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Seeing the Truth About Childhood Schizophrenia

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Reproduction in whole or in part without permission is prohibited.


Elizabeth Montagnese, M.D.

Adult, Child and Adolescent Psychiatrist

Quittie Glen Center for Mental Health in Annville, Pennsylvania

PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy

education

Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants

(PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted

before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing

any therapies described in this educational activity.

This program has been supported by an educational grant from Bristol-Myers Squibb

Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or

the companies that support educational programming. A qualified healthcare professional should always be consulted before using any

therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education

Speaker: Dr. Montagnese is board certified in adult, child, and adolescent psychiatry by the American

Board of Psychiatry and Neurology. Dr. Montagnese provides comprehensive psychiatric evaluation

and treatment for individuals, couples and families. Her primary area of focus is working with children

and adolescents but she also treats adults.Dr. Montagnese received her medical degree at Wayne

State University in Detroit, Michigan. She completed her general psychiatry and child psychiatry

training at the Penn State University Milton S. Hershey Medical Center.Dr. Montagnese is the medical

director at Family and Children Services of Central Pennsylvania. This is a United Way funded

nonprofit agency that serves the greater Harrisburg, York and Lancaster areas. To contact her at this

agency please call 717-238-8118.

Speaker Disclosure: Dr. Montagnese has no actual or potential conflicts of interest in relation to

this program


This program has been supported by an educational grant from Bristol-Myers Squibb

Accreditation:

Pharmacists 798-000-09-075-L01-P

Pharmacy Technicians 798-000-09-075-L01-T

Target Audience: Pharmacists & Technicians

CE Credits:

1.0 Credit hour or 0.1 CEU for

pharmacists/technicians

Expiration Date: 10/20/2011

Program Overview: This program is designed to assist pharmacists review the facets of childhood

schizophrenia, as well as the benefits of managing this disorder with medications. Their knowledge of

available treatment options for children with schizophrenia will be enhanced. The program includes

information on pharmacologic treatments, drug interactions, patient counseling, and a question/ answer

period.

Objectives:

• To state the theories associated with the causes of childhood schizophrenia, as well as detrimental

affects that this disorder may have on its victim’s lives, incorporating information on the prevalence of

this predicament.

• To list therapeutic agents used in the treatment of childhood schizophrenia, and be able to state an

agent’s dosage schedule, mechanism of action, and side effects.

• Review the pharmacist’s role in counseling patients on drug treatment strategies and medication

adherence to improve quality of life and long-term maintenance of childhood schizophrenia patients.


“Jani’s at the mercy of her mind.”

LA Times story, June

29, 2009

Jani Schofield, 6

year old

Severe symptoms

since toddlerhood

“There is something

wrong with her brain.”




Epidemiology of Childhood-Onset

Schizophrenia (COS)

RARE!!!!!

1 in 40,0000

Adult-onset schizophrenia (AOS): 1% general

population

M:F ratio: 1.5-2.2:1

Very rarely diagnosed before age 5

Usually diagnosed between 7-12 years old

Schizophrenia Statistics

Emil Kraeplin documented cases of COS in 1919

Typical age of onset: males: 18 years of age

females: 25 years of age

Top 10 causes of disability worldwide

Cost of Schizophrenia: 1990-accounted for 2.5% of health care expenditures+ nondirect costs($45 billion)

2002- $62.7 billion for direct and nondirect costs

Unemployment rate is 70-80%

10% of those permanently disabled

What is Childhood Schizophrenia?

Neurodevelopmental

disorder

Fundamental continuity

between AOS and COS

Differences in Childhood

Schizophrenia

More severe illness

Worse prognosis

More insidious onset

Harder to treat

Misdiagnosis is common




Diagnostic Difficulties with COS

Complex disorder with diverse presentation

Psychosis and thought disorder are difficult to assess in children

Children’s concept of reality changes with time

Disorganized behavior/speech can be common in nonpsychotic children

Symptoms change, emerge, evolve over time

Rare disorder: lack of clinical familiarity

Devastating illness - Life sentence

Clinicians don’t want to get it wrong

Large overlap with other disorders

Diagnosing COS

Mean onset of symptoms: 4.6 years

Mean onset of psychosis: 6.9 years

Mean onset of diagnosis: 9.5 years

5 year time

lag

DSM Criteria for Schizophrenia

Two or more of following for 1 month: (A Criterion)

Delusions

Hallucinations

Disorganized speech

Disorganized behavior

Negative symptoms: flat affect, avolition, alogia

Only 1 if delusions bizarre or voice keeping commentary or 2 voices conversing

DSM Criteria for Schizophrenia

Social/occupational dysfunction

Disturbance for at least 6 months with at least 1 month with criterion A

Not due to substance, medical condition, mood

disorder or PDD




Schizophrenia Subtypes

Catatonic

Paranoid

Disorganized

Undifferentiated

Residual

What is

psychosis?What is real vs. fantasy

Think of “A Beautiful Mind”

Positive Symptoms

Symptoms associated with

distorted reality

Delusions

Hallucinations

Things present in

those with

schizophrenia as

compared to

those without.

Negative Symptoms

Affective blunting

Poverty of speech

Thought blocking

Adequate grooming

Lack of motivation-apathy

Anhedonia

Social withdrawal

Things absent from those

with schizophrenia as

compared to those

without.




Hallucinations

Think of 5 senses: visual, auditory, olfactory,

gustatory, tactile

Usually frightening, morbid, macabre

Can be friendly, company

Hallucinations in COS

Most common presenting symptom

Auditory hallucinations: 80% of COS

Visual hallucinations: 30% of COS

Tactile/olfactory hallucinations: rare

Developmental considerations

Hallucinations in isolation = schizophrenia

Imaginary friends > 7yrs old: cause for concern

Auditory Hallucinations

Usually negative

Command

Conversing

Commenting

Persecutory

May be friendly

Visual HallucinationsAlmost always accompanied by auditory hallucinations




Delusions

A fixed false belief

Bizarre-illogical

Nonbizarre- can really occur

Persecutory

Somatic

Ideas of reference

Grandiose

Religious ideas

Difficult to assess in children

50-60% of COS

Childhood themes: monsters,

animals, family, fantasy figures

Less complicated in childhood

Thought Disorder is disruption in flow of conscious verbal thought

that is inferred from spoken or

written language.

Flight of ideas

Derailment

Thought blocking

Pressured speech

Tangentiality

Perseveration

Word salad

Neologisms

Echolalia

Illogical

Thought Disorder in COS

40-60-100% of COS

Difficulty with assessment and definition in

children

Disturbance of Affect in COS

74% of COS

Blunted

Flat

Inappropriate




The Prodrome

Onset of decline from baseline functioning

“Latent schizophrenia”

Don’t meet full criteria

Nonspecific symptoms

Important: early detection is protective

The Prodrome

cognitive functioning

overall functioning

social isolation

personal hygiene

Difficulties with

attention

Change in emotions

Flattening of affect

The Prodrome

Bizarre preoccupations

Change in sleep/appetite

Aggression, anxiety

Neuromotor or sensory changes

Abnormal eye tracking movements

Brief, intermittent psychosis

Differential Diagnosis of COS

Pervasive developmental disorder

Affective disorders

PTSD

Conduct

Developmental language disorder

Cognitive problems

Conduct disorders

Personality disorders

Dissociative disorder

Substance abuse




Differential Diagnosis of COS

General medical causes:

Delirium

Seizures

CNS lesions

Neurodegenerative disorder

Toxins

Infections

Theories of Causation

Genetic

No family history: 1%

First degree relative: 10%

Identical twin: 50%

Gene markers: GAD1 affecting GABA and neureglin

Theories of Causation

Prenatal insults

Infection

Birth trauma

Rh incompatibility

Abnormal protein and NT Synthesis

Excessive glutamate release (excito-toxic damage)

Structural Brain Abnormalities

Hot area of research

Lateral ventricular volume

Total and regional gray matter volumes

Basal ganglia volumes




Structural Brain Abnormalities in COS

Gray matter loss in back to front pattern

White matter loss in front to back pattern

Exaggerated synaptic pruning

Slower brain growth

Lopsided brain growth

Composite MRI scan data showing areas of gray

matter loss over 5 years, comparing 12 normal

teens (left) and 12 teens with childhood onset

schizophrenia. Red and yellow denotes areas of

greater loss. Front of brain is at left.


Similar changes as AOS

Differs from other neuropsychiatric

disorders

Not yet diagnostic

May predict presymptomatic

adolescents

Copyright restrictions may apply.

Gogtay, N. Schizophr Bull 2007 0:sbm103v1-103; doi:10.1093/schbul/sbm103

Comparison of the Patterns of Cortical Gray Matter (GM) Loss in Childhood-Onset Schizophrenia

(COS) (Between Ages 12 and 16 Years) to That Seen in Normal Cortical Maturation (Between

Ages 4 and 22 Years)


Unaffected family members: early loss of gray

matter, normalizes by age 20

Help in finding genetic markers

Help in identifying trajectory influences




Morbidity and Mortality

People with schizophrenia that are in the public mental

health system die 25 years earlier that the general

population!!

Schizophrenia can be lethal.

Course of Disease

4 phases: prodrome, acute, recuperative, recovery/residual phase

Chronic illness

No cure

Very treatable

Without treatment-downhill course

Diagnostic Work Up

Comprehensive diagnostic evaluation

Labs: complete metabolic panel, thyroid, urinalysis, toxicology screen, HIV, chromosomal analysis, folate, B12, RPR

Screen for infections, heavy metals (Wilson’s)

EEG

MRI

Cognitive testing

Treatment of COS

Comprehensive, multi-modal

Psychological needs

Social needs

Educational needs

Cultural needs

Family needs

Physical needs




Treatment of COS

Psychopharmacology

Psychotherapy: individual and family

Case management

Educational interventions

Social skills training

Inpatient/day treatment

Neurological/medical services

Residential treatment

Rarely, ECT

Now, let’s get to the meds

Antipsychotics revolutionized treatment

Chlorpromazine (Thorazine) – 1952

1st of the “Typical” antipsychotics

First used as an anesthetic

How do antipsychotics work?

Target dopaminergic neurons

Increase dopamine=psychosis

Dopamine blockers

Atypicals also block serotonin

Typical agents affect nigrostriatal tract and mesolimbic tract

Nigrostriatal area also affects involuntary movements

Reason for EPS

Antipsychotic Use in Children

Most use in children is “off label”

Lack adequate data in children

Small sample sizes

Need more controlled trials

Younger patients are more sensitive to adverse

effects of drugs as compared to adults




Antipsychotic Use in Children

Start low and go slow!

Continual monitoring

Routine labs

Baseline and serial weight, height and BMI

Dietary education

FDA Approval of Atypical Antipsychotics

for COS

Risperidone and Aripiprazole are approved for childhood schizophrenia for ages 13-17 yrs.

June, 2009: FDA advisory panel recommended approving Quetiapine and Olanzapine for treatment of childhood schizophrenia for ages 13-17 yrs.

Pre-med workups

Labs

ECG

Informed consent

Atypical Agents

Newer

Affect D2 and 5HT(2A) receptors

Reason for increased efficacy

Affects positive (D2) and negative (5HT)

symptoms

Don’t effect nigrostriatal tract as much-less EPS

Affect mesolimbic and mesocortical tracts




Side Effects of Atypicals

Weight gain!!!!!

Increased glucose, lipids, triglycerides: Metabolic Syndrome

Sedation and anticholinergic symptoms

Extra pyramidal symptoms: akathesia, dystonia, Parkinsonism

Common reason for medication noncompliance

Side Effects of Atypicals

Increased prolactin levels: gynecomastia, galactorhea

Can also cause Neuroleptic Malignant Syndrome and Tardive Dyskinesia

Thought to cause less EPS and less chance of Tardive Dyskinesia

How do we choose an atypical?

Side effect profile- make them work for patient

Any absolute contraindications or medical risks

Other meds: drug-drug interactions

Cost!!!!

Insurance

Patient/family perceptions

Doctor’s own perceptions about meds

Atypical Agents

Generic Name Trade Name Daily Dosage

(mg)

Forms available

Aripiprazole Abilify 10-30 INJ, soln, tabs-D

Clozapine Clozaril 25-900 tabs-D

Olanzapine Zyprexa 5-20 INJ, tabs-D

Palipaeridone Invega 6-12 tabs

Quetiapine Seroquel 300-800 tabs

Risperidone Risperdal 1-12 tabs-D, soln, INJ

Ziprasidone Geodon 40-160 tabs




Risperidone (Risperdal)

1993

Only depot form of atypical-not used in children

Depot form q 2 weeks

Weight gain, sedation and high prolactin most common

Above 6 mg daily- EPS

Olanzapine (Zyprexa)

Very sedating

Excessive weight gain

Metabolic syndrome

Quetiapine (Seroquel)

Moderate for weight gain

Slit lamp eye exam recommended-cataracts, not often done

Very sedating

Used in low doses for sleep-off label

Aripiprazole (Abilify)

Not a full DA antagonist

“Dopamine stabilizer”

Agonist in areas of low activity

More weight neutral

Low incidence of metabolic syndrome




Clozapine (Clozaril)

1989

Weight gain

Seizures

Excessive salivation

Agranulocytosis- serious, fatal

Weekly – biweekly WBC count

Specific protocol-complex to manage

Used in refractory cases: in children, only after failure of 2 other atypical antipsychotics

In children: 1/3 those started on clozapine discontinue due to severe side effects

Ziprasidone (Geodon)

2001

Short acting injectable available

Can be used for acute agitation

More weight neutral than other atypicals

Lower incidence of metabolic syndrome

Cardiac side effects

Typical Antipsychotics

Still use these

Generally more second line in COS

Recent debate that risks comparable to

atypicals

Much cheaper

Haloperidol, chlorpromazine, perphenazine

“Jani’s at the mercy of her mind.”




References

Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision, American Psychiatric Association, 2000

Physicians Desk Reference, 2008

Schizophrenia, A Clinician’s Guide, 1995, American Psychiatric Press

Lieberman JA, Stroup TS, McEvoy JP, et al, “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia”, N Engl J Med, 2005;353: 1209-1223

NIMH, Questions and Answers about the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness Study (CATIE), http://www.nimh.gov/healthinformation.catieqa.cfm

Wu EQ, Birnbaum HG, et al,“The Economic Burden of Schizophrenia in the United States in 2002”, JClinPsych, 2005, Sept;66(9):1122-1129

Practice Guidelines for the Treatment of Patients with Schizophrenia, Second Edition, 2002, American Psychiatric Association

Practice Parameters for the Assessment and Treatment of Children and Adolescents With Schizophrenia, J.Am.Acad.ChildAdolesc.Psychiatry, 40:7 Supplement, July 2001

References

Lieberman, J., “Metabolic Changes Associated with Antipsychotic Use”, PrimCare Companion J Clin Psychiatry 2004;6(suppl 2):8-13.

Battaglia, J., “Compliance with Treatment in Schizophrenia”, Medscape CME.

Narasimhan, M., Bailey, S.B., “Schizophrenia, Metabolic Syndrome, and Antipsychotics Challenges, Controversies, and Clinical Management, Medscape CME.

Childhood Schizophrenia, Child and Adolescent Psychiatry, 2nd Ed.,Lewis, M., 1996, M., 629-635.

White, T., Afshan, A., Schulz, C., “The Schizophrenia Prodrome,” Am.J.Psychiatry, 163(3):376-380, March 2006.

Shari Roan, “Jani’s at the mercy of her mind,” Los Angeles Times, June 29, 2009.

Russel, A., “The Clinical Presentation of Childhood-Onset Schizophrenia,” Schizophrenia Bulletin, 20(4): 631-646, 1994.

References

Gogtay, N., Rapport, J., “Childhood-Onset Schizophrenia: Insights From Neuroimaging Studies, J.Am.Acad.ChildAdolesc.Psychiatry,” 47(10) 1120-24, Oct. 2008.

Greenstein et al, “Remission Status and Cortical Thickness in Childhood-Onset Schizophrenia,” J.Am.Acad.ChildAdolesc.Psychiatry, 40 (10) 1133-40, Oct. 2008.

Rapport et al, “Autism Spectrum Disorder and Childhood-Onset Schizophrenia: Clinical and Biological Contribution to a Relation Revised,” J. Am.Acad.ChildAdolesc.Psychiatry, 48 (1) 10-18, Jan.2009.

Notes

http://www.nimh.gov/healthinformation.catieqa.cfm

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