Comparison with previous studies
The onset of mental disorders, including schizophrenia and other psychotic disorders, commonly occurs in adolescence due to important changes in the brain structure with complex interactions among biological, psychological and social factors [
10]. Most of the antipsychotic users identified in this study with a diagnosis of schizophrenia were adolescents in the age range 13–17 years, consistent with other studies from Canada, Taiwan, and Denmark [
7,
8,
22].
There were more males than females receiving atypical antipsychotics in this study, similar to previous findings that also revealed gender differences with male predominance [
6,
23,
24]. The fact that schizophrenia, like other mental disorders, is involved in complex biological (hormonal) and psychosocial interactions seems to cause gender differences. For many years, several studies have reported gender differences in the age at onset for schizophrenia [
25]. Males have an earlier age at onset for schizophrenia (before 25 years) than females (after 25 years) [
26]. An increasing number of studies are examining this topic and exploring the association between gender differences and the aetiology of psychosis disorders. Oestrogen seems to be psychoprotective and to influence the development and functioning of the brain in females, whereas hypothalamic–pituitary–gonadal dysfunction can influence both sexes [
27]. On the other hand, some recent studies argue that the usual male predominance found in schizophrenia has become less apparent or that there is no gender difference [
4,
7,
8]. Evidence regarding the gender difference in the risk of schizophrenia is still inconclusive [
23].
While there is a significant increase in the use of atypical antipsychotics in children and adolescents worldwide, there are important gaps involving effectiveness, safety and effects in long-term use [
11,
28]. Approximately 36% of patients aged 12 or below were using some of these atypical antipsychotics (risperidone, clozapine, olanzapine, quetiapine or ziprasidone), and none of these medications are approved for use in this age range (under 13 years) for the treatment of schizophrenia according to the National Sanitary Surveillance Agency (ANVISA-Brazil), Food and Drug Administration (FDA-US), or Medicines & Healthcare products regulatory Agency (MHRA-UK) [
15,
16,
29].
Olanzapine, risperidone and quetiapine are approved for the treatment of schizophrenia only from 13 years old according to the ANVISA and FDA, while clozapine and ziprasidone are not approved for use among children and adolescents [
16,
29]. However, the use of these drugs is increasing worldwide and exposes patients to potentially unnecessary harm.
Two systematic reviews assessed the effects of the use of antipsychotics in children (
n = 6 RCTs, 256 participants before 13 years) [
11] and adolescents (
n = 13 RCTs, 1112 patients 13–18 years) [
28] diagnosed with schizophrenia and identified benefits in using antipsychotics, but neither could conclude that any one antipsychotic is better than another, except clozapine. Clozapine is a good option for children and adolescents with treatment-resistant schizophrenia [
9,
11,
14]. However, children and adolescents were more likely to show adverse effects; for instance, olanzapine, risperidone, and clozapine were often associated with weight gain in adolescents [
12,
28]. Children who received clozapine showed a higher rate of neutropenia [
11].
The high prescription rate of risperidone followed by olanzapine for the treatment of children and adolescents with schizophrenia has been confirmed in other studies [
7,
17,
30]. This can be attributed to the increase in the diagnosis of schizophrenia and other mental disorders in this age group, the implementation of diagnostic criteria for schizophrenia, improved access to intervention services and an increase in treatment capacity [
4,
8].
In addition, the diagnosis is complex, and the psychotic experience may be misdiagnosed as early-onset schizophrenia or be the manifestations of other mental disorders, such as behavioural disorders, anxiety disorders, affective disorders and developmental disorders [
1,
14]. The use of off-label atypical antipsychotics to treat these disorders is also a common practice and can inflate the consumption of these medicines [
17,
30,
31]. To verify this hypothesis, further and extensive research should be conducted.
This scenario in the real world is a concern, given the expansion in the profile of users of antipsychotics and the diagnoses for which they are used. The majority of antipsychotic use is off-label, and the effects on the developing brain of early and prolonged exposure to atypical antipsychotics are unknown [
31,
32].
For instance, among antipsychotics, risperidone is often used for the treatment of disruptive behaviour disorders, including aggression and conduct disorders, attention-deficit-hyperactivity disorder (ADHD) and autism, despite little evidence regarding its effectiveness [
33]. Evidence has shown that risperidone reduces aggression and conduct problems compared to placebo in patients aged 5 to 18 years old [
33]. The effectiveness of risperidone in the treatment of ADHD is unclear [
34], and autism shows some benefits in irritability, repetition and social withdrawal [
35].
The prescribed doses are in compliance with the Brazilian clinical protocol, although there is no specific protocol for treatment in children and adolescents in the country [
20]. The doses also corroborate the dosage recommended by British National Formulary for children, which recommends starting with low doses and gradually titrating upwards over the weeks [
15].
Although no guidelines recommend gender as a factor in the choice of antipsychotic or dose, patient gender should be considered by clinicians. Data are conflicting, and clinical implications exist, suggesting that females have a better response to antipsychotic treatment and require lower doses than males [
36‐
38]. We found a slight sex difference only in the dose of quetiapine and risperidone for males in the 13–17 year age group. Another study conducted in Taiwan found no gender difference in the prescribed doses of atypical antipsychotics [
7]. The clinical response to antipsychotic treatment seems to vary between males and females, and more studies are needed.
Strengths and limitations
To our knowledge, this is the first study to investigate gender differences in children and adolescents who received atypical antipsychotics with a diagnosis of schizophrenia in Brazil. The data were double checked, which increases the reliability of the findings. The database used represents the users of the public health system that covers more than 75% of the Brazilian population. There are few studies that report a large and representative population of children and adolescents who received antipsychotics in real words.
There are some limitations. The database is reliable and representative for studies of drug use, but they record only supply of the drugs, not whether the drugs were taken. We were unable to explore the concurrent use of other psychotropic drugs, adverse reactions, and the reasons that led clinicians to off-label use in children under 13 years of age. There was also no information on whether off-label use was a shared decision between clinicians and parents/caregivers.