Gerald Hurowitz, M.D.·Published 7 May 2009·10 min read
Key points
In theory at least, the onset of schizophrenia could be prevented if an intervention reduced the premorbid 'risk' status.
Because of the very small number of trials of antipsychotics conducted with child and adolescent patients, it is necessary to extrapolate most evidence on drug efficacy from studies in adults.
The rationale for psychosocial family interventions follows from the association between high EE and the risk of relapse in schizophrenia (Leff & Vaughn 1985; Dixon & Lehman 1995).
Whether CBT is equally effective with younger patients, or those with predominant negative symptoms, remains to be established.
General principles
While antipsychotic drugs remain the cornerstone of treatment in child and adolescent onset schizophrenia, all young patients with schizophrenia require a multimodal treatment package that includes pharmacotherapy, family and individual counselling, education about the illness and provision to meet social and educational needs (Clark & Lewis 1998).
Primary prevention and early detection
In theory at least, the onset of schizophrenia could be prevented if an intervention reduced the premorbid 'risk' status. However, the difficulty with the premorbid phenotype as currently conceived (subtle social and developmental impairments) is its extremely low specificity and positive predictive value for schizophrenia in the general population, assuming that these premorbid features are a causal risk factor (Erlenmeyer-Kimling et al. 2000). Future refinement of the premorbid phenotype is likely to include genetic and neurocognitive markers in order to achieve acceptable sensitivity and specificity. At present, primary prevention remains on the distant horizon.
In contrast to primary prevention, the aims of early detection are to identify the onset of deterioration in vulnerable individuals with a high predictive validity. Predictive power increases markedly in adolescence around the onset of the prodrome (Davidson et al. 1999).
Recent work has attempted to identify 'high-risk' or early prodromal states with the aim of intervening to prevent the active phase of schizophrenia (McGrorry & Sing 1995; Yung et al. 1996). However, only about one-fifth of these 'high-risk' cases go on to develop frank psychosis and it has proved impossible to distinguish these 'high-risk' cases from others who remain non-psychotic. Clearly, interventions directed at 'high-risk' or prodromal states need to benefit the whole population at risk, the majority of whom will not develop schizophrenia. A pragmatic stance would be to monitor children and adolescents with a strong family history and/or suggestive prodromal symptoms to ensure prompt treatment of psychosis.
Strong claims have been made that early recognition and treatment of psychotic symptoms in schizophrenia improves outcome.
The association between a long duration of untreated psychosis (DUP) and poor long-term outcome in schizophrenia (Loebel et al. 1992; Wyatt 1995; Birchwood et al. 1997) supports this view.
A similar association has been found in child and adolescent onset psychoses (Hollis 1999). While the association between DUP and poor outcome seems secure, the causal connection is far less certain. DUP is also associated with insidious onset and negative symptoms which could confound links with poor outcome. While there are good a priori clinical reasons for the early treatment of symptoms to relieve distress and prevent secondary impairments, as yet it remains unproven whether early intervention actually alters the long-term course of schizophrenia.
Written and revised by
Gerald Hurowitz, M.D.
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Because of the very small number of trials of antipsychotics conducted with child and adolescent patients, it is necessary to extrapolate most evidence on drug efficacy from studies in adults.
This seems a reasonable approach given that schizophrenia is essentially the same disorder whether it has onset in childhood or adult life. However, age-specific factors such as the greater risk of extrapyramidal side-effects (EPSs) and treatment resistance to traditional antipsychotics in younger patients (Kumra et al. 1998b) should also influence drug choice.
The typical antipsychotic haloperidol has been shown to be superior to placebo in two double-blind controlled trials of children and adolescents with schizophrenia (Pool et al. 1976; Spencer & Campbell 1994). It is estimated that about 70% of patients show good or partial response to antipsychotic treatment, although this may take 6 - 8 weeks to be apparent (Clark & Lewis 1998). The main drawbacks concerning the use of high-potency typical antipsychotics such as haloperidol in children and adolescents is the high risk of EPSs (produced by D2 blockade of the nigrostriatal pathway), tardive dyskinesia and the lack of effect against negative symptoms and cognitive impairment. Treatment with typical antipsychotics is also associated with enlargement of the caudate nucleus which can be reversed with clozapine (Frazier et al. 1996). Clozapine (the prototypic atypical) has been shown to be superior to haloperidol in a double-blind trial of 21 cases of childhood onset schizophrenia (Kumra et al. 1996). Large open clinical trials of clozapine confirm its effectiveness in child and adolescent onset schizophrenia (Siefen & Remschmidt 1986; Remschmidt et al. 1994). Similar, although less marked, benefits of olanzepine over typical antipsychotics in childhood onset schizophrenia have been reported (Kumra et al. 1998a).
Drawing this evidence together, a strong case can be made for the first-line use of atypicals in child and adolescent schizophrenia (clozapine is only licensed in the UK for treatment-resistant schizophrenia). Treatment resistance in child and adolescent patients should be defined as follows:
1non-response with at least two conventional antipsychotics (from different chemical classes) each used for at least 4 - 6 weeks; and/or
2significant adverse effects with conventional antipsychotics.
While atypicals reduce the risk of EPSs, they can produce other troublesome side-effects (usually dose-related) including weight gain (olanzapine), sedation, hypersalivation and seizures (clozapine). The risk of blood dyscrasias on clozapine is effectively managed by mandatory routine blood monitoring. However, knowledge about potential adverse reactions with the newest atypicals is very limited in child and adolescent patients. A further consideration is the cost of newer atypicals compared with traditional antipsychotics. In the UK, a 1-month supply of haloperidol costs less than £2, compared with £100 - 120 for the newer atypicals and £200 for clozapine. Although economic studies of cost-effectiveness have suggested that the costs of the atypicals are recouped in reduced inpatient stays and indirect social costs (Aitchison & Kerwin 1997), the availability of these drugs, particularly in developing countries, may well be limited because of their high cost. In the late 1990s, the use of atypical antipsychotics by UK child psychiatrists was still low. Over a 2-year period, only 10% of child and adolescent psychiatrists who prescribed antipsychotics in the Trent Health Region had used an atypical drug (Slaveska et al. 1998).
Currently, there is no clear consensus about the choice of antipsychotics in children and adolescents with schizophrenia.
Some authorities suggest starting with a trial of a traditional antipsychotic (e.g. haloperidol) with substitution of an atypical if the traditional antipsychotic is either not tolerated or ineffective after 6 - 8 weeks (Clark & Lewis 1998). However, clinical trial evidence suggests that clozapine is the most effective antipsychotic in child and adolescent onset schizophrenia, although its use is restricted to treatment-resistant cases.
A very powerful case can be made for using atypicals such as olanzapine, quetiapine or risperidone as a first-line treatment, given that child and adolescent onset schizophrenia is characterized by negative symptoms, cognitive impairments, sensitivity to EPSs and relative resistance to traditional antipsychotics.
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Psychosocial and family interventions
The rationale for psychosocial family interventions follows from the association between high EE and the risk of relapse in schizophrenia (Leff & Vaughn 1985; Dixon & Lehman 1995).
The overall aim is to prevent relapse (secondary prevention) and improve the patient's level of functioning by modifying the family atmosphere. Lam (1991) conducted a systematic review of published trials of psychoeducation and more intensive family interventions in schizophrenia and drew the following conclusions. First, education packages on their own increase knowledge about the illness but do not reduce the risk of relapse.
Secondly, more intensive family intervention studies with high EE relatives have shown a reduction in relapse rates linked to a lowering of EE. Thirdly, family interventions tend to be costly and time-consuming with most clinical trials employing highly skilled research teams. Whether these interventions can be transferred into routine clinical practice is uncertain.
Fourthly, interventions have focused on the reduction of EE in 'high-risk' families. Whether low EE families would also benefit from these interventions is less clear. This is particularly relevant to the families of children and adolescents with schizophrenia as, on average, these parents express lower levels of criticism and hostility than parents of adult onset patients (J.R. Asarnow et al. 1994). Hence, routine family interventions aiming to reduce high EE may be well-intentioned but misguided in their focus.
Cognitive - behaviour therapy
In adult patients, cognitive therapy has been used to reduce the impact of treatment-resistant positive symptoms (Tarrier et al. 1993). Cognitive - behaviour therapy (CBT) has been shown to be effective in treating negative as well as positive symptoms in schizophrenia resistant to standard antipsychotic drugs, with efficacy sustained over 9 months of follow-up (Sensky et al. 2000). Whether CBT is equally effective with younger patients, or those with predominant negative symptoms, remains to be established.
Cognitive remediation
Cognitive remediation is a relatively new psychological treatment which aims to arrest or reverse the cognitive impairments in attention, concentration and working memory seen in schizophrenia (Hayes & McGrath 2000; Wykes et al. 2000). The results of an early controlled trial in adults are promising, with gains found in the areas of memory and social functioning (Wykes et al. 2000). The relatively greater severity of cognitive impairments in child and adolescent patients suggests that early remediation strategies may be particularly important in these younger patients. Helpful advice can also be offered to parents, teachers and professionals, such as breaking down information and tasks into small manageable parts to reduce demands on working memory and speed of processing.
Organization of treatment services
It is a paradox that patients with very early onset schizophrenia have the most severe form of the disorder yet they often receive inadequate and poorly co-ordinated services. One reason for this state of affairs may be that the core responsibility for schizophrenia is seen to lie within adult psychiatric services. In the UK, community-based child and adolescent mental health services (CAMHS) provide the first-line assessment and care for child and young adolescent psychoses, with only about half of these cases referred to specialist inpatient units (Slaveska et al. 1998). While inpatient admission is often unnecessary, generic CAMHS services are usually not well placed to provide a comprehensive assessment and treatment service for very early onset psychoses. First, the very low population prevalence of psychosis reduces the predictive value of diagnosis outside specialist centres. Secondly, community-based services often lack familiarity with newer therapies for psychoses including atypical antipsychotics.
One possible model would be to establish specialist regional very early onset psychosis teams serving a population of about 5 million, akin to specialist cancer centres. These expert teams would be primarily outpatient-based but with access to inpatient facilities if required. Hence, the focus would be quite different from the more traditional general purpose adolescent inpatient unit. The teams could offer early diagnostic assessments for children and younger adolescents with suspected psychotic disorders and set up treatment plans in collaboration with more local child and adult psychiatric services. Ideally, these teams would be linked to a university academic centre with an interest in psychosis research and treatment evaluation.
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Conclusions
The last decade has seen a dramatic growth in our understanding of the clinical course and neurobiological correlates of schizophrenia presenting in childhood and adolescence. It is now clear that adult-based diagnostic criteria have validity in this age group and the disorder has clinical and neurobiological continuity with schizophrenia in adults. Child and adolescent onset schizophrenia is a severe variant of the adult disorder associated with greater premorbid impairment, a higher familial risk, more severe clinical course and poorer outcome. The poor outcome of children and adolescents with schizophrenia has highlighted the need to target early and effective treatments and develop specialist services for this high-risk group. The last decade has witnessed the introduction of new atypical antipsychotics with improved side-effect profiles and efficacy, and these drugs are likely to replace the traditional antipsychotics as first-line drug therapy for child and adolescent onset schizophrenia.
However, a fundamental understanding of the underlying genetic and neurobiological basis of schizophrenia is still to be achieved. The finding of a progressive reduction in brain volume in very early onset patients and reduced synaptic density in the prefrontal cortex suggests the possibility that excessive synaptic elimination during adolescence may underlie the aetiology of schizophrenia. While significant advances in the next decade are likely to flow from technical developments in molecular genetics and neuroimaging, advance is limited by the defining diagnostic paradigm of schizophrenia. It is widely recognized that the clinical syndrome of schizophrenia contains considerable aetiological and clinical heterogeneity. Therefore, the challenge will be to identify the genetic, neurobiological and cognitive basis of this heterogeneity. Real advance in the field will depend on a more sophisticated understanding of the interplay between genetics, neurodevelopment and environment. This will involve identifying the molecular genetic basis of neurocognitive susceptibility traits for schizophrenia. The developmental mechanisms that translate neurocognitive risks into disorder will need to be understood. Unravelling neurocognitive and clinical heterogeneity should lead to improvements in our ability to deliver individually targeted treatments, as well as the ability to identify 'at risk' children and adolescents in order to prevent the onset of psychosis.
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