs Phenelzine, isocarboxazid

RIMA Moclobemide

SNRI Venlafaxine

SSRIs Escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Others Nefazodone, mianserin, reboxetine, tianeptine, bupropion, mirtazapine

First line Antidepressants

Side effects Cost / availability Serotonin Selective Reuptake Inhibitors (SSRIs)

The SSRI medications include fluoxetine , paroxetine , sertraline, fluvoxamine, citalopram and escitalopram .

Milnacipran

Second Line Antidepressant

Newer Antidepressants A number of newer antidepressants including venlafaxine XR, nefazodone, bupropion SR, mirtazapine, and reboxetine have been recently approved for the treatment of MDD. These medications may be especially effective as "second-line" treatment in cases when a person has not responded that well to an SSRI

Forth line antidepressant

Monoamine Oxidase Inhibitors (MAOIs) The MAOIs including phenelzine, tranylcypromine and isocarboxazid, are effective in treating depression. However, while effective, the MAOIs have side-effects that make them mostly a second- or third-line choice for treatment.

SSRIs

General considerations about SSRIs

Compared to TCAs, all SSRIs show a greater selectivity for inhibition of serotonin re-

uptake than for norepinephrine re-uptake.

SSRIs provide an advantageous safety profile.

SSRIs lack TCA-like anticholinergic, cardiovascular, sedative and weight-increasing

properties.

SSRIs lack affinity for the various receptors implicated in TCA-induced adverse effects.

Hale (1997); Leonard (1996)

General considerations about SSRIs

Currently five drugs in this class with different structures,

pharmacokinetic profiles and secondary pharmacology (Preskorn, 1996)

Improved safety and tolerability profile compared with tricyclic

antidepressants and MAOIs lack of anticholinergic, histaminergic and cardiovascular effects

Clinically meaningful differences between the SSRIs efficacy in specific subgroups

side-effect profile

Comparative properties of SSRIs

SSRI Active metabolite

Fluoxetine

Sertraline

Paroxetine

Elimination half-life

Fluvoxamine

Escitalopram

Norfluoxetine

-

-

-

-

Citalopram -

Hale (1997); Sanchez et al (2002)

Zimeldine Norzimeldine

1-3 days (parent drug)1-3 weeks (metabolite)

26 hours

24 hours

15 hours

30 hours

8 hours (parent drug)31 hours (metabolite)

33 hours

Comparative pharmacokinetic profiles of SSRIs

SSRI Mean half-lifeSteady-state plasma levels

PK profile similar in adults & elderly Chirality

Citalopram 33 hoursa 7-14 days in adults NoYess-enantiomer activer-enantiomer inactive

Fluoxetine + norfluoxetine (active metabolite)

5 Days15 daysa

6-8 weeks, longer at higher doses and in the elderly

NoYess-r-fluoxetine & s-norfluoxetine potent SSRIs

Fluvoxamine 15.6 hours 7 days Yes No

Paroxetine 21 hours7 days, longer at higher doses and in the elderly

NoNo

Sertraline 26 hours 7 days Yes No

aprolonged in the elderly; PK, pharmacokinetic

Escitalopram 30 hours 7-14 days No No

Relevance of drug half-life

Long elimination half-life contributes to potential toxicity by promoting drug accumulation.

Long elimination half-life increases the likelihood of drug-drug interactions.

Half-life is important for the wash-out period.

Longer half-life may be a protection against abrupt discontinuation symptoms.

Preskorn (1997)

Binding to plasma proteins

Escitalopram and citalopram

50%

van Harten (1993); Sanchez et al (2002)

Fluvoxamine

77%

Other SSRIs TCA

over 90%over 90%

Inhibitory effects of SSRIs on drug metabolising CYP450 isoenzymes

Greenblatt et al (1998)

Degrees of inhibition and the resultant potential for elevation of substrate plasma levels:minimal 10%; mild 10-50%; moderate 50-200%; substantial > 200%.aextrapolation from in vitro data; bat usually effective minimum dose.

SSRI CYP1A2 CYP2C19 CYP2D6 CYP3A3/4 Reference

Citalopram Minimala Minimal Mildb Minimal Preskorn (1997)

Sertraline MinimalMinimalMildMinimalGreenblatt et al (1998)

Fluoxetine and norfluoxetine

Flu

Minimal MildSubstantial Mild

Lemberger et al (1988)

Ozdemir et al (1998)

Fluvoxamine SubstantialSubstantialMildModerateKragh-Sorensen et al (1981)

Paroxetine MildMildSubstantialMildPreskorn (1997)

Escitalopram Minimal Minimal Mild Minimal Moltke et al (2001)

Dosing regimen for SSRIs

Drug Dosing regimen (mg/day) Comment

Escitalopram Initial: 10 Use lower doses in the elderly (10 mg)

Range: 10-20 T½ approx 40 hours in elderly

Citalopram Initial: 20

Range: 20-60 Recommended maximum in the elderly: 40 mg

Fluoxetine Initial: 20

Range: 20-60

Fluvoxamine Initial: 50-100

Range: 100-300

Paroxetine Initial: 20

Range: 20-50 Recommended maximum in the elderly: 40 mg

Sertraline Initial: 50

Range: 50-200Doses > 150 mg should not be used for longer than 8 weeks

Treatment of Depression:Facing the Problem

Pharmacokinetics & Parmacodynamics alterations Drug-drug interactions Lower tolerance of side-effects Require simplicity of dosing

PSYCHOTHERAPY

AUGMENTATION

Augmantation

Augmentations - Mood Stabelizers - Lithium - Lamotrigine - Pindolol - Buspirone - Tricyclic

Augmantation

Antipsychotic Atypical - Risperdone - Olanzapine - Clozapine - Ziprazidone Typical - Metylphenidate - Tianeptine –increase serotonin reuptake

ECT

ECT

TMS

SLEEP DEPRIVATION

LIGHT THERAPY

Conclusions:

Depression is under diagnosed and under treated

Current therapies offer improved tolerability and efficacy

These needs are fulfilled by Selective Serotonin Re-uptake inhibitors (SSRI’s)

SSRI’s are recommended as the first drug of choice for MDD treatment