Natural Medicines for Psychotic Disorders
Hoenders, H. J. Rogier; Bartels-Velthuis, Agna A.; Vollbehr, Nina K.; Bruggeman, Richard;
Knegtering, Henderikus; de Jong, Joop T. V. M.
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JOURNAL OF NERVOUS AND MENTAL DISEASE
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10.1097/NMD.0000000000000782
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Hoenders, H. J. R., Bartels-Velthuis, A. A., Vollbehr, N. K., Bruggeman, R., Knegtering, H., & de Jong, J. T.
V. M. (2018). Natural Medicines for Psychotic Disorders: A Systematic Review. JOURNAL OF NERVOUS
AND MENTAL DISEASE, 206(2), 81-101. https://doi.org/10.1097/NMD.0000000000000782
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Natural Medicines for Psychotic Disorders
A Systematic Review
H.J. Rogier Hoenders, MD, PhD,* Agna A. Bartels-Velthuis, PhD,*
† Nina K. Vollbehr, MSc,*
Richard Bruggeman, MD, PhD,
† Henderikus Knegtering, MD, PhD,†‡§
and Joop T.V.M. de Jong, MD, PhD||¶
Abstract:Patients with psychotic disorders regularly use natural medicines,although it is unclear whether these are effective and safe. The aim of this study was to provide an overview of evidence for improved outcomes by natural medi-cines. A systematic literature search was performed through Medline, PsycINFO, CINAHL, and Cochrane until May 2015. In 110 randomized controlled trials, evidence was found for glycine, sarcosine, N-acetylcysteine, some Chinese and ayurvedic herbs, ginkgo biloba, estradiol, and vitamin B6 to improve psy-chotic symptoms when added to antipsypsy-chotics. Ginkgo biloba and vitamin B6 seemed to reduce tardive dyskinesia and akathisia. Results on other compounds were negative or inconclusive. All natural agents, except reserpine, were well tolerated. Most study samples were small, study periods were generally short, and most results need replication. However, there is some evidence for beneficial effects of certain natural medicines.
Key Words: Psychosis, natural products, complementary medicine
(J Nerv Ment Dis 2018;206: 81–101)
D
espite much progress in treatment options in the last century, the pharmacological treatment of psychotic disorders is often unsatis-factory, as expressed in persistent positive, negative, cognitive and affective symptoms, and problems in social functioning (Kane and Correll, 2010). Psychotic symptoms are often only partially resolved (Rummel-Kluge et al., 2010), especially cognitive and negative symptoms (Buckley and Stahl, 2007). Apart from clozapine, second-generation antipsychotics are generally as effective as first-generation antipsychotics for positive symptoms, but the promise of greater efficacy for negative symptoms has not been fulfilled (Leucht et al., 2012). Many patients continue experiencing persistent symptoms and relapses during treatment with antipsychotics, particularly when they fail to adhere to prescribed medications (Van Os and Kapur, 2009). Psychiatric medication adherence is a problem because many patients do not want them or consider them unnecessary (Cooper et al., 2007), or experience undesired adverse effects (Pai and Vella, 2012). For antipsychotics, these adverse effects include weight gain, sexual dysfunction, glycemic and lipid dysfunction, extrapyramidal symptoms (EPS), and sedation (Stahl, 2008).Many patients with psychotic disorders use nonconventional medicines or treatments in the hope of decreasing undesired adverse
effects or a more successful recovery (Hazra et al., 2010; Stevinson, 2001). Nonconventional medicine includes therapeutic lifestyle changes and complementary and alternative medicine (CAM) (Hoenders, 2013). Complementary medicine comprises diagnostics, treatments, and pre-vention strategies based on theories accepted in biomedicine and substan-tiated by some scientific evidence (two or more randomized controlled trials [RCTs]), but for various (cultural or practical) reasons are no part of biomedicine (Hoenders et al., 2011). Alternative medicine comprises diagnostics, treatments, and prevention strategies using other than the ba-sic concepts of biomedicine. So far, there is little proof for the efficacy of the latter treatments and/or considerable controversy about their scientific validation (Lake, 2007). Natural medicine is part of complementary med-icine, using agents produced by living organisms (plant, tree, seed, vege-table, fruit, animal, and human) instead of nonnatural (i.e., chemical) agents only being obtained from laboratory experiments (Porter, 1998). Some patients prefer natural medicines, assuming that natural is better and will cause fewer adverse effects. This is obviously not (always) true, as the natural environment contains agents that can be toxic to humans. The molecular structure and dosage of a substance rather than its source determine its effect on human health (Topliss et al., 2002). Besides, herbal medicines can cause undesired effects including interactions with prescription medication (Ernst, 2003a, 2003b).
Hazra et al. (2010) reported a lifetime and 1-year prevalence rate of CAM use in Canadian psychotic outpatients of 88% and 68%, re-spectively. A major difficulty these patients encounter is the heteroge-neity in treatment options with CAM, ranging from possibly interesting agents to useless, or even dangerous, ones (Ernst, 2003b). For instance, the concomitant use of antipsychotics and Chinese herbs was found to induce significantly improved clinical outcomes com-pared with antipsychotics only (Rathbone et al., 2007). However, a small but significant number of patients concomitantly treated with Chinese herbs have a greater risk of developing worse outcomes (Zhang et al., 2011b).
In recent years, patients' preferences and views have received more attention in making treatment choices (e.g., shared decision mak-ing [Elwyn et al., 2000] and“patient-centered care” [Gill, 2013]). The introduction of patient's choice in deciding which antipsychotic to choose has been proposed (Morrison et al., 2012). However, it is diffi-cult for both patients and physicians to make informed decisions in the absence of reliable information on the emerging evidence for CAM or natural medicine. Considering its high usage in psychotic patients, there is an urgent need for readily available scientific information.
This article reviews the literature on the efficacy and safety of natural medicines for psychotic disorders.
REVIEW Materials and Methods
Literature Search and Study Selection
Studies were identified by a literature search in Medline, PsycINFO, CINAHL, and Cochrane, until May 2015, in accordance
*Lentis, Center for Integrative Psychiatry;†University of Groningen, University Medical
Center Groningen, University Center for Psychiatry, Rob Giel Research Center; ‡Lentis Mental Health Institution; §University of Groningen, University Medical Center Groningen, Neuroimaging Center; ||University of Amsterdam, Amsterdam, the Netherlands; and ¶Boston School of Medicine, Boston, Massachusetts. Send reprint requests to H.J. Rogier Hoenders, MD, PhD, Lentis, Center for Integrative
Psychiatry, Hereweg 80, 9725 AG Groningen, the Netherlands.
E‐mail: hjr.hoenders@lentis.nl.
Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permis-sion from the journal.
ISSN: 0022-3018/18/20602–0081
with the Medline RCT filter. The search terms (MeSH Thesaurus and free search terms) used were schizophrenia, psychosis, psychoses, psy-chotic (disorder), schizophreniform AND (R)CT, review AND comple-mentary medicines, herbs, vitamins, supplements (search terms, in
Ayurveda, brahmyadiyoga, branched-chain amino acids [BCAA], Chinese herbs,D-cycloserine,D-serine, daotan decoction, dehydroepi-androsterone [DHEA], docosahexaenoic acid [DHA], eicosapentaenoic acid [EPA], estradiol, fatty acid, fish oil, folic acid, ginkgo biloba, glycine, jiawei lingguizhugan tang, jieyu anshen decoction,
L-stepholidine,L-theanine, manganese, methylfolate, N-acetylcysteine [NAC], N-methylglycine, niacine, omega-3, orengedokuto, rauwolfia serpentina, saikokaryukotsuboreito, sarcosine, sarsasapogenin, sele-nium, shakuyakukanzoto, shuizhi dahuang mixture, suo quan, tongdatang serial recipe [TDT], traditional Chinese medicine [TCM], vitamin B complex, vitamin B3, vitamin C, vitamin D, vitamin E, and zinc). After systematic deduplication, 1465 hits (abstracts) were retrieved (Table 1).
Next, abstracts about the following topics were included: a) ef-fects of natural medicines on psychotic symptoms in schizophrenia spectrum nonaffective disorders and b) effects of natural medicines on the adverse effects of antipsychotics. Those excluded were a) nonrandomized Studies
Database Trials Reviews Total
Medline 511 629 1140 CINAHL 62 22 84 PsycINFO 245 129 374 Cochrane 253 20 273 Total 1069 800 1871 Total deduplicated 1467
(controlled) trials; b) mechanism studies exploring the effects of natural medicines; c) animal studies; d) affective disorders/other disorders/no disorder/(relapse) prevention; e) conference abstracts; f ) book chapters; g) clinical trial registrations; h) comments, addenda, corrigenda, and letters; i) non-English languages (e.g., Chinese, Japanese, Hebrew, German, and Spanish); and (j) duplicate hits that had not been removed systematically. Second, two authors (H.J.R.H. and A.A.B.V.) indepen-dently indicated whether papers—based on the abstracts—should (pos-sibly) be included. Consultation followed about dubious cases and in case of discordance. Thereupon, 427 studies remained, of which the full papers on RCTs were retrieved and studied. Of these, another 160 were excluded. A flowchart of the study selection is presented in Figure 1. We found 147 reviews and checked whether RCTs in their reference lists matching our inclusion criteria were included. Eight RCTs with a Jadad score of 3 or higher (see paragraph on risk of bias assessment and Table 2) found through cross-references were added. Eighteen RCTs were excluded because of a Jadad score less than 3. The reviews (not shown in Table 3) will be contrasted to our findings in the Discussion section.
Classification of Agents
The RCTs included were divided into six groups based on sup-posed underlying mechanisms of action (Table 3). For a good grasp of the results, we briefly present the working mechanisms of the agents from five groups (not from the group“other substances”).
(i) Omega-3 fatty acids. Polyunsaturated fatty acids (PUFAs) are essential for brain functioning (Tsalamanios et al., 2006). They have multiple important biological roles, including membrane functioning, neurotransmission, signal transduction, and eicosanoid synthesis. Re-search suggests that PUFA level reduction is related to schizophrenia (Berger et al., 2006). Concordant with these findings, omega-3 PUFA may have positive effects in the treatment of schizophrenia (Emsley et al., 2002; Peet, 2008).
(ii) Glutamate. Besides dopamine, glutamate is thought to play a role in schizophrenia (Tsai and Lin, 2010). On the basis of the hypoth-esis that the glutamatergic system may be compromised in schizophre-nia, the use of N-methyl-D-aspartate (NMDA) receptor modulators may compensate for alterations in the glutamate system (Singh and Singh, 2011). Agents with coagonistic properties to (glutaminergic) NMDA receptors are glycine (full, endogenous agonist),D-serine (full, endoge-nous agonist), D-cycloserine (partial, exogenous agonist),D-alanine (partial, endogenous agonist), and sarcosine (= methylglycine, acting as a reuptake inhibitor of glycine and source of glycine). The glycine transporter-1 (GlyT-1) plays a pivotal role in
maintaining the glycine concentration within synapses at a subsaturating level. Sarcosine is a GlyT-1 inhibitor, meaning that its presence results in increased glycine concentrations. Lower cerebral glycine levels are suggested to be found in patients with schizophrenia. The administration of sarcosine is therefore proposed to relieve symp-toms of schizophrenia when added to nonclozapine antipsychotics (Lane et al., 2006). Whereas the mechanisms of NAC are now begin-ning to be understood, NAC is probably exerting benefits beyond being a precursor to the antioxidant glutathione, also modulating glutamater-gic, neurotropic, and inflammatory pathways (Dean et al., 2011).
(iii) Eastern (Chinese and ayurvedic) herbs. Eastern herbs are provided in the context of treatment with complete systems of medicine that evolved over thousands of years, such as TCM and Ayurveda. These treatments include prescription of herbal com-pounds, massage, diet, acupuncture, and the regulation of lifestyle (Clifford, 1994; Kaptchuck, 2000). Most clinical studies were per-formed on acupuncture (beyond the scope of this review) and on herbal compounds.
(iv) B vitamins. Nobel laureate Linus Pauling proposed a way of understanding and treating psychiatric disorders by correcting malfunctions in the body's chemistry, calling this approach “orthomo-lecular psychiatry” (Pauling, 1968). His idea was partly built on studies by Osmond and Hoffer (1962) and Hoffer and Osmond (1964), reporting good results when treating patients with schizophrenia with large doses of vitamins, especially vitamin B3. Hoffer (1971, 1972) published two more positive results with B vitamins. However, attempts to replicate his findings seem to have failed (Ban and Lehmann, 1975; Wittkopp and Abuzzahab, 1972). The contradicting findings may be explained because vitamine B is suggested to be effective in early psy-chosis but not in chronic schizophrenia (Hoffer and Osmond, 1964). One of the proposed mechanisms is abnormal one-carbon metabolism due to vitamin deficiencies (Hoffer, 2008). Variable levels of the com-ponents of one-carbon metabolism (folic acid [= vitamin B9] and vita-min B12) and consequently altered levels of homocysteine and phospholipid DHA have been reported both in medicated patients and in medication-naive first-episode psychotic patients (Kale et al., 2010). Folate status in patients with schizophrenia correlates inversely with negative symptoms (Goff et al., 2005).
(v) Antioxidants. Oxygen is essential in life but also generates re-active molecules (so-called free radicals) throughout the body. These free radicals are potentially harmful because they can damage essential molecules such as DNA and the enzymes necessary for proper cell functioning. Antioxidants may capture these reactive free radicals and convert them back to less reactive forms of the molecules (Singh
TABLE 2. Jadad Scale for Assessing the Quality of RCTs
Item Description Scoring
Randomization Was the study described as randomized (this includes the use of words such as randomly, random, and randomization)?
1 point Was the method to generate the sequence of randomization described and
appropriate (table of random numbers, computer generated, etc)?
+1 point Was the method to generate the sequence of randomization described
inappropriate (patients were allocated alternately, or according to date of birth, hospital number, etc)?
−1 point
Blinding Was the study described as double blind? 1 point
Was the method of double blinding described and was it appropriate (identical placebo, active placebo, dummy, etc)?
+1 point Was the study described as double blind but the method of blinding was
inappropriate (e.g., comparison of tablet vs injection with no double dummy)? −1 point An account of all patients Was there a description of withdrawals and dropouts? 1 point
TA B LE 3 . Ov erview o f Ef fe ct s o f N atural M edi cin es fo r P sycho ti c D is or de rs Stu d y a Stud y P opu latio n D o sage o f Na tur a l Me dic a tio n (Daily) A lso A P? AP Dosage Ef fects o f N atural Med icines b Ad ve rse Effec ts o f Na tu ral Med ic ine s b N ,D es ig n , De sc ri p ti o n o f T reatm en t/ Co n tr o l Gr ou p D ro p o u t Du ra ti on of Stud y (a n d F o llo w-U p , If A ppl ic a b le) N eg a ti ve sx P ositi v e sx C og niti v e sx D ep re ss iv e sx Gen er a l P syc h opa th ol og y Ad ve rse Sid e-Effects A P 1. Omeg a-3 V addadi et al. (1 9 89) Pati en ts pr edo m in an tly di ag nosed w ith schizophr eni a (m ean age 52. 7 y ) w it h mo v em ent d iso rd er s 12 cap su les co nta ini ng 45 m g γ -l inoleni c aci d + 360 mg linol eic ac id Y es + (W MS ) + (C PR S) + E PS (S AS) 0 TD (A IM S ) 0 N = 48; c-o (21 A P + efamol/ p lac, 17 AP + pl ac/ ef amol ) 10 (ns p er gr ) 2 × 1 6 w k F ent on et al. (2 0 01) Ou tpatients (1 8– 65 y) w ith sc hi zo ph re ni a or sc hi zoaf fect iv e di so rder 3ge th y l E PA Y es 0( PA N S S ) 0( PA N S S ) 0( R B A N S ) 0( M A D R S ) 0( C G I) 0T D( A IM S ), EP S (S A S) Respir ator y inf ec tion an d d ia rr h ea N =9 0 (45 A P + EP A, 4 5 AP + p lac) 15 (8 in EP A g r, 7 in p la c gr ) 16 wk P eet et al. (2 0 01) c O u tpa tie nts (mean age 44 .2 y) wit h schi zophreni a 2gE PA o r 2gD H A Y es 0 (P ANSS ) + (P A N S S) n. r. N =5 5 (4 5 ct ; 15 AP + EP A, 1 6 AP + DHA, 14 AP + p lac) 10; ns per g r 3 mo P eet et al. (2 0 01) c Ou tpatients (m ean age 44 .2 y) w ith sc hi zoph re nia 2gE PA o r 2gD H A At st ar t no, la te r in tr ia l y es +( PA N S S ) + (l es s u se o f ant ipsych o ti c medi cati on) 0 N =3 0 (1 5 E PA , 15 p lac) 3i np la c gr , 1 in EP A g r 3m o E m sl ey et al. (2 0 02) Pati en ts (1 8– 55 y) w ith sc hi zo ph re ni a 3 g E -E PA Y es 0 (P ANSS ) 0 (P ANSS ) + (P ANSS subscal e) 0 E PS (ESRS) + dyski ne si a (E SR S) 0 N = 4 0 (2 0 AP + E-EP A, 2 0 AP + p lac) 1i n E-E PA g r 12 wk P eet and Horr o b in (2 0 02) O u tpa tie nts (20 –62 y) w ith sc hi zo ph re ni a 1, 2, or 4 g E-EP A Ye s 0 (P A N S S ) + (P ANSS for 2 g g r on C lo z) 0( PA N S S ) + (P ANSS for 2g g r on C lo z) 0 (MADR S ) 0 (P ANSS ) + (P A N SS for 2g g r on Clo z) 0E P S (S A S , LUNSE R S), ak at hisi a (B AR S) , TD (A IM S ) 0 N = 122 (31 A P + pl ac, 2 9 A P + 1g r E -E ,2 8 AP + 2 g r E-E, 2 7 AP + 4g r E -E ) 1i np la c gr , 5 in 1g g r, 5 in 2 g gr , 2i n4 gg r 12 wk E m sl ey et al. (2 0 06, 2008) d Pa tie nts (18 –60 y) wi th schizophr eni a or schi zoaf fec ti v e d iso rd er m eet in g DSM-IV cr it er ia for T D 2 g E -E PA Y es 0 (P ANSS ) 0 (P ANSS ) 0 dyski nesi a, EP S (ES RS ) 0 H DL, L DL, tr ig ly ce ri d es, se ru m prolacti n , Hb, b lood pres su re, hear t rat e Increase in bl ee di n g ti m e an d BM I N = 8 4 (4 2 AP + E-EP A, 4 2 AP + p lac) 11 in E-EP A gr , 1 8 in p lac g r 12 wk Berg er et al. (2 0 07) (1 5– 29 y ear ol ds) Pati en ts (1 5– 29 y) w ith at le as t 1 cur rent p sy choti c symptom 2gE -E PA R is p ,O la n , or Q u et 0 (SANS) 0 (B PR S, CGI , GAF , S OF AS) + E P S (S AS ), less u se of A P 0 N = 8 0 (4 0 AP + E-EP A, 4 0 AP + p lac) 5i nE -E PA gr , 6 in pl ac g r 12 wk Man te ghi y et al . (2 0 08) In pati ent s di agno se d wi th schi zophreni a (mean age 37. 4 y ) 6gf is h o il + 1080 mg EP A + 720 mg DHA Ri sp 0 (P ANSS ) 0 (P ANSS ) 0 (P ANS S) 0 (P A N S S ) Gast ro in tes tin al adv erse ef fects (in 3) N = 106, 8 5 c-t (4 2R is p+ ω -3, 4 3 Ri sp + p lac) 21, ns per g r 6 wk T o k tam et al. (2 0 10) Pa tie nts diagn osed w ith sc hi zo ph re ni a, bip olar I disord er , or sch izoa ffecti ve di sord er (1 8– 60 y) 900 mg EPA/ DHA Ol an 0 (FB S, fa st in g in su li n, H b A1c , HOMA-IR) n. r. N =4 1 (2 0O la n+ ω -3 [4 schi zophr/ schizoaf f] , 2 1 Olan + p lac [8 schi zophr/ schizoaf f] ) n. r. 6 w k Omega-3 + vi ts E a nd C Bent sen et al . (2 0 13) (o m eg a-3 and v it s E+C ) Pati en ts wit h schi zophreni a or rel ated p sycho se s (18 –39 y ) 2g E PAa nd /o r 364 mg vit E + 1gv it C Y es 0 (P AN N S , in hi g h PU FA p ati en ts ) 0( PA N N Si n hi gh P U FA pa tie n ts )− (P A NNS , EP A and vits alone , in lo w PU FA p atie nts) 0( PA N N S , EP A + vits , in lo w P UF A pa tie n ts ) − (m o re u se o f AP in vi ts g r) SA E s in 9p at ie n ts (n o li n k betw een tr ea tm en t and numb er of S A Es) N = 104 (25 AP + p la c + pl ac, 2 8 AP + p la c + vi t E + C , 3 3 AP + E PA + pl ac, 1 8 A P + EP A + v it E+ C ) 3i np la c+ pl ac g r, 8 in p lac + vi t g r, 7 in E PA + p la c gr , 6i nE PA + vi t g r 16 wk
2 . Gl utama te Gl ycine Ja vit t et al . (1 9 94) Ma le p ati en ts di agnosed wi th schi zophreni a (mean age 3 7 y ) 2– 0. 4 g /k g bo dy w ei gh t Y es + (P ANSS ) 0 (P ANSS ) 0 (P A N S S su bsc ale) 0 E PS (ESRS), TD (AIMS) No SA E s; tempo ra ril y lo w er ext rem ity w ea kne ss (1 ) N = 1 4( 7A P+ gl yc, 7 AP + p lac) 0 8 wk d-b, 8w k gl yc fo r ev er y one 4 Heres co et al . (1 9 96) In p ati en ts (2 2– 60 y) di agnosed wi th schi zophreni a, con si d ered to b e trea tmen t resistan t 4– 0. 8 g /k g bo dy w ei gh t Y es + (P ANSS ) 0 (P ANSS ) + (P ANSS subscale) +( PA N S S subscale) +( PA N S S su bsc ale) 0T D( A IM S ), EPS (SA S) 0 N =1 2 c-o (7 AP + gl yc/ p lac, 4 AP + plac /g lyc ) 1 (on pl ac, in p lac/ g ly c gr ) 2× 6 w k , 2w kw o before and in b etw ee n 4 Heres co -Le vy et al . (1 9 99) P ati ents (m ean age 38 .8 y) di agnosed wi th schi zophreni a w h o are tr eatm ent resi stant 4– 0. 8 g /k g bo dy w ei gh t Y es + (P ANSS ) 0 (P ANSS ) + (P ANSS subscale) +( PA N S S subscale) + (BP RS ) 0 T D (A IM S ), EPS (SA S) Na use a an d vomitin g (1 ) N =2 2 c-o (10 A P + pl ac/ g ly c, 9 AP + gl yc /plac ) 3( 2o np la c, 1o ng ly c) 2× 6 w k , 2w kw o before and in b etw ee n 4 P o tk in et al. (1 9 99) Ho sp italize d pa tie nts (a ge n.r .) with ch ron ic sc hi zoph re nia 30 g C lo z 400 –12 00 mg/da y 0 (SANS) − (B PR S sub scal e) 0 (BP RS ) 0 N =2 4 (1 2 Cl o z + g ly c, 12 C loz + pla c) 3i ng ly c gr , 2 in pl ac g r 12 wk 4 E v ins et al. (2 0 00) C lin ic al ly st ab le ou tpa tie nt s (m ean ag e 39 y) w ith sc hi zoph re nia 60 g C lo z 0 (SANS, PANSS ) 0 (P ANSS ) 0 (P ANSS subscale) 0 (BPRS ) n .r . N =3 0( 27 ct ; 14 C loz + gl yc, 13 C loz + pla c) 2o np la c, 1o ng ly c 8w k 4 Ja vit t et al . (2 0 01) In pat ients (mean age 39 .6 y) di ag no se d w ith sc hi zo ph re ni a 0. 8 g /k g bo dy w ei gh t Y es + (P ANSS ) + (P ANSS subscale) +( PA N S S subscale) 0 E PS (S AS ), ak at hisi a (B AR S) , TD (A IM S ) 0 N =1 2c -o (6 AP + gl yc/p lac, 6 AP + plac/gl yc ) 02 × 6 w k , 4w kw o before and 2w ki n bet w een 4 Heres co et al . (2 0 04) In pa tie nts (2 2– 60 y) dia gnos ed wi th sc hi zoph re nia , w ho are treatm ent re sistan t, an d pr es en tly tr eat ed 0. 8 g /k g bo dy w ei gh t Olan, R is p + (P ANSS ) + (P A N S S) + (P ANSS subscale) +( PA N S S subscale) + (BP RS ) + EP S (S A S ), TD (A IM S ) No S A E s; mil d upper ga st ro in te st in al tract di scomfor t wi th nau sea (2) N =1 7c -o (1 g r AP + gl yc/p lac, 1g r A P+ pla c/ gl yc ) 3o ng ly c 2 ×6w k , 2w kw o before and in b etw ee n 4 Di az et al . (2 0 05) Inpa tients (mea n ag e 44.7 y ) d iagn ose d with sc hizoph re nia, w h o are tr ea tm ent re si sta n t, an d pr es ent ly tr eat ed 60 g Y es 0 (P ANSS ) 0 (P ANSS ) 0 (B P R S , G A F ) 0 E P S (E S R S , SA S ) na us ea an d vomitin g (1 ) N =1 2c -o (6 AP + pla c/ gl yc , 6 AP + gl yc /plac ) 1o ng ly c 2 8w k 3 Bu cha na n et al. (2 00 7) (a ls o re por te d unde r D -c yc lo serin e) Pa tie nts (18 –64 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r n. r. Y es, no Clo z + (S A N S ) fo r gl yc by co nv en tiona l an tipsy chot ic s 0 (ne uropsyc hol og ical te st ba tte ry) 0 (BP RS, C GI) 0 E P S (S A S ), TD (A IM S ) na us ea an d dr y m ou th N =1 65 (55A P + bo th pl ac , 56 AP + d-c + pla c, 54 A P + gl yc + p la c) 10 in plac gr , 1 0 in d-c g r, 12 in gl y c g r 16 wk 3 D -S erin e T sai et al . (1 99 8) Da y pro g ram and inp atie nts patient s (m ean age 33 y) dia gnos ed wi th sc hi zoph re nia 30 mg/ k g bo dy w ei gh t Y es + (SANS) + (P AN S S ) + (P ANSS su b scal e, WC ST ) 0 (H A M -D ) + (CGI) 0 (P ANS S su bsc ale) 0T D( A IM S ), ak at hi si a (B A R S) , E PS (SAS) no SA Es ; in somnia (2 ), na use a (2), diar rh ea (1), const ip at io n (1) N =3 1( 17 AP + plac , 14 A P + d -s ) 3i np la c gr , 0 in d-s g r 6w k 4 T sai et al . (1 99 9) In pat ients (mean age 41 y ) di agnosed w ith sc hi zo ph re ni a 30 mg/ k g bo dy w ei gh t Cl o z 0 (P A N S S , S A NS ) 0 (P ANSS ) 0 (P ANSS subscale, WC ST ) 0 (HAM-D) 0 (P A N S S su bsc ale, C GI) 0T D( A IM S ), ak at hi si a (B A R S ), EPS (SA S) 0 N =2 0( 10 Clo z + d-s, 10 C loz + pla c) n. r. 6 w k 3 H er es co-Le vy et al. (2 00 5) In p ati en ts (1 8– 70 y) di agnosed wi th schi zophreni a, tr eatment re sis tant, an d presentl y treated 30 mg/ k g bo dy w ei gh t Olan, R is p + (P AN S S , S A NS ) +( PA N S S ) +( PA N S S subscale) +( PA N S S subscale) + (BP RS ) + EP S (S A S ), TD (A IM S ) 0 N =3 9, c-o (1 9 A P + d-s/ pl ac , 20 AP + plac/d-s) 32 × 6 w k , 2w kw o before and 3w kw o in b etw ee n 4 L an e et al. (2 00 5) (a ls o re p o rt ed under sarc o si n e) In p ati en ts (1 8– 60 y) di agnosed wi th schi zophreni a 2go r2g sarco sin e Risp 6 m g/da y or less 0 (SANS) 0 (P ANSS ) 0 (P ANSS subscale) 0 (P ANSS subscale) 0( PA N S S su bsc ale) 0 E PS (SAS), ak at hi si a (B A R S ), T D (A IM S) no SA Es ; e.g. , w ei ght ga in , pa lp itatio ns, in somnia, fatig ab ility , or th ost at ic di zz in es s, w eigh t lo ss , tensio n, sali va tio n N =6 5( 23 Risp + plac, 21 R is p + d-s, 21 R is p + sar ) 3i np la c gr , 2 in d-s g r, 3i ns ar g r 6w k 5 L an e et al. (2 01 0) (a ls o re p o rt ed under sarc o si n e) In pa tie nts (1 8– 60 y) dia gnos ed wi th sc hi zoph re nia 2go r2g sarco sin e Y es 0 (P AN S S , S A NS ) 0 (P ANSS ) 0 (P ANSS subscale) 0 (P ANSS subscale) 0 (QoL , GA F ) 0 E P S (S A S ), ak at hi si a (B A R S ), T D (A IM S) no SA Es ; e.g. , w ei ght ga in , in somnia, fatig ab ility , sed ation , pa lp itatio ns N =6 0( 20 AP + plac , 20 A P + sa r, 20 A P + d-s) 1i ns ar g r, 4i nd -s gr , 4 in pl ac g r 6w k 5 (C ont inue d o n n ex t p a g e)
TA B LE 3 .(C ont in ued ) Stu d y a Stud y P opu latio n D o sage o f Na tur a l Me dic a tio n (Daily) A lso A P? AP Dosage Ef fects o f N atural Med icines b Ad ve rse Effec ts o f Na tu ral Med ic ine s b N ,D es ig n , De sc ri p ti o n o f T reatm en t/ Co n tr o l Gr ou p D ro p o u t Du ra ti on of Stud y (a n d F o llo w-U p , If A ppl ic a b le) N eg a ti ve sx P ositi v e sx C og niti v e sx D ep re ss iv e sx Gen er a l P syc h opa th ol og y Ad ve rse Sid e-Effects A P W eiser et al . (2 0 12) In p ati en ts an d ou tpa tie n ts (1 8– 64 y) di agn os ed w ith sc hi zo ph re ni a or sc hi zoaf fect iv e di so rder 2 g Y es 0 (SANS, PANSS ) 0 (P ANSS ) 0 (MA T R IC S ) 0 (P ANSS subscal e) M outh so res N = 195 (97 AP + d -s , 98 A P + pla c) 23 in d-s gr , 2 3 in pl ac g r 16 wk D'So uza et al. (2 0 13) ( D -seri n e + computer ized co g n it iv e re tr ai ning [C R T ]) Pa tie nts (18 –65 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r 30 mg/ k g bo dy w ei gh t Y es, not Lam, Car o r Cl oz 0 (P ANSS ) 0 (P ANNS) 0 (C G I) + (d if fe re n ti al si te ef fe ct s o n indi vi dual test per for mance for d-s + C R T) 0 (C D S ) 0 (P ANNS subscal e) 0E P S (N R S ) + Akathisi a (B AR S, in Indi an d-s g r) N = 104 (27 d-s + co ntr ol CR T [1], 27 pla c + C R T [2 ], 24 d-s + CR T [3], 24 pla c + con tr ol CR T [4]) 2( 1 1 at fu ) in g r 1 , 5( 1 0 at fu ) in g r 2 , 3( 9a t fu ) gr 3, 3 (9 at fu ) in gr 4 1 2 wk + 24 wk fu Er m ilo v et al. (2 01 3) In pa tie nts (m ean ag e 50 y) di ag no se d w ith sc hi zo ph re ni a 3g O la n in APg r 15 –3 0 m g + (P ANNS , le ss im pro vem en t in d-s gr than in Ola g r) +( PA N N S , le ss imp ro v emen t in d-s g r than in Ol a g r) 0 E PS (S AS ), TD (A IM S ) 0 N =1 8 (1 0 d-s, 8 O la n) 5i nd -s gr , 3 in Olan g r 10 wk D -Cy clo serine R os se et al . (1 99 6) Pa tie nts (m ean ag e 38 .1 y) with ch ron ic sc hi zoph re nia 3 0 m g M o l 50 m g t.i .d. 0 (S A N S ) 0 (B P R S ) 0 (B P R S ) n .r . N =1 3 (3 Mo l + 10 m g d-c, 6 M ol + 30 mg d-c, 4M ol + pl ac ) 04 w k V an B erck el (1 99 9) Pa tie nts (18 –60 y) dia gnos ed wi th sc hi zoph re nia 1 0 0m g y es 0( PA N S S ) − (P AN S S ) − (P ANNS subscal e, CG I) 0 E PS (E SR S) 0 N =2 6 (1 3 AP + d -c , 1 3 AP + p la c) 1i nd -c g r 8w k H er es co-Le vy et al. (2 00 2) P ati en ts (m ean ag e 40 .0 y) di ag no se d w ith sc hi zo ph re ni a, wh o w er e tr eat ment re si st ant 50 mg Y es + (P ANSS ) 0 (P ANSS ) 0 (HAM-D) + (P ANSS subscal e) 0 E PS (S AS ), TD (A IM S ) 0 N = 24, c-o (1 6 ct , 8 A P + d-c/pla c, 8 AP + p la c/ d-c) 3o nd -c , 5o np la c 2× 6 w k , 2w kw o in b etw ee n D un ca n et al . (2 00 4) Male sub jects (m ean age 51 .8 y) dia gnos ed wi th sc hi zoph re nia , wh o d is p la y ed prominent nega tive sy m pto ms 50 mg Y es 0 (SANS, BP RS sub sc ale) 0 (C P T , SST M SP ) 0 (B PR S) 0 E PS (S A S ) 0 N =2 2 (1 0 AP + d -c , 12 A P + pla c) 04 w k Go ff et al. (2 00 5) e Ou tpatients (mea n age 46 .5 y) di ag no se d w ith sc hi zo ph re ni a 5 0 m g Y es 0 (P AN S S , S A NS ) 0( PA N S S ) 0( e. g ., W A IS scales , St ro op, W C S T ) 0 (HAM-D) 0 (GAS, Q oL) 0 E P S (SAS), TD (A IM S ) n. r. N =5 5 (2 7 AP + d -c , 28 A P + pla c) 13 in d-c g r, 16 in p la c gr ) 24 wk Yu rg el un -T od d et al. (2 00 5) In pa tie nts and ou tpa tie nt s (3 6– 58 y) dia gnos ed wi th sc hi zoph re nia 50 mg Y es + (P ANSS ) 0 (P ANSS ) + (t emporal lobe act iv at ion) 0 (f ront al lobe act iv at ion) n. r. N =1 2 (6 AP + d-c, 6 AP + plac ) 08 w k Bu cha na n et al. (2 00 7) (a ls o re p o rt ed under glyci n e) Pa tie nts (18 –64 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r n. r. Y es, n o C loz 0 (SANS) 0 (neuro- psychol o g ical te st ba tt er y) 0 (BP RS , C G I) 0 EP S (SA S) , TD (A IM S ) 0 N = 165 (55 A P + plac + p lac, 56 AP + d-c + pl ac, 54 AP + gl yc + p lac) 10 in plac gr , 10 in d -c gr , 1 2 in gl y c g r 16 wk Go ff et al. (2 00 8) S ta ble patients (1 8– 65 y) dia gnos ed wi th sc hi zoph re nia 50 mg Y es, n o C loz + (SANS) 0 (P ANSS ) 0 (co gn it iv e tes t batt er y) 0( C G I) 0 N =3 8 (19 A P + d-c, 1 9 AP + p la c) 3i nd -c g r, 2( 3a t f. u .) in p lac g r 8 w k, f. u. + 2w k Go ttlie b et al. (2 01 1) Ou tpatients (1 8– 65 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve di sord er (d ep resse d ty pe), an d w ho ha d ex pe rie nc ed pe rsi st ent de lu si on s despite treatm en t with A P 50 mg Y es 0 (S APS, PS Y R A T S ) + (f ir st d -c, gr eater reduct ions in d elu si o n al se v erit y ) 0 (AB A, PR T-BT ) + (f ir st d-c, g reat er re d u cti ons in beli ef con v ic ti on) 0 N = 21, c-o (11 AP + d-c/ plac, 10 AP + plac /d -c) 1i np la c – d-c g r 3w k , 3vis it s, 2 doses (vi sit 1 and 2 ) Cain et al. (2 01 4) Ou tpatients (1 8– 65 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r, de pr es se d typ e 50 mg Y es, no Clo z 0 (SANS) + (S ANS for sub s wit h cli n icall y si gn xa t ba se li ne ) 0( M A T R IC S ) + (a u d it o ry discri minat io n ta sk ) 0 N =4 0 (36 w ere tr eated ; 1 8 AP + d -c , 18 A P + pla c) 4b -t ; 1 in d-c g r, 3 in p lac g r 8w k
D -A lan in e Tsai et al. (20 06) Da y pro gram an d inp at ie nt s (me an age 33 y) dia gno se d w ith sc hi zoph re nia 100 mg /kg body w eig ht Y es + (S ANS ) + (P A N SS ) + (P ANS S subscale) 0 (HAM-D) + (C GI ) 0 (P AN S S subscal e) 0T D( A IM S ), ak at hisi a (B AR S ), EP S (S A S) no S A Es; ins o m n ia an d nausea (1) N =3 2 (18 A P + pl ac, 14 AP + d -a ) 1i n p la cg r 6 w k 4 Sa rco si n e Tsai et al. (20 04) Da y pro gram an d inp at ie nt s (me an age 32 y) dia gn os ed w ith sc hi zo ph re ni a 2 g Y es + (S ANS ) + (P A N SS ) + (P ANS S subscale) 0 (HAM-D) + (P ANSS subscal e, BP RS ) 0 E PS (S AS ), ak at hisi a (B AR S ), TD (A IM S ) no S A Es; tach y car di a (2) N =3 8 (1 7 A P + sa r, 21 AP + plac) 2( 1i n each gr ) 6w k 4 Lan e et al. (2 00 5) (a ls o repo rt ed u nder D -s eri n e) In pa tie nts (1 8– 60 y) dia gno se d w ith sc hi zoph re nia 2go r2g D -s er in e R isp 6 m g/da y or less + (SANS) + (P A N S S ) + (P ANSS subscale) +( PA N S S subscale) + (P ANSS subscal e) 0 E PS (S AS ), ak at hisi a (B AR S ), TD (A IM S ) no S A Es; e.g. , w ei ght gain , palp it ati ons, ins o m n ia , fa ti gab ili ty , ortho st ati c di zziness, w ei ght loss, tensi on, sa li v ati on N =6 5 (2 3R is p+ pl ac, 21 Ri sp + d -s , 21 R is p + sar ) 3i n p la cg r, 2i nd -s g r, 3i ns ar g r 6w k 5 L an e et al. (2 00 6) In pa tie nts (m ean ag e 36 y) dia gn os ed w ith sc hi zo ph re ni a 2 g Cl o z 0 (P ANSS ) 0 (P ANSS ) 0 (P ANSS subscale) 0 (P ANSS subscale) 0 (P ANSS subscal e) 0 E PS (S AS ), ak at hisi a (B AR S ), TD (A IM S ) in so mn ia (2 ) N =2 0 (1 0 C lo z + sa r, 10 C loz + p lac ) 06 w k 4 L an e et al. (2 00 8) Ho sp italize d patien ts (1 8– 60 y) diag nos ed with sc hizop h re nia 1 o r 2 g n o 0 (P ANSS ) 0 (P ANSS ) 0 (Q o L ) No SAEs; ins o m n ia (6 ), w ei ght gain (3 ), sedati on (1), consti pat ion (1 ), fa ti gab ili ty (1 ) N =2 0( 1 1 2 g sa r, 9 1 g sa r) 3i n 1 gg r, 1i n2 gg r 6w k 4 Lan e et al. (2 01 0) (a ls o repo rt ed u nder D -s eri n e) In pa tie nts (1 8– 60 y) dia gno se d w ith sc hi zoph re nia 2o r2g D-s er in e Y es + (P ANSS, SANS) +( PA N S S ) +( PA N S S subscale) +( PA N S S subscale) + (QoL, GA F ) 0 E P S (SAS), ak at hisi a (B AR S ), TD (A IM S ) No SAEs; e. g ., w ei ght gain , ins o m n ia , fa ti gab ili ty , sedati on, palp it ati ons N =6 0 (20 A P + pl ac, 20 AP + sar , 20 AP + d -s ) 1 in sa r gr , 4o nd -s , 4i np la cg r 6w k 5 N-a cety l cy stein e Ber k et al . (20 08) In pa tie nts and ou tpatient s (mea n ag e 36 .6 y) dia gno se d w ith sc hi zoph re nia 2 g Y es + (P ANNS) 0 (P ANSS ) 0 (digi t span, w o rd lear ni ng, tr ail makin g , v erbal fl uenc y) +( C G I) 0 (G A F, SOF A S) 0T D( A IM S ), EP S (S A S) + ak at hisi a (B A R S ) 0 N =1 4 0 (71 A P + pl ac, 69 A P + NAC ) 56, ns per g r 2 4 w k , f.u. at 28 wk 4 La v o ie et al . (20 08) Ou tpatients (mea n age 31 .9 y) di ag no se d with sc hizop h re nia 2 g Y es 0 (audi to ry discri m inat ion task, P 300 ) + (M MN ) n. r. N =9 c-o (2 d-o; 5 AP + N A C /plac , 2A P+ p lac /N A C ) 2 , ns pe r g r 2 × 2 w k 3 3. E a ster n h erb s Naid oo (1 956) In pa tie nt s (1 7– 70 y) w ith sc hi zo ph re ni a 10 mg Res erp in e no + (c lin ic al im p ro v em en t) No SAEs; n asal congest ion , pe ri or bi tal ed em a, diar rhea , ep ig as tr ic pain , sali va ting , ps eu do -p ar kin son ian state, se ve re he ada ch es, de ep pa in s in limbs N =8 0( 2 0 p la c [A] , 20 ser p asi l [B ], 20 p lac + ect [C ], 2 0 se rp as il + ect [D ]) n. r. 11 w k of pl ac o r tr eatment , th en trea tm ent for al l grou ps (A + B ser pas il, C + D re se rpi n e) n s fo r h ow ma ny w eeks 3 M ah ale ta l. (1 97 6) Ou tpatients (1 6– 45 y) w ith sc hi zo ph re ni a 12 g T agar a or 12 g B rahm yadiy og a Chlor o nl y in A P -g r Fi rs t m o n th 200 mg , second mont h 300 mg +/ 0 (B b et ter th an pl ac and Ta g ar a, n o sign di f w ith chlor ) +/ 0 (B b et ter th an pl ac an d T ag ar a, no si gn dif wi th ch lo r) 0( M P Q , S A E ) n .r . N = 1 36 (108 ct ; 27 ta gara, 27 B , 2 7 plac, 27 Chl o r) 28 (ns p er gr ) 2 mo 3 Mu nd ew ad i et al. (2 00 8) (am: B acopa monni er i, n ar dostach ys jat ama n si ) Pa tie nts (18 –60 y) w ith sc hi zo ph re ni a 80 0m gB ac op a Mo nn ie ri (acti ve ) plu s 40 0 m g Nard osta ch ys Ja ta m an si (a ct iv e) Olan in cont ro l g r 10 mg dd + (as ef fect iv e as AP) (P ANSS) + (as ef fect iv e as AP ) (P A N S S) + (as ef fe cti v e as AP) (cli n ical im p ro v em en t) + (le ss w eigh t ga in th an AP ) No SAEs; vo m it in g an d diar rhea (2) N =2 0 0 (9 7 ay u rve di c medici n e, 10 3 A P ) 1 2 in am gr , 15 in A P g r 78 wk 3 C he n et al . (2 00 8a , 200 9) d Pa tie nts (18 –45 y) dia gno se d w ith sc hi zoph re nia 2 .7 g W S K Y R is p M ax 8 m g/da y 0 (S A N S , PANSS ) 0 (P ANSS ) + (W C ST) + (HAM-D) + (Q oL, S DS S, lo w er u se o f AP ) 0T D( A IM S , RS ES E) No SAEs; e. g ., tremor , insomnia, akat h isia, somnolence, headache, w eight gain , const ipat io n N =1 2 0 (6 0r is p+ WS KY , 6 0 ri sp + p lac) 2i n W S K Yg r, 2i np la cg r 8w k 5 (Cont inue d o n n ex t p a g e)
TA B LE 3 .(C ont in ued ) Stu d y a Stud y P opu latio n D o sage o f Na tur a l Me dic a tio n (Daily) A lso A P? AP Dosage Ef fects o f N atural Med icines b Ad ve rse Effec ts o f Na tu ral Med ic ine s b N ,D es ig n , De sc ri p ti o n o f T reatm en t/ Co n tr o l Gr ou p D ro p o u t Du ra ti on of Stud y (a n d F o llo w-U p , If A ppl ic a b le) N eg a ti ve sx P ositi v e sx C og niti v e sx D ep re ss iv e sx Gen er a l P syc h opa th ol og y Ad ve rse Sid e-Effects A P Chen et al. (2 0 08b) In pa tie nts and ou tpa tie nt s (1 8– 45 y) di ag nosed w ith schizophr eni a 2.7 g W S K Y R is p 0 (P ANSS ) 0 (P ANSS ) 0 (W C ST ) 0 (HAM-D) + (SDSS) 0 T D (AI M S , RS ES E) No SAEs; e. g ., tremor , akat h is ia , ins o m n ia , somnolence, const ipat io n , w ei ght gai n , si gh t d im N = 200 (100 ri sp + W S KY , 100 ri sp + p la c) 2i np la cg r, 4i n WKS Y g r 8w k Xiao et al. (2 011) P at ie nt s (m ea n ag e 50 .5 y) di ag no se d w ith sc hi zo ph re ni a 200 mg Sarsasapo genin Ri sp 0 (P ANSS ) 0 (P ANSS ) 0 (W M S, mW AIS) 0 (CGI ) No SAEs; e. g ., abnor mal E CG , tremor , akat h is ia , dro w si ness N =9 0 (4 4r is p+ pl ac, 4 6 ri sp + sa rs) 5i np la cg r, 5i ns ar s g r 8w k 4. B v it s Vit B 1 (thi amin) Sack s et al . (1 98 9) (a ls o ace ta zo lamid e) P ati en ts (m ean ag e 39 .1 y) w ith sc hi zoph re nia 2 g A ce tazo la mide plus 1 .5 g Thiamine Y es + (SAP S) + (SANS) No SAEs; some in creased ur ina tio n N = 26, c-o (24 ct; 13 AP + A+ T /p la c, 1 1 AP + pl ac/ A + T 2 , ns pe r g r 2 × 8 w k , 4w kw o before and in b etw ee n Vit B 3 (nia cin/ni co tinic a cid , n iacina m ide/nicoti n amid e) Kl ine et al. (1 9 67) (n icotin am id e) M ale in patients (2 3– 52 y) wi th sc hi zoph re nia 1 g Y es 5 of 20 0 F ree d ra w ing te st 0 B P R S ; 0 R R S ; 0W P R S n. r. N =2 0 (1 0 p la c, 10 1 g or 2g N AD) 02 0 d ay s M elt zer et al. (1 9 69) (n icotin am id e) M ale pa tie nts (2 0– 35 y) wi th sc hi zoph re nia 2g T h io ri d a-zi n e in5o f 1 0 0I M P S 0 B D I n .r . N =1 0 c-o (5 plac + pl ac/N A D /p lac , 5t hi + pl ac/N A D /p lac ) 19 w k Gre enb au m (1 97 0) (ni ac inam ide) (4 –12 ye ar ol ds ) Ch ildren (4 –12 y) di ag nosed w ith schizophr eni a n. r. n. r. 0 (WISC, S FBT) 0 (beh av iou r rati ngs) N =5 7 (1 7 n ia c, 16 n iac + tr an quil izer , 24 p lac) 06 m o Ram sa y et al. (1 97 0) (n icotin ic ac id , nico tinam ide) P ati ents (m ean age 29 .5 yr ) diag no sed with sc hizoph re nia Ni co ti ni c acid 3go r nico tinam ide 3g P h eno- th ia zi de 0B P R S 0M M P I 0 HOD N =3 0 (P h + 10 n ic, Ph + 1 0 n a, 10 P h + p lac) 06 m o An an th et al. (1 97 2) (n icotin ic ac id , nico tinam ide) In pa tie nts (m ean ag e 26 .6 y) w ith sc hi zoph re nia Ni co ti ni c acid 2go r nico tinam ide 2g Chlor + (BPRS, le ss ch lo r in ni c g r) − (m or e chlor in na g r, m ore hospital d ay s in ni c g r and n a g r) No SAEs; rash in ni c g r (1) an di nn ag r( 1 ) N =3 0 (9 chlor + ni c, 10 ch lor + na, 11 ch lor + pl ac) 6c t, 3i n na g r, 2 in p la c gr , 1i nn ic g r 2y Mc G rat h et al. (1 97 2) (n icotin am id e) In pa tie nts (m ean ag e 31 .9 yr ) diag no sed w ith sc hi zo ph re ni a 3g Y es 0 (r ec ov ery ra te ) n .r . N = 184 (132 n a, 13 3 p lac) 43 in na g r, 3 8 in p lac g r 12 mo Ananth et al. (1 9 73) (n icotin ic ac id ) (also re por ted un der vi t B 6) In pa tie nts (m ean ag e 41 .7 y) w ith sc hi zoph re nia 3g Y es + (BP RS , N O S IE ) A bno rm al li v er fu ncti on, leuk openi a, w ei ght lo ss , in n ic g r (5 ,1 ,1 ), in nic + p y r g r (5 ,1 ,2 ), w eig h t gain (1 ), h ypot ensi on (2 ) in n ic + p y r g r N =3 0 (1 0 n ic + py r, 1 0 ni c + pl ac, 1 0 pl ac + p yr ) 1i np y r g r, 2i nn ic + py r g r, 1i nn ic g r 48 wk W itt en bo rn et al. (1 97 3) (n ia cin ) In pa tie nts and ou tpa tie nt s (m ean ag e 28 .8 y) w ith sc hi zo ph re ni a 3g Y es 0 (ho sp it ali zati on, use o f tr an q u il iz er s, WP RS , R N R S ) Pi g m en te d h yperkerato si s (i n abou t 1 /3 rd of th e subj ects) N = 140 (75 ct, 47 3 000 mg ni aci n , 2 8 6m gn ia ci n ) 65 ns per g r 2 4 m o De utsch et al. (1 97 7) (n icotin ic ac id , nico tinam ide) In pa tie nts (a ge n.r .) w ith sc hi zo ph re ni a 315 0 m g Nicotin ic ac id or 31 50 m g nicoti na m id e Ye s 0 (BP RS , C GI, NOS IE I) 14 d if fer ent adv erse ef fect s, not m en ti oned N =3 0 (10 A P + n ic, 10 AP + n a, 10 AP + p lac) 1i nn mg r, 5i nn ic g r 48 wk P etr ie et al. (1 98 1) (n icotin ic ac id ) (also re por ted un der vi t B 6) In pa tie nts (m ean ag e 41 .7 yr ) w ith sc hi zoph re nia 30 0 m g Y es + (BP RS , n ic gr an d p y r gr ) 0 (BP RS , n ic + py r g r) 0 (NOSIE ) Abno rm al li v er fu ncti on te sts, h ypot ensi on, w ei ght lo ss , fl ushi ng of the sk in , d er m ati ti s N =3 0 10 AP + ni c + p y r, 10 AP + n ic + pl ac, 1 0 A P + p y r + p lac) 1i np y r g r, 2i nn ic + py r g r, 1i nn ic g r 48 wk
Vit B 6 (pyri doxi ne) Ananth et al. (1 9 7 3 ) (a ls o re po rte d un de r vit B 3) In pa tie nts (m ean ag e 26 .6 yr ) w ith sc hi zoph re nia 75 mg Y es + (BP RS , N O S IE ) N au se a an d vomitin g (1 ), di zz in es s (1 ), tach yc ard ia (1), w ei ght ga in (1), flus hin g of sk in (2 ), de rm atitis (2 ) N = 30 (10 ni c + py r, 10 ni c + pla c, 10 pla c + pyr ) 1i np y r g r, 2i nn ic + py r g r, 1 in ni c g r 48 wk 4 P etr ie et al. (1 9 81) (a ls o re por te d unde r vit B 3) In pa tie nts (m ean ag e 41 .7 y) w ith sc hi zoph re nia 75 mg Y es + (BPRS , ni c g r an d pyr gr) 0 (BPRS , ni c + py r g r) Ab no rm al liv er fu nctio n tests, hy po te ns io n, w eigh t lo ss , fl ush ing of th e sk in, der m atitis N =3 0 (10A P + nic + py r, 10 A P + nic + pla c, 10 A P + py r + pl ac ) 1i np y r g r, 2i nn ic + py r g r, 1 in ni c g r 48 wk 4 L er ner et al. (2 00 1, 20 02 ) d In pa tie nts (2 8– 71 y) wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r 4 0 0m g Y es 0( PA N S S ) 0( PA N S S ) 0 (C G I) +T D( E S R S ) 0 N =1 5, c-o (8 AP + vit B6 /plac , 7 A P + p lac /v it B 6 ) 02 × 4 w k , 1w kw o in b etw ee n 3 L er ner et al. (2 00 4) In pa tie nts (m ean ag e 42 .4 y) w ith sc hi zoph re nia or sc hizo af fe cti ve dis or de r 1200 mg Y es + (CGI, BP RS) + N IA (BA R S ) 0 N =2 0( 10 A P + vit B 6, 10 AP + plac ) 0 5 da ys 4 Mio do w nik et al. (2 00 6) (a ls o a g ro up on mian serin ) In pa tie nts (m ean ag e 41 .8 y) w ith sc hi zoph re nia , sc hizo af fe cti ve dis or de r or bi po la r af fecti ve diso rde r 1200 mg Y es + (BPRS , C GI; in B6 g r and mian g r) + N IA (B A R S ) 0 N =6 0( 23 A P + vit B 6, 20 AP + m ian , 17 A P + pla c) 0 5 da ys 4 L er ner et al. (2 00 7) In pa tie nts (m ean ag e 46 .8 y) di ag no se d w ith sc hi zo ph re ni a or sch izoa ffecti ve dis or de r 1200 mg Y es +T D (E S R S ) N o S A E s; ac ne (1), aller gic reac tion (1 ) N =5 0, c-o (2 8 A P + vi t B6 /plac , 22 A P + p lac /v it B 6 ) 10 on v it B 6, 4o np la c 26 w k (2×1 2 wk + 2 wk wo in bet w een ) 3 Vi t B 9 (f o li c a ci d ) Godfre y et al. (1 9 90) (meth ylfola te) Ou tpatients (mea n age 44 .8 y) di ag no se d with m ajor de pr es si on or sc hi zoph re nia 15 mg Y es + (cli n ical ra ti ng scal e) n. r. N = 17 (su bgr of 41 ; 9 A P + me t, 8 AP + plac ) 06 m o 3 Hi ll et al . (2 0 11) (fo lic ac id ) Ou tpatients (1 8– 68 y) dia gnos ed wi th sc hi zoph re nia 2m g Y es 0( S A N S ) +e ff ec t o f MT HFR g t) 0( PA N S S ) 0( e. g .,W A IS , WC ST ) 0 (C D SS ) 0 (GAF , Q oL) n .r . N =3 8 (19 A P + fa, 19 AP + p lac) 5i nB 1 1 g r, 5i np la cg r 12 wk 4 Vi ts B1, B 6 , an d B 12 Jo shi (1 98 2) P at ie nts (a ge n.r .) with ac ute sc hi zoph re nic ps yc ho si s 10 0 m g B 1 plus 50 m g B6 pl us 10 00 μgB 12 Chlo r, T rif 150 mg dd , 15 mg dd 0 (be ha vi or scal e) + les s ect' s in vi t gr 0 N = 6 0 (3 0 vit inj , 30 p lac in j) 1n sp er g r 4w k , f-u1y r 4 Vi ts B6, B 9 , an d B 12 Le vi ne et al . (2 00 6) In pa tie nts (a ge n.r .) w ith sc hi zo ph re ni a 2m gf ol ic ac id pl us 25 m g py ri doxin e pl us 40 0 μgB 12 Y es + (P A N S S ) +( PA N S S ) +( W C S T ) 0( D S , RA VL T, CF D) 0T D (A IM S ) n .r . N = 55, c-o (20 A P + vi t/ pl ac, 22 AP + p lac/vi t) 13 (2 ns; 5o np la c, 6o n v it s) 2× 3 m o 3 Vi ts B9 and B 1 2 Ro ff man et al. (2 01 3) (f o lic ac id and B 1 2 ) Ou tpatients (mea n ag e 45 .5 y) w ith sc hi zoph re nia 2m gf o la te p lu s 400 μgB 1 2 Y es + (S ANS , no si g di f, mo st ly fo r FO LH 1 ge no typ es ) +( PA N S S , n o si g d if ) Wo rs en in g of ps yc ho si s in 3( 2 in vi t g r, 1i np la cg r) N = 140 (94 A P + fa + B 12, 46 AP + p lac) 16 in fo l + B12 g r, 3i np la cg r 16 wk 4 5. A n ti o x id an ts Vi t C B ha va nie ta l. (1 96 2) M ale in patients (2 0– 30 y) w ith sc hi zo ph re ni a 10 m g/k g bo dy w ei gh t No 0 (e. g ., recall , att ent ion, im it at io n) 0( m ot or fu nct io ni ng ) n. r. N =3 1 (15 ascorbi c acid , 16 p lac) n. r. 1 0 da ys 4 Da kh ale et al. (2 00 5) Ou tpatients (mea n age 38 .6 y) di ag no se d w ith sc hi zo ph re ni a 50 0 m g O la n , Q u et , Zi pr 10/2 00/ 40 mg/da y + (BP RS ) + (r ed uc e of se ru m M D A ) 0 N = 4 0 (2 0 AP + vi t C , 2 0 AP + p lac) 4i np la cg r, 1i n v it g r 8w k 5 Gin k g o bi lo ba Zh ou et al . (1 99 9) P ati en ts (m ean ag e 43 .4 y) w ith sc hi zoph re nia 3 6 0 m g H al 0, 25 mg−kg 1da y − 1 0 (SANS) + (S A P S) + (SOD le v el s) + (l es s be ha vi ou ra l to xi ci ty and sy m pt oms of ne rv ou s sys te m ) 0 N =5 4 (27 H al + E G b, 27 Hal + pl ac) n. r. 1 2 w k 3 (C ont inue d o n n ex t p a g e)
TA B LE 3 .(C ont in ued ) Stu d y a Stud y P opu latio n D o sage o f Na tur a l Me dic a tio n (Daily) A lso A P? AP Dosage Ef fects o f N atural Med icines b Ad ve rse Effec ts o f Na tu ral Med ic ine s b N ,D es ig n , De sc ri p ti o n o f T reatm en t/ Co n tr o l Gr ou p D ro p o u t Du ra ti on of Stud y (a n d F o llo w-U p , If A ppl ic a b le) N eg a ti ve sx P ositi v e sx C og niti v e sx D ep re ss iv e sx Gen er a l P syc h opa th ol og y Ad ve rse Sid e-Effects A P Zh an g et al. (2 01 1a ), P ati en ts (m ean ag e 44 .4 y) di ag no se d w ith sc hi zo ph re ni a 3 6 0 m g H al 0, 25 mg−kg 1da y − 1 0 (SANS) + (S A P S) + (SOD le v el s) + (l es s be ha vi ou ra l to xi ci ty and sy m pt oms of ne rv ou s sys te m ) n. r. N =8 2 (43H al + E gb , 39 H al + pl ac ) n. r. 1 2 w k Zh an g et al. (2 00 1b , 20 06 ) d In pa tie nts (m ean ag e 44 .6 y) di ag no se d w ith sc hi zo ph re ni a 3 6 0 m g H al 0, 25 mg−kg 1da y − 1 0( S A N S ) + (S A P S ) 0( B P R S ) + (b et te r im m un e func tio n, les s be ha vi our al to xi ci ty and sy m pt oms of ne rv ou s sys te m ) 0 N =1 09 (56H al + E gb, 53 Ha l + pl ac ) 1i n E gb gr , 5i n pl ac gr 12 wk Zh an g et al. (2 01 1a ) M ale in patients (m ean age 45 .3 y) dia gnos ed wi th sc hi zoph re nia 2 4 0 m g Y es 0 (P ANSS ) 0 (P ANSS ) 0 (C P T , S troop) + T D (AIMS) 0 N =1 57 (78A P + Eg b, 79 A P + pla c) 4i n pl ac g r, 1i n E gb g r 12 w k, f. u. +6 m nts Vi t E E lka she f et al. (1 99 0) Ou tpatients (mea n age 56 .6 y) di ag no se d w ith sc hi zo ph re ni a or sch izoa ffecti ve dis or de r 12 00 IU Y es 0 (BP RS ) + E P S (A IM S ) no S A E s; m ild dia rrhea (1) N =1 0, c-o (8 ct; 5 AP + vit E/p lac , 3 AP + pla c/ vit E ) 2, ns pe r gr 2× 4 wk , 2w k w o be fo re S ch m id te ta l. (1 99 1) In pa tie nts and ou tpa tie nt s (m ean age 45 y) w ith sc hi zo ph re ni a, de pr es si on , or sc hizo af fe cti ve ps yc ho ses 200 IU Y es 0 E PA (A IM S ) Ne gl igi ble N =1 9, c-o (1 1 A P + vi t E/p lac , 8 AP + pla c/ vit E ) 2 in eac h gr 2 × 1 4 d ay s Eg an et al . (1 99 2) In pa tie nts and on e out pa tie nt (m ean age 43 .9 y) dia gnos ed wi th sc hi zoph re nia , sc hizo typ al pe rs on ali ty , bip olar disord er , or de pr es si on 16 00 IU Y es +T D (A IM S ) fo r tho se <5 y 0 N =2 1, c-o (1 0 A P + vi t E/p lac , 11 AP + plac /v it E ) 1, ns pe r gr 2 × 6 w k S hr iq uie ta l. (1 99 2) Pa tie nts (18 –70 y) with TD 12 00 IU Y es 0 E PS (A IM S, ESRS) n. r. N =2 7, c-o (1 g r AP + vit E /pl ac , 1 gr AP + plac /v it E ) 02 × 6 w k, 2– 3w k w o in betw ee n Ad ler et al. (1 99 3) In pa tie nts and ou tpa tie nt s (a ge n.r .) w ith TD 16 00 IU Y es +T D (A IM S ) 0 N =2 9( 28 ct ; 16 A P + vit E , 12 A P + pla c) 3; 1 ns per g r; 2o n vi t E 8– 12 wk A kh ta r et al . (1 99 3) In pa tie nts (m ean ag e 54 .8 y) w ith TD 12 00 IU Y es +T D (T D R S ) 0 N =3 2( 17 A P + vit E , 15 AP + plac ) 04 w k Da biri et al. (1 99 4) Ou tpatients (3 0– 70 y) with TD 12 00 IU Y es +T D (A IM S ) D ia rr h ea( in 1 ) N =1 2( 6 A P+ vit E , 6 AP + plac ) 1i n vi t Eg r 1 2 w k La m et al. (1 99 4) In pa tie nts (m ean ag e 61 .8 y) di ag no se d w ith sc hi zo ph re ni a 12 00 IU Y es 0 (BP RS ) 0 TD (AIM S ) n.r . N =1 6, c-o (1 g r AP + vit E /pl ac , 1g r A P+ pla c/ vit E ) 4, ns pe r gr 2× 6 wk , 2w k w o be fore and in betw ee n Lo hr an d Caligiu ri (1 99 6) P ati en ts (m ean ag e 48 ,8 y) w ith sc hi zoph re nia , bip olar disord er , or un ip ol ar di so rd er 16 00 IU Y es 0 (BP RS ) + TD (AIM S ) n.r . N =5 5( 35 ct , 17 A P + vit e, 18 A P + pla c) 20 , ns per gr 2 m o Dore vi tc h et al. (1 99 7a ) P ati en ts (m ean ag e 64 .6 y) di ag no se d w ith sc hi zo ph re ni a or sch izoa ffecti ve di so rder 16 00 IU Y es 0 (BP RS ) 0 TD (AIM S ) 0 N =4 0, c-o (1 g r AP + pla c/ vit E , 1g r A P+ vit E /pl ac ) 2o np la c 2×8 w k, 4w k w o in betw ee n Dore vi tc h et al. (1 99 7b ) P ati en ts (mean age 63 .2 y) di ag nosed w ith sc hi zo ph re ni a 16 00 IU Y es 0T D( A IM S , CPK le vels) n. r. N =1 0, c-o (1 g r AP + vit E /pl ac , 1 gr AP + plac /v it E ) n .r . 2× 8 w k, 4w k w o in betw ee n Ad ler et al. (1 99 9) Pa tie nts (m ean ag e 50 .4 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r 16 00 IU F lu , H al , R is p 0 (BP RS , G A F ) 0 T D (A IM S ), ak at hi si a (B A R S ), EPS (SA S) 0 N =1 58 (7 3 A P+ vit E , 85 AP + plac ) 22 in vi t Eg r, 29 in pl ac g r 1y
S al m as ie ta l. (2 00 9) Pati en ts (1 8– 49 y) wit h schi zophreni a 12 00 IU Olan 0 (insu lin re sistan ce ) n. r. N =3 6( 32 ct , 15 O lan + vit E , 17 O lan + pl ac) 4, ns pe r gr 8 w k 3 M ela to n in S ha m ir et al. (2 00 1) In pat ients (mean age 64 .2 y) di ag no se d wit h schizophrenia 10 mg Y es +T D (A IM S ) 0 N = 24, c-o (22 ct , 10 A P + pla c/ me l, 12 AP + m el/p la c) 2, ns pe r gr 2× 6 wk , 4w k w o in betw ee n 4 6 . O the r sub st an ce s Mu lt iv it a m in s Altma n et al. (1 97 3) In pa tie nts (m ean ag e 72 y) w ith sc hi zoph re nia or or ga ni c brai n sy nd ro me 15 m g B 1 pl us 10 m g B2 pl us 5m g B 6 pl us 50 m g niac inam idep lus 10 m g ca lciu m pa nto the na te pl us 300 mg vi t C Ye s 0( M IB S ) 0 N =1 51 (7 5 A P+ vit, 76 AP + pla c) of wh ich 81 with sc hi zo ph re ni a 6i n vi t g r, 13 in pla c gr 6w k 4 V aug ha n an d Mc C on agh y (1 99 9) Ou tpatients (m ean age 31 y) dia gnos ed wi th sc hi zoph re nia 60 00 IU vi t A pl us 13 45 mg B 1 pl us 3520 m g B 3 pl us 6223 m g B6 pl us 25 mg B12 plus 28 22 mg vi t C pl us 20 4 m g vi t E pl us 5. 2 m g folic ac id Ye s 0 (BS I, BD I) 0 N =2 2( 10 A P + vit E + die t trea tmen t, 9 AP + plac + di et ch allen ge) 1i n pl ac g r, 0i n vit E gr 5m o 4 Hormon es P ran ge (1 97 9) (p roti leri n) F emale inp at ie nts (m ean age 32 .7 y) di ag nosed w ith schizophr eni a 0. 5 m g pro tile ri n or 2m gn ia ci n, bo th on ce in tr av en ou s No + (BP RS ) 0 N =1 2, c-o (6 P ro /nia c, 6n ia c/ P ro ) 02 × 1 5 d ay s 4 Akhon dzadeh et al . (2 0 03) (e st ra d io l) P ati en ts (m ean ag e 28 .0 y) di ag no se d w ith sc hi zo ph re ni a 0. 5 m g H al 0 (P ANSS ) + (P A N S S) + (P A N S S su bsc ale) n. r. N =3 2 (16H al + es tr, 16 Ha l + pl ac ) 08 w k 3 S trou s et al. (2 00 3) (DHE A) In pa tie nts (m ean ag e 37 .4 y) di ag no se d w ith sc hi zo ph re ni a 10 0 m g Y es + (P A N S S , S A NS ) 0 (P A N S S ) + (HA M -D) + (P A N S S sub sc ale) + (HAM -A) n. r. N =3 0 (15A P + DH E A , 15 AP + plac ) 3i np la cg r 6 w k 4 N ac hs ho nie ta l. (2 00 5) (DHE A) In pa tie nts (m ean ag e 40 .8 y) di ag no se d w ith sc hi zo ph re ni a or sch izoa ffecti ve dis or de r 10 0 m g Y es 0 (B P R S ) + pa kin soni sm (SHRS) 0 N =3 4 (18A P + DH E A , 16 AP + plac ) 3i nD H E A gr , 1 in pl ac g r 7d ay s 4 Ritsner et al. (2 00 6) (DHE A) P ati en ts (m ean ag e 36 .4 y) di ag no se d w ith sc hi zo ph re ni a or sch izoa ffecti ve dis or de r 2 0 0 m g Y es + (P ANNS) + (P ANNS) + (s ub sc al es of th e C A N T A B) + (P ANNS subs cale ) 0( Q o L ) 0 T D (A IM S ), EPS (ESRS) 0 N =6 2, c-o (1 g r AP + DH E A /p lac , 1g r A P+ pl ac/DH EA ) 7n sp er g r 2 × 6w k 4 S trou s et al. (2 00 7) (DHE A) In pa tie nts (m ean ag e 34 .0 y) di ag no se d w ith sc hi zo ph re ni a 1 5 0 m g O la n 0 (S A N S ) 0 (n eu tco gniti ve ba tte ry) + ak ath isia (B A R S ), EPS (SA S) N =4 0 (20O la n+ DH E A , 20 O lan + pl ac) 4 in DHEA gr, 5 in pla c gr Ol an K o et al . (200 8) (t es to st er on e) M ale in patients (m ean age 36 .7 y) di ag nosed w ith schizophr eni a 5 m g Y es + (P ANNS) 0 (P ANNS) 0 (C DSS ) 0 (DIE P S S ) 0 N =3 0 (15A P + pl ac , 15 A P + tes ) 2i nt es g r, 2i np la c gr ; + 5 in tes g r at f-u, + 4 in p lac g r at f-u 1× 4 w k, 2 w k f-u 4 K ulkar ni et al. (2 00 8) (e st ra d io l) F emale inp at ie nts an d out pa tie nts (m ean age 33 .6 y) di ag nosed w ith schizophr eni a, schi zoaf fec ti v e d iso rd er , o r schizophr eni for m di so rder 100 μg Y es 0 (P ANSS ) + (P A N S S) + (P ANSS) + (P A N S S su bsc ale) n. r. N =1 02 (56A P + es tr, 46 A P + pla c) 5e st r g r; 10 pla c gr 2 8 da ys 5 Rit sner (201 0) (DHEA an d PR E G ) O u tpa tie nts (m ean age 35 .8 y) di ag nosed w ith schizophr eni a or schi zoaf fec ti v e di so rder 30 or 20 0 m g PR E G or 40 0 m g DHEA Y es 0 fo r all g rou ps (P ANS S) +f or 30 m g/ PREG g r 0f or 20 0m g PREG /4 00 mg DH E A g r (P ANS S) 0f or al lg ro up s (CANT AB) 0f or al lg ro up s (CGI, GAF ) + for 30 mg P R EG/400 mg DHE A g r 0 for 200 mg PR E G g r o n EP S (ES R S ) 0f or al l g ro up so na ka th is ia (B A R S ) 0 N =5 8 (16A P + PREG 30 m g, 10 A P + P R E G 20 0 m g, 16 AP + D HEA 40 0 m g, 16 A P + pla c) 2i n 30m g PREG gr , 4i n 20 0 m g PREG gr , 3i n 40 0 m g DH E A g r, 5i n pl ac gr 8w k 5 (C ont inue d o n n ex t p a g e)
TA B LE 3 .(C ont in ued ) Stu d y a Stud y P opu latio n D o sage o f Na tur a l Me dic a tio n (Daily) A lso A P? AP Dosage Ef fects o f N atural Med icines b Ad ve rse Effec ts o f Na tu ral Med ic ine s b N ,D es ig n , De sc ri p ti o n o f T reatm en t/ Co n tr o l Gr ou p D ro p o u t Du ra ti on of Stud y (a n d F o llo w-U p , If A ppl ic a b le) N eg a ti ve sx P ositi v e sx C og niti v e sx D ep re ss iv e sx Gen er a l P syc h opa th ol og y Ad ve rse Sid e-Effects A P K u lkar n i et al. (2 0 11) (e st ra d io l) M ale pa tie nts (m ean age 32 .0 y) di ag nosed w ith schizophr eni a, schi zoaf fec ti v e d iso rd er , o r schizophr eni for m di so rder 2 m g Y es 0 (P ANSS ) 0 (P ANSS ) + (P ANSS subscal e) 0 N =5 3 (26A P + es tr, 27 A P + pla c) 01 4 d ay s Inosit o l L ev ine et al . (1 9 94) In pa tie nts (m ean ag e 41 .5 y) di ag no se d w ith sc hi zo ph re ni a 12 g Y es 0 (P ANN S ) 0 (P ANNS) n. r. N =1 4, c-o (1 2c t; 7A P+ ino sitol/ plac, 5A P + pla c/ino sitol ) 2, ns pe r gr 2 × 4 w k , no w o G a m m a -h yd ro xy bu ty ra te Sch u lz et al. (1 9 81) P ati en ts (m ean ag e 25 y) di ag no se d with sc hizoph re nia 16 g n .r . 0 (BP RS ) 0 N =7 (a ll pa tien ts pl ac/GH B/ pl ac ) 01 0– 29 da ys L ev y et al. (1 9 83) M ale in p ati ent s (m ean age 43 .6 y) di ag nosed w ith schizophr eni a 12 g F lu 5 m g/ d 0 (BP RS , C G I) n o S A E s; asympt oma tic br adycar di a in 1 N =1 1, c-o (1 g r Flu + GH B/ ch l hy , 1g r F lu +c hl hy /GHB) 1o np la c 2 ×3w k Des-ty r-g a mma-endorph in V er h oe ve n et al . (1 9 79) Pa tie nts (m ean ag e 38 .3 y) with ch ron ic sc hi zoph re nic sc hizo af fe cti ve ps yc ho si s 1 m g Y es + (ps yc ho tic sy m pt oms ra ting scale ) +( co n ta ct , emoti o n al re spons iv en es s) 0 N =6 ,c -o (3 AP + DTGe /plac , 3A P + pl ac/DTGe ) 0 2 × 8 da ys, 6w kf -u A rt em isi n in Di ck er son et al . (2 0 11) Ou tpatients (mea n ag e 47 .3 y) dia gnos ed wi th sc hi zoph re nia or sc hizo af fe cti ve dis or de r 20 0 m g Y es −− − 0 N =6 6 (33A P + ar t., 33 A P ) 9( 7 ina rt . g r, 3i n A Pg r) 12 wk W ang et al . (2 0 14) In pa tie nts and ou tpa tie nt s (m ean age 23 .9 y) dia gnos ed wi th sc hi zoph re nia or sc hi zoph re nif or m dis or de r 80 m g arteme th er Ris 1– 6m g + −− − 0 N =1 00 (50A P + ar te m et he r, 50 A P ) 12 (4 in ar teme th er gr , 4i n A Pg r) 8w k N. B. W h en “Al so AP? ” is ans w ered wi th “ye s,” th en the subj ect s u sed d if fe rent typ es o f A P; wh en 1 A P is m ent ioned , th en all u sed that one. V it amin B 3 can be admi ni st ered in th e for m o f n ia cin, ni coti ni c aci d, ni aci namide, o r n icot in amide. NMD A agoni sts: ful l, endo geno us: g ly cin e, D -ser ine; p ar ti al: D -c ycl o serine (e xo geno us) , D -a la ni ne (e n d o g eno u s) . Gl y cine tr an sp o rt er inhi bi tor (G lyT -1): sarcosine, also cal led N -met h y lg ly ci n e. V it amin B 9 can be admi ni st ered in th e for m o f foli c acid an d m eth y lf olat e. A, ac etaz olam id e; AB A, Alter nati ve B eliefs A sses smen t; A IMS ,Ab no rm al In vo lun ta ry M ov em ent S ca le ;α -L A, al pha -l ip oi d aci d; am ,a yu rv ed ic me di ci ne ;A P, an tip sy ch ot ic s; B ,b rah m yad iy og a; B A RS ,B ar ne s A ka th is ia Rating S cale; BDI, Be ha vi ou r D istur ba nc e In ven tor y; B MI ,b od y m as s index ;B P D ,b or der line pe rs on ali ty dis or de r; Brief P sych ia tri c Ratin g S ca le; B SI, B ri ef S ympto m In ve ntor y; b-t ,b efor e treatm en t; C ANT AB ,C am brid ge Au tom ated N eu rop sy cho lo gi cal Te st Batte ry; Car ,ca rbam aze pin e; C DS S, Calg ar y D ep ress io n S ca le for S ch izo ph ren ia ;C FD ,C om ple x F igu re Dra w in g; CGI, clin ical gl ob al impre ssio n sca le; ch lh y, ch lo ra lh yd rat e; C hl or ,c hl or pr om azi ne; ch ol es te ro l; C loz ,c lo za pin e; c-o, cr os s-ove r; C P K ,s er um cr ea tin e pho sp ho ki na se ;C P R S, C om pr ehe ns iv e P sy ch op at ho lo gic al R ati ng S ca le ;C P T, C o ntin uo us P erfo rm an ce Te st; ct, comp le te d trea tment; d-a, D -alan ine; d-c, D -c yc los er ine ;d -b ,d ou bl e-blind ;dd ,d ai ly do se ;D IE PS S, D ru g-In du ce d Ex tr ap yr am id al S ym pt om s Sc ale ;d -o, dr op ou t; D sp an ; d-s, D -s erine ; DTGe ,d es -tyr -g amm a-en do rp hin ; ECG, el ec tro card io gram; ECT ,e lectro co nv ulsi ve th erap y; E-E, eth yl-eico sap oe nta eon ate; E -EP A ,e th yl-eic osa pe nt ae no ic ac id; Eg b, ex tr ac t of gi ng ko bi lob a; ESR S ,E xtr ap yr ami da l R atin g S ca le; estr ,estra diol; fa, folic acid; FBS ,fastin g blo od sug ar; F lu, F lu ph en az in e; F ol, fol ate; F OLH1, hy dr ol as e 1; f-u ,f ol lo w -up ;GAF ,G lo ba lA ss ess m en to f F un ct io ni ng ;GAS ,g alacto rrh ea ame no rrhe a sy nd ro me; gl yc ,gl ycerin e; gr ,g rou p; H al, H alo pe rido l; HAM -A, H am ilt on An xiety S cale ;HAM -D ,H am ilto n D ep ress io n S cale; Hb, hem og lob in ;Hb A1 c, he mo glo bin A1 c; HDL ,h igh -de ns ity lipo pr otein e; HO D ,Hof fe r-Osmo nd D ia gn ostic ;HOM IR, homeostatic m odel ass essm en to f in sulin res is tan ce ;I M PS, in pa tien tmultid ime nsion al psychi at ric sca le ;i nj, injection ;IU ,i nt er natio nal un it; L am, lamotrig ine; L D L ,lo w -d ensity lipo pro teine; LUNSERS ,Li ver poo lU ni ve rsity Neuro leptic S ide Ef fe ct s R at in g S ca le; M ADRS, Mon tgo mery-Å sb er g D ep ress io n R at in g S ca le; M A T RICS ,M ea sure an d T re at m en tR es ear ch to Im pr ov e C og niti on in S ch iz oph re nia ;MD A ,ma lon di ad eh yd e; m el, m elaton ine; m et, me th yl folate; m ian, mianserin; MIBS ,i npatien tb eh avio ur for m; MMN ,mism atch ne ga tivity ;M MP I, M inn es ot a M ultip hasic P er son ality In ve nto ry; Mo l, m olin do ne; MPQ, multip hasic question na ir e; M T H F R gt, m eth yl en et etr ah yd red uc tase ge no typ e; m W AIS ,M od if ied Chin ese versio n of th e W ec hsle r A du lt In telligen ce S cale ;na ,n ic otina m id e; N A D ,n ico tin am ide ad en in e din ucl eo tid e; ni ac ,n ia ci na m ide ;n ic ,n ic ot inic ac id; N O S IE ,N ur se s O bs er va tion S ca le fo r In pa tie nt Ev al ua tion ;n.r ., not re po rt ed ;N R S ,S im ps on -A ng us Ne uro lo gi cal Ra ting S cal e; ns, no tsp eci fi ed ;n x, sy mp to ms; O lan ,olan zap ine ;ω -3, ome ga -3; PANS S ,P os iti ve an d N eg ati ve S yn dr om S ca le; P h, phe no thiaz ide; pl ac, plac eb o; PO ET ,P erc ep tio n of E m otion s T est; P ro ,p rotirelin ;P R T-BT ,P rob ab ili ty Reaso ni ng T ask –Be ad T as k; P SYRA TS, P sy ch otic S ympto m R at ing S cale s; py r, pyrid ox in e; Que t, quet ia pi ne ;Q oL ,q ua lity of life; R A V L T, R ey Au V erb al L ear ni ng Te st ;R B ANS ,R epe atab le B atter y fo r the As sess men to f Neu rop syc ho lo gi cal S ta tus; R is ,r is pe rid on e; RNRS ,R ut ge rs Nurse 's R at in g S ca le ;RRS ,R oc klan d R atin g S cale ;RS E S E ,Rating S ca le for E xt ra py ramid al S id e E ff ects; S A E ,sp iral after ef fe ct; SAE s, se ri ou s ad ve rse ev ents; SA NS ,S cale fo r th e A ss essm en to f N eg at iv e S ym S A P S ,S cale fo r th e A ss essm en to f P os iti ve S ym pto ms; sar ,s arc os in e; sa rs, sa rsas ap og enin ;S AS ,S imp so n-An gu s S cale ;sc hiz oaf f, sc hizo af fe cti ve ;s ch izo ph r, sch iz op hre nia ;S DS S, so cial dis ability sc ree ning sch ed ule; SFBT ,S eq uin Fo rm Biard T es t; SHRS, S t. Hans Ratin g S ca le; sig (dif), si gn if ic an t(d if feren ce ); S OD ,s up ero xi de di smuta se; S S oc ia lan d O ccu pa tion al F un ction ing As sess men tSc ale; SOP S ,Sc ale of P sy ch osis -ri sk S ympto ms; S S T MS P, S ter nb er g S ho rt Te rm Me mo ry S cann ing P arad ig m; su bs ,s ub je ct s; sx ,s ym pto m s; T ,thia m ine ;T D R S, T ar di ve D ys ke ne si a R atin g S cale ;tes, tes to ste ro ne; th i, thio rida zi ne ;t .i.d ., th ree tim es a da y; T rif, T rifl up er az in e; vit(s), vi ta m in(s ); W ech sler Ad ult Inte lli ge nc e S ca le ; W CS T, W isco ns in C ard S or ting T es t; W IS C , W ec hsle r In tellige nse S ca le fo r C hildre n; wk , w ee k( s); W M S , W ec hsle r M em or y S ca le; w o, w ash ou t; WPRS , W itte nb or n P sychiatric Rating S cale ; WS K Y , W ar m-S upp le me nting K idn ey Y an g; y, yea r( s) ; Zip r, Z ip ra si don e. aClassi fi ed per agent , in o rder of y ear of p u b licat ion. bScoring o f ef fect s: + = p o si ti v e ef fect, − = n eg at iv e ef fect, 0 = n o ef fect . cT w o separat e tri als p ub li shed in one ar ti cl e. dO n e tr ia l, p ub li sh ed in tw o arti cle s. eP aper s no t id enti fied in o rigi nal se arch b u t found in ref erence li sts or ot her w is e.
et al., 2010). Research suggests that oxidative damage (maybe due to defective enzyme systems) may contribute to the course and outcome of schizophrenia (Fendri et al., 2006; Mahadik and Mukherjee, 1996; Mahadik et al., 2001) and is already present in patients with first-episode psychosis (Flatow et al., 2013).
Ascorbic acid (vitamin C), an antioxidant vitamin, plays an im-portant role in protecting free radical-induced damage in the body. It is present in brain tissue and dopamine-dominant areas in higher con-centrations compared with other organs (Harrison and May, 2009). Ginkgo biloba, an extract of the leaves of the ginkgo biloba tree, is also suggested to have antioxidant properties (Maclennan et al., 2002), improving brain circulation at the microvascular level (Kuboto et al., 2001; Sun et al., 2003; Yan et al., 2008) and, thus, improving outcome in psychosis.
Long-term treatment with antipsychotics is associated with a va-riety of movement disorders, including tardive dyskinesia (TD). Both dopamine receptor supersensitivity and oxidative stress-induced neuro-toxicity in the nigrostriatal system are suggested to be involved in its pathogenesis (Kulkarni and Naidu, 2003). The pineal hormone melato-nin is a potent antioxidant and attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus (Shamir et al., 2001). Thus, treatment with antioxidative agents may have a beneficial effect for both treatment of psychotic symptoms and pre-vention of TD. Vitamin E has been suggested for TD because it is a lipid-soluble antioxidant that decreases free radical formation (Herrera and Barbas, 2001).
Risk of Bias Assessment
Two assessors (A.A.B.V. and N.K.V.) independently rated the methodological quality of the eligible RCTs using the Jadad scale (Jadad et al., 1996). Interrater agreement on the Jadad scores before consensus discussion amounted to 0.83. Besides, H.J.R.H. indepen-dently rated a random selection of 17 papers (15%) from the selected RCTs. Interrater agreement of all three assessors was 0.71. Any scoring disagreements between the assessors were resolved through consensus discussion between these three authors. The 110 RCTs with a Jadad score of 3 or higher were included in the current review, categorized into six groups (see the Classification of agents section).
For each of the 110 studies fulfilling the selection criteria, the following assessments were made: which natural agent was used; was this combined with antipsychotics, and if so, which antipsychotics and what dosage; the effect of the natural agent on negative, positive, cognitive, depressive, and general symptoms and on adverse effects of antipsychotics; possible adverse effects of the natural agent; number of participants in the study; control group characteristics; number of dropouts; study duration; and Jadad score. The results are shown in Table 3.
Results
In total, 110 RCTs that matched the inclusion criteria were identi-fied. Detailed effects are given in Table 3. Most of the studies were per-formed in the United States, followed by (in decreasing order) Israel, Canada, Taiwan, China, India, United Kingdom, Australia, Iran, South Africa, Switzerland, the Netherlands, Austria, Ireland, Korea, and Norway.
(i) Omega-3 Fatty Acids
Eleven RCTs on omega-3 were included (Bentsen et al., 2013; Berger et al., 2007; Emsley et al., 2002, 2006, 2008; Fenton et al., 2001; Manteghiy et al., 2008; Peet et al., 2001; Peet and Horrobin, 2002; Toktam et al., 2010; Vaddadi et al., 1989), and one combined omega-3 with vitamins E and C (Bentsen et al., 2013). In studies combining antipsychotics with omega-3 PUFA, one (from five) study on negative symptoms in schizophrenia found some positive ef-fect (in patients using clozapine; Peet and Horrobin, 2002), two (from four) found some positive effect on positive symptoms (Peet et al.,
2001; Peet and Horrobin, 2002; one only in patients using clozapine [Peet and Horrobin, 2002]), one (from two) on cognitive symptoms (Vaddadi et al., 1989), none (from three) on depressive symptoms, and four (from eight) on general psychopathology (Emsley et al., 2002; Peet et al., 2001; Peet and Horrobin, 2002; Vaddadi et al., 1989; one only in patients using clozapine [Peet and Horrobin, 2002]). One (from one) study on omega-3 PUFA without antipsychotics reported a decrease of positive symptoms (Peet et al., 2001). Three (from six) reported less adverse effects of antipsychotics (EPS and/or dyskinesia) (Berger et al., 2007; Emsley et al., 2002; Vaddadi et al., 1989). Two studies reported less use of antipsychotics in the omega-3 PUFA group (Berger et al., 2007; Peet et al., 2001). One study reported an increase in positive symptoms by omega-3 (EPA), but only among those with low levels of red blood cell PUFA. This effect disappeared when EPA was combined with vitamin E and vitamin C (Bentsen et al., 2013). Some nonsevere adverse effects of omega-3 PUFA were reported, such as mild gastrointestinal problems and increased bleeding time.
(ii) Glutamate
Nine RCTs on glycine (Buchanan et al., 2007; Diaz et al., 2005; Evins et al., 2000; Heresco et al., 1996, 2004; Heresco-Levy et al., 1999; Javitt et al., 1994, 2001; Potkin et al., 1999), eight onD-serine (D'Souza et al., 2013; Ermilov et al., 2013; Heresco-Levy et al., 2005; Lane et al., 2005, 2010; Tsai et al., 1998, 1999; Weiser et al., 2012), ten onD-cycloserine (Buchanan et al., 2007; Cain et al., 2014; Duncan et al., 2004; Goff et al., 2005, 2008; Gottlieb et al., 2011; Heresco-Levy et al., 2002; Rosse et al., 1996; Van Berckel et al., 1999; Yurgelun-Todd et al., 2005), one onD-alanine (Tsai et al., 2006), five on sarcosine (Lane et al., 2005, 2006, 2008, 2010; Tsai et al., 2004), and two on NAC (Berk et al., 2008; Lavoie et al., 2008) were included.
Glycine improved negative symptoms when combined with an-tipsychotics in six (from seven) studies (Buchanan et al., 2007; Heresco et al., 1996, 2004; Heresco-Levy et al., 1999; Javitt et al., 1994, 2001), but not when combined with clozapine (two studies) (Potkin et al., 1999; Evins et al., 2000). Positive symptoms improved in one study (Heresco et al., 2004), worsened in another (with clozapine) (Potkin et al., 1999), and did not change in five (from seven) studies (Diaz et al., 2005; Evins et al., 2000; Heresco et al., 1996; Heresco-Levy et al., 1999; Javitt et al., 1994); cognitive improvement was shown in four (Heresco et al., 1996, 2004; Heresco-Levy et al., 1999; Heresco et al., 2004; Javitt et al., 2001) and no change in two (from seven) studies (Buchanan et al., 2007; Evins et al., 2000); depressive symptoms diminished in four (from four) studies (Heresco et al., 1996, 2004; Heresco-Levy et al., 1999; Javitt et al., 2001); and improvement of general psychopathology was shown in three (from eight) studies (Heresco et al., 1996, 2004; Heresco-Levy et al., 1999). No adverse effects of glycine were reported, except some mild gastrointestinal complaints.
D-Serine was shown to improve positive, negative, and cognitive symptoms and general psychopathology in two (from six) studies when added to antipsychotics (Heresco-Levy et al., 2005; Tsai et al., 1998). The three largest studies with the highest Jadad score did not show a sig-nificant effect ofD-serine on any symptom (Lane et al., 2005; Lane et al., 2010; Weiser et al., 2012). In four (from six) studies,D-serine did not improve adverse effects of antipsychotics (Lane et al., 2005, 2010; Tsai et al., 1998, 1999). Insomnia, weight gain, palpitations, and other adverse effects ofD-serine were reported. One study found improvement byD-serine without antipsychotics, but this was signifi-cantly less compared with the improvement in the olanzapine group; D-serine, however, caused less adverse effects (Ermilov et al., 2013).
D-Cycloserine showed an improvement of negative symptoms in three (from nine) studies when added to antipsychotics (Goff et al., 2008; Heresco-Levy et al., 2002; Yurgelun-Todd et al., 2005); some
