Transcript Major Depression PPT

Pharmacologic
Treatment of
Depression
Ten Leading Causes of
Disability in the World
Type of Disability
Cost (in
DALYs)
Cumulative
%
of Cost
Unipolar major depression
42,972
10.3
Tuberculosis
19,673
14.9
Road traffic accidents
19,625
19.6
Alcohol use
14,848
23.2
Self-inflicted injuries
14,645
26.7
Bipolar Disorder
13,189
29.8
War
13,134
32.9
Violence
12,955
36.0
Schizophrenia
12,542
39.0
Iron deficiency anemia
12,511
42.0
Antidepressants - History
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1958
1958
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%
Mild-moderate
decrease in HAM- improvement
D
Nonresponse < 25% decrease
in HAM-D
No clinically
meaningful response
~ 10%
~ 25%
Efficacy vs
Effectiveness
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
Major Depression
• Syndromal classification with
disturbances of mood, neurovegetative
and cognitive functioning
Major Depression
At least 5 of the following symptoms
present for at least 2 weeks (either #1
or #2 must be present):
1) depressed mood
2) anhedonia – loss of interest or
pleasure
3) change in appetite
4) sleep disturbance
Major Depression
5) psychomotor retardation or
agitation
6) decreased energy
7) feeling of worthlessness or
inappropriate guilt
8) diminished ability to think or
concentrate
9) recurrent thoughts of death or
suicidal ideation
Major Depression
• Symptoms cause marked distress
and/or
impairment in social or occupational
functioning.
• No evidence of medical or substanceinduced etiology for the patient’s
symptoms.
• Symptoms are not due to a normal
reaction to the death of a loved one.
Special Diagnostic
Considerations
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Bereavement
Late life onset
Subtypes
Cluster B personality disorders
Bereavement and
Late Life Depression
• 25 – 35% of widows/widowers
meet diagnostic criteria for major
depressive disorder at 2 months.
• ~15% of widows/widowers meet
diagnostic criteria for major
depressive disorder at one year.
• This figure remains stable
throughout the second year.
Subtypes of Depression
• Atypical
 Reverse
neurovegetative
symptoms
 Mood reactivity
 Hypersensitivity to rejection
 MAO-I’s and SSRI’s are more
effective treatments
Subtypes of Depression
 Psychotic
(~10% of all MDD)
• Delusions common, may have
hallucinations
• Delusions usually mood
congruent
• Combined antidepressant and
antipsychotic therapy or ECT is
necessary
Subtypes of Depression
 Melancholic
• No mood reactivity
• Anhedonia
• Prominent neurovegetative
disturbance
• More likely to respond to
biological treatments
Subtypes of Depression
 Catatonic
• Motoric immobility (catalepsy)
• Mutism
• Ecolalia or echopraxia
What is the course of
antidepressant
response?
Why a temporal delay for
maximal therapeutic
benefit
 -adrenergic
regulation
 5-HT2
receptor down-
receptor down-regulation
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
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
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
Uptake 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
Selective NorepinephrineSerotonin Reuptake Inhibitors
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Venlafaxine (Effexor) Duloxetine (Cymbalta):
 relatively devoid of antihistaminergic,
anticholinergic, and antiadrenergic
properties
 nonselective inhibitor of both NE and 5HT uptake.
Adverse effects: GI , Sexual dysfunction,
hypertension (venlafaxine)
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
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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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Treatment
Course
 One episode – 50% chance of
reoccurence
 Two episodes – 70% chance of
reoccurence
 Three or more episodes - >90%
chance of reoccurence
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