Genetics

Twin studies have suggested the heritability of schizophrenia to be as high as 83% (Reference Cannon, Kaprio and LonnqvistCannon 1998). However, one of the most significant implications of twin, adoption and family studies in schizophrenia is that they challenge the idea that what is inherited is a categorical psychiatric disorder. Similar to autism, genetic studies in schizophrenia have shown that the genetic liability to schizophrenia extends to schizotypal personality disorders and other conditions viewed as lying on the broader schizophrenia spectrum (Reference Erlenmeyer-Kimling, Squires-Wheeler and AdamoErlenmeyer-Kimling 1995). These results suggest that what is inherited in schizophrenia is likely to be underlying neurodevelopmental and psychological traits that interact with environmental factors to determine liability to the disorder.

Cannabis and schizophrenia

Acute intoxication with cannabis and other illicit substances, such as stimulants and hallucinogens, can precipitate psychotic symptoms or exacerbate existing psychotic illness. Cannabis confers an overall twofold increased risk of later schizophrenia (Reference Arseneault, Cannon and WittonArseneault 2004). In the Dunedin cohort, Reference Arseneault, Cannon and PoultonArseneault et al (2002) showed that the association was strongest for the youngest cannabis users, with 10.3% of those who were using cannabis at 15 years of age developing schizophreniform disorder by the age of 26. So far, cannabis use has not been directly implicated in adolescent schizophrenia – possibly because of the relatively lower prevalence of cannabis use in younger adolescents and a short duration between exposure and psychotic outcome. However, cannabis use is associated with earlier age at onset of schizophrenia in adults (Reference Arendt, Rosenberg and FoldagerArendt 2005). Studies of gene–environment interaction (Reference Caspi, Moffitt and CannonCaspi 2005), taken together with human (Reference Dean, Bradbury and CopolovDean 2003) and animal (Reference Pistis, Perra and PillollaPistis 2004) neuropharmacological studies, suggest that cannabis may enhance the risk of schizophrenia in vulnerable individuals during a critical period of adolescent brain development.

Structural brain abnormalities

The brain changes reported in childhood-onset schizophrenia appear to be very similar to those described in adult schizophrenia, supporting the idea of an underlying neurobiological continuity. Children with childhood-onset schizophrenia (onset at less than 13 years of age) in the NIMH study had smaller brains, with larger lateral ventricles and reduced prefrontal lobe volume, than healthy young people (Reference Jacobsen and RapoportJacobsen 1998). As in adult studies, reduced total cerebral volume is associated with negative symptoms of schizophrenia (Reference Alaghband-Rad, Hamburger and GieddAlaghband-Rad 1997). Childhood-onset patients have a higher rate of developmental brain abnormalities than controls, including an increased frequency of cavum septum pellucidum (Reference Nopoulos, Giedd and AndreasenNopoulos 1998). In patients with adolescent schizophrenia there is evidence of ventricular enlargement and reduced volume of the prefrontal cortex and thalamus (Reference James, Smith and JayaloesJames 2004).

Premorbid social and developmental impairments

Adolescent schizophrenia is associated with poor premorbid functioning and early developmental delays (Reference Alaghband-Rad, McKenna and GordonAlaghband-Rad 1995; Reference HollisHollis 1995 Reference Hollis2003). Similar types of developmental and social impairments in childhood have been reported in adult-onset schizophrenia, but premorbid impairments appear to be more common and severe in adolescent schizophrenia. In the Maudsley study of adolescent schizophrenia (Reference HollisHollis 2003) significant early delays were particularly common in the areas of language (20%), reading (30%) and bladder control (36%). A consistent characteristic in the premorbid phenotype is impaired sociability, with about a third of individuals with adolescent schizophrenia having significant premorbid difficulties in social development affecting the ability to make and keep friends.

Premorbid IQ in adolescent schizophrenia is reduced and lower than in adult schizophrenia (Reference Alaghband-Rad, McKenna and GordonAlaghband-Rad 1995; Reference HollisHollis 2000). In about a third of child- and adolescent-onset cases, the young person has an IQ below 70, with the whole distribution of IQ shifted down compared with both adolescent affective psychoses and adult schizophrenia.

Premorbid psychopathology

A diverse range of clinical diagnoses, including attention-deficit hyperactivity disorder (ADHD), conduct disorder, anxiety, depression and autism spectrum disorders, may precede the diagnosis of schizophrenia in children and adolescents (Reference Schaeffer and RossSchaeffer 2002). However, there is a lack of any specific premorbid diagnosis that could practically aid early clinical identification of those at high risk of schizophrenia. A more promising line of research has demonstrated a strong link between self-reported psychotic symptoms in childhood and later schizophrenia (Reference Poulton, Caspi and MoffittPoulton 2000). In the Dunedin cohort study, psychotic symptoms at age 11 increased the risk of schizophreniform disorder at age 26 but not of other psychiatric diagnoses. Relative to the rest of the cohort, those identified at age 11 with ‘strong’ psychotic symptoms also had significant impairments in motor development, receptive language and IQ (Reference Cannon, Caspi and MoffittCannon 2002). Although none of these individuals met criteria for a diagnosis of schizophrenia during adolescence, it appears that isolated or attenuated psychotic symptoms, in combination with pan-developmental impairment, constitute a significant high-risk premorbid phenotype.

Is it possible to identify young people ‘at risk’ of psychosis and schizophrenia?

Research has examined the feasibility of detecting and treating young people in the ‘at-risk’ stage, prior to the development of psychosis. This approach rests on three assumptions:

1. 1 it is possible to detect such people

2. 2 these people will be at markedly increased risk of later psychosis

3. 3 an effective intervention will reduce this risk.

There is evidence to support assumptions 1 and 2 in people with a strong family history of psychosis, who are therefore at high genetic risk (Reference Miller, Lawrie and HodgesMiller 2001), and in those reporting particular perceptual abnormalities (Reference Klosterkotter, Hellmich and SteinmeyerKlosterkotter 2001).

Various criteria have been developed in an attempt to identify a ‘high-risk’ phenotype. Features typically include: transient or attenuated psychotic symptoms; a decline in psychosocial functioning; and enhanced familial risk of psychosis. Early studies conducted in specialist centres suggested that up to 50% of ‘high-risk’ individuals made the transition to a firm diagnosis of a psychotic disorder within 12 months (Reference Yung, Philips and YuenYung 2003). However, more recent studies suggest that transition rates are considerably lower, at 10–15% (Reference Fusar-Poli, Bonoldi and YungFusar-Poli 2012), and that the ‘high-risk’ phenotype is clinically heterogeneous and unstable over time (Reference van Os and Murrayvan Os 2013). Mood disorder and substance misuse are particularly prevalent in these samples. Given the low rate of transition to frank psychosis in these help-seeking and functionally impaired individuals, treating the presenting problems (e.g. depression, substance misuse and paranoia) may be a more sensible strategy than intervening with the primary purpose of preventing the onset of psychosis.

Prodromal symptoms and onset of psychosis

Before the onset of psychosis, young people typically enter a prodromal phase characterised by a gradual but marked decline in social and academic functioning that precedes active psychotic symptoms. An insidious deterioration prior to the onset of psychosis is typical of the presentation of adolescent schizophrenia, and is more common in schizophrenia than in affective psychoses (Reference Hollis, Rutter, Bishop and PineHollis 2008). Non-specific behavioural changes such as social withdrawal, declining school performance, and uncharacteristic and odd behaviour begin, on average, over a year before the onset of positive psychotic symptoms. In retrospect, it can be seen that these behavioural changes were often early negative symptoms, which had their onset well before positive symptoms such as hallucinations and delusions.

Early recognition of the disorder is difficult, as premorbid cognitive and social impairments gradually shade into prodromal symptoms before the onset of active psychotic symptoms. Prodromal symptoms can include odd ideas, eccentric interests, change in affect, and unusual or bizarre perceptual experiences. Although these features can also occur in schizotypal personality disorder and autism spectrum disorder, in a schizophrenic prodrome there is usually progression to more severe dysfunction.

Clinical characteristics

Even if strict adult definitions of schizophrenia (DSM-5 or ICD-10) are applied, there are age-dependent variations in phenomenology. Adolescent schizophrenia is characterised by a more insidious onset, negative symptoms, greater disorganisation (incoherence of thought and disordered sense of self), hallucinations in different modalities and, for relatively fewer patients, systematised or persecutory delusions (Reference Green, Padron-Gayol and HardestyGreen 1992).

A wide variety of anomalous perceptual experiences may occur at the onset of an episode of schizophrenia, leading to a sense of fear or puzzlement which may constitute a delusional mood and herald a full psychotic episode. These anomalous experiences may include the sense that familiar places and people and their reactions have changed in some subtle way. These experiences may result from a breakdown between perception and memory (of familiar places and people) and associated affective responses (salience given to these perceptions). For example, a young person at the onset of illness may study their reflection in the mirror for hours because it looks strangely unfamiliar, or misattribute threatening intent to an innocuous comment, or experience family members or friends as being unfamiliar, leading to a secondary delusional belief that they have been replaced by a double or alien. In summary, some clinical phenomena in schizophrenia can be understood in terms of a loss of normal contextualisation and coordination of cognitive and emotional processing.

Clinical assessment

The assessment of a child or adolescent with possible schizophrenia should include a detailed history, mental state and physical examinations and laboratory tests. A baseline psychometric assessment is also desirable. A detailed understanding of specific cognitive deficits in individual cases of adolescent schizophrenia can be particularly helpful in guiding education and rehabilitation. The neurological examination should focus on abnormal involuntary movements and other signs of extrapyramidal dysfunction.

Physical investigations

The potential range of physical investigations and laboratory tests in suspected cases of child- and adolescent-onset schizophrenia are listed in Table 1. It is usual to obtain a full blood count, liver and thyroid function tests and a drug screen (urine or hair analysis). The high yield of cytogenetic abnormalities reported in childhood-onset schizophrenia (Reference Nicholson, Giedd and LenaneNicholson 1999) suggests the value of cytogenetic testing, including karyotypying for sex chromosome aneuploidies and fluorescent in situ hybridisation (FISH) for 22q11.2 deletion syndrome (22q11DS or velocardiofacial syndrome).

TABLE 1 Physical investigations in child- and adolescent-onset psychoses

Developmental issues in assessment

The child’s cognitive level will influence their ability to understand and express complex psychotic symptoms such as passivity phenomena, thought alienation and hallucinations. In younger children, careful distinctions have to be made between developmental immaturity and psychopathology. For example, distinguishing true hallucinations from normal subjective phenomena like dreams and communication with imaginary friends may be difficult for younger children. Developmental maturation can also affect the spatial localisation of hallucinations. Internal localisation of hallucinations is more common in younger children and makes these experiences more difficult to subjectively differentiate from inner speech or thoughts. Formal thought disorder may also appear very similar to the pattern of illogical thinking and loose associations seen in children with immature language development. Negative symptoms can appear very similar to non-psychotic language and social impairments, and can also be easily confused with anhedonia and depression.

Differential diagnosis

Psychotic symptoms in children and adolescents are diagnostically non-specific, occurring in a wide range of functional psychiatric and organic brain disorders. The differential diagnosis of children and adolescents with suspected schizophrenia is summarised in Box 1. Referral for a neurological opinion is recommended if neurodegenerative disorder is suspected (see below).

Pharmacological treatments

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. However, it should be noted that children and adolescents show a greater sensitivity to a range of antipsychotic-related adverse events, including extrapyramidal side-effects (EPSE) and treatment resistance with traditional antipsychotics (Reference Kumra, Jacobsen and LenaneKumra 1998), and weight gain, obesity and metabolic syndrome with atypical antipsychotics (Reference de Hert, Dobbelaere and Sheridande Hert 2011).

Head-to-head comparisons of atypical and typical antipsychotics (e.g. risperidone v. olanzapine v. haloperidol) in adolescents with schizophrenia have reported similar efficacy against psychotic symptoms, but a differing profile of adverse effects (Reference Sikich, Frazier and McLellenSikich 2008). These findings broadly replicate results from the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) pragmatic study that found no overall difference in effectiveness between typical and atypical antipsychotics in adults, whereas there were differences in tolerability and side-effect profiles (Reference Lieberman, Stroup and McEvoyLieberman 2005). In younger patients (children and adolescents), EPSE are more common with haloperidol and high-dose risperidone than with olanzapine. Weight gain and obesity are most common with olanzapine, less common with risperidone and least common with haloperidol. Sedation is greater with olanzapine and haloperidol than with risperidone (Reference Toren, Ratner and LaorToren 2004). Further evidence is emerging that children and adolescents experience more rapid and serious weight gain on olanzapine and risperidone than do adults (Reference de Hert, Dobbelaere and Sheridande Hert 2011). Morbid obesity (body mass index BMI >90th percentile) is found in up to 50% of adolescents and young people chronically treated with atypical antipsychotics (Reference Theisen, Linden and GellerTheisen 2001). Complications of obesity include hyperglycaemia (type 2 diabetes), hyperlipidemia and hypercholesterolemia. It is recommended that dietary advice (reducing carbohydrate intake) combined with regular exercise should be prescribed before initiating antipsychotics in children and adolescents.

Psychosocial interventions

Short-term course

Adolescent schizophrenia characteristically runs a chronic course, with only a minority of cases making a full symptomatic recovery from the first psychotic episode. The Maudsley follow-up study (Reference Hollis, Rutter, Bishop and PineHollis 2008) found that only 12% of young people with schizophrenia admitted to hospital were in full remission on discharge, compared with 50% of those with affective psychoses. The short-term outcome of schizophrenia presenting in early life appears to be worse than that of a first episode in adulthood. If full recovery does occur, then it is most likely within the first 3 months of onset of psychosis. In the Maudsley study, adolescent-onset patients who were still psychotic after 6 months had only a 15% chance of achieving full remission, whereas over half of those who had active psychotic symptoms for less than 3 months made a full recovery (Reference Hollis, Rutter, Bishop and PineHollis 2008). The clinical implication is that the course over the first 6 months of illness is the best predictor of remission.

Long-term outcome

A number of long-term follow-up studies of child- and adolescent-onset schizophrenia all describe a typically chronic, unremitting long-term course, with severely impaired functioning in adult life (Reference Hollis, Rutter, Bishop and PineHollis 2008). However, the generally poor outcome of early-onset schizophrenia conceals considerable heterogeneity. In most studies, about one-fifth of young patients have a good outcome with only mild impairment, whereas at the other extreme about one-third are severely impaired, requiring intensive social and psychiatric support.

Prognostic factors

The predictors of poor outcome in adolescent-onset schizophrenia include premorbid social and cognitive impairments, a prolonged first psychotic episode, extended duration of untreated psychosis and the presence of negative symptoms (Reference Hollis, Rutter, Bishop and PineHollis 2008).

Organisation of treatment services

It is a paradox that patients with child- or adolescent-onset schizophrenia have the most severe form of the disorder, yet they often receive inadequate and poorly coordinated services. Possibly this is because the responsibility for schizophrenia is seen to lie with adult psychiatric services, which have a remit that typically does not extend to patients under 18 years of age. In the UK, services for adolescents with psychosis and schizophrenia are provided by community-based child and adolescent mental health services (CAMHS) or, in some areas, by early intervention in psychosis (EIP) teams, which provide services for young people from age 14 upwards. The NICE clinical guideline for psychosis and schizophrenia in children and young people recommends that the assessment of young people with psychosis in EIP services should include access to a psychiatrist with training in child and adolescent mental health (National Institute for Health and Care Excellence 2013). However, there remain significant gaps in the provision of comprehensive services for adolescents with schizophrenia, including access to crisis and assertive outreach services and psychosocial interventions.