Orthomolecular Treatment ForSchizophrenia: A Review (Part Two)

Raymond J. Pataracchia, B.Sc, N.D.'

IntroductionThis two-part review on sclTizuphre-

nia describes various segments of theschizophrenic population that fall intostibgroups of distinct biochemical imbal-ance. To recap, these subgroups includeessential fatty acid deficiency, inadequatenutriture. dysglycemia, food intolerance,digestive compromise, nialabsorption.Linder-methylation. vitamin R^ deficiency,Bh deficiency, vitamin C deficiency, zincdeficiency, heavy metal toxicity, brain hy-pothyroidism, and hyjioadrenia. Comple-mentary alternative medicine (CAM) has akey role in the treatment of .schizophrenia.In Part Two of this review, we discussheavy metal toxicity, B,, deficiency, zincdeficiency, brain hypothyroidism, andhypoadrenia.

Heavy Metal Toxicity in SchizophreniaMost heavy metals are free radicals

that induce oxidative stress {lipid peroxi-dation) and have an affinity for brain tis-sue.' ̂ Free radical-mediated neurotoxicityand oxidative stress are implicated as acausative factor in schizophrenia." Thesefree-radicals have the ability to compro-mise and/or destroy brain tissue and. inso doing, decrease the availability of viablebrain tissue. Note that other mechanismsof brain tissue compromise are involvedin schizophrenia, so the added burden oftoxic metals is to be avoided.

Elevated heavy metal levels are as-sociated with schizophrenic patliology.'"It is not uncommon to see toxic levels ofcopper, lead, mercury, aluminum, arsenicand cadmium In schizophrenics. We findsome ofthe most advanced schizophreniccases having three or more heavy metals.

I. Natiimpathic Metiiral Hcseurch Clinic, 20 E^linlon Aveiiut-Hast. Suite«'4-ll. lorunlo, Ontario. Canada. M'^i' IA9.

Heavy metal toxicity is also associatedwith ADHD, anxiety, OCD, depression,bipolar disorder and dementia.

Heavy metals are excreted by us-ing the body's metal-removing protein,metallothionein.-'^ In the process of rid-ding the body of heavy metals, this proteinloses zinc.'" Zinc loss in schizophrenia inturn compromises the ability to transcribeproteins and make neurotransmitters.Investigators recognize compromisedbrain protein transcription pathways inschizophrenia.^" Zinc deficiency is as-sociated with schizophrenia and otherpsychiatric pathologies including mooddysfunctitin and dementia.''

Lead disrupts mental function.'-Toxic lead levels are associated withpsychosis." Lead toxicity is also associ-ated with behaviour disturbance, mooddisorder, learning disabilities, insomnia,immune compromise, brain damage anddelayed infant development. Lead hasbeen found to disrupt the carriage ofthyroid hormone (T4) into the brain."'''If you are a city dweller, you are exposedto lead and the risk of lead toxicity riseswith age. With widespread pesticide use,lead accumulates in the food chain. Leadis found in paints, print colour, glass,batteries, rust protectants, alloys and oldwater pipes and bathtubs.""

Mercury is toxic and has no thera-peutic use; in fact, it disnipts dopamineand norepinephrine metabolism.' It isnot uncommon to find elevated mercuryin patients with .schizophrenia. Mercuryis found in fluorescent lights, vaccines,thermometers, and fish, animals, andplants exposed to toxic environments.Dental fillings contain on average about40% mercury which has the potential toleach with electrolytic decay. Mercury

95

Journal of Orthomolecular Medicine Vol. 23. No. 2, 2008

often causes headaches, nervous irrita-bility, memory decline, depression, rapidfatigue, nausea, stomach aches and aller-gic susceptibilities."' Mercury has a strongaffinity for the brain but also sequestersin the liver, kidney, and spleen.

Aluminum can be toxic in patientswith schizophrenia, mood disorders.Alzheimer's Disease and digestive systempathologies. Aluminum disrupts enzymefunction and is well-documented todisrupt cognition, learning and memory.Environmental sources of aluminuminclude aluminum cookware (especiallyfrom heating and deglazing with an acidsuch as vinegar or wine), drinking boxes,processed cheese, deodorants, and drink-ing water (aluminum is more soluble inour acidic magnesium deficient drinkingwater)."*

In excessive concentrations, copperhas a toxic effect and. in schizophrenia,contributes to excess catecholamineoxidation, the end products of which areunstable toxic hallucinogens."''' We havefound copper toxicity to be the most com-mon heavy metal pattern in schizophrenia.It is also associated with ADHD, autism,depression, anxiety, bipolar disorder andparanoia. With copper toxicity we see clini-cal zinc deficiency.̂ '' Copper is abundantin food and water as it is found in soil,pesticides and animal feed. Since WorldWar II we have been exposed to greaterlevels of copper due to copper piping inmodern homes and the widespread useof birth control pills (estrogen based).Estrogen dominance is associated withhigher circulating copper levels and copperis thought to transfer via placenta fromgeneration to generation.̂ " Other coppersources include copper tea pots, coppersulfate treated Jacuzzis or swimming pools,drinking water, dental fillings, prenatalvitamins, and copper IUD's. Neuroleptics,antibiotics, antacids, cortisone. Tagamet,Zantac, and diuretics often encouragecopper dominant biochemistry.

The liver produces the copper regu-lating proteins metallothionein andceruloplasmin and, with low thyroidfunction, their hepatic protein synthesisis diminished. The body attempts to re-move excess copper by excreting it out ofthe liver via gall bladder excretion to thebowel. Vitamin B̂ , vitamin C, and zinc arehelpful clinically because of their physi-ological antagonism to copper.

Schizophrenics relapse when thyroidfunction is low.-' Poor thyroid func-tion encourages heavy metal retention.Conversely, heavy metals seem to play amajor role in blocking peripheral enzymeconversion of T4 to T3.^^-' Heavy metalremoval involves mobilizing and eliminat-ing the metal and this is often best doneafter thyroid function has been optimized.The organs involved in the elimination ofthe metal tend to function more efficientlywhen thyroid metabolism is intact. It isalso essential to avoid environmentalexposures to heavy metals.

Zinc and B̂ Deficiency in Schizophre-nia

Zinc and iron are the most con-centrated metals in the human brain.Zinc is important to several biochemicalpathways as over 200 enzymes are zinc de-pendant. Zinc deficiency is very commonin schizophrenia.^^ Insufficient levels ofzinc are also associated with depression,dementia, mental retardation, learningdisability, lethargy and apathy.^ Zinc isessential for the synthesis of serotoninand melatonin.^" It is crucial to braindevelopment because it plays a majorrole in protein synthesis.̂ "'̂ *" In the brain,zinc lowers excitability by moderatingNMD A receptor release of excitatory glu-tamate. Zinc is involved in the synthesisof inhibitory G ABA by the modulation ofglutamate decarboxylase activity. Amongthe zinc-dependant proteins are metallo-thionein which is essential for heavy metalregulation and zinc bioavailability. The

96

Orthomolecular Treatment For Schizophrenia: A Review (Part Two)

synthesis of Zn-thionein and CuZnSODare essential in preventing oxidativedamage.^" Zinc protects against fatty-acid peroxidation which destroys neuronstructure and function. Zinc is involvedin neuronal plasma membrane structureand functioning and, may play a key rolein blood brain barrier integrity.-" Zinc isinvolved in storing biogenic amines insynaptic vesicles and. in axonal transport.The biogenic amine histamine regulatesnucleus accumbens activity, which is re-sponsible for filtering sensory informationand communicating with the amygdala,ventral tegmentum. and hypothalamus.In the limbic system, zinc is involved inthe metabolism of emotional regulation.In the hypophysis and hypothalamus, zincis involved in Imrmonal metabolism.

Vitamin B,, (pyridoxine) is involvedin the decarboxylation of tyrosine, trypto-phan, and histadine into the neurotrans-mitters norepinephrine, serotonin, andhistamine respectively.^" B,, deficienciesare associated with schizophrenia, de-pression and behaviour disorders. It isa cofactor in homocysteine re-methyla-tion.-'' B,, has been found useful in memoryacquisition, with just a 20mg dose. "' It hasdemonstrated usefulness in controllingneuroleptic-induced akathisia and drug-induced movement disorders." " B,, isessential for the synthesis of antioxidantssuch as metallothionein. glutathione. andCOQK, which help prevent neuronal oxida-tive stress. B,, (and zinc) are involved in thesynthesis of glutamic acid decarboxylase(GAD) which blocks excitotoxicity witheventual secondary oxidative damage. B,,is also essential for glutathione peroxidaseand glutathione reductaso which art' help-ful in preventing mitochondrial decay.

The major neurotransmitters of thebrain are derived from protein building-blocks and precisely assembled accordingto messenger RNA (mBNA) transcriptionof neuronal DNA templates. Brain tissuesamples of schizophrenics have been as-

sessed with high-dimensional biology andfound to be compromised in basic mRNAtranscription and protein synthesis.'These perturbations influence an arrayof neuronal changes in the schizophrenicbrain among which are neurotransmittersynthesis and mitochondrial functioning.Oxidative stress can cause these per-turbations and the ensuing changes inneuronal structure and function may beintegral in understanding schizophrenicpathophysiolog}'.

It is interesting to note here that zincand vitamin B̂ together are needed by thebody as co-factors for neurotransmittersynthesis; zinc is needed for transcriptionand B,, is needed for transamination. Pre-vious investigators have described B,, andzinc depletion in the context of pyrolluria.In this metabolic syndrome, li,, and zincinteract with 2.4-dimethyl-3-ethylpyrroleand are readily

Hypoadrenia in SchizophreniaThyroid and adrenal function are

compromised in many schizophrenics.-' "The thyroid and adrenal are pivotal endo-crine glands. Many symptoms common toadrenal dysfunction are seen in thyroiddysfunction and vice versa. The adrenalworks in concert with the thyroid glandand often both glands need to be sup-ported together.'"'^

Hypothalamic-Pituitary-Adrenal axisdysregulation is integrally associated withschizophrenia.^'" The adrenal glands areinvolved in stress response, sugar me-tabolism, electrolyte balance, peripheralepinephrine synthesis, blood pressureregulation, and sex hormone metabolism.Many schizophrenics who are heaxy cof-fee drinkers have low adrenal function.Low adrenal symptoms include slug-gishness on waking, stress intolerance,lack of enjoyment, post-traumatic stress,addiction, dizziness, low blood pressure,fluctuant body temperature, insomnia at4am, immune compromise, hyjioglycemia.

97

Journal of Orthomolecular Medicine Vol. 23, No. 2, 2008

dermatitis, PMS, phobia and poor übido.Schizophrenics can be warm at times andat other times cold with trouble adaptingto daily temperature extremes. Fluctuantbody temperatures and heat intoleranceare a sign of low adrenal function whichoften accompanies low thyroid function.*"Adrenal symptoms are a good indicatorof adrenal status. In some cases, salivatesting is useful to assess the adrenal hor-mones DHEA and cortisol. Cortisol is partof the stress response but elevated cortisoldisturbs mental function. Cortisol levelsare commonly elevated in schizophren-ics and depressives.̂ ''̂ ** Adaptogens andsupplements can be used effectively tosupport adrenal function without elevat-ing cortisol.

Hypothyroidism in SchizophreniaActive thyroid hormones are re-

sponsible for enabling cells, at the DNAievel, to maintain their metabolic rate.Thyroid hormones also maintain oxygenavailability in the brain and elsewhere.With healthy thyroid hormone function,our cells produce energy and completetheir tasks efficiently. When tissue cellsincluding neurons have energy, they workefficiently. When thyroid function is low,cells remain in a state of hypofunction.Hypofunctioning cells work slowly andproduce minimal energy. Consequently,fewer enzymatic reactions occur, cellsdon't give off heat and core body tem-perature decreases. Intolerance to cold isa typical complaint in low thyroid func-tion. '̂ When body temperature is insuf-ficient, enzymatic reactions do not occuras readily, yet these reactions are neededthroughout the body for, among otherthings, neurotransmitter synthesis. It isnot uncommon to have schizophrenicsreport that they feel warm despite havinglow average body temperature.

Low thyroid s}Tnptoms are seen oftenin psychosis.-'"''̂ '̂ In treatment-refractorydepression, psychiatric 'thyroid augmen-

tation' treatment is frequently applied."̂ '̂"̂The most obvious low thyroid symptomsinclude impaired cognition, easy weightgain, fatigue, pain, headache, irritability,anxiety, panic, PMS, depression, poormemory, poor concentration, insomnia,constipation, indigestion, hair loss, highcholesterol and frequent infection.̂ '"-'̂ "''''The digestive tract of a low thyroid patienthas poor motility and slow stool transitwhich results in constipation and ineffi-cient nutrient absorption.'"*' ln low thyroidpatients, core body temperatures are oftenso low that digestive enzymes do not reaclitheir reaction threshold. Patients withvaried non-specific complaints often havelow thyroid function.

Classic hypothyroidism, occurring ina small percentage of schizophrenics, isa problem with the inability to produceadequate thyroid hormone. In classic"conventional" hypothyroidism, bloodtests show low output of thyroid hormoneT4 with elevated thyroid stimulating hor-mone (TSH) levels. Immune involvementas in Hashimoto's thyroiditis is usuallyseen in 80% of classic hypothyroid cases.Othman et al. assessed a sample of 249chronic schizophrenics and reported aprevalence of tbyroid antibodies in 20%of cases.'" Many blood thyroid imbalancesare found to correlate with the degree ofsymptom presentation, as for example, inacute psychotic episodes."̂ **

The reliance on thyroid blood tests inschizophrenia leads practitioners astraybecause a large portion of schizophren-ics are euthyroid with "normal" bloodtest measures but, paradoxically, havea low core body temperature and lowthyroid symptoms {fatigue, psychosis,depression, etc). There is no accepteddiagnostic agreement on this physiologi-cal state, however Wilson's TemperatureSyndrome (WTS) has emerged as a condi-tion that meets this criteria, WTS factorsin the possibility of inefficient peripheralconversion of T4 to active T3 despite

98

Orthomolecular Treatment For Schizophrenia; A Review (Part Two)

having adequate circulating thyroid hor-mone T4.'''̂ ''''''' In classic hypothyroidismand WTS, we can implement desiccatedthyroid, sustained release T3 (T3-SH) andbotanical medicine.

Brain HypolhyroidismIhe brain is highly dependent on

thyroid hormone for the regulation ofdopamine, norepinephrine, and serotoninpathways.'^'^'''' Brain hypothyroidism hasbeen described by Hatterer et al. as astate that occurs when systemic T4 doesnot readily cross into the brain.*'- Activethyroid hormone T3 is synthesized inthe brain by brain type 11 5'deiodinaseconversion of T4 to T3.'''''' Brain neuronstherefore depend on a ready supply of T4.The choroid plexus of the brain producestransthyretin (TTR), a transport proteinthat binds T4 and transports it acrossthe blood-cerebral spinal fluid barrier tothe brain."^ Transthyretin is significantlydownreguiated in the cerebral spinal Huid(CSF) of schizophrenics versus healthycontrols."^ This suggests that schizo-phrenics lack adequate amounts of T4in the brain. Without adequate T4, braincells remain hypo-metabolic and thismay, among other things, reduce neu-rotransmitter synthesis and disrupt theregulation of dopamine, norepinephrine,and serotonin.

Huang et al. suggest that low CSFtransthyretin may prove useful as abiomarker for early diagnosis of schizo-phrenia.''"' Also of interest is the fact thatlead has been linked to the reduction ofCSr transthyretin in humans.'^ ' ' ReducedCSF transthyretin is also seen in depres-sion and suicidal propensity.'""'^ Manyschizophrenics and depressives relapsewhen thyroid function drops.''

Peripheral blood thyroid levels canbe normal in (he context of brain hypo-thyroidism. T4 to T3 conversion by braintypell 5'-deiodinase can be inhibited bycortisol.''""'' This is important because

cortisol levels are commonly elevated inschizophrenics, especially during stress.Cortisol is an adrenal stress hormoneand, during stressful periods, we tend toconserve energy by shutting down thyroidhormone production.

Anti-thyrodal AdrenochromeAdrenochronie is a quinone and

many molecules in this class are anti-thyroidal. In schizophrenia, a ready supplyof oxidized adrenaline may account forthyroid compromise. Adrenochrome hasthe ability to induce oxidative stress andfunctional changes in thyroid tissue andperipheral metabolism/" ̂ '̂ It is not knownto what degree adrenochrome damagesthe thyroid gland. Skoliarova suggeststhat functional changes can be inferredfrom the strtictural "deterioration" ofthe thyroid and hypophysis of chronicschizophrenics autopsied 20 minutes tofive hours post-mortem."'̂

Thyroid TreatmentThere are some remarkable stud-

ies reporting the outstanding efficacyof thyroid therapy in acute and chronicschizophrenia. A study by Danziger re-ported in 1958, showed that 100 days ofoptimally dosed desiccated thyroid orthyroxine with B-complex lead to the fullrecovery of 54 (45%) of 80 scbizophren-ics.**" Twenty of the 80 patients were giventhyroid therapy alone while 60 of the 80patients were given thyroid plus shock(HCT) therapy!̂ Fifteen (75%) of the 20patients given thyroid therapy recoveredfully and, 39 (65%) of the 60 patients giventhyroid therapy plus ECT recovered fully.Of the 15; two were sick for 60 or moremonths, two were sick 24-59.9 months,three were sick 12-23.9 months, two weresick 12-23.9 months, and six were sick lessthan 6 months. t)f the 39; six were sick for60 or more months, five were sick 24*59.9months, five were sick 12-23.9 months, sixwere sick 12-23.9 months, and 17 were

99

Journal of Orthomolecular Medicine Vol. 23, No. 2, 2008

sick less than six months. After discharge,the incidence of relapse was very smallwith a maintenance treatment that keptthe basal metabolic rate (BMR) in check.Full recovery was defined appropriately;that is, being "symptom-free, returningto a former place in society/occupationand accepted as well by family, friendsand co-workers." Tbe prognosis of the80 patients at the onset of the study was"generally unpromising" as they weretreatment refractory to ECT, psycho-analysis, and psychotherapy (all wereneuroleptic naïve).

Manyofthe 80 schizophrenic patientsreported by Danziger required high dosesof desiccated thyroid (128-1280 mg) orracemic thyroxine (1-9 mg). Of the 54patients that recovered with thyroidtherapy or thyroid plus ECT, only fourrequired 640 mg or more of desiccatedthyroid and, only two required up to4mg of thyroxine. Such doses were prob-ably required to combat adrenochrome'santi-thyroid effects and, to make up forthe lack of T4 transport from the CSFto the brain ("brain hypothyroidism").Hoskins and others report on the toler-ance of schizophrenics for even higherdoses of desiccated thyroid than thoseused by Danziger.'*"''̂ To enable goodtreatment outcome, the BMR is raised toa level that likely improves the functionand production of respiratory enzymesin the cerebrum.*^ In Danziger's study,first-episode cases had the best responsehowever, one third of the chronic cases(five plus years post-onset) experiencedfull recovery as well.

A double-blind efficacy study reportedby Lochner et al. in 1963 used T3 {L-tri-iodothyronine) treatment in a six-weektrial on 30 chronic male schizophrenicseight plus years post-onset.**^ Typicaltranquilizers prescribed at the time werediscontinued in a wash-out period severalweeks prior to treatment. Patients wereincluded if they tolerated withdrawal

without exhibiting aggressive behaviour.15 subjects were randomly assigned tothe thyroid group and another 15 subjectsto the placebo control group. Red bloodcell uptake of I'"-T3 was normal for allsubjects at baseline; they were euthyroidaccording to blood tests. The treatmentgroup received 50 meg of T3 b.i.d. for oneweek, then 100 meg b.i.d. (200 meg perday) for six weeks.

In this short treatment period, sevenof the 15 patients treated with T3 re-sponded very well. They had improvedmotor activity, work performance, spon-taneity, sociability and logical/relevantthinking. Some reported they were"more lively" and could "think better."Mood improved and they showed inter-est in their environment. They showedimprovements in executive functioning;some voiced "plans for the future" andwanted to visit relatives, return to workand resume family relationships outsideof tbe hospital. Five of the 15 patientshad some worsening. Two of these fivepatients were responsive and cooperativewith generally better mood but, exhibitedhallucinations and delusions that hadbeen repressed and were tense, restless,and loquacious. Another two of thesefive patients became non-conversiveand tense witb masked faciès and mo-tor retardation. The last of these fivepatients became incoherent, irritable, andexplosive with increased hallucinations,delusions, and activity. Tbe remainingthree of the 15 experienced no change.All schizophrenics returned to their pre-vious state shortly after discontinuationof treatment Lochner's study was repro-duced by Scheuing and Flach with thesame cohort and, a consensus of resultswas determined."*' The results with T3 areimpressive when you consider the shorttreatment duration, the chronicity ofthe cohort and, the failure to implementoptimal dosing strategy. Doses of 200 megof T3 may have been too high for those

100

Orthomolecular Treatment For Schizophrenia: A Review (Part Two)

patients that aggravated in the given six-week time-frame of the study. Conversely,200 meg may not have been a high enoughdose for those schizophrenics that did notrespond. To this author's knowledge, theuse of T3 in first-episode schizophreniahas not been fully investigated.

Hoffer also reports on 12 schizo-phrenic patients treated on nicotinic acidand optimally dosed desiccated thyroid."'Of the 11 patients that completed thetreatment, nine had benefited. Six of thenine were moving toward rapid recoveryand had very much improved. The remain-ing three were improving consistent withincreasing doses of desiccated thyroid.The average maintenance dose of desic-cated thyroid was 300 mg per day.

As adrenochrome reducing nutrients,vitamin B( and C play a key role in reduc-ing the oxidative stress on the thyroid

gland. This thyroid link may explain inpart, why vitamin B, and C yield suchgood success in treatment. As a finalnote on thyroid function, blood testingcan help rule out the hyper-functioningstate typical of Grave's Disease.'" Grave's,in its active phase, is a state of thyroidhypcrfunction and botanicals are veryuseful in calming thyroid function andpreventing surgery and irradiation. Inlow thyroid states, botanical interven-tions are very useful to help support andrestore the thyroid gland and peripheralconversion.

OverviewFigure 1 (below) isa schematic of the

key causative factors of schizophrenia.Modern research continually confirmsthat these factors are important lo schizo-phrenic pathophysiology. This is why, in

Figure 1. Schizophrenia: Summary of Causative Factors.

101

Journal of Orthomolecular Medicine Vol. 23, No. 2, 2008

support of Dr. Hoffer's original work, wenow see down-regulated niacin recep-tors in the anterior cingulate cortex ofschizophrénies.** Tbe list of assessmentsand treatments described herein are notexhaustive but represent the core consid-erations of optimal complementary treat-ment for schizophrenia. Orthomoleculartreatment can be implemented safely asan adjunct to conventional psychiatrictherapy. Schizophrenics treated withorthomolecular medicine experiencepositive changes. Response is based onthe degree of severity and the durationof illness. We see schizophrenics whohave been sick for a year or two whostart responding within weeks. Schizo-phrenics sick over five years are lessresponsive initially but. improve withlong term care. The pathological dete-rioration of brain tissue in schizophreniashould impel us to use orthomoleculartreatment to keep oxidative stress atbay. The necessity of early screeningand early intervention is important forboth orthomolecular and conventionalpsychiatric treatment. In first-episodecases, a cocktail of desiccated thyroid(or T3-SR), vitamin B,, and vitamin Cmay the best early detection-interventionprogram ever developed. Complementarytreatments for schizophrenia have beenin the workings since the 1930s. A largeoutcome study is needed to comparethe efficacy of orthomolecular treat-ment versus psychiatric medication.Orthomolecular treatment should playa key role in mainstream mental healthcare and schizophrenic patients/familiesconstantly express their desire to see thathappen.**""" Conventional mental healthcosts are exorbitant in comparison toorthomolecular treatment costs andthe potential for improved quality oflife should empower practitioners to besteadfast in addressing core underlyingbiocbemistry."''

References1. Kelly G: Peripheral Metabolism of Thyroid

Hormones: A Review. Altern Med Rev. 20(X);S(4): 306-333.

2. Aschner M, Cherian MG, Klaassen CD, et al:Metallothioneins in brain-the role in physiol-ogy and pathology. Tnxicol Appl Pharmacol.1997; 142(2): 229-242.

3. Prabakaran S, Swatton JR, Ryan MM. Tor-rey EF, et al: Mitochondriai dysftinction inschizophrenia: evidence for compromisedbrain metabolism and oxidative stress. MolecPsychiat. 2004; 9(7): 684-697. 643.

4. YaoJK. Reddy RD. van Kämmen DP: Oxidativedamage and schizophrenia: an overview of theevidence and its therapeutic implications. CNS/Jrugs, 2001; 15(4); 287-310.

5. Kunert HJ. Norra C. Hoff P: Theorie.-; of de-lusional disorders. An update and review.Psyclwpathology. 2007: 40(3): 191-202.

6. WoU TL Kotun J. Meador-Woodruff JH:Plasma copper, iron, ceruloplasmin and fer-roxidase activity in schizophrenia. Scliizophrflfis. 2006; 86(1-3): 167-171.

7. Stanley PC. Wakwe VC: Toxic trace metals inthe mentally ill patients. Niger Postgrad Med/. 2002; 9(4): 199-204.

8. WallworkJC; Zinc and the central nervoussystem. Prog Food Nutr Sei. 1987; 11 (2); 203-247.

9. Ebadi M, Iversen PL. Hao R. et al; Expressionand regulation of brain metailothionein. Neu-rocheiiilnt. 1995: 27(1): 1-22.

10. Chimienti F, Jourdan F, Favier A, et al: Zincresistance impairs sensitivity to oxidativestress in HeLa cells: protection throughmetallothioneins expression. Free Hadic BiolMÍ;ÍÍ2001;31(10); 1179-1190.

11. Aschner M: The functional significance ofbrain metallothioneins. i-/li'£ii/, 1996; 10(10);1129-1136.

12. Goyer RA: Nutrition and metal toxicity. Am JClin Nutr. 1995; 61(3 Suppl): 646S-650S.

13. Bahiga LM, Kotb NA. FJ-Dessoukey FA: Neuro-logical syndromes produced by soiiie toxic met-als encountered industrially or environmentally.ZEmahrungswiss. 1978; 17(2): 84-88.

H.Zheng W, Lu YM, Lu GY. et al; Transthyre-tin, thyroxine, and retinol-binding proteinin human cerebrospinal lluid: effect of leadexposure. ro;«-/co/to. 2001; 61(1): 107-114.

Í5. Zheng W. Blaner WS, Zhao Q: Inhibition bylead of production and secretion of trans-thyretin in ihf choroid plexus: its relationto thyroxine transport at blood-CSF barrier.Toxicol Appl Pharmacol, 1999; 155(1): 24-31.

102

Orthomolecular Treatment For Schizophrenia: A Review (Part Two)

16. Wenzel KG, Pataracchia RJ: The Earth's Gißto Medicine: Minerals in Health and Disease.Alton, Ontario. KOS Publishing. 2005.

17. Rajanna B; Hobson M: Influence of mer-cury on uplaki' of [3H |(lopaniiiU' and[3H|norepinephrint' by ral brain synapto-somes. Toxicol Lett. 1985; 27( 1-3): 7-14.

18. Foster HD: What Really Causes Alzheimer'sDisease? 2004. (PDF at http://www.lidfoslfr.com)

19. Ritiobello MP. Scutari G. Roscólo R. et al:Oxidation of adrenaline and ils derivatives byS-nitrosoglutathione. Nitric Oxide. 2001; 5(1):39-46.

20.Johnson S: Micronutrit'nt accumulation anddepletion in scbizophrenia. epilepsy, autismand Parkinson's disease? Med Hypoth, 2001:56(5): 641-645.

21. Heinrich TW. Grahm G: HypothyroidismPresenting as Psychosis: Myxcdema Mad-ness Revisited. Prim Care Companion / ClinPsychiat, 2003; 5(6): 26(1-266.

22. Gupta P, Kar A: Cadmium induced thyroiddysfunction in cliieken: hepatic lype 1 iodo-tli)Tonine 5'-monodeÍodina.se activity and roleof lipid peroxidation. Cornp Biochern PhysiolC Pharmacol Taxical ¡indocrinal. 1999; 123( 1 ):39-44.

23. (iupta P. Kar A: Role of ascorbic acid in cad-mium-induced ihyroid dysftinclion and lipidperoxidatiun.y/1/J/j/ Toxicoi 1998; 18(5): 317-320.

24. Chaurasia SS. Kar A: Protective effects ofvitamin R against lead-induced deteriorationof membrane associated type-I iodothyronine5-moiiodeiodinase (5'I)-I} activity in malemice. Toxicology, 1997; 124(3); 203-209.

2.5. Rarregârd I.. IJndstedt ti. Schütz A, et ah Endo-crine function in mercury exposed chloral kaliworkers. Occiip linviron Med. 1994: 51(8): 536-540.

26. Pfeiffer CC Braverman VA\: Zinc, the brainand behaviour. ßio/Ps/c/i/a/. 1982; 17(4):513-532.

27. Noseworthy MD. Bray TM: Zinc deficiency ex-acerbates loss in blood-brain barrier integrityinduced hy hyperoxia measured by dynamicMKl. ProcSocExp Biol Meet 2000; 223(2); 175-182.

28. Mar/ Rli; Medical Nutril¡on from Marz. Port-land, OR. Omni-Press. 1997.

29. Levine J. Slahl / . Sola BA, et al; I lomocyste-ine-reducing strategies improve symptomsin chronic schizophrenic patients with hyper-homocysteinemia. ISiol Psychiat, 2006; 60 (3);265-269.

30. Deijen JB. van der Beek EJ, Orlebeke JF, et al:Vitamin R̂ supplementation in elderly men;efTecls on nujoci. memory, performance andmental effort. Psychopharmacology (Reri).1992; 109(4); 489-496.

31. Lerner V, Bergman J, Statsenko N, et al: Vi-tamin B,, treatment in acute neuroleptic-in-ducedakathisia:a randomized, double-blind.placeÍHJ-controlled study./(,"//>//'.syí7/ííí/, 2004:65(11); 1550-1554.

32.1-erner V. Kaptsan A. Miodownik C, et al: Vi-tamin B,, in treatment of tardive dyskinesia: apreliminary case series study. Clin Neurophar-macal. t999; 22(4): 241-243."

33. Sandyk R. Pardeshi R: Pyridoxine improvesdrug-induced parkinsonism and psychosis ina schizophrenic patient. Int J NeuroscL 1990;52(3-4): 225-232.

34. Wenzel KG: Orthomalecular Treatment forMental Health: Tlw Roll's of Hypoglycumia.Pyrroturia and Htstamine Disturbances. 2000Apr. Nutritional Medicine Today 29"" AnnualCtinference. Vancouver, BC.

35. Jackson JA. Riordan HD. Nealhery S. et al: Casefrom the Center: Urinary Pyrrole in Health andDisease. / Or//i«///ü//V/(>c¿ 1997; 12(2); 96-98.

36. Edelman E; Natural Healing for .Schizophre-nia: A Compendium of Nutritional Methods.Rugene. OR. Borage Rooks. 1996.

37. Hoffer A: Schizophrenia; an evolutionarydefense againsL severe stress.y Orthomol Med,1994; 9(4); 205-221.

38. Pfeiffer CC: Mental and Elemental Nutrients.New Canaan. CN. Keats Publishing. 1975.

39. Sohler A. Hotsztynska F.. Pfeiffer C'C; A RapidScreening Test for Pyroluria; Useful in Dis-tinguishing a Schizophrenic Subpopulation.Orlhomol Psychiat. 1974: 3: 273-279.

40. Pfeiffer CC. Iliev V: Pyrroluria. urinary mauvefactor, causes double deficiency of B,, and zincin schizophrenics, bed Proc. 1973; 32: 276.

41. Sohler A, Beck R, Noval Jj; Mauve factor re-identified as 2.4-dimethyl-3-ethylpyrrole andits sedative effect on the CNS. Nature. 1970;228(278); 1318-1320.

42.McGinnis WR. Audhya T. Walsh WJ. et al;Discerning the mauve factor, part I. AlternThe.r. 2OO8'(Mar/Apr); 14(2); 40-50.

43. Mello AA. Mello Ml-. Carpenter LL. et al; Up-date on stress and depression: Ihe role of thehypothalamic-pituitary-adrenal (HPA) axis.liev Bras Psiquiatr. 2003: 25(4); 231 -238.

44. Abdullatillin. Ash rafAP: Reversible subdini-cal hvpothyroidism in the presence of adrenalinsufficiency. Endocr Pract. 2006; 12(5); 572.

45. Candrina R, Giustina G: Addison'sdisease and

103

Journal of Orthomolecular Medicine Vol. 23. No. 2, 2008

corticosteroid-reversible hypothyroidism. /EndocrinolInvest. 1987; 10(5): 523-526.

46. Michel V. Peinnequin A, Alonso A. et al;Decreased heat tolerance is associated withhypothalamo-pituitary-adrenocorticai axisimpairment. Neurosci. 2007; 147(2): 522-531.

47. Ritsner M, Maayan R, Gibel A. et al; P.levationof the cortisol/dehydroepiandrosterone ratioin schizophrenia patients. Eur Neuropsycho-pharmacol. 2004; 14(4); 267-273.

48. Swigar ME. Kolakowska T. Quinlan DM;Plasma cortisol levels in depression and otherpsychiatric disorders; a study of newly admit-ted psychiatric patients. Psychol Med. 1979;9(3); 449-455.

49. Contreras F, Menchon JM. Urretavizcaya M.et al; Hormonal differences between psychoticand non-psychotic melancholic depression. /Affect Disord. 2007; 100(1-3); 65-73.

50. Bauer M. Undon HD. Silverman DH. et al; Thy-roid, brain and mood modulation in affectivedisorder: insights from molecular research andfunctional brain imaging. PharmacopsychiaU2003; 36 Suppl 3: S215-S221.

51. McGaffeeJ, Barnes MA. Lippmann S: Psychiat-ric presentations of hypothyroidism. Am FamPhysician. 1981; 23(5); 129-133.

52. Jackson IM: The thyroid axis and depression.Thyroid, 1998; 8(10); 951-956.

53. Oppenheimer JH. Braverman LE, Toft A, et al:A therapeutic controversy. Thyroid hormonetreatment: when and what? / Clin EndocrinolMetab. 1995; 80(10): 2873-2883.

54. Westphal SA: Unusual presentations ofhypothyroidism./Im/Med Sei, 1997:314(5):333-337.

55.1 leitman B. Irlzarry A; Hypothyroidism; com-mon complaints, perplexing diagnosis. NursePract, 1995; 20{3): 54-60.

56. Shafer RR. Prentiss RA. Rond JH; Gastrointes-tinal transit in thyroid disease. Castroenterol1984; 86(5 Ptl); 852-855.

57. Othman SS, Kadir KA. Hassan J, et a!; Highprevalence of thyroid function test abnormali-ties in chronic schizophrenia. Australian andNZ} Psychiat, 1994; 28: 620-624.

58. Roca RP, Blackman MR. Ackeriey SM. et al;Thyroid hormone elevations during acutepsychiatric illness; relationship to severity anddistinction from hyperthyroidism. EndocrineRes. 1990; 16(4); 415-447.

59. Lum SM. Nicoloff JT. Spencer CA, et al; Pe-ripheral tissue mechanism for maintenance ofserum triiodothyronine values in a thyroxine-deficient state in manj Clin Invest, 1984; 73(2);570-575.

60. Haddow JE. Paiomaki GE, Allan WC. et al;Materna! thyroid deficiency during pregnancyand subsequent neuropsychoioglcal develop-ment of the child. N EnglJMed, 1999; 341(8):549-555.

61. Brouwer A. Morse DC, Lans MC, et al: Inter-actions of persistent environmental organo-halogens with the thyroid hormone system;mechanisms and possible consequences foranimal and human health. Toxicol ¡ndHealth,1998; 14(1-2): 59-84.

62. Hatterer JA, 1 ierbert J. Hidaka C. et al; CSFtransthyretin in patients with depression. AmJPsychiar. 1993; 150(5); 813-815.

63. Schreiber G: The evolutionary and integrativeroles of transthyretin in thyroid hormone ho-meostasis./£'íiííoí;rmo/. 2002; 175(1); 61-73.

64. Wan C. Yang Y. Li H. et al: Dysregulation ofretinoid transporters expression in body flu-ids of schizophrenia patients./Proieome/ies,2006; 5(11); 3213-3216.

65. Huang JT. Leweke FM. Oxley D. et al: Diseasebiomarkers in cerebrospinal fluid of patientswith first-onset psychosis. PLoS Med. 2006;3(ll);e428.

66. Sullivan GM, Mann JJ. Oquendo MA. et al;Low cerebrospinal fluid transthyretin levels indepression: correlations with suicidal ideationand low serotonin function, Biol Psychiat.2006; 60(5); 500-506.

67. Sullivan GM, Hatterer JA, Herbert J, el al; Lowlevels of transthyretin in the CSF of depressedpatients. Am J Psychiat. 1999; 156(5): 710-715.

68. Hidal JT. Kaplan MM: Inhibition of thyroxine5-deiodination type II in cultured humanpiacental cells by cortisol. insulin, 3',5'-cyehcadenosine monophosphate, and butyrate.Metabolism, 1988; 37(7); 664-668.

69. Visser TJ. Leonard JL, Kaplan MM, et al: Ki-netic evidence suggesting two mechanisms foriodothyronine 5-deiodination in rat cerebralcortex. Proc Nati Acad Sei. USA. 1982; 79(16):5080-5084.

70. Foster HD; What Really Causes Schizophrenia?2003. (pdf at http://wvvw.hdfoster.com)

71. HofFer A: Thyroid and schizophrenia./Or/fto-mo/Aíeí¿ 2001; 16(4): 205-212.

72. Langer P, Földes O; Efîect of adrenaline onbiliary excretion of triiodothyronines in ratsmediated by alpha I-adrenoceptors and re-lated to the inhibition of 5'-monodeiodinationin liver. / Endocrinol Invest, 1988(Jul-Aug);11(7); 471-476.

73. Nauman A. Kamin 'ski T, Herbaczyn 'ska-Ce-dro K; In vivo and in vitro effects of adrenaline

104

Orthomolecular Treatment For Schizophrenia: A Review (Part Two)

on conversion of thyroxine to triiodothyronineand to reverse-triiodtjthyronine in dog liverand heart Eur I Clin Invest. l980(Jun);^10(3):189-192.

74. Ceremuzyn ski L. Herbaezyn ska-Cedro K,Broniszewska-Ardelt B. et ai: F.videnee forthe detrimental effect of adrenaline infused tohealthy dogs in doses imitating s|»ontaneoiissecretion after coronary occlusion. CardiovascHes. 1978(Mar): 12(3); 179-189.

75. MaayanML. lngbarSH;F.nectsofepinephrineon iodine and intermediary metabolism in iso-lated thyroid cells. ¿.Hf/otr/Ho/og)'. 1970(Sept);87(3); 588-595.

76. Holier A, Osmond H; The Hallucinogens. Aca-tiemic Press, New York. 1967.

77. HupkaS. Dumontjii;/?/ W/r» effect of adrena-line and o( her amines on glucose metabolismin sheep thyroid, heart, liver, kidney and tes-ticular slices./i/otV/c/;; Pharmacol. 1963 (Sep);12; 1023-1035.

78. Pastan I. Herring B. John.son P. el al; Sludit'son the mechanism by which epinephrinestimulates glucose oxidation in the thyroid. JHiol Chem. \ 962; 237(2): 287-290.

79. Skoliarova NA: Morphology of the endocrinesystem in schizophrenia according lo earlyautopsy findings (the hypophyseal-thyroidsystem). Zh Nevropalol Psikhialr Im S S Kor-sakom. 1975; 75(7); 10-15-53. (abstract only)

80. Dan/.iger L; Thyroid I herapy of schizophrenia.Dis Nerv Syst, 1958; 19(9): 373-378.

81. Hoskins RG, Sleeper FH; The thyroid factorin dementia Praecox. Am / Psvchi/tt. 1930; 87;4lt-432.

82. Hoskins R(i. Walsh A; Oxygen consumptitin("Basal Metabolic rate'") in schizojjhrenia: M.Distribution in 214 cases. AMA Arch NeurolPsychiat. 1932:28: 1346-1364.

83. Danziger I,. Kindwall JA: Thyroid therapy insome mental disorders. Dis Nerv Syst. 1953;14(1); 3-13.

84. Lochner KH. Scheuing MIÏ, Flach FF: 1 he ef-fect of L-triiodothyronine on chronic schizo-phrenic patients. Acta Psychiatr Scaud. 1963;39:413-26.

85. Scheuing MR. Flach FF: I heeíTect of 1,-lriiodo-thyronine on chronic schizophrenic patienls.Am j Psychiat. I964(nec); 121:594-59.5.

86. Miller CL. DulayJK; The high-affinity niacinreceptor FÍM74A is decreased in the anteriorcinguiate cortex of individuals with schizo-phrenia. Brain Res Bull. 2008; doi;10.l016/j.brainresbull.2008.03.015, (in press)

87. Zammit S. Lewis S. Ciunnell D. et al; Schizo-phrenia and neural tube defects: compari-sons from an epidemiological perspective.Schizophr Bull. 2007 Jul: 33(4 ): «53-858.

88. Reglaiid B; Schizophrenia and single-carboníne\íibo\\»m. Prog Neuropsychopharmncol BiolPsychiatry. 200.5"Sep; 29(7): i 124-1132.

89. Rö.ssler\V,SalizeHJ, van OsJ.et ai: Size of burdenof schi/^iphrenia and psychotic disorders. EurNeuropsychopfiarmacol. 2005; 15(4); 399-4Ü9.

105