Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, London, UK
Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, London, UK
Correspondence: Kate Baker, Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N1EH, UK. E-mail: k.baker{at}ich.ucl.ac.uk
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ABSTRACT |
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Aims To define psychopathologyin adolescents and young adults with 22q11 deletion syndrome.
Method Individuals with 22q11 deletion syndrome (n=25) and age- and IQ-matched comparison participants (n=25), along with their parents/carers, completed standardised semi-structured assessments.
Results Psychiatric disorders were more prevalent among those with the syndrome and included attention deficit, depression and anxiety; nearly half reported transient psychotic experiences. Inappropriate emotionality and disrupted social behaviour were also common. Poor functional adjustment was associated with schizotypal symptoms and was more marked in older individuals.
Conclusions 22q11 deletion syndrome is associated with significant psychopathology prior to adulthood. Double the proportion expected to develop schizophrenia reported psychotic phenomena. These findings imply a continuum of developmental disruption in 22q11 deletion syndrome, associated with declining mental health in early adulthood.
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INTRODUCTION |
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METHOD |
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Given the small sample sizes (although similar to previous studies of this rare condition), it is particularly important for study volunteers in both index and control groups to be representative of their populations. To avoid ascertainment bias towards high rates of disorder in subjects with 22q11 deletion syndrome we publicised the study via a national family support organisation and to all attendees at a multi-disciplinary clinic over several years. For the same reason, we did not recruit participants for either group from clinical services where referral was for behavioural or learning difficulties. Psychiatric disorder and behavioural problems were not exclusion criteria for comparison participants because this would have biased the results towards a low rate of psychopathological disruption, unrepresentative of adolescents and young adults with learning disabilities. To counterbalance self-selection biases, literature about the study provided to potential cases and controls stated that it was important for young people both with and without emotional and behavioural difficulties to take part in the research.
Instruments
A semi-structured interview of general psychopathology - the Child and
Adolescent Psychiatric Assessment (CAPA;
Angold et al, 1995) -
was selected as the primary instrument for obtaining a descriptive record of
each participant's current (previous 3 months) mental state. Interviews were
conducted by a research medical student (K.B.) following formal training. They
were reviewed by a senior clinician (D.S.) who was masked to the participants'
group membership. In all cases, the participant and one or two parents/carers
were interviewed using the appropriate CAPA schedule. Interviews took place at
the participants' homes, except for five participants who were assessed at
Great Ormond Street Hospital. Whenever possible, parents and offspring were
interviewed separately. Audio tape recordings and written notes were made
during the interview for later coding and scoring. Information obtained via
the CAPA was used to derive DSM-IV
(American Psychiatric Association,
1994) diagnoses and dimensional symptom scores. A symptom was
counted as present for dimensional scoring if the participant met intensity
criteria, regardless of whether frequency or duration criteria were met for
inclusion of the symptom into a diagnostic algorithm. Estimation of full-scale
IQ was carried out using abbreviated forms of age-appropriate Wechsler tests
according to published protocols described by Crawford et al
(1992) for individuals aged 16
years and over, or by Kaufman et al
(1996) for individuals aged
under 16 years.
Rating scales
Premorbid adjustment refers to poor or deteriorating social and adaptive
functioning prior to the onset of psychosis. These aspects of the
pre-psychotic state may represent a developmental negative
syndrome, continuous with that experienced in schizophrenia following onset of
psychosis, as shown by longitudinal analyses of psychiatric case notes
(Fenton & McGlashan,
1994). In this study, premorbid adjustment ratings were made using
information obtained during the introductory section of the CAPA interview
according to modified Cannon-Spoor scales
(Cannon et al,
1997).
Schizotypy refers to key personality features and subclinical psychopathological traits that are qualitatively similar to symptoms of a psychotic illness and may predict relative risk of schizophrenia-spectrum illness. They aggregate within families of individuals with schizophrenia and co-occur with neurocognitive dysfunctions (Nuechterlein et al, 2002). In this study, dimensional schizotypy ratings were derived from CAPA interviews according to ICD-10 (World Health Organization, 1992) criteria for schizotypal disorder (recommended for use in studies of at-risk populations; Gottesman & Erlenmeyer-Kimling, 2001). The validity of interview-based ratings was confirmed by administering a questionnaire measure of schizotypal features (the Junior Schizotypy Schedule; Diduca & Joseph, 1999) to participants with 22q11 deletion syndrome and controls with adequate literacy levels.
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RESULTS |
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The 22q11 deletion syndrome group displayed higher symptom scores on all dimensions assessed, except for oppositional defiance/conduct problems. A CAPA symptom summary score, for use in correlational analyses, was calculated for each participant as the sum of Z scores for each DSM-IV symptom dimension (attention, mood, anxiety, obsessive compulsions, oppositional defiance). Mean CAPA symptom summary scores were 1.4 (s.d.=2.9) for the 22q11 deletion syndrome group and -1.3 for the control group (s.d.=1.9). The larger standard deviation in this summary score for the 22q11 deletion syndrome group reflects the considerable variation in severity of psychiatric disorder within this population.
Two specific symptom clusters were reported commonly by participants with 22q11 deletion syndrome. Rapid emotional lability, characterised by frequent, angry outbursts, was a common and intrusive symptom present in 9 out of 25 participants with 22q11 deletion syndrome (36%); 12 out of 25 participants with the syndrome (48%) reported psychosis-like phenomena (corresponding to specific definitions within the CAPA glossary). These were generally of short duration and not perceived as being highly distressing or intrusive. Phenomena were diverse. Examples of delusional thinking included ungrounded fears of being targeted by the police and being watched through closed-circuit television. Examples of perceptual disturbances included auditory (voices talking about the individual, although not necessarily in derogatory terms) and visual hallucinations, in two cases associated with religious imagery and superstitious beliefs not shared by family members. Other abnormal experiences included passivity phenomena, depersonalisation and thought broadcast.
Schizotypy
A total of 21 out of 25 participants from the 22q11 deletion syndrome group
received at least one positive rating on the schizotypy scale, whereas only 3
out of 25 control participants received any positive ratings. Mean schizotypy
scores (out of 9) were 2.8 for 22q11 deletion syndrome participants (s.d.=2.0)
and 0.2 for control subjects (s.d.=0.5) (data not normally distributed,
Mann-Whitney U=59, P<0.0001). To assess the validity of
these schizotypy scores derived from CAPA items, correlations between scores
on the Junior Schizotypy Schedule questionnaire and on the interview-derived
scale were examined. Correlations between scores, for the 22q11 deletion
syndrome and comparison populations combined (Spearman's =0.34,
P=0.052) and the 22q11 deletion syndrome group alone (Spearman's
=0.55, P=0.004), confirmed the validity of interview-derived
schizotypy ratings.
Premorbid adjustment
Social-occupational functioning was found to be markedly impaired in
participants with 22q11 deletion syndrome relative to comparison participants
(displayed in Table 3), with
higher scores on all premorbid adjustment sub-scales except scholastic
adaptation. The majority of participants with the syndrome reported
impoverished social interactions and peer relationships, associated with lack
of interest in or tolerance of others, perceived lack of skill in social
situations or rejection by peers. Relative to comparison participants, they
also participated far less frequently in organised social activities, such as
attending youth clubs or taking part in hobbies. They usually preferred
solitary activities, which in some individuals were pursued in an obsessive
manner.
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Relationships between psychopathology, IQ and age
There was no significant association between general cognitive impairment
and the presence or severity of symptoms and functional impairments. The CAPA
symptom summary, the schizotypy score and the total premorbid adjustment score
were not correlated with estimated full-scale IQ within the 22q11 deletion
syndrome group. Total premorbid adjustment score was associated with age, with
greater impairment seen in older participants with the syndrome (Spearman's
=0.41, P=0.046). However, there was no significant relationship
between age and either CAPA summary score (Spearman's
=0.26,
P=0.22) or schizotypy rating (Spearman's
=0.12,
P=0.50).
Relationships between psychopathological indices
Partial correlations were computed for the three summary measures of
psychopathology, controlling for age because of the association with premorbid
adjustment scores in the 22q11 deletion syndrome group. This analysis was
justified only for the 22q11 deletion syndrome group, because of the limited
variance of scores in the comparison group. This indicated a highly
significant relationship between schizotypy scores and premorbid adjustment
(Spearman's =0.70, P=0.001) but only a weak trend towards a
relationship between CAPA summary score and premorbid adjustment (Spearman's
=0.35, P=0.14). Schizotypy scores and CAPA summary scores also
were unrelated to each other (Spearman's
=0.12, P=0.6).
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DISCUSSION |
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The majority of the subjects with 22q11 deletion syndrome reported symptoms of a schizotypal disorder, unlike matched comparison participants. The severity of their schizotypal features correlated with poorer social functioning and fewer interests. The premorbid adjustment scores (but not CAPA symptom counts or schizotypy) increased with age in the participants with the syndrome, implying greater functional impairment as the individuals approach the time of higher risk for onset of schizophrenia.
For all dimensional symptom and rating scales there was a wider distribution of scores for the 22q11 deletion syndrome group than for controls, but no evidence of bimodal distributions. In the population with the syndrome there were proportionately more young people who describe psychotic symptoms than the 25-30% who are predicted to go on to develop a psychotic illness. This suggests that there is a continuum of psychotic disorder within the 22q11 deletion syndrome group from mild to severe, with no clear division between affected and unaffected categories, at least during adolescence.
Comparison with previous studies of 22q11 deletion syndrome
There have been previous reports of mood-related psychopathology in
children and adolescents with 22q11 deletion syndrome
(Papolos et al, 1996; Arnold et al, 2001).
We have observed that other disruptions to thought and behaviour also are
common. The current study is the first to include a control group of
adolescents with learning disability, confirming that these features are not
non-specific consequences of neurodevelopmental disorder. Previous
case-control studies involving mostly younger children with 22q11 deletion
syndrome have found no marked differences between groups in rates of
psychiatric disorder (Swillen et
al, 2001; Feinstein
et al, 2002). The contrast with our findings in
adolescents could have a variety of explanations. First, critical
developmental processes relevant to the emergence of later psychotic illness
may occur during later childhood or around the time of puberty. Second,
subjective schizotypal phenomena may be present at an earlier age, but
individuals are not able to articulate these symptoms until they have reached
sufficient levels of cognitive and linguistic attainment. In middle childhood,
liability to psychotic symptoms may manifest as non-specific childhood
behavioural disturbance, such as separation anxiety, sleep disturbance and
somatic complaints (Miller et al,
2002a). We found self-report by adolescents to be an
essential resource for determining the presence and content of psychotic
phenomena. Previous investigators interviewed parents of individuals with
22q11 deletion syndrome but not the children themselves, and therefore would
not have been made aware of these features.
Comparison with studies of idiopathic schizophrenia
Schizophrenia is a late psychiatric manifestation of an abnormal
neurodevelopmental process, leading to aberrant neurological and psychological
functioning at several points along a developmental trajectory. Accordingly,
evidence of developmental disruption, in the form of specific cognitive
performance decrements and psychiatric symptoms during childhood and
adolescence, is detectable prior to the onset of major psychotic illness.
Evidence of this type has been obtained by retrospective report (e.g.
Cannon et al, 1997) and prospective epidemiological cohort studies (e.g.
Done et al, 1994).
The presence of psychotic experiences and other schizotypal phenomena in people with 22q11 deletion syndrome parallels developmental findings in idiopathic schizophrenia. For example, the Dunedin prospective cohort study found an association between self-reported psychotic symptoms at age 11 years and schizophreniform illness (but not mania or depression) at age 26 years (odds ratio 16.4). Nearly half (42%) of adult patients reported symptoms at this early age (Poulton et al, 2000). In genetic high-risk studies, the presence of psychosis-like phenomena during childhood and adolescence predicts the likelihood of adult-onset illness (Miller et al, 2002b; Ott et al, 2002). However, the predictive power of these phenomena is not high and there are significant false-positive and false-negative rates. Psychotic experiences and schizotypal characteristics during adolescence may be relatively common, reflecting neurodevelopmental deviations from the norm that do not necessarily lead to schizophrenia. Conversely, not all adults with schizophrenia report such experiences during adolescence. Therefore, early symptoms are likely to reflect genetically mediated neurodevelopmental disruption, which interacts in a currently unpredictable fashion with later neurobiological and psychosocial events to precipitate psychotic illness in a subset of individuals at high risk.
Our findings suggest that, whereas psychiatric symptoms may occur at at any time during adolescence in 22q11 deletion syndrome, the social and functional impairment associated with them increases over time. Within the limits of a cross-sectional study, it is arguable that the observed association between older age and poorer functional adjustment reflects a process of intra-individual functional decline. Genetic high-risk studies have not as yet collected sufficiently fine-grained data in an adequate sample to observe such a decline in individuals who develop adult-onset psychosis. However, recent clinical research aiming to facilitate early identification and preventive intervention for schizophrenia has identified high-risk groups of young people presenting to psychiatric services with prodromal symptoms. Recent reports from the largest such cohort indicate that, although attenuated psychotic symptoms are moderately predictive of risk of illness within a 12-month period, detection rates are greatly increased when measures of functional capacity and, crucially, recent functional decline are taken into account (Yung et al, 2004).
Longitudinal studies in high-risk groups (both genetically and clinically defined) have shown that psychopathological decline, which presages illness-onset, may be mirroring a process of neuropsychological (IQ and memory) and anatomical (medial temporal lobe) deterioration in already at-risk individuals (Cosway et al, 2000; Pantelis et al, 2003). Longitudinal follow-up of the present 22q11 deletion syndrome cohort will determine whether a similar trajectory characterises the emergence of debilitating psychotic illness in syndromal cases. Several small randomised controlled trials have now been carried out within clinically high-risk samples, to determine whether it is possible to prevent or delay deterioration by pharmacological or psychotherapeutic intervention. Findings from these trials have been mixed so far, limited by the small sample size and short periods of follow-up, but ongoing development of detection criteria and treatment protocols may yield results of clinical benefit to people with 22q11 deletion syndrome.
Implications for genetics, neurodevelopment and schizophrenia
Specific neurocognitive substrates appear to underlie susceptibility to
psychosis. The mechanisms involved in mediating risk for psychiatric illness
in people with 22q11 deletion syndrome are still speculative. Perhaps
haploinsufficiency for the protein product of a key gene at the 22q11 locus
impairs the development of a critical neurocognitive mechanism that has a
wide-ranging effect on psychological function. Individual symptoms arise
stochastically, as a consequence of unpredictable environmental interactions
with an abnormal trajectory of emotional-behavioural maturation. This model is
supported partially by the present findings: symptoms reported by participants
with 22q11 deletion syndrome varied widely in both type and severity.
Alternatively, haploinsufficiency of a key gene in the 22q11 region may render
vulnerable the development of many different neurocognitive processes. Each
symptom cluster (e.g. attention-deficit, psychotic phenomena) could have its
origin in different impairment processes of maturation or function. This
hypothesis is supported by the consistency between participants in the
characteristics of certain symptoms, such as angry outbursts and
psychosis-like phenomena, that suggest disruption to context-dependent emotion
regulation and reality monitoring. Early indications are that psychotic
phenomena in the adolescent cohort with 22q11 deletion syndrome are associated
with abnormal perceptual processing and impaired working memory systems. We
have evidence that distinct impairments in event-related electroencephalogram
potentials (mismatch negativity), evoked in response to unpredictable change
in an auditory stream, closely resemble abnormalities seen in idiopathic
schizophrenia (details available from the authors upon request). The
similarity in psychopathological features during adolescence and young
adulthood reported here provides additional support for the hypothesis that
parallel neurodevelopmental disruption occurs in 22q11 deletion syndrome and
in idiopathic schizophrenia. Further investigation of gene-brain-behaviour
relationships in people with 22q11 deletion syndrome may add much to our
understanding of developmental events contributing to the risk of psychotic
disorders and the mechanisms by which genetic factors influence individual
risk.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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Received for publication June 21, 2004. Revision received October 7, 2004. Accepted for publication October 12, 2004.
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