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. 2015 Apr;72(4):377-85.
doi: 10.1001/jamapsychiatry.2014.2671.

Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome

Jacob A S Vorstman  1 , Elemi J Breetvelt  1 , Sasja N Duijff  1 , Stephan Eliez  2 , Maude Schneider  2 , Maria Jalbrzikowski  3 , Marco Armando  4 , Stefano Vicari  4 , Vandana Shashi  5 , Stephen R Hooper  6 , Eva W C Chow  7 , Wai Lun Alan Fung  8 , Nancy J Butcher  9 , Donald A Young  7 , Donna M McDonald-McGinn  10 , Annick Vogels  11 , Therese van Amelsvoort  12 , Doron Gothelf  13 , Ronnie Weinberger  13 , Abraham Weizman  14 , Petra W J Klaassen  15 , Sanne Koops  1 , Wendy R Kates  16 , Kevin M Antshel  17 , Tony J Simon  18 , Opal Y Ousley  19 , Ann Swillen  11 , Raquel E Gur  20 , Carrie E Bearden  3 , René S Kahn  1 , Anne S Bassett  8 ; International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome
Collaborators, Affiliations

Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome

Jacob A S Vorstman et al. JAMA Psychiatry. 2015 Apr.

Abstract

Importance: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age.

Objective: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS.

Design, setting, and participants: Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years).

Main outcomes and measures: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test.

Results: Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward.

Conclusions and relevance: In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

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Conflict of interest statement

Conflict of interest disclosures

Stephen R. Hooper has provided consultation to Novartis. Opal Ousley is a collaborator in a Biomarin Pharmaceutical study. None of the other authors have declared a conflict of interest.

Figures

Figure 1
Figure 1. Flowchart of 22q11DS subjects’ selection steps
No explanatory legend required.
Fig. 2
Fig. 2. Cumulative plot of the mean annual IQ decline per age in 22q11DS (full longitudinal sample, Verbal, Performance and Full Scale)
For each year the average change in IQ is calculated and represented cumulatively for FSIQ, VIQ and PIQ for all 22q11DS subjects where two or more IQ test results were available between ages 8 and 24 years (n=388). Note that this graph is not a longitudinal “average” trajectory.
Fig. 3a–c
Fig. 3a–c. Cumulative plot of the mean annual IQ decline per age (Verbal, Performance and Full Scale) in 22q11DS, with psychosis vs. without psychosis
For each year the average change in IQ is calculated and represented cumulatively for both subgroups (subjects with 22q11DS with and those without a psychotic disorder) where two or more IQ test results were available between ages 8 and 24 years (n=388). Note that this graph is not a longitudinal “average” trajectory. This implies that the effect size of IQ decline between the two groups is not calculated by the absolute difference in IQ at any given age, but by the difference in slope. What can be observed is that in the subjects in whom a psychotic disorder is diagnosed the decline in IQ is steeper for most age points (p<0.001), but most pronounced for VIQ as illustrated by the larger effect size (partial Eta squared of 0.07 for VIQ, 0.04 for FSIQ and 0.01 for PIQ).
Fig. 3a–c
Fig. 3a–c. Cumulative plot of the mean annual IQ decline per age (Verbal, Performance and Full Scale) in 22q11DS, with psychosis vs. without psychosis
For each year the average change in IQ is calculated and represented cumulatively for both subgroups (subjects with 22q11DS with and those without a psychotic disorder) where two or more IQ test results were available between ages 8 and 24 years (n=388). Note that this graph is not a longitudinal “average” trajectory. This implies that the effect size of IQ decline between the two groups is not calculated by the absolute difference in IQ at any given age, but by the difference in slope. What can be observed is that in the subjects in whom a psychotic disorder is diagnosed the decline in IQ is steeper for most age points (p<0.001), but most pronounced for VIQ as illustrated by the larger effect size (partial Eta squared of 0.07 for VIQ, 0.04 for FSIQ and 0.01 for PIQ).
Fig. 3a–c
Fig. 3a–c. Cumulative plot of the mean annual IQ decline per age (Verbal, Performance and Full Scale) in 22q11DS, with psychosis vs. without psychosis
For each year the average change in IQ is calculated and represented cumulatively for both subgroups (subjects with 22q11DS with and those without a psychotic disorder) where two or more IQ test results were available between ages 8 and 24 years (n=388). Note that this graph is not a longitudinal “average” trajectory. This implies that the effect size of IQ decline between the two groups is not calculated by the absolute difference in IQ at any given age, but by the difference in slope. What can be observed is that in the subjects in whom a psychotic disorder is diagnosed the decline in IQ is steeper for most age points (p<0.001), but most pronounced for VIQ as illustrated by the larger effect size (partial Eta squared of 0.07 for VIQ, 0.04 for FSIQ and 0.01 for PIQ).
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Comment in

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