Download Major Depressive Disorders

Pharmacotherapy of
Depression and Anxiety
Vickie Corbett Ripley, PharmD, BCPP
Clinical Pharmacist Practitioner
Coastal Plain Hosptial
Rocky Mount, NC
1
Pharmacotherapy for
Major Depression
 Etiology
and Pathophysiology
 Diagnosis and clinical presentation
 Antidepressant efficacy
and side effects
 Treating major depression
 Special Populations
 Other treatment options
 Drug interactions
2
Limbic System Dysfunction
3
Spectrum of Psychiatric Disorders
ANXIETY
Panic disorder
GAD
OCD
Agoraphobia
4
AFFECTIVE
Major Depression
Bipolar Disorder
Dysthymia
PSYCHOSES
Schizophrenia
Schizoaffective
Neurotransmitters and Psychiatric
Pharmacotherapy
Anxiolytics
Norepinephrine
AntiDepressants
Serotonin
GABA, others
5
AntiPsychotics
Dopamine
Phases of MDD Treatment
S
e
v
e
r
i
t
y
6
Recurrence After Recovery
from Major Depression
n = 555 Unipolar Depressives (1985-1994)
100
Cumulative
Probability of
Recurrence, %
75
46
50
54
60 61
75
74
73
67 70
33
25
15
0
0.5 1
7
2 3 4 5 6 7 8
Time to Recurrence, years
The NIMH Collaborative Depression Study, 1977-1992
9 10
Diagnosis of mental illness

DSM IV (Diagnostic and Statistical Manual of
Mental Disorders – 4th edition)
– Lists criteria necessary to meet diagnosis
– Useful for standardizing diagnoses

To meet most diagnoses generally must
– Interfere with social or occupational functioning
– Must be interpreted in context of culture
8
Multiaxial Assessments
Axis I – Clinical Disorders
 Axis II – Personality disorders and
mental retardation
 Axis III – General medical conditions
 Axis IV – Psychosocial and
Environmental problems
 Axis V – Global assessment of
functioning (GAF)

9
Axis I disorders

Mood disorders
– Major depressive disorder
– Bipolar disorder

Anxiety disorders
–
–
–
–

10
Generalized anxiety disorders
Panic disorder
Social phobia
Obsessive Compulsive Disorder
Psychotic disorders - schizophrenia
DSM IV Classification of
Major Depressive Episode
Depressed mood and/or loss of Interest present
during a two week period
 Plus at least FOUR of the following symptoms:

– Weight change
– Sleep disturbance
– Psychomotor agitation or retardation
– Loss of energy
– Feelings of worthlessness/guilt
– Loss of ability to concentrate
– Suicidal ideations
11
Psychiatric Patient Presentation
 Chief
Complaint
 History of Present Illness
 Past Medical History
 Family and Social
Histories
 Medications
 Allegies
 Review of Systems
12
 Physical
Examination
 Mental Status Exam
– Appearance, behavior,
and speech
– Mood and Affect
– Sensorium
– Intelligence
– Thought process
 Labs
Symptoms of Depression
and Serotonin Function







13
Depressed or elated Mood
Appetite changes
Sleep changes
Decreased libido
Increased pain sensitivity
Circadian rhythm disturbances
Body temperature changes
Percent of Perfect Functioning
Physical and Social Functioning in
Depression and Chronic Illness
14
100
90
80
70
60
50
40
30
20
10
0
Physical Function
None
Hyper- Diabetes Arthritis
tension
Angina
Only
Wells, et al. J Amer Med Assoc 1989; 262:914-919
Social Function
CAD
Depression
S
I
G:
E
C
A
P
S
15
Symptoms of Depression
(Sig: E caps)
Sleep
Interest
Guilt
Energy
Concentration
Appetite
Psychomotor retardation
Suicidality
Treatment choices







16
Psychotherapy
Light
Exercise
Diet
Medication
Medication and Psychotherapy
Electroconvulsive therapy (ECT)
Psychotherapies




17
Interpersonal therapy
Cognitive therapy
Behavior therapy
Group therapy
Psychotherapy





18
Less severe
Less chronic
Nonpsychotic
Previous positive response
Medical contraindication to medication
Algorithm for Treatment of
Uncomplicated Major Depression

1st line: Favorite SSRI or TCA
– Failed trial: switch to alternative
– Partial response - increase dose, switch or augment
– Fully remits (maintain at least 4 to 6 months or longer)

2nd line: Switch or Augment
– Switch to other favorite - TCA or SSRI
– Augment with Li or TCA plus the SSRI (consult with psychiatrist)

19
3rd line: Failed or Partial response to 2nd line
– Consult with psychiatrist
– Switch (nefazodone, mirtazepine, bupropion, venlafaxine)
– Augment with Li or TCA plus the SSRI
Adapted from Kando JC et al: in Pharmacotherapy, 4th ed, Dipiro, eds., 1999, p 1156
Target Symptoms and
Therapeutic Response Rates
 Week
One:
– anxiety
– insomnia
– decreased appetite
 Weeks
two and three:
– increase in energy
– increase suicide risk
– increase in libido
20
 Up
to 4 to 8 Weeks:
– Improvement in
dysphoria or sadness
– improvement in
pessimism
– improvement in
anhedonia
Treatment strategies if no
response





21
Confirm compliance
Maximize dose
Change drug
Combine antidepressants
Augmentation therapy
Augmentation medications







22
Lithium
AED’s
Stimulants
Thyroid
Estrogen
Sleep aids
Pain meds
Melancholic Depression
 Clinical Presentation
–Subtype of severe depression
–Nearly complete absence of capacity for pleasure
–Diurnal mood swings (worse in the morning)
–Excessive guilt and weight loss
 Unclear
if SSRI’s as effective as TCA’s in
treatment
 Some data indicate that mirtazapine and
venlafaxine more effective than SSRI’s
23
Atypical Depression
 Clinical Presentation
–Weight gain or increased appetite
–Hypersomnia
–Heavy feeling in arms or legs (leaden
paralysis)
–Interpersonal rejection sensitivity
 MAOI’s
greater efficacy than TCA’s
 Efficacy of SSRI’s relative to
MAOI’s unclear
24
MDD with psychotic features
 Clinical
Presentation:
–Delusions or hallucinations present
during depressive episodes
 Usually
need an antidepressant
and an antipsychotic
25
Differentiation Between
Depression and Dementia
Area
Depression history (self/family)
Depression symptoms precede
cognitive deficit
Duration of Symptoms
Depression
Present
Dementia
Absent
Present
Weeks
Absent
Months-Years
Complains
Silent Concern

Cognitive Deficit
Cognitive Function Test
Performance deficits
Response to MSE questions
Inconsistent
"I don't Know"

Effort on Testing
Little
Consistent
Attempts to
answer
Tries hard





26
Baker FM. J National Med Assoc 1991; 83:340-344
Psychiatric Pharmacotherapy
Anxiolytics
Benzodiazepines
AntiDepressants
Tricyclics
MAO Inhibitors
SSRIs
Mood Stabilizers
27
AntiPsychotics
Phenothiazines
Butyrophenones
Atypicals
Serotonin receptors

5-HT 2
–
–
–
–
–
–
28
agitation
akathisia
anxiety
panic attacks
insomnia
sexual dysfunction
Serotonin receptors

5-HT 3
–
–
–
–
29
nausea
gastrointestinal distress
diarrhea
headache
Dopamine receptors

Stimulation can lead to
–
–
30
agitation
aggravation of psychosis
Norepinephrine receptors

Stimulation can lead to
–
–
–
31
activation
hypertension
panic
Alpha 1 adrenergic receptors

Blockade can lead to
–
–
–
32
dizziness
orthostatic hyotension
reflex tachycardia
Histamine receptors (H1)

Blockade can lead to
–
–
33
sedation
weight gain
Muscarinic cholinergic
receptors

Blockade can lead to
–
–
–
–
–
–
34
blurred vision
dry mouth
sinus tachycardia
constipation
urinary retention
memory impairment
Medications







35
TCA
MAOI
SSRI
SNRI (venlafaxine)
NDRI (buproprion)
NaSSA (mirtazipine)
SARI (nefazadone)
SSRI and New Antidepressants
Metabolism
Drug
T½, h
Active
Metab
Metab
T½
Time to
SS, days
NonLinear
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
Venlafaxine
Nefazodone
Mirtazapine
Citalopram
45-137
Yes
200-250
20-45
Yes
26
Yes
62-104
5-15
DMSert
21
---
No
4-10
Yes
15
---
No
3-4
Yes
4-6
Yes
9-11
3
No
2-4
Yes
18
3-4
Yes
20-40
---
No
5-10
No
35
Yes
49
7-17
No
36
Antidepressant Side Effects
Drug
Amitriptyline
 Doxepin
 Nortriptyline
 Desipramine
 Trazodone
 Bupropion
 Fluoxetine
 Sertraline
 Paroxetine
 Venlafaxine
 Nefazodone
 Mirtazapine

37
Sedation
++++
++++
+++
++
+++
-/+
-/+
++
+/++
++
++++
Anticholinergic
+++
+++
+++
++
+
+
+
+
++
Orthostatic
++++
+++
++
+++
+++
+
+
+
Adapted from: MJ Dewan et al J Geriatr Psychiat Neurol 1992; 40-44
Single mechanism drugs

Mostly noreinephrine
–
–

Mostly serotonin
–
–
38
desirpramine
buproprion
SSRI’s
nefazadone
Tricyclic Antidepressants
 Serotonin
reuptake Inhibition
 Norepinephrine reuptake inhibition
 Anticholinergic effects
 Alpha1 blockade
 Histamine blockade
39
Tricyclic Antidepressants
 Useful
in the treatment of a number of
conditions
40
–Depression
–Migraine prophylaxis
–Neuropathic pain
–Obsessive compulsive disorder (Clomipramine)
–Enuresis
–Panic disorder
–Sleep disorders
–Attention deficit / hyperactivity disorder
Tricyclic Antidepressants





41
Clomipramine (Anafranil) 25-250mg
Amitriptyline (Elavil) 50-300mg
Doxepin (Sinequan) 25-300mg
Imipramine (Tofranil) 30-300mg
Desipramine (Norpramin) 25-300mg
Tricyclic Antidepressant

Secondary amine

Greater NE relative to
5HT activity

Greater anticholinergic
effects
– Desipramine (Norpramine)
– Nortriptyline (Pamelor)
– Protriptyline (Vivactil)

42
Tertiary amine
–
–
–
–
–
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Imipramine (Tofranil)
Doxepine (Sinequan)
Trimipramine (Surmontil)
Tricyclic Antidepressant
 Secondary amine
– Desipramine -- 100 to 300 mg
– Nortriptyline -- 50 to 150 mg
– Protriptyline -- 15 to 60 mg
 Tertiary amine
– Amitriptyline -- 100 to 300 mg
– Clomipramine -- 100 to 250 mg
– Imipramine -- 100 to 300 mg
– Doxepin -- 100 to 300
– Trimipramine 100 to 300
43

With most TCA’s
start with 50 mg
and increase by 25
to 50 mg every 3
days (lower for
nortriptyline or
protriptyline)
TCA plasma concentrations

Nortriptyline - Curvilinear conc/response profile
– 50 to 150 ng/ml

Desipramine
– 125 to 300 ng/ml

Imipramine
– 200 – 300 ng/ml
Not routinely performed but can be useful in
certain situations
 Should be obtained at steady state (at least 1 week
after initiating or dose change)

44
TCA Adverse Events
 Anticholinergic
effects
 Antihistaminic effects
 Alpha1 adrenergic blockade
 Sexual dysfunction
 Cardiac conduction delays
– Can result in arrhythmias in overdose
 Decreased
seizure threshold
 Toxic in overdose
45
– Do not use in acutely suicidal patients
Preferred uses of TCA’s

Depression with
–
–
–
–
46
Pain
Fibromyalgia
Migraine
insomnia
Least preferred uses of TCA’s





47
Patients in whom anticholinergic effects would
be problematic
Overweight patients
Suicidal patients
Cardiac patients
Patients with dementia
Selective Sertotonin Reuptake
Inhibitors (SSRI’s)
 Fluoxetine
(Prozac)
 Paroxetine (Paxil)
 Sertraline (Zoloft)
 Fluvoxamine (Luvox)
 Citalopram (Celexa)
 Escitalopram (Lexapro)
48
Uses of SSRI’s
 Depression
 Social
phobia
 Panic disorder
 Obsessive compulsive disorder
 Bulimia Nervosa
 Post Traumatic Stress Disorder
 Pre Menstrual Dysphoric Disorder (Sarafem)
49
SSRI Dosing
 Dosing
– Fluoxetine -- 20 to 60 mg
– Paroxetine -- 20 to 50 mg
– Sertraline -- 50 to 200 mg
– Fluvoxamine -- 100 to 300 mg
– Citalopram -- 20 to 60 mg
– Escitalopram – 10 to 40 mg
 Relatively
safe in overdose
 Relatively safe in patients with cardiovascular
disease
50
SSRI Adverse Effects
 Gastrointestinal
– Nausea, vomiting, diarrhea
 Sexual
dysfunction
 Headache
 insomnia
 Fatigue
 Agitation
 Akathesia and dystonic reactions
– 5HT can reduce DA levels
51
Differences between SSRI’s
 Most
likely to cause sedation
– Paroxetine, fluvoxamine
 Paroxetine
– Mild anticholinergic effects
 Fluoxetine
– Higher rates of anxiety and nervousness
 Sertraline
– More diarrhea
52
When to use SSRI





53
First line monotherapy
Depression
Anxiety (start with low doses)
OCD
Panic
Least preferred use of SSRI





54
Patients with sexual dysfunction
Patients with secondary refractoriness
Patients with nocturnal myoclonus
Patients with consistent agitation
Patients with consistent insomnia
SSRI Withdrawal Syndromes
 More
likely to occur with short t1/2 agents
(paroxetine warning)
 May affect up to 1/3 of patients and more likely to
be reported with short half-life agents
 May be due to sudden decrease in available
synaptic 5HT in face of down-regulated receptors
 Onset in 24 to 72 hours and last up to 7-14 days
 Symptoms: dizziness, nausea, lethargy, headache,
flu-like symptoms, parasthesia (electrical “shocklike” sensations)
55
Discontinuation syndrome






56
Worse with short acting drugs
Taper dose
Flu-like symptoms
Anxiety
GI distress
Mood, appetite, sleep changes
Serotonin Syndrome
 Symptoms
–Altered mental status – confusion, agitation
–Autonomic dysfunction – diaphoresis,
tachycardia, BP changes, fever
–Neuromusucular abnormalities – clonus
 Allow
2 weeks between MAOI and
other antidepressant administration
–5 weeks for fluoxetine
57
Serotonin Syndrome
 Occurs
when several serotonergic
drugs combined
 Often involves MAOI’s as one of the
drugs
 Other serotonergic drugs implicated
»SSRI’s
»TCA’s
»Serotonin releasing agents (i.e. MDMA or
“ecstasy”)
»Dextromethorphan, meperidine, others
58
Nefazodone
(Serzone, Bristol-Myers Squibb)
Potent 5HT2 receptor antagonist
 Relatively weak 5HT reuptake inhibition
 Alpha1 receptor blockade
 Metabolism:

– OH-Nefazodone = 1.5 - 4 hours
– triazole-dione = 18 hours
– mCPP = 4-8 hours
Usual Dosage: 300 - 600 mg/day in 2 divided doses
 Preserves sleep architecture
 Potent CYP3A4 inhibitor

59
Therapeutic uses of
nefazadone

depression in association with
–



60
anxiety, agitation, sleep disturbances
Prior SSRI induced sexual dysfunction
Inability to tolerate SSRI’s
Tolerance to SSRI’s
Lest preferred use of
nefazadone




61
Patients with hypersomnia
Non-compliance with BID dosing
Retarded depression
Patients with difficulty with dose titration
Dual-Action Drugs

Norepinephrine and serotonin
clomipramine
– venlafaxine
– mirtizapine
–
62
NaSSA

Noradrenergic and specific serotonergic
antidepressant
–
63
mirtazipine (Remeron) 15-90mg
Mirtazapine (Remeron®, Organon)
 Initial
Dosing:
– Start with 15mg qd (hs) (supplied as 15 and 30 mg tablets)
– Average effective dose is 20-25mg qd
– Maximum dose=45mg qd
 Half
life
– Women have longer half-life than men 37 vs 26 hours
– Half-life allows for qd dosing
 Dosage
64
adjustments:
– Any dosage should be made after one to two weeks
– Adjust dose for hepatic disease
– Slow titration in the elderly
Mirtazapine (Remeron, Organon)
 Receptors: -5HT2 and 5HT3 antagonist, histamine 1,
minimal activity on alpha 1, muscarinic, and dopamine
 Common
Side Effects: Somnolence, dry mouth, weight
gain
 Cautions: Can precipitate mania, hepatotoxicity (dose
adjust in hepatic disease)
 Drug
Interactions: additive cognitive and motor CNS
depression, Metabolized by CYP2D6, 1A2, 3A4,Wait 14
days after stopping MAOI
 Dosing: Start with Start with 15mg qd, usually 20-25 mg
qd, maximum dose = 45mg qd
65
Therapeutic uses of
mirtazapine






66
Depression with anxiety or agitation
Depression with insomnia
Problems with SSRI’s
Weight loss
Severe depression
Loss of response to SSRI’s
Least preferred uses of
mirtazapine




67
Hypersomnia
Motor retardation
Cognitive slowing
overweight
SNRI

Serotonin/norepinephrine reuptake inhibitor
–
68
venlafaxine (Effexor) 75-375mg
Venlafaxine (Effexor, Wyeth-Ayerst)
Dose
 Serotonin
reuptake inhibition
 Norepinephrine reuptake inhibition
 Dopamine reuptake inhibition
 Usual
69
dose: 75 to 225 mg
Therapeutic uses of
venlafaxine





70
At low doses, use as an SSRI
At high doses has dual action
Patients with hypersomnia
Patients with GAD
Patients with weight gain
Least preferred use of
venlafaxine




71
Agitated patients
Patients with sexual dysfunction
Patients with insomnia
Patients with labile HTN
Venlafaxine Adverse Effects
 Nausea,
constipation
 Headache
 Dizziness
 Nervousness
 Somnolence
 Dry mouth
 Sexual dysfunction
 Increased blood pressure (monitor closely)
72
NDRI

Norepinephrine/dopamine reuptake inhibitor
–
73
buproprion (Wellbutrin) 200-450mg
Therapeutic uses of
buproprion







74
Patients with retarded depression
patients with hypersomnia
Non-responders to SSRI’s
Non-tolerators of SSRI’s
Patients concerned about sexual dysfunction
Patients concerned about weight gain
Patient with cognitive slowing
Least preferred use of
buproprion






75
Patients with seizure disorders
Patients who are seizure prone
Patients with head injury
Patients non-compliant with multiple daily doses
Patients with agitation
Patients with insomnia
Comparative Safety and Tolerability
Summary

Nausea
–Common with all
–Dose related, dissipates with use





76
Diarrhea- higher incidence with Sertraline
Dry Mouth- VEN, NEF > PAR, SER > FLU, FVX
Anorexia- More likely with Fluoxitine, Venlafaxine
Anxiety/nervousness- More common with Fluoxitine
Sexual Dysfunction- all SSRIs, Ven > Nefazodone
CL DeVane Human Psychopharmacology 1995; 10:S185-S193,
Monoamine Oxidase Inhibitors (MAOI’s)
Used in patients with atypical MDD/ anxiety
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Hypertensive crisis can occur when combined with
high tyramine foods or sympathomimetics

– Aged cheeses, sour cream, wines, beer, canned or processed meats,
fermented foods, coffee, chocolate
– Amphetamines, ephedrine, other decongestants

77
Doses: Phenelzine – 15 to 90 mg
Tranylcypromine – 20 to 60 mg
MAOI adverse effects
 All
agents
– Sexual dysfunction
– Mild anticholinergic effects
 More
likely with phenelzine
– Orthostatic hypotension
– Sedation
 More
likely with tranylcypromine
– Insomnia
78
Drugs Metabolized by Human
Liver Cytochromes P450s
Superfamily
P-450
Families
1
Subfamilies
A
Members
with narrow
therapeutic
index
79
1A2
3
2
C
2C9/19
Theophylline (S)-Warfarin
Imipramine Phenytoin
Carbamazepine
Tolbutamide
D. Rodrigues Pharmacogenetics Conf, May 1996
D
A
2D6
3A4
Imipramine
Desipramine
Amitriptyline
Nortriptyline
Thioridazine
Terfenadine
Cyclosporine
Triazolam
Imipramine
Carbamazepine
Inhibition of Cytochromes P450
80
Drug
1A2
2C
2D6
3A4
Fluoxetine
(Prozac)
Sertraline
(Zoloft)
Paroxetine
(Paxil)
Fluvoxamine
(Luvox)
Venlafaxine
(Effexor)
Nefazodone
(Serzone)
Mirtazapine
(Remeron)
Citalopram
(Celexa)
0
++
0
++/++
+/++
++/++
0
0
+++
0
++++
++
0
+++
0
0
0/+
?
0
0
0
++++
0
0
0
0
0/?
0/?
0/+
0
++++/++++ ++/+++
1A2
substrates/inhibitors




81
Antispychotics
TCA’s
Fluoroquinolones
theophylline
Drug interactions

1A2
– Fluvoxamine ++++
82
2D6
substrates/inhibitors





83
Antiarrhythmics
Antipsychotics
Beta blockers
Opiates
TCA’s
Drug interactions

2D6
–
–
–
–
84
Fluoxetine ++++
Sertraline +
Paroxetine ++++
Venlafaxine +?
2C
substrates/inducers/inhibitors





85
Barbiturates
NSAIDS
Warfarin
Antifungals
TCSA’a
Drug interactions

2C
– Sertraline
++
– Fluoxetine
++
– Fluvoxamine ++
86
3A4
substrates/inducers/inhibitors




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

87
Antiarrhythmics
Antifungal
Antihistamines
Antipsychotics
Barbiturates
Benzodizepines
Calcium channel blockers
Grapefruit juice
TCA’s
Drug interactions

3A4
–
–
–
–
88
Sertraline
+
Fluoxetine
++
Fluvoxamine +++
Nefazadone ++++
Drug Interactions - Herbal Remedies

St. John’s Wort (Hypericum perforatum)
– Drugs that interact with MAOIs

Ginko (Ginko biloba)
– Anticoagulants (2 cases), or ASA

Kava (Piper methysticum)
– Benzodiazepines (1 alprazolam case), alcohol

Ginseng (Siberian ginseng)
– potentiates MAOIs, stimulants (caffeine) and haloperidol

Yohimbine (Pausinystalia yohimbine) a2 antagonist
– TCA, MAOIs, antimuscarinic agents potentiate yohimbine
89
Wong AHC et al Archives Gen Psychiatry 1998; 55(11) 1033-1044
St. John’s Wort Reduces the
AUC of the HIV-1 PI Indinavir





Open-label, Eight healthy volunteers
(6M/2F) 29-50 yo
Indinavir 800 mg orally(q8h x4)
Blood samples 0-8 hours (AUCss)
Before and after SJW 300 mg tid x 14 d
(Hypericum Buyers Club)
AE’s: taste changes (50%), nausea (25%),
circumoral paresthesias (25%) associated
with indinavir. Reduced intensity and
duration with SJW.
Increased resistance and Tx failure?
100
Percent Decrease

75
50
25
0
AUC Cp 8h
90
Cp
max
Piscetelli SC Burstein AH, Alfaro RM, The Lancet, 2000; 355(9203) 12 Feb
Basic algorithm

Monotherapy
– Allow time for drug to work (4-6 weeks)
– Symptoms will resolve gradually
– Maximize dose
91
Selection of Antidepressant






92
Presenting symptoms
Previous response
Family history
Neurotransmitter profile
Co-morbid conditions
Human data





Side effect profile
Potential drug interactions
Patient age
Compliance
Cost
Monitoring Antidepressant Therapy
 Monitor antidepressant regimen
– Is the dosage appropriate?
– Response favorable and adequate?
– Side effects present?
 Review new chart entries
– New orders?
– New Diagnoses?
– Changes in life events?
 Review progress notes
– Physician, nursing, social service, psychiatric service
 Continue
therapy
– 9-12 months if first episode. If multiple: chronic maintenance
93
S.M. Feldman ASCP November 1995
Clinical Management of Treatment
Emergent Adverse Effects





94
Continuation of current pharmacotherapy
Dose Reduction
Trial period of discontinuing medication
Antidepressant substitution
Adjunctive therapy (cases reported)
Combining other medications






95
Add augmentation therapy
Consider drug interactions
Monitor other medications
- OTC’s and herbals
- beta blockers
- steroids
Combining medications


Use two drugs with different mechanisms
SSRI plus
– venlafaxine
– mirtazipine
– buproprion
– nefazadone
– Or combinations of non SSRI’s
96
Depression Co-Morbidity
Medical Illness
Terminal solid tumors
Stroke
Chronic medical illness
Chronic pain
Epilepsy
Parkinson's disease
Myocardial infarction
Diabetes mellitus
97
Depression Prevalence
25% to 38%
20% to 50%
15%
35% to >50%
11% to 30%
30% to 50%
20%
20%
Concurrent medical disorders






98
Asthma - avoid MAOI
Cardiac disease - avoid TCA
Dementia - avoid TCA and other anticholinergic
drugs
Seizures - avoid buproprion and TCA
Glaucoma - avoid TCA
HTN - watch orthostasis
Antidepressant Selection in
the Cardiac Patient
 Avoid
concomitant Type IA antiarrhythmics
(TCA with quinidine or procainamide)
 BUP, SSRIs, VFX, SRZ appear to be low risk
for arrhythmias and orthostatic hypotension
 Venlafaxine is associated with increases in BP
 MAOIs, Trazodone, maprotiline, amoxapine,
SSRIs, and venlafaxine have not been well
studied in CHF
99
APA Practice Guidelines, Am J Psychiatry
Comorbid MDD and Cardiac
Disease
 Tricyclic
antidepressants complicate and/or are
contraindicated in specific cardiac conditions
– Hx ventricular arrhythmia
– subclinical sinus node dysfunction
– conduction defects (including asymptomatic)
– prolonged QT intervals
– recent history of myocardial infarction
 Consider
using bupropion, fluoxetine, sertraline,
paroxetine, nefazodone, citalopram or ECT
100
APA Practice Guidelines, Am J Psychiatry
Comorbid MDD and Cardiac
Disease
 MAO
inhibitors may induce orthostatic
hypotension and lead to drug-drug interactions
 Monitor patient for emergence of cardiac
symptoms, ECG changes, or orthostatic BP
decrements
 Major depression is a major risk factor for
increased cardiac morbidity and mortality.
101
APA Practice Guidelines, Am J Psychiatry
Depression and
Coronary Artery Disease
102
Januzzi et al. Archives of Internal Med 2000;160(13):1913-21.
Case of JC









103
30 year old, married female, 4 children
Feelings of helpless, hopeless, worthless, guilt
Started with birth of last child 6 months ago
Sleepy and tired all the time, no energy
East too much
Decreased libido
No interest in much
FH + depression
No other medical problems
Case of BH







104
54 year old married female, 2 children grown
30 year hx MDD
Multiple medications have been tried
Medical Dx – fibromyalgia, IBS, chronic sinusitis
Meds – Remeron. Lortab, Bently, Allegra D,
various OTC and herbals
Previous Ads – Prozac, Paxil, AMI, Effexor,
Zoloft, Serzone, Celexa, “everything else”
c/o weight gain, still depressed
MDD Presentation in Late Life
Often lacks family history of depression
 Highest Suicide risk of all age groups

– twice the risk in elderly white males
– less in elderly black males
– same in females

Often associated with medical illness
– Stroke (50% develop clinically significant depression)
– Parkinson’s disease (40 to 90% have associated depression)

105
Typically seen by primary care physicians and may need
referrals to mental health specialist for certain aspects of
treatment
Diagnosis and Treatment of
Depression in Late Life
 Recognition
may be more difficult in late life
– “normal aging” and overshadowed by physical illness
 Similar
social and demographic risk factors:
– female sex, single (esp. widowed), stressful life events, lack of
supportive social network
 Treatment
with sufficient:
– doses (plasma concentrations) of antidepressants
– length of treatment (e.g. at least 6 to 12 weeks in the elderly) to
maximize likelihood of recovery
– maintenance treatment for 6 to 12 or more months
106
NIH Consensus Development Conference
MDD Symptomatology in Late Life
 Symptoms:
irritability, agitation, somatic delusions
 Somatic complaints:
pain syndromes (general, headache, chest, GI),
cardiac (palpitations, tightness),
abdominal (constipation)
 Loss of interest or pleasure may appear as apathy
107
Symptomatology in Late Life
(cont’d)
 Difficulty
in concentration may appear as
inattentiveness
 Disorientation, memory loss, distractibility as
“dementia”
– 10% of “senile or pseudo dementia” is actually depression
(now called “dementia syndrome of depression”)
– depression can coexist with dementia
 Heterogeneity
of geriatric depression
(early Vs late onset)
– early onset has more recurrences, more (+) family history
108
Response to Effective Treatment
of Depression in Late Life
 Majority
should expect partial or complete
remission of depressive symptoms
 Amelioration of pain and suffering
associate with physical illness
 Enhancement of general mental, physical
and social functioning
 Minimization of cognitive disability
109
NIH Consensus Development Conference
MDD Presentation in the Elderly
“R.M., a 71-year-old male, is brought for psychiatric
evaluation by his daughter, C.M., with whom he has been
living for the past 3 years. C.M. reports that R.M. had
been in good health until 3 months ago when he was noted
to keep to himself and began showing little interest in his
usual activities. She reports that he used to be a happy,
very outgoing personality He has lost weight over the past
4 months, has been noted to be irritable, anxious, and has
trouble falling asleep. He also frequently becomes
agitated over insignificant things. He has appeared on
occasion to be confused and slow in understanding
concepts. ....”
110
LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18
MDD Presentation in the Elderly
Cont’d
“...His recent physical examination is normal except for
benign prostatic hypertrophy (BPH). Laboratory
examinations are WLN except for a subnormal serum
creatinine. He currently is on no medication except for a
daily stool softener and a bulk laxative.
Mental Status Examination reveals a thin, nervous, sadappearing man. His responses to questions are slow. Affect
is sad. He shows no signs of delusions or hallucinations.
He shows mild impairments in his ability to think through
problems and mathematical exercises. He denies suicidal
ideation but feels hopeless at the present time.”
111
LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18
MDD Presentation in the Elderly
 “How
does a depressive episode in late life, such as
that in R.M., differ from a depressive episode earlier
in life?”
 “What is R.M.’s differential diagnosis?”
 “Should R.M. be placed on antidepressant therapy?”
 What factors would influence drug selection?
112
LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18
The Case of R.M., Cont’d
 How
does the pharmacokinetic profile of
the SSRI’s affect your choice?
 What are the significant drug interacts that
should be considered with R.M.’s
pharmacotherapy if treatment for other
common disorders were added?
113
For a first episode of depression
patients should be on medication for
at least 12 months
114
For a second episode of depression,
the patient should be on medication
for 2 to 3 years
115
For a third episode of depression,
most patients stay on medication for
life
116
When deciding to take a patient off an
antidepressant, the patient’s medical
and psychosocial situations must be
considered
117
Patient education




118
Do not perpetuate the stigma of psychiatric
illness
Treat the patient with the same empathy, respect
and concern you would treat a patient with a
medical disorder
Explain depression as a medical disorder
Do not be afraid to discuss the signs and
symptoms of depression
Patient education



119
Encourage compliance with medication
Help patients understand the medications and
common side effects
Help patients understand there is no magic
bullet, but most people are successfully treated
Questions
?
120