Manualof Clinical FourthEdition

AlanF. Schatzberg, M.D. KennethT. Norris, Jr., Professor and Chairman, Departmentof Psychiatryand Behavioral Sciences, StanfordUniversity School of Medicine, Stanford,California JonathanO. Cole, M.D. Professorof Psychiatry HarvardMedical School, Boston; SeniorConsultant, McleanHospital, Belmont; PsychiatricTraining Consultant, St.Elizabeth's Medical Center, Brighton,Massachusetts CharlesDeBattista, D.M.H., M.D. AssistantProfessor and Chief of DepressionClinic, Departmentof Psychiatryand Behavioral Sciences, StanfordUniversity School of Medicine, Stanford.California

Washington, DC London, England Noler 'l'lrr, :rrrtlrilr,,.iltirve worke

\finn S, Stowe ZN, Landry JC, et al: Sefiraline in breast milk and nursing in- fants, in 1995 New Research Program and Abstracts, American psychiat- t ric Association 148th Annual Meeting, Miami, FL,, May 20-25, 1,995. \Washington, DC, American Psychiatric Association, 1995, p 73 I \X/raggRn, Jeste DV: Neuroleptics and alternative treatments: management of behavioral symptoms and psychosis in Alzheimer,s disease and related conditions. Psychiatr Clin North Am 1I:195-21.3, 7988 \XzraggRE, Jeste DV: Overview of and psychosis in Alzheimer's disease.AmJ Psychiatry 1,46:577-587,I9B9 Herbalsand Yudofsky SC, Silver JM, Schneider SE: The use of beta blockers in the trear- ment of aggression. Psychiatry Letters 5:15-23, 1988 DietarySupplements

H..n"t remedies and dietarysupplementshave becomequite pop- ular in the past 10 years for the treatment of psychiatric symptoms. Sales of St.-John's-wort, omega-J fatty acids, and DHEA (dehydroepi- androsterone) have contributed to an estimated $6 billion in annual U.S. sales.As part of a1994 congressionalact,an alternative medicine and dietary supplements office was created at the National Institutes of Health to evaluate alternative agents. Herbal agents are, for the most part, considered food supplements and are therefore not subject to U.S. Food and Drug Administration (FDA) regulations. Vhile it is illegal for a food supplement to claim to be efficacious for a specific illness, there are few restrictions on a manufacturer's claiming that a food supplement helps with mood symptoms or gastrointestinal upset. The lack of FDA regulation and oversight of compounds leads to a number of other differences between pharmaceuticals and over- the-counter remedies. One imporlant difference is that efficacy does not need to be established in the case of a food supplement. In most

595

* 596 Manualof ClinicalPsychopharmacology Herbalsand DietarySupplements 597

Finally, some patients with serious illnesses such as depression cases, the data supporting the use of many of these compounds are or may be tempted to take over-the-counter prepa- anecdotal and do not compare to those required of prescription rations rather than to see a doctor. The general public often equates drugs. That is not to say that some herbals and supplements might "naittaI" with safe and good, while synthetic compound regarded not help. It is only to undedine that even herbal supplements as ex- $ with some suspicion. In addition, herbals and dietary r.i$pl.-.ntt tensively studied as St.-John's-wort have been poorly studied com- arc readlly avallable at the health food store or supermarket. There pared with any prescription . is no need to see a psychiatrist to obtain a prescriptiori for these Another important difference between herbals and prescription dietary supplements, and thus the stigma and cost associated with drugs is that the safety or optimal dosing of a food supplement does X! seeking p9ychiatric help are not a factor. However, since many psy- not have to be established before the compound is marketed. Pre- $ chiatric disorders are potentially life threatening, psychiatric self- n,$, scription drugs are required to undergo extensive testing in animals treatment would be analogous to patients with some forms of to determine risks, including those in pregnancy. Once the carcino- treating themselves rather than seeking medical assistance.Either ex- genic, mutagenic, pregnanry, and pharmacokinetic toxicological pro- ample of self-treatment may have disastrous consequences. files are established in animal testing, studies are then completed on That being said, it is also likely that some herbals and dietary healthy volunteers. Only then are the first efficacy studies completed. supplements will prove helpful for some patients. After all, many Herbals and food supplements are not typically subject to any effective compounds, from acetylsalicylic acid (aspirin) to digitalis, safety testing at all. Over-the-counter preparations, such as DHEA, were originally synthesized from products. It is important that cleady have hormonal properties and have had important side effects these dietary compounds be studied and refined. In this chapter, we in men and women. Yet, DHEA is still regarded as a food supplement review what is known about some of the more commonly used and thus not monitored or regulated. herbal and dietary supplements (Table 13-1) and offer some sugges- Still another important difference is that the processing andman- tions for their role in the treatment of psychiatric disorders. ufacturing of herbals and dietary supplements are far less consistent than with prescription medications. Herbals, for example, are not sim- ple molecules. They are plant derivatives, and different crops of the St.-fohn's-Wort (Hype ricu m Perforotum) same grown in different parts of the country or wodd, pro- St.-John's-wort ( perforatum) has been employed for cen- cessed by different methods, may yield very different products. Thus, turies in treating avaieLy of ailments. The has been used in re- the pharmacological properties of one batch of an herbal produced cent times primarily for a range of disorders from external wound by the same manufacturer processed in a consistent way may be dif- healing to the treatment of mild anxiety and depression. In medieval ferent from those of the next batch. Some of these herbals are subiect times, St.-John's-wort was often carried into battle in amulets worn to rapid oxidation in room air and thus lose their pharmacological around the neck to prevent evil from befalling a soldier. Since mental properties quickly. In addition, the shelf life of most herbal supple- illness was often attributed to demonic or witches' spells, it is prob- ments is unknown, and there is evidence that many compounds are able that medieval peoples were using it for ailments such as depres- held in warehouses for months before being distributed to retail out- sion and anxiety. lets. The result is that some, perhaps many, herbals are pharma- A mythology surrounds St.-John's-wort. Known in biblical times cologically inert by the time they are consumed. Although many as the Rose of Sharon, St.-John's-wort is said to have grown in the subjects may claim benefits from using inert herbals, the bloodied ground after the beheading of St. the Baptist and blos- response rate for some psychiatric disorders is also quite high. John 598 Manualof Clinical Psychopharmacology Herbalsand DietarySupplements 599

t6 g soms everyJune (around o o St.John's Day). The plant is found on every L continent L t .9 except Antarctica. In the northwest , it grows G @ o) ^, tr F o tr9.e 6 wildly and is also referred to as Klamath , since it gro*s exten- P I N :l' R ! F+iHo -s o sively along the banks of the Klamath Riveq or goatweed, since goats (o bo ! o : -.:5! tend to feed on it. sheepherders and goatherds are ? \z-3 d not fond ofgoat- T' 6 ii = I ! o

^l I 600 Manualof ClinicalPsychopharmacology Herbalsand DietarySupplements 601

arations to treat mild to moderate depression. At least 30 European wort has been associated with inducing mania or hypomania in sus- studies support the use of St.-John's-wort in treating depression. ceptible patients, but less commonly. Most, but not all, of these studies suggested that'St.-John's-wort is Serious drug interactions appear to be uncommon' There have more effective than placebo and r.-:raybe as effective as comparison been rare repofts of a syndrome associated withshe use of agents, usually antidepressants administered at low doses. selective serotonin reuptake inhibitors (SSRIs).Thus, man$ chnicians The European studies have been criticized for a number of methodo- advise against using the herb with an SSRI.Theoretically, St'-John's- logical problems, including unclear entry criteria, inadequate dosing wort may enhance the sedating effects of narcotics and benzodiaz- of comparison agents, and lack of scientific rigor. epines. is that St.-John's-won is 1) St.-John's-wort has also been preliminarily studied in the treat- A more recent pharmacokinetic finding # ment of gastric distress and topically in the treatment of first-degree an inducer of the 3A3/4 enzyrne. This is i$ burns and myalgias. These uses have been much less investigated responsible for metabolizing most drugs used in medical practice, than has its utilify in treating depression. including channel blockers, oral contraceptives, many anti- biotics, and glucocorticoids. St.-John's-wort has been noted to en- llfiochanismof Action hance the metabolism of protease inhibitors in AIDS patients and has been pop- HWeNcum perforatum is not a simple molecule and contains many thus render these drugs less effective. St'-John's-wort AIDS patients in some prac- potentially active constituents. It is unclear which, if any, of these ular for treating depressive symptoms in AIDS regimens may components contribute to the effects of the herb. Standard tices, and the addition of St.-John's-wort to some and hyperforan extracts of St.-;ohn's-wort have been shown to have prove problematic. mild serotonin reuptake-blocking properties. There is little evidence Oosageand Administrati$n that St.iJohn's-wort produces any significant inhibition of mono- amine oxidase (MAO) in vitro, although such an effect is commonly Determining the appropriate dosage of St.-John's-wort presents some attributed to the herb. Hypericin also has affinity for sigma receptors, difficulry, since every prepatation-and perhaps every batch--of the may inhibit COMT (-O-methyltransferase), and may enhance herb is vaiable. The typical dose is 0.2-1' mg of the hypericin or 900- GABA (y-aminobutyric acid) receptors. 1,,g00mg/day of the whole herb taken in two or three divided doses. People also take 1 g up to three times a day of the dried herb in a $ide &f{eetsand $rug lmteraet,oms tea fypically boiled in 150 mL of water and then strained. People who orally per day and then St.-John's-wort is considered to be well tolerated. The most colnmon use St.-John's-wort typically startat 30M00 mg prescription antide- side effects of St.-John's-wort are gastrointestinal upset, photoderma- increase the dosage every 1'-2 weeks. As with several weeks. titis, and . In clinical trials, approximately 180/oof patients who pressants, the effects may not be seen for the effects appeat to took St.-John's-wort reported side effects. This is considerably lower Our experience with St.-John's-wort is that Given the results of than the side effects report with most standard antidepressant. Rela- be modest but not negligible in many patients. not advising patients to use tively few people stop St.-John's-wort because of side effects. There the two fecent controlled trials, we afe St.-John's-wort for at least has been an isolated report of a reversible neuropathy associated it. If it is to be used, we suggest stopping with a preparation of St.-John's-wort, and an antnaT study that sug- 3 days before starting an SSRIor . gested reduced fertility. Like prescription antidepressants, St.-John's-

) 602 Manualof Clinicalpsychopharmacology Herbalsand DietarySupplements 605

Omega-3Fatty Acids velop a fishlike odor to their breath. Some preparations of omega-3 fatty acids may be more likely to cause this fish odor than are others. omega-3 fatty acids are building blocks of in the same way that There may be a tendency for omega-3 fatty acids at high doses to amino acids are the building blocks of proteins. They are found abun- acl as ablood thinner and reduce clotting times. Thus, the corhbination dantly in coldwater fish, such as salmon and haribut, and are also found of high doses of ome ga-3 fatty acids plus other blood thinners,rincluding in canola and soybean oil. The tfuee most cofi'non forms of omega-3 aspirin, coumadin, or , may be problematic in some patients. fatty acids are oc-linolenic acid, eicosapentaenoic acid, and docosa- no known serious drug interactions betweent.omega-3 ' There are hexaenoic acid. There has been a recent interest in the role of omega- fatfy acids and mood stabilizers, antidepressants, or antipsychotics. 3 fatty acids in the treatrnent of bipolar disorder and attention- deficlt/ hyperactivity disorder. V In addirion, diets deficienr in omega-3 fatty acids Sosageamd .&dc$is? istratis*l *$ have been associated with increased rates of atherosclerotic disease. tfeatment , The dose of omega-3 fatty acids studied as an adjunctive Capsule {Js*sand &Nechanismsf Actlom for bipolar disorder has been 9'6 g/day in divided doses' doses are usually 3,000 mg, so 1 capsule tid is probably sufficient. A number of reports over the past 10 years have suggested that af- 'w.e have recommended this regimen in combination with stan- fective illnesses may be associated with deficiencies of some omega- dard mood stabilizers to some patients because the risks of omega-3 3 fatty acids. For example, there appears to be some correlation be- fatty acids are small. In some patients, this regimen appears to be tween a higher ratio of to eicosapentaenoic acid in helpful in treating their symptoms. mofe severely depressed patients than in less severely depressed pa- tients. other studies have suggested that there may be lower levels of omega-J faty acids in the red blood membranes of depressed Kava(Piper MethYsticum) patients than in healthy control subjects. Furthermore, there is some Kava has been used for many years in folk medicine, and in Polynesia limited evidence that omega-J fatty acids may impact signal transduc- it is used as a cefemonial beverage to induce relaxation. The kava plant tion in a manner analogous to . is indigenous to the islands of the south Pacific and belongs to the pep- A recent double-blind study reported that adding supplemental per family. In the past 2years,kavahas enjoyed significant popularity omega-J fatty acids to the drug regimens of bipolar patients im_ in the United States as an over-the-counter treatrnent for "stress." proved rheir outcomes (Stoll et al. 1999).In this study, J0 patienrs with bipolar disorder were randomized to receive either omega-J {Jses supplements or olive (as oil a control) for 4 months. They continued People use kava fot avaiety of ailments, including anxiety and agita- taking standard mood stabilizers. The omega-3-treated patients ex_ tion. A small amount of data suggests that when taken orally, in ex- perienced longer remission and more complete resolution of symp- tracts that contain 70o/okavapyrones, kava symptomatically relieves toms than did the placebo-treated patients. A larger controlled trial is nervous anxiety. There are anecdotal reports that kava may worsen currently under way. depressive symptoms in some patients with major depressive disorder' a topical treatment for Si'deK'ffect$ e*!d Srwg lmt*rae*isns Although kava is used in folk medicine as skin diseases, for treating urogenital complaints, and for treating res- The most corrunon side effects are a tendency toward belching and piratory ailments, there is no significant evidence thatkava helps any gastrointestinal distress at higher doses. In addition, patients may de- of these conditions.

^) 604 Manualof Clinicalpsychopharmacology Herbalsand DietarySupplements 605

&{ee*xam*sms* &e*iexx &osageand &dxt*i*t&s*ratlmxx piper The mechanism of action of metbysticum, like that of other The oral dose of kava varies but typically ranges from 60 to 120 mg , has not been fully elucidated. There is some evidence that of kavapyrones efiracted from the kava root' A tea made frgm kava kava lactones act as GABA in a manner similar to benzodi- root is typically taken one to three times a day' Kava extrac$parc of- azepines. However, the effect on GABA receptors is neither as potent ten taken on a prn basis. Extended use of kava may be habit forming' nor as specific as it is with . In addition, kava may our experience is that kavamay have some role in the t{eatment mildly block reuptake, but it has no known effects states. However, kava appears to have few advantages on the system. of anxiety a ' It .{r over benzodiazepines and is less potent than use, includ- fr $ide &ffectsend OrugNmtenactis,ts appears to be able to induce intoxication, and long-term ing the risk of dependence, has not been evaluated adequately' W'e ",b rn2001', German physicians began to report a possibre rerationship be- currently advise patients to avoid the use of kava with benzodiaz- tween kava use and hepatic damage. There were at least 30 known epines, atypical antipsychotics, and sedating antidepressants, which cases of in Switzerland and Germany, and in some of include and . these cases, the person required liver transplants. In 2002, theherb was banned in France, and both American and Canadianauthorities, includ- ing (Voleri on o Offi cin ol i sl the FDA, put out a waming thatkavahas been associated with he_ patic damage. In the United states, at least 60 cases, with at least 4river Like most herbs, valerian has been used throughout , the transplants, have been associated with kava use since 199g. Therefore, United States, and Central America for many years in folk medicine' kava should generally not be used at this time for any pu{pose. The root of the valerian plant has been made into teas and liquid so- Kava has also been associated with a number of other side effects, lutions for a variety of ailments and is also used as a flavoring for paticulady when taken at high doses for periods longer thanl2weeks. some beverages and foods. The most corrrmon side effects of kava are similar to those of and benzodiazepines. These include sedation, ataxia,and motor incoor- l,fses dination. Kava should not be used before driving or operating hear.y The primary uses for valerian have been in the symptomatic treatrnent machinery. Tolerance to increasing doses of kava has been reported, but of anxiety and insomnia.Yaleianhas been shown to reduce sleep Ia- it is unclear whether withdrawal symptoms occur after prolonged use. tenry and possibly improve total sleep in some reports' Its use as an Extended use of high doses of kava has been associated with a adlunctive agent in depression has not been tested. In addition, people pellagra-type illness with symptoms such as dry flaky skin, reddened have used valeian for , intestinal pain, and dysmenorrhea' eyes, and a discoloration of the hair. Additionally, gastrointestinal side although there are no reliable data to support these uses' effects and headaches have been reported with oral use of the herb. Kava appears to potentiate the effects of other central neryous &,treehanisme$ Ae*tetl (CNS) system dsplsssants, including alcohol, benzodiazepines, and A speculated mechanism by which valeian could impact anxiety and . There are reports of , delirium, and temporary insomnia is through some effect on GABA. Valerenic acid, derived from equilibrium problems associated with the combination of kava and the breakdown of GABA in the cNS alcohol. valerian toot, appears to inhibit and thus may faalitate GABAminergic neurotransmission. GABA is the

^) 606 Manualof Clinicalpsychopharmacology Herbalsand DietarySupplements 607

sexual most prevalent inhibitory in the cNS. Benzodiazepine ports and an open-label study of ginkgo in SSRi-induced hypnotics and anxiolytics work as indirect agonists of GABA. dysfunction. $XdeX#fect$ emd Sraxg Xrx**re€*te$?s lWsekaxx$smef P*€t&*Nt -ls car- The primary side effects of valerian are sedation and drowsiness. Like The ginkgolide derivatives of the leaf may increase cerebr#and of^fuee rad- other cNS depressants, valeiancan induce ataxia, motor incoordina- diovascular blood flow. It also appears to be a harvester the activity ot tion, and , particulady at high doses. overdoses have been icals. In addition, ginkgo has been shown to inhibit is spec- associated with abdominal cramping, tremot ataxia, and confusion. platelet activating factor. Its mechanism in sexual dysfunction at the time 'd There is the potential for valerian to potentiate the effects of ,rlut.d to result from increased pudendal blood flow, but other *,'h cNS depressants, including alcohol, benzodiazepines and bar- of this Writing there are no supporting data' biturates. valerian has been reported to prolong thiopental and pen- tobarbital effects. SideE{fects and DrugInteractions orally or Bosageamd Administs,a{lom The whole leaf is associated with allergic reactions when taken have been applied topically. In the elder$,leaf erttacts in high doses Extracts of 2-3 mg of valeian are bleeding' usually taken one to three times assoclated with confusion and with increased susceptibility to per day in a tincture or a tea. valerian is thought to have a low ad- Because ginkgo antagonizes platelet activatingfactor' it increases dictive potential, and some reports suggest There is that the herb must be the risk of bleeding with antiplatelet drugs and warfarin' taken for a dr.iration of 24 weeks to inhibitors' be maximally effective. speculation that ginkgo can potentiate the effects of MAO Other, more mild side effects include , gastrointestinal rashes (Sommer and Schatzbery2002)' Ginkgo(Ginkgo Biloba) upset, and Sosageamd Adnrinlstration Ginkgo is an ancient folk remedy that has been used for hundreds of sexual dysfunction, ginkgo is taken aI'a dosage and even thousands of years. The ginkgo tree is found in Asia, and For the treatment Case reports suggest that ginkgo may need to be the leaves of the tree are processed to make tablets, capsules, or a of 1.20-240 mg/day. sexual liquid solution. used daily for several weeks to treat antidepressant-induced mg/ side effects. For Alzheimer's disease, the daily dosage is 180-360 &Jses day (Sommer and Schatzberg2002)' .WehavetriedtouseginkgotofeYersesSRl-inducedsexualdys- Ginkgo is commonly used in the United Statesfor memory problems poody as function; in the patients studied, we found that it works as associated with aging. our group participated in a study that found ginkgo biloba at a dosage of 120 mg/day to be significantly mostotherrecommendedantidotes.However,sincenotreatment more ef_ effects, and works reliably in alleviating SSRl-induced sexual side fective than placebo in retarding progression of (Le Bars et be more benign than some antidotes' it may be al. 1'997).The use of ginkgo for depression since ginkgo may has focused on reducing more trying. Sildenafil (Yiagra) and appear to be antidepressant-associated sexual dysfunction. The worth evidence support- effect in sex- effective than ginkgo, but there is an important placebo ing the use of ginkgo for this purpose has been limited to case re_ ual antidotes. Supplements 609 608 Manualof ClinicalPsychopharmacology Herbalsand Dietary

S-Adenosylmethionine(SAMe) S*deK{fects e*nd ffix'axg &xrterae**sms SAMe appears to be well tolerated in most people' The most com- S-Adenosylmethionine (SAMe) is currently the second most popular mon side effect is , which is associated with increasing the over-the-counter treatment for depressive symptoms after St.-John,s- dose of sAMe. There have been a few reports of SAMe',siijreasing wort. Several books have been devoted to the subject of SAMe in anxiety in some depressed patients and also inducing hypomania in treating depression, and some health food stores are having trouble susceptible patients. l keeping it in stock. SAMe has been used, both orally and intrave- ; There are no known drug interactions for SAMe' nously, in treating major depression and, as anecdotally reported, has been used to augment standard fl1 antidepressants. Sosageend &dm*Kistratimts fl n$, &"lses The rypical srarring dosage of sAMe is 40G€00 mg/day, with the dos- age increasing to a maximum of 1,600 mg/day' Since SAMe has a Like many over-the-counter pteparutions, SAMe is used in treating short halflife, the compound should be dosed two to three times per many ailments. It has been less well studied in major depression than day. It appears to take 24 weeks before benefits can be assessed. has St.-John's-wort. One meta-analysis suggested that SAMe is about Intravenous and intramuscular iniections of SAMe have typically in- 17o/o-380/omore effective than placebo, which would make it compa- volved doses of }OC:41OOmg. It is unclear whether the injection of rable to the average antidepressant. However, randomized, head-to- sAMe has significant clinical advantages over the pafenteral form of head comparisons of SAMe and a standard antidepressant are lacking. the compound, but the intravenous form increases the Thus, it is not possible to accurately determine how SAMe compares of the compound, since SAMe undergoes a significant first-pass effect. with antidepressants in the same pertinent population. There have W'e have recommended SAMe to the occasional patient who is been some reports that the addition of 200 mg of SAMe to a standard getting an inadequate response to one antidepressant and who pre- dose of resulted in faster response compared with pla- fers not to add a standard augmenting agent, such as lithium, or an- cebo. The studies of SAMe typically involved mild to moderate de- other antidepfessant to the original agent. SAMe is more expensive pression. than a generic antidepressant, and its utility is questionable' Another studied use of SAMe is in the treatment of osteoarthritis. There have been preliminary studies of the use of SAMe in treating fibromyalgia and AlDS-related myelopathy. lnositol &f*eckanXsxno$&ction has been used for many yeafs and has been reported to be of benefit for some psychiatric disorders, including depression and panic. sAMe is involved inavariety of transmethylation reactions, including Inositol appears to be effective in some animal models of depression. those involved in the synthesis and activation of monoamine neu- clinical experience with inositol as an antidepressant has been limited, rolransmitters. Thus, it can potentially increase the activity and but, anecdotally, it has not been helpful to some patients' availabillty of serotonin, norepinephrine, and . There are limited data suggesting that SAMe may also block the reuptake of ?,fscs monoamines. SAMe does appear to cross the blood-brain barrier, but The use of inositol in treating major depression has been limited to it has a short half-life (1.5 hours). a few small studies. one recent study comparcd 12 g of inositol with 610 Ma4galof ClinicalPsychopharmacology Herbalsand DietarySupplements 6l I

plapebg in 28 patients with major depression for 4 weeks and found Uses study of inositol tha{ inositol was superior. Another, more recent DHEA has been studied in major depression. One recent study placebo in ef- addpd to an SSRIfound no difference ftom an SSRIor (\7'olkowitz et al. 1999) found that 90 mg/day of DHEA fog 5 weeks ficaq' or in speed of onset. resulted in significant improvement in the condition of 5i$ut of 11 patients, whereas placebo did not lead to a response in any of the Mechanisrnof Action patients. Another study in geriatric patients found that low levels of DHEA were correlated with depressive symptoms. Ttgq mechanism of action of inositol as a potential adjunctive treat- rpent of depression is largely unknown. There is evidence that ino- lUlechanismof Aetion {dt' sitol can reverse desensitization of serotonin receptors and may affect l DHEA is metabolized into androstenidione, which is then converted n"|} otner monoamlnes. to both androgens and . Thus, it can increase the levels of both estrogens and androgens in men SideEffects and DrugInteractions and women. SideEffects and DrugInteractions Side effects of inositol appear to be very limited. Doses up to l8 g/day Reponed side have not been associated with consistent side effects. Some patients effects include hirsutism and voice deepening in women, hair loss and complain of gastrointestinal distress with higher doses' Inositol/leci- an increased risk for prostate cancer in men, and liver dysfunction thin combinations have been associated with a fish-type odor. in both sexes. DHEA may potentiate or antagonize other sex steroids. Administration Dosageand Dosageand Administration 12 g/day taken The dose of inositol used in the treatment is typically The dosage of DHEA reported to help depression ranges from 50 to orally in a powder form or in tablets. 200 mg/day. It appears unlikely that inositol is effective as an adjunctive agent. At this time we are advising against the use of DHEA either alone However, inositol might be worth considering early in the algorithm or in combination with antidepressants. The limited known benefits in some depressed patients as an augmenting agent' Our limited ex- in depression are outweighed by significant potential risks. perience with inositol indicates that it is as benign as it is ineffective. Bibliography () DHEA Agnoli A, Andreoli V, Casacchia M, et al: Effect of S-adenosyl-r- (SAMe) upon depressive symproms. psychiatr DHEA has gained popularity in recent years as an over-the-counter J Res L3:43_54, 1976 Barkai A, Dunner D, Gross H, et al: Reduced myo-inositol levels in cerebrospinal hormonal preparation that is said to reYefse problems associated with fluid from parients wirh a-ffecrive disorder. Biol psychiatry 13:6>72, 1978 aging, including sexual dysfunction, muscle wasting, fatigue, and Bennett DA Jr, Phun L, Polk JF, et al: Neuropharmacology of St._John,s_wort memory difficulties. There is limited evidence that DHEA has any of (Hypericum). Ann Pharmacother 32:120L-lZOg, lggS these benefits, but a growing body of datahas indicated that DHEA Bottiglieri t Hyland K: s-Adenosylmethionine levels in psychiatric ancl rrt,r. patients. may be problematic in some rological disorders: a review. Acta Neurol Scand Suppl 154:1g-26, lt)().l I 612 Manualof ClinicalPsychopharmacology Herbalsand DietarySupplements 615

Bressa GM: S-Adenosyl-r-methionine (SAMe) as antidepressant: meta-analy- Perry EK, PickeringAI, \rang \(rW, et al: Medicinal plants and Alzheimer's sis of clinical studies. Acta Neurol Scand Suppl t54:7-1.4, t994 disease:from ethnobotanyto phyotherapy. J PharmPharmacol 5I:527- Einat H, Karbovski H, KorikJ, et a\: Inositol reduces depressiveJike behav- 534,1999 iors in two different animal models of depression. Psychopharmacology pietta PG, Gardanac,Mauri PL:Identification of Ginkgo biloba flavoonolme- (Ber\) 144:158-152, 1.999 tabolitesafter oral administrationto humans.J chromatogr B Bigmed sci Fava M, Giannelli A, Rapisarda V, et al: Rapidity of onset of the antidepres- Appt 593:249-255,t997 sant effect of parenteral S-adenosyl-r-methionine. Psychiatry Res 56: ReyJM,W.alter G: (stJohn's wort) in depression:pest 295-297,1995 or blessing?Med J Aust I59t583-586, t998 Frey R, Metzler D, Fischer P, et al: Myo-inositol in depressive and healthy RitschelwA, \(agensonnerD, HeringerEA: Statisticalevaluation of the effect 1H-magnetic .{l subjects determined by frontal resonance spectroscopy at of 3 stimulantsof cellular metabolism[in German]. SchweizRundsch i,f 1.5 tesla. J Psychiatr Res 32:417420, 1998 Med Prax 59:1278-1283,t97O "&, .rJragensonner !, GlissonJ, Crawford R, Street S: The clinical applications of Ginkgo biloba, St. Ritschel\7A, D, HeringerEA: Statisticalevaluation of the effect Med Prax 59: John's wort, saw palmetto, and soy. Nurse Pract 24:28, 31,35-36 passim of 3 stimulantsof cellular metabolism.schweiz Rundsch lq:uiz 47491,1999 1278-1283,t97O placebo-controlled Hadley SK, Petry lJ: Medicinal herbs: a primer fot primary care. Hosp Pract salmaggip, BressaGM, Nicchia G, et al: Double-blind, (Off Ed) 34(6):1.05-t06, t09-tI2, 715-11'5 passim, L999 study of s-adenosyl-r-methioninein depressedpostmenopausal women. Hypericum Depression Trial Study Group: Effect of Hypericum perforatum PsychotherPsYchosom 59 :3440, 1993 extractwith (St. John's wort) in major depression: a randomized controlled trial. Sandberg-GertzenH: An open trial of Cedemin,a Ginkgo biloba (letter) comments].Am JAMA 287:1807 -1 814, 2OO2 pAF-antagonisticeffects for ulcerativecolitis [see Josey ES, Tackett RL: St. John's wort: a new alternative for depression? Int J Gastroenterol88:615416, L993 (letter). Psychiatry59689, J Clin Pharmacol Ther 37:111-1.19, L999 schneck c: st. John's worr and hypomania J CIin Kim HL, StreltzerJ, Goebert D: St.John's wort for depression: a meta-analysis t998 wort in of well-defined clinical trials. J Nerv Ment Dis L87:532-538, 1999 shelton RC,Keller MH, GelenbergA, et al: Effectivenessof St.John's 285:t978-t986, Kofman O, Bersudsky ! Vinnitsky I, et al: The effect of peripheral inositol maior depression:a randomizedcontrolled trial. JAMA injection on rat motor activity models of depression. Isr J Med Sci 29: 2001. 580-586,1999 SommerBR, schatzbergAF: Ginkgp biloba and related compoundsin A1z- Le Bars PL, Katz MM, Berman N, et al: A placebo-controlled, double-blind heimer'sdisease. Psychiatric Annals 32:13-18,2002 randomized trial of an extract of Gingko biloba for dementia. North Stoll AL, severuswE, FreemanMP, et al: omega-3 fatty acidsin bipolar dis- Arch Gen American EGb Study Group. JAMA278:1.327-1332, 1997 order: a preliminary double-blind, placebo-controlledtrial. Lecrubier Y, Clerc G, Didi R, et al: Efficary of St.John's wort extract \X/S5570 Psychiatry56:4Q7 412, 1999 Pharm in major depression: a double-blind, placebo-controlled trial. Am J Psy- Vitiello B: Hypericum perforatum extractsas potential antidepressants.J chiarry L59:L36L-1,355,2002 Pharmacol5L:51'3-517, 1999 (SAD). Lewin LM, Szeinberg A, Lepkifker E: Gas chromatography mcasurement of \Theatley D: Hypericum in seasonalaffective disorder cuff Med Res myo-inositol in human blood, cerebrospinal fluid and senrinal fluid, Clin Opin 1,5:33-37,1999 Chim Acta 45:361-368, 1973 volkowitz oM, Reusw, Keebler A, et al: Double-blind treatmentof maior de- Miccoli L, Porro V, Bertolino A: Comparison between the itntidepressant pressionwith dehydroepiandrosterone.AmJ Psychiatry1'56:646-449' 7999 by psychiatric activity of S-adenosylmethionine (SAMe) and that ol some tricyclic yagerJ, SiegfreidsL, DiMatteoTL: Use of alternativeremedies drugs. Acta Neurol 33:243-255, 1978 patients:illustrative vignettes and a discussionof the issues Am J Psy- chiatry 156:r432-t438,7999