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Integrative Medicine and Psychiatry: An Evidence Based Approach Part I. Marlene P. Freeman, M.D. Associate Professor, Harvard Medical School Director of Clinical Services, Perinatal and Reproductive Psychiatry Program; Medical Director, CTNI Massachusetts General Hospital.

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integrative medicine and psychiatry an evidence based approach part i

Integrative Medicine and Psychiatry: An Evidence Based ApproachPart I

Marlene P. Freeman, M.D.

Associate Professor, Harvard Medical School

Director of Clinical Services, Perinatal and Reproductive Psychiatry Program; Medical Director, CTNI

Massachusetts General Hospital


Disclosure: Past 12 months

  • Grant Support: Forest, Lilly, Glaxo SmithKline (Investigator Initiated Trials)
  • Consulting: PamLab, Bristol Myers Squibb
  • Honoraria for medical editing: DSM Nutritionals
  • No promotional speaking, No stock; No consulting
complementary and alternative medicine cam
Complementary and Alternative Medicine (CAM)
  • Defined as “a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine (NCCAM, 2002)”
  • The American Psychiatric Association developed a task force to assess CAM in psychiatry
    • Evidence Base and Safety for CAM treatments in Major Depressive Disorder
why focus on cam
Why Focus on CAM?
  • Use of CAM treatments has increased over past several decades
  • Approximately 40% of adults in the U.S. use at least one CAM therapy annually
    • CAM use among children approximately 12%, or about 1 in 9 children; Children are five times more likely to use CAM if a parent/other relative uses CAM.
  • Americans spend over $33 Billion annually out of pocket on CAM therapies

Barnes et al., 2008; Eisenberg et al., 1998; Nahin et al., 2007

cam the most commonly used by us adults
CAM: the Most Commonly Used by US Adults
  • Natural nonvitamin/nonmineral products (18%)
    • Most common: fish oil/omega 3/DHA, glucosamine, echinacea, flaxseed oil or pills, and ginseng
  • Deep breathing exercises (12.7 %)
  • Meditation (9.4 %)
  • Chiropractic or osteopathic manipulation (8.6 %)
  • Massage (8.3 %)
  • Yoga (6.1 %)

Barnes et al., 2008

cam associations with likelihood of use
CAM: Associations with Likelihood of Use

Use greatest among:

  • Women (42.8%, compared to men 33.5%)
  • Ages 30-69 (30-39 years: 40%, 40-49 years: 40%, 50-59 years: 44%, 60-69 years: 41%)
  • Higher levels of education (Masters, doctorate or professional: 55%)
  • Higher income (poor: 28.9 percent, near poor: 30.9 percent, not poor: 43.3 percent)

Barnes et al., 2008

prevalence of cam use
Prevalence of CAM Use
  • Use in psychiatry:
    • One study showed use by 63% of inpatients
    • MDD most common indication
    • Over half of those with Major Depressive Disorder (MDD) and/or other depressive disorders use CAM treatments
    • Most patients did NOT disclose use of CAM to their psychiatrist

Tindle et al., 2005; Elkins et al, 2005; Kessler et al., 2001;

considerations in evaluating the evidence base
Considerations in Evaluating the Evidence Base
  • CAM treatments are popular and appealing to patients
    • Internet and other sources may inflate perception of data base
    • Patient preference and accessibility sometimes precludes full evaluation, risk/benefit discussions in optimal medical decision-making process
    • Psychiatrists often not well educated about CAM; may be uncomfortable discussing
googled results
Googled results
  • Omega-3 and depression: > 6,550,000 hits
  • Folate and depression: > 1,140,000 hits
  • Acupuncture and depression: >9,510,000 hits
  • St John’s Wort and depression: > 2,200,000 hits
considerations in evaluating the evidence base1
Considerations in Evaluating the Evidence Base
  • Few CAM treatments have been systematically studied for clear psychiatric indications with adequate outcome measures
  • Control conditions: finding appropriate control conditions can be challenging (i.e., exercise)
  • Some treatments have long-standing use in other cultures; may have literature available in other languages – cultural biases, language access issues
how to sort it out the apa cam task force process
How to sort it out?The APA CAM Task Force Process
  • Identification of widely used treatments with some randomized controlled trials (RCTs) for major depressive disorder – clinical relevance
  • Process of preparing and reviewing evidence tables for efficacy from published trials, discussions of methodology and safety [adapted from APA treatment guideline process]
  • Review of efficacy, risks, treatment recommendations, future research directions

APA CAM Task Force Members: M. Freeman; M. Fava, M. Trivedi, J. Lake; D. Mischoulon; K. Wisner

the apa cam task force process highlights selected cam treatments for mdd
The APA CAM Task Force Process:Highlights: Selected CAM treatments for MDD
  • Omega-3 fatty acids
  • St. John’s Wort
  • S-adenosyl-methionine (SAMe)
  • Folate
  • Light therapy
  • Acupuncture
  • Exercise
  • Mindfulness based psychotherapies

APA Task Force Report, JCP, 2010

omega 3 fatty acids
Omega-3 fatty acids
  • Studied as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (not the plant source alpha-linolenic acid)
  • Meta-analyses show benefit over placebo for unipolar and bipolar depression, with substantial heterogeneity
  • Few studies demonstrate benefit as monotherapy

Parker et al., 2006; Freeman et al., 2006; Su et al., 2008; Nemets et al, 2007

























Structures of fatty acids


















Hibbeln J


Essential Fats: Metabolism and Dietary Sources



18:2n-6 linoleic acid, LA

Canola oil


Soy bean oil

Safflower oil

Corn oil

Flax seed

competition for

D6 and D5 desaturase

and elongation


Leaf plants






eicosapentaenoic acid,

20:4n-6, arachidonic acid








Series 2

Series 3







Series 4

Series 5



22:6n-3, docosahexaenoic acid,


platelet activity

(brain, retina, testis)

immune responses

smooth muscle

Bone health





18:3n-3 linolenic acid, LNA

Hibbeln J

apa subcommittee on omega 3 fatty acids
APA Subcommittee on Omega-3 Fatty Acids
  • American Psychiatric Association’s Committee on Research on Psychiatric Treatments assembled a subcommittee (2003-2006)
  • Omega-3 Subcommittee: invited participants with expertise in omega-3 fatty acids and psychiatry
  • Charged with examining the evidence for omega-3 fatty acids across disorders, critical evaluation of treatment data, and recommendations for future research

American Heart Association Recommendations

  • Cardiovascular Benefits
    • Decreased risk for arrhythmias, thrombosis
    • Decrease triglycerides
    • Decrease atherosclerotic plaque growth
    • Improve endothelial function
    • May lower blood pressure
    • Reduce inflammatory response

Kris-Etherton et al., AHA Nutrition Committee, 2003


American Heart Association Recommendations

  • AHA Recommendations:
    • All adults should eat fish > 2 times per week
    • Patients with coronary heart disease should consume 1 g EPA + DHA per day
    • A supplement may be useful in patients with hypertriglyceridemia (2-4 g per day)
      • >3 g per day should be monitored by a physician

Kris-Etherton et al., AHA Nutrition Committee, 2003

omega 3 fa putative mechanisms of action
Omega-3 FA: Putative Mechanisms of Action
  • Increased serotonergic, dopaminergic neurotransmission
  • Alteration of protein phosphorylation, protein kinases
  • Impact on protein kinase C
  • Decreased phosphatidylinositol-associated second messenger activity
  • Immunological effects
  • Vagal mechanisms
  • Increased dendritic arborization and synaptogenesis
  • Regulation of gene expression
  • Increased membrane fluidity

Hibbeln et al., 1998; Yao et al., 2004; Chalon, 2006; Coull et al., 2000; Popoli et al., 2000; Mirnikjoo et al., 2001; Kinsella et al., 1990; Logan and Katzman, 2005; Villa et al., 2002; Calderon and Kim, 2004; Wainwright, 2002; Kitajka et al., 2002; Carlezon et al., 2005

meta analysis mood disorders
Meta-analysis: Mood disorders
  • Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p=0.02)
  • Results were highly heterogeneous
    • important to examine the characteristics of each individual study to note the differences in methodology

Freeman et al., American Psychiatric Association Subcommittee Report, 2006

apa omega 3 fa subcommittee treatment recommendations
APA Omega-3 FA Subcommittee: Treatment Recommendations
  • Endorsed AHA guidelines
    • Considered particularly relevant
      • high comorbidity between psychiatric disorders and cardiovascular disease
      • lifestyle factors (e.g., smoking, obesity) in populations with psychiatric diagnoses,
      • metabolic effects of some psychotropics

Freeman et al., 2006

apa omega 3 fa subcommittee treatment recommendations1
APA Omega-3 FA Subcommittee: Treatment Recommendations
  • Adults should consume fish > twice/week
  • Patients with mood, impulse-control, or psychotic disorders should consume 1 g EPA + DHA per day
  • Supplements may be useful in patients with mood disorders, 1-9 g per day

(> 3 g per day should be monitored by a physician)

Freeman et al., 2006

st john s wort
St. John’s Wort
  • Herbal remedy with great popularity in Europe; mixed opinions in the U.S.
  • Usually studied as hypericum extract
  • Some randomized controlled trials in MDD favorable, especially in mild to moderate MDD
  • Less convincing in more severe MDD, and large federally funded studies in the U.S. diminished interest

Shelton et al., 2001; Hypericum Study Group, 2002; Lecrubier et al., 2002;

Linde et al., 2005

st john s wort1
St. John’s Wort
  • Two U.S. large trials (HAM-D scores >20): did not demonstrate difference between St. John’s Wort and placebo on primary outcomes
  • Shelton et al. (2001)
    • 200 participants: St. John’s Wort or placebo for eight weeks
    • No statistically significant difference between groups - primary outcome was decrease on HAM-D
  • Hypericum Study Group trial (2002)
    • 340 patients: St. John’s Wort, sertraline, or placebo, 8 wks
    • Both St. John’s Wort and sertraline performed similarly to placebo on the primary outcome of change on HAM-D scores, response rates (HAM-D, CGI).
    • Highlights concerns about placebo-response rates and methodology in MDD studies, since sertraline did not perform better than placebo
  • Other studies: positive results:
    • Lecrubier et al. 2002: another large trials, investigators did find a significant difference between St. John’s Wort and placebo in mild to moderate depression (N=375)
    • Fava et al, 2005: modest but significant advantage over fluoxetine and placebo (N=135)
st john s wort2
St. John’s Wort
  • Important drug-drug interactions
  • Appears to induce metabolism of concomitant medication via the cytochrome P450 system
  • May reduce efficacy of other drugs, including:
    • Antiretrovirals
    • Immunosuppressants
    • Antineoplastic agents
    • Anticoagulants \Digoxin
    • Oral contraceptives (unintended pregnancies have been reported)

Roby et al., 2000; Mannel et al., 2004; Schwarz et al., 2003

accessibility challenges of study
Accessibility, Challenges of Study
  • Example: accessibility may add to the methodological challenges of study
  • Study of St. John’s Wort vs. Placebo:
    • those assigned to St. John’s Wort had variable adherence verified by metabolite blood levels
    • placebo group was found to have a surprising number of participants with notable St. John’s Wort metabolite levels (Vitiello et al., 2005)
s adenosyl l methionine same
S-adenosyl-L-methionine (SAMe)
  • Occurs naturally in humans; needed as a methyl donor in synthesis of important compounds with implications for mood
  • Agency for Healthcare Research and Quality (AHRQ) systematically assessed database for MDD, and found evidence to support further research
  • Studies generally show benefit over placebo and equivalence to tricyclics
  • Studied mostly as monotherapy; small study supported role as augmentation strategy

Papakostas et al., 2003; AHRQ, 2002; Mischoulon and Fava, 2002;

Delle Chiaie et al., 2002; Bressa et al., 1994

  • Available orally, although intramuscular and intravenous available and used in some early studies
  • Published studies support that SAMe 1600 mg provided orally for trials of 3-6 weeks (ranges studied 200-1600 mg/d)
  • Some studies show benefit by 10 days of treatment over placebo
  • Studies have generally been of short duration (4-6 weeks)
  • Side effects/Considerations:
    • Expensive
    • Generally well tolerated; reports of mild gastrointestinal symptoms, sweating, dizziness, anxiety
    • Mania reported in studies of bipolar depression
    • Better tolerated than tricyclic antidepressants

Goren et al., 2004; Alpert et al., 2004; Mischoulon and Fava, 2002;

Delle Chiaie et al., 2002

augmentation with same
Augmentation with SAMe
  • Papakostas et al., 2010

N=73 SRI nonresponders with MDD, 6-week, double-blind, randomized trial of adjunctive oral SAMe (target dose: 800 mg/twice daily).

    • HAM-D response and remission rates were higher for patients treated with adjunctive SAMe (36.1% and 25.8%, respectively) than adjunctive placebo (17.6% versus 11.7%, respectively).
    • No statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason (20.6% versus 29.5%, respectively), due to adverse events (5.1% versus 8.8%, respectively), or due to inefficacy (5.1% versus 11.7%, respectively)
    • SAMe may be an effective, well-tolerated, and safe adjunctive treatment strategy for MDD

Am J Psychiatry, 2010

  • Low folate levels associated with poorer and slower response to SSRIs
  • Treatment studies as adjunctive treatment showed benefit for patients on fluoxetine, most pronounced for women
    • Those who received folate vs. placebo more likely to be responders, have less side effects (0.5 mg/d)

Papakostas et al., 2004; Papakostas et al., 2005; Coppen and Bailey, 2000

  • No evidence for monotherapy
  • Low risk
  • Protective against birth defects– 0.4-1 mg recommended for women of reproductive age
  • Reasonable to suggest use as an adjunctive strategy in addition to antidepressants, especially for women

Folate: Perinatal Considerations

  • No specific study of folate as an intervention for perinatal depression
  • Women who are pregnant or planning to become pregnant are advised to take 0.4-1 mg of folate daily to decrease birth defects, particularly neural tube defects (McDonald et al., 2003)
  • However, one epidemiological study did not find a relationship between folate intake and postpartum depression (Miyake et al., 2006)
bright light therapy
Bright light therapy
  • Few rigorously done studies with adequate controls, outcome measures
  • Meta-analysis done by APA subcommittee found that significant benefit in seasonal and non-seasonal MDD, although number of studies that reached criteria for inclusion based on design were small
  • Some reports of mania

Golden et al., 2005; Epperson et al., 2004; Kripke et al., 1992

  • Part of Traditional Chinese Medicine, some have voiced concerns about its study as separate entity
  • Systematic reviews and meta-analyses fail to demonstrate consistently positive results over control conditions
  • Control conditions challenging- some use “sham” points, other conditions (i.e., massage)
  • Evidence base is limited by flawed methodology, very inconclusive evidence at this time for efficacy
  • Generally low risk

Halbreich , 2008; Wang et al., in press; Leo and Ligot, 2007; Smith and Hay, 2005

  • For most individuals, exercise is important and indicated for overall health benefits
  • Epidemiological studies support benefits for decreased risk of depression
  • Methodological weaknesses in studies include: difficulty selecting appropriate control conditions, difficulty blinding to condition, adequate follow-up of effects
  • Dose of exercise very important component in terms of design, assessment of efficacy

Brown et al., 2005; Strawbridge et al., 2002; Lawlor et al., 2001;

Dunn et al., 2001; Trivedi et al., 2006

  • Treatment studies support further research as an adjunctive treatment; role as monotherapy
  • May be especially important considering the high comorbidity with cardiovascular disease, obesity, and other medical problems experienced at high rates by those with mood disorders
  • Unless there are medical contraindications, should be recommended as part of overall treatment plan
    • Dunn et al., 2005; Blumenthal et al., 2007; Trivedi et al., 2006
vitamin d
Vitamin D
  • Vitamin D – different forms, groups of steroids
  • Pro-hormone calcidiol
  • Vitamin D3 – calcitriol
    • 1, 25 dihydroxy cholecalciferol (calcitriol)
    • produced when ultraviolet light interacts with 7-dehydrocholesterol
    • Binds to vitamin D receptors (steroid receptors, including those in the brain)
    • More production with natural sun exposure (high UV index), some from tanning beds
    • Light boxes- filter out UV rays to deliver bright white light
    • Unclear if supplementation with vitamin D2 equivalent
vitamin d1
Vitamin D
  • Deficiency- bone softening disorders such as rickets
  • Most studies suggesting health benefits are association studies (not treatment studies)
  • Hypervitaminosis D- excess supplementation can be toxic, generates hypercalcemia, can cause birth defects, renal impairment
  • Typically up to 250 micrograms/day (10,000 IU) in adults recommended
  • Benefits of supplementation unclear
vitamin d and depression association studies
Vitamin D and Depression:Association Studies
  • Number of association studies demonstrating lower vitamin D levels inversely associated with depression (although not all studies show this)
    • Examples: Hoogendijk et al., Arch Gen Psychiatry, 2008; Hoang et al., Mayo Clin Proc 2011; Ganji et al., Int Arch Med 2010; Wilkins et al., Am J Geriatr Psychiatry
  • Higher intake of vitamin D associated with lower risk of depression in older women (Bertone-Johnson et al., Am J Clin Nutr, 2011)
vitamin d and prevention prospective study
Vitamin D and Prevention?Prospective Study
  • Milaneschi et al., J Clin Endocrinol Metab 2010
    • Prospective cohort study, N=531 women, 423 men > 65 years of age
    • Serum 25(OH)D levels at baseline, 3 and 6 years
    • Center for Epidemiological Studies Depression Scale (CES-D) >16 identified as depressed
    • Low vit D defined as < 50 nmol/liter
    • Both women and men experienced a significantly greater risk of developing depressive symptoms with lower vitamin D levels, relationship more robust in women
      • Women – Hazard ratio of 2.0
      • Men- Hazard ratio of 1.6
treatment studies
Treatment Studies
  • Vitamin D supplementation on symptoms of depression in overweight/obese subjects
    • N=441; used Beck Depression Inventory BDI
    • At baseline, did a cross-sectional study:
      • Low D3 levels (<40 nmol/liter associated with higher BDI scores
    • Treatment Study
      • Randomized to Vit D 20,000 IU or 40,000 IU or placebo per week for one year
      • Significant improvement in depressive scores among the two vitamin D groups compared to placebo after one year
  • (Jorde et al., J Internal Med 2008)
treatment studies1
Treatment Studies
  • Prevention of Seasonal Affective Disorder?
    • Women aged 70 or older, N=1621
    • Vitamin D 800 IU vs no supplementation (randomized)
    • No difference in depression scores between May and October
treatment studies2
Treatment Studies
  • Healthy young adults randomized to assess cognitive and emotional functioning (not depressed)
    • N=128, double-blind, placebo controlled
    • 5000 IU cholecalciferol or placebo x 6 weeks
    • No differences on cognitive or emotional batteries
    • History of mood disorder exclusionary

Dean et al., PLOS ONE, Nov 2011

vitamin d and perinatal depression
Vitamin D and Perinatal Depression
  • Deficiency increases risk of obstetrical complications
    • Inversely related to risk of gestational diabetes and glycemic control
    • Reported to increase the risk of pre-eclampsia, although not consistently Vitamin D deficiency is more likely in African American women compared to Caucasian women
  • Vitamin D and Perinatal Depression?
    • One study did not find Vitamin D related to risk of MDD during pregnancy
    • Lower levels of vitamin D associated with higher EPDS scores in one postpartum sample (N=97)
    • Mothers with low vitamin D status have lower levels in breastmilk, putting infants at risk of deficiency
    • Beneficial to assess vitamin D status in pregnant and lactating women?
      • impact upon depression risk is unclear at this time

McLeod et al., Diabet Med 2011; Brannon and Picciano, Annu Rev Nutr 2011; Bodnar et al., Public Health Nutr 2011; Murphy et al., J Am Psychiatr Nurses Assoc, 2010; Haggerty, Breastfeed Med, 2011

  • “Vitamin D and Depression”
    • About 8,030,000 results

CAM vs. Standard Antidepressant Trials

CAM for Major Depressive Disorder:

A Meta-analysis of Patient Characteristics, Placebo Response Rates, and Treatment Outcomes Relative to Standard Antidepressants

Freeman et al., 2010

  • Are participants in trials of CAM therapies similar to those in standard antidepressant (AD) trials, or not?
    • Do they have less severe MDD?
    • Different expectations/beliefs? Are they more likely to be placebo responders?
    • More likely to drop out if they experience side effects?
cam vs standard antidepressant trials
CAM vs. Standard Antidepressant Trials
  • Objectives:

To compare

    • patient characteristics
    • placebo-response rates
    • outcome differences in active treatment compared to placebo

in randomized controlled trials (RCTs) of Complementary and Alternative Medicine (CAM) and standard antidepressants for major depressive disorder (MDD)

cam vs standard antidepressant trials1
CAM vs. Standard Antidepressant Trials
  • Method:
    • Pubmed/Medline and reference lists from identified studies searched for studies eligible for inclusion
    • Selected RCTs for MDD that included validated diagnostic assessment and baseline/outcome measures of severity.
    • Assessment limited to widely used CAM agents most frequently studied in RCTs with pill placebo: St. John's Wort, Omega-3 fatty acids, and S-adenosyl-L-methionine (SAMe)
cam vs standard antidepressant trials2
CAM vs. Standard Antidepressant Trials

Study criteria:

  • MDD diagnosis verified
  • Were at least four weeks in duration.
  • Used an oral preparation of active treatment and placebo.
  • Presented entirely original data.
  • Focused on the treatment of adults.
  • Did not exclusively treatment of patients with treatment-resistant depression, or other depressive disorders
  • Used verified outcomes measures

320 AD (n=298, 93.2%) or CAM (n=22, 6.8%) vs placebo comparisons from 185 clinical trials pooled, N=46,842 randomized to treatment with either an antidepressant (n=28,345, 60.5%), a CAM (n=1,502, 3.2%), or placebo (n=16,995, 36.2%).

Six trials included treatment arms with both CAM and standard AD vs placebo

cam vs standard antidepressant trials3
CAM vs. Standard Antidepressant Trials
  • Results
    • No significant difference in depression severity at baseline
    • No significant difference in age
    • More women in CAM treatment studies than standard AD studies
treatment with either ad or cam resulted in significantly greater response rate than placebo
Treatment with either AD or CAM resulted in significantly greater response rate than placebo

Percent Response rate

relative risk of discontinuing therapy vs placebo due to adverse events higher with ad than cam
relative risk of discontinuing therapy vs placebo due to adverse events higher with AD than CAM

D/C due to AEs (%)

  • p=0.007 comparing the risk ratio of d/c due to AE of AD(total) vs Pbo to CAM vs Pbo
  • P=0.502 comparing the risk ratio of d/c due to AE of AD(non-CAM) vs Pbo to AD(CAM) vs Pbo

D/C= Premature discontinuaiton of therapy. AEs= adverse events, CAM= Complementary and Alternative Medicine, AD= antidepressant, Pbo=placebo

placebo-response rates significantly lower in CAM (31.7%) versus antidepressant-only (37.7%) studies (p=0.002)

Treatment Recommendations

  • Actively inquire about and encourage discussion regarding CAM use
    • patients may not realize they should, may feel uneasy doing so
  • Educate patients that “natural” is not always safe
  • Individuals with depression need/deserve to have the appropriate evaluation and full discussion of available treatment options
    • easy access to CAM treatments may impose burden on patients to self treat
    • Inflation of evidence per internet
  • Complementary and Alternative Medicine is an important area in Psychiatry
    • Psychiatrists and patients need a better understanding of the evidence base from balanced sources
    • Good quality, systematic, controlled trials are needed
    • Individuals with MDD can and should be aware of those treatments that have general health benefits and may play a role in an overall treatment plan
    • Efficacy, safety, acceptability, and accessibility are key issues for treatment for MDD