1. Metyrosine and PsychosisMetyrosine and Psychosis
Carlo Carandang, MD, FAPACarlo Carandang, MD, FAPA
PsychiatristPsychiatrist
Presentation for the DepartmentPresentation for the Department
of Psychiatry, Philippine Generalof Psychiatry, Philippine General
Hospital, Manila, the University ofHospital, Manila, the University of
the Philippinesthe Philippines
February 24, 2014February 24, 2014

2. ObjectivesObjectives
 Clinical utility of metyrosineClinical utility of metyrosine
 Discuss case report of metyrosine in psychosisDiscuss case report of metyrosine in psychosis
associated with VCFSassociated with VCFS
 Discuss proposed clinical study of metyrosine forDiscuss proposed clinical study of metyrosine for
acute treatment resistant psychosisacute treatment resistant psychosis

3. Metyrosine- clinical indicationsMetyrosine- clinical indications
 Metyrosine FDA indicated forMetyrosine FDA indicated for
pheochromocytomapheochromocytoma
 excessive norepinephrine and epinephrine areexcessive norepinephrine and epinephrine are
producedproduced
 Metyrosine competitively inhibits the enzymeMetyrosine competitively inhibits the enzyme
tyrosine hydroxylasetyrosine hydroxylase
 Inhibition of tyrosine hydroxylase leads to aInhibition of tyrosine hydroxylase leads to a
decrease of dopamine, epinephrine anddecrease of dopamine, epinephrine and
norepinephrine levelsnorepinephrine levels

5. Metyrosine- dosing and SEsMetyrosine- dosing and SEs
 Half-life of about 4 hours after a singleHalf-life of about 4 hours after a single
dosedose
 Dosing: initiate at 250mg QID, then titrateDosing: initiate at 250mg QID, then titrate
to maximum of 4grams/dayto maximum of 4grams/day
 Sedation, tremor and diarrhea mostSedation, tremor and diarrhea most
common adverse effectscommon adverse effects

6. Other Possible Clinical Uses ofOther Possible Clinical Uses of
MetyrosineMetyrosine
 Carandang C and Scholten M (2006).Carandang C and Scholten M (2006).
Metyrosine in Psychosis Associated withMetyrosine in Psychosis Associated with
22q11.2 Deletion Syndrome: A Case22q11.2 Deletion Syndrome: A Case
Report.Report. Journal of Child and AdolescentJournal of Child and Adolescent
Psychopharmacology.Psychopharmacology.

7. Velocardiofacial SyndromeVelocardiofacial Syndrome
(VCFS)(VCFS)
 First described by Robert Shprintzen in 1978First described by Robert Shprintzen in 1978
 From Latin wordsFrom Latin words
 Velum = palateVelum = palate
 Cardia = heartCardia = heart
 Facies = faceFacies = face
 Recent literature uses nomenclature denoting geneticRecent literature uses nomenclature denoting genetic
deletion: 22q11.2 Deletion Syndrome (22q11.2 DS)deletion: 22q11.2 Deletion Syndrome (22q11.2 DS)
 VCFS also known as:VCFS also known as:
 Shprintzen Syndrome, DiGeorge Syndrome, CraniofacialShprintzen Syndrome, DiGeorge Syndrome, Craniofacial
Syndrome, or Conotruncal Anomaly Unusual Face SyndromeSyndrome, or Conotruncal Anomaly Unusual Face Syndrome

8. Velocardiofacial SyndromeVelocardiofacial Syndrome
(VCFS)(VCFS)
 Not uncommonNot uncommon
 Prevalence 1 in every 4,000 newbornsPrevalence 1 in every 4,000 newborns
 8% of all cleft palate patients8% of all cleft palate patients

9. VCFS Is a Risk Factor forVCFS Is a Risk Factor for
SchizophreniaSchizophrenia
 Prevalence of schizophrenia amongPrevalence of schizophrenia among
patients with VCFS ranges from 10% topatients with VCFS ranges from 10% to
30%30% (Shprintzen et al. 1992, Pulver et al. 1994, Murphy et al.(Shprintzen et al. 1992, Pulver et al. 1994, Murphy et al.
1999)1999)
 Amongst those with schizophrenia,Amongst those with schizophrenia,
prevalence of VCFS ranges from 1% toprevalence of VCFS ranges from 1% to
2%2% ((Horowitz et al. 2005, Murphy 2002, Karayiorgou et al. 1995Horowitz et al. 2005, Murphy 2002, Karayiorgou et al. 1995))

10. VCFS Clinical FeaturesVCFS Clinical Features
 Clinical FeaturesClinical Features
 Cleft palateCleft palate
 Heart defectsHeart defects
 Characteristic faciesCharacteristic facies
 Hypernasal speechHypernasal speech
 Learning disabilitiesLearning disabilities

11. Velocardiofacial SyndromeVelocardiofacial Syndrome
(VCFS)(VCFS)
Facial Findings:Facial Findings:
• Elongated faceElongated face
• Almond-shaped eyesAlmond-shaped eyes
• Wide noseWide nose
• Small earsSmall ears
Pictures From: Shprintzen RJ: Velocardiofacial Syndrome. Otolaryngol Clin North Am 33(6), 2000.

13. VCFSVCFS
 Results from hemizygous deletion of theResults from hemizygous deletion of the
long arm of chromosome 22, spanning 22long arm of chromosome 22, spanning 22
well-characterized genes, including COMTwell-characterized genes, including COMT
genegene
 Only 10% of cases are inheritedOnly 10% of cases are inherited
 For other 90%, cause of deletion unknownFor other 90%, cause of deletion unknown
 Diagnosis confirmed by fluorescence inDiagnosis confirmed by fluorescence in
situ hybridization (FISH)situ hybridization (FISH)

15. TBX-1 (T-box transcription factor)
CRKL
UFD1L (Ubiquitination degradation)
HIRA(transcription factor)
Centromere
DGCR6
IDD/DGCR2
TSK/DGS-G
ES2/DGS1
GSCL (Goosecoid-like homeobox gene)
CTP (Citrate transporter) CLTCL
TMVCF
CDCrel-1
GP1b (Platelet glycoprotein)
T10
COMT (Catechol-O-methyltransferase)
ARVCF
LZTR-1 (Transcriptionfactor)
ZNF74
CDC45L
RANBP1
Human Ch22q11.2
Heparin cofactor
90% 8%

16. Psychosis and VCFSPsychosis and VCFS
 Hypothesized that psychosis associated withHypothesized that psychosis associated with
22q11.2 deletion syndrome may be associated22q11.2 deletion syndrome may be associated
with excess catecholamines from a functionalwith excess catecholamines from a functional
deficiency of catechol-O-methyltransferasedeficiency of catechol-O-methyltransferase
(COMT)(COMT)
 Deficiency of COMT could result from either orDeficiency of COMT could result from either or
both:both:
 Half-dose expression (only one copy of allele)Half-dose expression (only one copy of allele)
 Presence of low-activity COMT variant on the non-Presence of low-activity COMT variant on the non-
deleted alleledeleted allele

17. Metyrosine (DemserMetyrosine (Demser®)®)
 A key step in the biosynthesis ofA key step in the biosynthesis of
dopamine involves the conversion ofdopamine involves the conversion of
tyrosine to dihydroxyphenylalaninetyrosine to dihydroxyphenylalanine
(DOPA)(DOPA)
 This rate-limiting step is catalyzed byThis rate-limiting step is catalyzed by
the enzyme tyrosine hydroxylasethe enzyme tyrosine hydroxylase
 The catalytic conversion is blocked byThe catalytic conversion is blocked by
the competitive inhibitor, α-the competitive inhibitor, α-
methyltyrosine (metyrosine)methyltyrosine (metyrosine)

18. Metyrosine (DemserMetyrosine (Demser®)®)
 Metyrosine competitively inhibits the enzymeMetyrosine competitively inhibits the enzyme
tyrosine hydroxylasetyrosine hydroxylase
 Inhibition of tyrosine hydroxylase leads toInhibition of tyrosine hydroxylase leads to
decrease of dopamine levels and reduction ofdecrease of dopamine levels and reduction of
psychotic symptomspsychotic symptoms
 Psychosis associated VCFS are relativelyPsychosis associated VCFS are relatively
unresponsive to currently used antipsychoticsunresponsive to currently used antipsychotics
(Graf et al. 2001, Gothelf et al. 1999)(Graf et al. 2001, Gothelf et al. 1999)

20. Intervention Studies of VCFSIntervention Studies of VCFS
PsychosisPsychosis
 Graf et al. 2001, case series, N=5Graf et al. 2001, case series, N=5
 Metyrosine was effective in reducingMetyrosine was effective in reducing
neuropsychiatric symptoms in 4 patientsneuropsychiatric symptoms in 4 patients
 Carandang and Scholten, 2006 (in press),Carandang and Scholten, 2006 (in press),
case reportcase report
 Metyrosine effective in treating psychosisMetyrosine effective in treating psychosis
resistant to antipsychoticsresistant to antipsychotics

21. Case ReportCase Report
 15 year-old male presents for 115 year-old male presents for 1stst
psychpsych
hospitalizationhospitalization
 Diagnosed VCFS in early childhoodDiagnosed VCFS in early childhood
 RFA: Aggression towards motherRFA: Aggression towards mother
 Multiple mood symptoms lasting monthsMultiple mood symptoms lasting months
 Mood lability,Mood lability, tearfulness, hypersomnia, socialtearfulness, hypersomnia, social
withdrawal, apathy, and declining schoolwithdrawal, apathy, and declining school
performanceperformance

22. Case ReportCase Report
 While in NYC, ran away for 2 days on theWhile in NYC, ran away for 2 days on the
subwaysubway
 After NYC trip, convinced he will beAfter NYC trip, convinced he will be
miserable if he lives with his parents in themiserable if he lives with his parents in the
countryside, and would be happy if hecountryside, and would be happy if he
lived in a big citylived in a big city
 Threatened mother with knife, as she wasThreatened mother with knife, as she was
a barrier to his moving to the big citya barrier to his moving to the big city

23. Case ReportCase Report
 Early childhood: speech and motor delaysEarly childhood: speech and motor delays
 Age 4, problems with attention: a trial ofAge 4, problems with attention: a trial of
methylphenidate led to a negative reactionmethylphenidate led to a negative reaction
 Elementary school: problems processingElementary school: problems processing
multi-step directionsmulti-step directions
 Recent testing: verbal IQ 85, performanceRecent testing: verbal IQ 85, performance
IQ 83IQ 83

24. Case ReportCase Report
 Premorbid functioning otherwise normalPremorbid functioning otherwise normal
 average student, friendly and affectionate personaverage student, friendly and affectionate person
 VCFS confirmed by FISH age 12VCFS confirmed by FISH age 12
 Hypernasal speech, typical facies, learning deficitsHypernasal speech, typical facies, learning deficits
 No other medical problemsNo other medical problems
 2 paternal first cousins and a maternal aunt had2 paternal first cousins and a maternal aunt had
mood disordersmood disorders

25. Case ReportCase Report
 Additional Symptoms:Additional Symptoms:
 Poor hygiene, poor eye contact, dysarthria,Poor hygiene, poor eye contact, dysarthria,
non-spontaneous/telegraphic speech, affectnon-spontaneous/telegraphic speech, affect
blunted, guarded, and exhibited significantblunted, guarded, and exhibited significant
mood lability. Thought processes weremood lability. Thought processes were
concrete. No loosening of associations wereconcrete. No loosening of associations were
noted. He perseverated on moving to the bignoted. He perseverated on moving to the big
citycity
 DDx: prodromal schizophrenia vs. moodDDx: prodromal schizophrenia vs. mood
disorderdisorder

26. Case ReportCase Report
 Psychosis Clinic: Structured Interview forPsychosis Clinic: Structured Interview for
Prodromal Syndromes (SIPS)Prodromal Syndromes (SIPS)
 Scoring of the SIPS was in the psychotic rangeScoring of the SIPS was in the psychotic range
with regards to the unusual thought contentwith regards to the unusual thought content
 While his belief about “moving to the big city to beWhile his belief about “moving to the big city to be
happy” was not the bizarre or typical beliefshappy” was not the bizarre or typical beliefs
associated with psychosis, the patient held this beliefassociated with psychosis, the patient held this belief
with unwavering conviction and had acted on thiswith unwavering conviction and had acted on this
belief in aggressive and risky ways.belief in aggressive and risky ways.
 His pervasive thoughts also affected his academic,His pervasive thoughts also affected his academic,
social, and family functioning.social, and family functioning.
 Patient had minimal insight into the seriousness of hisPatient had minimal insight into the seriousness of his
dangerous behaviors.dangerous behaviors.

27. Case ReportCase Report
 However, the clinicians and researchers inHowever, the clinicians and researchers in
the psychosis specialty clinic had difficultythe psychosis specialty clinic had difficulty
giving a diagnosis of psychosis (despitegiving a diagnosis of psychosis (despite
the scoring on the SIPS), as this was anthe scoring on the SIPS), as this was an
atypical presentation for psychosis.atypical presentation for psychosis.
Nonetheless, the working diagnosis wasNonetheless, the working diagnosis was
Psychotic Disorder NOS, with thePsychotic Disorder NOS, with the
differential including prodromal psychosisdifferential including prodromal psychosis
and Delusional Disorder.and Delusional Disorder.

28. Case ReportCase Report
 In the ensuing months, patient enduredIn the ensuing months, patient endured
multiple psychiatric hospitalizationsmultiple psychiatric hospitalizations
 22ndnd
psych hosp was for suicide attemptspsych hosp was for suicide attempts
 Aripiprazole (Abilify®) was started andAripiprazole (Abilify®) was started and
titrated to 10mg daily. The patient initiallytitrated to 10mg daily. The patient initially
responded, as he was less labile, lessresponded, as he was less labile, less
withdrawn, and more animated.withdrawn, and more animated.
 Discharged on aripiprazoleDischarged on aripiprazole

29. Case ReportCase Report
 Readmitted the next month for his thirdReadmitted the next month for his third
hospitalization for self-harm behaviors, andhospitalization for self-harm behaviors, and
eventually discharged.eventually discharged.
 1 month later, behaviors again worsened. He1 month later, behaviors again worsened. He
had been making excessive attempts tohad been making excessive attempts to
communicate with his friend, which prompted acommunicate with his friend, which prompted a
call from the friend’s parents to the patient’scall from the friend’s parents to the patient’s
parents.parents.
 Precipitated a rapid decompensation, where thePrecipitated a rapid decompensation, where the
patient barricaded himself in his room and cutpatient barricaded himself in his room and cut
both his forearms.both his forearms.

30. Case ReportCase Report
 Police were summoned to escort the patient toPolice were summoned to escort the patient to
the hospital (4th hospitalization)the hospital (4th hospitalization)
 When police arrived, the patient attempted toWhen police arrived, the patient attempted to
stab the officer with a knife, who blocked thestab the officer with a knife, who blocked the
attempt and disarmed the patient.attempt and disarmed the patient.
 Parents had never seen this level of aggressionParents had never seen this level of aggression
with their son, and opined that the treatment withwith their son, and opined that the treatment with
aripiprazole worsened his symptoms.aripiprazole worsened his symptoms.

31. Case ReportCase Report
 Inpatient attending consulted with an expert onInpatient attending consulted with an expert on
VCFS. The expert recommended a trial ofVCFS. The expert recommended a trial of
metyrosine (Demser®), as many patients withmetyrosine (Demser®), as many patients with
VCFS have a COMT deficiency.VCFS have a COMT deficiency.
 Aripiprazole was discontinued and metyrosineAripiprazole was discontinued and metyrosine
was titrated to 1750mg daily. The patient hadwas titrated to 1750mg daily. The patient had
significant response to metyrosine, as hesignificant response to metyrosine, as he
exhibited less mood lability and was lessexhibited less mood lability and was less
perseverative on his belief of moving to the bigperseverative on his belief of moving to the big
city to be happy.city to be happy.
 He was discharged on a maintenance dose ofHe was discharged on a maintenance dose of
metyrosine 1000mg daily, and exhibitedmetyrosine 1000mg daily, and exhibited

32. Case ReportCase Report
 While on metyrosine, the patient was able toWhile on metyrosine, the patient was able to
avoid hospitalization, attend school, and engageavoid hospitalization, attend school, and engage
in relationships with family and friends.in relationships with family and friends.
 Patient reported improved moods, less irritability,Patient reported improved moods, less irritability,
and denied fixed ideations. In addition, he noand denied fixed ideations. In addition, he no
longer believed that it was absolutely necessarylonger believed that it was absolutely necessary
for him to live in the big city to be happy.for him to live in the big city to be happy.
 Continued to function on metyrosine for over 1Continued to function on metyrosine for over 1
year, at which time he was transferred toyear, at which time he was transferred to
another psychiatrist.another psychiatrist.

33. (Carandang and Scholten, in(Carandang and Scholten, in
press, 2006)press, 2006)
InnovativeInnovative
 ““The treatment of metyrosine for VCFSThe treatment of metyrosine for VCFS
psychosis represents a first in psychiatry, wherepsychosis represents a first in psychiatry, where
a known biochemical abnormality in a psychiatrica known biochemical abnormality in a psychiatric
disorder was corrected by a treatment thatdisorder was corrected by a treatment that
targets the biochemical pathway, leading totargets the biochemical pathway, leading to
reduction of psychiatric symptoms.”reduction of psychiatric symptoms.”

34. Can metyrosine work for psychosisCan metyrosine work for psychosis
not associated with VCFS?not associated with VCFS?
 Inhibition of tyrosine hydroxylase byInhibition of tyrosine hydroxylase by
metyrosine leads to a decrease ofmetyrosine leads to a decrease of
dopamine, epinephrine anddopamine, epinephrine and
norepinephrine levelsnorepinephrine levels
 Decrease production of dopamine shouldDecrease production of dopamine should
address the dopaminergic excess seen inaddress the dopaminergic excess seen in
psychosispsychosis

35. HypothesisHypothesis
 Metyrosine will reduce psychotic symptoms as itMetyrosine will reduce psychotic symptoms as it
will reduce dopamine levelswill reduce dopamine levels
 Blocking dopamine receptors via antipsychoticBlocking dopamine receptors via antipsychotic
medications may not be enough to reducemedications may not be enough to reduce
psychotic symptoms, so reducing the productionpsychotic symptoms, so reducing the production
of dopamine by inhibiting tyrosine hydroxylaseof dopamine by inhibiting tyrosine hydroxylase
may ameliorate psychotic symptomsmay ameliorate psychotic symptoms

36. Proposed Study: Metyrosine inProposed Study: Metyrosine in
Acute PsychosisAcute Psychosis
 Inclusion Criteria:Inclusion Criteria:
 Patients diagnosed with schizophrenia (DSM-Patients diagnosed with schizophrenia (DSM-
IV criteria)IV criteria)
 Patients have acute psychotic episode andPatients have acute psychotic episode and
admitted to an inpatient psychiatry unitadmitted to an inpatient psychiatry unit
 Ages 18-65Ages 18-65

37. Treatment Algorithm and PatientTreatment Algorithm and Patient
FlowFlow
 Stage 1Stage 1: Atypical antipsychotic for 3 weeks. Will start: Atypical antipsychotic for 3 weeks. Will start
an atypical antipsychotic not prescribed previously.an atypical antipsychotic not prescribed previously.
Titrate over 1 week to the following: olanzapine 20mgTitrate over 1 week to the following: olanzapine 20mg
daily, risperidone 6mg daily, quetiapine 600mg daily, ordaily, risperidone 6mg daily, quetiapine 600mg daily, or
ziprasidone 60mg BID. If no response by week 2, thenziprasidone 60mg BID. If no response by week 2, then
titrate to the following: olazapine 30mg daily, risperidonetitrate to the following: olazapine 30mg daily, risperidone
8mg daily, quetiapine 800mg daily, or ziprasidone 80mg8mg daily, quetiapine 800mg daily, or ziprasidone 80mg
BID.BID.
 If no or partial response to atypical antipsychotic, thenIf no or partial response to atypical antipsychotic, then
taper and discontinue atypical antipsychotic over 1 week,taper and discontinue atypical antipsychotic over 1 week,
then go to Stage 2.then go to Stage 2.

38. Treatment Algorithm and PatientTreatment Algorithm and Patient
FlowFlow
 Stage 2Stage 2: Assign randomly, double-blinded, the following: Assign randomly, double-blinded, the following
protocolprotocol
 Metyrosine for 3 weeksMetyrosine for 3 weeks
 Placebo for 3 weeksPlacebo for 3 weeks
 Titrate metyrosine according to following schedule:Titrate metyrosine according to following schedule:
Initiate metyrosine at 250mg QID, then titrate to 500mgInitiate metyrosine at 250mg QID, then titrate to 500mg
QID for 1 week. If no response by week 2, then titrateQID for 1 week. If no response by week 2, then titrate
metyrosine to 750mg QID.metyrosine to 750mg QID.
 At conclusion of acute trial, will break blind and followAt conclusion of acute trial, will break blind and follow
responders on metyrosine maintenance for 6 months.responders on metyrosine maintenance for 6 months.

39. Why study metyrosine forWhy study metyrosine for
psychosis?psychosis?
 Current atypical antipsychotics, the current goldCurrent atypical antipsychotics, the current gold
standard for treating psychosis, is associatedstandard for treating psychosis, is associated
with metabolic syndromewith metabolic syndrome
 Metyrosine not associated with metabolicMetyrosine not associated with metabolic
syndromesyndrome
 Sedation, tremor and diarrhea are the mostSedation, tremor and diarrhea are the most
common adverse effects of metyrosinecommon adverse effects of metyrosine

40. Market AnalysisMarket Analysis
 Schizophrenia has a 1.1% prevalenceSchizophrenia has a 1.1% prevalence
 World population is 7.046 billionWorld population is 7.046 billion
 77.5 million people with schizophrenia77.5 million people with schizophrenia
 If metyrosine has a market share of 10%,If metyrosine has a market share of 10%,
then 7.8 million people with schizophreniathen 7.8 million people with schizophrenia
may benefitmay benefit
 Current cost of Metyrosine in the States isCurrent cost of Metyrosine in the States is
in the order of hundreds of dollarsin the order of hundreds of dollars