Complementary and Alternative Medicine (CAM) Treatments for Mood Disorders: Are They Safe and Effective?

Arun V. Ravindran, MB, PhD, FRCPC, FRCPsych

Professor and Director, Global Mental Health and Fellowship Training, Department of Psychiatry, University of Toronto

Chief, Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health, Toronto

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Disclaimer

Dr. Ravindran has no conflict of interest to report. He has no financial interest and has not received any form of support from any companies that produce or market any compound or instrument or procedure described in this presentation as a main treatment form.

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CAM Therapies: Some Notable Statistics

Over 1/3 of adult population uses some form of CAM therapies

Visits to CAM practitioners exceed visits to primary care clinicians

CAM users tend to be female, younger, better educated and employed

Approximately 2/3 of patients with diagnosed depression and anxiety use CAM therapies as primary or adjunct treatments

The perceived helpfulness of CAM therapies is similar to that of conventional treatments

Kessler et al., Am J Psychiatry, 2001

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Evaluating CAM Treatments

“Natural is better and safer” – not necessarily true

Limitations Quality of evidence:

Few and poorer quality of RCTs Variation in formulation and quality of agents Mostly short-term studies Few studies in severe forms of depression

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Caveats and Cautions

In general, psychotherapy and pharmacotherapy should be considered before CAMs

More as adjunctive than as monotherapy Only guideline and not “standard of care” Evidence limited to English publications

“Clinical support/use” – utility and practicality

Ravindran et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. V. Complementary and alternative medicine

treatments. J Affect Disord., 2009

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Criteria for Levels of EvidenceLevel Criteria

1 At least 2 RCTs with adequate sample sizes, preferably placebo-controlled, and/or meta-analysis with narrow confidence intervals

2 At least 1 RCT with adequate sample size and/or meta-analysis with wide confidence intervals

3 Non-randomized, controlled prospective studies or case series or high-quality retrospective studies

4 Expert opinion/consensus

Line of Treatment Criteria

First-Line Level 1 or Level 2 evidence plus clinical support

Second-Line Level 3 evidence or higher plus clinical support

Third-Line Level 4 evidence or higher plus clinical support

Fourth-Line Level 1 or Level 2 evidence for lack of efficacy, plus clinical support

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Complementary & Alternative TherapiesA) Physical Treatments

Light therapy Sleep deprivation Exercise Yoga Acupuncture

B) Nutraceuticals Omega-3 fatty acids DHEA Tryptophan SAMe

C)Herbal Remedies St. John’s Wort Other herbal remedies

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What is Light Therapy and How Effective is It for Mood Disorders? Exposure to bright light using a device Seasonal MDD

1st line of treatment As effective as SSRIs No maintenance/prophylactic studies

Non-seasonal MDD Less robust evidence Combination with SSRIs is more effective

Bipolar Depression Helps but may trigger mixed state

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What Efficacy has Sleep Deprivation shown in MDD? Total vs. partial treatment options Difficult to design RCTs – mostly small studies

Comparison with light therapy, exercise and combinations with antidepressants

Drawbacks Difficult to sustain treatment Rebound depression Tolerance of deprivation effects

Conclusion Unlikely to be of value in day-to-day practice Possible use as a 3rd line augmentation in mild to moderate

depression Co-administration of antidepressants may prolong benefit

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Is Exercise Beneficial for MDD? High vs. low frequency/intensity, aerobic vs. non-

aerobic Recommended – Min. 3x/week, 30 mins+ Recent meta-analyses (2) – better than no

treatment, mixed results against psychological treatments*

RCTs – exercise + medication superior to either alone

Some evidence for long-term benefit and prophylaxis

Recommendation 2nd line augmentation in mild to moderate MDD

Pinquart et al., Aging Ment Health, 2007

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What is the Neuroscientific Basis for the Benefit of Exercise?

Increases expression of genes for neurotropins

Stimulates growth and development of new cells and increases neuronal plasticity

Increase in monoaminergic neurotransmission

Possible modulation of interleukin 6.

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Just standing here doing nothing for TWENTY MINUTES! Boy, am I

STRESSED!

Hi, everybody. Let’s start de-stressing by just sitting

quietly doing nothing for twenty minutes.

YOGA Class

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What is Yoga? An ancient physical art incorporating controlled

breathing, specialized postures and meditation Yoga forms evaluated in depression:

SKY (emphasis on cyclical hyperventilative breathing) MDD (2 RCTs, 3 open trials) and dysthymia (3 open

trials) Iyengar yoga (emphasis on precise postures, use of props)

MDD (1 RCT, 2 open trials) Hatha yoga (emphasis on individualized practice)

MDD (1 RCT, 1 open trial) Dysthymia (1 RCT, 1 open trial)

Advantages: Low cost, non-invasive, self-supervised, highly tolerable

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What Physiological Mechanisms Mediate the Beneficial Effects of Yoga?

Reducing sympathetic tone and normalizing heart rate variability

Normalization of HPA axis dysregulation Effect on the limbic system Activation of antagonistic neuromuscular

system

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Is Yoga Useful for MDD? Most studies – 4-8 weeks, 4x/week Difficulty in blinding and placebo control RCTs

Better than no treatment in MDD Few comparisons to medication

Yoga as good as TCAs in MDD Combination superior to medication alone

Useful as monotherapy or augmentation in dysthymia No published data in bipolar disorder

Recommendation Use as 2nd line augmentation and for prophylaxis in mild to

moderate depression

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Efficacy Study of Yoga to Treat Residual Depressive Symptoms

16-week augmentation pilot study with a randomized, cross-over design in both unipolar and bipolar patients

Subjects: Outpatients currently taking antidepressants Experiencing significant residual depressive

symptoms 8 weeks of Breathing Focused Yoga + 8 weeks of

psychoeducation, or the inverse Primary efficacy measure – MADRS Secondary efficacy measures – CGI, Q-LES-Q

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Results

On the MADRS and CGI, patients on yoga showed significant improvement compared to the psychoeducation group

Both yoga and psychoeducation improved quality of life

*p<0.05

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Efficacy Study of Yoga for Social Anxiety Disorder

8-week augmentation pilot study with a randomized, cross-over design in patients with moderate-severe social anxiety disorder

Subjects: Outpatients, mostly unmedicated Experiencing significant social anxiety symptoms that

impact functionimg 8 weeks of Breathing Focused Yoga or wait-list

Primary efficacy measure – LSAS Secondary efficacy measures – CGI, Q-LES-Q

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Results – need new graphs

On the LSAS and CGI, patients on yoga showed significant improvement compared to wait-list

There was no impact on quality of life; however, the patient sample was also in the severe range

*p<0.05

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Assessing the Benefits of Acupuncture

Acupuncture has proven analgesic and anaesthetic effects

Benefits mediated by: The opioid system Nitric oxide through gracile nucleus/thalamus Monoaminergic stimulation Glutamate and GABA

Methodological problems, especially blinding

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What is the Evidence for Acupuncture for MDD? Treatments

4-8 weeks with 2-16 needles MDD

2 RCTs – as good as antidepressants No difference compared to sham treatment in 2 studies Mixed results from other studies One meta-analysis – benefits but small effect size

Bipolar Depression and Hypomania Targeted and non-targeted treatment improved symptoms

Overall, safe and well tolerated but current data is inadequate to make a recommendation (based on English literature only)

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What are Nutraceuticals?

Non-prescription natural health products, usually concentrated forms of natural substances

They are often used to support general physical and mental well-being

Approved by Health Canada: Omega-3 fatty acids, tryptophan, S-adenosyl-L-methionine (SAM-e), folic acid, inositol, amino acids, and alpha-lactabumin (as an ingredient in approved compounds)

Not yet approved in Canada: Dehydroepiandrosterone (DHEA) and acetyl-L-carnitine are not currently licensed in Canada.

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What are Omega-3 Fatty Acids and What Mediates Their Benefit? Essential polyunsaturated fatty acids integrated in

multiple biological systems Focus on eicosapentaenoic acid (EPA) and

docosahexaenoic acid (DHA) Thought to improve brain and immune functioning Mechanism of action still unknown

? Improving integrity of neural cell membranes and myelin

Form & Usage Variable duration of use – 4 to16 weeks Variable dosing of EPA, DHA or combination (at least 1000

mg)

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Do Omega-3 Fatty Acids Alleviate MDD? Meta-analyses

1 negative, 2 positive for use as monotherapy or augmentation in mild to moderate MDD

Safe and well tolerated Diarrhoea, nausea and fishy taste Watch for bleeding and switch to mania

Conclusion Likely benefit as 2nd line monotherapy or

augmentation to antidepressants in mild to moderate depression

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How Useful Are Omega-3 Fatty Acids in Bipolar Disorder?

Rates of bipolar disorder correlate inversely with consumption of fish As with MDD, EPA is more relevant

Data:

Likely more beneficial for bipolar depression than mania. ? Stabilize membrane fluidity

RCTs

Monotherapy (1)Stoll et al. (+)

Adjunct (2)Frangou et al. (+)

Keck et al. (-)

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EPA for Bipolar Depression

Two parallel studies of efficacy and biology

Efficacy †

12 week double-blind RCT (n=51)

Augmentation with EPA (1-2 gms) or Placebo

**EPA superior to Placebo on HAM-D and CGI (p=0.04)

Biology ‡

MRS before and after 12 weeks of EPA or Placebo augmentation

(n=18 females)

**Higher levels of N-acetyl aspartate (NAA) with EPA vs.

Placebo (p=0.02)

† Frangou et al., Brit J Psychiatry, 2006‡ Frangou et al., J Psychopharmacol., 2007

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How Useful is S-adenosyl-L-methionine (SAMe) for MDD? Amino acid functioning as methyl donor Dose & duration

Oral – 800 mg to 1000 mg (2-8 weeks) IV/IM – 200 mg to 400 mg (2-8 weeks)

Systematic reviews (6) – mostly small studies Superior to placebo, equal to TCAs for mild to moderate

depression Good safety and tolerability Short-term and monotherapy data only

Recommendation 2nd line monotherapy in mild to moderate depression

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Does Dehydroepiandrosterone (DHEA) have Benefits for MDD?

Anti-aging nutritional supplement ? Effect on neurogenesis and neuroprotection Dose & Duration

30-45 mg/day for 6-8 weeks Some evidence for benefit as monotherapy as well as

augmentation in major and minor depression, and in medically ill

Paucity of safety data Sex hormone effects

Recommendation 3rd line augmentation agent Short-term use only

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What is the Evidence for Tryptophan in MDD? 5-HT precursor Dose and duration

2-4 g/day, up to 12 weeks

Most data as adjunctive agent Mostly negative Some benefit for sleep Association with E.M.S.? Specific to one manufacturer

Conclusion Insufficient evidence to support use in MDD

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Have Other Nutraceuticals been Evaluated in MDD? Reasonable evidence:

Adjunctive folic acid

Preliminary evidence: Acetyl-L-carnitine (monotherapy) Amino acid mixture (augmentation) Multivitamins (augmentation)

No evidence: Alpha Lactalbumin Inositol

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What is St. John’s Wort? How Does It Work? Herb commonly prescribed in Europe for

depression Mechanism of action unknown

May have serotonergic and dopaminergic effects No regulation of formulation, though hyperforin is

usually the main ingredient Dose & duration

Variable formulations (500 mg to 1000 mg) 4-12 weeks

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What is the Efficacy of St. John’s Wort in MDD? Early meta-analyses (2) – superior to placebo in MDD

(but methodological problems) Recent meta-analyses (5)– equal to antidepressants,

mixed results vs. placebo Cautions

Psychiatric drug interactions not well studied Interaction with antibiotics, anti-coagulants, oral

contraceptives, etc. Reports of induced mania and serotonin syndrome

Recommendation 1st line monotherapy in mild to moderate depression 2nd line augmentation in more severe depression

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Is St. John’s Wort Useful in Bipolar Disorder?

No RCTs in bipolar disorder, either as monotherapy or as adjunct

Many reported cases of SJW-induced hypomania Increased risk of switch with advanced age

Inadequate data to make recommendations

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Free and Easy Wanderer Plus (FEWP) for Mood Disorders

Chinese herbal mixture for multiple mood and anxiety symptoms

Acute Treatment as Adjunct † (Bipolar Depression and Mania)

12 week double-blind RCT (n=235)CBZ, CBZ+FEWP, CBZ+Placebo

**CBZ superior to Placebo for Depression and Mania

**CBZ+FEWP superior to CBZ for Depression

Acute Treatment as Monotherapy ‡

(Unipolar and Bipolar Depression)

12 weeks double-blind RCT (n=149)FEWP or Placebo

**FEWP superior to Placebo on HAM-D, MADRS and CGI for both illnesses † Zhang et al. J Psychiatr Res. 2007, 41, 360-369

‡ Zhang et al. J Psychiatr Res. 2007, 41, 828-836

Maintenance Treatment as Adjunct ‡ (Bipolar Depression and Mania)

26 week continuation RCT (n=188)CBZ+FEWP, CBZ+Placebo

**CBZ+FEWP = lower discontinuation rate, fewer side effects, lower CBZ plasma levels

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What are the Data with Other Herbal Remedies?

Herbs studied: Crocus sativus (saffron) Echium amoenum (borage) Gingko biloba Lavandula (lavender) Rhodiola rosea (roseroot) Japanese herbal formulations

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Other Herbal Remedies (Cont’d) Few RCTs with small numbers Variation in formulation, dose, duration Short-term data only (4-8 weeks) Recommendation: Crocus sativus for mild to

moderate depression as a 2nd or 3rd line monotherapy

Insufficient evidence to recommend other herbs

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Conclusions: CAM Treatments for Depressive Disorders Most robust evidence – Light therapy in seasonal

depression. Evidence and clinical support in mild-moderate MDD

Light therapy – augmentation Exercise/yoga – augmentation Omega-3 fatty acids – monotherapy or augmentation SAM-e – monotherapy St. John’s Wort – monotherapy

Bipolar disorder Omega-3 fatty acids - augmentation

Inconclusive evidence at present for other physical, herbal or nutraceutical therapies

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