Download DEPRESSION

DEPRESSION
PREVALENCE OF
CLINICAL DEPRESSION
(1994)
• LIFETIME
• YEARLY
• Bipolar
17% (?)
10%
5%
TREATMENT OF DEPRESSION IN PRIMARY
CARE*
• Depression: 2nd. Most Common
Disorder in Primary Care
• 40% Diagnostic Hit Rate
• 87% Somatic Sx, 13% Mood Sx
(Greist, 2002)
A RECURRING ILLNESS
• 20% SINGLE EPISODE
• 80% RECURRENT or CHRONIC
Depression: Fluctuating Course
•
•
•
•
N= 431 ( ¼ : 1st.episode, ½ recurrent, ¼ : double D.)
12 year Follow-up
Symptomatic: 58%, 42%: Sx-free
Time Symptomatic:
> 15% MDD
> 43% Sub-Syndromal ……
Depression: Fluctuating Course
•
•
•
•
N= 431 ( ¼ : 1st.episode, ½ recurrent, ¼ : double D.)
12 year Follow-up
Symptomatic: 58%, 42%: Sx-free
Time Symptomatic:
> 15% MDD
> 43% Sub-Syndromal ……
WORLD HEALTH ORGANIZATION
STUDY
• Each day in Primary Care Medical Settings:
> 25% of patients have Clinical Depression
> 10% have Anxiety Disorders
> 10% have Substance Abuse Disorders
cont.
MOST COMMON DISORDERS SEEN IN
PRIMARY CARE
• Hypertension
• Depression
• Anxiety Disorders
Most “Reactive Depressions”
If they reach the intensity level of
Major Depression, will show
vegetative symptoms.
BIOLOGIC SYMPTOMS
•
•
•
•
•
ANHEDONIA
SLEEP DISTRUBANCES
APPETITE DISTURBANCES
LOSS OF SEXUAL DRIVE
FATIGUE
Dysthymia
“Ill-Humor”
• 5% Of the Population (lifetime
prevalence)
• Most eventually also develop
Major Depression

Dysthymia
• Pharmacologic Outcome:
33% Excellent Response
33% Good Response
34% Poor Response (Akiskal, 1997)
Has the
Success of
Antidepressants
Been Over-Sold?
15
Patients Recruited in
Antidepressant Drug Studies
Zimmerman, et al. (2002)
• N= 346 (MDD, outpatient practice)
• 86% would be excluded
from drug studies
ITT: Intent to Treat
Response Rates: MDD
• Single Antidepressant trial
• Do not tolerate:
15%
• No response:
35%
• “Responders”:
50%
ITT Rates
• “Responder” = 50%  HAM-D, or
HAM-D Score of 7 or less
• Responders:
> Full Responders: HAM-D < 7
50%
> Partial Responders:
HAM-D: 9-14:
50%
ITT: The Rest of the Story
• “Full Responders”:
> 18% truly asymptomatic
> 82% subtle residual
symptoms
Nierenberg, et al. (1999)
Partial Responders:
Is Symptomatic Improvement
Good Enough?
Partial Responders
• Time to Next Episode:
* 3 times longer to next episode
remitters vs. partial
responders
• Quality of life
(espec. Social Functioning)
Evidence-Based
Medicine and
Treatment
Algorithms
Depression
Implications for
Treatment Success
1. Hopelessness and Drop-outs
(long time to response)
2. Compliance: high risk patients
3. Extreme response to side effects
4. Premature discontinuation
(skepticism about meds : 62% ↑ in DC)
5. Patient preferences
6. Inaccurate diagnosis
Rating Scales
First weeks of Treatment
•
•
•
•
•
Aim to get some immediate relief
Medication strategies
Exercise
Bright light (details later)
Combat social withdrawal
26
On-Line Algorithms
• International Psychopharmacology
Algorithm Project:
endorsed by WHO
www.IPAP.org
• www.MHC.com
(also P 450: drug interactions)
Choosing a
First-line
Antidepressant
29
Targeting Neurotransmitters
NE:
norepinephrine
5-HT: serotonin
DA:
dopamine
33
NEWER GENERATION
ANTIDEPRESSANTS
• SSRIs: Serotonin (5-HT)
• NRIs: Norepinephrine (NE)
• Dual Action:
Wellbutrin: NE and Dopamine
Effexor: 5-HT and NE (SNRI)
Remeron: 5-HT and NE (SNRI)
Cymbalta (duloxetine): 5-HT and NE
Pristiq 5-HT and NE
Neurotransmitters and Behavior
• Serotonin:
Anxiety, Rumination, Irritability,
Aggression, Suicidality
Shelton and Tomarken (2001); Metzner, (2000)
Neurotransmitters and Behavior
• Catecholamines:
Dopamine and Norepinephrine:
Anhedonia, Apathy, Impaired
Attention
Shelton and Tomarken (2001); Metzner, (2000)
Antidepressants Agorithm
Texas Medication
Algorithm Project
TMAP
ANTIDEPRESSANT ALGORITHM
With Anxiety or Agitation:
SSRIs
Anergic:
Atypical:
PMDD:
38
Activation vs Switching
• Activation: within hours; anxiety
and/or initial insomnia
• Switching: 3+ weeks; manic
symptoms
39
Benzodiazepine Augmentation
Start up
(Ward Smith, et al.)
• Check for history of substance abuse
• Antidepressant and tranquilizers
• Early response…fewer drop outs
40
Benzodiazepine use: HMO Setting
(Samari, 2007)
• N: 2440
• Treated for 2 years with
tranquilizers
• Percent of those requesting
increased doses: 1.6 %
41
ANTIDEPRESSANT ALGORITHM
With Anxiety or Agitation:
Anergic: Wellbutrin
Atypical
PMDD
42
Stimulant augmentation
with anergic depressions
43
ANTIDEPRESSANT ALGORITHM
With Anxiety or Agitation:
Anergic
Atypical: watch for bipolar
PMDD
44
ANTIDEPRESSANT ALGORITHM
Pre-Menstrual Dysphoria:
SSRIs
45
ANTIDEPRESSANT ALGORITHM
Very Severe and/or Recurrent:
Dual Action:
Effexor, Pristiq, Cymbalta,
Remeron, Wellbutrin
46
Standard vs. Targeted Treatment
Improved
% of Patients Improved
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
96%
65%
Standard Targeted
Metzner, 2000
47
•
GUIDELINES for
MEDICAL TREATMENT of
DYSTHYMIA
• IRRITABILITY: SSRIs
• LOW ENERGY, APATHY, LOW-GRADE
ANHEDONIA: Wellbutrin
not based on empirical studies
Additional Considerations
in Medication Choices
• Side Effects
• Patient Preferences
• Pharmacokinetics
PHASES OF TREATMENT
• ACUTE: Until Asymptomatic
• CONTINUATION: 6 months @
Same Dose
• MAINTENANCE: Third Episode:
Lifetime Treatment
→
Continuation Phase
of Treatment
•
•
•
•
•
Minimum of six months…same dose
Patient-initiated discontinuation
High rates of acute relapse
Serotonin and emotional blunting
Dampens dopamine
Antidepressant
Discontinuation Syndromes
• Symptoms: nausea, dizziness,
malaise, electric shock-like
sensations
• Most likely:
Paxil, Effexor, Cymbalta, Pristiq
• Least likely: Prozac
Maintenance
Phase
ADEQUATE TRIAL
• DOSE
• COMPLIANCE
• TIME
• BLOOD LEVELS
TIME TO RESPONSE
 EARLY RESPONDERS:
2-4 WEEKS
 LATE RESPONDERS:
 SEVERE SYMPTOMS
 FIRST EPISODE BEFORE 18
 LONG DURATION
(more than three months)
4-6 WEEKS
Response
• Remission
• Partial
• Poor
Overview: Options for
Inadequate Response
Optimization
Augmenting
> Combination Treatments
Switching Drug Classes
Optimization
 dose;  time
Augmenting:
Combination
Switching
Classes
e.g serotonin  norepinephrine
reuptake inhibitor
Empirical Studies
STAR-D: Sequenced
Treatment
Alternatives to Relieve
Depression (NIMH)
STAR-D
(2007)
• N= 4100
• Ages 18-75
• Average patient:
3 medical illnesses
• 65%: psychiatric co-morbidity
62
STAR-D
• 80%: chronic or recurrent
• 25%: have been depressed
for 2+ years
• 53%: anxious depressions
63
STAR-D Rating Scale
page
Side effect scale
Page
Overview: Options for
Inadequate Response
Optimization
Augmenting
> Combination Treatments
Switching Drug Classes
65
STAR-D
(2006)
PHASE ONE:
Celexa: average doses 40 mg
Response rates: 60%
Remission rates: 30%
Average time to remission: 7 weeks
KEY: aggressive dosing
66
STAR-D
(2006)
PHASE TWO
Non-remitters: randomized:
> Switch
> Augmentation
67
STAR-D: Switch
(2006)
Effexor:
Wellbutrin:
Zoloft:
25%
21%
17%
Average time to remission:
six weeks
68
STAR-D: Augment
(2006)
Wellbutrin:
BuSpar:
30%
30%
Augmenting: slightly higher yield
than switching
69
New Study
70
STAR-D: After Phase 2
•55% reach remission
71
STAR-D
(2006)
PHASE Three:
> Switch:
nortriptyline (tricyclic)
or Remeron
> Augment:
lithium
T3
72
STAR-D
(2006)
PHASE Three:
> Switch:
nortriptyline or Remeron 13%
> Augment:
lithium
20%
T3
20%
73
T3 Augmentation
•
•
•
•
4 double bind studies: indicate efficacy
STAR-D study: very high yield
Few Side Effects
Dose: Cytomel 25-75 micrograms qd
74
STAR*D
Final Outcomes
67%
Complete remission
75
STAR-D
Cumulative Sustained
Recovery Rate
43%
76
STAR-D Monotherapy
STAR-D Monotherapy
STAR-D Augmentation
Guidelines
What Can Be Learned from
STAR-D
•
•
•
•
Use of rating scales
Aggressive dosing
Some suggestions: next steps
Testament to the difficulties in
treating very severe depression
Head-to-Head Comparisons: SSRIs
• N= 26,000……….117 trials
• Efficacy and tolerability
• Among SSRIs: Sertraline (Zoloft)
comes out on top
• Lexapro #2
(not generic….no drug-drug interactions)
• Cochran Database Surveys (2009)
81
Head-to-Head Comparisons
• SSRIs: versus Effexor and Remeron
better efficacy (dual action drugs)
• SSRIs versus Wellbutrin:
Wellbutrin: better tolerability
• Best for headaches: Elavil
Cochran Database Surveys (2009)
82
PARTIAL RESPONSE
STRATEGIES
• FIRST: Check Compliance &
Substance Abuse
• INCREASE DOSE
• AUGMENT
Other augmentation
Strategies
Augmentation Strategies
• Lithium: 0.3-0.6 mEq/l
>  relapse x 3
> 7 fold  suicides
THYROID
• Adding T3 or T4: augmentation
• T4 for rapid cycling
• Hypothyroid in Lithium therapy
Thyroid Augmentation
• T4: levo-thyroxine:
> Synthroid, Levothyroid, Levoxyl
> 1 mcg per pound of weight qd
• T3: triiodothyronine:
> Cytomel
> 25-75 mcg. qd
Hypothalamus

TRH

Pituitary

TSH

Thyroid
T3  Gland T4
TSH
Thyroid Stimulating
Hormone
Depression and
Hypo-Thyroid
The most common medical
cause of depression (10%)
Grade I:  T3 and T4:  TSH
Grade II: Normal T3/T4, but  TSH
(Wolkowitz, 2003; Zweifel, 1997)
“Normal” TSH Levels
High Normal Range 3.0
|
|
Median
1.3
|
|
Low Normal Range 0.3
miliIU/Liter
“Normal” TSH Levels
High Normal Range
|
|
Median
|
|
Low Normal Range
3.0
2.5
1.3
0.3
miliIU/Liter
Stimulant Augmentation
MAOIs
New MAOI:
Emsam
selegiline transdermal:
6-12 mg per day
Augmentation Strategies
• Atypical Antipsychotics:
* Zyprexa *Abilify
*Geodon *Risperdal
* Seroquel
?
Reducing Treatment-Resistant
Unipolar Depression
MADRS Total: Acute Treatment
Fluoxetine
Mean Change
from Baseline (LOCF)
Improvement
0
(n=10)
-5
Olanzapine
(n=8)
*p<0.05 vs Flx.
+p<0.05 vs Olz.
-10
-15
*+
-20
0
*+
*+
*
*+
*+
*+
*+
1
2
3
4
5
6
7
Weeks of Double-Blind Therapy
Mean modal dose during double-blind therapy: Flx = 52 mg/d, Olz = 12.5 mg/d, Olz + Flx = 13.5 mg/d + 52 mg/d.
Shelton RC et al. Am J Psychiatry 2001; 158:131-134.
8
Olanzapine/
Fluoxetine
(n=10)
Folic Acid
• Low serum levels in treatmentresistant depression and early
relapse
• Co-factor: Serotonin
• 500 mcg 2 X per day
• With Depakote: 1-2 mg per day
High Intensity Light Therapy
• Seasonal and
non-seasonal
• Caution with:
Bipolar
POOR RESPONSE
STRATEGIES
• CHECK COMPLIANCE and
SUBSTANCE ABUSE
• INCREASE DOSE
• SWITCH CLASSES:
e.g. SSRI  NE
NE  SSRI
Within Class Switches
• Reasons for switch:
> Tolerability
> Efficacy (espec. with partial Response)
• Two SSRI failures: switch classes
LATE EMERGING SEROTONIN
SIDE EFFECTS
• SEXUAL DYSFUNCTION
> Inorgasmia

• APATHY and EMOTIONAL BLUNTING
• WEIGHT GAIN (10% after one year)
Prevalence Sexual
Problems / Complaints
• Reporting: 14%
• Elicited on questionnaire 60%
• N: 6300: only 29% had no
other risk factors except
antidepressant exposure……
Prevalence Sexual S.E.
without other probable causes
•
•
•
•
•
Celexa, Lexapro, Effexor
Zoloft, Paxil
Prozac, Remeron
Serzone
Wellbutrin
30%
28%
24%
14%
7%
Clayton, et al. 2002
LATE EMERGING SEROTONIN
SIDE EFFECTS
• SEXUAL DYSFUNCTION
> Inorgasmia
• APATHY and EMOTIONAL BLUNTING
• WEIGHT GAIN (10% after one year)
GENDER DISTRIBUTION
DEPRESSION
Disorder
Female : Male
• CHILDREN
• TEENS
• ADULTS
1:1
2:1
2:1
• BI-POLAR I
• BI-POLAR II
1:1
2:1
Premenstrual Dysphoric
Disorder: PMDD
 Average female: 400 periods
 70 %: PMS at some point in time
 30 %: significant PSM
 4 %: PMDD
Premenstrual Dysphoric
Disorder: PMDD
Premenstrual exacerbation
of Major Depression symptoms
90% of women who successfully
commit suicide: premenstrual
Premenstrual Dysphoric
Disorder: PMDD
Treatments:
> reduce caffeine, alcohol, salt,
sugar, and stop smoking
> exercise
> Serotonin antidepressants
> St. John’s Wort (case reports)
Premenstrual Dysphoric
Disorder: PMDD
Antidepressant treatments
Must target Serotonin
Intermittent versus
continuous
Quick onset of actions
PMDD and SEROTONIN
Fluctuating estrogen levels can have
an impact on
Tryptophan hydroxylase
(rate-limiting enzyme for production of 5-HT)
Allopregnenolone
• Neuro-steroid: synthesized in
the brain
• Potent GABA-A agonist
• Low levels in MDD CSF
(↑ with successful treatment)
Allopregnenolone
• PMDD: marked reduction
• Rapid increase with SSRIs
but not with nonserotonin antidepressants
Premenstrual Dysphoric
Disorder: PMDD
Calcium supplementation
2 double blind, placebo controlled
studies
1200 mg per day (4 Tums)
55% vs 36%
Myths about Pregnancy
and “Well Being”
• Risks of major depression: prenatal and
postpartum: 21% (highest risk for women)
• Risks of discontinuing medications:
Bipolar: 83% acute relapse
Major depression: 68% relapse
116
Depression
and Pregnancy
Depression and pregnancy:
> Hypercortisolemia
> Substance abuse
> Suicide attempts
> Post-partum exacerbation
(bonding and attachment)
Depression and Pregnancy
Depression and pregnancy:
> Hypercortisolemia
> Substance abuse
> Suicide
> Poor self care
> Post-partum exacerbation
(bonding and attachment)
FDA RATINGS:
USE DURING PREGNANCY
A:
B:
C:
D:
X:
No Risk. Well controlled studies
No Evidence of Risk
Risk Cannot Be Ruled Out
Positive Evidence of Risk
Contraindicated in Pregnancy
120
Newer Antidepressants
and Pregnancy
• FDA classifications: all “C” except:
• Paxil: D
> Discontinuation syndrome
> 2nd and 3rd trimester exposure:
risk of cardiac defects
(2% vs 1%)
121
Antidepressants: Meta-analysis
(Einarson and Erinarson, 2005)
•
•
•
•
N: 1774 exposed fetuses
First trimester exposure
Major malformations: 2-3%
This equals the base rate in
un-exposed fetuses
122
Antidepressants: Risks
(Hauser, et al., JAMA 2009)
• Small but statistically non-significant
increase in miscarriages
• Not compared to
non-depressed subjects
• Premature birth: 20% greater: in
both medicated and non-med
mothers
123
Antidepressants: Risks
• No specific birth defects
• ??? Cardiac defects in SSRIs ???
124
The Jury is Still Out
126
PSYCHOTIC DEPRESSIONS
•
•
•
•
Antidepressants (AD)
Antipsychotics (AP)
AD + AP
ECT
35%
45%
75%
90%
Note: Continuation Phase: One Year
AD and AP
Electroconvulsive
therapy
ECT: Electro-convulsive
Therapy
Shock Treatments
V
DEPRESSION IN CHILDREN and
ADOLESCENTS
MAJOR
DEPRESSION
• Children
3%
• Teens:
10%
35% recurrent
50% bipolar
Depression in Young Children
•
•
•
•
Luby, et al. (2002)
N=49
Using DSM-IV criteria: 12 Dx as MDD
Thus must use modified criteria…
MDD Children: Modified Diagnostic
Criteria
• Most of the day, more days than not
• Play: themes of death, suicide, selfdestruction (61%)
• Depressed or irritable mood or
Diminished interest plus 4 Sx
(vs 5 for adults)
SYMPTOMS IN
CHILDREN
•
•
•
•
•
•
ANHEDONIA / WITHDRAWAL (60%)
IRRITABILITY (81%)
LOW SELF-ESTEEM (78%)
SCHOOL FAILURE
LONLINESS
VEGETATIVE Sx: Sleep and
Appetite Disturbance (80%)
• LOW ENERGY (58%) …..
Child and Adolescent
Depression:Additional Signs
•
•
•
•
•
•
•
Vague, non-specific physical complaints
Running away from home
Being bored
Extreme sensitivity to rejection or failure
Reckless behavior; Acting Out
Difficulty with relationships
Substance Use / Abuse
Problems with
the studies
Meta analysis:
Effect Size: 0.25
TAD S
Treatment for Adolescents with Depression Study
Effectiveness Outcomes
(2004)
Random Assignment
•
•
•
•
•
•
NIMH Study
N: 432
Placebo
Prozac
Cognitive Behavioral Therapy
Combo: drug and CBT
Responders
Percent
Treatment Response:
Week 12
100
90
80
70
60
50
40
30
20
10
0
71
61
43
COMB
FLX
CBT
35
PBO
TAD S
Effect Size
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
COMB
FLX
CBT
TAD S
Time to Onset of Effects
• Anxiety: 1-2 weeks
• Depression: 4-6 weeks
but responders in 10-12
week range !
Paxil and Increased Suicidality
• UK study…N=1300 adolescents
• Increased suicidality:
Placebo: 1.2%
Paxil:
3.4%
• No actual Suicides
• 33 suicidal incidents …..
Paxil and Increased Suicidality
• Acute Treatment data
• Discontinuation
• State of Connecticut:
Human Implications
TADS
(2004)
• At baseline: 29% suicidal ideas
• Attempts: 1.6%
• Actual Suicides: 0
Suicidality
Is Reduced
Overall
29.2
30
27
Percent
25
20
14.6
13
15
11.6
10
5
CDRS13 > 1
SIQ >= 31
2.7
0
Baseline
Week 6
Week 12
TAD S
FDA Data
N= 4400
N= 300
http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065s1.htm
All trials, all indications
(Fixed effect model)
Risk ratio
(95% CI)
% Weight
Study
CELE(MDD,18)
CELE(MDD,94404)
EFFEX(MDD,382)
EFFEX(MDD,394)
PAXIL(MDD,329)
PAXIL(MDD,377)
PAXIL(MDD,701)
PAXIL(SAD, 676)
PROZ(MDD,HCCJ)
PROZ(MDD,HCJE)
PROZ(MDD,X065)
PROZ(OCD,HCJW)
REMER(MDD,045)
SERZ(MDD,141)
SERZ(MDD,187)
ZOLO(MDD,501001)
ZOLO(MDD,501017)
0.42 (0.15,1.15)
0.41 (0.16,1.04)
1.82 (0.75,4.39)
0.84 (0.37,1.88)
2.00 (0.96,4.18)
0.70 (0.25,1.97)
3.92 (0.45,34.50)
4.73 (0.23,97.73)
0.90 (0.26,3.12)
0.78 (0.44,1.39)
0.71 (0.35,1.45)
0.90 (0.08,9.58)
0.81 (0.40,1.65)
0.80 (0.33,1.94)
1.28 (0.58,2.79)
1.04 (0.44,2.45)
0.93 (0.43,1.99)
Overall (95% CI)
0.93 (0.75,1.15)
.01
.1
1
7.2
8.9
4.2
7.1
5.8
4.9
0.6
0.3
2.6
13.7
8.7
0.9
9.0
6.2
6.6
5.8
7.4
10
100
Risk ratio
Emergence of Suicidality
147
Discontinuation
All trials, all indications
(Fixed effect model)
Risk ratio
(95% CI)
% Weight
Study
CELE(MDD,18)
CELE(MDD,94404)
EFFEX(MDD,382)
EFFEX(MDD,394)
PAXIL(MDD,329)
PAXIL(MDD,377)
PAXIL(MDD,701)
PAXIL(SAD, 676)
PROZ(MDD,HCCJ)
PROZ(MDD,HCJE)
PROZ(MDD,X065)
PROZ(OCD,HCJW)
REMER(MDD,045)
SERZ(MDD,141)
SERZ(MDD,187)
ZOLO(MDD,501001)
ZOLO(MDD,501017)
0.82 (0.19,3.57)
0.60 (0.26,1.38)
2.50 (0.52,11.93)
0.81 (0.21,3.19)
1.55 (0.49,4.94)
0.80 (0.21,3.10)
1.69 (0.36,7.98)
8.79 (0.47,165.62)
0.67 (0.15,2.98)
1.34 (0.66,2.71)
0.88 (0.31,2.48)
1.09 (0.11,10.83)
1.31 (0.39,4.46)
0.51 (0.11,2.30)
1.29 (0.12,13.43)
1.75 (0.21,14.28)
1.50 (0.29,7.65)
Overall (95% CI)
1.11 (0.81,1.50)
.01
.1
1
10
100
Risk ratio
Worsening/Emergence of Suicidality/discont
5.1
18.3
3.1
5.8
6.1
6.2
3.7
0.7
3.7
16.5
8.5
2.0
5.9
7.3
1.9
2.1
3.1
149
Impact of Antidepressants on
Suicide Rates
• 1957-1985: USA: suicide rates  31%
• 1986-1999: USA: suicide rates  13.5%
• 1986-1999: 4-fold  Rx for
antidepressants
• Most people who die from suicide
were not receiving treatments for
depression
Grunebaum, et al. (2004)
CDC Data: Ages 5-14
(Am. J. Psychiatry, 2006)
1996-1998…Suicides: 933
Low rates of SSRI Rx:
1.7 / 100,000 / year
High rates of SSRI Rx:
0.7 / 100,000 / year
Impact on Prescribing
CDC: Lubell, et al. 2007
• 1990-2003: suicides  29% (ages: 10-24)
• 30-40% decrease in prescriptions for
antidepressants for kids and teens
• 2003-2004: teenage suicides
increased by 18%
When antidepressants
can provoke suicide
V:OTC
Products Endorsed By:
• USP (US Pharmacopia)
ST. JOHN’S WORT
157
Cochrane Data Base:
Systematic Studies
• Meta analysis
• St. John’s Wort; equal efficacy to
prescription antidepressants
• Linde, et al. (2008)
158
ST. JOHN’S WORT
TREATMENT
Reasons for use
900-1800 mg per day
Three, divided doses
Cost: $1.00 per day
159
ST. JOHN’S WORT
Side effects: mild GI, sedation.
No: weight gain
or sexual dysfunction
Watch for Drug-Drug Interactions!
Washout time before starting
another antidepressant:
5 Days
160
S-Adenosylmethionine
SAM-e
Comprehensive review of literature
(Papakostas, et al. , 2003)
76 studies world-wide
Comparable efficacy to ADs
Much better tolerated
162
SAM-e
Treatment: Major Depression
400-1600 mg per day
$3-5 per day
IV Dosing
Methyl donor:  serotonin
and norepinephrine
163
SAM-e
So Far lack of significant drugdrug interactions
Problems:  homocysteine
Take: B vit. including Folate
Can provoke mania
Treats osteoarthritis
164
Low Folic Acid: Associated with
• Depression:
> meta analysis: 10 epidemiologic
studies:
> significant relationship
between low folate and
depression (Gilbody, et al. 2007)
165
Low Folic Acid: Associated with
• Decreased CSF metabolites:
Serotonin
(5-HIAA)
Dopamine
(HVA)
Norepinephrine (MHPG)
• Depression may lead to
low folate
166
Folic Acid
Low serum levels in treatmentresistant depression and
early relapse
Low folate: increased risk for
dementia
167
Folic Acid
Dosing: 500 mcg per day
Significant augmenter vs placebo
Prozac…took ten weeks (Coppen, 2000)
Deplin (L-methylfolate)
> no advantage over folic acid
With Depakote: 1-2 mg per day
168
Omega-3
Fatty Acids:
essential fatty acids
Families of Fatty Acids
Omega-3
> LNA: seed and nut oils
> EPA: fish oil
> DHA: fish oil
Omega-6
> LNA: seed and nut oils
> Soy bean oil and corn oil
> Arachidonic acid: Animal Tissue
170
Omega 3:6 ratios
• Typical USA diet: 1:20
• Ideal:
1:3
Omega 3 Fatty Acids:
Bipolar Disorder
Mixed findings
(Stoll, et al. 1999; Peet and Horrobin, 2002; Nemets, et al., 2002)
172
Omega-3 and Depression
• Fish oil: Much better bio-availability
• 1-2 grams a day (EPA + DHA)
• 6 published studies: major depression
> all: add-on studies
> all significant better than placebo
• ↑ omega 3, ↑ serotonin and
dopamine transmission
173
Omega-3, Pregnancy and
Major Depression
(Su, Chin, et al. 2008)
•
•
•
•
•
•
N: 36
8 weeks, double blind, placebo
EPA: 2.2 grams, DHA: 1.2 grams
Response: Omega-3: 62%...placebo: 27%
Remission: Omega-3: 38%...placebo: 18%
No side effects
Omega-3 Fatty Acids
Side effects: GI
(diarrhea, nausea)
Take with food…ginger root
or ginger ale
The mercury issue
175
176
5-HTP
Tryptophan 
5-HTP
5-HT (serotonin)
5-HTP
2 well controlled double-blind
studies (total 108)
300 mg per day (600 TRD)
Main Side effect: Sedation (pm)
Compounding pharmacy
Watch for serotonin syndrome
Other OTC Options
• Melatonin
• Kava Kava
• Valerian
CAUTION!
High-Intensity
Light Therapy
High Intensity Light Therapy
SAD and winter blues: 1:4
Psychoanalytic views of
seasonal mood changes (1945)
High Intensity Light Therapy
Dosing: 2500 lux
Average time: 20 minutes
Morning light is 2 x more
effective
Effects seen: 2-3 days
Lost with placebo or
discontinuation
High Intensity Light Therapy
Use in non-seasonal depression
Side effects:
nausea, jitteriness, eye strain,
dizziness
Blue lights: forget it
High Intensity Light Therapy
Contraindications:
macular degeneration,
retina diseases,
post cataract surgery
UV effect on the skin
Bipolar disorder
Dawn Simulation
Sunlight Exposure
(melanocytes…endorphins)
Exercise Dosing
•
•
•
•
10,000 steps per day
Aerobic …in keeping with fitness
Two 10 minute sessions a day
20 minutes: 3 times a week
St. Mom’s Wort
Given to pre-schoolers:
renders them
unconscious
for 6 hours
Practice Case: 1
• 54 year old man. Profession: undertaker. No
history of depression.
• 6 months ago funeral home was sold and he
was not hired by the new owner. He had
worked for the former funeral home for 25
years
• 3 months of unsuccessful job searching. Felt
frustrated. Possibly low grade depression
Practice case: 1
• 3 months ago at family gathering, a relative
made a comment about his “chronic
unemployment”
• From that point there has been a downward
spiral…increasing low self-esteem..
increasing depression
Clinical Symptoms
•
•
•
•
•
•
•
Marked apathy and anhedonia
Early morning awakening
11 pound weight gain
Suicidal ideas
Fatigue
Social withdrawal (impact on job search)
No sex drive (impact on marriage)
Other factors to consider
•
•
•
•
•
•
Caffeine use: 4 – 12 oz. cups of coffee per day
Occasional alcohol use
Chronic headaches (takes OTC meds)
No significant medical illnesses
No use of prescription drugs
No drug abuse
Initial Questions
• What is the diagnosis?
• Given the clinical picture, what class of
antidepressants should be considered as a
first-line choice?....and why?
• He is started with an antidepressant (one that
does not require initial titration)…the dose is
considered to be in the therapeutic range
Three weeks
• He reports: no noticeable
changes since starting medication
treatment
• What do you do first? And why?
(highest yield next step strategies)
You implement
revised treatment plan
• Week 6 (since first dose): no improvement
• What do you do?...and why
New Strategy Works
• 4 weeks into new treatment: 20%
improvement on current medications…
• What do you do?
• New scenario: 4 weeks: 50% improvement
• 4 additional weeks: still at 50% improvement
• What do you do?
New Scenario
• Week 3 into the initial treatment and you
discover that the patient has cold intolerance.
• What might this suggest and how might it
affect your treatment?
New Scenario:
Different Presenting Clinical Symptoms
•
•
•
•
•
•
•
Significant anxiety; lots of rumination
Early morning awakening
11 pound weight loss
Suicidal ideas
Anger outbursts and marked irritability
Social withdrawal (impact on job search)
No sex drive (impact on marriage)
Questions
• Given the clinical picture, what class of
antidepressants should be considered as a
first-line choice?....and why?
• He reports that after the first day of treatment
there is an increase in anxiety and
agitation…what is going on and what might
you do to address this situation?
Side Effect Problems:
how might you address each?
• Significant nausea
• Onset of initial insomnia
• After he begins to respond positively, there is
some return of libido…he is relieved…
• 4 weeks later he reports an inability to reach
an orgasm..what is likely to be happening?
• What can you do?
Side Effect Problems:
how might you address each?
• Different scenario: after 4 weeks, he starts to
experience impotency…what is happening/
• What might you do?
New Scenario
• Treatment is successful…
he has reached remission.
• What do you do now?
New Scenario
• Treatment is successful…
he has reached remission.
• 2 months into continuation he
reports break-thru depressive
Sx….what might be
happening?....what can you do?