St. John's wort is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors)  are limited (SOR: A, 1 systematic review). A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects. Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety. N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don't appear effective in treating major depressive disorder (SOR: A, 1 systematic review.

Evans, Rachael

Montoya, Cathy C.

Moss, Shannon B.

University of Missouri: MOspace

Evidence-based answers from the  Family Physicians Inquiries Network99jFPoNlINE.com Vol 60, No 2  |  FEbruary 2011  |  ThE jourNal oF FamIly PracTIcEEvidEncE-basEd answErARachael Evans, DO; Shannon Moss, PhDBaylor Family Medicine Residency at Garland, Garland, TexCathy C. Montoya, MLSHouston Community College, Houston, TexSt. John’s wort is safer than older antidepressants, but hasn’t been compared extensively with newer drugs, such as SSRIs.	 Which	nutritional	therapies	are	safe	and	effective		for	depression?i -  	 st.	 john’s	 wort	 is	 effective	 for	 short-term	 relief	 of	 mild	 to	moder-ate	depression	(strength	of	recommendation	[SOR]:	A;	1	systematic	review).	Its	safety	pro-file	is	superior	to	older	antidepressants;	data	comparing	 it	 with	 newer	 antidepressants	(such	as	selective	serotonin	reuptake	inhibi-tors)	are	limited	(SOR:	A,	1	systematic	review).A	 small	 but	 statistically	 significant	clinical	 benefit	has	 been	demonstrated	 for	saffron,	 lavender,	 borage,	 dan	 zhi	 xiao	 yao	(SOR:	B,	1	systematic	review	and	3	random-ized	controlled	trials),	folate	(SOR:	A,	1	sys-tematic	review),	and	S-adenosylmethionine	(SAMe)	(SOR:	A,	1	meta-analysis	and	1	sys-tematic	review).	Most	trials	of	these	prepa-rations	 were	 short	 and	 small,	 limiting	 the	ability	to	detect	adverse	effects.	Tryptophan	 (SOR:	A,	 1	 systematic	 re-view)	 and	 5-hydroxytryptophan	 (5-HTP)	(SOR:	A,	1	systematic	review)	have	demon-strated	superiority	over	placebo	in	alleviat-ing	symptoms	of	depression,	but	concerns	exist	about	their	safety.	N-3	long-chain	polyunsaturated	fatty	ac-ids	(n-3	PUFAs)	and	omega-3	fatty	acids	don’t	appear	 effective	 in	 treating	 major	 depres-sive	 disorder	 (SOR:	A,	 1	 systematic	 review.)Evidence summaryTABLE W1	 (see	 page	 100a)	 summarizes	 study	results	 and	 recommendations	 for	 nutritional	therapies	for	depression.1-16St. John’s wort works as well as  standard antidepressantsA	recent	Cochrane	review	suggested	that	St.	John’s	wort	is	more	effective	than	placebo	in	patients	 with	 mild	 to	 moderate	 depression	and	as	effective	as	standard	antidepressants.1	Other supplements also have benefits A	 systematic	 review	 of	 4	 small	 randomized	controlled	trials	(RCTs)	suggested	that	saffron	(30	 mg)	 is	 superior	 to	 placebo	 in	 treating	short-term	depression	 (6	weeks).	Treatment	and	outcomes	were	equivalent	 to	fluoxetine	and	imipramine.2	A	later	RCT	yielded	results	consistent	with	the	systematic	review.3	Combined	 lavender tincture	 (60	 drops	per	day)	and	imipramine	were	more	effective	than	imipramine	alone	in	1	small	RCT.4	Borage,	 a	 traditional	 Persian	medicine,	was	superior	 to	placebo	in	reducing	depres-sive	symptoms	in	1	small	RCT.2	Dan zhi xiao yao,	 a	 traditional	 Chinese	medicine,	was	as	effective	as	the	tricyclic	anti-depressant	maprotiline	in	1	small	RCT.2	Three	RCTs	suggested	that	folate	may	be	used	 to	 supplement	 conventional	 treatments	for	 depression,	 but	 it	 isn’t	 clear	whether	 this	would	help	patients	with	normal	folate	levels.5	A	 meta-analysis	 of	 13	 controlled	 clinical	trials	and	a	later	systematic	review	of	11	articles	including	2	RCTs	concluded	that	SAMe	is	more	effective	 than	 placebo	 and	 as	 efficacious	 as	tricyclic	 antidepressants	 in	 treating	major	de-pression	 in	 adults.	However,	 further	 trials	 are	needed	to	answer	questions	about	absorption,	mechanism	of	action,	and	bioavailability.6,7Tryptophan’s benefit comes with risk In	 a	 Cochrane	 review	 of	 2	 RCTs,	 tryptophan	100 ThE jourNal oF FamIly PracTIcE  |   FEbruary 2011  |   Vol 60, No 2A small but statistically significant clinical benefit has been found for saffron, lavender, borage, dan zhi xiao yao, folate, and SAMe.referencesand	 5-HTP	 were	 superior	 to	 placebo	 in	 al-leviating	 symptoms	 of	 depression.	 How-ever,	 some	 published	 case	 reports	 have	linked	 tryptophan	 use	 to	 potentially	 fatal	eosinophilia-myalgia	syndrome.8	No clear evidence for inositol  or n-3 PUFAsA	 Cochrane	 review	 of	 4	 small	 double-blind	RCTs	 investigating	 inositol	 as	 a	 nutritional	supplement	in	depression	treatment	failed	to	find	clear	evidence	of	therapeutic	benefit.9	Three	 RCTs	 demonstrated	 significantly	higher	red	blood	cell	membrane	levels	of	n-3	PUFAs	 in	 nondepressed	 patients	 compared	with	depressed	patients.10	However,	a	system-atic	 review	 of	 12	 RCTs	 failed	 to	 demonstrate	any	benefit	of	n-3	PUFA	supplementation	over	placebo	in	treating	depressed	mood.11	The	au-thors	concluded	that	larger	trials	are	needed	to	demonstrate	efficacy	because	of	marked	het-erogeneity	among	the	RCTs.z Safety issues. A	recent	Cochrane	review	found	fewer	adverse	effects	for	St.	John’s	wort	than	tricyclic	antidepressants.1	The	most	com-mon	adverse	reactions	were	sensitivity	to	light,	skin	 symptoms,	 gastrointestinal	 symptoms,	and	agitation.	Data	comparing	St.	John’s	wort	with	newer	antidepressants	are	lacking.	St.	 John’s	 wort	 does	 have	 pharmacoki-netic	 interactions	 and	 should	 not	 be	 taken	concurrently	 with	 other	 antidepressants,	immunosuppressants,	 anti-HIV	 drugs,	 cou-marin-type	anticoagulants,	or	certain	antineo-plastic	agents.17	Reviews	 of	 meta-analyses,	 case	 reports,	population	studies,	RCTs,	and	other	literature	have	 reported	virtually	no	adverse	effects	 for	PUFAs;18	 trials	 investigating	 saffron,	 laven-der,	 borage,	 dan	 zhi	 xiao	 yao,	 folate,	 SAMe,	and	inositol	also	reported	no	safety	concerns.	However,	the	size	and	duration	of	these	stud-ies	limit	their	ability	to	detect	significant	prob-lems.2,5,6,9	As	previously	noted,	 concerns	exist	regarding	an	association	between	tryptophan	and	eosinophilia-myalgia	syndrome.8	RecommendationsThe	World	Federation	of	Societies	of	Biological	Psychiatry	doesn’t	recommend	St.	 John’s	wort	for	moderate	to	severe	depression,	but	suggests	it	can	be	considered	for	treating	mild	to	moder-ate	depressive	episodes	provided	the	prescriber	considers	 potential	 pharmacokinetic	 interac-tions	with	other	medications	and	understands	possible	variations	in	purity	and	potency	of	ex-tracts.19	The	Federation	also	states	that	St.	John’s	wort	 is	 an	 alternative	 for	 patients	 reluctant	 to	take	traditional	antidepressants.	 														JFP	 1.			Linde	K,	Berner	MM,	Kriston	L.	St.	 John’s	wort	 for	major	de-pression.	Cochrane Database Syst Rev.	2008;(4):CD000448.		 2.			Sarris	J.	Herbal	medicines	in	the	treatment	of	psychiatric	disor-ders:	a	systematic	review. Phytother Res.	2007;21:703-716.	 3.			Akhondzadeh	Basti	A,	Moshiri	E,	Noorbala	AA,	et	al.	Compari-son	of	petal	of	Crocus sativus L.	and	fluoxetine	in	the	treatment	of	 depressed	 outpatients.	 Prog Neuropsychopharmacol Biol Psychiatry.	2006;31:439-442.		 4.			Akhondzadeh	 S,  Kashani	 L,	 Fotouhi	A,	 et	 al.	 Comparison	 of	Lavandula angustifolia Mill.	 tincture	 and	 imipramine	 in	 the	treatment	of	mild	to	moderate	depression.	Prog Neuropsycho-pharmacol Biol Psychiatry. 2003;27:123-127.		 5.			Taylor,	MJ,	Carney	S,	Geddes	J,	et	al.	Folate	for	depressive	disor-ders.	Cochrane Database Syst Rev. 2003;(2):CD003390.		 6.			Bressa	 GM.	 S-adenosyl-l-methionine	 (SAMe)	 as	 antidepres-sant.	Acta Neurol Scand Suppl.	1994;154:7-14.		 7.			Williams	AL,	Girard	C,	Jui	D,	et	al.	S-adenosylmethionine	(SAMe)	as	treatment	for	depression.	Clin Invest Med.	2005;28:132-139.		 8.			Shaw	 K,	 Turner	 J,	 Del	 Mar	 C.	 Tryptophan	 and	 5-hydroxy-tryptophan	 for	 depression.	 Cochrane Database Syst Rev.	2002;(1):CD003198.		 9.			Taylor	MJ,	Wilder	H,	Bhagwager	Z,	et	al.	Inositol	for	depressive	disorders.	Cochrane Database Syst Rev.	2004;(2):CD004049.		 10.			Williams	 AL,	 Katz	 D,	 Ali	 A,	 et	 al.	 Do	 essential	 fatty	 acids	have	 a	 role	 in	 the	 treatment	 of	 depression?	 J Affect Disord.	2006;93:117-123.		 11.			Appleton	KM,	Hayward	RC,	Gunnell	D,	et	al.	Effects	of	n-3	long-chain	 polyunsaturated	 fatty	 acids	 on	 depressed	mood.	Am J Clin Nutr. 2006;84:1308-1316.		 12.			Akhondzadeh	S,	Fallah-Pour	H,	Afkham	K,	et	al.	Comparison	of	Crocus sativus L.	and	imipramine	in	the	treatment	of	mild	to	moderate	depression.	BMC Complement Altern Med.	2004;4:12.		 13.			Akhondzadeh	S,	Tahmacebi-Pour	N,	Noorbala	AA,	et	al.	Crocus sativus L.	in	the	treatment	of	mild	to	moderate	depression.	Phy-tother Res. 2005;19:148-151.		 14.			Noorbala	 AA,	 Akhondzadeh	 S,	 Tahmacebi-Pour	 N,	 et	 al.	Hydro-alcoholic	extract	of	Crocus sativus L.	versus	fluoxetine	in	the	treatment	of	mild	to	moderate	depression.	J Ethnophar-macol.	2005;97:281-284.	 15.			Moshiri	 E,	 Basti	 AA,	 Noorbala	 AA,	 et	 al.	 Crocus sativus L.	(petal)	 in	 the	 treatment	 of	 mild-to-moderate	 depression.	Phytomedicine. 2006;13:607-611.		 16.			Sayyah	M,	Sahhah	M,	Kamalinejad	M.	A	preliminary	random-ized	double	blind	clinical	 trial	on	the	efficacy	of	aqueous	ex-tract	of	Echium amoenum	in	the	treatment	of	mild	to	moderate	major	depression.	Prog Neuropsychopharmacol Biol Psychia-try. 2006;30:166-169.	 17.			Schulz	V.	Safety	of	St.	John’s	wort	extract	compared	to	synthetic	antidepressants. Phytomedicine. 2006;13:199-204.		 18.			Lee	S,	Gura	KM,	Kim	S,	et	al.	Current	clinical	applications	of	ome-ga-6	and	omega-3	fatty	acids.	Nutr Clin Pract. 2006;21:323-341.	 19.			Bauer	M, Bschor	T,	Pfennig	A,	et	al.	World	Federation	of	Societ-ies	of	Biological	Psychiatry	(WFSBP)	guidelines	 for	biological	treatment	 of	 unipolar	 depressive	 disorders	 in	 primary	 care.	World J Biol Psychiatry. 2007;8:67-104.	jFPoNlINE.com Vol 60, No 2  |  FEbruary 2011  |  ThE jourNal oF FamIly PracTIcENuTrITIoNal ThEraPIES For DEPrESSIoN100aTABLE W1What	the	studies	say	about	nutritional	therapies	for	depression Supplement Study typeNumber of subjects comparison groupoutcome  measure results conclusion Sorborage (Echium amoenum)1 small rcT 352,16 Placebo ham-D Improved ham-D scores significantly at week 4 (borage 18.3 ± 3.9 vs placebo 21.9 ± 3.9; t=2.51; P=.02); no significant difference at  Week 62,16Superior to placebo in reducing symptoms of depressionbDan zhi xiao yao1 small rcT 632 maprotiline ham-D, SDS, SaS, scale for traditional chinese medicine syndrome and symptom differentiation87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) as effective as maprotiline in treating depressionbFolate cochrane review of  3 rcTs2475 Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels)ham-D Superior to placebo (NNT=5, defined as 50% reduction in ham-D); comparable to trazodone (rr=0.97; 95% cI, 0.14-2.01)7may have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levelsaInositol cochrane review of  4 rcTs1419 Studies 1-3: placebo plus conventional antidepressants Study 4: placebo onlyham-D, maDrSPooled estimate of effect of all 3 studies (SmD= −0.08; 95% cI,  −0.45 to 0.30)No clear evidence of therapeutic benefit alavender (Lavandula angustifolia)1 small rcT 454 Imipramine ham-D Imipramine plus lavender showed significant effect compared with imipramine alone (F=26.87; DF=3.01; P<.0001)Synergistic effect suggested when used with imipraminebbDI, beck Depression Inventory; cI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; ham-D, hamilton Depression rating Scale; maDrS, mont-gomery-asberg Depression rating Scale; muFas, monounsaturated fatty acids; n-3 PuFas, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; or, odds ratio; PuFas, polyunsaturated fatty acids; rbc, red blood cell; rcT, randomized controlled trial; rr, relative risk; SaS, self-rating anxiety scale; SDS, self-rating depression scale; SFas, saturated fatty acids; SmD, standard weighted mean difference; Sor, strength of recommendation; SSrI, selective serotonin reuptake inhibitor.coNTINuEDThE jourNal oF FamIly PracTIcE  |   FEbruary 2011  |   Vol 60, No 2100bTABLE W1What	the	studies	say	about	nutritional	therapies	for	depression	continued Supplement Study typeNumber of subjects comparison groupoutcome measure results conclusion Sorn-3 long-chain poly-unsaturated fatty acidsSystematic review including  3 rcTs;10meta-analysis of 12 rcTs1110210103211Various comparison groups includedSerum SFas, muFas, PuFas; rbc membrane levels n-3 PuFas2ham-D, bDI3Systematic review:10 Study 1: n=30; ES=3.61Study 2: n=24; ES=1.2 Study 3: n=48; ES=2.43meta-analysis:11Pooled ES=0.13;  95% cI, 0.01-0.25Significantly higher rbc membrane levels of n-3 PuFas in nondepressed vs depressed patients10No significant effect for supplementation11larger trials with adequate power needed2,3aS-adenosyl-methionine (Same)meta-analysis of 13 rcTs,6 systematic review including  2 rcTs73996787Placebo and conventional antidepressantsham-D NNT=2.5 for ham-D decrease of ≥25%;6NNT=6.25 for ham-D decrease of ≥50%6may have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7aSaffron (Crocus sativus)Systematic review of  4 small rcTs, 1 later rcT3012401340144015403Imipramine12 Placebo13,15 Fluoxetine5,14ham-D Systematic review: Study 1: imipramine and saffron equally efficacious (F=2.91; P=.09)12Study 2: Improved ham-D scores: −12.20 ± 4.67 (saffron) vs −5.10 ± 4.71 (placebo) (P<.0001)13Study 3: Improved ham-D scores: saffron petal −12.00 ± 4.10; fluoxetine −13.50 ± 4.91; difference between 2 treatments not significant (P=.27)14Study 4: Improved ham-D scores: −14.01 ± 5.53 (saffron petal) vs −5.05 ± 4.63 (placebo) (P<.0001)15Study 5:5 NNT=10Efficacy of extract and petal suggested to treat mild to moderate depressionlarge-scale trials are warrantedbcoNTINuEDjFPoNlINE.com Vol 60, No 2  |  FEbruary 2011  |  ThE jourNal oF FamIly PracTIcENuTrITIoNal ThEraPIES For DEPrESSIoN100cTABLE W1What	the	studies	say	about	nutritional	therapies	for	depression	continued Supplement Study typeNumber of subjects comparison groupoutcome measure results conclusion SorSt. john’s wort (Hypericum perforatum L.)cochrane review of  29 rcTs54891 SSrIs, tri/tetracyclic antidepressants,  placeboresponder rate ratioSt. john’s wort vs placebo:     9 larger trials: rr=1.28; 95% cI, 1.10-1.491    9 smaller trials: rr=1.87; 95% cI, 1.22-2.871St. john’s wort vs SSrIs: 12 trials: rr=1.00;  95% cI, 0.90-1.111St. john’s wort vs tricyclics: 5 trials: rr=1.02; 95% cI, 0.90-1.151Effective for treating mild to moderate depressionaTryptophan  and  5-hydroxy-tryptophan (5-hTP)cochrane review of  2 rcTs648 Placebo ham-D NNT=2.78 vs placebo (or=4.1;  95% cI, 1.28-13.15Superior to placebo Insufficient evidence regarding safetya

Which nutritional therapies are safe and effective for depression?

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