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Metyrosine and Psychosis

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“Metyrosine and Psychosis”
Manila, Philippines; February 24, 2014
Presentation to the Department of Psychiatry and Research Department, University of the Philippines (Manila) College of Medicine, Philippine General Hospital.
*Clinical utility of metyrosine
*Discuss case report of metyrosine in psychosis associated with VCFS
*Discuss proposed clinical study of metyrosine for acute treatment resistant psychosis

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Metyrosine and Psychosis

  1. 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. 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. 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
  4. 4. 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
  5. 5. 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.
  6. 6. 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
  7. 7. 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
  8. 8. 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))
  9. 9. VCFS Clinical FeaturesVCFS Clinical Features  Clinical FeaturesClinical Features  Cleft palateCleft palate  Heart defectsHeart defects  Characteristic faciesCharacteristic facies  Hypernasal speechHypernasal speech  Learning disabilitiesLearning disabilities
  10. 10. 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.
  11. 11. 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)
  12. 12. 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%
  13. 13. 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
  14. 14. 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)
  15. 15. 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)
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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.
  23. 23. 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.
  24. 24. 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
  25. 25. 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.
  26. 26. 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.
  27. 27. 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
  28. 28. 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.
  29. 29. (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.”
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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.
  34. 34. 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.
  35. 35. 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
  36. 36. 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

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