Orthomolecular Botanical Treatments -for Schizophrenia

8/13/2019 Orthomolecular Botanical Treatments -for Schizophrenia

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Orthomolecular and Botanical Treatments toHelp Alleviate the Side Effects of AtypicalAntipsychotic DrugsJonathanE.Prousky, N.D., FRSH, Rosalyn Hayman, B.Sc, N.D.

AbstractThe current standard o f care forschizo-phrenicpa tients such as continual med icationwith atypical antipsychotic drugs does moreharm thangood Areviewofthe literaturerevealed that in addition to causing thewellknow n sideeffectsof extrapyramidalsymptoms and tardive dyskinesia sideeffects such ashyperprolactinemia sexualdysfunction weightgain diabetes cardiacarrhythmias andevena worsening of psy-chosis when used long-term) are commonoccurrences.Specific orthomolecularandbotanical treatments mighthelppreventand/orreduce someofthese negativesideeffects. The m osteffectiveapproach is toinstitute all the components of an idealtreatment program as advocated byDrAbram Hoffer This is the onlyapproachthat facilitates genuine recovery am ongchronicsch izophrenic patients.Introduction

The newer atypical class of antipsy-chotic drugs (APDs) are considered amajor advance over the older, typicalAPDs. Like the typicalAPDs,the atypicalonesarejust as efficacious at treating thepositive sym ptoms of the illness, such ashallucinations and delusions, yet claimto have a broader spectrum of efficacyover the older drugs which results infewer side effects.' The first part of thisreport will review the main side effects

focus on orthomolecular and botanicaltreatments that appear to have value interms of prevention and/or reduction ofside effects.Extrapyramidal SymptomsExtrapyramidal symptoms (EPS) area neurological side effect of antipsychoticmedication, involving involuntary move-ments such as tardive dyskinesia (TD),tremors and rigidity (parkinsonism), bodyrestlessness (akasthisia), muscle contrac-tions (acute dystonia), and changing inbreathing and heart rate (neuroleptic ma-lignant syndrome). This latter syndrome ispotentially fatal if not treated and can bea sudden occurrence within the first fewweeks of treatment. It includes musclerigidity, tremors, high fever, labile bloodpressure, cognitive dysfunction, and au-tonomic disturbances.

TD usually occurs with prolongedtreatment with neuroleptic drugs. Thetypical manifestations of TD are lipsmacking, sucking, and facial grimacing.These symptoms often last for years andcan be irreversible.^T is one of the mostfrequently encountered and distressingside effects of antipsychotic treatment,and often requires antiparkinsonian medi-cations. In general, the atypical APDs arelesslikely tocause acuteEPSandT thanthe typical or older class ofdrugs.For ex-ample, quetiapine, a first line atypical an-


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Journal of Orthomolecular Medicine Vol.21,No. 1, 2006

of orofacial dyskinesia in patients previ-ously treated with haloperidol.^ However,when risperidone is used a t higher doses,it has resulted in levels ofEPSsimilar tothe typical APDs.HyperprolactinemiaAntipsychotic drugs, through theirmechanism of dopamine antagonism,cause elevated serum prolactin levels.Elevated prolactin levels have direct andindirect roles in the development of breastcancer, osteoporosis, cardiovasculardisease, and sexual dysfunction.' Morespecifically, sustained hyperprolactinemiainduces hypogonadism, causing estrogendeficiency in women and testosteronedeficiency in men. In women, the mostcommon consequences of elevated pro-lactin levels include amenorrhea, dyspa-reunia (difficult or painful intercourse),galactorrhea, gynecomastia, and impairedmental functioning. In men, the problemswith elevated prolactin levels tend toprimarily affect sexual function and fer-tility.' With the exception of risperidone,hyperprolactinemia is more ofaconcernwith the typicalAPDsthan with the neweratypical ones.

In women on typicalAPDs,the ensu-ing side effects of menstrual irregularitiesrange from 15-91%and galactorrhea from10-50%.Hyperprolactinemia-induced hy-pogonadism leads to low estrogen levelsand possibly a worsening of the psycho-pathology in female patients becauseestrogen is believed to have antipsychoticproperties. The estrogen deficiency alsoleads to symptoms such as vaginal dry-ness during intercourse and loss of li-bido.Long-term, it can cause decreased

then reaching a plateau. Haloperidol at15 mg/day is associated with sustainedhyperprolactinemia.' The atypical APDsare weaker dopamine-type 2 receptor(D2) antagonists than the typical classofdrugs,and thus do not affect prolactinlevels to the samedegree.In three trials ofquetiapine at certain doses, the drug didnot cause a sustained elevation of serumprolactin levels.' Risperidone is an excep-tion am ongst the atypical APDs, causingdose-related increases in prolactin levelssimilar to typical drugs such as haloperi-dol.The increases are seen in both menand women, with the m ean increases be-ing greater in women than in men. Theearly studies on risperidone used the drugin highdoses,but current clinical practiceuses lowerdoses 4mg/day).Itisnot clearwhether the lower doses of atypical APDshave less of an effect on prolactin levels.'The conflicting results in the literaturemay be the result of the following: (1)whether or not tolerance develops to theprolactin-elevating effects of the atypicaldrugs;and (2) whether there's a correla-tion between prolactin concentration andpsychopathology.' Overall, the side effectscaused by hyperprolactinemia, such asgalactorrhea and sexual dysfunction, leadto noncompliance among schizophrenicpatients.'Sexual ysfunctionMost patients on APDs experiencesome sort of sexual dysfunction, whichmay include loss of interest (libido), de-creased arousal (poor vaginal lubricationor erectile dysfunction), and anorgasmia(inability to have an orgasm). Surveyssuggest that as much as 40% of women


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Orthomolecular and Botanical Treatments for Side Effects of Antipsychotic Drugs

nism involves inhibition of dopaminerelease due to dopamine blockage at D2receptors that may impair libido and erec-tion. Another mechanism has to do withblockage of the alpha-adrenergic path-way in the periphery, which may lead topriapism (a painful and sustained penileerection which is a urologic emergency),galactorrhea, amenorrhea, gynecomastiaand vaginal dryness (due to estrogen de-ficiency). Alterations in serotonin, whichparticipates in initiating arousal throughits vasodilatory effects in the periphery,can negatively affect sexual function.Finally, non-specific central nervous sys-tem (CNS) effects, such as sedation, cancause a decrease in the desire for sexualactivity.

As a whole, the primary mechanismof sexual dysfunction induced by thesedrugs is probably the direct dopamineantagonism with some additional indirecteffects due to hyperprolactinemia.' Sexualdysfunctionisan importan t problem withthe typical APDs, and to a lesser extentwith the newer atypical drugs. Nonethe-less, it remains an under-appreciatedproblem.W eight Gain and Diabetes M ellitus DM )

A common side effect of APDs, es-pecially the atypical APDs, is excessiveweight gain. In fact, it is now believed tobe the most prominent long-term sideeffect associated with these newer drugsand should be highly considered whentreatment plans are designed, becauseof the obvious medical consequences ofobesity.'The weight gain may be related toincreased appetite (due to drug interac-

gain(BWG),insulin resistance, increasedappetite and related endocrine changes.'It is hypothesized that clozapine causesweight gain by increasing adipose tis-sue, which leads to insulin insensitivity,glucose intolerance, and when severe,diabetes mellitus (DM). * In one report,58% of patients on clozapine gained atleast 10%over baseline.'' Several cases ofclozapine-induced diabetic ketoacidosishave also been reported.'

One cohort study found tha t pa tientsbeing treated with typicaloratypical PDsare at greater risk of developingDMthanthe general population. The patients inthe risperidone and haloperidol cohortsshowed the greatest risk. Patien ts onolanzapine averaged weight gains of5.4 kg over the first six to eight monthsof treatment and had a 20% increasedrisk of developing DM than patients onrisperidone who averaged weight gainsof 3.9 kg. * Quetiapine has been shownto cause lower levels of weight gain thanother atypicalAPDs.However, the typicalAPD,haloperidol, causes less BWG thanthe o the r drugs.** It also ap pears th atadolescents experience m ore BWG com-pared to other populations when takingatypical APDs.CardiovascularSideEffectsClozapine poses a risk of myocar-ditis, especially during the first monthof therapy. A 2002 advisory by HealthCanada reported an association betweenclozapine use and pericarditis, myo-cardial infarction, pericardial effusion,cardiomyopathy, heart failure, and mitralinsufficiency.'' In addition, antipsychoticdrugs,including some atypicalAPDs,may


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Journal of Orthomolecular Medicine Vol.21,No. 1, 2006

who manufactures the drugs), none of theatypical drugs were found to cause QTelevations that were considered clinicallysignificant.^Implications of Use During Pregnancyand L actationA study involving lactating womentaking clozapine found the level in theirforemilk to be 2 .8 to 4.3 times the level ofclozapine in the maternal plasma, but nostudies have been done to accurately as-sess the direct implication of these levelson the breastfeeding neo nate .Clozapine and olanzapine increasethe risk of significant weight gain, andDM puts the infant at greater risk forperinatal mortality, prematurity, con-genital abnormalities (e.g., neural tubedefects), macrosomia and, as previouslystated, increases the chances of develop-ing DM in the future. Physicians shouldalso be aware that stopping antipsychoticmedication when pregnant or post-par-tum, especially abruptly, could have thepotential consequence of causing a psy-chotic relapse in the patient, which maybe severe and include maternal suicideand infanticide.

Avoidance of phenothiazines are rec-ommended because of their associationwith significant increases in congenitalabnormalities. As well, clozapine, orcombinations of typical APDs, with dos-ages within their upper ranges should beavoided during pregnancy and lactation,until further evidence determines themto be safe.Blood DyscrasiasClozapine has a well known, albeit,

weeks, which makes this drug problematicas it disrupts a patient's quality of life.''Additional Side EffectsPatients on quetiapine are recom-mended to have regular follow-up eyeexaminations every six months, due tospeculation that the drug may be linkedto lens abnormalities such as cataracts. *'''Thyroid function may also be effected byquetiapine, since higher end doses wereshown to cause a 20% decrease in totaland free thyroxine.' This maybe one of thereasons why olanzapine and quetiapineare associated with a fairly high incidenceof drowsiness. Unlike some of the otheratypical APDs, insomnia is a commonadverse effect caused by risperidonetherapy.'' Additionally, risperidone shouldbe used with caution in patien ts also tak-ing indinavir and ritonavir because such acombination can induce reversiblecoma.' *Another atypical APD, clozapine, caninduce dose-dependent seizures.

One of the newer at3'pical drugs onthe market is aripiprazole, which is sup-posed to have fewer side effects com paredto the other atypical APDs. It still hasbeen shown to cause headaches, nausea,vomiting, constipation, dyspepsia, ortho-static hypotension, tachycardia, insomnia,somnolence, and tremors.'^ Table (p.21)summarizes the main side effects causedby selected atypical and typical APDs.Worsening the Long-term OutcomeContinuous use ofAPDshas actuallybeen shov\n to worsen the long-term out-come in schizophrenic patients . Althoughtbese drugs are effective in treating acutepsychotic sym ptoms, theydonot improve


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Orthom olecular an d B otanical Trea tm ent s for Side Effects of An tipsychotic Drugs

Table 1 .Summ ary o fthe main side effects caused by selected atypica l andtypical PDs

A n t i p s y c h o t i cA g e n tR i s p e r i d o n e( a t y p ic a l a g e n t )

C l o z a p i n e( a t y p ic a l a g e n t )

O i a n z a p i n e( a t y p ic a l a g e n t )

Q u e t i a p i n e( a t y p ic a l a g e n t )

A r i p i p r a z o l e( a t y p ic a l a g e n t )

H a l o p e r i d o l( t y p i c a l a g e n t )

E P S T D

D o s e - d e p e n d e n tin c r e a s e s i n E P S .A t h i g h d o s e s ,i n c i d e n c e o f E PS iss i m i la r t o t h a t s e e nw i t h H a l o p e r i d o lD o s e - d e p e n d e n tin c r e a s e s i n E PS

D o s e - d e p e n d a n ti n c r e a s e s i n E P S

L o w in c id e n c e o fEP S a c r o s s a l l d o s e s

L e s s e r e x t e n t

Yes

H y p e r p r ol a c t in e m i aYes





Yes

W e i g h t G a in

Yes

Y e s , a n d in c r e a s e dr i s k o f d e v e l o p i n ga d u l t -o n s e t D M

Y e s , a n d in c r e a s e dr i s k o f d e v e l o p i n ga d u l t -o n s e t D ML e s s e r e x t e n t



S e x u a i






Yes

O t h e r

I n s o m n i a , in c re a s e d Q Ti n t e r v a l , a n d i n te r a c -t io n w i t h i n d i n a v i r a n dr i t o n a v i r

M i n i m a l r is k o f l i f e -t h r e a t e n i n g b l o o d d y s -c ra s ia s ( a g r a n u l o c y t o s i s ) ,c a r d i o v a s c u l a r t o x i c i t y ,d r o w s i n e s s , a n d d o s ed e p e n d e n t s e i z u r e sQ r t h o s t a t i c h y p o t e n s i o na n d d r o w s i n e s s

Q r t h o s t a t i c h y p o t e n s i o na n d l e n s a b n o r m a l i t i e s

G l s y m p t o m s , in s o m n i a ,t r e m o r s , a n d t a c h y c a r d i a

H ig h e r r is k f o r a d u l t -o n s e t D M , e s p e c i a lly w i t hi n c r e a s i n g a g e

tional neuroleptics, which showed that inthe developing world, where patients arekept on the drugs for a short period oftime, patients had exceptionally good socialoutcome compared to the poor long-termoutcome of patientsin the developed world

effects of the drugs. Patients can becomesuper-sensitized to dopamine (thoughtto be the mediator of psychosis), so thatwhen they abruptly stop the drugs, theyhave a higher tendency towards psycho-sis. * This mechanism makes medicated


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also increase the density of D2 recep-tors,making patients m ore vulnerable topsychosis, and probably reduce lifespanwhen used long term. Ironically, modernpsychiatry seems to be prescribing themto an increasing number of patients,including those at risk of developingschizophrenia. The real goal should be tominimize their use and to wean patientsoff of them very slowly.Managingthe SideEffects of Drowsiness,Exhaustion, Eatigue, and SomnolenceAll the atypical APDs cause somecombination of drowsiness, exhaustion,fatigue, and somnolence. One of the bestorthomolecular methods to combat theseside effects is injectable vitaminB 2 (hy-droxocobalamin). Newbold has writtenabout the therapeutic uses of injectablevitamin B12 as an antidote for over-se-dation. In Newbold's report, he recalleda case involving one of his clients, anactress,who wasdealing bootleg Quaalu-des as a source of income. She apparentlytreated her clients with 6000 meg (micro-grams) of injectable hydroxocobalaminwhen they would become over-sedatedfrom these pills and would be unable toleave her premises. Fromgivingthem highdoses of injectable hydroxocobalamin,she was able to reverse their sedationenabling them to leave her apartment. Inthe same report, Newbold also discussedanothercaseinvolvingacomatose patientwith marked symptoms of over-sedationinduced by bootleg Quaaludes and ex-cessive amounts of vodka. This patientalso responded to injectable hydroxo-cobalamin, but required 9000 meg of itin order to regain consciousness and be

tients on atypical APDs with injectablehydroxocobalamin due to symptoms ofover-sedation. I am impressed with thevitamin's ability to perk these patientsup andhelpthem make it through the day.It is not a cure-all, but it does improvequality oflife.The recommended dose tostar t with is 5000 meg once or twice eachweek. Generally patients respond favor-ably within24to48hours after their firstinjection. Instead of feeling excessivelysleepy, many of these patients reportmore energy and an increased alertness.Patientswhodo not respond to the inject-able vitaminB 2should be provided withsupplemental calcium and magnesiumsince these minerals help vitaminB 2gainentrance into the cells.''M anag ing the Side Effects of EPSOther symptoms that are believedto occur less frequently with the atypicalAPDs are the EPS. However, I (Prousky)have seen several patien ts vth some de-gree ofEPSwhile on the atypical APDs,and most of these patients have beenprescribed benztropine mesylate to dealwith them . tJnfortunately, the addition ofbenztropine mesylate merely adds moremental symptoms to patients alreadystruggling with their psychiatric condi-tion (e.g., confusion, disorientation, andmemory impairment).Thebotanical med-icine, ginkgo biloba extract (GBE) mightbe helpful. In a study involving treat-ment resistant schizophrenic patients,the addition of 360 mg per day of GBEwith haloperidol was shown to decreaseEPS and enhance effectiveness of thedrug.'* Even though this study assessedthe combination of GBE with a typical


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effectiveness might also allow patien ts toreduce their dosages and experience fewerside effects from their medications.In addition toG B E , there a r e anumberof nutritional treatm ents tha t would helpreduce and/or prevent EPS that includeascorbic acid, manganese, phosphatidyl-choline, pyridoxine hydrochloride, andvitamin E (d-alpha tocopheryl acetate).Werbach has summ arized various studiesdemonstrating the effectiveness of thesenutrients to reduce and /or eliminate TD

among patients taking typical APDs.^Although none of these nutritional agentsh vebeen subjected t o cliniced trials involv-ing patients on atypical APDs, they prob-ably have a similar spectrum of efficacywhen used in combination with this classof antipsychotic m edications.Table (be-l o w ) lists these orthomolecular agents andtheir corresponding dose ranges.Managing Sexual ysfunctionIn male schizophrenic patients, anumber of viable orthomolecular and/orbotanical options exist that should helpreverse some of the sexual dysfunction as-sociated with the use of atypical APDs.L arginine One of the first agents tobe considered is L-arginine. This aminoacid is abiologic precursor to nitric oxide,whichpl ysan importantrolein endothe-lium-dependent processes.^' In fact, prob-

lems with penile endothelial L-arginineare thought to be responsible for part ofthe pathogenesis of erectile dysfunction(ED). In a small clinical trial involvingmen with E D , 4 0 of the treatm ent groupon 2.8 g of L-arginine daily for two weeksdemonstrated improvements comparedto no improvements among men in theplacebo group.^^ In a larger trial, 50 menwith ED were given 5 g of L-arginine perday or a matching placebo for six weeks.There was a subjective improvementamong 3 1 of the men in the L-argininegroup. '*Another study combined 1.7 g ofL-arginine with increasing doses of pyc-nogenol in a three-month trial involving40 men with E D. All the m en took 1.7 gof L-arginine during the first month, andthen during the second m onthweregiven40 mg of pycnogenol twice daily withthe same dose of L-arginine. During thethird month, tbe dose of the pycnogenolwas increased to 40 mg three times dailywith the same dose of L-arginine. At theend of the second month, 80% reporteda normal erection, and by the end of thethird month this therapeutic responseincreased to 92.5%. Other benefits thatwere noted included a quicker erection inresponse to stimulation, and an increasedduration of erection. inseng Another agent that mightbenefit male schizophrenic patients is

Table 2 . Orthomolecular and botanical agents to reduce and /or eliminate EPSand TD associated w ith atypical APDs.

S u p p l e m e n tA s c o r b i c A c i d R e c o m m e n d e d a i ly o s a g e1 3 0 0 4 0 0 0 m g


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panax ginseng. Tbe active compounds inpanax ginseng, tbe ginsenosides, inducerelaxation of the smooth muscle of tbecorpus cavernosum in rabbitsbyaugment-ing tbe release of nitric oxide.^*'^' Clinicaltrials involving human subjects bave dem-onstrated tbat panax ginseng can improveerectile function and sexual satisfaction.In one trial, 90 patientsv eredivided intotbreegroups:thepanax ginsenggroup,tbeplacebo, and tbe trazodone group.^* Eventbough parameters such as intercoursefrequency, premature ejaculation, andmorning erection after trea tmentweretbesamein alltbreegroups,thepanax ginsenggroup did bave a significant improvementin penile rigidity, girtb, duration of erec-tion, libido, and patient satisfaction. Tbeoverall efficacy of panax ginseng on EDwas60%compared toonly30%among tbeplacebo and trazodone groups.

A more recent randomized, double-blind, placebo-controlled, crossover studyassessed the efficacy of panax ginsengamong 45 men with ED.^' One group ofmen were given 900 mg of panax ginsengthree times daily for eight weeks. Theotber group wasgiven an identical lookingplacebo tbree tim es daily for eigbt weeks.After tbe eigbtweeks,each groupwassub-jected to a two week washout period andthen received crossover treatment withplacebo orpanax ginseng for an additionaleigbt weeks. Tbe men on panax ginsengscored significantly higher on tbe Inter-national Index of Erectile Function (IIEF)compared to men on placebo. The panaxginseng group also bad better penile tiprigidityasmeasuredby adevice called tbeRigiScan, compared to tbe placebo group.The authors of this study were unable to

belping both male and female schizo-phrenic patients suffering from sexualdysfunction. Altbougb the reports onGBE assessed its value in treating sexualdysfunction induced by antidepressantmedications, it might offer some benefitto scbizophrenic patients on atypicalAPDs. The first report of GBE's abilityto improve ED involved male geriatricpatients taking antidepressant medica-tions.^ While these pa tients were takingGBE to improve tbeir memory, many oftbem noticed an improvement with tbeirerections. The dosages used in this trialwere 40-60 mg capsules taken twice daily,and was increased to 120 mg twice daily.The average dose during tbe trial was207 mg/day. Around 76% of the patien tsfound GBE to be effective at restoring allaspects of tbeir sexual response, includ-ing erectile function. The mechanismresponsible forGBE spositive effects uponsexual function had to do with its abilityto augment nitric oxide syntbase (e.g.,increase nitric oxide availability). Thesepositive effects occurred in the presenceof serotonin, which can impede nitricoxide production.^'

Another trial evaluated the effective-ness of GBE for antidepressant-inducedsexual dysfunction.^^ Twenty-four pa-tients participated in the trial, with anequal num ber of men and women. Therewas a significant improvement in sexualresponse after three and six weeks ofuse.However, the data was inconclusivesince the therapeutic response to GBEwas so variable among the patients. Ina smaller trial involving botb male andfemale patients, GBE was not successfulat helping any of the nine male patients,


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160 mg for the next two weeks, and 240m g for the rem aining fourweeksofth e trial.All participants were given a questionnairebefore taking either GBE or placebo, andafter the second, forth, and eighth weeks.Unfortunately, no statistical sigrdficance wasachieved for patients on GBE compared tothose on placebo. Nonetheless, GBE mightbe helpfiil. It should be prescribed to maleand female schizophrenic patien ts sufferingfrom sexual dysftinction induced by theatypical APDs. Table 3, (below) lists theorthomolecular and botanical agents thatm ight reduc e the sexual dysfunction associ-ated with atypical APDs.Managing yperprolactinemiaThe most well known botanical agentthat lowers prolactin levels is vitex agnuscastus. In a review of i t s prolactin-reducingeffects. Brown reported: (1) that vitex invitro inhibited the basal and the thyrotro-pin-releasing hormone (TRH) stimulationof prolactin levels; and (2) that it containsconstituen ts tha t directly bind to the dopa-mine receptors of the anterior pituitaiy.^^For these reasons, it is inadvisable for anyschizophrenic patient currently taking anyof the atypical APDs to concomitantly usevitex as a means to lower prolactin levels.Atypical PDs a r e dopam ine-receptor block-ing agents, and taking vitex would reducetheir effectiveness.

The or thomolecular agent , gamma-am inob utyric acid (GABA), should also be

avoided. GABA is an inhibitory neu rotran s-m itter with anxiolytic pro perties similar toclonazepam and other benzodiazepines.^Like vitex, GABA has the ability to aug-ment dopamine release and reduce pro-lactin secretion. G AB A s exact biochemicalmechanisms are not well understood, buts tudies using animal models have beenhelpful in elucidating some of them. Inone in vitro study, the GABA (B) recepto ragonist, baclofen, was shown to inhibit th ebasal and thyrotropic releasing hormone-stimulated prolactin secretion in anteriorpituita ry cells. In anoth er rat experim ent,it was concluded t ha t endogen ous GABA.by acting through GABA (A) receptors,influences the basal and diurnal changesof tuberoinfundibular dopam inergic neu-ronal activity, and consequently prolactinsecretion .^ Since ther e areG B receptors(A and B types) located in the ante riorpituitary, orally adm inistered GABA migh tstimulate these pituitary receptors caus-ing a release of dopamine and a drop inprolactin secretion. Although it is unclearif orally adm iniste redG B can effectivelygain entran ce into the C N S th e use of thisagent should b e avoided due to its poten tialeffects upon dopamine, and its potentialantagonistic effects upon atypical APDs.At present, the authors of this report areunaware of any or thomolecular and/orbotanical agents that can lower prolactinlevels witho ut possibly comp rom ising theeffectiveness of the atypical APDs.

Table 3 . Ortho m olecular an d botanical agents to reduce and/o r el imin atesexual dysfunction associated with atypical APDs


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Managing Weight ainBesides the well known lifestylemeasures that are time-tested in termsof losing weight (e.g., diet and exercise),supplementation witb green tea extractsbould help to control some of the weightgain produced by tbe atypical APDs. Inone human trial involving ten bealtbymen, tbe administration of green teaextract containing 50 mg of caffeine and90 mg of epigallocatechin gallate (EGCG)given three times daily with meals pro-duced statistically significant results.^'Specifically, green tea extract increasedthe 24-hour energy expenditure, reducedthe 24-bour respiratory quotient, andincreased the 24-hour urinary excretionof norepinephrine(NE).Tbe investigatorsconcluded that green tea extract, apartfrom caffeine's thermogenic properties,controlled body composition through itssympathetic activation of tbermogenesis,fat oxidation, or from a combination ofthese two factors.

In anotber study, tbe catecbin-poly-pbenols and caffeine found in green teaextract stimulate tbermogenesis by S)rm-patbetically releasing norepinepbrine.Tbe catecbin-polypbenols from green teaextract increases norepinepbrine via tbeirinhibition of catecbol-0-metbyl-transfer-ase (the enzyme tbat degrades NE), andtbe caffeine content inhibits transcel-lular phosphodiesterases (enzymes tbatbreakdown NE-induced cyclic adenosinemonophospbate). Tbe possible net effectsare sympathetic stimulation of tbermo-genesis and improved weigbt control. Tbebeneficial effects of green tea ex tract bavebeen more formally studied in an opentrial of moderately obese patients. *' An

composition by inbibition of gastric andpancreatic lipases and from tbe stimula-tion of tbermogenesis.Tbese studies demonstrate that greentea extract can have a favorable effectupon body composition. However, tbeuse of green tea extract also increasesthe production of NE and sbould be usedwitb caution in all scbizophrenic patients.Tbeoxidized derivative of norepinepbrine,noradrenocbrome, l ikely contributesto tbe psycbosis of scbizopbrenia. Any

increase in norepinepbrine, therefore,could be detrimental, fo offset tbis prob-lem, make sure tbat green tea extract isgiven with a complement of antioxidants.Caffeine-free green tea extracts wouldproduce less NE since it would not bavetbe same type of S)mipathetic stim ulationwhen compared to extracts containingcaffeine. The optimal dose of green teaextract appears to be 270 mg daily that isstandardized to25%catechins (expressedas EGCG).Manag ing DiabetesPatients on atypical APDs can devel-op drug-induced glucose intolerance andbave a syndrome tbat mimics adult-onsetdiabetes. In terms of diabetes control andprevention, tbe m ost important ortbomo-lecular agent appears tobechromium. Formanyyears,chromium was tbougbt to beinvolved in the glucose-tolerance factor(GTF) molecule tbat presumably increasesinsulin sensitivity. Tbe composition ofGTF, as isolated from yeast, is made ofcbromicion,nicotinicacid and the aminoacids glycine, glutamic acid, and cyste-ine. * However, GTF of anyt rpebas nevebeen found in human tissues. More re-


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sues (e.g., liver, kidney, spleen, intestine,testicles, and brain). This oligopeptide isalso comprised ofthe amino acids glycine,cysteine, glutamic acid, aspartic acid, andhas a multinuclear chromic assembly inwhich the chromic centers are bridgedby the anionic ligands, oxide and/or hy-droxide.''^ This LMWCr compoundispartof an insulin amplification system thatregulates glucose homeostasis through acomplex series of biochemical reactionsoccurring at the insulin receptor.' ''^ In astudy involving 185 adult-onset diabeticpatien ts, there were significant decreasesin the concentration of fasting and two-hour glucose levels, insulin, hemoglobinAIC.and total cholesterol among patientssupplem ented with 1000 meg of chromi-um picolinate compared to those on 200meg of chrom ium picolinate or placebo.Thus, chromium as part of the LMWCr.should have the abilitytoimprove glucosetolerance and increase insulin sensitiv-ity in schizophrenic patients with poorglucose control.

In terms of toxicity, Lamson and Pla-za have summarized the chromium litera-ture,and have evaluated its mechanismsof action and exceptional safety profile.According to these investigators, thereis no dem onstration of general chromiumtoxicity in animals at a dose that wouldextrapolate to humans as1 5 mgdaily. *'One of these investigators has even used3000-4000megof chromium as nicotinategiven twice daily to adult-onset diabeticpatients for months to years resulting intremendous reductions of glucose andlipid levels w ithou t any increases in bloodurea nitrogen, liver enzymes, or otherlaboratory abnormalities. It is interesting

that tbe glucose intolerance resultingfrom atypical APDs disrupts chromiumbomeostasis and creates an increasedmetabolic need that can be met onlythrough high-dose supplementation. Ican recall one patient who had positivebodycompositionchanges,suchasweigbtloss, following a few months of taking3000 meg of cbromium from yeast eachday. Altbougb fasting glucose measure-ments were not done prior to and afterthe cbromium intervention, the bodycomposition cbanges in tbis one patientwere probably a reflection of improvedglucose bomeostasis.Tbedose ranges tbatare likely of value among scbizopbrenicpatients on atypical APDs are 1000-4000meg of cbromium given twice daily.Managing Cardiovascular Side EffectsTbe most worrisome cardiovascularside effects are tbe cardiac arrbytbmiastbat in rare cases can lead to unexplaineddeatb. Tbe best way to manage and/orprevent cardiac arrbytbmias is tbrougbdaily supplementation witb fisb oil. Ina randomized, double-blind, placebo-controlled trial, 65 patients witb cardiacarrbytbmias (witbout coronary beart dis-ease or beart failure) were followed forsix montbs, and were divided into twogroups. ** One group was given 3 g dailyof encapsulated fisb oil (equivalent to 1g daily of omega-3 PUFA), wbereas tbeotber group was given 3 g daily of oliveoil as placebo. In tbe fisb oil group tberewere considerable lipid-modifying ben-efits tbat included a decrease of serumtriglycerides, total cbolesterol, low-den-sity lipoprotein cbolesterol. plasma freefatty acids, and tbromboxane B2. and


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Journal of Ortbomolecular Medicine Vol. 2 1 . No. 1. 2006

lets).Unlike tbe fisb oilgroup,no positivecbanges occurred in tbe placebo group.Tbe results of tbis study demonstratedtbat fisb oil supplementation bas anti-arrbytbmic effects, and can reduce tbeincidence of fatal myocardial infarctionand sudden cardiacdeatb.For tbe reasonscited in this study, and from tbe conclu-sions of otber investigators, *'' its seemsprudent tbat all scbizopbrenic patientstaking atypical APDs are supplementedwitb fisb oils due to tbeir anti-arrbytb-mic and lipid-modifying effects. In termsof tbe optimum dosage, scbizopbrenicpatients sbould consume a daily amountof fisb oil tbat is recommended for pa-tients witb and witbout coronary beartdisease (CHD). For cardioprotection, tbedaily dose sbould con tain 450-1000 m g o feicosapentaenoic acid (EPA) and docosa-bexaenoic acidCase ReportTbe following case report is an excel-lent example of tbe effectiveness of tbeortbomolecular and botanical approach.T b e patient w a s eventually bleto discon-tinue m ost of h i s mainstream treatments(except for risperidone), and significantlyrecover from his diagnosis of schizoaffec-tive disorder.The patient, a 24-year-old Hispanicmale, first presented to Dr. Prousky's pri-vate naturopatbic practice on November13,2004, for chief complaints ofscbizoaf

fective disorder and obesity. H e describeda history of being unwell emotionally fromthe age of 15 onwards. His symptomsbecame more severe at the age of 16wben be started bearing messages frombillboards, would spend countless bourssurfing tbe Internet, was emotionallyveryBat, had a belief tbat 100% of tbe biblewas true, and that tbe devil was forcinghim to do things. He would read exces-sively and did report some occasionalthougbts of violence. D u e to bismoods,beparticipated in a hospital-based programfor depression tha t belped very much. Hispast medical history did include a suicideattem pt at the age of 2 1 for wbieh he washospitalized and released shortlythereafter. Review of systems illuminated otherproblems tba t consisted of glaucoma, mildmusculoskeletal complaints, obesity, andshortness of breath . H is weight w a s about200 pounds in the year2000.Since beingprescribed risperidone in 2 0 0 1 bis weigbtincreased to 2 6 0 pounds.His current pre-scription medications were risperidone (3mg daily), olanzapine (20 mg daily), andbupropion bydrochloride (150 mg daily).T h e patient's family bistory revealed somegenetic predisposition to schizophrenia,as his paternal grandmother was diag-nosed with tbis disorder at 60 years old.On physical examination, the patientwas well nourished, clinically obese, hadhigh to normal blood pressure, and mildtacbycardia. All of his main systems were

Table 4 . Patient's First Set of HOD Results.H O D T e s t I t e m s D e c e m b e r 2 4 R e s u lt s


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Ortbomolecular and Botanical Treatments for Side Effects of Antipsycbotic Drugs

within normal limits. He was prescribedvitamin Bs (250 mg daily), niacinamide(1000 mg three times daily), vitamin C(1000 mg tbree times daily), cbromium(1000 meg tbree times daily), liquid fisboil 1teaspoon twicedaily)providing closeto 2 gof EPA, zinc (50 mgdaily),and wastold to discontinue all dairy and milkproducts. Regular use of dairy and milkproducts canbeassociatedwitbpsychosisand depression.^^On December 13. 2004, tbe patientreturned for a follow-up. He reported anincreased sense of alertness and vigorfrom tbe treatments. He also describedsymptoms of social anxiety wbere hewould feel scared to talk to people, andwould even avoid teachersanciclassmateswhile completing his auto mechanic pro-gram. He did have some depression sincetbe last visit, and experienced suicidalideation on tbree separate occasions sincetbe initial visit. His vitals were withinnormal limits. The patient was giventhe Beck Anxiety Inventory (BAI) andtbe Beck Depression Inventory (BDI) tofill-out. His BAI score was 33, indicatingmoderate anxiety. His BDI score was 26,indicating moderate depression. Labora-tory tests showed a normal CBC, normalfasting plasma glucose, and an abnorm allipid profile shovwng the patient to be atan above averagerisk for coronary beartdisease. Tbe patient was switcbed fromthe niacinamide to niacin at a dose of1500 mg tbree times daily to help controlbispsychiatric symptoms and to favorablyimpact b is lipid profile.Hewas also givenL-glycine for bis symptoms ofpanic,at adose of 2000 mg sublingually as needed.An intramuscular injection of vitaminB121500 meg) was alsoprovided.Thepatient

the greater the probability of tha t patien tbaving schizophrenia. For a patient witba pre-established diagnosis, theHODtestcan also be used to evaluate tbe severityofmental disturbances and assessapatient'sresponse to treatment. In this patient'scase, his total score did indicate tbatbe was symptomatic. If his total scoreswere to decline over time, it would be anindication of improvement.About six weeks later,onJanuary 26,2005,tbe patien t returned for anotber ap-pointment. He felt that he was no longersymptomatic in terms of his diagnosisof scbizoaffective disorder. The niacincaused the patient tovomit,sohe reducedthe dose to 1000 mg three times daily. Hedid not like the taste of L-glycine so henever really tried tbe treatment. He didfeel tbat bis anxiety bad improved about10%. The patient was given another in-tramuscular injection, but tbe dose wasdifferentasit now contained folic acid (0.5mL or 2.5 mg) and bad a greater concen-tration of vitaminB12 1 mLor 5000 m eg)He was asked to retry the L-glycine andreturn in another 5 to 6 weeks.

On March 7, 2005, tbe patient feltthat bis diagnosis was better describedas social anxiety disorder with somesymptoms of schizoaffective disorder.He did not try tbe L-glycine as be wasinstructed to do. In terms of bis anxiety,he felt about 20-30% better tban tbe lastvisit.He wasgiven another intramuscularinjection of folic acid 2.5 mg)and vitaminB12(5000 meg).The patient returned for ano ther ap-pointm ent on April20,2005.He had seena new psychiatristwhorecommended tba tthe patien t complete a series of cognitive


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Journal of Orthom olecular Medicine Vol. 2 1 No. 1, 2006

psychiatrist also instructed the patientto continue w^ith risperidone (4 mg atbedtime), and bupropion hydrochloride(150 mg daily). The patient did report abetter sense of well being, even though hefelt more depressed during the previousweek. His only problemv rasfear. He wasunable to look at people when riding thesubway because of the way people lookedback at him. He also thought that peoplewere judging him. For his anxiety, thepatient was prescribed L-taurine at adose of 1500 mg twice daily to be takenaway from food. He was also prescribedginkgo biloba extract (180 mg daily) tohelp with depression, the side effects ofrisperidone, and for erectile dysfunction.Another intramuscular injection of folicacid (2.5 mg) and vitamin B12 (5000 meg)was given to the patient.

The patient had one more follow-upon June 27,2005.He reduced the risperi-done to 2 mg daily on his own. He alsodiscontinued the citalopram and bupro-pion hydrochloride. He did not feel worsethan before and, in fact, indicated that hewas more alert and required less sleep.He did not complain of any vnthdrawalsymptoms from discontinuing the medi-cations. His social anxiety seemed muchimproved. H e was able to cover for his fa-ther a s a courier and interact with people.This would not have been possible just afew months previously. The patient justcompleted his auto mechanic program,

and was excited about going to college inthe fall for accounting. He also remarkedthat h is paranoid thoughtsweregone,andwere much better since stopping the twomedications. The patient was instructedto stay on the orthomolecular and bo-tanical treatments. He was also advisedto continue avoiding all milk and dairyproducts. Iassured him tha t as long as heremained consistent with the program, hehad very little chance of a relapse.I received the patient's final set ofHOD results o n une30,2005.A s evident,the patient's scores dramatically improveddemonstrating the effectiveness of theorthomolecular and botanical approach.(See Table 5, below).DiscussionThe goals of this reportwereto reviewthe known side effects of the atypicalAPDs, and clarify some of the best ortho-molecular and botanical strategies thatmight have value in terms of side effectprevention and/or reduction. Even withthis knowledge, schizophrenic patientsfind themselves in an unfortunate pre-dicament. Should they stay on the atypi-cal APDs and suffer extreme metabolicconsequences despite using adjunctiveorthomolecular and botanical treatments?Hoffer has written about the tranquilizerpsychosis, and how the atypical APDsmake chronic schizophrenic patientssick. In tha t same report, he mentions

Table 5 .Patient's final set of H O D resultsH O D T e s t I t e m s J u n e 2 5 R e s u l ts


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how these drugs dam age the brain anddecrease the odds these patients can everrecover. Even with adjunctive ortho m o-lecular and botanical treatments, it is ex-tremely difficult for schizophrenic patientsto fully recover or considerably improvewhUe remaining on atypical APDs.

Another option is for schizophrenicpatients to go off of their atypical APDsand suffer the consequences of havingterrible vwthdrawal symptoms and a re-currence of their psychoses. This choiceis also inadequate. We propose a thirdand mo re reasonable solution, wh ich is tovery slowly (over months and sometimesyears) withdraw from the atypical APDsand include the components of an idealt rea tment program. The components ofsuch an ideal treatment, as reported byHoffer, include: (1) shelter; (2) decency,understanding, support, safety, and pri-vacy; (3) psychiatric treatment; and (4)orthomolecular treatment.^' All of thesecom pon ents are equally imp ortant . M uchof the success of this ideal tre atm en t pro -gram depends on the skill of the treatingclinician and the com pliance and p atienceof the patien t . Orthomolecular interven-tions do no t wo rk imm ediately, and ma nym on ths mig ht go by before therap eutic ef-fects are noticed. W e do recom me nd tha tdu ring t he lengthy proc ess of recovery, cli-nicians utilize m any of the orthomo lecularand botanical approaches to minim ize thedam agin g me tabolic effects of these dru gs.Pat ients need to know that they cannotbegin the process of drug withdraw al untilthey begin to feel better. Once this hap-pens, the atypical APD can be slowly re-duced over many m on ths an d even years.If th e dru g is w ithd raw n too rapidly, very

The atypical APDs cause numerousside effects such as EPS, hyperprolac-tinem ia, weight gain, diabetes, fatigue, andcardiac arrhythmias. Some of these sideeffects m ight be reduc ed an d/ or preven tedby us ing specif ic or tho m ole cu lar andbotanical treatments. Controlled clinicaltrials are needed to properly evaluate th eef fec t iveness tha t or thomolecular andbotanica l agents have upon mit iga t ingth e side effects of atypical APD s. At pre s-ent, Hoffer's ideal tre atm en t plan app earsto be the only effective approach thatenables chronic schizophrenic pa t ientsthe opportunity to fully recover withoutmetabol ic dys func t ion and long- te rmbrain damage.Ac knowle dge m e n t sWrit ten consent was obtained fromthe patient for publication of this report.Special than ks goes to M rs. Erynn M arcusfor her editing and review of this report.References1. TandonR Halbreich U: he secondgeneratio'atypical' antipsychotics: similar improved effi-cacy bu t different neuroendoc rine side effects.Psychoneuroendocrinology 2003;28:1-7.2. Carvalho RC, Silva RH, Abilio PN, et al: An-tidyskinetic effects of risperidone on animal

models of tardive dyskinesia in mice. BrainRes Bull 2003;60:115-124.3. SchulzSC,ThomsonR Brecher M: Th e efficacyof quetiapine vs baloperidol and placebo: ameta-analytic study of efficacy.Schizophr Res2003;62(1-2): 1-12.4. LalondeP:Evaluating Antipsycfiotic Medica-tions: P redic tors of Clinical Effectiveness. an}Psychiatry 2003;48(suppl 1):3S-12S.5. Halbreicb U, Kinon BJ, Gilmore JA, et al: El-evated prolactin in patients with schizophre-nia: mechanisms and related adverse effects.Psychoneuroendocrinology 2003; 28:53-67.


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chotic treatment. Psychoneuroendocrinology2003; 28:69-82.9. Baptista T, Kin NMKN, Beaulieu S, de BaptistaEA: Obesity and related metabolic abnormali-ties during antipsychotic drug administration:mechanisms, management and research perspec-tives.Pharmacopsychiatry 2002;35:205-219.

10.Avram AM, PatelV,TaylorHC,etal:Euglyce-micclamp studyinclozapine-induced diabeticksto ciAosis.AnnPharmacother,2001;35 11):1381-1387.11.BuseJB,Cavazzoni P, Hornbuckle K, et al: Aretrospective co hort study of diabete s m ellitusand antipsychotic treatment in the UnitedStates./C//nEpidemiol,2003;56:164-170.12.Taylor DM: Apripiprazole: a review ofitsphar-macology and clinicaluse.Int] ClinPract,2003;57 1):49-54.13.Pa tton SW, Misri S, Corral MR, et al: An ti-psychotic medication during pregnancy andlactation in wom en w ith schizophrenia: evalu-ating the risks.C an ]Psychiatry 2002;47 10):959-965.14.JoverF,Caud radoJM , Andreu L, Merino J: Re-versible coma causedbyrisperidone-ritonavirinteraction.ClinNeuropharmacol2002;25 5):251-253.15.Lerner V: High dose olanzapine for tre atm ent-refractory schizophre nia.ClinNeuropharma-col,2003;26 2):58-61.16. Wbitaker R: The case against antipsychoticdrugs: a 50-year record of doing more harmthan good.Med Hypotheses 2004;62:5-13.17.Newbold HL: Vitam in B12b as an antid ote forover-sedation.Med Hypotheses 1989;30:1-3.

18.ZhangXT,ZhouDF,Zhang PY, etal: double-blind, placebo-controlled trial of extract ofGinkgo biloba added to haloperidol in treat-ment-resistant patients with schizophrenia./ClinPsychiatry 2001;62 11): 878-88 3.19. As a complementary agent, GBE likely hasother positive effects. It bas antioxidantproperties and should help to suppress theproduction of adrenochrom e an d/or expediteits removal from the circulation. GBE alsoincreases blood flow to the central nervoussystem and sho uld m itigate some of the cere-bral cortex atrophy tha tisassociated witb the

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tile dysfunction with pycnogenol and L-argi-nine./Sex M anta/Ther,2003; 29:207-213.26.Chen X, Lee TJ: Gin senos ides-indu ce nitricoxide-mediated relaxation of the rabbit cor-pus cavernosum. Br JPharmacol,1995; 115:15-18.27.ChoiYD,Rha KH, ChoiHK:In vitro andinvivoexperimental effect of Korean red ginseng onerection./Urol,1999; 162:1508-1511.28.ChoiHK Seong D H, Rha KH: C linical efficacyof Korean red ginseng for erectile dysfunction.Int] Impot Res 1995;7:181-186.29.HongB,JiYH, Ho ngJH, etal:A dou ble-blindcrossover study evaluating the efficacy ofKorean red ginseng in patients with erectiledysfunction:apreliminary repo rt./Urol,2002168:2070-2073.30.Cohen AJ, BartlikB:Ginkgo biloba for antide-pressant-induced sexual dysfunction./Marita/Ther, 1998;24:139-143.31. Marcocci L, Maguire JJ, Droy-Lefaix MT, etal: The nitric oxide-scavenging propertiesof Ginkgo biloba extract EGb 761.Biochem iophysR es Commun 1994;201:748-755.32.WheatleyD:Ginkgo biloba in the treatm ent ofsexual dysfunction due to antidepressan t drugs.HumanPsychopharmacol1999;14:512-513.33 .Ashton AK, AhrensK Gupta S, etal:A ntidepressant-induced sexual dysfunction and Ginkgoh^AohSi.Am JPsychiatry 2000; 157:836-837.34.Kang BJ,LeeSJ, KimMD,etal: placebo-controlled, double-blind trial of Ginkgo biloba forantidepressant-induced sexual dysfunction.HumanPsychopharmacol,2002;17:279-284


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cells. Mechanism of action coupled to endo-crine effects, Neuroendocrinoiogy 2001; 73:334-343.38.Lee TY, Pan JT: Involvement of central GAB-Aergic neurons in basal and diurnal changesof tuberoinfundibular dopam inergic neuronalactivity and pro lactin sec retion.LifeSci 2001;68 ;1965-1975.39.D ulloo AG, Duret C RohrerD, et al: Efficacy ofa green tea extract rich in catechin polyphe-nols and caffeine in increasing 24-h energyexpenditure and fat oxidation in huma ns.AmJCiinNutr 1999; 70:1040-1045.40.Dulloo AG, Seydoux J, Girardier L, et al; Greentea and thermogenesis: interactions betweencatechin-polyphenols, caffeine and sympa-thetic activity,IntJObesRelatMetabDisord2000;24: 252-258,

41. Chantre P , Lairon D: Recent findings of greentea extract AR25 (Exolise) and its activityfor the treatment of obesity. Phytomedicine2002;9:3-8,42. Toepfer EW, Mertz W, Polansky MM, et al:Preparation of chromium-containing mate-rial of glucose tolerance factor activity fromBrewer s yeast extr acts and by synthesis, /AgricFoodChem 1977;25; 162-166,43 .Vincent JB: Quest for the molecular mecha-nism of chromium action and its relationshipto diabetes,NutrRev 2000;58; 67-72.44 .Davis CM, Vincen t JB; Chromium in carbohy-drate and lipidmetabolism./5(o//orgC/zem,1997;2; 675-679.45. Vincent JB; M echanisms of chromium action;low-molecular-weight , chromium-bindingsubstance./i4m CollNutr 1999;18; 6-12.46 .An derso n RA, Cheng N , Bryden NE, et al;Elevated intakes of supplemental chromiumimprove glucose and insulin variables in indi-viduals with type II diabetes.D iabetes 1997;46;1786-1791.47 .Lam son DW , Plaza SM; The safety and efficacyof high-dose chrom ium, Altern MedRev 2002;7; 218-235,48 .Singer P , W irth M; Can n-3 PUFA reduce car-diac arrhythmias? Results of a clinical trial.Prostaglandins Leukot Essent Fatty Acids2004;71; 153-159.49 .Xiao YF, Ke Q, Chen Y, et al; Inhibito ry effect

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Orthomolecular Botanical Treatments -for Schizophrenia