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Genetic testing in psychiatry promises to improve patient care through
advances in personalised medicine. However, there are few clinically
To determine whether patients with a well-established genetic subtype of
schizophrenia show a different response profile to the antipsychotic
clozapine than those with idiopathic schizophrenia.
We retrospectively studied the long-term safety and efficacy of clozapine
in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS
group) and half matched for age and clinical severity but molecularly
confirmed to have no pathogenic copy number variant (idiopathic
Both groups showed similar clinical improvement and significant
reductions in hospitalisations, achieved at a lower median dose for those
in the 22q11.2DS group. Most common side-effects were similarly prevalent
between the two groups, however, half of the 22q11.2DS group experienced
at least one rare serious adverse event compared with none of the
idiopathic group. Many were successfully retried on clozapine.
Individuals with 22q11.2DS-schizophrenia respond as well to clozapine
treatment as those with other forms of schizophrenia, but may represent a
disproportionate number of those with serious adverse events, primarily
seizures. Lower doses and prophylactic (for example anticonvulsant)
management strategies can help ameliorate side-effect risks. This first
systematic evaluation of antipsychotic response in a genetic subtype of
schizophrenia provides a proof-of-principle for personalised medicine and
supports the utility of clinical genetic testing in schizophrenia.
Patients with chromosome 22q11.2 deletion syndrome (22q11DS) are at a seven fold increased risk of developing seizures. However, only a fraction of these patients exhibit structural abnormalities such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) that are known to cause seizures and to be associated with 22q11DS. In this study we used a dedicated seizure imaging protocol to look for additional structural abnormalities in these individuals that may explain the elevated risk of seizure disorder in this patient group.
Nineteen consecutive adult subjects with 22q11DS underwent a 3 Tesla MRI with a dedicated high-resolution seizure protocol. Neurological exam was performed in all patients. Genome-wide analysis excluded the presence of other pathogenic microdeletions or duplications.
Structural abnormalities were found in 11 of 14 subjects with sufficient image quality. These included three patients with PNH, one of whom had associated PMG. In addition, there was a surprisingly high prevalence of unilateral hippocampal malrotation (HIMAL), observed in 9 of 14 cases (64%). EEG findings showed interictal epileptiform discharges with focal distribution in four patients and generalized discharges in one patient.
The results suggest that, in addition to other known structural abnormalities, 22q11DS is associated with HIMAL. It has been suggested that this developmental abnormality of the hippocampus may predispose or otherwise contribute to epileptogenesis. However in this study we observed HIMAL in a large proportion of patients, with and without epilepsy. Therefore, other as yet unknown factors may contribute to the high prevalence of epilepsy in this population.
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