Kelly Foster, MD, Hatos Prize Winner st Century Psychiatry Prize: Complementary Treatment Options in Psychiatry

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1 , Hatos Prize Winner st Century Psychiatry Prize: In the near future, due to both financial and ethical concerns, many have hypothesized that the drug industry will slow, if not halt, further development of drugs which penetrate the central nervous system. This possibility could be detrimental to the tens of thousands of patients suffering from mental health disorders, for whom current treatment options might not provide enough relief. With the NIMH reporting lifetime prevalence of anxiety disorders approaching 28.8% and depression 16.8%, it is essential to continue the search for additional treatment regimens beyond what is in our current armamentarium. It is up to physicians and researchers to turn our collective heads towards the oftentimes dismissed alternative treatments, many of which have thousands of years of historical use in other civilizations. With further development and knowledge of these modalities, it is possible that we could integrate new augmenting agents into our current western medicine regime and provide increasing amounts of relief to those in pain. The definition of Complementary and Alternative Medicine (CAM) must be addressed any time a discussion of alternative or integrative treatments is raised. Currently, it appears that CAM is exclusionary, understood as what it is not (traditional western medicine which has been backed by rigorous trials) more than what it is. A more modern view of complementary medicine is that which complements, or works alongside, our current medications. The term alternative could be replaced with in lieu of,and integrative suggests parallel use with the currently adopted biomedical model in western society. It does not solely imply herbal or dietary supplements but also encompasses manual process (such as massage and acupuncture), mind-body exercises (like Tai Chi and yoga), and therapies (including hypnosis and progressive muscle relaxation). It is imperative to consider, however, that as standards and research evolve, what is at one time considered alternative may eventually become a primary first line medication. Consider, for example, the evolution of Digitalis, an anti-arrhythmic drug used for patients suffering from atrial fibrillation. In 1785, William Withering observed symptomatic improvement of Congestive Heart Failure when a patient took a common herbal remedy. He was ultimately able to extract the curative agent and discovered the flowering plant Foxglove was responsible for such results.1 This historical account is necessary to remember when we are quick to dismiss the host of remedies patients can bring into our offices. Another reason to be aware of complementary treatment modalities in psychiatric practice is its abundance in the population at large. Most patients who subscribe to the use of alternative agents report them to be equally, if not more, effective than standard therapeutics offered by drug companies today3, even though scientific evidence of such is lacking, as there are relatively few published randomized control trials using adequate sample size and approximating the academic rigor of standard medication trials. Patients also believe that CAM therapies have fewer side effects and are more safe than prescription drugs. The issue of safety will be discussed later in this essay, however a good practitioner cannot refute the fact that conventional medications do have side effects and are not 100% safe. Recent reports2 have found that almost 40%t of adults in the

2 2 United States visit CAM providers, and 10% of those sought treatment for a psychiatric diagnosis. It is estimated that up to 67% of patients suffering from depression or anxiety attempt to alleviate symptoms using a combination of non-conventional treatments alongside standard therapeutic ones, however a large survey showed that only 38% of patients reveal this information to their practitioners.3 This lack of disclosure can be frightening to a provider for many reasons, one of which is the potential for drug-drug interactions, of which the patient may not be aware. From a medical point of view, at least a vague knowledge about alternative remedies is necessary in order to educate and treat patients best. For example, without such knowledge, one might not know that Kava and vallerian (touted to alleviate symptoms of anxiety) can potentiate the effects of benzodiazepines and alcohol; Ginsing (claimed to help with depression, negative symptoms of schizophrenia, and memory) can potentiate MAOi s, leading to hypertensive crisis; St John s Wort, when combined with MAOi s, can lead to serotonin syndrome; Green tea and dandelion can function as diuretics and should be avoided in patients on Lithium; Yerba Mate or Kola Nut can lead to agitation or worsening psychosis in patients with Bipolar disorder or Chronic Paranoid Schizophrenia.5 Following are some of the more popular options utilized by people in the community for management of their anxiety and depression. Of course, many other remedies are also available, but my intent is to discuss primarily the oral formulations to which patients are exposed. I also hope to address some of the concerns with the purity and safety of many herbs and dietary supplements. It is imperative to keep in mind that research is always being updated and re-tested, so before applying this information into treatment of a patient, a new literature search is strongly recommended. Treatment Options for Unipolar Depression St. John s Wort (Hypericum Perforatum) has historically ranked among the most frequently utilized herbs, though it fell in popularity after awareness to drug-drug interactions was brought to the attention of the public. Nonetheless, it remains a treatment option with some validating findings and should not be discounted immediately. It is believed that the hyperforin component of the herb probably plays the most significant role in its anti-depressive effects, and, particularly, it exerts its effect on several neurotransmitters by inhibiting the reuptake of serotonin, norepinephrine, dopamine, GABA, and L-glutamate in vitro. Although several studies have compelling evidence that this medication is superior to placebo and as effective as conventional antidepressants in the treatment of mild to moderate depression, two larger scale studies (n=200 and n=340) demonstrated less moving findings in the treatment of severely depressed patients. In one of these studies, in which all patients had HAM-D scores over 20, administering 300mg of St. John s Wort 3-4 times daily was no more useful than placebo; however, in this article there were unusually low remission rates in both groups, and no comparator to conventional antidepressants was available.14 In the other study, comparing St. John s Wort to sertraline (50-100mg) and placebo, HAMD and CGI scores were measured after eight weeks and demonstrated no significant difference between the three groups13. Some criticisms of this study include that sertraline did not separate from placebo, either, as well as a potentially subtherapeutic dose of zoloft, and a truncated length of observation (eight weeks). A more recent meta-analysis 12, in which 13 randomized

3 3 double-blind controlled studies comparing St. John s Wort with SSRI, showed that both have equal efficacy and tolerability in treating major depression as qualified by DSM or ICD-10. Many practitioners dread this herb because it is a known CYP450 inducer, particularly CYP3A4, which metabolizes approximately 50% of all conventional medications. Rather than fear this consequence, however, awareness is essential so that careful monitoring can occur to ensure the metabolism of other drugs is not affected. If this were ignored, for example, a patient could clot (due to induction of Warfarin) or become unintentionally pregnant (because oral contraceptives are subtherapeutic). Adverse effects primarily include gastrointestinal, as well as dizziness, fatigue, sedation, headache, and dry mouth. Also reported are non-specific weight loss and photosensitivity (especially after overdose or in individuals with HIV or HEP C), however, these appear more rare in reports. Notably, St. John s Wort has a lower withdrawal phenomenon when compared to SSRI s, and this can been viewed as a potential advantage for its use. In pregnancy data, case reports indicate that infants who were exposed in utero appear to demonstrate similar phenomenon to those exposed to SSRI s (weak cry, jitteriness, etc), however, in 54 human pregnancies no major malformations have been reported. When recommending to clients, it is recommended that we use 300mg BID of the same brands tested in clinical trials (Kira (LI 160) or Remotiv (ZE 117), or those highly rated by thirdparty evaluators, as listed below for best results. Omega-3 Essential Fatty acids, including EPA (eicosapentoic acid) and DHA (docosahexanoic acid) are another supplement being used in increasing proportions recently. Cross national analysis reveals not only cardioprotective effects of its use but also an inverse relationship between O3FA s and major depression, postpartum depression, and bipolar disorder 24. There have also been studies linking poor diets (those low in fish, fruits, and vegetables) and suicide attempts. A large cohort tally found that women with higher O3FA consumption during pregnancy have less depressive symptoms. Although mixed results continue to be published regarding its use as either monotherapy or augmentation, the positive findings appear to shine when EPA:DHA ratio is 2:1 and doses are between 1-9.6g/day. It is notable, although not yet fully understood why, that the positive studies appear when EPA fraction is used higher than DHA25,26,27. It is also important to note that these key components (EPA and DHA) must be obtained from fish, and although shorter chain omega 3 essential fatty acids such as ALA (obtained from plant sources such as Chia seeds) can theoretically be converted into longer chain EPA and DHA, this only occurs in a small percentage, so it is less efficient than capsules containing direct fish oil. Further research is needed to identify if supplementation in other periods of life can also be useful, such as MDD during the menopausal transition, however, existing literature is promising.28 From a societal perspective, as women are becoming increasingly concerned about mercury exposure in pregnancy (the FDA currently recommends that pregnant women consume no more than 12 oz/week of low mercury containing fish and 18 oz/month of high mercury fish due to media-induced fears of autism, etc.), they are consuming less fish overall, including those high in O3FA s (such as mackerel and tuna). Women need to be educated that moderation is key, and the lowest mercury-containing fish, including salmon and herring, can offer good levels of omega 3FA s as well as other important health benefits. Ultimately, if the choice is made to recommend O3FA adjunctively to a

4 4 patient s current antidepression regimen, then help a patient choose a formulation containing EPA component greater than DHA at doses above 1g/day, up to a maximum of 9g/day. Side effects of the use of supplementation of O3FA s include diarrhea, nausea, and a fishy aftertaste from the pill. Caution has also been raised when using >3g/day due to a presumed bleeding risk, although more recent studies don t validate this concern. Interestingly, some studies have found that Omega 3FA use in pregnancy might help prevent preterm labor.29 This is an important consideration, given the known association between untreated depression in pregnancy and preterm delivery. Folate (synthetically, folic acid) is another nutritional supplement with many studies citing efficacy as an augmenting agent to conventional antidepressants, with the belief that it exerts its effect by impacting the synthesis of neurotransmitters including serotonin, dopamine, and norepinephrine.6 In the arena of consultation psychiatry, there is an obvious association between folate deficient patients (due to alcoholism, dementia, and eating disorders amongst others) and depression. Interestingly, many recent studies which include depressed patients with no underlying folate-deficiency anemia also show promising findings when folate is added to the treatment plan7. Current practice reveals that many practitioners are recommending methylfolate (Deplin) or folinic acid (Leucovorin), both of which cross the blood-brain barrier, over folate, and, in essence, are proceeding directly to the final conversion for use at the cellular level. One reason for this bypass is that it has been recently discovered that a certain percentage of the population cannot properly metabolize folate. Whether this lack of conversion is due to medication interactions which inhibit conversion (including Lamotrigine, Carbamezapine, Valproic Acid or Methotrexate), or an inherited polymorphism C677T variant of the enzyme methylene tetrahydrofolate reductase (which is more common in patients with depression)17, the effect is the same. Additionally, 5MHTF does not appear to mask underlying B-12 deficiency as excess folate administration could do. One oftencited study, in which 127 unipolar depressed patients with HAM-D >20 had 20mg/day fluoxetine randomly augmented with either folate 500mg/day or placebo, found that the addition of folate provided symptomatic relief in both genders, however, findings were more pronounced in women18. They also noted a lessened side effect profile experienced from the prozac when folate was added to the regimen. Though additional studies are needed to fully examine which patients are most likely to respond to folate augmentation, there appears to be no contradiction to its recommendation, particularly for women. At minimum, women in their childbearing years should be taking 400micrograms folate daily to prevent neural tube defects, or 5mg if they have a condition or medication that might increase the risk of this malformation. Side effects are few, if any, and the cost of use is much less than the addition of a second antidepressant. Along the line of nutritional supplementation, another hot item lately is SAM-e (Sadenosyle l-methionine), a methyl donor in multiple body reactions, ultimately facilitating the synthesis of multiple functional components in the brain, in theory helping both with membrane fluidity as well as general functioning of brain amines. It is formed biologically from the building blocks of folate and methylfolate. Although there are few large rigorous studies, those that are available indicate SAM-e is equally effective as tricyclic antidepressants and often has a faster response, seen by 10 days.11 Notably,

5 5 most older studies used parenteral administration, rather than oral; however, a recent large study (n=576, HAM-D >18), comparing 400mg IM SAM-e to 1600mg oral SAM-e to 150mg imipramine for four weeks, demonstrated that all were equally effective10 Current practice suggests it is safe to combine with conventional antidepressants. In fact, there is increased efficacy for SSRI non responders when augmentation with SAMe at 800mg BID was begun9. Most practitioners recommend dosing SAM-e between 800-1,600mg/day (divided), generally starting at 400mg daily, and instruct on improved bioavailability when taken before meals and combined with vitamin B-12 and folate. Side effects are generally negligible, especially when compared to conventional medications, but when they do exist they are mild and transient, including headache, insomnia, jittery, dry mouth, and loose stools. Notably, no sexual effects have been reported, however case reports of mania and anxiety would limit the use of this treatment to unipolar depression at this time. Unfortunately, SAM-e is rather costly, which remains a significant limiting factor in its use. Rhodiola Rosea (aka Arctic Root, Golden Root, Roseroot) is a remedy worthy of more attention in the western market. Although, like most other CAM therapies, it has limited studies in the U.S., it is a drug that has been utilized in Russia for the treatment of depression and anxiety for over 40 years (and, anecdotally, for the treatment of impotence, memory, and fatigue). Many studies still require translation, although few English studies have touted early evidence of its utility, particularly in conditions characterized by lethargy and asthenia. In a six-week, double-blind, placebo-controlled study of 89 patients with mild-to -moderate depression, doses of mg/day provided a 7-9 point reduction in the HAM-D.30 Making this remedy even more interesting is that drug-drug interactions are minimal to none, and side effects are negligible. Chromium also offers promise for some patients, particularly those suffering from atypical symptoms such as diurnal mood variation, hyperphagia and hypersomnia. A small double-blind placebo controlled study using ug/day of chromium showed significant relief in atypical symptoms, however, there was no notable change in HAM-D scores19. The side effects in this drug must be considered, too, as those such as insomnia, psychomotor activation, and vivid dreams lead one to conclude that they should be avoided in patients with a history of bipolar disorder. Due to the fact that chromium increases efficiency of insulin utilization, it may be particularly of aid in the diabetic population with comorbid depressive features. As with Rhodiola, chromium demands more attention in the future and a watchful eye for new revelations. Given many of our medications work on the serotonin pathway, a theoretical alternative treatment includes the amino acid L-tryptophan or its metabolite 5-HTP, both precursors in the pathway to development of the monoamine Serotonin (5HT). Unfortunately, the majority of the literature does not appear to support this theory into the translation of reduction of depressive symptoms, nonetheless it is important to be aware of, as many patients may be using this remedy. The advantage is thought to be that both can cross the blood brain barrier, however, when orally administered a significant amount is converted peripherally. Carbidopa is oftentimes co-administered to block this rapid

6 6 translation before it has the chance to reach the brain. Side effects, when reported, include sedation and nausea. Light therapy boxes are becoming an increasingly affordable and acceptable option for the public, selling for under $200 on Amazon.com. A bright light box containing 10,000lux white light placed inches from the eyes for 30 minutes every morning has been proven as effective monotherapy for seasonal affective disorder31 as well as a convincing augmentation strategy for non-seasonal depressions32, including premenstrual dysphoric disorder (when if used in the luteal phase, a reported 50% decrease in HAM-D was observed) and postpartum depression. Typical side effects include jitteriness, nausea, and headache, and due to reports of mania induction, it is best avoided in those with a history of bipolar disorder. Also, if a patient is taking medications which render them more sensitive to light, an opthalmology consultation is recommended. Treatment Options for Anxiety Disorders Kava (Piper Methysticum) has long been used by pacific island cultures with no reported ill effect for the treatment of anxiety, as a remedy for insomnia, and for inciting a generalized feeling of calm similar to that of alcohol. Unfortunately, Kava became an herb of concern after reports of severe liver damage were revealed in 1998, resulting in an FDA consumer warning against ingestion of the herb in 2002, as well as removal entirely from the shelves of many European countries. It is noteworthy that the controlled trials using doses less than 400mg/day since 1997 have not shown any ill effect validating this concern, which leads to the consideration that the rare finding could be due to product contamination or poor preparation standards. The kavalactones (the active components of the plant, at least 15 subtypes are present in the plant) are believed to act in different ways on the brain, including GABAa potentiation, MAOb inhibition, and noradrenergic inhibition. One meta-analysis of three studies using an average of 210mg/day Kava found a response within 2-4weeks of a 9.7 point reduction in HAM-A scores compared to placebo15. A 2003 update with over 600 participants further validated these findings, and even later studies comparing the anxiolytic effects of Kava to benzodiazepines also supported the role of this herb in the management of anxiety disorders16. As therapeutic doses of Kava administration do not tend to produce the side effect of sedation, it places this herb at an advantage over many other standard options. It is recommended that ingestion is kept at less than 250mg/day to minimize potential for hepatotoxicity (with a goal typical daily dose between mg Kava), and that it is used primarily for the short term (less than 24 weeks). Side effects include dermatologic (allergic) reactions, extrapyramidal symptoms, apathy (primarily with long-term exposure), antiplatelet activity, and hepatotoxicy. This herb should be avoided in patients with a history of liver disease, concurrent benzodiazepine use, Parkinsons disease, or pregnancy. Chamomile has been utilized in tea preparations over the counter for many years, and although hundreds of ailments are claimed to be treated with its consumption, from a psychiatric position it appears primarily utilized at night to aid in sleep onset and relaxation. In 2009, researchers sought to evaluate in a double-blind fashion whether

7 7 German chamomile separated from placebo in the treatment of patients suffering from generalized anxiety disorder. Fifty-seven patients were separated with half receiving 440mg -1gm pharmaceutical grade tablets derived from German chamomile (Marticaria Recuttia), and the other half taking placebo for eight weeks. Results found a 50% reduction in HAM-A scores with few reported side effects.33 When side effects are reported, they commonly include minor allergic reactions, atopic dermatitis (skin rash), drowsiness or sedation. One concern in the literature is the potential to stimulate the uterus (and possibility for miscarriage), however, it appears that Roman chamomile (but not German) is reported to be an abortifactant. Although the small studies appear to be hopeful, obviously, much larger studies are needed before suggestion can be made to patients. Vallerian is also an herb often used for anxiety and depression, but it is primarily indicated for short-term management of insomnia. Though there is little scientific backup to indicate if it is truly helpful, anecdotally patients continue to report relief. In pregnancy, there are no controlled data, but case reports have not shown any signs of toxicity. Although folklore indicates a long history of the use of passionflower for the management of anxiety, only three randomized double-blind human trials are found in a literature search: two small studies comparing the herb to placebo, and one small pilot comparison evaluating 45 drops of passionflora versus 30mg/day of oxazepam. Notably, few side effects were found in any of the studies looking at the herb, and in the benzodiazepine comparison, passionflower was equivalent in performance of the reduction of GAD symptoms with less cognitive effects34. It is an herb worthy of more research and larger studies. Overall, when considering the multiple complementary and alternative treatment options available in today s market, the fact remains that there are a limited number of highquality studies conducted with the same academic rigor as conventional medications, and in some cases the potential for placebo control is almost impossible (such as with yoga or relaxation breathing). Nonetheless, as our standard medications fail to treat a significant percentage of our population, or have intolerable side effects, many people continue to turn to a holistic modality of healing in search of relief. It is essential that as practitioners we embrace the potential of this field, while keeping our scientific standards in mind. The concern many professionals have about the use of non-westernized medicine cannot be discounted. The U.S. FDA regulates dietary supplements as food, not drugs, so they can be sold without proof of safety or efficacy.20 Quality assurance is difficult, as is consistency between batches. Due to such, many contaminated products are imported into the U.S. unregulated. We cannot forget, for example, the FDA ban on over-the-counter tryptophan in 1990 after contaminated supplements caused 38 deaths and 1500 cases of eosinophilia-myalgia syndrome. Although it has been allowed back into our pharmacies since 2002, and is often used in compounding pharmacies for various purposes, the outrage experienced due to the suspected trace impurities produced during drug manufacturing must be noted. Also, Huang and colleagues collected over 2500 samples from eight large hospitals in Taiwan in 1992, and found almost 25% of the products to be

8 8 contaminated with chemicals not prescribed or labeled, including steroids, phenobarbitol, and acetaminophen amongst others 22. Patients must be educated that natural is not synonomous with safe, and they should be informed that dietary supplements are only subject to USP (U.S. Pharmacopeia, a non-profit public health organization) standards when they are labeled as such. USP verified stickers on the sides of supplements or herbs indicate that they have passed the rigorous quality assurance and safety test21, however limited by the fact that testing is voluntary by the manufacturer, so many companies do not chose to have it done. Subscription to third-party vendor sites such as consumerlab.com can also inform both the patient and the practitioner immediately of product recalls or new warnings, as well as offer choices of reputable brands to consumers. K In summary, we need to be open minded and educated about the various options available to our population, beyond that which we are comfortable prescribing. CAM treatments can be quite expensive, and many have concerning side effect profiles or lack data proving their effectiveness. We must take a certain amount of responsibility in enlightening ourselves to these alternatives, with the ultimate goal of providing the most well-rounded care to our clients. References 1. Goldthorp WO (2009). "Medical Classics: An Account of the Foxglove and Some of its Medicinal Uses by William Withering, published 1785". Brit Med J 338: b National Health Interview Study 3. Kessler et al: the use of complementary and alternative therapies to treat anxiety an depression in the United States. Am J Psychiatry 158: , Eisenburg et al: trends in alternative medicine use in the United States, : results of a follow up survey. JAMA 280: , Ellinoy, Lake, Hobbs: Patient Safety in Mental Health Care, Washington DC, American Psychiatric Publishing, Inc, 2007, pp Freeman et al: Complementary and Alternative medicine in major depressive disorder: the American Psychiatric Association task force report. J Clin Psych 71(6):669-81, alpert et al: Folinic acid (leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann CLin Psych. 14(1):33-38, Papakostas et al: S-Adenosyl Methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder, a doubleblind, randomized clinical trial. Am J Psych 167:942-48, Hoenders et al: The Dutch Complementary and Alternative Medicine (CAM) Protocol: To Ensure the Safe and Effective Use of Complementary and Alternative Medicine Within Dutch Mental Health Care. J Alt Comp Medicine, April Delle Chiaie et al: efficacy and tolerability or oral and intramuscular S-adenosyl-Lmethionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramin in 2 multicentar studies. AM J Clin Nutr 76 (suppl): 1172s- 76s, Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. 12. Rahimi et al, Efficacy and tolerability of Hypericum perforatum in major depressive

9 9 disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis Prog Neuropsychopharmacol Biol Psychiatry Feb 1;33(1): Hypericum depression trial study group: effect of hypericum perforatum (St. John s Wort) in major depressive disorder: a randomized conrolled trial. JAMA 287: , Shelton et al: effectiveness of St. John s Wort in major depressoin: a randomized controlled trial: JAMA 285: , Pittler and Ernst : efficacy of kava extract for treating anxiety: systematic review and meta-analysis. j clin psychopaharmacol 20:84-89, Boerner et al: kava-kava extract LI 150 is as effective as oprpramol and busprione in generalized anxiety disorder: an 8-week randomixed, double-blind, multicentar clinical trial in 129 outpatients. phytomedicine 10 (suppl):38-49, Kelly CB et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004;18: Coppen and Bailey. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord 60: , Mcleod and Golden: Chromium treatment of depression Int J Neuropsychopharmacol 3:311-14, Cohen and Schouten: Legal, Regulatory, and Ethical Issues in Complementary and Alternative Treatments in Mental Health Care, Washington DC, AMerican Psychiatric Publishing, Inc, 2007, pp U.S. Pharmacopoeia: Huang et al: adulteration by synthetic therapeutic substances of traditional chinese medicines in Taiwan. j clinical pharmacol 37: , consumer lab.com 24. Freeman et al: Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psych 67(12): , 2006p 25. Su et al: Omega-3 fatty acids in major depressive disorder: a preliminary doubleblind, placebo controlled trial. Eur Neuropsychopharmacol 13:267-71, Peet and horrobin, a dose-ranging exploratory study of the effects of ethyleicosapentaenoate in patients undergoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 59:913-19, Nemets et al: Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 159:477-79, 2002% 28. Freeman et al: Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial. Menopause 18 (3) , Olsen et al: Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 340(8811):118, Darbinyan et al: Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nordic J of Psych. 61(5): , Golden et al: the efficacy of light therapy in the the treatment of mood disorders: a review and meta-analysis of the evidence. AM J Psychiatry 162(4):656-62, Even et al: Efficacy of Light Therapy in nonseasonal depression: a systematic review. J Affect Disord. 108(1-2):11-23, Amsterdam et al: A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J CLin

10 10 Psychopharmacol. 29(4):378-82, Akhondzadeh et al. Passionflower in the treatment of generalized anxiety: a pilot double-blind, placebo-controlled trial with oxazepam. J Clin Pharm Ther 26(5):363-7, 2001