Pediatric PsychosisPediatric Psychosis
Jess P. Shatkin, MD, MPHJess P. Shatkin, MD, MPHVice Chair for EducationVice Chair for EducationNYU Child Study CenterNYU Child Study Center
New York University School of MedicineNew York University School of Medicine
Learning ObjectivesLearning Objectives Residents will be able to:Residents will be able to:
1.1. Distinguish developmentally Distinguish developmentally ““normalnormal”” experiences from true psychosis in experiences from true psychosis in children.children.
2.2. Differentiate early from very early onset Differentiate early from very early onset schizophrenia.schizophrenia.
3.3. Describe an adequate work-up for a child Describe an adequate work-up for a child treated with an antipsychotic medication.treated with an antipsychotic medication.
4.4. Use BazettUse Bazett’’s Formula to calculate a QTc.s Formula to calculate a QTc.
Schizophrenia vs. PDDSchizophrenia vs. PDD Much of the early work on childhood Much of the early work on childhood
““schizophreniaschizophrenia”” was really about autism was really about autism Individuals with autism do not appear to Individuals with autism do not appear to
be at increased risk for schizophrenia be at increased risk for schizophrenia There does seem to be an increased risk There does seem to be an increased risk
of psychosis among those with Aspergerof psychosis among those with Asperger’’ss In the presence of PDD, schizophrenia is In the presence of PDD, schizophrenia is
diagnosed only if prominent delusions or diagnosed only if prominent delusions or hallucinations have been presenthallucinations have been present
What is Developmentally What is Developmentally Normal?Normal?
Most children who exhibit psychotic or Most children who exhibit psychotic or psychotic-like symptoms do not have a psychotic-like symptoms do not have a true psychotic disordertrue psychotic disorder
Transient hallucinations are Transient hallucinations are occasionally observed in preschool occasionally observed in preschool children (visual & tactile are most children (visual & tactile are most common) and are prognostically benigncommon) and are prognostically benign Hypnogogic & hypnopompic hallucinationsHypnogogic & hypnopompic hallucinations
Loosening of associations and illogical Loosening of associations and illogical thinking decrease markedly after about thinking decrease markedly after about age 6 – 7 years in childrenage 6 – 7 years in children
Early Signs of SchizophreniaEarly Signs of Schizophrenia Children at increased risk for schizophrenia Children at increased risk for schizophrenia
tend to have abnormalities of gait, posture, tend to have abnormalities of gait, posture, and muscle tone (e.g., neurologic soft signs)and muscle tone (e.g., neurologic soft signs)
Hallucinations, thought disorder, and Hallucinations, thought disorder, and flattened affect are common in EOSflattened affect are common in EOS
Children with schizophrenia show 3 Children with schizophrenia show 3 characteristic communication deficits:characteristic communication deficits: Loose associationsLoose associations Illogical thinkingIllogical thinking Impaired discourse skillsImpaired discourse skills
Epidemiology of Epidemiology of SchizophreniaSchizophrenia
1:10,000 children1:10,000 children Rare before age 13, but the incidence Rare before age 13, but the incidence
steadily increases during adolescencesteadily increases during adolescence Peak onset is aged 15 – 30 yearsPeak onset is aged 15 – 30 years Youngest childhood diagnosis is 3 Youngest childhood diagnosis is 3
yearsyears 2:1 Male to Female2:1 Male to Female
Dementia Praecox & Dementia Praecox & SchizophreniaSchizophrenia
Emile Kraepelin, German psychiatrist, 1887Emile Kraepelin, German psychiatrist, 1887 Distinguished DP from manic depressionDistinguished DP from manic depression
Paul Eugen Bleuler, Swiss psychiatrist, 1912Paul Eugen Bleuler, Swiss psychiatrist, 1912 Renamed DP as Schizophrenia (from Greek, Renamed DP as Schizophrenia (from Greek, ““to to
split the mindsplit the mind””) to emphasize the cognitive ) to emphasize the cognitive impairmentsimpairments
Believed that the Believed that the ““negativenegative”” symptoms were the symptoms were the defining characteristicsdefining characteristics
Identified the 4 As:Identified the 4 As: Affective bluntingAffective blunting Loosening of AssociationsLoosening of Associations AutismAutism Ambivalence or indecisivenessAmbivalence or indecisiveness
““PositivePositive”” Symptoms Symptoms Kurt Schneider, German psychiatrist, 1930Kurt Schneider, German psychiatrist, 1930 Believed that the Believed that the ““positivepositive”” symptoms were symptoms were
most characteristic in separating most characteristic in separating schizophrenia from other psychotic illnessesschizophrenia from other psychotic illnesses
11stst Rank Symptoms (involved ego Rank Symptoms (involved ego boundaries)boundaries) Auditory hallucinationsAuditory hallucinations Believing an external force to be acting upon oneBelieving an external force to be acting upon one’’s bodys body Thought withdrawalThought withdrawal Thought insertionThought insertion Thought broadcastingThought broadcasting Ideas of referenceIdeas of reference
Findings from Findings from Adult Schizophrenia StudiesAdult Schizophrenia Studies
Alterations in brain size and structure Alterations in brain size and structure (particularly the hippocampus) & fronto-(particularly the hippocampus) & fronto-striatal dopaminergic dysfunctionstriatal dopaminergic dysfunction
Perinatal complicationsPerinatal complications Minor physical anomalies (neurological Minor physical anomalies (neurological
soft signs)soft signs) Disruption of fetal development during the Disruption of fetal development during the
22ndnd trimester of pregnancy (suggested by trimester of pregnancy (suggested by lack of gliosis, which would demonstrate lack of gliosis, which would demonstrate injury but only occurs by 3injury but only occurs by 3rdrd trimester) trimester)
Neuroimaging Studies in Neuroimaging Studies in ChildrenChildren The most consistent findings from The most consistent findings from
neuroimaging studies are ventricular neuroimaging studies are ventricular enlargement and reduced total brain volumeenlargement and reduced total brain volume
Longitudinal studies of patients with EOS have Longitudinal studies of patients with EOS have demonstrated progressive ventricular demonstrated progressive ventricular enlargementenlargement
Siblings of patients with EOS have smaller total Siblings of patients with EOS have smaller total cerebral volume and total frontal and parietal cerebral volume and total frontal and parietal gray matter volumes than volunteers gray matter volumes than volunteers (suggesting a possible genetic trait marker)(suggesting a possible genetic trait marker)
Measurable differences in glucose metabolism, Measurable differences in glucose metabolism, irregular ANS arousal, and problems with visual irregular ANS arousal, and problems with visual tracking of moving objects have also been tracking of moving objects have also been demonstrated in children with schizophreniademonstrated in children with schizophrenia
Gray Matter LossGray Matter Loss MRI brain scans of adolescents reveal fluid filled
cavities in the middle of the brain enlarging abnormally between ages 14 and 18 in teens with early onset schizophrenia, suggesting shrinkage in brain tissue volume. These children lose 4-5x as much gray matter in their frontal lobes as normal teens.
This gray matter loss engulfs the brain in a progressive wave from back to front over 5 years, beginning in rear structures involved in attention and perception, eventually spreading to frontal areas responsible for organizing, planning, and other "executive" functions impaired in schizophrenia. The final loss pattern is consistent with that seen in adult schizophrenia.
Gray Matter Loss contGray Matter Loss cont’’dd While the healthy teens lose an average of 1 percent of gray
matter per year, the schizophrenic patients lose up to 5 percent a year, with loss greatest among individuals with the most severe symptoms (e.g., hallucinations, delusions, bizarre and psychotic thoughts, and depression) and spreading to areas controlling sensory and motor functions.
By 18, the teenagers in one study had lost 25 percent of their gray matter in certain brain areas.
In another study, siblings of EOS patients had significantly thinner gray matter in left prefrontal and bilateral temporal areas beginning at age 8 with less significant thinning in right prefrontal and inferior parietal areas. These deficits were no longer present by age 20. Higher global functioning was associated with the lessening of GM thinning in the sibling group. These findings support the hypothesis that GM development is mostly genetically driven in frontal and temporal areas and more environmentally based in the less-affected parietal domains.
In the pictures you will now see, red/pink areas indicate gray matter cell loss; while blue/green areas indicate cell stability.
MRI imaging showing differences in brain ventricle size in twins - one schizophrenic, one not
Coronal MR scans from a normal comparison subject (left), and chronic schizophrenic (right). Note increase in CSF, ventricular enlargement, decreased gray mass, etc.
Brain Activity in Brain Activity in SchizophreniaSchizophrenia
Decreased brain activity in schizophrenia subjects (S) compared to normal controls (N) in an fMRI study examining executive functioning.
Genetics of SchizophreniaGenetics of Schizophrenia Concordance: averages 46% for monozygotic Concordance: averages 46% for monozygotic
twins, as high as 60% in some studies; 14% for twins, as high as 60% in some studies; 14% for dizygotic twinsdizygotic twins
Siblings (1Siblings (1stst degree relatives) of schizophrenics degree relatives) of schizophrenics have a 10% chance of developing the diseasehave a 10% chance of developing the disease
Risk increases to 17% for persons with one Risk increases to 17% for persons with one sibling and one parent with the disease; and sibling and one parent with the disease; and 46% for children of two schizophrenic parents46% for children of two schizophrenic parents
Children with one schizophrenic parent have a Children with one schizophrenic parent have a 5-6% chance of developing the disease5-6% chance of developing the disease
Prognostic Indicators for Prognostic Indicators for SchizophreniaSchizophrenia
GoodGood Acute OnsetAcute Onset Short duration of illnessShort duration of illness Lack of prior psychiatric Lack of prior psychiatric
historyhistory Presence of affective Presence of affective
symptoms or confusionsymptoms or confusion Good premorbid Good premorbid
adjustmentadjustment Steady work historySteady work history MarriageMarriage Older age at onsetOlder age at onset
BadBad Insidious OnsetInsidious Onset Long duration of illnessLong duration of illness History of psychiatric History of psychiatric
problemsproblems Affective bluntingAffective blunting Obsessive-Compulsive Obsessive-Compulsive
symptomssymptoms History of aggressionHistory of aggression Pre-morbid personality Pre-morbid personality
disorderdisorder Poor work historyPoor work history CelibacyCelibacy Young age at onsetYoung age at onset
Premorbid & Prodromal PhasesPremorbid & Prodromal Phases Premorbid PhasePremorbid Phase
Preschool period characterized by nonspecific Preschool period characterized by nonspecific concernsconcerns
Early school-age period with nonspecific impairments Early school-age period with nonspecific impairments in attention and behavior (also possible behavior in attention and behavior (also possible behavior problems and developmental delays in problems and developmental delays in language/motor skills); also difficulties in interpersonal language/motor skills); also difficulties in interpersonal relations and problem-solving skills; lower IQ, solitary relations and problem-solving skills; lower IQ, solitary play, excessive anxiety have also been notedplay, excessive anxiety have also been noted
Prodromal PhaseProdromal Phase Follows the premorbid phaseFollows the premorbid phase Results in the development of psychosisResults in the development of psychosis Psychosis is usually gradual/insidiousPsychosis is usually gradual/insidious Best predictor of outcome is premorbid functionBest predictor of outcome is premorbid function
(Schaeffer & Ross, 2002; Davies & Russell et al, 1998)(Schaeffer & Ross, 2002; Davies & Russell et al, 1998)
Differential Diagnosis of Differential Diagnosis of Childhood PsychosisChildhood Psychosis
Schizophrenia and schizoaffective Schizophrenia and schizoaffective disorderdisorder
Bipolar Disorder Bipolar Disorder DepressionDepression Pervasive Developmental Disorders Pervasive Developmental Disorders Anxiety (particularly OCD)Anxiety (particularly OCD) PTSDPTSD Substance AbuseSubstance Abuse Medication Induced Medication Induced
Psychosis in ChildrenPsychosis in Children Most common causes of psychosis in Most common causes of psychosis in
children are anxiety and depressionchildren are anxiety and depression Brief psychotic phenomena may be Brief psychotic phenomena may be
observed in dissociative states, observed in dissociative states, following trauma, in relations to following trauma, in relations to borderline PD, and in other borderline PD, and in other conditionsconditions
Very Early Onset Very Early Onset SchizophreniaSchizophrenia Defined as developing before age 13 yearsDefined as developing before age 13 years
0.1-1% schizophrenia presents prior to age 10 yrs 0.1-1% schizophrenia presents prior to age 10 yrs ((““very, very rarevery, very rare”” before 6 y/o) before 6 y/o)
Male preponderance in early years (about 2:1 < 14 Male preponderance in early years (about 2:1 < 14 years of age) but not beyondyears of age) but not beyond
Early onset = poor prognosisEarly onset = poor prognosis Premorbid personality abnormalities (e.g., unusual Premorbid personality abnormalities (e.g., unusual
personality styles, neurodevelopmental abnormalities, personality styles, neurodevelopmental abnormalities, language problems, motor problems and a language problems, motor problems and a preponderance of negative symptoms) spells poor preponderance of negative symptoms) spells poor prognosisprognosis
There may be at least two clinical phenotypes of There may be at least two clinical phenotypes of schizophrenia: one characterized by longstanding schizophrenia: one characterized by longstanding neurobehavioral difficulties of early onset, and the neurobehavioral difficulties of early onset, and the other type develops in a previously other type develops in a previously ““normalnormal”” person person
Early Onset Schizophrenia Early Onset Schizophrenia (EOS)(EOS) Early-Onset Schizophrenia (develops after puberty to Early-Onset Schizophrenia (develops after puberty to
18 years)18 years) 4% presents prior to age 15 yrs4% presents prior to age 15 yrs The content of delusions and hallucinations in this age The content of delusions and hallucinations in this age
group often reflects developmental concerns (e.g., group often reflects developmental concerns (e.g., hallucinations may have to do with monsters, pets, or hallucinations may have to do with monsters, pets, or toys and delusions revolve around aspects of identity toys and delusions revolve around aspects of identity and are less complex and systematic than in adults)and are less complex and systematic than in adults)
Hallucinations are relatively commonHallucinations are relatively common Auditory hallucinations are most frequent (somatic and Auditory hallucinations are most frequent (somatic and
visual hallucinations less so)visual hallucinations less so) Delusions are present in about 50% of casesDelusions are present in about 50% of cases Irrational or magical thinking and loosening of Irrational or magical thinking and loosening of
associations are relatively commonassociations are relatively common Both preschool (very early) and childhood (early) onset Both preschool (very early) and childhood (early) onset
are commonly insidious; acute in only about 25% of are commonly insidious; acute in only about 25% of casescases
Adolescent Onset Adolescent Onset SchizophreniaSchizophrenia
The frequency of onset of psychotic The frequency of onset of psychotic illness increases markedly and illness increases markedly and symptomatology is similar to that of symptomatology is similar to that of adultsadults
The male predominance extends into The male predominance extends into adolescenceadolescence
Clinical ExaminationClinical Examination Because children usually have no experience of Because children usually have no experience of
knowledge of psychotic phenomena, they may knowledge of psychotic phenomena, they may misunderstand the questions during a misunderstand the questions during a psychiatric interviewpsychiatric interview
Questions regarding rare phenomena, such as Questions regarding rare phenomena, such as psychotic symptoms, typically have the highest psychotic symptoms, typically have the highest rates of false-positives in structured interviewsrates of false-positives in structured interviews
Normal human thought and memory processes Normal human thought and memory processes include hearing internal voices and include hearing internal voices and experiencing false beliefsexperiencing false beliefs
Clinical Examination (2)Clinical Examination (2) Collateral information is necessaryCollateral information is necessary Behavioral observations are often Behavioral observations are often
more useful than interpersonal more useful than interpersonal observations and interview questionsobservations and interview questions e.g., does the child start fights with other e.g., does the child start fights with other
children who are clearly much bigger and children who are clearly much bigger and threatening (demonstrating consistent threatening (demonstrating consistent poor judgment)poor judgment)
Projective Testing can be usefulProjective Testing can be useful
Assessing HallucinationsAssessing Hallucinations
Assessing Hallucinations (2)Assessing Hallucinations (2)
Assessing DelusionsAssessing Delusions
Assessing Delusions (2)Assessing Delusions (2)
The Validity of Self-ReportThe Validity of Self-ReportThe validity of psychotic symptoms should The validity of psychotic symptoms should be questioned when:be questioned when:
1)1) The reports are inconsistent and there is no other The reports are inconsistent and there is no other documented evidence other than self-reportdocumented evidence other than self-report
2)2) The qualitative nature of the reports is not typical The qualitative nature of the reports is not typical of psychosis (e.g., greatly detailed descriptions or of psychosis (e.g., greatly detailed descriptions or reports more suggestive of fantasy or reports more suggestive of fantasy or imagination)imagination)
3)3) The reported symptoms occur only at specified The reported symptoms occur only at specified times or are clearly reinforced by environmental times or are clearly reinforced by environmental circumstances (e.g., hearing voices only after a circumstances (e.g., hearing voices only after a fight)fight)
Common ComorbiditiesCommon Comorbidities
Behavioral problemsBehavioral problems Substance abuseSubstance abuse History of childhood maltreatment & History of childhood maltreatment &
abuseabuse
Treatment: To Treat or Not to Treatment: To Treat or Not to TreatTreat
The interval between onset of psychosis and The interval between onset of psychosis and initiation of treatment varies in studies between initiation of treatment varies in studies between 0.4 – 3.2 years0.4 – 3.2 years
Prolonged untreated psychosis may lead to Prolonged untreated psychosis may lead to neurotoxicity and poorer clinical outcomesneurotoxicity and poorer clinical outcomes
Accumulating evidence linking earlier treatment Accumulating evidence linking earlier treatment and better prognosisand better prognosis
No clear relationship between duration of No clear relationship between duration of untreated psychosis and the risk of relapse as untreated psychosis and the risk of relapse as yetyet
Mixed data regarding untreated psychosis and Mixed data regarding untreated psychosis and cognitive deteriorationcognitive deterioration
0
10
20
30
40
50
60
70
80
90
100
Good Treatment is Good Treatment is Sufficiently ComprehensiveSufficiently Comprehensive::One Year Relapse Rates With Integrated Services for People with One Year Relapse Rates With Integrated Services for People with
Schizophrenia Schizophrenia
54%
27% 23%14%
Percent
Falloon, IRH, Held, T, Coverdale, JH, Roncone, R, Laidlaw, TM. (1999) Psychosocial Interventions for Schizophrenia: A review of long term benefits of international studies. Psychiatric Rehabilitation Skills, 3, 268-290
Case Management &
Medication
+ Family Education
+ Problem Solving
+ Social Skills Training
•The combination of optimal psychosocial and pharmacological intervention for management of symptoms has been termed “illness management and recovery”
Use of AntipsychoticsUse of Antipsychotics The number of children prescribed antipsychotics The number of children prescribed antipsychotics
increased 5x between 1995 and 2003 to an increased 5x between 1995 and 2003 to an estimated 2.5 million each yearestimated 2.5 million each year
Antipsychotic use saw a 73% increase between Antipsychotic use saw a 73% increase between 2001 – 2005 in those under 18 y/o vs. adults who 2001 – 2005 in those under 18 y/o vs. adults who experienced a 13% increase during this same time.experienced a 13% increase during this same time.
Total use of atypical antipsychotics is accounted for Total use of atypical antipsychotics is accounted for by 85% adults and 15% childrenby 85% adults and 15% children
This translates to an increase from 3.81/1000 in This translates to an increase from 3.81/1000 in 2001 to 6.6/1000 in 2005; by contrast 11/1000 2001 to 6.6/1000 in 2005; by contrast 11/1000 adults use an atypical antipsychotic (Medco, 2005)adults use an atypical antipsychotic (Medco, 2005)
Rates appear to be slowing, however: 22% growth Rates appear to be slowing, however: 22% growth in 2003, 14% in 2004, and 3.4% in 2005in 2003, 14% in 2004, and 3.4% in 2005
Over 50% of the prescriptions are for children with Over 50% of the prescriptions are for children with ADHD and other non-psychotic illnessADHD and other non-psychotic illness
Cooper et al, Journal of Ambulatory Pediatrics, 2006Cooper et al, Journal of Ambulatory Pediatrics, 2006
Who Gets Antipsychotics?Who Gets Antipsychotics? Medicaid-insured youth are about 4x Medicaid-insured youth are about 4x
more likely as privately insured kids to more likely as privately insured kids to fill Rx for antipsychoticsfill Rx for antipsychotics Only a minority of privately insured kids Only a minority of privately insured kids
(32.6%) and Medicaid-insured kids (26.9%) (32.6%) and Medicaid-insured kids (26.9%) are given these medications for a are given these medications for a diagnosis of schizophrenia, BP Disorder, or diagnosis of schizophrenia, BP Disorder, or PDDPDD
Crystal et al, 2009Crystal et al, 2009
22ndnd Generation Generation Antipsychotics in KidsAntipsychotics in Kids
State Medicaid study, 2001 – 2005State Medicaid study, 2001 – 2005 41% of kids treated with an antipsychotic 41% of kids treated with an antipsychotic
did not have a diagnosis for which did not have a diagnosis for which antipsychotics are supportedantipsychotics are supported
Indications: ADHD, MDD, CD, ODD, Adj Indications: ADHD, MDD, CD, ODD, Adj D/OD/O
Evidence by medication:Evidence by medication:Evidence Aripiprazole Olanzapine Quetiapine RisperidoneZiprasidoneStrong 10.8 21.6 64.2 Plausible 16.2 3.6
Weak 22.9 29.1 45.9 1.7 56.9None 77.1 43.9 32.6 30.6 43.1Pathak et al, 2010
Duration of Untreated Duration of Untreated PsychosisPsychosis
The Duration of Untreated Psychosis (DUP) prior to first The Duration of Untreated Psychosis (DUP) prior to first psychiatric admission adversely affects acute treatment psychiatric admission adversely affects acute treatment response and short-term outcome in schizophrenia. response and short-term outcome in schizophrenia.
In one recent study, 58 schizophrenic patients were In one recent study, 58 schizophrenic patients were assessed at their first psychiatric admission and after a 15-assessed at their first psychiatric admission and after a 15-year course of the illness. The 15-year outcome in different year course of the illness. The 15-year outcome in different domains was compared between patients with different domains was compared between patients with different DUPs prior to the first psychiatric admission. DUPs prior to the first psychiatric admission.
A longer DUP was associated with more pronounced A longer DUP was associated with more pronounced negative, positive and general psychopathological negative, positive and general psychopathological symptoms, as well as lower global functioning, 15 years after symptoms, as well as lower global functioning, 15 years after the first psychiatric admission, even after effects of other the first psychiatric admission, even after effects of other factors possibly related to the long-term outcome were factors possibly related to the long-term outcome were controlled for. controlled for.
The findings underline the importance of establishing health The findings underline the importance of establishing health service programs for the early detection and treatment of service programs for the early detection and treatment of schizophrenic patients with the aim of shortening the DUP schizophrenic patients with the aim of shortening the DUP and improving the course and outcome of schizophrenic and improving the course and outcome of schizophrenic patients.patients.
--Bottlender et al, 2003--Bottlender et al, 2003
Medication Side EffectsMedication Side Effects Extrapyramidal side effects include:Extrapyramidal side effects include:
DystoniasDystonias AkathisiaAkathisia Parkinsonism (rigidity and tremor)Parkinsonism (rigidity and tremor) DyskinesiasDyskinesias Tardive dyskinesiaTardive dyskinesia
It is believed that there is a greater risk of It is believed that there is a greater risk of developing TD with the older, typical developing TD with the older, typical antipsychotic drugs.antipsychotic drugs.
Lower the seizure thresholdLower the seizure threshold Neuroleptic Malignant Syndrome – the drugs appear Neuroleptic Malignant Syndrome – the drugs appear
to cause the temperature regulation centers to fail, to cause the temperature regulation centers to fail, resulting in a muscle rigidity and protein resulting in a muscle rigidity and protein breakdown, kidney damage and 30% mortality; breakdown, kidney damage and 30% mortality; medical emergencymedical emergency
DysphoriaDysphoria
Medication Side Effects (2)Medication Side Effects (2) Children are more vulnerable to EPSChildren are more vulnerable to EPS
This has long been known for children who This has long been known for children who were exposed to conventional antipsychoticswere exposed to conventional antipsychotics
EPS is related to D2 receptor occupancy in EPS is related to D2 receptor occupancy in adults and children have a greater density of adults and children have a greater density of D1 and D2 receptors than adultsD1 and D2 receptors than adults
Chart reviews to date indicate probably Chart reviews to date indicate probably less vulnerability when children are less vulnerability when children are treated with atypical antipsychoticstreated with atypical antipsychotics
Medication Side Effects (3)Medication Side Effects (3)
Additional concerning side effects of Additional concerning side effects of atypical antipsychotics include:atypical antipsychotics include:
1)1) SedationSedation2)2) Prolactin elevationProlactin elevation3)3) Weight gainWeight gain4)4) Cardiac toxicityCardiac toxicity
Prolactin Meta-AnalysisProlactin Meta-Analysis Meta-analysis of 29 studies of antipsychotics from 1965 – 2008, Meta-analysis of 29 studies of antipsychotics from 1965 – 2008,
including haloperidol, pimozide, risperidone, olanzapine, clozapine, including haloperidol, pimozide, risperidone, olanzapine, clozapine, ziprasidone, and quetiapineziprasidone, and quetiapine
All antipsychotics, except clozapine, ziprasidone, and quetiapine, All antipsychotics, except clozapine, ziprasidone, and quetiapine, increase the mean prolactin level from baseline values of 8.0 ng/mL increase the mean prolactin level from baseline values of 8.0 ng/mL to 25-28 ng/mL after 4 weeks of treatment to 25-28 ng/mL after 4 weeks of treatment
The most and best data are available for risperidone. Five The most and best data are available for risperidone. Five risperidone studies (n = 577) show an increase of prolactin level risperidone studies (n = 577) show an increase of prolactin level from 7.8 ng/mL to 17.7 ng/mL after 1 year of treatment, and two from 7.8 ng/mL to 17.7 ng/mL after 1 year of treatment, and two risperidone studies (n = 60) show an increase from 7.4 ng/mL to risperidone studies (n = 60) show an increase from 7.4 ng/mL to 24.9 ng/mL after 2 years of treatment. 24.9 ng/mL after 2 years of treatment.
Aggregated over all antipsychotics, prolactin-related side effects, Aggregated over all antipsychotics, prolactin-related side effects, such as gynecomastia, galactorrhea, irregular menses, and sexual such as gynecomastia, galactorrhea, irregular menses, and sexual dysfunction, were reported by 4.8% of the children and adolescents.dysfunction, were reported by 4.8% of the children and adolescents.
No data are available on bone mineral density in relation to No data are available on bone mineral density in relation to antipsychotic-induced hyperprolactinemia in children and antipsychotic-induced hyperprolactinemia in children and adolescents. adolescents.
Roke et al, 2009Roke et al, 2009
Metabolic Side EffectsMetabolic Side Effects A study of South Carolina Medicaid claims data A study of South Carolina Medicaid claims data
retrospectively compared 4140 children & retrospectively compared 4140 children & adolescents (<18 years) who were prescribed adolescents (<18 years) who were prescribed conventional or atypical antipsychotics from 1998 conventional or atypical antipsychotics from 1998 through 2003 and 4500 children who did not through 2003 and 4500 children who did not receive psychotropic medication.receive psychotropic medication.
Compared with controls, children treated with Compared with controls, children treated with antipsychotics had significantly higher rates of antipsychotics had significantly higher rates of obesity (OR = 2.13), type 2 diabetes (OR = 3.23), obesity (OR = 2.13), type 2 diabetes (OR = 3.23), cardiovascular conditions (OR = 2.70), and cardiovascular conditions (OR = 2.70), and orthostatic hypotension (OR = 1.64), but not orthostatic hypotension (OR = 1.64), but not hypertension, dyslipidemia, or cerebrovascular hypertension, dyslipidemia, or cerebrovascular events. events.
McIntyre & Jerrell, 2008McIntyre & Jerrell, 2008
Monitoring GlucoseMonitoring Glucose Medicaid claims data study of 5,370 Medicaid claims data study of 5,370
children aged 6 – 17 years prescribed children aged 6 – 17 years prescribed antipsychotic medications from July 1, antipsychotic medications from July 1, 2004 – June 30, 2006 2004 – June 30, 2006
Researchers found that glucose Researchers found that glucose screening was performed in only 31.6% screening was performed in only 31.6% and lipid testing in only 13.4%.and lipid testing in only 13.4%.
Arch Pediatr Adolesc Med, 2010; 164:344-51Arch Pediatr Adolesc Med, 2010; 164:344-51
SATIETY StudySATIETY Study Nonrandomized SGA Treatment Indications, Effectiveness and TolerabilityNonrandomized SGA Treatment Indications, Effectiveness and Tolerability in in
Youth (SATIETY) cohort study, 2001 – 2007, at LIJ inpatient/outpatientYouth (SATIETY) cohort study, 2001 – 2007, at LIJ inpatient/outpatient N = 338, agedN = 338, aged 4 to 19 years, with ≤ 1 week prior antipsychotic trmt4 to 19 years, with ≤ 1 week prior antipsychotic trmt Diagnoses: 130/47.8% had ASD, 82/30.1% had schizophrenia spectrum, Diagnoses: 130/47.8% had ASD, 82/30.1% had schizophrenia spectrum,
60/22.1% had disruptive or aggressive behavior disorders (small comparison 60/22.1% had disruptive or aggressive behavior disorders (small comparison group of 15 kids who refused participation)group of 15 kids who refused participation)
Intervention involved treatment with aripiprazole, olanzapine,Intervention involved treatment with aripiprazole, olanzapine, quetiapine, or quetiapine, or risperidone for 12 weeksrisperidone for 12 weeks
After a median of 10.8 weeks of treatment, weight increased by 8.5 kg with After a median of 10.8 weeks of treatment, weight increased by 8.5 kg with olanzapine (n = 45),olanzapine (n = 45), by 6.1 kg with quetiapine (n = 36),by 6.1 kg with quetiapine (n = 36), by 5.3 kg with by 5.3 kg with risperidone (n = 135),risperidone (n = 135), and by 4.4 kg with aripiprazole (n = 41)and by 4.4 kg with aripiprazole (n = 41) compared with compared with the minimal weight change of 0.2 kg in the untreated comparison group the minimal weight change of 0.2 kg in the untreated comparison group (n = 15).(n = 15).
With olanzapine and quetiapine, respectively, mean levels increasedWith olanzapine and quetiapine, respectively, mean levels increased
significantly for total cholesterol (15.6 mg/dL and 9.1 mg/dL), triglycerides significantly for total cholesterol (15.6 mg/dL and 9.1 mg/dL), triglycerides (24.3(24.3 mg/dL and 37.0mg/dL and 37.0 mg/dL), non–high-densitymg/dL), non–high-density lipoprotein (HDL) cholesterol lipoprotein (HDL) cholesterol (16.8 mg/dL and 9.9 mg/dL), and ratio of triglycerides to HDL(16.8 mg/dL and 9.9 mg/dL), and ratio of triglycerides to HDL cholesterolcholesterol
With risperidone,With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL)triglycerides increased significantly (mean level, 9.7 mg/dL) Metabolic baseline-to-end-pointMetabolic baseline-to-end-point changes were not significant with aripiprazole changes were not significant with aripiprazole
or in the untreatedor in the untreated comparison group.comparison group. Correll et al, 2009Correll et al, 2009
Lab ValueLab Value BaselineBaseline 4 Weeks4 Weeks 8 Weeks8 Weeks 12 Weeks12 Weeks QuarterlyQuarterly AnnuallyAnnually Every 5 Every 5 YearsYears
Personal Family Personal Family HistoryHistory
XX XX
Weight (BMI)Weight (BMI) XX XX XX XX XX
Waist Waist CircumferenceCircumference
XX XX
Blood PressureBlood Pressure XX XX XX
Fasting Plasma Fasting Plasma GlucoseGlucose
XX XX XX
Fasting Lipid Fasting Lipid ProfileProfile
XX XX XX
Monitoring Patients on Atypical Monitoring Patients on Atypical AntipsychoticsAntipsychotics
Source: Diabetes Care, February 2004Source: Diabetes Care, February 2004
-20
0
20
40
60
80
100
olanzapine(Zyprexa)
quetiapine(Seroquel)
risperidone(Risperdal)
ziprasidone(Geodon)
Blood GlucoseCholesterolTriglycerides
Impact of Different Impact of Different Antipsychotics Antipsychotics
on Metabolic Measures on Metabolic Measures
Meyer et al, Schizophr Res 2008;101:273-86
No Data Less than 4% 4% to 6% Above 6%
Mokdad et al. Diabetes Care. 2000;23:1278-1283.
Diabetes and Gestational Diabetes Trends: Diabetes and Gestational Diabetes Trends: US Adults, BRFSS 1990US Adults, BRFSS 1990
www.diabetes.org.
No Data Less than 4% 4% to 6% Above 6% Above 10%
Diabetes and Gestational Diabetes Diabetes and Gestational Diabetes Trends: Trends:
US Adults, Estimate for 2010US Adults, Estimate for 2010
50-59 y
60-69 y
70-74 y
0
5
10
15
20
25
30
Diagnosed Diabetes, General Population Diagnosed Diabetes, Schizophrenic Patients
Harris et al. Diabetes Care. 1998; 21:518.Mukherjee et al. Compr Psychiatry. 1996; 37(1):68-73.
Schizophrenic:General: 50-59 y
60-74 y75+ y
Percent of population
Prevalence of Diagnosed Diabetes in General Population Versus Schizophrenic Population
Assessment of Co-Morbid Assessment of Co-Morbid IllnessesIllnesses
In the In the CATIE CATIE (Clinical Antipsychotic Trials of (Clinical Antipsychotic Trials of Intervention Effectiveness) study, evaluations Intervention Effectiveness) study, evaluations of referred consumers revealed quality of referred consumers revealed quality breaches including that:breaches including that:
• 30% of individuals who met diagnostic criteria 30% of individuals who met diagnostic criteria for diabetes were receiving no treatment.for diabetes were receiving no treatment.
• 88% with elevated cholesterol were not on a 88% with elevated cholesterol were not on a lipid-lowering agent.lipid-lowering agent.
• 62% of those meeting criteria for hypertension 62% of those meeting criteria for hypertension were receiving no anti-hypertensive were receiving no anti-hypertensive medication.medication.
Monitoring Monitoring RecommendationsRecommendations
Baseline lab workBaseline lab work CBC, lytes, BUN/Cr, LFTs, Thyroid, prolactin, CBC, lytes, BUN/Cr, LFTs, Thyroid, prolactin,
glucose, height/weight, lipids, UToxglucose, height/weight, lipids, UTox Physical ExaminationPhysical Examination Electrocardiogram (ECG) Electrocardiogram (ECG)
Prior to use and subsequently (particularly for Prior to use and subsequently (particularly for risperidone, olanzapine, quetiapine, and risperidone, olanzapine, quetiapine, and ziprasidone)ziprasidone)
Acceptable parametersAcceptable parameters PR < 200 msPR < 200 ms QRS duration < 120 msQRS duration < 120 ms QTc < 460 msQTc < 460 ms
ShatkinShatkin’’s Guidelines to Antipsychotic s Guidelines to Antipsychotic TreatmentTreatment
Prior to TreatmentPrior to Treatment Fasting blood glucose, lipid panel, LFTs, chemistry, CBC, prolactin (if Fasting blood glucose, lipid panel, LFTs, chemistry, CBC, prolactin (if
indicated), and TSH/T4 (quetiapine)indicated), and TSH/T4 (quetiapine) During TreatmentDuring Treatment
Regularly inquire about menstruation, nipple discharge, sexual Regularly inquire about menstruation, nipple discharge, sexual dysfunction and pubertal developmentdysfunction and pubertal development
Check serum prolactin if problems with the aforementioned are noted; if Check serum prolactin if problems with the aforementioned are noted; if serum prolactin is elevated, consider oral contraceptives as culprit and serum prolactin is elevated, consider oral contraceptives as culprit and run a pregnancy test, also obtain a TSH and serum creatinine b/c run a pregnancy test, also obtain a TSH and serum creatinine b/c hypothyroidism and renal failure can also increase prolactin; if prolactin hypothyroidism and renal failure can also increase prolactin; if prolactin is repeatedly >200 ng/mL or does not decrease even after changing to is repeatedly >200 ng/mL or does not decrease even after changing to a prolactin sparing antipsychotic (e.g., quetiapine, clozapine, a prolactin sparing antipsychotic (e.g., quetiapine, clozapine, aripiprazole), obtain an MRI of the sella turcica for pituitary adenoma or aripiprazole), obtain an MRI of the sella turcica for pituitary adenoma or parasellar tumor. Because prolactin levels often rise early and then parasellar tumor. Because prolactin levels often rise early and then taper off to normal levels over 12 months, it may be prudent to follow taper off to normal levels over 12 months, it may be prudent to follow levels for 6 – 12 months before making major changes in regimen levels for 6 – 12 months before making major changes in regimen (unless side effects are troubling)(unless side effects are troubling)
Body height and weight at each visit and BMIBody height and weight at each visit and BMI RE: BMI = (weight in kg) / (height in meters)2 or BMI = (weight in RE: BMI = (weight in kg) / (height in meters)2 or BMI = (weight in
pounds x 703) / (height in inches)2pounds x 703) / (height in inches)2 Blood pressure at each visitBlood pressure at each visit Quarterly measurements of waist circumferenceQuarterly measurements of waist circumference Follow-up fasting blood glucose at 3 & 6 months and annually thereafter Follow-up fasting blood glucose at 3 & 6 months and annually thereafter
(inquire regularly about unintended weight loss, polydypsia, & polyuria)(inquire regularly about unintended weight loss, polydypsia, & polyuria) Annual TSH/T4 (quetiapine)Annual TSH/T4 (quetiapine) Follow-up fasting lipid panel at 3 months and then every 6 – 12 months Follow-up fasting lipid panel at 3 months and then every 6 – 12 months
thereafter if results are normal and BMI percentile values are stablethereafter if results are normal and BMI percentile values are stable Document, document, document!!!Document, document, document!!!
ECG: QT Interpretation (1)ECG: QT Interpretation (1) QTc duration is the single best parameter QTc duration is the single best parameter
for assessing unstable ventricular for assessing unstable ventricular depolarizationdepolarization Upper Limits:Upper Limits:
Adults = 470 msAdults = 470 ms Boys = 450 msBoys = 450 ms Girls = 460 msGirls = 460 ms
Medication induced increases in QTc by > Medication induced increases in QTc by > 10% suggests need for investigation10% suggests need for investigation
ECG: QT Interpretation (2)ECG: QT Interpretation (2)Pretreatment ScreeningPretreatment Screening Congenital Risk FactorsCongenital Risk Factors
Family/past h/o congenital deafness, palpitations, Family/past h/o congenital deafness, palpitations, prolonged QT diagosed by ECG, & "drop attacks," prolonged QT diagosed by ECG, & "drop attacks," such as syncope or seizures (not dx as seizures)such as syncope or seizures (not dx as seizures)
Acquired Risk FactorsAcquired Risk Factors Blood labs: Ca++, K+, MG++, LFTs, BUN/Cr Blood labs: Ca++, K+, MG++, LFTs, BUN/Cr
(hypokalemia, hypermag, and hypercal can cause (hypokalemia, hypermag, and hypercal can cause prolongation)prolongation)
ECGECG Physical exam: BP/HRPhysical exam: BP/HR Review current medicationsReview current medications
ECG: QT Interpretation (3)ECG: QT Interpretation (3)Calculating QTcCalculating QTc Leads II and V5 are most sensitiveLeads II and V5 are most sensitive Measure QT from start of Q wave to end of T Measure QT from start of Q wave to end of T
wave (if non-significant U wave); measure to wave (if non-significant U wave); measure to end of U wave if presentend of U wave if present
Bazett's Formula: QTc = actual QT/square Bazett's Formula: QTc = actual QT/square root of preceeding R-R interval in secondsroot of preceeding R-R interval in seconds Overestimates at rates > 100 bpmOverestimates at rates > 100 bpm
Flattened T waves themselves tend to be Flattened T waves themselves tend to be innocuous in children & adolescents, but innocuous in children & adolescents, but flattened T waves may reveal significant U flattened T waves may reveal significant U waves (greater than 1/3 the height of the T waves (greater than 1/3 the height of the T wave) not previously visible, suggesting wave) not previously visible, suggesting prolonged ventricular repolarizationprolonged ventricular repolarization
Current FDA Approvals Current FDA Approvals for Schizophreniafor Schizophrenia
Risperidone (Risperdal®)Risperidone (Risperdal®) Acute treatment of Schizophrenia (13 – 17)Acute treatment of Schizophrenia (13 – 17)
Aripiprazole (Abilify®)Aripiprazole (Abilify®) Acute treatment of Schizophrenia (13 – 17)Acute treatment of Schizophrenia (13 – 17)
Quetiapine (Seroquel®)Quetiapine (Seroquel®) Acute treatment of Schizophrenia (13 – 17)Acute treatment of Schizophrenia (13 – 17)
Olanzapine (Zyprexa®)Olanzapine (Zyprexa®) Acute treatment of Schizophrenia (13 – 17)Acute treatment of Schizophrenia (13 – 17)
Risperidone for Risperidone for SchizophreniaSchizophrenia
In a 6-week, randomized, double-blind, placebo-controlled study, In a 6-week, randomized, double-blind, placebo-controlled study, adolescents aged 13-17 years with acute exacerbation of schizophrenia adolescents aged 13-17 years with acute exacerbation of schizophrenia were randomized to placebo, flexible doses of risperidone 1-3 mg/day, or were randomized to placebo, flexible doses of risperidone 1-3 mg/day, or risperidone 4-6 mg/day. risperidone 4-6 mg/day.
Clinical response defined as > or =20% reduction in PANSS total scoreClinical response defined as > or =20% reduction in PANSS total score 160 subjects; placebo (n = 54), risperidone 1-3 mg/day (n = 55), or 160 subjects; placebo (n = 54), risperidone 1-3 mg/day (n = 55), or
risperidone 4-6 mg/day (n = 51). risperidone 4-6 mg/day (n = 51). Significant improvements occurred in both risperidone groups versus Significant improvements occurred in both risperidone groups versus
placebo (p < 0.001) in PANSS total change scores (placebo, -8.9 [16.1]; placebo (p < 0.001) in PANSS total change scores (placebo, -8.9 [16.1]; risperidone 1-3 mg, -21.3 [19.6]; risperidone 4-6 mg, -21.2 [18.3]) and risperidone 1-3 mg, -21.3 [19.6]; risperidone 4-6 mg, -21.2 [18.3]) and clinical response rates (35%, 65%, 72%, respectively). clinical response rates (35%, 65%, 72%, respectively).
Overall AE rates were more common in risperidone groups (75% and Overall AE rates were more common in risperidone groups (75% and 76%) versus placebo (54%). Risperidone 4-6 mg/day had a higher 76%) versus placebo (54%). Risperidone 4-6 mg/day had a higher incidence of extrapyramidal disorder, dizziness, and hypertonia than incidence of extrapyramidal disorder, dizziness, and hypertonia than risperidone 1-3 mg. No prolactin-related AEs occurred. Overall EPS risperidone 1-3 mg. No prolactin-related AEs occurred. Overall EPS severity was low. severity was low.
The benefit-risk profile suggests that a dose of 1-3 mg/day might be The benefit-risk profile suggests that a dose of 1-3 mg/day might be optimal for this population.optimal for this population.
Haas et al, 2009Haas et al, 2009
Abilify for SchizophreniaAbilify for Schizophrenia N = 302; adolescents with schizophrenia aged 13 to 17 yearsN = 302; adolescents with schizophrenia aged 13 to 17 years Randomized to 10 mg or 30 mg per day of aripiprazole or Randomized to 10 mg or 30 mg per day of aripiprazole or
placebo. After 6 weeks, mean changes for positive subscale placebo. After 6 weeks, mean changes for positive subscale scores were: -7.6 (10 mg); -8.1 (30 mg); and -5.6 (placebo). Mean scores were: -7.6 (10 mg); -8.1 (30 mg); and -5.6 (placebo). Mean total score change for Positive and Negative Symptoms Scores total score change for Positive and Negative Symptoms Scores (PANSS) were: -26.7 for 10-mg and -28.6 for 30-mg aripiprazole (PANSS) were: -26.7 for 10-mg and -28.6 for 30-mg aripiprazole compared with -21.2 for placebo.compared with -21.2 for placebo.
Both doses of active drug resulted in significantly higher rates of Both doses of active drug resulted in significantly higher rates of remission compared with placebo: 54% in patients on the low remission compared with placebo: 54% in patients on the low dose, 58% for those on the high dose, and 36% for those taking dose, 58% for those on the high dose, and 36% for those taking placebo.placebo.
Aripiprazole was generally well tolerated, and there were no Aripiprazole was generally well tolerated, and there were no reported suicides or deaths during the study. AEs were more reported suicides or deaths during the study. AEs were more frequent in the active-treatment groups, particularly at the higher frequent in the active-treatment groups, particularly at the higher dose, and included akathisia, extrapyramidal symptoms, dose, and included akathisia, extrapyramidal symptoms, somnolence, and tremor. somnolence, and tremor.
CPK levels were at times elevated in both active-treatment CPK levels were at times elevated in both active-treatment groups, but metabolic measures, including prolactin, glucose, and groups, but metabolic measures, including prolactin, glucose, and lipid levels, were no different from those with placebo. No weight lipid levels, were no different from those with placebo. No weight gain noted in lower dose; higher dose weight gain averaged 0.2 gain noted in lower dose; higher dose weight gain averaged 0.2 kg kg
Am J PsychAm J Psych, 2008, 2008
Treatment of Early-Onset Treatment of Early-Onset Schizophrenia Spectrum Disorders Schizophrenia Spectrum Disorders
(TEOSS) Study(TEOSS) Study Double-blind multisite trial randomly assigned pediatric pts
w/early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5–20 mg/day), risperidone (0.5–6 mg/day), or molindone (10–140 mg/day, plus 1 mg/day of benztropine) for 8 weeks (n = 116)
The primary outcome was response to treatment, defined as a CGI improvement score of 1 or 2 and 20% reduction in PANSS post-treatment
No significant differences were found among treatment No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom 34%; risperidone: 46%) or magnitude of symptom reduction. reduction.
Olanzapine and risperidone were associated with Olanzapine and risperidone were associated with significantly greater weight gain, and olanzapine showed significantly greater weight gain, and olanzapine showed the greatest risk of weight gain and increases in fasting the greatest risk of weight gain and increases in fasting cholesterol, LDL, insulin, and liver transaminase levels. cholesterol, LDL, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. Molindone led to more self-reports of akathisia.
Am J PsychAm J Psych, 2008, 2008
Prior Treatment Studies in Prior Treatment Studies in SchizophreniaSchizophrenia
ClozapineClozapine One RDBPCT found clozapine statistically superior One RDBPCT found clozapine statistically superior
to haloperidol (6 weeks, 21 children and to haloperidol (6 weeks, 21 children and adolescents); Kumra et al, 1996.adolescents); Kumra et al, 1996.
Two small open label trials & one retrospective Two small open label trials & one retrospective study have also been favorable (Frazier et al, study have also been favorable (Frazier et al, 1994; Turetz et al, 1997; Remschmidt et al, 1994)1994; Turetz et al, 1997; Remschmidt et al, 1994)
RisperidoneRisperidone One open label trial, one retrospective study, and One open label trial, one retrospective study, and
one case series are all favorable (Armenteros et one case series are all favorable (Armenteros et al, 1997; Grcevich et al, 1996; Quintana and al, 1997; Grcevich et al, 1996; Quintana and Keshevan, 1995)Keshevan, 1995)
Prior Treatment Studies in Prior Treatment Studies in Schizophrenia (2)Schizophrenia (2)
OlanzapineOlanzapine Two favorable open label studies (Findling Two favorable open label studies (Findling
et al, 2003; Quintana et al, 2007)et al, 2003; Quintana et al, 2007) Two NIMH negative open label studies in Two NIMH negative open label studies in
treatment resistant children (Kumra et al, treatment resistant children (Kumra et al, 1998; Grothe et al, 2000)1998; Grothe et al, 2000)
QuetiapineQuetiapine One favorable open label trial (Shaw et al, One favorable open label trial (Shaw et al,
2001)2001)
