Childhood-Onset Schizophrenia 

Updated: Mar 25, 2019
Author: Marshal E Ash, DO; Chief Editor: Caroly Pataki, MD 

Overview

Background

Childhood-onset schizophrenia is a severe form of psychotic disorder that occurs at age 12 years or younger and is often chronic and persistently debilitating, with worse outcomes than patients who have later onset of symptoms.[1]  The definition of childhood schizophrenia has evolved over time and is now believed to be a virulent childhood version of the same disorder exhibited in adolescents and adults. The differentiation and significance of “childhood-onset,” versus “early onset,” versus “adult onset” is being explored, especially as it pertains to its utility to determine prognosis. One study of 88 patients found the age cut-off of 12 years old to lack utility. They instead suggested a cut-off age of 14.7 years of age based on higher levels of positive symptoms and poorer psychosocial functioning under this cut-off and better outcomes over this cut-off.[1]

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) cautions that although the essential features of schizophrenia are the same in childhood, it is harder to diagnose. Symptoms such as disorganized speech and behavior, which are typically present in schizophrenia, also occur in many disorders of childhood onset (e.g., autism spectrum disorder, obsessive compulsive disorder,[2] and attention-deficit hyperactivity disorder). It is important to consider these more common disorders of childhood before attributing symptoms to schizophrenia.[3]

Diagnostic criteria (DSM-5)

DSM-5 diagnostic criteria for schizophrenia requires at least two of the following five symptoms to be present for a month.[3] At least one of these must be (1), (2), or (3):

  1. Delusions

  2. Hallucinations

  3. Disorganized speech

  4. Grossly disorganized or catatonic behavior

  5. Negative symptoms

Other criteria include a markedly lower level of functioning in one or more major areas, such as work or school, interpersonal relations or self-care; persistence of continuous signs of disturbance for at least 6 months; the ruling out of schizoaffective disorder; and the exclusion of substance abuse or another medical condition that may be causing the disturbance.

In patients with a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms or schizophrenia are also present for at least 1 month (or less if successfully treated).

In addition to the five symptom domain areas identified in the diagnostic criteria, the assessment of cognition, depression, and mania symptom domains is vital for making critically important distinctions between schizophrenia and other psychotic disorders. The American Psychiatric Association removed schizophrenia subtypes from the DSM-5 because they didn’t appear to help with providing better targeted treatment, or predicting treatment response. However, those individuals meeting the criteria for catatonia would receive an additional diagnosis of catatonia associated with schizophrenia to indicate the presence of the comorbidity.

The following duration specifiers are used only after 1-year duration of the disorder and they are not in contradiction to the diagnostic course criteria:

  • First episode, currently in acute episode

  • First episode, currently in partial remission

  • First episode, currently in full remission

  • Multiple episodes, currently in acute episode

  • Multiple episodes, currently in partial remission

  • Multiple episodes, currently in full remission

  • Continuous

The validity of a diagnosis of childhood-onset schizophrenia has been a point of concern for some, due to difficulty in differentiating pediatric patients’ reports of visual hallucinations from imaginary figures (which may be developmentally normal). One study on the validity of a diagnosis of early-onset schizophrenia in Denmark found a correspondence of 88.8%, comparing the diagnosis listed in the Denmark registry to a clinical diagnosis based on symptoms reported in patient records. The validity increased when the diagnosis was made on an inpatient unit (91.5%) as opposed to outpatient settings (71.9%). The validity of a diagnosis of the whole sample of early-onset schizophrenia was 83.5%, while the validity of only those with “very early onset schizophrenia” (synonymous with childhood-onset schizophrenia) was slightly lower at 82.8%. Interrater reliability was near-identical between the two groups.[4]

Etiology

No definite single etiology of schizophrenia has been identified. Most theories accept both genetic and environmental contributions for the causation of childhood-onset schizophrenia (COS).

A review of the data from the Environmental Risk Longitudinal Twin Study of British Children found that childhood psychotic symptoms are familial and heritable. These symptoms are associated with social risk factors; cognitive impairments at age 5 years; home-rearing risk factors; behavioral, emotional, and educational problems at age 5 years; and comorbid conditions such as self-harm. Therefore, childhood psychotic disorders may be a marker of an impaired developmental process.[5]

In addition, compared with the usual onset of schizophrenia in late adolescence or early adulthood, the emergence of earlier-onset schizophrenia during childhood may be due to increased genetic loading for schizophrenia or early central nervous system (CNS) damage due to an environmental factor.

Genetic risk

Several factors suggest a genetic risk. First-degree relatives of patients with early-onset schizophrenia (EOS) have a 5 to 20 times higher risk of developing schizophrenia compared to the general population. First-degree relatives of children with schizophrenia have a higher prevalence rate of schizophrenia and schizophrenia spectrum disorders.[6]  A twin study in Denmark concluded the twin of a patient with schizophrenia had a 4.7 times increased risk of developing schizophrenia themselves if the first twin was diagnosed or presented with illness before 22 years old. They did not study more specific age ranges under 22 years old, but did say (based on their age divisions above 22 years) that overall decreasing age at first diagnosis significantly increased the risk of second-twin diagnosis.[7]

In the Pittsburgh High-Risk Study, findings among young relatives of schizophrenia patients included the following:[8]

  • High proportions of axis I psychopathology, especially attention deficit hyperactivity disorder (ADHD) and conduct disorder

  • Increased expressed emotion among relatives

  • A trend for more psychopathology in offspring of relatives with high expressed emotion

  • Impaired attention, spatial working memory, and executive functions

  • Increased soft neurologic signs

  • Volume reductions in the amygdala, hippocampus, and superior temporal gyrus

  • Decreased slow-wave sleep

First-degree relatives of individuals with schizophrenia have impairment in ocular smooth pursuit movements similar to that found on examination of patients with schizophrenia. One study found that healthy siblings of patients with COS had decreased cerebral gray matter in the same pattern as was seen in the patients.[9]  

Examination of National Institute of Mental Health patients with onset of schizophrenia before age 13 years revealed a 10% rate of cytogenetic abnormalities.[10] Certain genome mutations have also been significantly linked with EOS including 1q21.1, 15q13.3, and 22q11.2 deletion syndrome and could account for 0.5%–1% of cases. In addition, associations with several schizophrenia-susceptibility genes in adult patient cohorts were replicated in the childhood-onset schizophrenia patients, including DAOA, NRG1, DTNBP1, and GAD1.[11] A study of Han Chinese patients found the gene rs139887 in SOX10 to be associated with males with early-onset schizophrenia.[12]  A different study of 385 Han Chinese patients found a specific polymorphism in the serotonin 2A receptor to “confer susceptibility to schizophrenia with early age of onset.”[13]  Rare genetic variations to miRNA (involved in brain development) were found to be 50% more prevalent in patients with early-onset schizophrenia than in the control population.[14]  There was also an excess of novel copy number variants that overlapped or disrupted known genes in patients when compared with the nontransmitted parental “control” chromosomes.[15]  A published case study in Boston revealed two patients who developed schizophrenia before 7 years of age who both possessed copy number variants at 16p13.11, a locus associated with both adult-onset schizophrenia and autism spectrum disorder.[16]

A study of 177 patients in Sweden found greater global DNA hypomethylation (conveying genetic instability) in leukocytes of patients with schizophrenia compared to controls, with this finding even more pronounced in patients with early-onset schizophrenia.{ref204-INVALID REFERENCE} Studies are underway to investigate the correlation of DNA methylation and gender differences in early-onset schizophrenia.[17]

Neurodevelopmental and neuroanatomical abnormalities

Several studies have described complications during pregnancy and delivery in adults who subsequently develop schizophrenia. The combination of genetic risk and evidence of acquired damage has suggested a neurodevelopmental theory with early CNS abnormalities that contribute to an increased vulnerability to schizophrenia later in life. An increase in minor dysmorphic features has suggested prenatal-onset problems. An increase in hypoxia-associated complications was demonstrated to increase the odds of developing earlier-onset schizophrenia.

The neuroanatomy of persons with COS has been examined by neuroimaging. As in adults with schizophrenia, the most consistent finding has been enlargement of the lateral ventricles. Although static in adults, the abnormalities in brain morphology evolve during adolescence. The possibility of a neurodegenerative process has been raised but also questioned.[18]

The literature has revealed a compelling story for gray matter deficits in individuals with COS. Specifically, Rapoport et al demonstrated that adolescents with schizophrenia have significantly greater decreases in frontal and temporal gray matter volumes than those observed in healthy age-matched controls (see the images below).[19, 20] The investigators additionally found the children with schizophrenia to have more cortical gray matter loss than children with transient psychosis. 

Greenstein et al. reported that cortical thickness loss in childhood-onset schizophrenia appears to localize with age to prefrontal and temporal regions that are seen in patients with adult-onset schizophrenia, regardless of medication.[21]  Another study showed that childhood-onset schizophrenia patients who met criteria for remission had thicker gray matter in prefrontal, temporal, and parietal cortices compared with nonremitted patients, suggesting a possible relation of brain plasticity with prognosis.[22]

The Edinburgh High-Risk Study suggested that in high-risk subjects (defined as subjects who had at least 2 close relatives with schizophrenia) the change from vulnerability to psychosis may be preceded by reduction in size and deteriorating function of the temporal lobe.[23]

In a systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls, meta-analysis suggested that the whole brain and hippocampal volume are reduced and that ventricular volume is increased in affected patients relative to healthy controls.[24]  Furthermore, brain magnetic resonance scans obtained in childhood-onset schizophrenia subjects, their nonpsychotic full siblings, and matched health comparison subjects between the ages of 10 and 29 years that measured the total, left, and right hippocampal volumes showed that patients with childhood-onset schizophrenia had a fixed reduction in hippocampal volumes when compared with nonpsychotic siblings and health comparison subjects. In addition, no significant volumetric or trajectory differences were noted between nonpsychotic siblings and healthy comparison subjects. Therefore, decreased hippocampal volume may represent an intermediate disease phenotype.[25]

A study of siblings of patients with childhood-onset schizophrenia found an association between volumetric differences of the right superior frontal gyrus and cerebellum and late in learning performance on the weather prediction task (a test of cognitive skill learning). The authors suggested some of these volumetric abnormalities may be “potential endophenotype[s] for schizophrenia.” They suggested the genetic risk was “most apparent in adolescence” as these abnormalities normalized as the siblings reached adulthood.[26]

Studies of nonpsychotic siblings of childhood-onset schizophrenia patients have shown a pattern of prefrontal and temporal gray matter deficits during early ages that seem to normalize by the time the subjects reach late adolescence.[27] These results were replicated by Mattai et al., who also showed nonpsychotic siblings of childhood-onset schizophrenia patients have early gray matter deficits that improve over time, suggesting that late adolescence may be a critical time for greatest localization of deficits in probands or normalization in nonpsychotic siblings.[28]

A study looking at striatal volume and shape compared patients with childhood-onset schizophrenia, their siblings, and healthy controls. They found patients with childhood-onset schizophrenia displayed “subregional striatal shape differences,” particularly inward displacement of the anterior portion of the striatal head and outward displacement at the posterior portion of the striatal head. Siblings of these patients at least partially displayed these shape variations.[29] These findings are of particular interest as “tracts from the striatal head project extensively to the prefrontal cortex,” which shows cortical thickness deficits in patients with childhood-onset schizophrenia.[30]

Studies of white matter connectivity in childhood-onset schizophrenia have found abnormalities in the left and right cuneus (occipital lobe, visual cortex) in both patients with childhood-onset schizophrenia and their siblings, though they couldn’t find a statistically significant correlation between these abnormalities and the severity of clinical symptoms.[31] Another study of white matter abnormalities proposed abnormalities of the left inferior longitudinal fasciculus and left inferior fronto-occipital fasciculus as “possible biomarkers of vulnerability for developing schizophrenia.”[32] Another study observed white matter growth deficits in non-psychotic siblings of patients with childhood-onset schizophrenia, but these deficits normalized with age.[33]

A study reviewing MRI data asked if abnormal cortical maturation was confined to developmental modules in the brain. They found patients with childhood-onset schizophrenia had “altered maturational trajectories of cortical areas” involved in the cingulo-fronto-temporal developmental module.[34]

One study found patients with childhood-onset schizophrenia displayed “delayed maturation of occipitotemporal connectivity, with unaffected siblings displaying a milder phenotype.” This delay normalized in the unaffected siblings by mid-adolescence, and normalized in the patients with childhood-onset schizophrenia by early adulthood. Occipitotemporal connectivity is associated with the inferior longitudinal fasciculus, in which developmental delays may be associated with hallucinations.[35]

Patients diagnosed with childhood-onset schizophrenia were found to have reduced strength of short-distance functional connectivity, though “longer anatomical distances were relatively normal in the COS group.” The authors of that study found this to be consistent with the idea of “‘overpruning’ of short-distance connections” in childhood-onset schizophrenia.[36]

When studying working memory networks, it was found that patients diagnosed with early onset schizophrenia displayed a similar abnormal pattern of dorsolateral prefrontal cortex connectivity as adults diagnosed with schizophrenia.[37]

Childhood schizophrenia. Early and late gray matte Childhood schizophrenia. Early and late gray matter deficits in schizophrenia. Areas of gray matter loss, shown in red and yellow, spread from back-to-front (right to left) over 5 years in composite MRI scan data from 12 teens with childhood-onset schizophrenia, beginning at age 14 (left). Red and yellow denotes areas of greater loss. Source: Paul Thompson, MD, UCLA, Laboratory of Neuroimaging. NIMH media file.
Childhood schizophrenia. Rate of gray matter loss. Childhood schizophrenia. Rate of gray matter loss. Composite MRI scan data showing areas of gray matter loss over 5 years, comparing 12 normal teens (left) and 12 teens with childhood-onset schizophrenia. Red and yellow denotes areas of greater loss. Front of brain is at left. Source: Paul Thompson, MD, UCLA, Laboratory of Neuroimaging. NIMH media file.

Cannabis use

Evidence from 6 longitudinal studies in 5 countries showed that regular cannabis use predicts an increased risk of a schizophrenia diagnosis or of reporting symptoms of psychosis.[38]

One study found that 74% of cannabis use disorders subjects had the onset of cannabis use disorder before the onset of positive psychotic symptoms. These subjects were predominately male, younger at study entry, had an earlier age at onset of positive symptoms, less educational attainment, a lower self-socioeconomic status, better premorbid childhood social adjustment, a trend for poorer premorbid childhood academic adjustment, less motor abnormalities, but more severe hallucinations and delusions.

However, in the multivariate analysis only male sex, worse socioeconomic status, better premorbid childhood social adjustment, and more severe positive symptoms at study entry were associated with a lifetime history of cannabis use disorder. The authors concluded that although cannabis use precedes the onset of illness in most patients, no significant association existed between onset of illness and cannabis use disorders that was not accounted for by demographic and clinical variables.[39]

Nevertheless, another study used the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) to assess for a possible association between cannabis use, traumatic events, and psychotic symptoms in adolescence. Cannabis use and childhood trauma were significantly associated with a risk of experiencing psychotic symptoms. When cannabis use and childhood trauma occurred within the same patient, the risk for psychotic symptoms increased beyond the risk posed by either factor alone. However, only 14 participants in the study reported experiencing psychotic symptoms. Therefore, these findings must be replicated.[40]

A 2012 study obtained T1-weighted MRIs from adolescents with earlier-onset schizophrenia (EOS), cannabis use disorders (CUD), EOS plus CUD, and healthy controls. In the EOS group and the CUD group, the left superior parietal region had smaller gray matter volumes compared with healthy controls. The combined EOS/CUD group showed similar findings, but no additive effect was found. Nevertheless, the combined EOS/CUD group had smaller gray matter volumes in the left thalamus compared with the CUD and healthy control groups.[41]

Early adolescent cannabis use coupled with a specific genetic vulnerability may be a risk factor for the development of schizophrenia.

A 2015 literature review concluded that “cannabis alters the course of psychosis by triggering early onset of disease in a vulnerable youth population.” While multiple theories as to how this might happen were noted—substance abuse influencing psychiatric disorders, psychiatric disorders influencing substance abuse, independent and mutually exclusive processes—they refrained from ascribing to one particular mechanism.[42]

Early childhood trauma

As previously stated, early childhood trauma has been correlated with childhood psychotic symptoms. One study found 93.1% of patients with early-onset schizophrenia “had experienced adverse life events during childhood,” 46.9% had “experienced traumatic events.”[4]

Specifically, Arsenault et al. obtained data from the Environmental Risk longitudinal Twin Study, which interviewed mothers when their children were aged 5, 7, 10, and 12 years on whether the children had experienced maltreatment by an adult, bullying by peers, or involvement in an accident. When the children were aged 12 years, they were asked about bullying experiences and psychotic symptoms. Children who experienced maltreatment by an adult or bullying by peers were more likely to report psychotic symptoms at age 12 years than were children who did not experience maltreatment. The finding of higher risk of psychotic disorders was observed whether these events occurred early in life or later in childhood. In addition, this finding remained significant when sex, socioeconomic deprivation, internalizing or externalizing problems, children’s genetic liability to developing psychosis, and IQ were controlled.[43]

Furthermore a prospective cohort study of 12-year-old children assessed the risk of psychotic symptoms using the Psychosis-like Symptoms Interview. Children who had been victims of bullying at ages 8 and/or 10 years, independent of prior psychopathology, family adversity, or child’s IQ, had a 2-fold increase in risk of psychotic symptoms. The risk increased when victimization was chronic or severe.[44]

Infections

One study also found a link between viral CNS infections and later psychosis. Specifically, a national cohort of children born between 1973-1985 was followed by using Swedish national registers to determine the association between CNS infections at age 0-12 years and admissions for nonaffective psychotic illnesses from the 14th birthday (N=2269). There was a slightly increased risk of nonaffective psychotic illness associated with viral CNS infections, as well as schizophrenia. There was no increased risk in relation to bacterial infections. Exposure to mumps virus or cytomegalovirus were associated with later psychosis.[45] However further research into this correlation is needed.

Immunology

Some are focusing their attention on immunological markers as potential biomarkers of schizophrenia, some even working towards finding a causal relationship between immune processes and schizophrenia. One such study implicated an autoimmune component of schizophrenia, noting platelet-associated autoantibodies (PAA) to be elevated in patients with childhood-onset schizophrenia compared to a group of children diagnosed with conduct disorder. The authors of this study suggested measuring PAA as a possible diagnostic biomarker of childhood-onset schizophrenia.[46]  Another study found a statistically significant correlation between negative symptoms of early-onset schizophrenia and IL-4 and IL-10 levels.[47]

Neurotransmitters and schizophrenia

Most psychologic, pharmacologic, and neuroimaging studies of childhood-onset schizophrenia have suggested dysfunction in the prefrontal cortex and limbic system. The neurotransmitter implicated in the pathophysiology of schizophrenia is dopamine. Medications that increase dopaminergic activity may induce a schizophreniform psychosis, and medications that block postsynaptic D2 receptors help alleviate symptoms of schizophrenia.

Other neurotransmitters may also be involved in the pathophysiology of schizophrenia. Glutamate has been implicated based, in part, on the production of psychotic symptoms by phencyclidine and the presence of N -methyl-D-aspartate (NMDA) receptor dysfunction.[48] Serotonin may be important. The new atypical antipsychotic medications have prominent serotonergic effects. Preliminary studies suggest gamma-aminobutyric acid (GABA) may be important. N-acetylaspartate may play a role as well, as one study found lower levels in the prefrontal cortex and thalamus in patients with early-onset schizophrenia. These levels responded and normalized after six months of treatment with atypical antipsychotics.[49]

Miscellaneous potential etiologies

No one single etiology has been identified for childhood-onset schizophrenia, and likely it is multifactorial. As such, many are attempting to identify potential causes, contributing factors, or biomarkers related to childhood-onset schizophrenia.

In a study of patients at a Nigerian tertiary care center, patients with childhood-onset versus adolescent-onset psychosis were more likely to have mothers who were ill during pregnancy or infancy. The authors suggested maternal illness may be a relevant component of childhood-onset schizophrenia.[50] Another study examined a possible link between early-onset schizophrenia and maternal small-cell lung cancer. Those authors suspected a connection due to the potentially prodromal aspect of the autoimmune nature of small-cell lung cancer. Their sample size was small, but they did find a statistically significant association between the two.[51]

Another study looked at the effect of oxidative stress in the pathogenesis of schizophrenia. The study authors found total antioxidant status was significantly associated with baseline cognitive function in early-onset psychosis (low total antioxidant status being associated with lower cognitive performance.)[52]

Epidemiology

Childhood-onset schizophrenia (COS) is rare in the United States; in preadolescents, the estimated prevalence is less than 1 case per 10,000 population. The number of new cases significantly increases during late adolescence, reaching an approximate prevalence of 1% for later-onset schizophrenia. Data from the British National Surveillance study suggests the 1-year incidence of COS of 0.21/100,000 and 1-year outcomes were poor. One study found that 11% of patients with First Episode Schizophrenia and 23% of patients at Clinical High Risk for psychosis reported remembering their first psychotic symptoms as presenting in childhood.[53]

One study in Denmark found the incidence of early-onset schizophrenia to increase when comparing the time period of 1971–1994 to 1994–2010. However, diagnostic criteria for early-onset schizophrenia changed during this time including letting go of a previous restriction that only allowed the diagnosis to be made in inpatient settings. While diagnostic incidence may have increased, it may have been accounted for by these changes in diagnostic criteria.[54]

Globally, schizophrenia with an onset later in life appears to have an equal prevalence, with a possible increase in prevalence in urban populations. Most studies demonstrate an average male-to-female incidence of schizophrenia of 1.5–2:1; this ratio is continually being re-examined and challenged.[54] Males have a slight but statistically significant earlier age at onset, as well as higher rates of comorbid pervasive developmental disorder (PDD) and attention deficit/hyperactivity disorder (ADHS) when compared to females. The higher rates of comorbid PDD and ADHD with childhood-onset schizophrenia, however, mirror the same male-to-female ratios found in adult-onset schizophrenia.[55]

No studies of overall prevalence of childhood-onset schizophrenia in underdeveloped countries are available. A study of 409 pediatric patients with psychotic symptoms in Nigeria found 40.8% to have a diagnosis of schizophrenia, with 8.1% of the 409 patients being younger than 12 years old. Compared to pediatric patients with adolescent-onset psychotic symptoms, patients with childhood-onset psychotic symptoms were found to have less family history of psychiatric illness, more maternal illness during pregnancy, more illness in infancy, and overall more diagnoses of psychotic disorder due to another general medical condition as opposed to other diagnoses of psychosis.[50]

The 2006 Aetiology and Ethnicity in Schizophrenia and Other Psychoses Study (AESOP), a large, population-based case-control study conducted over two years in three study centers in England in adults, reported all psychoses were more common in the black and minority ethnic group compared with the white British group.[53] A British study of early-onset non-affective psychosis published in 2015 found no “preference” of gender, race, or ethnicity.[56]

One Finnish study also of early-onset schizophrenia found a statistical significance regarding birth interval. Patients with early-onset schizophrenia more often were born within 1–2 years of their nearest sibling.[57] Interestingly, the effect of season of birth on diagnosis of schizophrenia has been the focus of multiple studies. A 2017 study of data from Korean patients was consistent with studies of other nationalities finding a predominance of winter births (particularly January and February) for patients diagnosed with early-onset schizophrenia.[58]

In a child younger than 13 years, the onset of schizophrenia is rare and is generally insidious, carrying a worse prognosis. Onset of the disorder in the adolescent years is more common and may have an acute or insidious onset. In general, the earlier the onset of schizophrenia, the poorer the outcome.

Prognosis

The prognosis for childhood-onset schizophrenia and adolescent-onset schizophrenia is worse than that observed in adult-onset schizophrenia. As adults, these children experience the following:

  • Fewer close social relationships

  • Less likely to be married[59]

  • Less academic achievement

  • More unemployment

  • Less capacity for independent living

Patients with an onset before adolescence and those with an insidious onset appear to have a worse response to medication and a worse prognosis. Patients with early-onset non-affective psychosis displayed multiple readmissions and trials of multiple antipsychotics at one-year follow up.[56]

An increased risk of death from suicide is present in patients with schizophrenia. In large follow-up studies of childhood-onset schizophrenia, the mortality rate from suicide is 5–11%. Approximately 10% of adults with schizophrenia commit suicide. Children and adolescents with psychotic disorders were more likely to display suicidal behaviors (ideation 32% vs 6.7%, planning 20% vs 0%, attempts 20% vs 0%), and more likely to display these behaviors than even children and adolescents diagnosed with depression. No difference was appreciated in rates of suicidal behavior between children versus adolescents with a psychotic disorder.[60]

Violence is also a potential problem, particularly for the adolescent with paranoid ideation. Patients diagnosed with early-onset schizophrenia spectrum disorder were more likely to display violence before 15 years old, and “present early conduct problems,” but were also less likely to be violent after 18 years old compared to patients diagnosed with adult-onset schizophrenia.[59] Other complications arise from poor self-care, impulsivity leading to injury or sexually acquired diseases, and substance abuse. One study found early-onset psychosis (not just schizophrenia) was associated with more agitation and aggression, lifetime substance use disorder, antisocial personality disorder, and interaction with the legal system.[61]

In follow-up studies, more than 50% of children with schizophrenia have persistent severe impairment in social skills and limitations in academic and occupational achievement. One study published in 2016 found patients with childhood-onset schizophrenia spectrum disorder were twice as likely to be diagnosed with ADHD and twice as likely to have speech, language, and learning disabilities compared to patients with adolescence-onset schizophrenia.[62] Patients with early-onset schizophrenia performed worse on neurocognitive tests compared to the control group. But even more interestingly, patients with early-onset schizophrenia and a family burden of psychosis performed worse than those without a family burden of psychosis.[63]

The duration of untreated psychosis has been a point of study for many as it appears to have implications in prognosis, especially at two years. A longer duration of untreated psychosis along with a more severe clinical picture at first presentation was associated with a poorer two-year course. The authors of that study speculated this association to be a finding of arrested development rather than deterioration.[64] A longer duration of untreated psychosis was also associated with lower rates of PANSS remission at two-year follow-up.[65] Conversely, a shorter duration of untreated psychosis was associated with greater improvements in executive function.[66]

One small study found shorter gestational length did not increase the risk of early-onset schizophrenia diagnosis, but it did worsen neurocognition within the early-onset schizophrenia population.[67]

Patient Education

Psychoeducation is essential for families of children with schizophrenia. They need to be educated about the causes, symptoms, natural history, therapy, adverse effects of medication, and complications of childhood-onset schizophrenia.

Families must also know the warning signs of impending relapse. High levels of expressed emotion have been associated with an increased risk of relapse in adults with schizophrenia and can possibly contribute to problems in children with schizophrenia.

Once children with schizophrenia are in remission, teach them to self-monitor for signs of possible relapse. Inform these children about possible adverse effects of medication.

For patient education information, see Mental Health and Behavior Center, as well as Schizophrenia.

 

Presentation

History

Most children who develop schizophrenia have disturbances of behavior and cognition before the onset of characteristic symptoms of psychosis. Delays in speech and language and delays in acquisition of motor milestones are noted in approximately one half of these children. Children who develop schizophrenia have higher rates of impaired social skills and school achievement before presenting signs of schizophrenia. Approximately one third of the children develop symptoms of inattention, hyperactivity, aggression, or rage.

One half of these children have received previous diagnoses, including pervasive developmental disorders (PDDs), attention deficit hyperactivity disorder (ADHD), and internalizing disorders (eg, bipolar disorder, depression, anxiety disorders). In a study of child/adolescent patients in South Carolina diagnosed with schizophrenia spectrum disorder, patients diagnosed with schizophrenia were commonly also diagnosed with speech/language/educational disabilities, MR/ID, PDD/ASD, CD/ODD, ADHD.[68] In one study, psychotic symptoms appeared, on average, 2.5 years after the initial clinical presentation, and the diagnosis of schizophrenia was made a mean of 2 years after the onset of psychosis.

All of the characteristic symptoms of schizophrenia have been described in persons with childhood-onset schizophrenia. Ballageer et al found that bizarre behavior and negative symptoms were more common in individuals with adolescent-onset schizophrenia compared with those with onset during the adult years.[69]

Compared with adults with schizophrenia, children with schizophrenia have catatonia less often. Changes in affect are common, with blunting or inappropriate affect observed in approximately two thirds of children with schizophrenia. In addition, patients with childhood-onset schizophrenia suffer from significant sleep disturbances, which are highly related to symptom severity.[70]

Hallucinations and delusions

Hallucinations and delusions become more complex and elaborate with increasing age. Hallucinations (auditory more common than visual) are usually the presenting symptom and are reported by approximately 80% of children who receive the diagnosis of schizophrenia.

A study by David et al. showed that 94.9% of patients who had documented childhood-onset schizophrenia had auditory hallucinations, 80.3% had visual hallucinations, 60.7% had somatic/tactile hallucinations, and 29.9% had olfactory hallucinations. Somatic/tactile and auditory hallucinations occurred almost exclusively in patients who also had visual hallucinations. Patients who had visual hallucinations had lower IQ scores, earlier age of onset, and more severe illness in comparison to patients who did not have visual hallucinations.[71] True hallucinations are usually vivid but not detailed, usually elicit a response from the child, and occur when the child is fully awake.[72] Delusions are present in approximately 60% of patients. Delusions and thought disorders were most predictive of true non-affective psychosis in childhood-onset schizophrenia via a UK study.[56]

Thought disorder and impaired cognition

Approximately one half of children with schizophrenia have a formal thought disorder, although assessment may be more difficult in children than in adults. Caplan and associates demonstrated that loose associations and illogical thinking can be documented reliably.[73, 74, 75] Adolescents with early-onset schizophrenia displayed deficits in Theory of Mind assessment and executive function compared to adolescents without early-onset schizophrenia.[76] Poverty of speech was not documented. In one study of adolescents, speech samples were obtained from 105 subjects identified as being clinical high risk for a first episode of psychosis (CHR). CHR patients who subsequently experienced psychosis (CHR+) had an elevated rate of illogical thinking and poverty of content in their speech when compared with typically developing controls and CHR patients who did not have a psychotic episode.[77]

Cognitive functioning is often impaired at the onset of childhood schizophrenia. In most series of children with schizophrenia, the average full-scale intelligence quotients (IQs) have been in the 80s, with particular deficits in verbal comprehension, language, and short-term memory. Attention and executive functioning may be impaired. A subsequent decline in full-scale IQ appears to be due to failure to learn rather than to loss of function.

Gochman et al reported that long-term trajectory of IQ measures appears stable, and level cognitive functioning extends 13 years or longer after the onset of psychosis, despite chronic illness and concomitant, progressive loss of cortical gray matter.[78]

When studying siblings of patients diagnosed with childhood-onset schizophrenia, siblings displayed cognitive skill learning deficits compared to the healthy control group. When given the WPT (weather prediction test, an assessment of learning probabilistic associations), siblings of patients with childhood-onset schizophrenia performed worse than the control group after both 50 trials and 800 trials. The authors of that study suggested “that a behavioral impairment in probabilistic classification learning in healthy, unaffected siblings mirrors the deficits seen in patients and thus may reflect genetic liability for the disease.”[79]

Substance abuse

Substance abuse occurs more frequently in individuals with psychosis than in the general population. Patients should be asked about their use of tobacco, alcohol, prescribed medications, nonprescribed medications, and drugs of abuse using a respectful and nonjudgmental approach. Details about the route of administration; quantity, frequency, duration, and pattern of use; and the duration of the current level of use should be elicited.[80]

Physical Examination

Abnormalities in the neurologic examination are observed in as many as one half of adults with new-onset schizophrenia. In one study, Karp et al found significantly more signs of neurologic dysfunction in adolescents with earlier-onset schizophrenia.[81]

The most common abnormalities in individuals with adult schizophrenia are "soft signs," including incoordination, persistence of developmental reflexes, and impaired ocular pursuit movements. Neurological soft signs were found in adolescents with schizophrenia as well.[82]

Adolescents with earlier-onset schizophrenia have persistence of primitive reflexes. Compared with a healthy control group, the number of primitive reflexes does not decrease with advancing age in adolescents with schizophrenia. Children with schizophrenia are commonly reported to have delayed motor development and impaired coordination.

Formal measurements of ocular smooth pursuit have demonstrated abnormalities in individuals with childhood-onset schizophrenia.

Research on handedness and schizophrenia has remained replete with inconsistencies.[83]

 

DDx

Diagnostic Considerations

The diagnosis of schizophrenia requires the exclusion of mood disorders with psychotic features (bipolar disorder), substance-induced psychotic disorder, and psychosis due to a medical condition. The following conditions should be considered when evaluating a child or adolescent with suspected schizophrenia:

  • Psychosis secondary to epilepsy; psychosis not otherwise specified; and psychosis, single episode

  • Neurodegenerative disorders

  • Central nervous system (CNS) tumor

  • Progressive organic CNS disorder (eg, sclerosing panencephalitis)

  • Schizoaffective disorder

Chromosomal disorder: 22q11 deletion syndrome

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory studies are performed as part of an assessment for the differential diagnosis of schizophrenia. Toxicology screens may be needed if substance abuse is suggested. Liver function studies, copper, and ceruloplasmin are part of the workup for Wilson disease. Obtain porphobilinogen levels for porphyria. Human immunodeficiency virus (HIV) titers, Venereal Disease Research Laboratory (VDRL) testing, or heavy metal screening may also be needed.

If the child has intellectual disability or dysmorphic features, include a karyotype in the genetic assessment. One example is the 22q11 deletion syndrome, or velocardiofacial syndrome.[84] Other preliminary reports suggest 5q involvement.

Other general medical conditions may contribute to psychotic symptoms. According to Giannitelli et al., the following things should cause clinicians to have an increased level of suspicion for general medical conditions:

“Several clinical and historical features appear to warrant an increased index of suspicion of organic factors: (1) Atypical aspects of the clinical history and course, including: (a) acute and/or very early onset; (b) onset apparently triggered by surgery, viral infection, or medications; (c) cognitive or developmental regression. (2) Atypical symptomatic features: (a) confusion; (b) catatonia (Consoli et al., 2012)[85] ; (c) rare and serious neurological adverse reactions to treatment. (3) Presence of co-occurring physical symptoms, for example: (a) suspicion of seizures; (b) malar rash; (c) gastro-intestinal signs; (d) dysmorphic features.”

Those authors suggest of a wide array of imaging and laboratory studies to pursue, based on the clinical and historical presentation; readers are encouraged to refer to that article for further information.[86]

MRI or CT scanning

Neuroimaging with magnetic resonance imaging (MRI) or computed tomography (CT) scanning (if MRI is not available) should be part of the evaluation of new-onset psychosis. MRI helps to exclude certain organic causes of psychosis. Demyelination is observed in the child with leukodystrophy. Atrophy is observed in some children with neuronal ceroid lipofuscinosis. Ventricular enlargement and gray matter loss are consistent with, but not diagnostic of, childhood-onset schizophrenia.

EEG

Perform electroencephalography (EEG) if episodic symptoms or signs are present in the evaluation of a child with psychosis. In children who receive clozapine, obtain an EEG because of the increased risk of seizures associated with clozapine.

ECG

Obtain an electrocardiogram (ECG) before starting a low-potency antipsychotic as well as before starting medication and as part of follow-up care of a child who receives pimozide. Having a baseline ECG is important for patients with childhood-onset schizophrenia as some medications used to treat psychosis have the potential of prolonging the QTc and having a baseline measurement could be of benefit.

Histology

Neuropathologic studies are available for persons with later-onset schizophrenia but not for children with schizophrenia. Postmortem studies have demonstrated reduced volume of the hippocampus. Gliosis has not been found, suggesting that no active inflammatory process occurs.

Psychologic Testing

Initially, a baseline diagnostic framework is formed by the recommended Mental Status Examination. Structured or semistructured interviews are beneficial for the initial assessment and monitoring symptoms during follow-up care.

Other standard instruments include the following:

  • Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS)[73]

  • Brief psychiatric rating scale (BPRS)

  • Positive and Negative Syndrome Scale (PANSS)

Projective tests, such as the Rorschach, may be helpful in eliciting further symptoms. The Thematic Apperception Test may also be helpful in eliciting additional information. However, diagnosis is confirmed by comprehensive clinical assessment. Psychologic testing of cognitive function is essential for treatment planning. The Stroop test, the Wisconsin Card Sorting Test, and the Mazes test all were found to significantly separate a group of patients diagnosed with early-onset schizophrenia from a control group based on executive functioning skills; a study published in the Scandinavian Journal of Psychology suggested the Stroop test was able to discriminate the best of the three.[87]

The National Institute of Mental Health developed a scale and scoring algorithm clinicians can use to predict accurate diagnoses of childhood-onset schizophrenia. Higher levels of both positive and negative symptoms together with lower levels of depression indicate higher probability that a child has childhood-onset schizophrenia rather than another diagnosis with psychosis.[88]

 

Treatment

Approach Considerations

Acute inpatient care is necessary for persons with behaviors dangerous to self or others. The child with schizophrenia who is severely impaired may need day treatment programs or hospitalization until the child is stabilized and not considered a danger to self or others.

Pharmacotherapy is essential in the treatment of individuals with childhood-onset psychosis. Electroconvulsive therapy (ECT) has also been used adjunctively in rare cases.

Medical Care

Pharmacotherapy

The first-line agents are neuroleptics. Newer atypical antipsychotic agents are generally chosen as the initial medications of choice.

Repeating assessment for medication adverse effects using standard measures is essential. The abnormal involuntary movement scale (AIMS) is one such standard measure. Possibly one third of children on antipsychotics develop withdrawal dyskinesias.

Recommendations for monitoring adults on atypical antipsychotics include checking the following:

  • Weight at baseline; 4, 8, and 12 weeks; and then quarterly

  • Blood pressure at baseline, 12 weeks, and annually

  • Fasting plasma glucose level at baseline, 12 weeks, and annually

  • Fasting lipid profile at baseline, 12 weeks, and every 5 years

Similar recommendations regarding atypical antipsychotics are not yet available for children and adolescents, but careful monitoring of weight, blood pressure, and glucose and lipids levels seems warranted. Correll et al. examined the cardiometabolic effects of olanzapine, quetiapine, risperidone, and aripiprazole in a 12-week trial of children and adolescents who had mood disorders, psychotic disorders, or disruptive-behavior disorders. Significant weight gain was seen with each of these medications, with olanzapine and quetiapine causing the most weight gain. In addition, olanzapine and quetiapine significantly increased total cholesterol and triglycerides. Risperidone also significantly increased triglycerides. As a result of these findings, the authors concluded that cardiometabolic monitoring occur biannually after the first 3 months of treatment.[89]

Interestingly, a 24-month study found differences in side effects between medications (particularly higher BMI in olanzapine and neurological side effects in risperdal) at the six-month follow up that were no longer significant at 12 and 24 months.[90] And while antipsychotics have been found to increase risk of metabolic syndrome, one study found the increased risk for metabolic syndrome in patients with first episode of psychosis existed even before initiation of antipsychotics. Patients 12–17 years old with psychosis had larger waist circumferences, higher cholesterol, and higher low-density lipoprotein. A diagnosis of schizophrenia was associated with higher CGI-severity scores and blood lipids. Again, these findings all existed before antipsychotic medication exposure.[91]

Many second-generation antipsychotics have been approved by the FDA in recent years for adolescents to treat schizophrenia including aripiprazole, lurasidone, olanzapine, quetiapine, paliperidone, and risperidone.

The second-generation antipsychotics iloperidone (Fanapt), asenapine (Saphris), cariprazine (Vraylar), and ziprasidone (Geodon) are approved for adult-onset schizophrenia, but not yet for pediatric patients.[92]

Ultra–high-risk intervention studies are exploring the use of antidepressants.[93]

A systematic review of data from 11 studies of antipsychotics (aripiprazole, haloperidol, molidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone) on early-onset schizophrenia symptoms found only haloperidol, olanzapine, and risperidone had statistically significant positive effect on positive symptoms of PANSS scores at six-week follow-up compared to placebo.[94]

A retrospective cohort study of patients with early-onset schizophrenia diagnosed with comorbid mood or emotional disregulation disorders or comorbid cognitive impairment found treatment with atypical antipsychotic monotherapy was associated with less use of acute psychiatric services over time compared to treatment with multiple atypical antipsychotics or a single atypical antipsychotic plus an antidepressant or psychostimulant. Treatment with a single atypical antipsychotic plus a mood stabilizer did, though, show increased/stronger association.[95]

Transcranial magnetic stimulation

A case series in France suggested transcranial magnetic stimulaiton (TMS) may be therapeutic in the treatment of early-onset refractory auditory hallucinations in patients with childhood-onset schizophrenia. The patients in this study found benefit lasting one month after treatment.[96]

Psychosocial Management

The child with schizophrenia requires multimodal care. This should include social skills training, a supportive environment, and a structured individualized special education program. A history of involvement with early education programs has been associated with greater response not only to social interventions but also to antipsychotics.[97]

Supportive psychotherapy is used to encourage reality testing and to help the child monitor for warning symptoms of impending relapse.

Cognitive behavioral therapy has been used successfully in adults with schizophrenia and may help improve coping with schizophrenia and monitoring of beliefs and attributions.

Cognitive remediation therapy in addition to treatment-as-usual in patients with early-onset schizophrenia was found to significantly improve verbal memory, executive function, daily living and adaptive functioning, and improvements in family burden. The findings of this study suggest there is still room for cognitive improvements even after being optimized on psychopharmacotherapy.[98]

Psychoeducational group interventions over 9 months focused on problem-solving strategies in the form of parallel parent and child groups led to significantly greater improvement in PANSS general scores and fewer emergency department visits compared to the non-structured interventions. No differences were found in hospitalization rates between the two groups.[99]

If a patient has known or suspected substance abuse, the patient should be referred to a substance abuse treatment program.

Diet

Typical and atypical antipsychotic medications may stimulate the appetite. Low-calorie snacks and limitation of total intake at meals may help prevent excess weight gain. Weight and body mass index (BMI) should be monitored in all patients on atypical antipsychotics.

In a randomized, double-blind, placebo-controlled trial to study the preventive effect of omega-3 polyunsaturated fatty acids (PUFAs) in adolescents and young adults with subthreshold psychosis, Amminger et al a difference of 22.6% between the treatment group and the placebo group in the cumulative risk of progression to full-threshold psychosis.[100]

Consultations

Due to the pervasive problems of the child with schizophrenia, a team approach is needed. Involve nursing, speech and language therapy, and occupational and physical therapy. A case manager may facilitate care.

A psychologist is an essential part of the evaluation and treatment team. Because of the expected cognitive impairments, the mental health clinician should obtain intelligence quotient (IQ) and achievement testing for adequate educational planning. Projective tests, such as the Rorschach or the Thematic Apperception Test, may be helpful in eliciting additional information. However, their reliability and validity are not superior to a competent interview.

A child neurologist and geneticist may be needed to help evaluate for possible organic etiologies.

Children taking chlorpromazine and thioridazine should be checked for retinopathy and lenticular changes by an ophthalmologist.

Long-Term Monitoring

The frequency of regular outpatient visits is determined by the presence of continuing symptoms. Many children with schizophrenia have a residual phase with predominantly negative symptoms that can be socially disabling.

During residual phase or remission, monitor the child with schizophrenia for recurrence of positive symptoms (eg, hallucinations, delusions) that may signal a relapse or worsening of negative symptoms.

Monitor for any new symptoms or episodes of mania. Approximately 15–20% of children with an initial diagnosis of schizophrenia may be found later to have bipolar disorder, schizoaffective disorder, or one of the disorders listed in the differential diagnosis.

Prevention

Treatment before the emergence of psychosis is under investigation.

In very preliminary work, first-degree relatives of patients with schizophrenia who had suggestive symptoms and neuropsychologic deficits received risperidone with a subsequent reduction in suggestive symptoms and improvement in attention and working memory.[101]

In a randomized controlled trial that compared risperidone and cognitive behavior therapy with intervention for symptoms in individuals at very high risk for schizophrenia, fewer people in the active treatment group progressed to a first episode of psychosis.[102]

This preliminary finding raises the possibility that children with prodromal symptoms of schizophrenia can be treated before the emergence of psychosis. Further study is required before such therapy can be recommended.

 

Medication

Medication Summary

Historically, atypical antipsychotics are the first-line therapy for individuals with childhood-onset schizophrenia.

Many second-generation antipsychotics have been approved by the FDA in recent years for adolescents to treat schizophrenia including aripiprazole, lurasidone, olanzapine, quetiapine, paliperidone, and risperidone.

The second-generation antipsychotics iloperidone (Fanapt), asenapine (Saphris), cariprazine (Vraylar), and ziprasidone (Geodon) are approved for adult-onset schizophrenia, but not for pediatric patients.

Non-approved second-generation antipsychotics

These medications are approved for adult-onset schizophrenia, but not for pediatric patients. For discussion purposes, information is included here.

Iloperidone (Fanapt) is approved for adult-onset schizophrenia, but not for pediatric patients. It is structurally similar to risperidone and paliperidone. It was FDA approved for the treatment of adult-onset schizophrenia in 2009. It blocks dopamine D-2 receptors and serotonin 5HT-2A receptors but can block histamine receptors and alpha-adrenergic receptors. Consequently, it can cause sedation, weight gain, dizziness, orthostatic hypotension, and reflex tachycardia. Rarely, it can cause electrocardiogram changes, most specifically, QTC interval prolongation. In addition, higher doses of iloperidone can cause extrapyramidal effects and hyperprolactinemia. It has not received indication for the treatment of childhood- or adolescent-onset schizophrenia.[92]

Asenapine (Saphris) is approved for adult-onset schizophrenia, but not for pediatric patients. It is a dibenzo-oxepino pyrrole medication that blocks D-2 and 5HT-2A receptors and has a high affinity for other dopamine and serotonin receptors, histamine receptors, and alpha-adrenergic receptors, but does not have significant anticholinergic effects. It was approved by the FDA in 2009 for the treatment of adult-onset schizophrenia. It can cause somnolence, dizziness, decreased oral sensation, akathisia, parkinsonian symptoms, and weight gain. It can rarely cause prolongation of the QTC interval and hyperprolactinemia. Asenapine has not been approved for use in children or adolescents with schizophrenia or psychotic symptoms.[92]

First Generation Antipsychotics (Typical)

Class Summary

Controlled trials of haloperidol and loxapine are available, as are single-blind trials of thioridazine and thiothixene. However, thioridazine is no longer a preferred medication because of its significant cardiac toxicity and risk of death.

Although little difference in the efficacy of individual typical antipsychotics is observed, a difference in the adverse effect profile is noted. High-potency antipsychotics (eg, haloperidol) have an increased risk of extrapyramidal adverse effects, whereas low-potency antipsychotics cause more sedation and orthostatic hypotension. Extrapyramidal adverse effects can occur early, late, or during withdrawal.

Problems that occur early include dystonia, parkinsonism, akathisia, and neuroleptic malignant syndrome (NMS). Dystonia affects adolescent boys more often, but parkinsonism is less common in children. The late-appearing and withdrawal adverse effects include choreiform movements or, less commonly, dystonia. Other adverse effects of antipsychotics include weight gain,[103] photosensitivity, decreased white blood cell count, jaundice, blurred vision, constipation, amenorrhea, and gynecomastia.

Haloperidol (Haldol)

Haloperidol is a high-potency antipsychotic of the butyrophenone class that is available in tablet, solution, and injectable forms.

A study published in 1992 compared the efficacy of haloperidol versus placebo in 16 children diagnosed with very-early-onset schizophrenia ranging in age from 5–11 years. Haloperidol was associated with a significant reduction in positive and negative symptoms when compared with placebo.

Haloperidol decanoate is a depot formulation available for monthly intramuscular (IM) injection.

Thioridazine (Mellaril, Mellaril-S)

Thioridazine is a low-potency neuroleptic that demonstrated effectiveness in reducing symptoms in children with schizophrenia in a controlled trial. This agent is administered orally and is available in tablet, concentrate, and suspension forms. However, significant arrhythmogenic effects limit use of this medication.

Second Generation Antipsychotics (Atypical)

Class Summary

Generally, second generation antipsychotics are chosen as first-line antipsychotic therapy. As of February 2017, aripiprazole, lurasidone, olanzapine, quetiapine, risperidone, and paliperidone have been FDA approved for treatment of schizophrenia in adolescents.

Several studies have been performed investigating the efficacy of atypical antipsychotics in the treatment of childhood-onset schizophrenia. Specifically, A 6-week international, multisite, placebo-controlled trial showed that aripiprazole (10–30 mg),[104] olanzapine (2.5–20 mg),[105] quetiapine (400 mg or 800 mg),[106]  paliperidone (1.5 mg, 3 mg, or 6 mg; 6 mg or 12 mg based on weight),[107] and risperidone (1–3 mg or 4–6 mg)[108] were superior to placebo in improving the Positive and Negative Syndrome scale (PANSS) total score in adolescents aged 13–17 years.

In addition, another study found that risperidone (1.5–6 mg) was superior to a pseudoplacebo of risperidone (0.15–0.6 mg) in treating adolescent-onset schizophrenia.[109] One study found that 279 adolescent schizophrenic patients randomized over an 8-week trial to either low- or high-dose risperidone had significantly lower PANSS in the high-dose than in the low-dose group.[110] In one study, paliperidone did not separate from placebo (at doses of 1.5 mg, 6 mg, or 12 mg), but response rates were significantly superior in both the medium- and high-dose arms.[111] One trial looked at ziprasidone (40–80 mg/d target dose in patients weighing < 45 kg and 80–160 mg in the others) compared with placebo. However, this trial was discontinued when it was determined that the placebo response rate was higher in South America and Asia than in the United States and Europe.[112, 113]

In addition, several head-to-head trials have been conducted comparing the efficacy of several second-generation antipsychotics. Symptom response was not clinically significantly different between olanzapine, risperidone, and haloperidol[114] or between olanzapine and quetiapine[115] in youth with schizophrenia or psychosis. However, one small study demonstrated that clozapine was superior to haloperidol,[116] standard-dose olanzapine,[117] or high-dose (up to 30 mg) olanzapine.[118]  A network meta-analysis studying aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, ziprasidone, and molindone found all antipsychotics to be equally efficacious in treatment of children and adolescents with schizophrenia spectrum disorder, except ziprasidone which was found to be inferior to other antipsychotics. All antipsychotics (except ziprasidone and asenapine) were found to be superior to placebo. Aripiprazole and quetiapine were found to have greatest tolerability (while still having significant adverse side effects.)[119]

In the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study, the efficacy of olanzapine and risperidone was compared with molindone (a first-generation antipsychotic medication) in the treatment of early-onset schizophrenia and schizoaffective disorder in a double-blind multisite trial. No significant difference in response rates on the PANSS was found among treatment groups after 8 weeks of treatment with either olanzapine (2.5–20 mg/day), risperidone (0.5–6 mg/day), or molindone (10–140 mg/day, plus 1 mg/day of benztropine). However, olanzapine and risperidone were associated with greater weight gain, whereas molindone caused more reports of akathisia.[120]

Extrapyramidal adverse effects are less common than those observed with the traditional antipsychotics, although they have been reported with both clozapine and risperidone. Sedation has occurred with all available atypical antipsychotics. Furthermore, studies show that children and adolescents appear to have a higher risk of EPS, akathisia, prolactin elevation, sedation, and metabolic effects of atypical antipsychotics than adults.[121]  A study of adverse outcomes of treatment of early-onset schizophrenia—particularly medication discontinuation and psychiatric hospital admission—found that the choice among risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone made no difference; there were no statistically significant differences in these two outcomes among these medications.[122]

Weight gain has been a problem with all currently available atypical antipsychotics, although weight gain may be less of a problem with ziprasidone. Pediatric patients with childhood-onset schizophrenia are already at higher risk for obesity and metabolic syndrome. Prescribing second-generation antipsychotics may put these patients at even greater risk for weight-gain and development of metabolic syndrome. It’s suggested clinicians consider the addition of metformin when initiating pediatric patients on second-generation antipsychotics. This is not yet standard of care, but could be considered based on clinical circumstances.[123] In adults, metformin has been shown to reduce the incidence of diabetes by 31% in adults, hence the interest in considering it as a potential metabolic syndrome preventive therapy in the pediatric sphere.[124]

Aripiprazole shown beneficial as maintenance therapy in adolescents, delaying time to exacerbations of psychotic symptoms compared to placebo.[125]

Paliperidone is a major active metabolite of risperidone and the first oral agent that allows once-daily dosing. It is thought to mediate central receptor antagonism of D2 and 5HT2A, and it also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Paliperidone has no affinity for cholinergic, muscarinic, or beta-adrenergic receptors. One case study was found describing the successful use of bromocriptine in mitigating the side effects of paliperidone, hyperprolactinemia and tremor.[126]

Patients treated with olanzapine had higher BMI compared to patients treated with other antipsychotics at six months, but no longer significantly higher at twelve and twenty-four months.[90]

Patients treated with risperidone had worse neurological side effects compared to other antipsychotics at six months, but no longer statistically significantly worse at twelve and twenty-four months.[90]

In a systematic review and Network Meta-Analysis, ziprasidone was found to have “limited or no effect on decreasing total and positive symptoms” in the treatment of schizophrenia in patients less than nineteen years old.[119]

Clozapine is available as a tablet or oral-disintegrating tablet. Though plasma concentrations vary, therapeutic monitoring (checking plasma clozapine levels) should be considered to monitor for medication adherence and assessing for dose adjustment needs.[127]

One small retrospective chart review found clozapine to be safe in the use of treatment for childhood onset schizophrenia; this study noted only three cases (out of 17) of transient neutropenia, and no agranulocytosis or severe infections. They did find more tachycardia on discharge in the clozapine treatment group compared to the control group.[128]  One study found younger age, male sex, and African American ethnicity to be risk factors for developing neutropenia in children and adolescents being treated with clozapine. Overall rates of neutropenia were found to be higher in children and adolescents compared to adults treated with clozapine.[129]

Despite these risks and concerns, clozapine is generally safe and effective in the treatment of refractory early onset schizophrenia.[130]  And, the general tolerability of clozapine is comparable to that of other atypical antipsychotics.[90]  Not only that, but treatment of early onset schizophrenia with clozapine was associated with less discontinuation and greater occupational outcomes at twenty years old compared to non-clozapine use.[131]

Aripiprazole (Abilify)

Aripiprazole improves positive and negative schizophrenic symptoms and is indicated for treatment in adults with schizophrenia and acute manic and mixed episodes associated with bipolar disorder. It is also approved by the FDA to treat schizophrenia in adolescents. Aripiprazole shown beneficial as maintenance therapy in adolescents, delaying time to exacerbations of psychotic symptoms compared to placebo. This agent is hypothesized to work differently than other antipsychotics; it is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist that antagonizes serotonin (5HT2A). Aripiprazole is available as a tablet, oral disintegrating tablet, oral solution, or intramuscular injection. Injection is indicated for the treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed.

Paliperidone (Invega)

Paliperidone is indicated in adults for the acute and maintenance treatment of schizophrenia. It is also approved by the FDA to treat schizophrenia in adolescents. This agent is a major active metabolite of risperidone and the first oral agent that allows once-daily dosing. It is thought to mediate central receptor antagonism of D2 and 5HT2A, and it also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Paliperidone has no affinity for cholinergic, muscarinic, or beta-adrenergic receptors. One case study was found describing the successful use of bromocriptine in mitigating the side effects of paliperidone, hyperprolactinemia and tremor. This agent is available as an extended-release delivery system via osmotic pressure.

Olanzapine (Zyprexa)

Olanzapine is indicated in adults for treatment of schizophrenia and acute mixed or manic episodes associated with bipolar disorder. It is also approved by the FDA to treat schizophrenia in adolescents. It may inhibit serotonin, muscarinic, and dopamine effects. The efficacy of this agent in schizophrenia is mediated through a combination of dopamine and 5HT2A antagonism, and it also antagonizes muscarinic M1-5, histamine H1, and adrenergic alpha-1 receptors. Olanzapine is available as a tablet, oral-disintegrating tablet, or intramuscular (IM) injection. IM injection is indicated for the treatment of agitation associated with schizophrenia and bipolar I mania.

Patients treated with olanzapine had higher BMI compared to patients treated with other antipsychotics at six months, but no longer significantly higher at twelve and twenty-four months.

Quetiapine (Seroquel)

Quetiapine is an antipsychotic medication used for long-term management of schizophrenia and is indicated in adults for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, and acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy to lithium or divalproex. It is also approved by the FDA to treat schizophrenia in adolescents. This agent is available in tablet form and may act by antagonizing dopamine and serotonin effects. Quetiapine's improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, Parkinsonism, and tardive dyskinesia.

Risperidone (Risperdal, Risperdal Consta)

In children and adolescents, risperidone is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. In adults, this agent is indicated for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and schizophrenia. It is also approved by the FDA to treat schizophrenia in adolescents. Patients treated with risperidone had worse neurological side effects compared to other antipsychotics at six months, but no longer statistically significantly worse at twelve and twenty-four months.

Risperidone is an atypical antipsychotic with potent effects on serotonergic system by binding to dopamine D2-receptor with 20 times lower affinity than for 5HT2-receptor affinity. Open-label studies suggest its effectiveness in the treatment of childhood-onset schizophrenia. Risperidone is available as a tablet, oral-disintegrating tablet, oral solution, or long-acting intramuscular injection

Lurasidone (Latuda)

Benzoisothiazol derivative medication that is structurally related to buspirone. It blocks D-2 and 5HT-2A receptors. It has a high affinity for serotonin 5HT-7 receptors and moderate affinity for alpha-2-adrenergic receptors. It does not have significant anticholinergic or antihistaminic effects. It is a partial agonist at 5HT-1 receptors. Adverse effects include akathisia, parkinsonian symptoms, nausea, agitation, and somnolence. It was approved by the FDA in 2010 for the treatment of adult-onset schizophrenia and now it is indicated for schizophrenia in adults and adolescents (aged 13–17 y).

Ziprasidone (Geodon)

Ziprasidone is indicated in adults for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features, and schizophrenia; intramuscular (IM) injection is indicated for the treatment of acute agitation in adults with schizophrenia in whom treatment with ziprasidone is appropriate and who need IM antipsychotic medication for rapid control of the agitation.

This agent antagonizes dopamine D2, D3, 5HT2A, 5HT2C, 5HT1A, 5HT1D, is alpha1adrenergic, and has a moderate antagonistic effect for histamine H1. Ziprasidone moderately inhibits reuptake of serotonin and norepinephrine. This medication is available as a tablet and IM injection.

Clozapine (Clozaril, Fazaclo)

Clozapine is indicated in adults for management of severely ill patients with schizophrenia who fail to respond adequately to standard pharmacological treatment and for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior based on history and recent clinical state.

Clozapine has been demonstrated to be: (1) effective for childhood-onset schizophrenia in double-blind studies as well as (2) superior to haloperidol in treatment of children with schizophrenia. However, this agent remains second-line because of its major adverse effects. Start clozapine only after failure of medication trials using 2-3 antipsychotics from different classes. This agent is available as a tablet or oral-disintegrating tablet. 

 

Benzodiazepines

Class Summary

Benzodiazepines have been used in combination with antipsychotic agents early in the treatment of acute psychosis when sedation is needed.

Lorazepam (Ativan)

Lorazepam has been used acutely in agitated children with schizophrenia and may also be helpful in reducing akathisia. This agent is available for oral and parenteral use.

Antiparkinsonian Agents

Class Summary

Anticholinergic medications have been used to prevent and treat acute dystonia, Parkinsonism, and neuroleptic malignant syndrome. These agents have also been used for tardive dyskinesia.

Benztropine (Cogentin)

Benztropine can be started concurrently with antipsychotic medications to prevent or control extrapyramidal reactions that occur as adverse effects of neuroleptic agents.

Antihistamines

Class Summary

Antihistamines are possibly useful for the treatment of extrapyramidal adverse effects of antipsychotic agents (eg, dystonia, akathisia). They have also been used for sedation and as mild hypnotics.

Diphenhydramine (Benadryl, Anti-Hist, Diphenhist)

Diphenhydramine can be administered acutely for dystonic reactions or long term for medication-induced Parkinsonism and akathisia.

Beta-adrenergic Blockers

Class Summary

Beta-adrenergic blockers have been used to treat akathisia, tremor, anxiety, and aggression.

Propranolol (Inderal)

Propranolol may be helpful in treating akathisia.

Dopamine Agonist

Class Summary

Neuroleptic malignant syndrome (NMS) is an adverse effect of antipsychotic agents and is characterized by fever, muscle rigidity, and autonomic dysfunction. NMS has been treated with dopamine agonists (eg, bromocriptine, amantadine). Other medications used include dantrolene sodium, benztropine, and diphenhydramine.

Bromocriptine (Parlodel)

Bromocriptine is a dopamine agonist that reduces the mortality rate of neuroleptic malignant syndrome.