Transcript Real-World Pharmacologic Treatment of Depression B. Anthony

Real-World
Pharmacologic Treatment
of Depression
B. Anthony Lindsey, MD
Professor and Vice Chair
UNC Department of
Psychiatry
Antidepressants - History
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1958
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1982
1988
1989
1994
1994
1996
Monoamine oxidase inhibitors (MAOIs)
Tricyclics (TCA’s)
Trazodone (Deseryl)
Fluoxetine (Prozac)
Bupropion (Wellbutrin)
Nefazodone (Serzone)
Venlafaxine (Effexor)
Mirtazapine (Remeron)
Treatment Response
Categories
PREVALENCE
IN RCTS
STATE
OBJECTIVE
CRITERION
CLINICAL
STATUS
Remission
HAM-D ≤ 7
No residual
psychopathology
~ 40%
Response
≥ 50% decrease in
HAM-D without
remission
Substantially improved,
but with residual sxs
~ 25%
Partial
response
25%-50% decrease Mild-moderate
in HAM-D
improvement
~ 10%
Nonresponse
< 25% decrease
in HAM-D
~ 25%
No clinically
meaningful response
Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE):
comparing patients with unipolar major depressive disorder who recovered from
intake MDE with residual subsyndromal depressive symptoms vs.
asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96; P<0.0001.
Why Is Achieving Remission
Important?
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Residual symptoms put patients at high risk of
relapse and recurrence
– Patients with residual symptoms after
medication treatment are 3.5 times more likely
to relapse compared to those fully recovered
(Judd et al, 1998)
– This risk is greater than the risk associated
with having ≥ 3 prior depressive episodes
– Similar finding exists after response to
cognitive therapy
What is the course of
antidepressant
response?
Why a temporal delay for
maximal therapeutic
benefit
 -adrenergic
regulation
 5-HT2
receptor down-
receptor down-regulation
Antidepressant
medications have
essentially
equivalent efficacy
Tricyclic Antidepressants
(TCAs)
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Characteristic three-ring nucleus
Clinical effects
 Normalization of mood and resolution of
neurovegetative symptoms
Biochemical effects
 Inhibit monoamine uptake at nerve terminals
 May potentiate action of drugs that cause
neurotransmitter release
Temporal delay of weeks for clinical effects,
although biochemical effects are immediate
Mechanism of action of
TCAs
“Tertiary” TCAs
imipramine
amitriptyline
clomipramine
“Secondary” TCAs
desipramine
nortriptyline
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Inhibit 5-HT uptake
(weaker inhibition of NE uptake)
Inhibit NE uptake
(weaker inhibition of 5-HT uptake)
TCA Metabolism
imipramine
desipramine
N
N
N
H3C
CH3
H
N
CH3
amitriptyline
nortriptyline
N
H3C
CH3
tertiary amines
H
N
CH3
secondary amines
In vivo action of TCAs
If one administers a tertiary TCA
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If one administers a secondary TCA 
there is always both the tertiary
and the secondary amine in the
circulation
there is only the secondary
amine in the circulation.
Neuropharmacology of
TCAs
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Inhibit monoamine uptake (NE and 5HT)
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Muscarinic cholinergic antagonism
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H1 histamine antagonism
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1-adrenergic antagonism
TricyclicsContraindications
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QTc greater than 450 msec
Conditions worsened by muscarinic
blockade (eg myasthenia gravis, BPH)
pre-existing orthostatic hypotension
Seizure disorder
Side effect profile of TCAs
 Dry
mouth
 Constipation
 Dizziness
 Tachycardia
 Urinary retention
 Impaired sexual funtion
 Orthostatic hypotension
Low therapeutic index of
TCAs
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Cardiotoxicity: resulting from combination of:
 Conduction defects, arrhythmias
Delirium
Potentiation of effects of other sedating drugs
Consequences
 suicide
 requires care in prescribing
 monitoring drugs that might have synergistic
effects on monoamine function
Monoamine Oxidase
Inhibitors (MAOIs)
Irreversibly inhibit monoamine oxidase
enzymes
 Effective for major depression, panic
disorder, social phobia
 Drug interactions and dietary
restrictions limit use
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Biochemistry of MAO
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Occurs as two isoenzymes
 MAO-A –
• Oxidizes norepinephrine,
serotonin, tyramine
 MAO-B
 selective for dopamine
metabolism
Dietary and Drug
Interactions
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Increased stores of catecholamines sensitize patients
to effects of sympathomimetics
Accumulation of tyramine (sympathomimetic) = high
risk of hypertensive reactions to dietary tyramine
 requires dietary restrictions
Interactions with other sympathomimetic drugs
 Antidepressants
 OTC cold remedies
• phenylpropanolamine
 Meperidine
 L-dopa
Examples of MAOIs
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Irreversible, non-selective MAOIs
 phenelzine
 isocarboxazid
 tranylcypromine
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Selective MAO-B inhibitors
 deprenyl (selegiline)
 loses its specificity for MAO-B in antidepressant doses
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Reversible monoamine oxidase inhibitors
(RIMAs)
 Moclobemide – not approved
 Appears to be relatively free of food/drug interactions
Transdermal Selegiline
(Emsam)
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Potentially effective antidepressanteffect size less than most other
antidepressants
Dietary restrictions are unnecessary at
the 6 mg dose but probably required
at the 9 and 12 mg doses
Drug interactions are still a major
issue
VERY costly- ~$500/month
Serotonin syndrome
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Evoked by interaction between serotonergic agents
 e.g., SSRIs and MAOIs
 Combination of increased stores plus inhibition
of reuptake after release
Symptoms
 Hyperthermia
 Muscle rigidity
 Myoclonus
 Rapid changes in mental status and vital signs
Can be lethal
Selective Serotonin Uptake
Inhibitors
(SSRIs)
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Currently marketed medications
 fluoxetine (Prozac).
 sertraline (Zoloft).
 paroxetine (Paxil)
 fluvoxamine (Luvox)
 citalopram (Celexa)
 escitalopram (Lexapro)
Selectively inhibit 5-HT (not NE) uptake
Differ from TCAs by having little affinity for muscarinic,
as well as many other neuroreceptors
Selective Serotonin Reuptake
Inhibitors
(SSRIs)
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Much higher therapeutic index than TCAs
or MAO-I’s
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Much better tolerated in early therapy
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Equal or almost equal in efficacy to TCAs
Side effects associated
with SSRIs
 Nausea
 Sexual
dysfunction
 Delayed ejaculation/anorgasmia
 Anxiety
 Insomnia
 Hyponatremia
Selective NorepinephrineSerotonin Reuptake Inhibitors
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Venlafaxine (Effexor), Duloxetine
(Cymbalta), Desvenlafaxine(Pristiq) :
 relatively devoid of antihistaminergic,
anticholinergic, and antiadrenergic
properties
 nonselective inhibitor of both NE and 5HT uptake.
Adverse effects: GI , Sexual dysfunction,
hypertension (venlafaxine, desvenlafaxine),
hyponatremia
Other antidepressants
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Trazodone
 mixed 5-HT agonist/antagonist
• 1 antagonist
• H1 antagonist
Nefazodone (Serzone)
 5 HT2 antagonist
Bupropion (Wellbutrin; Zyban)
 Inhibits uptake of DA and NE
 antismoking properties probably involves
parent molecule
 Lacks sexual side effects
 Seizure risk
 Mirtazapine
(Remeron)
 2 antagonist
 5H2 and 5HT3 antagonist
 Net effect selective increase in 5HT1A
function
 H1 antagonist
advantages: sedation, no adverse
sexual effects
Antidepressants and drug
interactions
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Pharmacodynamic
– Additive effects with alcohol and other sedating drugs
– MAOI interactions
Pharmakokinetic
– Cytochrome P450-2D6 inhibition
 Fluoxetine and paroxetine
 Increased levels of TCAs, antipsychotics, warfarin
– Cytochrome P450-3A4 inhibition
 Nefazodone and fluvoxamine
 Increased levels of terfenadine, astemizole, cisapride –
can cause fatal arrhythmias
Other uses for antidepressants
 Panic
Disorder
 Obsessive Compulsive Disorder
 Only the ADs that inhibit serotonin
reuptake
Social Phobia
 Post Traumatic Stress Disorder
 Premenstrual Dysphoric Disorder
 Chronic pain syndromes
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When Do You Characterize
a Response As Treatment
Resistant?
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After a patient has been on an antidepressant at for a
reasonable amount of time at an adequate dose
No commonly accepted time point
– Most drug trial data comes from 8 week long studies
– If no onset of response by weeks 4 or 6, there is a 7388% chance of not having onset of response by end of
8 wk trial (Nierenberg et al, 2000), so 4 weeks is a
reasonable point to increase dose
– An 8-12 week course is consistent with acute
treatment framework and allows patients 8 weeks at a
dose expected to produce response
A Working Definition of
Treatment Resistant
Depression
6-8 weeks of at least a middle
range dose without remission
What Are the Clinical
Features Associated With
TRD?
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Incorrect primary diagnosis
– Is there a secondary cause of the depressive
symptoms (e.g., substance-induced mood
disorder from prescription meds or ethanol,
hypothyroidism, hypercalcemia )
– Is their primary psychiatric diagnosis wrong
(?bipolar, schizoaffective, cluster B personality
DO)?
– Is there an unrecognized depressive subtype?
 Psychotic depression
What Are the Clinical
Features Associated With
TRD?
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Patient factors
-acceptance of diagnosis
-compliance
Physician factors
-Underdosing
-Inadequate length of treatment
 Electroconvulsive
Therapy
– Response rate in patients with
 inadequate medication trials: 86%
 adequate trials: 50%
– Probably treatment of choice for
catatonic states
STAR D
http://www. star-d.org
STAR-D
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Level 1
– Initial Treatment: Citalopram
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Level 2
– Switch To:
bupropion
 sertraline
 Venlafaxine
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– Augment With:
bupropion
 buspirone
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Level 3
– Switch To:
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mirtazapine or nortriptyline
– Augment With:
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Lithium or T3
Level 4
– Switch To:
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Tranylcypromine or mirtazapine combined with
venlafaxine
How Effective is an SSRI in
Real World Practice?
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~1/3 met criteria for remission (HAM-D ≤ 7)
~ 1/2 met criteria for response (≥ 50%
decrease in depressive severity)
(Trivedi et al, Am J Psychiatry, 2006)
Treatment Outcomes (%
Remission)
(L-2 Switch)
HRSD-17 QIDS-SR-16
30
26.6
25.5
24.8
25.0
Percent
21.3
20
17.6
10
0
BUP-SR
(n=239)
Rush et al., N Engl J Med 2006;354(12):1231-42
SERT
(n=238)
VEN-XR
(n=250)
Treatment Outcomes (% Remission)
(L-2 Augmentation)
HRSD-17
50
39.0
Percent
40
30
QIDS-SR-16
29.7
30.1
32.9
20
10
0
BUP-SR
(n=279)
Trivedi et al., N Engl J Med 2006;354(12):1243-52
BUS
(n=286)
Remission Rates
Through Levels 1 and 2
80
Percent
60
40
53.0%
32.9%
30.6%
L-1
L-2*
20
0
Overall
TREATMENT OUTCOMES
L-3 Switch
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D)
mirtazapine
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nortriptyline
Remission (HAM-
12.3%
19.8%
TREATMENT OUTCOMES
L-3 Augmentation
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Lithium
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T3
Remission (HAM-D)
15.9%
24.7%
TREATMENT OUTCOMES
L-4 Switch
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(HAM-D)
Tranylcypromine
mirtazapine + venlafaxine
Remission
6.9%
13.7%
STAR*D SUMMARY
Patients suffering from major
depression (primarily with chronic
disease and multiple recurrences) in
Primary and Specialty Care settings
have a 30% chance of achieving full
remission with an adequate dose of
citalopram
STAR*D SUMMARY
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Patients who did not remit with
citalopram had a 1 in 4 chance of
achieving remission by switching to
bupropion, sertraline or venlafaxine
and a 1 in 3 chance of responding to
augmentation of the citalopram with
bupropion or buspirone
There was no clear advantage in
switching antidepressant class
STAR*D SUMMARY
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Depressed patients who fail to respond
to two antidepressant trials are have
a 12-20% remission rate with another
single antidepressant agent and a 1625% remission rate with T3 or lithium
augmentation
STAR*D SUMMARY
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While there is indisputable evidence
for real world effectiveness of available
antidepressant medications, many
patients do not achieve remission.
There is a pressing need to develop
more effective treatments for
depression and also to elucidate
factors that may help us choose from
our currently available treatments.
References
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Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR,
sertraline, or venlafaxine-XR after failure of SSRIs for depression.
N Engl J Med. Mar 23 2006;354(12):1231-1242.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication
augmentation after the failure of SSRIs for depression. N Engl J
Med. Mar 23 2006;354(12):1243-1252.
Fava M, Rush AJ, Wisniewski SR, et al. A Comparison of
Mirtazapine and Nortriptyline Following Two Consecutive Failed
Medication Treatments for Depressed Outpatients: A STAR*D
Report. Am J Psychiatry 2006; 163:1161-1172.
Nierenberg AA, Fava M, Trivedi MH, et al. A Comparison of Lithium
and T3 Augmentation Following Two Failed Medication Treatments
for Depression: A STAR*D Report. Am J Psychiatry 2006;
163:1519-1530.
www.ids-qids.org