Transcript Alternative Therapies for Major Depressive Disorder: a critical

Non-conventional Treatment of
Mood Disorders
What the evidence suggests
21st Annual DBSA Conference
15 October 2011
James Lake, MD
Private Practice, Monterey
Chair, International Network of Integrative Mental Health
(www.INIMH.org)
Disclosures
 none
Definitions
 Conventional treatments—accepted in
mainstream medicine (emphasis is on
prescription drugs and psychotherapy)
 CAM (complementary and alternative)
treatments—not currently accepted in
mainstream medicine (egs: herbs, other
natural products, acupuncture, yoga)
 Integrative treatments—combinations of
conventional and CAM treatments
CAM Rx trends in mental health
 Two thirds of patients hospitalized for a
mental health problem used a CAM therapy
within the past year (Elkins et al., 2005)
 Few patients disclose CAM use to family
physician or psychiatrist resulting in
treatment failures, delays and safety issues
(Eisenberg et al., 1998; Kessler et al., 2001)
Integrative Rx—considerations
 Psychiatrists and CAM practitioners should be
familiar with evidence for CAM/integrative Rx
choices to give appropriate, safe advice
 Most appropriate Rx determined by
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sx type and severity
co-morbid medical or psychiatric DO
previous conventional and CAM Rx and response
Personal, cultural preferences
cost and local availability
Integrative Rx—Basics
 When previous Rx not effective or no
previous similar episode, start with most
validated Rx targeting core symptom(s)
 For severe sx always start Rx with first-line
conventional medications
 For moderate sx consider evidence-based
use of adjunctive CAM Rx
 When initial Rx ineffective consider
conventional or CAM Rx with pt signed
informed consent of risks and benefits
Alternative and Integrative
Treatments of Depressed Mood
What the evidence suggests
Emerging context of CAM Rx for
depressed mood
 CAM use greater among individuals
diagnosed with any DSM-IV disorder
(Unutzer 2000)
 Limited efficacy of conventional Rx in severe
depression; no benefit in moderate
depression (Kirsch 2008)
 Two thirds of severely depressed
outpatients use CAM Rx while taking
prescription medications (Kessler 2001)
CAM Rx in Depressed mood
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Vitamins
St. John’s wort
Omega-3 fatty acids
SAMe
Amino acids
DHEA
Light therapy
Acupuncture
Exercise
Folate, B-12, thiamin and D
In depressed mood
Folate
 Studies of folate (1 to 5mg) in depressed
populations (elderly, concurrent alcohol
dependence, concurrent dementia) consistently
show significant improvement (Guaraldi et al.,
1993; Di Palma et al., 1994; Glória et al., 1997;
Passeri et al., 1993)
 Folate as add-on to antidepressant in folate
deficient depressed patients (N = 24) showed
more improvement than placebo (Godfrey et
al., 1990)
Folate—treatment issues
 Folate taken alone is probably beneficial
 More studies needed to confirm optimal
form and dosing
 Adding to antidepressants is reasonable
when treating depressed folate deficient
patients
 Partial responders to antidepressants may
benefit by adding folate
 Depressed individuals with normal folate
levels may benefit from folate or
methylfolate
B-12, thiamin
 Patients with higher B12 levels show
more robust response to
antidepressants (Hintikka 2003)
 Oral B12 (800 μg/d) suggested as addon Rx to antidepressants
 Some report consistent improvements
in mood and energy with daily thiamin
(50-mg)
Vitamin D
 Literature review supports association between depressed
mood and low vitamin D levels (Parker & Brotchie 2011)
however…
 Not clear whether deficiency is cause or effect of
depressed mood
 Possible association with SAD not rigorously examined
 Insufficient research to support vitamin D augmentation
with antidepressants
 Bottom line: insufficient evidence for vitamin D
supplementation in depressed patients, but reasonable for
depressed patients at risk of vitamin D insufficiency or
where low vitamin D levels found
St. John’s wort
(Hypericum perforatum)
In depressed mood
St. John’s Wort
 Meta-analysis of controlled trials on SJW found
serious design problems and inconsistent
outcomes (Linde et al., 2005)
 Two large well designed studies found no
difference between SJW and placebo on
primary outcome measures in MDD (Shelton et
al., 2001; Hypericum Study Group, 2002)
 However…another large trial found significant
difference between SJW and placebo in mildmoderate depression (Lecrubier et al., 2002).
St. John’s wort—treatment
issues
 Safety issues—induces liver enzymes lowering
blood levels of anti-HIV drugs, cancer drugs,
anticoagulants, digoxin, OCPs and hormones
(Roby et al., 2000; Mannel et al., 2004)
 Reasonable for mild to moderate depression,
however recent U.S. studies do not show
efficacy over placebo
 Drug interactions limit use and pose safety
considerations
Essential fatty acids
In depressed mood
Omega-3s—general health benefits
 Fish, algae and flaxseed oil
 Deficient in average American diet
 Cardiovascular benefits—decrease risk of
stroke and arrhythmias, reduce triglycerides,
decrease atherosclerosis (Kris-Etherton 2003)
 AHA recommends fish twice weekly, and 1
g/day EPA + DHA for heart disease (KrisEtherton 2003)
 May reduce oxidative brain damage and slow
age-related cognitive decline (Cole 2005;
Morris 2005)
Omega-3s in depressed mood
 Meta-analyses show benefits in unipolar and
bipolar depression (Parker 2006; Freeman
2006; Lin and Su 2007)
 However…results difficult to interpret due to
– Inconsistent findings
– Different study designs
Stand-alone vs. add-on therapy
EPA vs DHA vs both Omega-3s
Variability in dosing
Variability in study length
Omega-3s in depressed mood
 DHA as monotherapy in depressed adults: no
benefit over placebo (Marangell et al., 2003)
 DHA/EPA monotherapy in depressed children:
moderate benefit over placebo (Nemets et al., 2006)
 DHA/EPA add-on to antidepressants: no benefit
over placebo (DHA dose higher than EPA) (Grenyer
et al., 2007)
 EPA (1 g) alone vs Prozac (20 mg) vs EPA +
Prozac: similar efficacy with EPA and Prozac.
Combined Rx superior to either (Jazayeri 2008)
Omega-3s in depression—
bottom line
 Low-risk add-on therapy for depressed
patients with significant cardiovascular and
health benefits endorsed by APA (Freeman
2006)
 Most findings support lower doses (1-2
gm/day)
 Add-on EPA or EPA/DHA probably most
beneficial, less evidence for DHA alone
 Stand-alone omega-3s in depression more
effective with EPA alone or EPA>DHA
S-adenosyl-methionine
(SAMe)
In depressed mood
SAMe
 Equal efficacy of IV or oral SAMe and
antidepressants with good tolerance
(Delle Chiaie 2002; Pancheri 2002)
 Meta-analysis of controlled trials (total
patients=1,015)—no significant
differences in outcomes between
SAMe and antidepressants (AHRQ
Publication 2002; http://www.ahrq.gov)
SAMe—treatment issues
 Stability is issue—degrades rapidly
over several months on shelf.
(Spillmann 1996)
 Adverse effects: insomnia, lack of
appetite, constipation, nausea, dry
mouth, sweating, dizziness, and
nervousness (Spillmann 1996)
 Small % responders switch to mania
(Carney 1987)
Amino acids and DHEA
Amino acids: L-tryptophan, 5HTP, tyrosine, Acetyl-L-carnitine
DHEA is a prohormone
L-tryptophan and 5-HTP
 L-tryp and 5-HTP both +/- effective but 5HTP crosses blood-brain barrier at higher
rate, converted into serotonin more
efficiently, and greater antidepressant effect
 Antidepressant effect starts between 100mg
and 300mg/day
 >15 controlled trials show consistent
positive effects in moderate depressed
mood (Birdsall 1998)
5-HTP
 63 depressed patients randomized to
fluvoxamine 150mg vs 5-HTP 300mg similar
improvements in mood (Poldinger 1991)
 Case reports Rx-refractory pts improving
when 5-HTP 300mg combined with TCAs,
MAOIs or SSRIs; no serious side effects
reported (van Praag 1984; Sargent 1998;
Kline 1980; Mendlewicz 1980)
L-tyrosine
 Obtained through diet or synthesized from
phenylalanine; essential precursor for synthesis
of epinephrine, norepinephrine and dopamine
 Essential for synthesis of NGF and thyroxin
 Deficiency frequent in depressed mood (Grevet
2002)
 Beneficial doses 500-1500mg/day
 Caution—high doses increase cancer risk
(Harvie 2002)
Acetyl-L-carnitine (ALC)
 Neuroprotective, may reduce cognitive
impairments in normal aging, dementia, and
traumatic brain injury
 Depressed demented patients taking 2-3gm/day
reported greater improvements in mood and global
functioning than placebo (Bella 1990)
 Severely depressed elderly patients taking 500-mg
4x/day achieved full remission (Gecele 1991)
 Few or no adverse effects; can be safely
combined with antidepressants
Dihydroepiandosterone (DHEA)
 Pro-hormone. Mechanism involves serotonin,
GABA, NMDA, other neurotransmitters
 30mg 2x/day 50% reduction in sx severity (most
remained on antidepressants)
 Moderately depressed adults given 90-mg 3 wks
followed by 150-mg 3x/day 3 wks reported 50% sx
reduction, improved sexual fx (Schmidt 2005)
 Depressed HIV positive patients taking 200 to 500
mg/day reported significant improvements in mood
and fatigue (Rabkin 2000)
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Light exposure therapy
In depressed mood
Bright light exposure therapy
 Systematic review—all published studies on
bright light exposure for non-seasonal
depression found “modest…promising antidepressive efficacy, especially when
administered during the first week of
treatment, in the morning, and as an
adjunctive treatment to sleep deprivation
responders (Tuuainen 2004).”
Bright light exposure therapy
 More recent reviews report mixed findings
 Comparable efficacy of bright light and
antidepressants for SAD and nonseasonal depressed mood
 Ineffective alone but may improve
response when combined with
antidepressant in non-seasonal
depression (Golden 2005; Even 2008)
Light exposure—treatment issues
 Mechanism unclear—full-spectrum bright light
probably modulates CNS melatonin, serotonin
and dopamine (Neumeister 2004).
 Safe effective alternative to antidepressants in
pregnant depressed women (Epperson 2004)
 Uncommon side effects: jitteriness, headaches
(10%), mild nausea (16%) (Terman 2005)
 Sporadic cases of hypomania reported
(Epperson et al., 2004; Terman 2005)
Acupuncture
In depressed mood
Acupuncture
 Efficacy difficult to evaluate due to:
– Differences in study designs
– Concurrent use of other conventional or CAM
Rx
– Different Chinese vs Western medical
diagnoses
– Use of different acupuncture protocols
 Most systematic reviews included only English
language studies (Mukaino 2005; Smith and Hay,
2005; Leo and Ligot, 2007)
Acupuncture—research and Rx
issues
 No significant clinical differences between
manual acupuncture and electroacupuncture and sham or waitlist.
 Insufficient data to conclude differences in
efficacy of acupuncture vs antidepressants
 Uncommon adverse effects: bruising,
fatigue, nausea. Rare serious risks: HIV,
hepatitis B and C (Vincent 2001)
Research and treatment issues
 No agreement on standardized sham
acupuncture
 Possible beneficial effects from stimulating
specific acu-points used as sham points
 Significant differences in type of
acupuncture, duration, frequency and
number of sessions limit analysis of pooled
treatment outcomes from different study
designs
Exercise
In depressed mood
Exercise
 Treatment studies consistently show benefit
of aerobic exercise (Dunn 2005; Penninx
2002; Mather 2002; Herman 2002)
 Some studies show mood benefits of
resistance training (Singh 2005; Singh 2001)
 Beneficial effects of exercise on mood may
be sustained over time (Babyak 2000)
 Long-term longitudinal studies needed
Alternative and Integrative
Treatments of Bipolar Disorder
What the evidence suggests
Conventional Rx—limitations
 50% of BD pts discontinue Rx
because of AEs: tremor, weight
gain, elevated liver enzymes (Fleck
et al., 2005)
 High relapse rate in BD pts on
maintenance mood stabilizers
(Boschert 2004)
CAM use in Bipolar Disorder
 High % BD pts use CAM together
with prescription Rx (Andreescu
2008)
 Weak evidence for most CAM Rx
(Ernst 2003; Dennehy 2004)
 BD pts may be at high risk for AEs
due to concurrent use of conventional
Rx (Vazquez 2002; Izzo 2004)
Non-conventional Rx
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Exercise
Omega-3 EFAs
N-acetyl-cysteine
Adjunctive folate in acute mania
Adding choline to lithium
Trace lithium
Proprietary nutrient formula
St. John’s wort plus bright light in SAD
Acupuncture
Exercise
 Adjunctive (plus medication) exercise may
increase in brain-derived neurotrophic factor
stimulating increased neurogenesis (Sylvia
et al. 2009)
 But…BD pts who exercise probably have
healthier lifestyles than non-exercisers
(causality difficult to establish)
 Large prospective trials needed to
determine effect size
Omega-3 fatty acids
 4-mo PCRT (N=30) BD pts treated with
Omega-3s (9.6gm/d) vs placebo while
continuing mood stabilizers (Stoll 1999)
 Omega-3 group remained in remission
significantly longer than placebo
 Pts taking Omega-3 fatty acids only
remained in remission significantly longer
than placebo group
Review findings—omega-3s in
Bipolar Disorder
 5 studies met inclusion criteria however uneven
quality (Montgomery & Richardson 2008)
 One study (N= 75) adequate quality/size for
analysis—small benefit of omega-3s over
placebo for depressive phase not mania
 CONCLUSIONS: Findings must be regarded
with caution due to limited data. Acute need for
well-designed adequately powered PCRTs
Omega-3 fatty acids—safety
issues
 Case report of hypomania induced by
high doses of omega-3s (Kinrys 2000)
 Rare cases of increased bleeding
times, but not increased bleeding risk
in pts taking aspirin or anti-coagulants
 Omega-3s should be regarded as
viable adjuvant Rx of mania and bipolar
illness
N-acetyl cysteine (NAC)
 Amino acid with strong anti-oxidant properties
used to treat inflammatory disorders (Dodd, Dean
et al. 2008)
 May reduce symptoms of depressed mood but not
mania in stable bipolar patients when combined
with mood stabilizers
 24-week PCRT (N=75) stable BD patients taking
NAC (1g/d) vs placebo with mood stabilizer
showed significant improvements in depression
(Berk et al 2008).
 Non-significant improvements in mania
Folate + Valproic acid in acute
mania
 3 week DBPCT (N=88) BD I manic
patients randomized to folic acid
(3mg) + valproate vs placebo +
valproate (Behzadi et al. 2009)
 Statistically significant difference in
YMRS at 3 weeks suggesting folate
effective adjuvant to valproate in
acute mania
Adding choline to lithium
 Choline is required for biosynthesis of
acetylcholine (Ach); low Ach levels are
known cause of mania (Leiva 1990).
 Case study of Rx-refractory rapidcycling BD pts taking lithium—four of
six responded to addition of 2,0007,200 mg/day free choline (Stoll 1996)
 Need large DB prospective studies
Adding choline to lithium
 Small PCRT found
phosphatidylcholine 15gm to
30gm/day reduces severity of both
mania and depressed mood in BD
pts (Stoll 1996)
 Sx recurred when Rx discontinued
Trace lithium supplementation
 Small open study suggests BD I pts
with mania or depressed mood improve
with low doses (50 micrograms/meal)
of a natural lithium preparation (Fierro
1988)
 Responders had undetectable post-Rx
serum Li+ levels
 Need large PCRTs to replicate findings
Proprietary nutrient formula
 Proprietary nutrient formula containing 36
separate constituents may reduce manic sx
when taken with conventional mood
stabilizers (Popper 2001; Kaplan 2001).
 Proposed mechanism: correction of
metabolic errors that predispose individuals
to become symptomatic when micronutrient
dietary deficiencies (Kaplan 2001).
Proprietary nutrient formula
 First series took 32 capsules daily in
four divided doses over 6 mos. 11 pts
reduced mood stabilizers by half while
improving clinically
 Second series 13 out of 19 BD pts
remained stable after discontinuing
mood stabilizers (Simmons 2003)
Proprietary nutrient formula
 Two PCRTs on-going in U.S. and
Canada to determine most efficacious
nutrients, simplify Rx and minimize AE
risk
 Protocol starts with 6 capsules TID
then 3 capsules TID after two months
Proprietary multi-ingredient
formula—safety concerns
 Micronutrient-medication interactions require
gradual dose reductions (Popper 2001)
 Lowering mood stabilizer doses too rapidly
risks worsening while keeping medications
at therapeutic doses may cause toxicity
 Large prospective studies needed to
clarify whether formula is beneficial and
safe alone or as augmentation therapy
Acupuncture
 2 12-wk sham-controlled randomized trials on
adjunctive acupuncture adjunctive to mood
stabilizers for sx of depression (N=26) and
hypomania (N=20) in outpts dx;d BD I & II
(Dennegy et al. 2009)
 Rx-arm received treatment at specific
acupoints addressing target sx. Sham group
received non-specific acupuncture Rx
 RESULTS: all patients improved; greater
improvement with targeted Rx for both phases
 Few transient negative side effects and no
attrition related to acupuncture
International Network of Integrative
Mental Health www.INIMH.org
 Advance a global vision for an integrated whole person
approach to mental health care through education,
research, networking and advocacy
 Create community and opportunities for nurturing personal
and professional connections
 Promote evidence-based conventional and CAM therapies
for the betterment of mental healthcare
 Educate, support and inspire mental health professionals
and trainees at all career levels in all world regions
 Facilitate collaborative efforts between researchers and
clinicians
General resources
 My website:
www.IntegrativeMentalHealth.net
 Textbook of Integrative Mental Health
Care, Lake, Thieme Medical Publishers,
September, 2006
 A Clinical Manual of Complementary and
Alternative Treatments in Mental Health,
eds. Lake and Spiegel, American Psychiatric
Press, Inc., January, 2007
 Integrative Mental Health Care: A
Therapist’s Handbook, Lake, Norton, 2009