Ortho and Botanical Treatments to Alleviate Side Effects of Atypical Antipshy Drugs

7/27/2019 Ortho and Botanical Treatments to Alleviate Side Effects of Atypical Antipshy Drugs

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

o oroacial dyskinesia in patients previ-ously treated with haloperidol.2 However,when risperidone is used at higher doses,

it has resulted in levels o EPS similar tothe typical APDs.4

HyperprolactinemiaAntipsychotic drugs, through their

mechanism o dopamine antagonism,cause elevated serum prolactin levels.Elevated prolactin levels have direct andindirect roles in the development o breastcancer, osteoporosis, cardiovascular

disease, and sexual dysunction.5 Morespecically, sustained hyperprolactinemiainduces hypogonadism, causing estrogendeiciency in women and testosteronedeciency in men. In women, the mostcommon consequences o elevated pro-lactin levels include amenorrhea, dyspa-reunia (dicult or painul intercourse),galactorrhea, gynecomastia, and impaired

mental unctioning. In men, the problemswith elevated prolactin levels tend toprimarily aect sexual unction and er-tility.6 With the exception o risperidone,hyperprolactinemia is more o a concernwith the typical APDs than with the neweratypical ones.

In women on typical APDs, the ensu-ing side eects o menstrual irregularitiesrange rom 15-91% and galactorrhea rom

10-50%. Hyperprolactinemia-induced hy-pogonadism leads to low estrogen levelsand possibly a worsening o the psycho-pathology in emale patients becauseestrogen is believed to have antipsychoticproperties. The estrogen deciency alsoleads to symptoms such as vaginal dry-ness during intercourse and loss o li-bido. Long-term, it can cause decreased

bone mineral density and osteoporosis.Compared to healthy men, male schizo-phrenics on conventional APDs reportgalactorrhea.6

Haloperidol can raise serum prolactinlevels as early as 72 hours ater initiatingtreatment, the rise continuing or 6-9 days

then reaching a plateau. Haloperidol at15 mg/day is associated with sustainedhyperprolactinemia.6 The atypical APDs

are weaker dopamine-type 2 receptor(D2) antagonists than the typical classo drugs, and thus do not aect prolactinlevels to the same degree. In three trials oquetiapine at certain doses, the drug didnot cause a sustained elevation o serumprolactin levels.7 Risperidone is an excep-tion amongst 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 mean increases be-ing greater in women than in men. Theearly studies on risperidone used the drugin high doses, but current clinical practiceuses lower doses (4 mg/day). It is not clearwhether the lower doses o atypical APDshave less o an eect on prolactin levels.6

The conficting results in the literature

may be the result o the ollowing: (1)whether or not tolerance develops to theprolactin-elevating eects o the atypicaldrugs; and (2) whether theres a correla-tion between prolactin concentration andpsychopathology.6 Overall, the side eectscaused by hyperprolactinemia, such asgalactorrhea and sexual dysunction, leadto noncompliance among schizophrenicpatients.6

Sexual DysfunctionMost patients on APDs experience

some sort o sexual dysunction, whichmay include loss o interest (libido), de-creased arousal (poor vaginal lubricationor erectile dysunction), and anorgasmia(inability to have an orgasm). Surveyssuggest that as much as 40% o women

and 60% o men on typical APDs reportthese symptoms.8 Because o its depress-ing eects on quality o lie, patients ratesexual dysunction as the most distressingside eects o drug therapy.

There are several ways by which thesedrugs aect sexual unction. One mecha-


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Orthomolecular and Botanical Treatments or Side Eects o Antipsychotic Drugs

nism involves inhibition o dopaminerelease due to dopamine blockage at D2receptors that may impair libido and erec-

tion. Another mechanism has to do withblockage o the alpha-adrenergic path-way in the periphery, which may lead topriapism (a painul and sustained penileerection which is a urologic emergency),galactorrhea, amenorrhea, gynecomastiaand vaginal dryness (due to estrogen de-ciency). Alterations in serotonin, whichparticipates in initiating arousal throughits vasodilatory eects in the periphery,

can negatively aect sexual unction.Finally, non-specic central nervous sys-tem (CNS) eects, such as sedation, cancause a decrease in the desire or sexualactivity.

As a whole, the primary mechanismo sexual dysunction induced by thesedrugs is probably the direct dopamineantagonism with some additional indirect

eects due to hyperprolactinemia.8

Sexualdysunction is an important problem withthe typical APDs, and to a lesser extentwith the newer atypical drugs. Nonethe-less, it remains an under-appreciatedproblem.

Weight Gain and Diabetes Mellitus (DM)A common side eect o APDs, es-

pecially the atypical APDs, is excessive

weight gain. In act, it is now believed tobe the most prominent long-term sideeect associated with these newer drugsand should be highly considered whentreatment plans are designed, becauseo the obvious medical consequences oobesity.1

The weight gain may be related toincreased appetite (due to drug interac-

tion with the brain monoaminergic andcholinergic systems), and to the endocrineeects o hyperprolactinemia.9 Clozapineand olanzapine both induce glucose dys-regulation and dyslipidemia, the develop-ment o which may be associated withthe combination o sudden body weight

gain (BWG), insulin resistance, increasedappetite and related endocrine changes.9

It is hypothesized that clozapine causes

weight gain by increasing adipose tis-sue, which leads to insulin insensitivity,glucose intolerance, and when severe,diabetes mellitus (DM).4 In one report,58% o patients on clozapine gained atleast 10% over baseline.4 Several cases oclozapine-induced diabetic ketoacidosishave also been reported.10

One cohort study ound that patientsbeing treated with typical or atypical APDs

are at greater risk o developing DM thanthe general population.11 The patients inthe risperidone and haloperidol cohortsshowed the greatest risk.11 Patients onolanzapine averaged weight gains o5.4 kg over the rst six to eight monthso treatment and had a 20% increasedrisk o developing DM than patients onrisperidone who averaged weight gains

o 3.9 kg.4

Quetiapine has been shownto cause lower levels o weight gain thanother atypical APDs. However, the typicalAPD, haloperidol, causes less BWG thanthe other drugs.4 It also appears thatadolescents experience more BWG com-pared to other populations when takingatypical APDs.

Cardiovascular Side Effects

Clozapine poses a risk o myocar-ditis, especially during the rst montho therapy. A 2002 advisory by HealthCanada reported an association betweenclozapine use and pericarditis, myo-cardial inarction, pericardial eusion,cardiomyopathy, heart ailure, and mitralinsuciency.4 In addition, antipsychoticdrugs, including some atypical APDs, may

cause electrocardiogram (ECG) changesthat can lead to drug-induced arrhythmiaand, rarely, sudden unexplained death.7

In one study, risperidone showed a sig-nicant increase in QT interval durationcompared to placebo,12 yet in anotherstudy (albeit conducted by the company


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who manuactures the drugs), none o theatypical drugs were ound to cause QTelevations that were considered clinically

signicant.7

Implications of Use During Pregnancyand Lactation

A study involving lactating womentaking clozapine ound the level in theiroremilk to be 2.8 to 4.3 times the level oclozapine in the maternal plasma, but nostudies have been done to accurately as-sess the direct implication o these levels

on the breasteeding neonate.13Clozapine and olanzapine increase

the risk o signicant weight gain, andDM puts the inant at greater risk orperinatal mortality, prematurity, con-genital abnormalities (e.g., neural tubedeects), macrosomia and, as previouslystated, increases the chances o develop-ing DM in the uture. Physicians should

also be aware that stopping antipsychoticmedication when pregnant or post-par-tum, especially abruptly, could have thepotential consequence o causing a psy-chotic relapse in the patient, which maybe severe and include maternal suicideand inanticide.

Avoidance o phenothiazines are rec-ommended because o their associationwith signicant increases in congenital

abnormalities. As well, clozapine, orcombinations o typical APDs, with dos-ages within their upper ranges should beavoided during pregnancy and lactation,until urther evidence determines themto be sae.13

Blood DyscrasiasClozapine has a well known, albeit,

minimal risk, o lie-threatening blooddyscrasias (agranulocytosis). This is oneo the major reasons why the drug is usedprimarily or patients reractory to otherAPDs and is not rst-line therapy. Pa-tients on clozapine require regular bloodmonitoring and surveillance every 1 to 2

weeks, which makes this drug problematicas it disrupts a patients quality o lie.4

Additional Side EffectsPatients on quetiapine are recom-mended to have regular ollow-up eyeexaminations every six months, due tospeculation that the drug may be linkedto lens abnormalities such as cataracts.4, 7

Thyroid unction may also be eected byquetiapine, since higher end doses wereshown to cause a 20% decrease in totaland ree thyroxine.7 This may be one o the

reasons why olanzapine and quetiapineare associated with a airly high incidenceo drowsiness. Unlike some o the otheratypical APDs, insomnia is a commonadverse eect caused by risperidonetherapy.4 Additionally, risperidone shouldbe used with caution in patients also tak-ing indinavir and ritonavir because such acombination can induce reversible coma.14

Another atypical APD, clozapine, caninduce dose-dependent seizures.15

One o the newer atypical drugs onthe market is aripiprazole, which is sup-posed to have ewer side eects comparedto the other atypical APDs. It still hasbeen shown to cause headaches, nausea,vomiting, constipation, dyspepsia, ortho-static hypotension, tachycardia, insomnia,somnolence, and tremors.12Table 1 (p.21)

summarizes the main side eects causedby selected atypical and typical APDs.

Worsening the Long-term OutcomeContinuous use o APDs has actually

been shown to worsen the long-term out-come in schizophrenic patients. Althoughthese drugs are eective in treating acutepsychotic symptoms, they do not improve

patients lives in the long run.

16

The rstpivotal study to show this was the 1960National Institute o Mental Health studythat ound the drugs to have short-termbeneit but higher relapse rates i usedlong-term.16 The World Health Organiza-tion later conducted a study on conven-


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Table 1. Summary o the main side eects caused by selected atypical andtypical APDs

Anti-psychotic EPS&TD Hyperpro- WeightGain Sexual Other

Agent lactinemia Risperidone Yes Yes Lesser extent(atypical agent)

Clozapine Lesser extent Lesser extent(atypical agent)

Olanzapine Lesser extent Lesser extent(atypical agent)

Quetiapine Lesser extent Lesser extent Lesser extent(atypical agent)

Aripiprazole Lesser extent Lesser extent Lesser extent Lesser extent(atypical agent)

Haloperidol Yes Yes Lesser extent Yes(typical agent)

Minimal risk of life-threatening blood dys-crasias (agranulocytosis),cardiovascular toxicity,drowsiness, and dosedependent seizures

Dose-dependentincreases in EPS.At high doses,incidence of EPS issimilar to that seenwith Haloperidol

Insomnia, increased QTinterval, and interac-tion with indinavir andritonavir

Orthostatic hypotensionand lens abnormalities

GI symptoms, insomnia,tremors, and tachycardia

Higher risk for adult-onset DM, especially with

increasing age

Yes, and increasedrisk of developingadult-onset DM

Dose-dependentincreases in EPS

Orthostatic hypotensionand drowsiness

Low incidence ofEPS across all doses

Dose-dependantincreases in EPS

Yes, and increasedrisk of developing

adult-onset DM

tional neuroleptics, which showed that inthe developing world, where patients arekept on the drugs or a short period otime, patients had exceptionally good socialoutcome compared to the poor long-termoutcome o patients in the developed worldwho are kept on the drugs chronically.16

In the late 1970s, Canadian investiga-tors at McGill University reported thatthe brains o patients treated with APDsdeveloped an increased density o D2 re-ceptors by 30% or more in an attempt tocompensate or the dopamine antagonistic

eects o the drugs. Patients can becomesuper-sensitized to dopamine (thoughtto be the mediator o psychosis), so thatwhen they abruptly stop the drugs, theyhave a higher tendency towards psycho-sis.16 This mechanism makes medicatedpatients more biologically vulnerable to

psychosis. The need or continued anti-psychotic treatment may itsel be druginduced.16

Atypical APDs have established det-rimental eects on metabolic unction,similar to the older, typical APDs. They


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also increase the density o D2 recep-tors, making patients more vulnerable topsychosis, and probably reduce liespan

when used long term. Ironically, modernpsychiatry seems to be prescribing themto an increasing number o patients,including those at risk o developingschizophrenia. The real goal should be tominimize their use and to wean patientso o them very slowly.

Managing the Side Effects of Drowsiness,Exhaustion, Fatigue, and Somnolence

All the atypical APDs cause somecombination o drowsiness, exhaustion,atigue, and somnolence. One o the bestorthomolecular methods to combat theseside eects is injectable vitamin B12 (hy-droxocobalamin). Newbold has writtenabout the therapeutic uses o injectablevitamin B12 as an antidote or over-se-dation.17 In Newbolds report, he recalled

a case involving one o his clients, anactress, who was dealing bootleg Quaalu-des as a source o income. She apparentlytreated her clients with 6000 mcg (micro-grams) o injectable hydroxocobalaminwhen they would become over-sedatedrom these pills and would be unable toleave her premises. From giving them highdoses o injectable hydroxocobalamin,she was able to reverse their sedation

enabling them to leave her apartment. Inthe same report, Newbold also discussedanother case involving a comatose patientwith marked symptoms o over-sedationinduced by bootleg Quaaludes and ex-cessive amounts o vodka. This patientalso responded to injectable hydroxo-cobalamin, but required 9000 mcg o itin order to regain consciousness and be

alert. From these experiences, Newboldsuggested that all patients with symp-toms o over-sedation rom overdoses osedatives, tranquilizers, and/or alcohol begiven a therapeutic trial o 9000 mcg ohydroxocobalamin.

I (Prousky) have treated several pa-

tients on atypical APDs with injectablehydroxocobalamin due to symptoms oover-sedation. I am impressed with the

vitamins ability to perk these patientsup and help them make it through the day.It is not a cure-all, but it does improvequality o lie. The recommended dose tostart with is 5000 mcg once or twice eachweek. Generally patients respond avor-ably within 24 to 48 hours ater their rstinjection. Instead o eeling excessivelysleepy, many o these patients reportmore energy and an increased alertness.

Patients who do not respond to the inject-able vitamin B12 should be provided withsupplemental calcium and magnesiumsince these minerals help vitamin B12 gainentrance into the cells.17

Managing the Side Effects of EPSOther symptoms that are believed

to occur less requently with the atypical

APDs are the EPS. However, I (Prousky)have seen several patients with some de-gree o EPS while on the atypical APDs,and most o these patients have beenprescribed benztropine mesylate to dealwith them. Unortunately, the addition obenztropine mesylate merely adds moremental symptoms to patients alreadystruggling with their psychiatric condi-tion (e.g., conusion, disorientation, and

memory impairment). The botanical med-icine, ginkgo biloba extract (GBE) mightbe helpul. In a study involving treat-ment resistant schizophrenic patients,the addition o 360 mg per day o GBEwith haloperidol was shown to decreaseEPS and enhance eectiveness o thedrug.18 Even though this study assessedthe combination o GBE with a typical

APD, similar positive results might alsooccur when combining GBE with atypicalAPDs. This drug-botanical combinationmight reduce EPS and enhance atypicalAPD eectiveness, possibly preventingurther increases in medication dosage.The ability o GBE to enhance medication


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eectiveness might also allow patients toreduce their dosages and experience ewerside eects rom their medications.19

In addition to GBE, there are a numbero nutritional treatments that would helpreduce and/or prevent EPS that includeascorbic acid, manganese, phosphatidyl-choline, pyridoxine hydrochloride, andvitamin E (d-alpha tocopheryl acetate).Werbach has summarized various studiesdemonstrating the eectiveness o thesenutrients to reduce and/or eliminate TDamong patients taking typical APDs.20

Although none o these nutritional agentshave been subjected to clinical trials involv-ing patients on atypical APDs, they prob-ably have a similar spectrum o ecacywhen used in combination with this classo antipsychotic medications. Table 2 (be-low) lists these orthomolecular agents andtheir corresponding dose ranges.

Managing Sexual DysfunctionIn male schizophrenic patients, anumber o viable orthomolecular and/orbotanical options exist that should helpreverse some o the sexual dysunction as-sociated with the use o atypical APDs.

L-arginine. One o the rst agents tobe considered is L-arginine. This aminoacid is a biologic precursor to nitric oxide,which plays an important role in endothe-

lium-dependent processes.21 In act, prob-

lems with penile endothelial L-arginineare thought to be responsible or part othe pathogenesis o erectile dysunction

(ED).22

In a small clinical trial involvingmen with ED, 40% o the treatment groupon 2.8 g o L-arginine daily or two weeksdemonstrated improvements comparedto no improvements among men in theplacebo group.23 In a larger trial, 50 menwith ED were given 5 g o L-arginine perday or a matching placebo or six weeks.There was a subjective improvementamong 31% o the men in the L-arginine

group.24 Another study combined 1.7 g oL-arginine with increasing doses o pyc-nogenol in a three-month trial involving40 men with ED.25 All the men took 1.7 go L-arginine during the rst month, andthen during the second month were given40 mg o pycnogenol twice daily withthe same dose o L-arginine. During thethird month, the dose o the pycnogenol

was increased to 40 mg three times dailywith the same dose o L-arginine. At theend o the second month, 80% reporteda normal erection, and by the end o thethird month this therapeutic responseincreased to 92.5%. Other benets thatwere noted included a quicker erection inresponse to stimulation, and an increasedduration o erection.

Ginseng. Another agent that might

beneit male schizophrenic patients is

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

Supplement RecommendedDailyDosageAscorbic Acid 1300-4000 mgGinkgo biloba extract 360 mg

Manganese 15-60 mgPhosphatidylcholine Dose equivalent to 2400-6400 mg of cholinePyridoxine hydrochloride 250-800 mgVitamin E 250-800 mg of d-alpha tocopheryl acetate


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panax ginseng. The active compounds inpanax ginseng, the ginsenosides, inducerelaxation o the smooth muscle o the

corpus cavernosum in rabbits by augment-ing the release o nitric oxide.26-27 Clinicaltrials involving human subjects have dem-onstrated that panax ginseng can improveerectile unction and sexual satisaction.In one trial, 90 patients were divided intothree groups: the panax ginseng group, theplacebo, and the trazodone group.28 Eventhough parameters such as intercourserequency, premature ejaculation, and

morning erection ater treatment were thesame in all three groups, the panax ginsenggroup did have a signicant improvementin penile rigidity, girth, duration o erec-tion, libido, and patient satisaction. Theoverall ecacy o panax ginseng on EDwas 60% compared to only 30% among theplacebo and trazodone groups.

A more recent randomized, double-

blind, placebo-controlled, crossover studyassessed the ecacy o panax ginsengamong 45 men with ED.29 One group omen were given 900 mg o panax ginsengthree times daily or eight weeks. Theother group was given an identical lookingplacebo three times daily or eight weeks.Ater the eight weeks, each group was sub-jected to a two week washout period andthen received crossover treatment with

placebo or panax ginseng or an additionaleight weeks. The men on panax ginsengscored signicantly higher on the Inter-national Index o Erectile Function (IIEF)compared to men on placebo. The panaxginseng group also had better penile tiprigidity as measured by a device called theRigiScan, compared to the placebo group.The authors o this study were unable to

explain the benets o panax ginseng interms o its hemodynamic and hormonalactions. Instead, it was purported thatpanax ginseng beneted ED due to itseects upon multiple mechanisms.

Gingko Biloba. Another botanicalmedicine, GBE, ought to be tried when

helping both male and emale schizo-phrenic patients suering rom sexualdysunction. Although the reports on

GBE assessed its value in treating sexualdysunction induced by antidepressantmedications, it might oer some benetto schizophrenic patients on atypicalAPDs. The rst report o GBEs abilityto improve ED involved male geriatricpatients taking antidepressant medica-tions.30 While these patients were takingGBE to improve their memory, many othem noticed an improvement with their

erections. 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 the trial was207 mg/day. Around 76% o the patientsound GBE to be eective at restoring allaspects o their sexual response, includ-ing erectile unction. The mechanismresponsible or GBEs positive eects upon

sexual unction had to do with its abilityto augment nitric oxide synthase (e.g.,increase nitric oxide availability). Thesepositive eects occurred in the presenceo serotonin, which can impede nitricoxide production.31

Another trial evaluated the eective-ness o GBE or antidepressant-inducedsexual dysunction.32 Twenty-our pa-tients participated in the trial, with an

equal number o men and women. Therewas a signicant improvement in sexualresponse ater three and six weeks ouse. However, the data was inconclusivesince the therapeutic response to GBEwas so variable among the patients. Ina smaller trial involving both male andemale patients, GBE was not successulat helping any o the nine male patients,

and was only helpul among three o the13 emale patients tested.33 In a placebo-controlled, double-blind trial or antide-pressant-induced sexual dysunction,37patients were randomized to receive GBEor a placebo.34 The participants on GBEreceived 120 mg or the rst two weeks,


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160 mg or the next two weeks, and 240mg or the remaining our weeks o the trial.All participants were given a questionnaire

beore taking either GBE or placebo, andater the second, orth, and eighth weeks.Unortunately, no statistical signicance wasachieved or patients on GBE compared tothose on placebo. Nonetheless, GBE mightbe helpul. It should be prescribed to maleand emale schizophrenic patients sueringrom sexual dysunction induced by theatypical APDs. Table 3, (below) lists theorthomolecular and botanical agents that

might reduce the sexual dysunction associ-ated with atypical APDs.

Managing HyperprolactinemiaThe most well known botanical agent

that lowers prolactin levels is vitex agnuscastus. In a review o its prolactin-reducingeects, Brown reported: (1) that vitex invitro inhibited the basal and the thyrotro-

pin-releasing hormone (TRH) stimulationo prolactin levels; and (2) that it containsconstituents that directly bind to the dopa-mine receptors o the anterior pituitary.35For these reasons, it is inadvisable or anyschizophrenic patient currently taking anyo the atypical APDs to concomitantly usevitex as a means to lower prolactin levels.Atypical APDs are dopamine-receptor block-ing agents, and taking vitex would reduce

their eectiveness.The orthomolecular agent, gamma-

aminobutyric acid (GABA), should also be

avoided. GABA is an inhibitory neurotrans-mitter with anxiolytic properties similar toclonazepam and other benzodiazepines.36

Like vitex, GABA has the ability to aug-ment dopamine release and reduce pro-lactin secretion. GABAs exact biochemicalmechanisms are not well understood, butstudies using animal models have beenhelpul in elucidating some o them. Inone in vitro study, the GABA (B) receptoragonist, bacloen, was shown to inhibit thebasal and thyrotropic releasing hormone-stimulated prolactin secretion in anterior

pituitary cells.37 In another rat experiment,it was concluded that endogenous GABA,by acting through GABA (A) receptors,infuences the basal and diurnal changeso tuberoinundibular dopaminergic neu-ronal activity, and consequently prolactinsecretion.38 Since there are GABA receptors(A and B types) located in the anteriorpituitary, orally administered GABA might

stimulate these pituitary receptors caus-ing a release o dopamine and a drop inprolactin secretion. Although it is uncleari orally administered GABA can eectivelygain entrance into the CNS, the use o thisagent should be avoided due to its potentialeects upon dopamine, and its potentialantagonistic eects upon atypical APDs.At present, the authors o this report areunaware o any orthomolecular and/or

botanical agents that can lower prolactinlevels without possibly compromising theeectiveness o the atypical APDs.

Table 3. Orthomolecular and botanical agents to reduce and/or eliminatesexual dysunction associated with atypical APDs

Supplement RecommendedDailyDosageL-Arginine (male patients only) 1.7-2.8 gPycnogenol (male patients only) 120 mgPanax Ginseng (male patients only) 2700 mgGinkgo Biloba Extract (male & female patients) 240 mg


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Managing Weight GainBesides the well known liestyle

measures that are time-tested in terms

o losing weight (e.g., diet and exercise),supplementation with green tea extractshould help to control some o the weightgain produced by the atypical APDs. Inone human trial involving ten healthymen, the administration o green teaextract containing 50 mg o caeine and90 mg o epigallocatechin gallate (EGCG)given three times daily with meals pro-duced statistically signicant results.39

Specically, green tea extract increasedthe 24-hour energy expenditure, reducedthe 24-hour respiratory quotient, andincreased the 24-hour urinary excretiono norepinephrine (NE). The investigatorsconcluded that green tea extract, apartrom caeines thermogenic properties,controlled body composition through itssympathetic activation o thermogenesis,

at oxidation, or rom a combination othese two actors.In another study, the catechin-poly-

phenols and caeine ound in green teaextract stimulate thermogenesis by sym-pathetically releasing norepinephrine.40The catechin-polyphenols rom green teaextract increases norepinephrine via theirinhibition o catechol-O-methyl-transer-ase (the enzyme that degrades NE), and

the caeine content inhibits transcel-lular phosphodiesterases (enzymes thatbreakdown NE-induced cyclic adenosinemonophosphate). The possible net eectsare sympathetic stimulation o thermo-genesis and improved weight control. Thebenecial eects o green tea extract havebeen more ormally studied in an opentrial o moderately obese patients.41 An

80% ethanolic dry extract o green teastandardized to 25% catechins (expressedas EGCG), was ound to decrease bothbody weight and waist circumerenceater three months o use. The authorso this study suggested that green teaextract might avorably infuence body

composition by inhibition o gastric andpancreatic lipases and rom the stimula-tion o thermogenesis.

These studies demonstrate that greentea extract can have a avorable eectupon body composition. However, theuse o green tea extract also increasesthe production o NE and should be usedwith caution in all schizophrenic patients.The oxidized derivative o norepinephrine,noradrenochrome, likely contributesto the psychosis o schizophrenia. Anyincrease in norepinephrine, thereore,

could be detrimental. To oset this prob-lem, make sure that green tea extract isgiven with a complement o antioxidants.Caeine-ree green tea extracts wouldproduce less NE since it would not havethe same type o sympathetic stimulationwhen compared to extracts containingcaeine. The optimal dose o green teaextract appears to be 270 mg daily that is

standardized to 25% catechins (expressedas EGCG).

Managing DiabetesPatients on atypical APDs can devel-

op drug-induced glucose intolerance andhave a syndrome that mimics adult-onsetdiabetes. In terms o diabetes control andprevention, the most important orthomo-lecular agent appears to be chromium. For

many years, chromium was thought to beinvolved in the glucose-tolerance actor(GTF) molecule that presumably increasesinsulin sensitivity. The composition oGTF, as isolated rom yeast, is made ochromic ion, nicotinic acid, and the aminoacids glycine, glutamic acid, and cyste-ine.42 However, GTF o any type has neverbeen ound in human tissues. More re-

cently, a naturally occurring oligopeptidelow-molecular weight chromium-bindingsubstance (LMWCr) has been proposedto be the biologically active orm o chro-mium.43 This compound has been oundin many dierent types o mammals, andis widely distributed in numerous tis-


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sues (e.g., liver, kidney, spleen, intestine,testicles, and brain). This oligopeptide isalso comprised o the 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.43 This LMWCr compound is parto an insulin amplication system thatregulates glucose homeostasis through acomplex series o biochemical reactionsoccurring at the insulin receptor.44,45 In astudy involving 185 adult-onset diabetic

patients, there were signicant decreasesin the concentration o asting and two-hour glucose levels, insulin, hemoglobinA1C, and total cholesterol among patientssupplemented with 1000 mcg o chromi-um picolinate compared to those on 200mcg o chromium picolinate or placebo.46Thus, chromium as part o the LMWCr,should have the ability to improve glucose

tolerance and increase insulin sensitiv-ity in schizophrenic patients with poorglucose control.

In terms o toxicity, Lamson and Pla-za have summarized the chromium litera-ture, and have evaluated its mechanismso action and exceptional saety prole.According to these investigators, thereis no demonstration o general chromiumtoxicity in animals at a dose that would

extrapolate to humans as 1050 mg daily.47One o these investigators has even used3000-4000 mcg o chromium as nicotinategiven twice daily to adult-onset diabeticpatients or months to years resulting intremendous reductions o glucose andlipid levels without any increases in bloodurea nitrogen, liver enzymes, or otherlaboratory abnormalities. It is interesting

to note that high supplemental doses ochromium would never come even closeto 1050 mg per day.

While on atypical APDs, many schizo-phrenic patients develop insulin resis-tance, increased appetite, and relatedendocrine changes. I (Prousky) speculate

that the glucose intolerance resultingrom atypical APDs disrupts chromiumhomeostasis and creates an increased

metabolic need that can be met onlythrough high-dose supplementation. Ican recall one patient who had positivebody composition changes, such as weightloss, ollowing a ew months o taking3000 mcg o chromium rom yeast eachday. Although asting glucose measure-ments were not done prior to and aterthe chromium intervention, the bodycomposition changes in this one patient

were probably a refection o improvedglucose homeostasis. The dose ranges thatare likely o value among schizophrenicpatients on atypical APDs are 1000-4000mcg o chromium given twice daily.

Managing Cardiovascular Side EffectsThe most worrisome cardiovascular

side eects are the cardiac arrhythmias

that in rare cases can lead to unexplaineddeath. The best way to manage and/orprevent cardiac arrhythmias is throughdaily supplementation with sh oil. Ina randomized, double-blind, placebo-controlled trial, 65 patients with cardiacarrhythmias (without coronary heart dis-ease or heart ailure) were ollowed orsix months, and were divided into twogroups.48 One group was given 3 g daily

o encapsulated sh oil (equivalent to 1g daily o omega-3 PUFA), whereas theother group was given 3 g daily o oliveoil as placebo. In the sh oil group therewere considerable lipid-modiying ben-ets that included a decrease o serumtriglycerides, total cholesterol, low-den-sity lipoprotein cholesterol, plasma reeatty acids, and thromboxane B2, and

an increase in high-density lipoproteincholesterol. The subjects in the sh oilgroup also had 46.9%, 67.8%, 71.8%, and100% ewer incidences o the our typeso arrhythmia monitored in this study(atrial premature complexes, ventricularpremature complexes, couplets, and trip-


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lets). Unlike the sh oil group, no positivechanges occurred in the placebo group.The results o this study demonstrated

that sh oil supplementation has anti-arrhythmic eects, and can reduce theincidence o atal myocardial inarctionand sudden cardiac death. For the reasonscited in this study, and rom the conclu-sions o other investigators,49,50 its seemsprudent that all schizophrenic patientstaking atypical APDs are supplementedwith sh oils due to their anti-arrhyth-mic and lipid-modiying eects. In terms

o the optimum dosage, schizophrenicpatients should consume a daily amounto sh oil that is recommended or pa-tients with and without coronary heartdisease (CHD). For cardioprotection, thedaily dose should contain 450-1000 mg oeicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA).51

Case ReportThe ollowing case report is an excel-lent example o the eectiveness o theorthomolecular and botanical approach.The patient was eventually able to discon-tinue most o his mainstream treatments(except or risperidone), and signicantlyrecover rom his diagnosis o schizoaec-tive disorder.

The patient, a 24-year-old Hispanic

male, rst presented to Dr. Prouskys pri-vate naturopathic practice on November13, 2004, or chie complaints o schizoa-

ective disorder and obesity. He describeda history o being unwell emotionally romthe age o 15 onwards. His symptoms

became more severe at the age o 16when he started hearing messages rombillboards, would spend countless hourssurng the Internet, was emotionally veryfat, had a belie that 100% o the biblewas true, and that the devil was orcinghim to do things. He would read exces-sively and did report some occasionalthoughts o violence. Due to his moods, heparticipated in a hospital-based program

or depression that helped very much. Hispast medical history did include a suicideattempt at the age o 21, or which he washospitalized and released shortly therea-ter. Review o systems illuminated otherproblems that consisted o glaucoma, mildmusculoskeletal complaints, obesity, andshortness o breath. His weight was about200 pounds in the year 2000. Since being

prescribed risperidone in 2001, his weightincreased to 260 pounds. His current pre-scription medications were risperidone (3mg daily), olanzapine (20 mg daily), andbupropion hydrochloride (150 mg daily).The patients amily history revealed somegenetic predisposition to schizophrenia,as his paternal grandmother was diag-nosed with this disorder at 60 years old.On physical examination, the patient

was well nourished, clinically obese, hadhigh to normal blood pressure, and mildtachycardia. All o his main systems were

Table 4. Patients First Set o HOD Results.

HODTestItems December2004ResultsTotal Score (TS) 40Perceptual Score (PerS) 4Paranoid Score (PS) 2Depression Score (DS) 10Ratio Score (RS) 4Short Form (SF) 1


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within normal limits. He was prescribedvitamin B6 (250 mg daily), niacinamide(1000 mg three times daily), vitamin C

(1000 mg three times daily), chromium(1000 mcg three times daily), liquid shoil (1 teaspoon twice daily) providing closeto 2 g o EPA, zinc (50 mg daily), and wastold to discontinue all dairy and milkproducts. Regular use o dairy and milkproducts can be associated with psychosisand depression.52

On December 13, 2004, the patientreturned or a ollow-up. He reported an

increased sense o alertness and vigorrom the treatments. He also describedsymptoms o social anxiety where hewould eel scared to talk to people, andwould even avoid teachers and classmateswhile completing his auto mechanic pro-gram. He did have some depression sincethe last visit, and experienced suicidalideation on three separate occasions since

the initial visit. His vitals were withinnormal limits. The patient was giventhe Beck Anxiety Inventory (BAI) andthe Beck Depression Inventory (BDI) toll-out. His BAI score was 33, indicatingmoderate anxiety. His BDI score was 26,indicating moderate depression. Labora-tory tests showed a normal CBC, normalasting plasma glucose, and an abnormallipid prole showing the patient to be at

an above average risk or coronary heartdisease. The patient was switched romthe niacinamide to niacin at a dose o1500 mg three times daily to help controlhis psychiatric symptoms and to avorablyimpact his lipid prole. He was also givenL-glycine or his symptoms o panic, at adose o 2000 mg sublingually as needed.An intramuscular injection o vitamin B12

(1500 mcg) was also provided. The patientwas given the Hoer-Osmond Diagnostic(HOD) test to determine the severity ohis schizoaective disorder.

The patients HOD test was re-ceived and scored on December 17, 2004(Table 4,p.28). The higher the total score,

the greater the probability o that patienthaving schizophrenia. For a patient witha pre-established diagnosis, the HOD test

can also be used to evaluate the severity omental disturbances and assess a patientsresponse to treatment. In this patientscase, his total score did indicate thathe was symptomatic. I his total scoreswere to decline over time, it would be anindication o improvement.

About six weeks later, on January 26,2005, the patient returned or another ap-pointment. He elt that he was no longer

symptomatic in terms o his diagnosiso schizoaective disorder. The niacincaused the patient to vomit, so he reducedthe dose to 1000 mg three times daily. Hedid not like the taste o L-glycine so henever really tried the treatment. He dideel that his anxiety had improved about10%. The patient was given another in-tramuscular injection, but the dose was

dierent as it now contained olic acid (0.5mL or 2.5 mg) and had a greater concen-tration o vitamin B12 (1 mL or 5000 mcg).He was asked to retry the L-glycine andreturn in another 5 to 6 weeks.

On March 7, 2005, the patient eltthat his diagnosis was better describedas social anxiety disorder with somesymptoms o schizoaective disorder.He did not try the L-glycine as he was

instructed to do. In terms o his anxiety,he elt about 20-30% better than the lastvisit. He was given another intramuscularinjection o olic acid (2.5 mg) and vitaminB12 (5000 mcg).

The patient returned or another ap-pointment on April 20, 2005. He had seena new psychiatrist who recommended thatthe patient complete a series o cognitive

behavior therapy or his social anxietydisorder. The patient was also attendinga weekly group or patients with socialanxiety disorder. The psychiatrist pre-scribed 20 mg o citalopram, and took himo the olanzapine. He was sleeping lesssince discontinuing the olanzapine. The


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psychiatrist also instructed the patientto continue with risperidone (4 mg atbedtime), and bupropion hydrochloride

(150 mg daily). The patient did report abetter sense o well being, even though heelt more depressed during the previousweek. His only problem was ear. He wasunable to look at people when riding thesubway because o the way people lookedback at him. He also thought that peoplewere judging him. For his anxiety, thepatient was prescribed L-taurine at adose o 1500 mg twice daily to be taken

away rom ood. He was also prescribedginkgo biloba extract (180 mg daily) tohelp with depression, the side eects orisperidone, and or erectile dysunction.Another intramuscular injection o olicacid (2.5 mg) and vitamin B12 (5000 mcg)was given to the patient.

The patient had one more ollow-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 eel worsethan beore and, in act, indicated that hewas more alert and required less sleep.He did not complain o any withdrawalsymptoms rom discontinuing the medi-cations. His social anxiety seemed muchimproved. He was able to cover or his a-ther as a courier and interact with people.

This would not have been possible just aew months previously. The patient justcompleted his auto mechanic program,

and was excited about going to college inthe all or accounting. He also remarkedthat his paranoid thoughts were gone, and

were 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. I assured him that as long as heremained consistent with the program, hehad very little chance o a relapse.

I received the patients nal set oHOD results on June 30, 2005. As evident,

the patients scores dramatically improveddemonstrating the eectiveness o theorthomolecular and botanical approach.(See Table 5, below).

DiscussionThe goals o this report were to review

the known side eects o the atypicalAPDs, and clariy some o the best ortho-

molecular and botanical strategies thatmight have value in terms o side eectprevention and/or reduction. Even withthis knowledge, schizophrenic patientsnd themselves in an unortunate pre-dicament. Should they stay on the atypi-cal APDs and suer extreme metabolicconsequences despite using adjunctiveorthomolecular and botanical treatments?Hoer has written about the tranquilizer

psychosis, and how the atypical APDsmake chronic schizophrenic patientssick.53 In that same report, he mentions

Table 5. Patients nal set o HOD results

HODTestItems June2005ResultsTotal Score (TS) 5Perceptual Score (PerS) 0Paranoid Score (PS) 0Depression Score (DS) 1Ratio Score (RS) 5Short Form (SF) 0


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how these drugs damage the brain anddecrease the odds these patients can everrecover. Even with adjunctive orthomo-

lecular and botanical treatments, it is ex-tremely dicult or schizophrenic patientsto ully recover or considerably improvewhile remaining on atypical APDs.

Another option is or schizophrenicpatients to go o o their atypical APDsand suer the consequences o havingterrible withdrawal symptoms and a re-currence o their psychoses. This choiceis also inadequate. We propose a third

and more reasonable solution, which is tovery slowly (over months and sometimesyears) withdraw rom the atypical APDsand include the components o an idealtreatment program. The components osuch an ideal treatment, as reported byHoer, include: (1) shelter; (2) decency,understanding, support, saety, and pri-vacy; (3) psychiatric treatment; and (4)

orthomolecular treatment.53

All o thesecomponents are equally important. Mucho the success o this ideal treatment pro-gram depends on the skill o the treatingclinician and the compliance and patienceo the patient. Orthomolecular interven-tions do not work immediately, and manymonths might go by beore therapeutic e-ects are noticed. We do recommend thatduring the lengthy process o recovery, cli-

nicians utilize many o the orthomolecularand botanical approaches to minimize thedamaging metabolic eects o these drugs.Patients need to know that they cannotbegin the process o drug withdrawal untilthey begin to eel better. Once this hap-pens, the atypical APD can be slowly re-duced over many months and even years.I the drug is withdrawn too rapidly, very

unpleasant withdrawal symptoms occur,in addition to an increased likelihood opsychosis. For more inormation on thecomponents o an ideal treatment plan,please reer to Hoers latest book onschizophrenia.54Conclusion

The atypical APDs cause numerousside eects such as EPS, hyperprolac-tinemia, weight gain, diabetes, atigue, and

cardiac arrhythmias. Some o these sideeects might be reduced and/or preventedby using speciic orthomolecular andbotanical treatments. Controlled clinicaltrials are needed to properly evaluate theeectiveness that orthomolecular andbotanical agents have upon mitigatingthe side eects o atypical APDs. At pres-ent, Hoers ideal treatment plan appearsto be the only eective approach that

enables chronic schizophrenic patientsthe opportunity to ully recover withoutmetabolic dysunction and long-termbrain damage.

AcknowledgementsWritten consent was obtained rom

the patient or publication o this report.Special thanks goes to Mrs. Erynn Marcus

or her editing and review o this report.

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Documents

Ortho and Botanical Treatments to Alleviate Side Effects of Atypical Antipshy Drugs