Canadian Guidelines for the Pharmacological Treatment of Schizophrenia Spectrum and Other Psychotic Disorders in Children and Youth

Abstract

Objective:

Schizophrenia spectrum and other psychotic disorders often have their onset in adolescence. The sequelae of these illnesses can negatively alter the trajectory of emotional, cognitive, and social development in children and youth if left untreated. Early and appropriate interventions can improve outcomes. This article aims to identify best practices in the pharmacotherapy management of children and youth with schizophrenia spectrum disorders.

Methods:

A systematic search was conducted for published guidelines for schizophrenia and schizophrenia spectrum disorders in children and youth (under age 18 years). Recommendations were drawn from the National Institute for Health and Care Excellence guidelines on psychosis and schizophrenia in children and youth (2013 and 2015 updates). Current guidelines were adopted using the ADAPTE process, which includes consensus ratings by a panel of experts.

Results:

Recommendations identified covered a range of issues in the pharmacotherapy management of children and youth with schizophrenia spectrum disorders. Further work in this area is warranted as we continue to further understand their presentation in the developing brain.

Conclusions:

Canadian guidelines for the pharmacotherapy management of children and youth with schizophrenia spectrum disorders are essential to assist clinicians in treating this vulnerable population. Ongoing work in this area is recommended.

Schizophrenia spectrum and other psychotic disorders are illnesses that carry significant morbidity and mortality for those affected. These illnesses often have their onset in adolescence and can significantly interfere with the normal trajectory of development. Early interventions with appropriate and stage-specific psychological and pharmacological modalities can, however, lead to better and, in some, optimal outcomes in this population. The following recommendations were developed to assist clinicians in providing pharmacological interventions for children and youth up to the age of 18 years (termed early onset) with schizophrenia spectrum and other psychotic disorders. The recommendations and associated discussions were drawn from a number of sources, with the greatest weight placed on evidence based on randomized controlled trials or systematic reviews available in this age range as well as consensus statements reflecting good clinical practice. These guidelines can be used with reference to our similar chapter for adults,¹ with particular emphasis here placed on a differential approach to pharmacological treatment for children and youth. In outlining these items, the working group has drawn primarily from the 2013 National Institute for Health and Care Excellence (NICE) guidelines for the treatment of psychosis and schizophrenia in young people.² The term “psychosis” in these guidelines refers to the group of psychotic disorders characterized by hallucinations or delusions and experiences that alter perception, thoughts, emotionality, and behaviour, all of which can markedly impair the trajectory of social, emotional, and physical health of a young person. These disorders include primarily schizophrenia but also schizoaffective disorder, schizophreniform, and delusional disorder. The key features that define these illnesses in youth and adults and assist in confirming an accurate and reliable diagnosis are outlined in our guidelines for the assessment and diagnosis of patients with schizophrenia and other spectrum disorders.^1,3

As with all mental disorders, schizophrenia spectrum and other psychotic disorders in youth are identified on the basis of clinical features. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V)⁴ emphasizes a dimensional perspective of symptom presentation that is particularly applicable to children and youth, recognizing that symptom domains for psychosis can differ depending on the age and stage of development and can potentially be a manifestation of multiple diagnostic categories. That is to say that children and youth’s interpretation of internal and external perceptual experiences can be influenced greatly by factors such as intellect and emotional maturity as well as by exposure to developmental stressors, environmental triggers, cultural dynamics, and family belief systems. The perception of a psychotic experience can in fact be a normal variant for very young children⁵ and indeed in isolation is relatively common and clinically benign even in adolescents, occurring in 15% to 20% in some studies.⁶ Furthermore, the perception of a psychotic experience may be the manifestation of a medical etiology or other psychiatric causes such as primary mood or anxiety disorder, obsessive–compulsive disorder, or posttraumatic stress disorder.⁵ Clinicians thus need to be aware that while many adults with schizophrenia report the initial onset of symptoms prior to age 18 years,⁷ the interpretation of the clinical significance of the psychotic experience in childhood and adolescence is complex. These factors emphasize the need for diagnostic diligence when evaluating children and youth seeking help for psychotic experiences: the experience may be significant for other illnesses that benefit from interventions specific to that etiology but may also, at the same time, herald a risk for the onset of the later development of schizophrenia or other psychotic spectrum disorder.^8,9

Children and youth with transient or attenuated psychotic symptoms who may be at a clinical high risk for developing psychosis and schizophrenia require recognition as earlier identification and interventions can improve outcomes.¹⁰ Predicting based on attenuated symptoms, which youth will convert to a psychotic disorder, is a challenge. Research and knowledge in this area have increased substantially in recent years. The specific recommendations for the assessment and approach to psychological and pharmacological interventions for persons at risk are addressed in our chapter that focuses on the high-risk population.¹¹ Diagnostic accuracy for youth with psychosis may be improved by the utilization of semistructured interviews designed for youth such as the Schedule for Affective Disorders and Schizophrenia for School-Age Children¹² or the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS).¹³ These interviews should only be utilized as an addition or augment to a comprehensive diagnostic assessment that includes interviews with the child or adolescent and the family plus a review of past health records and any other available information from resources such as school. Certainly, given the challenges in this field in attempting to recognize and treat youth with psychosis, expertise and skill in child and adolescent psychopathology and development are assets.

The prevalence of childhood-onset schizophrenia (prior to age 12 years) is quite rare, affecting 1.6 to 1.9 per 100,000 in the child population.¹⁴ The prevalence increases rapidly after age 14 years, particularly in males, and accounts for about 25% of all psychiatric admissions in young people between 10 and 18 years of age.¹⁵ While the course of illness is similar in early-onset cases to that of adult-onset cases, with symptoms in keeping with the phases of illness (prodrome, acute, recovery, residual), an important clinical characteristic associated with the early course of psychotic disorders is age. Early-onset psychosis is associated with more severe psychopathology.⁷ Left untreated, psychosis and schizophrenia in children and youth can contribute to major causes of morbidity and are associated with comorbid conditions, substance misuse, and physical health problems.¹⁶ The risk of suicide for persons with schizophrenia is higher in those with earlier onset.¹⁷ Furthermore, an earlier onset of psychosis predicts a potentially poorer prognosis, with about 30% requiring long-term intensive social, emotional, and psychiatric support.¹⁸ Other factors associated with poor long-term outcomes along with early onset include low premorbid social functioning, insidious onset, lower intellectual function, and negative symptoms.¹⁸ Of particular import, however, is that recent research shows that early identification and specialized stage-specific treatment that includes developmentally oriented, psychosocial, and cognitive-behavioural interventions, along with expert medical interventions, have the potential to alter this pessimistic course and optimize outcomes for this population.¹⁹

As with adults, the cornerstone of treatment for psychosis in children and youth is a comprehensive approach including both psychosocial and pharmacological (antipsychotic medication) interventions. While evidence supporting antipsychotic efficacy in this population is somewhat limited, it is certainly increasing.²⁰ The increased incidence of medical and psychiatric morbidity in this age group, secondary to the illness itself and heightened sensitivity to adverse effects of medication (such as metabolic disturbances and movement disorders), warrants heightened vigilance to identify and confirm the diagnosis before interventions with antipsychotic medication are offered to children and youth.^7,8 Early interventions for psychosis services often require expertise in identifying and treating early-onset presentations of psychosis. Consultation with or care within such specialized services can assist in providing the appropriate diagnosis and ongoing care for this younger population. These services also carry as their mandate the fostering of a seamless transition of care for children and youth with psychosis who require consistent longstanding intensive treatment.

In summary, confirming the diagnosis of psychosis early in the course of the illness, that is, in children and youth, can be difficult, but it is crucial to identify the most appropriate and least harmful treatment modalities. Meeting full diagnostic criteria according to the DSM-V for schizophrenia and other psychotic spectrum disorders is the threshold for pharmacological interventions suggested by these guidelines. Early interventions using both psychological and pharmacological modalities can foster optimal outcomes for youth, enhancing their potential to attain recovery. For best practice, these guidelines must be used in conjunction with those specific to psychological treatment recommendations for children and youth with schizophrenia spectrum and other psychotic disorders in order to foster optimal outcomes.²¹

Methods

The methods for the Canadian Schizophrenia Guidelines are described in brief here; please see the Introduction and Methodology paper for an in-depth description.

The Canadian Schizophrenia Guidelines were developed using the ADAPTE process.²² Recognizing that the development of guidelines requires substantial resources, the ADAPTE process was created to take advantage of existing guidelines and reduce the duplication of effort.

The first phase of the ADAPTE process, the setup phase, involved preparing for the ADAPTE process. We assembled a national multidisciplinary panel from across Canada, including stakeholders with expertise in schizophrenia and mental health, health policy, patient advocacy, and lived experience with schizophrenia. Endorsement bodies for the guidelines include the Canadian Psychiatric Association and the Schizophrenia Society of Canada, who were also heavily involved in the dissemination and implementation strategy.

The second phase of the ADAPTE process, the adaptation phase, involved the process of identifying specific health questions; searching for and retrieving guidelines; assessing guideline quality, currency, content, consistency, and applicability; decision making around adaptation; and preparing the draft-adapted guideline. We searched for guidelines on schizophrenia in guideline clearinghouses and on the websites of well-established guideline developers for mental health disorders including the NICE, the Scottish Intercollegiate Guidelines Network, the American Psychiatric Association, the American Academy of Child and Adolescent Psychiatry, and the European Psychiatric Association. A MEDLINE search was also performed using the terms “guideline” as the publication type and “schizophrenia” as the title or clinical topic. Inclusion criteria were that the guideline needed to be published after 2010, the guideline needed to be written in English, and recommendations had to be developed using a defined and systematic process. We identified 8 current guidelines that were potentially suitable for adaptation. These guidelines were reviewed and evaluated in duplicate using the AGREE II tool,²³ an instrument to evaluate the methodological rigour and transparency with which a guideline is developed. Based on this evaluation, we determined that 6 guidelines were of suitable quality and content for adaptation (Table 1). Recommendations from each guideline were extracted and divided based on content and reviewed by the relevant working group. Following the ADAPTE process, working groups selected guidelines and recommendations to create an adapted guideline. Each working group carefully examined each recommendation, the evidence from which the recommendation was derived, and the acceptability and applicability of the recommendation to the Canadian context. After reviewing the recommendations from the guidelines, the working groups decided which recommendations to accept and which to reject and which recommendations were acceptable but needed to be modified. Care was taken when modifying existing recommendations not to change the recommendations to such an extent that they were no longer in keeping with the evidence upon which they were based. Please see Appendix 1 for how and why recommendations in this article were modified from their original form.

Table 1.

Clinical practice guidelines used for the Canadian Schizophrenia Guidelines.

Guideline Developer	Guideline Title	Year Published
National Collaborating Centre for Mental Health commissioned by the NICE	Psychosis and schizophrenia in adults: treatment and management81 (clinical guideline number 178)	2014
National Collaborating Centre for Mental Health commissioned by the NICE	Psychosis and schizophrenia in children and young people: recognition and management4 (clinical guideline number 155)	2013
National Collaborating Centre for Mental Health commissioned by the NICE	Psychosis with coexisting substance misuse: assessment and management in adults and young people82 (clinical guideline number 120)	2011
Scottish Intercollegiate Guidelines Network	Management of schizophrenia83	2013
European Psychiatric Association	Guidance on early intervention in clinical high risk states of psychoses84	2015
American Psychiatric Association	Practice guidelines for the psychiatric evaluation of adults85	2016

NICE = National Institute for Health and Care Excellence.

Each working group developed a final list of recommendations from the included guidelines that were presented to the entire guideline panel at an in-person consensus meeting. Working group leaders presented each recommendation and its rationale to the panel. Anonymous voting by the entire panel using clicker technology was performed for each recommendation. Recommendations required agreement by 80% of the group to be included in the Canadian guidelines. If a recommendation did not receive 80% agreement, the group discussed the recommendation and whether minor modifications to the recommendation would alter the likelihood that the recommendation would pass. In these situations, recommendations were modified (as described above), and the group revoted at a later date using an online anonymous survey. Whenever modifications in wording were made to original recommendations, the text “modified recommendation from” appears in the Canadian Schizophrenia Guidelines, and the source of each recommendation is written beside the recommendation statement. The strength or grade of the recommendation is provided in parentheses, if applicable, using the system that the recommendation came from. The grades of recommendation for each guideline and their meaning are explained in brief in Table 2 (see the Introduction and Methodology paper for a more detailed description). Once the voting and consensus process was completed, each working group created a separate paper that contains all the recommendations adapted from the included guidelines, with accompanying text explaining the rationale for each recommendation.

Table 2.

Grade/strength of recommendation classification systems for included guidelines.^a

National Institute for Health and Care Excellence (NICE)
Strength of recommendations The wording used denotes the certainty with which the recommendation is made (the strength of the recommendation). Interventions that must (or must not) be used We usually use “must” or “must not” only if there is a legal duty to apply the recommendation. Occasionally, we use “must” (or “must not”) if the consequences of not following the recommendation could be extremely serious or potentially life threatening. Interventions that should (or should not) be used: a “strong” recommendation We use “offer” (and similar words such as “refer” or “advise”) when we are confident that, for the vast majority of patients, an intervention will do more good than harm and be cost-effective. Interventions that could be used We use “consider” when we are confident that an intervention will do more good than harm for most patients and be cost-effective, but other options may be similarly cost-effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient’s values and preferences than for a strong recommendation.
Scottish Intercollegiate Guidelines Network (SIGN) and European Psychiatric Association
Levels of evidence 1++: High-quality meta-analyses, systematic reviews of randomized controlled trials, or randomized controlled trials with a very low risk of bias; 1+: Well-conducted meta-analyses, systematic reviews, or randomized controlled trials with a low risk of bias; 1: Meta-analyses, systematic reviews, or randomized controlled trials with a high risk of bias 2++: High-quality systematic reviews of case control or cohort studies or high-quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal; 2+: Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal; 2: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3: Nonanalytic studies (e.g., case reports, case series) 4: Expert opinion Grades of recommendation A: At least one meta-analysis, systematic review, or randomized controlled trial rated as 1++ and directly applicable to the target population or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 1++ or 1+ C: A body of evidence including studies rated as 2+, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 2++ D: Evidence level 3 or 4 or extrapolated evidence from studies rated as 2+ Good Practice Point: recommended best practice based on the clinical experience of the guideline development group

^aThis is a condensed table; please see the Introduction and Methodology paper for full details.

During the finalization phase, the Canadian Schizophrenia Guidelines were externally reviewed by those who will be affected by their uptake: practitioners, policy makers, health administrators, patients, and their families. The external review asked questions about whether the users approve of the draft guideline, strengths and weaknesses, and suggested modifications. The process was facilitated through the Canadian Journal of Psychiatry and the Schizophrenia Society of Canada. The Canadian Psychiatric Association Clinical Practice Guidelines Committee reviewed and approved the guideline methodology process.

Results

General Principles of Care

While the principles outlined below did not emerge directly as a result of the ADAPTE process (as per the Methods section above), they are endorsed as values and principles of care worth stating as they are often shared by clinicians working with children and youth with schizophrenia and psychotic spectrum disorders:

• Having training, expertise, and experience working with youth and families can assist in best understanding the complexities of the identification, diagnosis, and treatment of psychosis at early stages.

• Assessments of the capacity to make treatment decisions occur on an ongoing basis according to parameters outlined by provincial standards.

• Treatment decisions should occur in partnership with the child/youth along with his or her caregiver. Fostering the child or youth’s autonomy and active participation in treatment decisions as much as possible helps to optimize treatment satisfaction and ongoing engagement.

• Offering ongoing psychoeducation regarding psychosis to both the young person and family will optimize treatment satisfaction and foster improved clinical outcomes.

• Acknowledging and addressing the impact of barriers such as comorbidity and stigma at specific stages of recovery can positively influence treatment decisions.

• Clinicians need to ensure that they communicate clearly and verify that they are well understood by parents or carers and the child or young person. This means taking into account the young person’s developmental level, emotional maturity, and cognitive capacity including any learning disabilities, sight or hearing problems, or delays in language development.

• Treatment interventions should be offered within a culturally competent atmosphere.

• Maintenance of the continuity of care and consistency of therapeutic relationships optimizes intervention outcomes. If a transition between care services or programs is unavoidable, a seamless transition process is preferred.

First Episode of Psychosis

Recommendation 1

Urgently refer all children and young people with a first presentation of sustained psychotic symptoms (lasting 4 weeks or more) to a specialist mental health service or early interventions in psychosis service, which includes a consultant psychiatrist with training in child/adolescent mental health.

                   [Modified recommendation from NICE (Strong)]

Schizophrenia spectrum disorders are among the most serious and persistent mental health disorders that can affect children and adolescents. Numerous studies support the benefits and improved outcomes of a shorter duration of untreated psychosis and illness in the population with a first episode of psychosis,²⁴ as is further discussed in the adult guidelines.¹ Literature regarding the benefits of early detection and a shorter duration of untreated psychosis exists in children and early adolescents,^25–27 including evidence for benefits to executive functioning.²⁶ Early detection and management are of utmost importance. In those assessed to be at a high risk, longitudinal follow-ups may even allow for the timeliest identification, management, and improved positive outcomes.¹⁰

Further study of the development of schizophrenia and its different stages will hopefully lead to the implementation of prevention and early intervention strategies.^28,29 Specialized services may aid in achieving these goals.^30,31 Specialized services should aim to optimize the accurate diagnosis of schizophrenia spectrum disorders at an earlier stage and to reduce the duration of untreated psychosis and of untreated illness. Research looking at factors associated with the duration of untreated psychosis will prove helpful in planning systems of care for this population.³²

Recommendation 2

Antipsychotic medication in children and young people with a first presentation of sustained psychotic symptoms should not be started in primary care unless it is done in consultation with a psychiatrist with training in child and adolescent mental health.

                   [NICE (Strong)]

The prescription rate of antipsychotics in children and adolescents, often off label, has been an increasingly recognized concern.^33–36 Antipsychotics are often prescribed for nonpsychotic and non-bipolar disorders³⁷ and in this age group often may not be indicated. Given the high side-effect potential and burden of these agents, their use should be most judicious and with clear indications.

As also discussed in the recommendation above, specialists with expertise in the area of psychosis are best suited for informing decisions about the initiation of antipsychotic pharmacotherapy and appropriate investigations and monitoring³⁸ in the context of a thorough biopsychosocial management plan.

Use of Antipsychotics

Recommendation 3

For children and young people with a first episode of psychosis, offer antipsychotic medication in conjunction with psychological/psychosocial interventions.

                   [Modified recommendation from NICE (Strong)]

One-third of all adults with schizophrenia have their onset before age 18 years.¹⁵ Schizophrenia identified in children and adolescents is clinically continuous with adult-onset schizophrenia.^18,39 Compared with adult onset, the early-onset phenotype carries worse prognostic factors including more severe expression of the illness, lower premorbid social/emotional adjustment, cognitive impairments, and negative symptoms. Furthermore, adolescents with psychosis have longer treatment delays than adults^39,40 possibly due to the misidentification of presenting symptoms. The earliest initiation of comprehensive treatment including both pharmacological and psychosocial interventions will lead to better outcomes.¹⁹ Antipsychotic medicine is as effective as with adults and should be offered once the diagnosis is confirmed.⁷

Recommendation 4

The choice of antipsychotic medication and mode of administration should be made by the parents/carers of younger children, or jointly with the young person and his or her parents/carers, and health care professionals. Provide age-appropriate information, and discuss the likely benefits and possible side effects of each drug, including the following:

• metabolic (including weight gain and diabetes),

• extrapyramidal (including akathisia, dyskinesia, and dystonia);

• cardiovascular (including prolonging the QT interval);

• hormonal (including increasing plasma prolactin); and

• other side effects (including unpleasant subjective experiences, interactions with other medications).

                   [Modified recommendation from NICE (Strong)]

There is a lack of evidence for efficacy differences or clinical superiority between the various antipsychotic classes or generations (except for clozapine for treatment-refractory cases)⁷ or modes of administration. As such, choosing an antipsychotic for this population must be made in conjunction with the patient and/or family, taking into account their choice and other factors including heightened vulnerability to adverse effects, administration preference (oral or intramuscular), side-effect profile, medical status of patient, pharmacodynamics , and risk for other iatrogenic morbidity. The need to monitor for adverse effects is paramount.^7,41

Recommendation 5

Before initiating or changing antipsychotic medication for a child or young person with schizophrenia, depending on the medication being considered and the clinical situation, an electrocardiogram is suggested particularly if

• it is specified in the Health Canada drug product database,

• a physical examination has identified a specific cardiovascular risk (such as the diagnosis of high blood pressure),

• there is a personal history of cardiovascular disease, and

• there is a family history of cardiovascular disease such as premature sudden cardiac death or a prolonged QT interval.

                   [Modified recommendation from NICE (Strong)]

Schizophrenia spectrum disorders are associated with an inherent 2- to 3-fold excess mortality, with the vast majority, regardless of the age of onset, related to cardiovascular illness or obesity-related cancer.⁴² Antipsychotic medication can contribute to cardiometabolic morbidity and mortality in this population, the risk for which requires monitoring and prevention. Markers of an increased risk have been associated with the duration of lifetime exposure to antipsychotic medication, reinforcing the need to assess all patients before and during treatment and to prioritize lower risk antipsychotics and the management of cardiometabolic adverse effects that may arise.⁴²

Recommendation 6

Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following:

• From a discussion with the child or young person and his or her parent or carer, record the side effects that the child or young person is most and least willing to tolerate.

• Record the indications and expected benefits and risks of oral antipsychotic medication and the expected time for a change in symptoms and appearance of side effects.

• At the start of treatment, give a dose below the lower end of the licensed range for adults if the drug is not licensed for children and young people and at the lower end of the licensed range if the drug is licensed for children and young people; slowly titrate upward within the dose range recommended by the Health Canada drug product database.

• Justify and record reasons for dosages above the dose range recommendations in the Health Canada drug product database.

• Record the rationale for continuing, changing, or stopping medication and the effects of such changes.

• Carry out a trial of the medication at the optimal dosage for 4 to 6 weeks.

•                    [Modified recommendation from NICE (Strong)]

Recommendation 7

Ensure that monitoring of physical health and the effects of antipsychotic medication in children and young people is occurring and that responsibility for this is clearly established between primary and specialty care.

                   [Modified recommendation from NICE (Strong)]

Given the lack of efficacy differences between antipsychotics (except clozapine), it is important to consider rational pharmacotherapy strategies when treating children and youth with psychosis. Patients with early-onset psychosis are a more vulnerable group than adults, often with a more severe expression of illness and neurodevelopmental deficits, leading to a potential increased risk for adverse events related to pharmacotherapy. Moreover, this population may have a potential positive response at lower doses of antipsychotic medicine than those used in adults.^43,44 Interventions must be timely but also judicious and cautious in terms of the selection of treatment options, dosing, and change strategies that have both optimizing efficacy and minimizing adverse effects as the targets.⁴⁵ Dosing should occur slowly and be targeted to efficacy rather than weight, and abrupt switches of medication should be avoided to minimize rebound phenomena.^45,46

Systematic monitoring of adverse effects (e.g., metabolic, neuromotor), using standardized scales if available starting from baseline, is crucial in order to increase the effectiveness of medication and decrease nonadherence.^7,46 It is important to maintain an honest and transparent approach with the youth and family at all intervals of the intervention in order to increase engagement in the process.

Treatment resistance is defined by a lack of satisfactory improvement for the patient despite adequate antipsychotic trials for 6 to 8 weeks.⁴⁷ Furthermore, it is also important to consider multiple causes of the inefficiency of medication before engaging in alternatives or a switch. Potential confounders might include nonadherence, medical illness, comorbidities including substance abuse, stressors, polypharmacy and drug interactions, adverse effects, poor optimization of current treatment, and need for psychosocial interventions.⁷

Recommendation 8

Discuss any nonprescribed therapies that children or young people, or their parents or carers, wish to use (including complementary therapies) with them. Discuss the safety and efficacy of the therapies and possible interference with the therapeutic effects of prescribed medication and psychological interventions.

                   [NICE (Strong)]

Maintaining a therapeutic alliance with the youth and family throughout the duration of treatment will positively affect the course and outcomes of illness.⁴⁸ The lack of alliance may be a predictor for poor engagement, which is directly related to medication nonadherence, rehospitalization rates, severity of symptoms, and dropout rates.⁴⁹ Youth with early-onset psychosis are particularly vulnerable to drop out in the first few years of illness.⁴⁸ It is imperative to utilize the opportunity for early treatment gains by maintaining a stance of transparency and honesty with the patient and family. Adopting an evidence-informed approach while also engaging in open discussions regarding the risk/benefit ratio of therapies important to the youth and family is of great value.

Recommendation 9

Discuss the use of cannabis, alcohol, tobacco, and prescription and nonprescription medications and drugs with the child or young person, and parents or carers, where this has been agreed on. Discuss their possible interference with the therapeutic effects of prescribed medication and psychological interventions and the potential of drugs to exacerbate psychotic symptoms.

                   [NICE (Strong)]

The comorbidity of schizophrenia and substance use disorder affects both early-onset high-risk cases as well as first-episode cases of schizophrenia. Amphetamines and other stimulants along with cannabis, alcohol, and nicotine are most commonly used by adolescents, which is also the group most at risk for the development of psychotic disorders.⁵⁰ Stimulants, often used by older adolescents as “study drugs,” that is, to maximize wakefulness, along with cannabis, may have harmful effects across the spectrum of psychotic disorders by triggering onset, worsening established psychotic symptoms, or precipitating relapse, which all contribute to the overall burden of psychosis.⁵¹ Furthermore, nicotine and alcohol use enhances morbidity risks already associated with the illness itself including an inherent 2- to 3-fold excess mortality, with the vast majority, regardless of the age of onset, related to cardiovascular illness and obesity-related cancer.⁴² According to international comparisons of alcohol and cannabis use by young people, Canada ranks among the leading countries for rates of prevalence.^52–54 It is thus especially important to discuss with young people, particularly those at a genetic risk for schizophrenia, the potential adverse effects of drug use on their health.

In the last decade, a vast amount of literature has supported the association between an increased risk for psychosis and exposure to cannabis, particularly in those individuals who are genetically vulnerable.^55,56 In terms of risk factors that carry a poor prognosis, cannabis use, other comorbidities (such as depression), and medication nonadherence are the 3 most strongly associated with poor outcomes including the risk of relapse.^57,58 Similar to other modifiable risk factors that may have a weak individual effect on outcomes, cannabis, if acting in concert at specific critical periods of neurodevelopment, may in fact impact the expression and neuroprogression of the genetic risk for schizophrenia.⁵⁸ Individuals who regularly use cannabis during adolescence double the risk of reporting psychotic symptoms or being diagnosed with schizophrenia during adulthood.⁵⁹ Longitudinal studies have identified a 40% greater risk of psychotic disorder in those who have ever used cannabis (controlling for other variables) in what may be a dose-dependent relationship between use and the risk of schizophrenia.⁶⁰ Further, some studies have reported that cannabis use at an earlier age may decrease the age of onset of the first episode of schizophrenia by 2.7 years.⁶¹ Cannabis use during treatment has also been associated with poor outcomes such as increased hospitalization rates, increased relapse rates, and worse medication adherence rates.⁶²

Recommendation 10

Do not initiate regular combined antipsychotic medication, except for short periods (e.g., when changing medication).

                   [NICE (Strong)]

Case reports supporting the unconventional use of antipsychotics in treatment-refractory schizophrenia in adults do exist; however, at this time, there is no clear evidence in youth with psychosis for a positive balance of increased efficacy versus the risk for adverse effects with combined antipsychotic use.⁷

Early Postacute Period

Recommendation 11

Review antipsychotic medication regularly as clinically indicated, including observed benefits and any side effects.

                   [Modified recommendation from NICE]

Recommendation 12

In the early period of recovery following an acute episode, reflect on the episode and its impact with the child or young person and his or her parents or carers, and make plans for recovery and possible future care using a realistically optimistic approach to recovery.

                   [NICE (Strong)]

Recommendation 13

Inform the child or young person and his or her parents or carers that there is a high risk of relapse if medication is stopped in the 1 to 2 years following an acute episode.

                   [NICE (Strong)]

Recommendation 14

If discontinuing/tapering antipsychotic medication, undertake it gradually, and monitor regularly for signs and symptoms of relapse.

                   [Modified recommendation from NICE (Strong)]

Recommendation 15

After discontinuing/tapering antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2 years.

                   [Modified recommendation from NICE (Strong)]

Despite the initial positive response to antipsychotic medication for most young people with a first episode of schizophrenia, a longer term prognosis is less impressive, with up to 80% experiencing a relapse within 5 years of the initial remitted episode.⁶³ Nonadherence to medication is one of the most profound predictors of relapse after a first episode of psychosis.⁶⁴ Strategies to prevent second and subsequent episodes are of great significance as the risk of persistent psychotic symptoms increases with repeated relapses.^65,66 Relapses may lead to a reduction in gray matter,⁶⁷ which can reduce responses to medication and negatively influence social, emotional, and vocational goal attainment, particularly in the younger population.⁶³

Overall, available evidence suggests that intensive psychosocial strategies, combined with low-dose antipsychotic medication, are effective in reducing relapse rates in youth and adults.⁶³ Maintaining a therapeutic alliance with close monitoring in the early years following the first episode is crucial in setting the parameters for long-term recovery.^68,69 Most specialized early psychosis programs have relapse prevention as a core component of treatment and have proven effective in reducing relapse rates.⁶³ Research investigating medication discontinuation strategies following remission is lacking in both adult and younger onset cases of schizophrenia. Generally, it does appear that the maintenance of medication is superior in preventing relapses; however, more trials are needed.⁶³ Nonetheless, in the younger population at an earlier stage of brain development, the long-term exposure to adverse effects of medication and associated impairments in social and occupational function must always be weighed against the risk of relapse and further illness episodes. The potential value of intensive psychosocial interventions matched with discontinuation strategies requires further investigation.

For youth with early psychosis, many, but not all, will require lifelong maintenance treatment with antipsychotic medication.⁶³ After a prolonged remission period, a small number may be able to discontinue antipsychotic medication with a re-emergence of psychotic symptoms. In such cases, given the high risk of relapse, longer term monitoring is recommended. Unfortunately, the exact length of treatment required after the first episode in early-onset psychosis in youth has not been adequately studied or clarified.

Subsequent Acute Episodes of Psychosis or Schizophrenia

Recommendation 16

For children and young people with an acute recurrence of psychosis or schizophrenia, offer antipsychotic medication in conjunction with psychological interventions (family intervention with individual cognitive behavioral therapy [CBT]).

                   [NICE (Strong)]

Recommendation 17

For children or young people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer antipsychotic medication or review the existing medication. The choice of drug should be influenced by the same criteria recommended for starting treatment. Take into account the clinical responses to and side effects associated with current and previous medication, and monitor as described in current recommendations.

                   [NICE (Strong)]

Up to 80% of patients with a first episode (adult) experience a relapse within 5 years of remission of the first episode.^63,64 Specialized programs have been found to be effective in preventing relapses, particularly those that include a combination of approaches such as outreach, cognitive behavioural therapy, medication, family support, and education.⁷⁰ More research is required that will allow us to individualize treatment in youth with psychosis, possibly through the identification of clinical biomarkers of response or the risk of adverse effects related to specific treatments.⁷

Hospital Care

Recommendation 18

If a child or young person needs hospital care, this should be in a setting appropriate to his or her age and developmental level.

                   [NICE (Strong)]

Management of Acute Aggression or Agitation

Recommendation 19

Health care professionals using urgent sedation and/or restraint in children and young people with schizophrenia should be trained and competent in undertaking these procedures in children and young people.

                   [NICE (Strong)]

Recommendation 20

Occasionally, children and young people with psychosis or schizophrenia pose an acute risk to themselves or others during an acute episode and may need urgent sedation. Be particularly cautious when considering high-potency antipsychotic medication (such as haloperidol) in children and young people, especially those who have not taken antipsychotic medication before, because of the increased risk of acute dystonic reactions in this age group.

                   [NICE (Strong)]

Recommendation 21

When clinically appropriate after urgent sedation, offer to the child or young person and caregivers the opportunity to discuss their experiences. Provide them with a clear explanation of the decision to use urgent sedation/restraint. Record this in their notes.

                   [NICE (Strong)]

Acute aggressive episodes and disruptive behaviour can occur in young people with psychosis as part of their presentation. Any form of aggression has the potential for severe and unexpected adverse outcomes for the patient and others. It is important to uncover the origin of the behaviour as it may have a bearing on the development of a treatment plan as well as the prevention of future aggression.

When dealing with aggressive or disruptive behaviour, it is recommended to start with nonpharmacological interventions; this can be successful in de-escalating the behaviour and minimizing the use of medications. If nonpharmacological techniques are insufficient to control the behaviour, the consideration of medication may be required. Oftentimes, an intramuscular option is preferred or required, particularly in the hopes of avoiding physical restraint, which can be very distressing for the young person and family.^71,72

Benzodiazepines (oral or intramuscular) are often used in emergency situations; they have a rapid onset of action and a good safety profile. It is important to be aware of the potential risk for a paradoxical response in young people.⁷³ The use of an antipsychotic may be preferred in cases where a diagnosis of schizophrenia is confirmed. Ideally, the use of an antipsychotic that has been of previous benefit to the youth is preferred.

When prescribing antipsychotics, the potential for adverse effects warrants attention. Extrapyramidal side effects including acute dystonia are notably associated with a younger age and the vulnerable developing brain, limiting the use of typical antipsychotics in the pediatric population.⁷⁴ There is insufficient evidence to support the prescription of antihistamines in cases of agitation.⁷⁵

Promoting Recovery and Providing Possible Future Care in Primary Care

Recommendation 22

Ensure that responsibility for monitoring the physical health of children and young people remains clearly established between primary care and specialty services. Monitoring the physical health of children and young people with schizophrenia should occur at least once a year or more often if clinically indicated. Primary care physicians/clinicians should bear in mind that people with schizophrenia are at a higher risk of cardiovascular disease than the general population.

                   [Modified recommendation from NICE (Strong)]

Second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs) are mostly used off label for Canadian children and youth. Aripiprazole has been approved for the treatment of youth under 18 years of age with schizophrenia.⁷⁶ The efficacy of SGAs does not come without their risks, as noted above. The risk of weight gain and associated metabolic abnormalities including dyslipidemia is greatest with olanzapine, followed by clozapine and quetiapine.^42,44,76 The risk of neurological side effects such as parkinsonism, akathisia, and other extrapyramidal effects is greatest with risperidone, olanzapine, and aripiprazole.^7,42,76 SGAs can cause other adverse effects of concern including sialorrhea, sedation, sexual dysfunction, and prolonged QTc.^42,76 Prescribers need to be well aware of these effects and the implications for individual patients and should consult with colleagues in primary care and pediatricians as required for effective management and treatment strategies in order to collaboratively avoid long-term and potentially iatrogenic health consequences. Evidence-based monitoring protocols are available for prescribers of SGAs (and FGAs) to assist in minimizing the risk for poor outcomes, and their use is strongly encouraged.⁷⁶ Good practice principles suggest adopting regular and consistent monitoring practices in collaboration with primary care when prescribing for youth with early-onset psychosis.

Recommendation 23

Offer clozapine to children and young people with schizophrenia whose illness has not responded adequately to pharmacological treatment, despite the sequential use of adequate doses of at least 2 different antipsychotic drugs each used for 6 to 8 weeks.

                   [NICE (Strong)]

Treatment resistance is defined by a lack of satisfactory improvement in symptoms, despite 2 adequate trials (6–8 weeks’ duration) of an antipsychotic.^47,70 As noted above, before considering a switch to clozapine or other augmentation strategies for which evidence might be lacking, it is important to investigate for other causes of inefficiency such as nonadherence, medical illness, comorbidities including substance abuse, stressors, polypharmacy and drug interactions, adverse effects, poor optimization of current treatment, and need for psychosocial interventions.^7,70

Clozapine has documented superior efficacy for adults and children/youth with treatment-resistant schizophrenia.^77–80 Furthermore, following the initial response, there are often increased clinical responses in the ensuing 6 to 8 months. Benefits of clozapine have been sustained in long-term maintenance studies, some for up to 2 to 9 years.⁷⁷ Importantly, many patients sometimes experience multiple adverse effects secondary to clozapine. However, tolerability related to potentially fatal hematological adverse events does not appear to be of much concern, evidenced by low discontinuation rates.^77,78 With rigourous and preventative monitoring strategies as required for a clozapine prescription in Canada, events such as neutropenia and agranulocytosis are transient/mild and rare, respectively. Metabolic abnormalities seem comparable to SGAs such as olanzapine and warrant similar judicious monitoring.⁸⁰ A switch to or initiation of clozapine for treatment-resistant patients certainly requires thoughtful consideration and transparency. Both the psychiatrist and patient/family must commit to the increased monitoring requirements and carefully balance the risk/benefit ratio of clozapine initiation.

Conclusions

The current guidelines were developed to assist clinicians in treating youth who present with symptoms in keeping with early-onset schizophrenia or other psychotic spectrum disorders. These guidelines do not present the sole standard of care and can be used in conjunction with good judgment in light of specific patient circumstances and available resources.

Research in the treatment of youth with schizophrenia or psychotic spectrum disorders is increasing. The importance of early detection, diagnosis, and indicated prevention in this population represents a significant paradigm shift in the perception of outcomes for youth with this illness. Previously held pessimistic attitudes toward a prognosis for youth with schizophrenia are no longer warranted. A comprehensive, thoughtful, and diligent approach to management, along with an honest and transparent stance with the patient and family regarding treatment, can enhance the patient’s potential to achieve positive results and optimal long-term outcomes.