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Seeing the Truth About Childhood Schizophrenia

Elizabeth Montagnese, M.D.Adult, Child and Adolescent PsychiatristQuittie Glen Center for Mental Health in Annville, Pennsylvania

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

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“Jani’s at the mercy of her mind.”

LA Times story, June 29, 2009Jani Schofield, 6 year oldSevere 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 casesof COS in 1919Typical age of onset:males: 18 years of agefemales: 25 years of ageTop 10 causes of disability worldwide

Schizophrenia Statistics

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

2002- $62.7 billion for direct and nondirectcosts

Unemployment rate is 70-80%

10% of those permanently disabled

What is Childhood Schizophrenia?

Neurodevelopmentaldisorder

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

Diagnostic Difficulties with COS

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

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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

To have the diagnosis, one must exhibit 2 or more of what is termed A criteria symptoms. These include delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms of flat affect, avolition or alogia(which means lack of speech). Only one symptoms is necessary if the person exhibits bizarre delusions or hallucinations to include a voice keeping a running commentary on everything the person is doing or multiple voices arguing, conversing or giving command hallucinations

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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

This is a given. There is always going to be social and occupational dysfunction to some degree. The disturbance in functioning and behavior have to have been present for at least 6 months with one month of Criterion A symptoms. Symptoms must not be solely due to substances, GMC, mood (MDD can have accompanying psychosis) or part of a pervasive developmental disorder.

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Schizophrenia Subtypes

Catatonic

Paranoid

Disorganized

Undifferentiated

Residual

There are 5 different types of schizophrenia. We will not spend much time going over the differences. Paranoid type is the most common.

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What is psychosis?

What is real vs. fantasyThink of “A Beautiful Mind”

Let’s start with some basics about the topic of psychosis since this is the hallmark feature of schizophrenia. What is psychosis? Basically it is the inability to distinguish reality from fantasy. Not knowing if experiences are real or not real. If you have seen the movie, “A Beautiful Mind” about the life of the Nobel winning mathematician John Nash, recall the scene where John is standing outside of his classroom. He is greeting his students as they enter class. This scene was illustrating a time of his life when he became more stable. He asked a female student, “Is that person standing next to you really there?” She replied, “what person”. They both smiled and he said something like “I didn’t think so”. He was experiencing psychosis but also showed some insight by acknowledging that he understood that his experience might not be based in reality

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Positive Symptoms

Symptoms associated with

distorted reality

Delusions

Hallucinations

Things present in those with schizophrenia as compared to those without.

What are “positive symptoms”? These are things that are present in individuals with schizophrenia as compared to those without. They include things are associated with a distorted sense of reality. These include delusions and hallucinations. These are the symptoms most responsive to medications. They are easier to treat.

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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.

Negative symptoms are things that are absent in those with schizophrenia as compared to those without. Eugen Bleuler, a Swiss psychiatrist prosedspecific criteria for diagnosing the disorder and actually called it Schizophrenia. Negative symptoms are known as Bleuler’s 4A’s which describe disturbance of affect, apathy, avolition, associations. Additionally included in negative symptomatology are anhendonia and social withdrawal. Basically those things that make an individual appear to check out of interacting with the world.

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Hallucinations

Think of 5 senses: visual, auditory, olfactory, gustatory, tactile

Usually frightening, morbid, macabre

Can be friendly, company

Hallucinations are distortions of experience/perception/sensation. Patients can many times described these in great detail. I recall one patient who had persistent perceptual disorder from chronically abusing methamphetamine. She had almost constant visual hallucinations that included seeing blood dripping from the trees or the branches appearing like claws. Intermixed in the trees would be faces with no eyes or dripping blood where the eyes should be. Although she had insight most of the time, they were so real and scary to her that it was quite disturbing and the question always was there underneath, “Is that real?” Patients can also experience friendly hallucinations. Once again, think of “A Beautiful Mind” John Nash had 3 repetitive hallucinations in the form of people. One was a menacing CIA agent. The other two heexperienced as friends, companions and to acknowledge that they were not real was in some respect, his abandonment of his friends.

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 negativeCommandConversingCommentingPersecutoryMay be friendly

Visual HallucinationsAlmost always accompanied by auditory hallucinations

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Delusions

A fixed false belief

Bizarre-illogical

Nonbizarre- can really occur

Persecutory

Somatic

Ideas of reference

Grandiose

Religious ideas

Delusions, a common positive symptoms of schizophrenia is any fixed, false belief. Nonbizarre delusions refer to those that could really occur. I recall a patient I had at the State Hospital who always claimed that he was very rich and his money was all tied up in a trust fund that his family was trying to keep from him. Later on I saw this man as an outpatient and found out this that was not delusional as we all had thought, but was real. This illustrates the need to involve family and check out some of the patients reports. Not everything they do or say is based on delusions.An example of a bizarre delusion would include believing that you are transmitting radio signals through special brain waves or believing that your family members are really alien imposters.

Delusions

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 COSBluntedFlatInappropriate

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 functioningoverall functioningsocial isolationpersonal hygiene

Difficulties withattention Change in emotionsFlattening of affect

The Prodrome

Bizarre preoccupationsChange in sleep/appetiteAggression, anxietyNeuromotor or sensory changesAbnormal eye tracking movementsBrief, 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 researchLateral ventricular

volumeTotal and regional

gray matter volumesBasal ganglia

volumes

Structural Brain Abnormalities in COS

Gray matter loss in back to front patternWhite matter loss in front to back patternExaggerated synaptic pruningSlower brain growthLopsided 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.

Structural Brain Abnormalities in COS

Similar changes as AOS

Differs from other neuropsychiatric disorders

Not yet diagnostic

May predict presymptomaticadolescents

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)

Structural Brain Abnormalities in COS

Unaffected family members: early loss of gray matter, normalizes by age 20

Help in finding genetic markers

Help in identifying trajectory influences

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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.

People with a diagnosis of schizophrenia die, on average, 25 years earlier than the general population. This is astounding and a significant public mental health problem. Suicide is a large cause of mortality in schizophrenia with ½of those with the diagnosis attempting suicide at least once and 10% of those with the diagnosis will complete suicide. However, it is becoming more clear that the disease itself and treatments shorten the life span of those afflicted in numerous ways. Some of the ways are modifiable. Some aren’t. What is important to study thoroughly though are these modifiable aspects so we can come up with new and innovative ways to treat the disorder that will provide for high quality and quantity of life. Newer pharmacotherapies have contributed to improved control of symptoms but there has been a cost. We will talk at length about side effects of medications that contribute to several disease states that can shorten the life of those with schizophrenia.

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Course of Disease

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

Chronic illness

No cure

Very treatable

Without treatment-downhill course

Schizophrenia is a chronic, waxing and waning disease. There is no cure, however it is very responsive to treatment. In fact, without treatment, individuals will show a downhill course. With relapse or cessation of treatment, symptoms are harder to push into remission and it is very hard to get back to previously levels of functioning.

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

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Now, let’s get to the meds

Antipsychotics revolutionized treatment

Chlorpromazine (Thorazine) – 1952

1st of the “Typical” antipsychotics

First used as an anesthetic

Treatment of schizophrenia was really revolutionized by the discovery of chlorpromazine in 1952. It was, like many other medication therapies, discovered by accident. It was used as an anesthetic agent. In patient with schizophrenia it was found that their psychosis improved when they were given this anesthetic and so started the pharmacological revolution in mental health.

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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

Psychotropic target specific types of neurons. These are called dopamanergicneurons- those that produce and are affected by dopamine. Dopamine is aneurotransmitter that is associated with psychosis. Very basically, increased dopamine=psychosis. These meds therefore work by blocking dopamine at the receptors sites in neurons. There are several neuronal tracts in the brain affected by these typical agents and include the nigrostriatal tract and mesolimbic tract. It is the nigrostriatal tract that is associated with involuntary movements that are as a result of these medications. These types of effects on movement are called extra pyramidal symptoms.

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

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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

Now let’s talk about the newer agents called atypical agents. They are atypical in that they affect different neurotransmitter systems. They not affect D2- the dopamine like the typicals but also the serotonin system referred to as 5HT. They affect dopaminergic neurons in different tracts, the mesolimbic and mesocortical tracts, not the nigrostriatal which we know is the cause of EPS. We think that atypical show increase efficacy because of affecting different NT systems. This is the reason atypicals are effective in treating the negative symptoms of schizophrenia.

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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

Extra pyramidal symptoms include akathesia. This is when a patient experiences an uncontrolled urge to move, to pace. It is very unpleasant and can be severe. Some patients have committed suicide because of being unable to deal with this. Dystonic reactions include muscle spasms. This commonly occurs in eye called oculogyric crisis, neck called torticollus, or back called opisthonus or tongue. EPS also encompasses Parkinsonian symptoms. This includes shuffling gait, tremor or masked faces- no facial expression. EPS is unpleasant, can be very frightening. Patients may not be able to swallow or turn their heads. It can be intolerable. It is a very common reason for med noncompliance.

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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

Extra pyramidal symptoms include akathesia. This is when a patient experiences an uncontrolled urge to move, to pace. It is very unpleasant and can be severe. Some patients have committed suicide because of being unable to deal with this. Dystonic reactions include muscle spasms. This commonly occurs in eye called oculogyric crisis, neck called torticollus, or back called opisthonus or tongue. EPS also encompasses Parkinsonian symptoms. This includes shuffling gait, tremor or masked faces- no facial expression. EPS is unpleasant, can be very frightening. Patients may not be able to swallow or turn their heads. It can be intolerable. It is a very common reason for med noncompliance.

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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

The development of atypicals has been thought of as groundbreaking in the treatment of schizophrenia. They are thought of to be more tolerable than typicals because of the lower incidence of EPS and TD. They do have many side effects and some serious ones at that. We choose medications by trying to make side effect profile work in favor of the patient. Ones that increase appetite would be a good choice for a patient who has a poor appetite or experienced weight loss. One causing sedation can help patients that experience severe agitation or sleep disruptions. In addition to looking at side effects, we have to look at contraindications. If a patient is heavy or has diabetes or hyperlipidemia, one would not pick an atypical with the highest association with weight gain. You must know every medication a patient is on. Many patients will not tell fully what meds they are on most by omission. They don’t count some things as meds or they simply forget. Cost must be a factor. I recently put a patient on an atypical that was not on her formulary and she informed me that the prescription was going to cost $600 per month. Most people could never afford this. So, we do have to work with insurance formularies. Also, patients or their families may have certain feelings about a particular medication based upon personal experience or the media and popular culture. It is important to know this before prescribing. Also, doctors get comfortable with certain meds, have their “favorites” and gravitate towards using these.

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Atypical Agents

Generic NameGeneric Name Trade NameTrade Name Daily DosageDaily Dosage(mg)(mg)

Forms availableForms available

AripiprazoleAripiprazole AbilifyAbilify 1010--3030 INJ, soln, tabsINJ, soln, tabs--DD

ClozapineClozapine ClozarilClozaril 2525--900900 tabstabs--DD

OlanzapineOlanzapine ZyprexaZyprexa 55--2020 INJ, tabsINJ, tabs--D D

PalipaeridonePalipaeridone InvegaInvega 66--1212 tabstabs

QuetiapineQuetiapine SeroquelSeroquel 300300--800800 tabstabs

RisperidoneRisperidone RisperdalRisperdal 11--1212 tabstabs--D, soln, INJD, soln, INJ

ZiprasidoneZiprasidone GeodonGeodon 4040--160160 tabstabs

This chart shows the various atypicals we now have in our armamentarium. These are the typical doses and the forms available. INJ stands for injectableformula, soln stands for solution and tabs are tablets, and tabD are rapidly dissovling tablets.

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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

Now let’s talk about each one individually. Risperidone was developed in 1993. It is currently the only atypical available in a depot or long acting injectable form. This type of administration of medication has a dramatic effect on improving treatment compliance. Some of the side effects seen with risperidone include weight gain, sedation and high prolactin. In fact, increased prolactin is highest with risperidone out of all the atypical. Once 6mg daily is exceeded, incidence of EPS begins to approach that of the typicals.

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Olanzapine (Zyprexa)

Very sedating

Excessive weight gain

Metabolic syndrome

Olanzapine is very sedating and can really pack the pounds on individuals who can go to develop a metabolic syndrome which includes diabetes, hyperlipidemia and hypertension.

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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

With quetiapine or seroquel, weight gain is less of an issue but sedation is more of one. In the past, there were recommendations that a slit lamp eye exam occur routinely to monitor for cataracts, but recently studies have not listed this issue as a concern. In very low doses, some practitioners may use this as a sleep aid but this is generally not recommended.

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Aripiprazole (Abilify)

Not a full DA antagonist

“Dopamine stabilizer”

Agonist in areas of low activity

More weight neutral

Low incidence of metabolic syndrome

Aripiprazole or abilify is a newer medication that works is a different fashion. It is not entirely a blocker and acts as a dopamine agonist in areas where there is low dopamine activity. It too is more weight neutral. I have had patients, though that have experienced weight gain on this. This is anecdotal, however just recently I stopped this medication after a 25 # weight gain in a young woman. This medication also tends to be activating therefore making not as useful for acute agitation.

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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

Clozapine was the first atypical developed. It has some significant, serious side effects but shows great efficacy especially in treatment refractory cases. Weight gain is significant. It is associated with agranulocytosis which is a serious life threatening complication. A type of WBC is depleted making a person very susceptible to fatal infection. Therefore, weekly WBC counts are part of the treatment protocol. In fact, pharmacists cannot dispense the medication without a copy of the weekly WBC count. This is costly, time consuming and leads to noncompliance. Clozapine therefore is usually reserved for treatment refractory cases. Also there is a great increase in the risk of seizures. Patients also commonly complain excessive salivation

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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

Ziprasidone is considered to be more “weight neutral” than some of the other atypicals. It is available in a short acting injectable form so can be useful for acute episodes. It can be used in the ER in place of haldol which was routinely used in ER setting to calm agitated patients with schizophrenia. It has much less incidence of EPS making this attractive.

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.”

ReferencesDiagnostic 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

ReferencesLieberman, 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”, MedscapeCME.

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.