EDITORIAL
Measuring Prodromal Symptoms in Youth With Developmental Disabilities: A Lesson From 22q11 Deletion Syndrome Doron Gothelf,
I
first encountered the 22q11 deletion syndrome (22q11DS) 20 years ago when it was better known as DiGeorge or velocardiofacial syndrome. I was in my first year of residency in psychiatry and working in a closed adult inpatient department. Most patients I treated had been diagnosed with schizophrenia. At that time, it was well established that schizophrenia has a strong genetic diathesis. It also was acknowledged that schizophrenia is not the result of a single gene mutation with a Mendelian inheritance pattern, but rather the endpoint of multiple gene variants interacting with unknown environmental factors. Encouraged by the developmental psychopathology approach of my mentor, the late Donald J. Cohen,1 I became involved in the search for a known genetic defect associated with a high risk for psychosis. I consulted with my medical geneticist teacher, and he referred me to the pioneering work of Karayiorgou et al.,2 who had tested 100 patients with schizophrenia using the fluorescent in situ hybridization technique and found that 2 of them had a hemizygous microdeletion in the long arm of chromosome 22 (22q11DS). My teacher also referred me to an earlier publication by Shprintzen et al.,3 who reported their clinical impression that more than 10% of their cohort of patients with velocardiofacial syndrome developed psychotic features, most commonly “chronic schizophrenia with paranoid delusions.” The 22q11DS microdeletion has since attracted the attention of a continuously growing community of psychiatrists and neuroscientists as a promising model for understanding the pathways leading from a known genetic defect to the evolution of schizophrenialike psychotic disorders. This journey turned out
MD
to have many more twists and turns than originally expected.
WHAT DO WE KNOW ABOUT THE PSYCHIATRIC ASPECTS OF 22Q11DS? We have since learned that approximately one third of individuals with 22q11DS develop a psychotic disorder (in most cases, “schizophrenialike”). Moreover, because 22q11DS is relatively common (occurring in 1 in 4,000 live births), it is currently the most common identifiable risk factor for schizophrenia.4,5 The age of psychosis onset in 22q11.2DS varies but is usually during adolescence and early adulthood.6 In addition to schizophrenia, individuals with 22q11DS are afflicted with high rates of other psychiatric morbidities, including attention-deficit/hyperactivity disorder and anxiety disorders, each affecting approximately one half of children with 22q11DS.4 We also learned that, similar to idiopathic schizophrenia, the psychotic disorder in 22q11DS is a gradual developmental process, with anxiety symptoms and decrease in verbal IQ being risk factors for the later development of psychotic disorders.6
PRODROMAL SYMPTOMS IN 22Q11DS ARE SIMILAR TO THOSE IN PATIENTS WITHOUT 22Q11DS
The focus of the article by Gur et al.7 in this issue of the Journal maps out the early signs of psychosis (also known as prodromal symptoms) in an impressively large sample of 157 8- to 25-year-old individuals with 22q11DS. Using the gold standard tool for assessing prodromal symptoms in schizophrenia, the Scale of
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
945
GOTHELF
Prodromal Symptoms (SOPS), the investigators found that 54% of the total sample were “psychosis-prone” or “prodromal,” with 82% of them displaying positive psychotic symptoms. The most common “positive” symptoms found in the study by Gur et al. were unusual thought content, suspiciousness, and perceptual abnormalities. The distribution of positive symptoms found in psychosis-prone individuals with 22q11DS is in line with the distribution of positive symptoms reported in patients with prodromal symptoms and without 22q11DS.8 This latter finding further suggests that the early psychotic symptoms that evolve in association with 22q11DS are similar to the early psychotic symptoms of patients with schizophrenia in the general population.
UNIQUE ASPECTS IN ASSESSING PRODROMAL SYMPTOMS IN 22Q11DS
One of the strengths of the article by Gur et al.7 is their highlighting of unique aspects that need to be considered in the assessment of prodromal symptoms in 22q11DS. The facts that individuals with 22q11DS have a mean IQ level of 75 and that their IQ ranges from a moderate intellectual disability to normal intellectual functioning raise several challenging issues. Although the mean IQ of patients without 22q11DS and with schizophrenia is also below average, the mean IQ in 22q11DS is significantly lower. Gur et al.7 decided to include only individuals with 22q11DS and an IQ of at least 70 because the SOPS interview contains some relatively sophisticated questions, which individuals with more profound intellectual disability cannot comprehend (e.g., “Does your experience of time seem to have changed? Is it unnaturally faster or unnaturally slower?”). Excluding individuals with 22q11DS and severe cognitive impairments would increase the validity of the findings and their ability to be generalized to those with non-22q11DS schizophrenia. However, it decreases the sensitivity of early identification of proneness to psychosis in 22q11DS because we know that individuals with 22q11DS and lower IQs are at greater risk for developing psychosis.9 The investigators correctly included younger individuals—as young as 8 years—taking into consideration that the onset of psychosis in 22q11DS also occurs early in life.10 This is in contrast to the older minimal age of study 946
www.jaacap.org
inclusion (i.e., mid-adolescence) in non-22q11DS prodromal studies.8 The fact that the SOPS was administered to individuals with developmental disability might account for the high rates of some symptoms found in individuals with 22q11DS in this study (e.g., ideational richness, trouble with focus of attention, and anxiety symptoms). These signs and symptoms tend to appear at a young age in those with 22q11DS.4 In consequence, a relatively sharp change from the grossly normal baseline that is characteristic of the prodrome in help-seeking individuals without 22q11DS is likely to be more gradual and less obvious in cohorts with 22q11DS.
YOUTH AND CAREGIVER COLLATERAL INTERVIEWS
The findings by Gur et al.7 suggest that the best approach to assess prodromal symptoms in 22q11DS is to conduct independent comprehensive assessments with the proband and the proband’s caregivers. The SOPS originated in adult psychiatry and thus was designed as a proband interview. In addition, it had to be taken into consideration that individuals with 22q11DS, even when they are young adults, are usually dependent on their parents or other adult caregivers who are still much involved in and supervise their lives. Interestingly, Gur et al. found that probands’ reports more commonly elicited positive symptoms, whereas parents’ reports included relatively higher negative symptoms. Most importantly, the positive symptoms were reported solely by the youths and not by the caregivers in 17% of cases, thus highlighting the importance of interviewing youth with 22q11DS in depth for the presence of psychosis-spectrum symptoms. Some individuals with 22q11DS admit that they do not report the presence of psychotic symptoms to their parents because they wish not to burden them with additional worries. Such a child–parent dynamic is common in individuals with developmental disabilities and further highlights the need for administering the 22q11DS SOPS interviews to the youths and their parents, and doing so separately.
APPLICATIONS FOR FUTURE RESEARCH After 2 decades of research, it is still unknown which of the nearly 100 known genes from the 3-Mb deletion region account for the remarkably high rates of schizophrenia in 22q11DS. The investigators conducting 22q11DS research have
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
EDITORIAL
recognized that there is a need for multisite studies and for recruiting large numbers of individuals with 22q11DS followed longitudinally from childhood to young adulthood to identify the pathways leading to schizophrenia in 22q11.2DS. Another essential preparatory step needed for the completion of this mission is adapting standardized clinical measurements of early psychotic symptoms in the general population, such as the SOPS, for use in 22q11DS studies. The article by Gur et al.7 is an essential step in this long and fascinating journey toward elucidating the pathways leading to schizophrenia in 22q11DS. &
Accepted June 13, 2014. Dr. Gothelf is with the Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, and affiliated with the Sackler Faculty of Medicine, Tel Aviv University. The writing of this editorial was supported by grants from Binational Science Foundation (2011378) and the National Institute of Mental Health (5U01MH101722-02). Disclosure: Dr. Gothelf reports no biomedical financial interests or potential conflicts of interest. Correspondence to Doron Gothelf, MD, Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, 52621, Tel Hashomer, Israel; e-mail: [email protected] 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.06.007
REFERENCES 1. Cicchetti D, Cohen DJ. Developmental Psychopathology: Theory and Method, Vol 1. New York: Wiley; 1995. 2. Karayiorgou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92:7612-7616. 3. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet. 1992;42:141-142. 4. Green T, Gothelf D, Glaser B, et al. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry. 2009;48:1060-1068. 5. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56:940-945.
6. Gothelf D, Schneider M, Green T, et al. Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. J Am Acad Child Adolesc Psychiatry. 2013;52:1192-1203. 7. Gur R, Yi J, Moore T, et al. Subthreshold psychotic symptoms in 22q11.2 deletion syndrome. J Am Acad Child Adolesc Psychiatry. 2014;53:991-1000. 8. Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65:28-37. 9. Gothelf D, Feinstein C, Thompson T, et al. Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry. 2007;164:663-669. 10. Usiskin SI, Nicolson R, Krasnewich DM, et al. Velocardiofacial syndrome in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 1999;38:1536-1543.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
947
Measuring Prodromal Symptoms in Youth With Developmental Disabilities: A Lesson From 22q11 Deletion Syndrome Doron Gothelf,
I
first encountered the 22q11 deletion syndrome (22q11DS) 20 years ago when it was better known as DiGeorge or velocardiofacial syndrome. I was in my first year of residency in psychiatry and working in a closed adult inpatient department. Most patients I treated had been diagnosed with schizophrenia. At that time, it was well established that schizophrenia has a strong genetic diathesis. It also was acknowledged that schizophrenia is not the result of a single gene mutation with a Mendelian inheritance pattern, but rather the endpoint of multiple gene variants interacting with unknown environmental factors. Encouraged by the developmental psychopathology approach of my mentor, the late Donald J. Cohen,1 I became involved in the search for a known genetic defect associated with a high risk for psychosis. I consulted with my medical geneticist teacher, and he referred me to the pioneering work of Karayiorgou et al.,2 who had tested 100 patients with schizophrenia using the fluorescent in situ hybridization technique and found that 2 of them had a hemizygous microdeletion in the long arm of chromosome 22 (22q11DS). My teacher also referred me to an earlier publication by Shprintzen et al.,3 who reported their clinical impression that more than 10% of their cohort of patients with velocardiofacial syndrome developed psychotic features, most commonly “chronic schizophrenia with paranoid delusions.” The 22q11DS microdeletion has since attracted the attention of a continuously growing community of psychiatrists and neuroscientists as a promising model for understanding the pathways leading from a known genetic defect to the evolution of schizophrenialike psychotic disorders. This journey turned out
MD
to have many more twists and turns than originally expected.
WHAT DO WE KNOW ABOUT THE PSYCHIATRIC ASPECTS OF 22Q11DS? We have since learned that approximately one third of individuals with 22q11DS develop a psychotic disorder (in most cases, “schizophrenialike”). Moreover, because 22q11DS is relatively common (occurring in 1 in 4,000 live births), it is currently the most common identifiable risk factor for schizophrenia.4,5 The age of psychosis onset in 22q11.2DS varies but is usually during adolescence and early adulthood.6 In addition to schizophrenia, individuals with 22q11DS are afflicted with high rates of other psychiatric morbidities, including attention-deficit/hyperactivity disorder and anxiety disorders, each affecting approximately one half of children with 22q11DS.4 We also learned that, similar to idiopathic schizophrenia, the psychotic disorder in 22q11DS is a gradual developmental process, with anxiety symptoms and decrease in verbal IQ being risk factors for the later development of psychotic disorders.6
PRODROMAL SYMPTOMS IN 22Q11DS ARE SIMILAR TO THOSE IN PATIENTS WITHOUT 22Q11DS
The focus of the article by Gur et al.7 in this issue of the Journal maps out the early signs of psychosis (also known as prodromal symptoms) in an impressively large sample of 157 8- to 25-year-old individuals with 22q11DS. Using the gold standard tool for assessing prodromal symptoms in schizophrenia, the Scale of
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
945
GOTHELF
Prodromal Symptoms (SOPS), the investigators found that 54% of the total sample were “psychosis-prone” or “prodromal,” with 82% of them displaying positive psychotic symptoms. The most common “positive” symptoms found in the study by Gur et al. were unusual thought content, suspiciousness, and perceptual abnormalities. The distribution of positive symptoms found in psychosis-prone individuals with 22q11DS is in line with the distribution of positive symptoms reported in patients with prodromal symptoms and without 22q11DS.8 This latter finding further suggests that the early psychotic symptoms that evolve in association with 22q11DS are similar to the early psychotic symptoms of patients with schizophrenia in the general population.
UNIQUE ASPECTS IN ASSESSING PRODROMAL SYMPTOMS IN 22Q11DS
One of the strengths of the article by Gur et al.7 is their highlighting of unique aspects that need to be considered in the assessment of prodromal symptoms in 22q11DS. The facts that individuals with 22q11DS have a mean IQ level of 75 and that their IQ ranges from a moderate intellectual disability to normal intellectual functioning raise several challenging issues. Although the mean IQ of patients without 22q11DS and with schizophrenia is also below average, the mean IQ in 22q11DS is significantly lower. Gur et al.7 decided to include only individuals with 22q11DS and an IQ of at least 70 because the SOPS interview contains some relatively sophisticated questions, which individuals with more profound intellectual disability cannot comprehend (e.g., “Does your experience of time seem to have changed? Is it unnaturally faster or unnaturally slower?”). Excluding individuals with 22q11DS and severe cognitive impairments would increase the validity of the findings and their ability to be generalized to those with non-22q11DS schizophrenia. However, it decreases the sensitivity of early identification of proneness to psychosis in 22q11DS because we know that individuals with 22q11DS and lower IQs are at greater risk for developing psychosis.9 The investigators correctly included younger individuals—as young as 8 years—taking into consideration that the onset of psychosis in 22q11DS also occurs early in life.10 This is in contrast to the older minimal age of study 946
www.jaacap.org
inclusion (i.e., mid-adolescence) in non-22q11DS prodromal studies.8 The fact that the SOPS was administered to individuals with developmental disability might account for the high rates of some symptoms found in individuals with 22q11DS in this study (e.g., ideational richness, trouble with focus of attention, and anxiety symptoms). These signs and symptoms tend to appear at a young age in those with 22q11DS.4 In consequence, a relatively sharp change from the grossly normal baseline that is characteristic of the prodrome in help-seeking individuals without 22q11DS is likely to be more gradual and less obvious in cohorts with 22q11DS.
YOUTH AND CAREGIVER COLLATERAL INTERVIEWS
The findings by Gur et al.7 suggest that the best approach to assess prodromal symptoms in 22q11DS is to conduct independent comprehensive assessments with the proband and the proband’s caregivers. The SOPS originated in adult psychiatry and thus was designed as a proband interview. In addition, it had to be taken into consideration that individuals with 22q11DS, even when they are young adults, are usually dependent on their parents or other adult caregivers who are still much involved in and supervise their lives. Interestingly, Gur et al. found that probands’ reports more commonly elicited positive symptoms, whereas parents’ reports included relatively higher negative symptoms. Most importantly, the positive symptoms were reported solely by the youths and not by the caregivers in 17% of cases, thus highlighting the importance of interviewing youth with 22q11DS in depth for the presence of psychosis-spectrum symptoms. Some individuals with 22q11DS admit that they do not report the presence of psychotic symptoms to their parents because they wish not to burden them with additional worries. Such a child–parent dynamic is common in individuals with developmental disabilities and further highlights the need for administering the 22q11DS SOPS interviews to the youths and their parents, and doing so separately.
APPLICATIONS FOR FUTURE RESEARCH After 2 decades of research, it is still unknown which of the nearly 100 known genes from the 3-Mb deletion region account for the remarkably high rates of schizophrenia in 22q11DS. The investigators conducting 22q11DS research have
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
EDITORIAL
recognized that there is a need for multisite studies and for recruiting large numbers of individuals with 22q11DS followed longitudinally from childhood to young adulthood to identify the pathways leading to schizophrenia in 22q11.2DS. Another essential preparatory step needed for the completion of this mission is adapting standardized clinical measurements of early psychotic symptoms in the general population, such as the SOPS, for use in 22q11DS studies. The article by Gur et al.7 is an essential step in this long and fascinating journey toward elucidating the pathways leading to schizophrenia in 22q11DS. &
Accepted June 13, 2014. Dr. Gothelf is with the Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, and affiliated with the Sackler Faculty of Medicine, Tel Aviv University. The writing of this editorial was supported by grants from Binational Science Foundation (2011378) and the National Institute of Mental Health (5U01MH101722-02). Disclosure: Dr. Gothelf reports no biomedical financial interests or potential conflicts of interest. Correspondence to Doron Gothelf, MD, Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, 52621, Tel Hashomer, Israel; e-mail: [email protected] 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.06.007
REFERENCES 1. Cicchetti D, Cohen DJ. Developmental Psychopathology: Theory and Method, Vol 1. New York: Wiley; 1995. 2. Karayiorgou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92:7612-7616. 3. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet. 1992;42:141-142. 4. Green T, Gothelf D, Glaser B, et al. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry. 2009;48:1060-1068. 5. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56:940-945.
6. Gothelf D, Schneider M, Green T, et al. Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. J Am Acad Child Adolesc Psychiatry. 2013;52:1192-1203. 7. Gur R, Yi J, Moore T, et al. Subthreshold psychotic symptoms in 22q11.2 deletion syndrome. J Am Acad Child Adolesc Psychiatry. 2014;53:991-1000. 8. Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65:28-37. 9. Gothelf D, Feinstein C, Thompson T, et al. Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry. 2007;164:663-669. 10. Usiskin SI, Nicolson R, Krasnewich DM, et al. Velocardiofacial syndrome in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 1999;38:1536-1543.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
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