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