Psychosis is characterized by impairment in reality testing and can be manifested by hallucinations, delusions, severe disturbances in cognition, and bizarre behaviors.1 Overall, the prevalence of psychosis in clinical samples of children and adolescents has been reported to be approximately 4% and 8%, respectively, and approximately 1% Ln community samples,'"3 with psychosis becoming more prevalent with increasing age.1 In clinical and epidemiological studies in adults, 3% to 5% indicated having had hallucinations before they were 21 years old.4,5 Most of these adults never told their parents or clinicians that they were experiencing hallucinations. Similar results were found in a study of children indicating the need for clinicians to actively inquire about the presence of psychotic symptoms when interviewing children.3
Psychosis in youth is manifested similarly to the adults, but hallucinations, in particular auditory, are the most frequent psychotic symptom in both children and adolescents.3,6,7 Also, delusions may be less elaborate and complex in children than in adolescents, perhaps as a function of their immature cognitive development. 1,2,6
Psychosis in children may be devastating, with negative consequences in the development and functioning in familial, social, and academic areas, as well as an increased risk for suicide. Therefore, there is a need for early recognition and efficacious treatment of psychotic symptoms in youth, particularly with the first psychotic episode, because early treatment has been associated with better prognosis.
The main goal of this article is to review the pharmacologic management of psychotic symptoms in children and adolescents. However, youth with psychotic symptoms also need psychosocial interventions to help them and their relatives understand their illness, improve their compliance with treatment, and implement psychosocial and educational rehabilitation programs during and after the psychotic episode.
Since psychotic symptoms are usually manifestations of several psychiatric, and sometimes medical and neurological, conditions and the successful treatment of the psychosis depends on the treatment of these primary conditions, the differential diagnosis and assessment of psychosis in youth is briefly reviewed first. Subsequently, the use of the antipsychotics in youth, the treatment of the psychiatric disorders more often associated with psychotic symptomatology, the continuation and maintenance treatment, and briefly, the psychosocial management of youth with psychosis are reviewed.
It is important to emphasize that there is a paucity of pharmacologic studies for children and adolescents with psychosis.8" 11 Until further information becomes available, child psychiatrists use the adult data. However, youth may respond differently to the antipsychotics than adult populations. For example, it appears that childhood-onset schizophrenia is more resistant to pharmacologic treatment and children are more sensitive to side effects from antipsychotics than adults.
ASSESSMENTAND differential DIAGNOSES
The first step before planning any treatment is to make an accurate diagnosis, because psychotic symptoms are usually the manifestations of underlying psychiatric and, less frequently, neurological or medical conditions. Also, when assessing psychotic symptomatology in children, it is important to take into account the child's cognitive and emotional developmental stage (eg, normal fantasy versus a psychotic symptom) and the increased likelihood to ascertain false-positive psychotic symptoms when mquiring about rare or bizarre symptoms because of children's high suggestibility.3,6
The most common psychiatric diagnoses in children and adolescents who are experiencing psychotic symptoms are major depressive disorder (MDD), bipolar disorder, and, more rarely, schizoaffective disorder and schizophrenic disorder.3"6 Thus, the need to carefully evaluate for the presence of depression, mania, hypomania, motivation, sleep, concentration, appetite, suicidal ideation, and other symptoms characteristic of mood disorders in youth with psychotic symptomatology. Mood disorders are usually comorbid with anxiety, disruptive, and substance abuse disorders that also require appropriate assessment and treatment for the successful management of the psychotic symptoms.12
Psychotic-like symptoms have also been reported in other psychiatric disorders such as anxiety, disruptive, personality, and posttraumatic stress disorders.1,3,6 Nevertheless, it is unclear whether these symptoms are actual psychotic symptoms or other perceptual alterations (eg, illusions). Psychotic symptoms or perceptual disturbances may also be secondary to use of substances (eg, marijuana, cocaine), use or abuse of prescribed medications (eg, corticosteroids, anticholinergics), medical and neurological illnesses (eg, seizures, migraine, brain tumors, and any other condition that can cause acute or chronic encephalopaties) during the process of falling asleep (hypnagogic hallucinations) or waking up (hypnopompic hallucinations), and in patients with narcolepsy.
It is critical to differentiate among these conditions because their pharmacologic treatment differs.6,710 For instance, sometimes it is difficult to distinguish between mania and schizophrenia in children and adolescents, in particular the first psychotic episode. Mania responds to mood stabilizers but these medications are not the first-line treatment for schizophrenia. Premorbid and family psychiatric history may help with the differential diagnosis between these two disorders. In fact, some investigators have suggested that the presence of persistent thought disorganization without learning disabilities, perceptual disturbances, unusual thoughts, brief psychotic episodes, and blunted affect, together with a family history for schizophrenia may increase the risk for schizophrenia.2,1315
However, youth with mood disorders may have schizophrenia-like symptomatology, making the differential diagnosis difficult. Youth who have psychotic symptoms secondary to substance abuse may only need to stop using the substances and if necessary temporarily treat their agitation and psychotic symptoms with the traditional antipsychotics, atypical antipsychotics, or benzodiazepines. On the other hand, if a psychotic child is suffering from a mood disorder, the treatment may only consist of administering an antidepressant or a mood stabilizer.
In order to make an accurate diagnosis it is necessary to perform a comprehensive cross-sectional and longitudinal psychiatric, neurological, and medical history and examinations. Psychiatric, medical, and neurological family history is also valuable. There are no laboratory tests that can be used to make a definitive psychiatrie diagnosis. However, in cases where there is suspicion of a medical or neurological illness, atypical clinical presentation, presence of dysmorphic features, or no response to treatment, laboratory tests (eg, thyroid function tests, ceraplasmin levels, screen for toxic substances, sedimentation rate, liver function tests, antinuclear factor), karyotype, and/or brain imaging may be indicated.
Baseline vital signs and laboratory tests should be obtained before administering some antipsychotics: supine, standing blood pressure, and pulse for antipsychotics that may induce postural hypotension, complete blood cell counts (CBC), and differential for most antipsychotics; electroencephalogram (EEG), electrocardiogram (ECG), and CBC before treatment with clozapine; ECG before administering thioridazine, pimozide, and some atypical antipsychotics; and glucose and lipid profile before administering the atypical antipsychotics. It is also recommended to evaluate the severity of the psychosis and baseline motor status using instruments such as the Brief Psychiatric Rating Scale for children16 and the Abnormal Involuntary Movement Scale.17 The evaluation of abnormal movements before starting the antipsychotics is important because dyskinesias or other abnormal movements may exist before treatment and indicate an increased propensity to develop extrapyramidal side effects (EPS), withdrawal, and tardive dyskinesia.8,9
Antipsychotics are grouped into typical (neuroleptics, traditional) and atypical (novel, new generation) categories. These medications are the main treatment for schizophrenia but are also used for the control of agitation, aggression, psychotic symptomatology associated with other psychiatric disorders (eg, mood disorders, mental retardation), medical and neurological conditions (eg, to diminish agitation, delirium), and pervasive developmental and tic disorders.8,10
This group of medications exert their antipsychotic effect, at least in part, by blocking the central dopamine receptors (in particular the D2 receptors). The traditional antipsychotics are subdivided into those with low and high potency to block the dopamine receptors (Table 1 ). All of these medications, when administered at equivalent doses and for at least 6 weeks, have been shown to be equally effective for the acute treatment of positive adult schizophrenic symptomatology (hallucinations and delusions) and prevention of recurrences. Except for a few randomized controlled trials comparing clozapine to haloperidol, loxapine to haloperidol, and placebo to haloperidol in small samples of children and adolescents with schizophrenia, no other randomized controlled trials have been conducted for the use of these compounds for the treatment of early-onset psychosis,8"10·18 These randomized controlled trials and open reports have shown that the typical antipsychotics are useful for the short-term treatment of positive schizophrenic symptoms (hallucinations, delusion, agitation), but they usually cause extrapyramidal side effects (EPS) (tremor, bradykinesia, stiffness, cogwheel rigidity, dystonia, and akathisia) and low-potency compounds sedation and anticholinergic side effects.
As a general rule, in adults with schizophrenia, the total daily dosage to treat schizophrenia should be equivalent to 300 mg/d of chlorpromazine.9·10-18 In children, lower doses of antipsychotics are efficacious8 and higher doses usually do not convey further benefit and increase the likelihood of side effects. In fact, in vivo neuroimaging studies using positron emission tomography and single photon emission computed tomography in adults, data from clinical studies in adult patients with schizophrenia, and data from animal models have indicated that low doses of haloperidol (2.5 to 5 mg/d) are enough to block at least 65% of the dopamine D2 receptors and produce a good therapeutic response. Higher doses of haloperidol will occupy more dopamine receptors but occupancy greater than 70% will be associated with higher prolactin levels and more EPS.19
The major problem with the antipsychotics is that they are not efficacious for the treatment of the negative symptoms of schizophrenia (eg, blunt affect and apathy), they usually are accompanied by side effects (EPS, sedation, possible cognitive dulling) that may interfere with the child's functioning, and they are associated with withdrawal and tardive dyskinesia, outweighing their beneficial effects.
Typical Antipsychotics Selective Side Effects*
Most of the side effects of the typical antipsychotics depend on their interactions with the dopamine, muscarinic, noradrenegic, histaminergic and other neurotransmitter systems (Table 1). The high-potency compounds have higher affinity for dopaminergic receptors and, as a result, induce more EPS and are associated with increased risk for withdrawal and tardive dyskinesia. Moreover, the presence of EPS may require the use of anticholinergic medications to counteract these side effects and these medications by themselves induce other side effects and cognitive disturbances. The high-potency antipsychotics increase prolactin secretion with associated menstrual disturbances, galactorrhea, gynecomastia, sexual dysfunction.
In contrast with the high-potency traditional antipsychotics, the low-potency antipsychotics have less affinity for the dopamine receptors and more affinity for the muscarinic, antihistaminergic, and adrenergic receptors. Therefore, they are associated with lower incidence of EPS but have more anticholinergic side effects (eg, dry mouth, constipation, tachycardia), postural hypotension, sedation, and weight gain. Also they, and in particular thioridazine and mesoridazine, may induce changes in the ECG such as prolonged PR and QTc intervals. The prolongation of the QTc interval (in children ** 0.46) is associated with life-threatening arrhythmias such as torsades de pointes. Symptoms that may indicate the patient is experiencing arrhythmia include dizziness, headaches, palpitations, nausea, vomiting, chest pain, and syncope.
Other side effects associated with the use of typical antipsychotics include gastrointestinal side effects (nausea, constipation, stomatitis), disturbances in the cognitive functioning (particularly the low-potency medications), blood dyscrasias (eg, agranulocytosis, thrombocytopenia), hepatic abnormalities (increase in the liver transaminases and, rarely, cholestatic jaundice), dermatological problems (atopies and photosensitivity), eye complications (chlorpromazine and thioridazine at high doses may induce lenticular and retinal pigmentation and retinitis pigmentosa), increased levels of triglycerides, and the neuroleptic malignant syndrome. The neuroleptic malignant syndrome, although rare, is a life-threatening side effect and is manifested by autonomic instability, hyperthermia, and rigidity. The rigidity is often associated with significant muscle breakdown, leading to myoglobinuria and acute tubular necrosis.
Many of these side effects are dosedependent and can be avoided by low initial doses with subsequent slow upward titration or taking the medications at certain times (eg, at bed time to avoid somnolence during the day). Sometimes patients develop tolerance to the side effects. The management of side effects is of prime importance because they affect the child's functioning and well being and they are one of the main causes of nonadherence to treatment.
Given the side effects of typical antipsychotics, the increased risk for tardive dyskinesia, the use of anticholinergic medications to counteract the EPS induced by the high-potency antipsychotics, the lack of efficacy treating negative symptomatology, and the uncertainty regarding the long-term side effects of these medications on a developing body, physicians have diminished the use of these medications in youth in favor of the atypical antipsychotics. However, the typical antipsychotics are still useful for the temporary management of agitation, hallucinations and delusions, secondary features of autism (eg, sterotypies, overactivity), and for the treatment of other conditions such as Tourette's syndrome.
If a patient develops dyskinesias while taking an antipsychotic, ideal management is immediate discontinuation of the antipsychotic if clinically feasible. However, it is important consider that discontinuation of use of the antipsychotics may produce withdrawal dyskinesias or worsening of tardive dyskinesia. The manifestations of tardive dyskinesia should be documented and the patient examined to exclude other causes of dyskinesia. Although the dyskinesia usually fades within several weeks, it has the potential to recur if the antipsychotic is reintroduced. If there is no alternative to reintroducing the antipsychotic, an atypical antipsychotic should be considered.
The typical antipsychotics are metabolized by hepatic cytochrome P450 enzyme system (CYP450) and can interact with other medications metabolized by the CYP450. However, the CYP450 studies were carried out in adults and before puberty some of these CYP450 enzymes may be more efficient or perhaps they have not yet matured.
This group of medications, of which clozapine is the prototype, includes risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.911 The atypical antipsychotics are efficacious for the short-term treatment of positive and negative psychotic symptoms in adults with schizophrenia and now are considered the first-line treatment for this disorder, with clozapine reserved for patients with treatment-resistant schizophrenia.10" 12.16-20 it js believed that their antipsychotic effects and fewer EPS are accounted for by the blockage of both the central serotonin (in particular the 5-HT2) and dopamine receptors (in particular the D2 receptors), with the peculiarity of blocking more of the serotonergic than the dopaminergic receptors (a higher ratio of serotonergic/dopaminergic antagonism).
The atypicals may also have affinity to other receptors including the muscarinic, histaminergic, and adrenergic receptors, accounting for many of their side effects. There is only one randomized controlled trial using the atypical antipsychotics in children and adolescents with schizophrenia. In this study, clozapine was found to be more efficacious and induced significantly fewer EPS than haloperidol for the treatment of both positive and negative symptoms of schizophrenia.21 However, the advantages of clozapine were limited by the presence of increased appetite and weight, sialorrhea, sedation, and, in a few cases, seizures and neutropenia. This randomized controlled trial, open studies, and case reports suggest that atypicals are beneficial for the treatment of youth with schizophrenia,9'11,18'22 but further short- and longterm studies are warranted.
Open studies and case reports suggest that the atypicals seem useful for the management of agitation, aggressive behaviors, tics, mania, severe irritability, secondary features of autism, severe behavioral problems, and anorexia nervosa9"11,23,24 but randomized controlled trials including larger samples and following patients for longer periods of time are necessary.
The severity of each side effect shown in Table 2 was subjectively ascertained from the available child and adolescent and adult studies and, given the limited pediatric literature, should be taken only as a guide.8-11,25'26 Most of the atypicals increase appetite, and body weight. Depending on the dose, particularly at the beginning of treatment, sedation, fatigue, gastrointestinal side effects, and headaches. Recently, the atypicals, in particular clozapine, olanzapine, and, to a lesser degree, quatiapine, have been associated with hyperlipidemia and new onset diabetes mellitus.10,25,27,28 However, it is not clear whether these complications are secondary to the body weight gain associated with the atypical antipsychotics, or the result of the agents themselves. Patients who have low pretreatment body mass index, are young, and are female seem to be at a higher risk to gain weight using the atypicals. The increased weight increases the risk for medical illnesses, impairs the patient's quality of life, induces low self-esteem, and increases the likelihood of noncompliance with treatment. Also, in addition to the usual ostracism from society toward people with psychosis, increased weight adds the stigma associated with obesity.
The atypicals have been associated with cognitive improvement in adult schizophrenic patients but have not been assessed in youth. If they cause sedation or have string anticholinergic properties they may interfere with a child's cognitive function and academic performance. Some of the atypicals can also induce hyperprolactinemia (gynecomastia, galactorrhea, menstrual and sexual disturbances) (Table 2, page 262). In addition, they are associated with gastrointestinal disturbances (nausea, loose stools, dysphagia), rashes, increased sweating, increased dream activity, flulike symptoms, and photosensitivity.10,11,26 Moreover, no information is available regarding the antipsychotics long-term side effects on growth, pubertal, and cognitive side effects.
Atypical Antipsychotics - Selective Side Effects- and Metabolism by the Cytochrome P450
Clozapine is the main atypical associated with life-threatening side effects including neutropenia (absolute counts less than 1500/mmp 3), agranulocytosis (neutrophil counts less 500/mmp 3), and myocarditis, requiring close laboratory monitoring. Clozapine also increases the risk for seizures or abnormal EEGs, myoclonus, eosinopmiia, fever, persistent tachycardia, and, less clearly, it has been associated with pulmonary embolism. Quetiapine has been associated with the development of cataracts in dogs. Although the development of cataracts in humans after quetiapine use is controversial, a baseline slit lamp examination with subsequent examinations sometimes has been recommended. Of all the atypical antipsychotics, ziprasidone causes the least weight gain but it increases the QTc interval more than other atypicals, requiring baseline ECG and subsequent monitoring. Combining ziprasidone with other medications that increase the QTc interval should be avoided in patients with congenital long QTc syndrome, prior cardiac arrhythmias, and family history of torsades de pointes or sudden death, in particular if these events occurred when the person was young.
Clozapine is a pregnancy category B (animal studies indicate no fetal risk, but there are no human studies) medication and the rest of the atypicals are classified as pregnancy C (there are not adequate animal and human studies). Although not well studied, many of the antipsychotics are secreted in the maternal milk.
Since several of the side effects depicted in Table 2 are dose dependent, the atypical antipsychotics should be initiated at low doses, with the dosages increased slowly. This will not only rmnimize the risk for side effects but increases the chance that the patient and/or his or her parents will adhere to the treatment. Only the pharmacokinetics of olanzapine has been studied in youth.29 This study shows that at the usual dose recommendation (5 to 10 mg/d) olanzapine has a half-life of 37.2 ± 5.1 hours.30 Similar to the typical antipsychotics, it appears that low doses of the atypicals for adults with schizophrenia (resperidol 2 to 4 mg/d; olanzapine 7.5 to 15 mg/d) are enough to occupy 65% to 70% of the D2 receptors and obtain a good therapeutic response.'9 Higher doses may be accompanied by more side effects and no further benefit.
Although the atypicals have a better EPS profile than the typical antipsychotics, baseline and subsequent neurological examinations are recommended to rule out the presence of dyskinesias. Also, a baseline CBC plus differential, fasting glucose, liver function tests, lipid profile, ECG, body mass index, and EEG and ECG for clozapine with routine monitoring (every 6 months) are recommended. Finally, similar to the typical antipsychotics, the atypicals are metabolized by hepatic CYP450 system and pharmacologic interactions with other medications metabolized by the CYP450 are common.
Major Depression With Psychosis
The selective serotonin reuptake inhibitors are efficacious and well tolerated by children and adolescents being treated for MDD.31'33 Youth with MDD and psychotic symptomatology may respond to treatment with only the selective serotonin reuptake inhibitors but no studies have been reported. In adults, only 20% to 40% of adults with psychotic MDD respond to tricyclic antidepressant monotherapy, and the range of placebo response is from very low to null.34 Although monotherapy with antidepressants may be effective, recovery appears to be greater and more rapid when antidepressants are combined with an antipsychotic. Usually the antipsychotics are slowly tapered after remission of the depression but it is not clear how long a depressed patient should be maintained on an antipsychotic. For adult depressed psychotic patients who do not respond to antidepressants plus antipsychotic treatment, electroconvulsive therapy has been found to be particularly effective.34
There are no randomized controlled trials of any antimanic medication for youth with bipolar disorder. However, the extant literature from case reports, open studies, and small controlled studies has suggested that the mood stabilizers may be effective for the treatment of bipolar youth.35 Bipolar patients with psychotic symptoms may respond to a mood stabilizer alone but preliminary reports have shown that they also need adjunctive pharmacotherapy with antipsychotics, particularly if they are too agitated to collaborate with treatment or until the mood stabilizers begin to exert their effect.36 A small doubleblind study showed that quetiapine in combination with valproate was more effective for the treatment of adolescents with mania than valproate alone.37 There are also a few reports in children and randomized controlled trials in adults suggesting that the atypical antipsychotics alone can successfully treat mania, and olanzapine in particular may be helpful for the treatment of dysphoric bipolar patients.38,39
CONTINUATION AND MAINTENANCE THERAPY
To avoid relapses and recurrences, adults with schizophrenia require lifelong maintenance antipsychotic treatment. Children with schizophrenia also may need lifelong maintenance treatment, although this has never been studied. However, since most children presenting for treatment are experiencing their first psychotic break, it is useful to consider a trial free of antipsychotics to re-evaluate the possible causes of the psychotic episode. Although the length of the treatment with antipsychotics in youth has not been studied, to consolidate the response and prevent relapse of symptoms, all patients should be offered continuation treatment for at least 6 months after complete symptom remission. Patients who have shown difficulty achieving remission, have early-onset psychosis, and a family history of schizophrenia or other psychotic disorders should be offered longer treatment (eg, 1 year). In children and adolescents with mood disorders plus psychosis antipsychotics may be slowly tapered down after the mood and psychotic symptoms have remitted. Children with accurate diagnoses of schizophrenia must be treated for long periods of time or for their lifetime to avoid further psychotic episodes and more deterioration in their cognitive, emotional, and social skills.
PSYCHOEDUCATION AND SUPPORTIVE THERAPY
The optimal pharmacologic management of children and adolescents with psychosis should also involve educational and psychosocial interventions. Education of the patient and family about the disease, nature of treatment, and prognosis is critical to engagement in treatment and enhancement of compliance.40 In addition, family conflicts that interfere with optimal pharmacologic outcome should be addressed. The psychological sears after the psychosis has remitted (eg, family conflict, poor self-esteem and social skills, peer rejection) need to be addressed with psychotherapy. Additionally, because the parents of children with psychosis may also be experiencing psychiatric problems and parental mental problems may lead to adverse outcomes, in order to successfully treat the child the clinician should assess the parents and refer them for treatment if appropriate.
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Typical Antipsychotics Selective Side Effects*
Atypical Antipsychotics - Selective Side Effects- and Metabolism by the Cytochrome P450