WK 1 SOCW 6443 Discussion 2: Ethical Dilemas for Mental Health Professionals

https://doi.org/ https://doi.org/

Ther Adv Psychopharmacol

2018, Vol. 8(8) 231 –239

DOI: 10.1177/ 2045125318765725

© The Author(s), 2018. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Therapeutic Advances in Psychopharmacology

journals.sagepub.com/home/tpp 231

Antipsychotics: Advances, Limitations, and Alternatives

Special Collection

Introduction Psychosis is an umbrella term for a clinical pres- entation conceptualized, both by the American Psychiatric Association1 and the World Health Organization,2 as a combination of hallucina- tions, delusions, disorganized thinking or behav- iour, negative or catatonic symptoms, and functional impairment.3 In the current diagnostic classification systems, impaired reality testing remains its hallmark. Psychotic symptoms are the essential feature of schizophrenia spectrum disor- ders, but may also be present in mood disor- ders,4–6 autism spectrum disorders,7 personality disorders,8,9 substance misuse6,10 and in the nor- mal population.11,12 Psychosis may add to impair- ment and disability,13 affect cooperation with treatment14 and increase stigma associated with mental health difficulties.15 The evaluation of psychotic symptoms and identification and treat- ment of psychosis are, therefore, important tar- gets of the assessment and intervention of patients seen by the mental health services.

The current prevailing explanatory model for psy- chosis, mainly developed through studies of schizophrenia, points towards the condition being neurodevelopmental in origin, with the interac- tion between genetic and environmental factors marking the beginning of brain pathophysiologi- cal processes long before the overt manifestation of clinical symptoms. Several lines of evidence suggest that psychosis is more severe, is associ- ated with more neurodevelopmental deviance and possibly has poorer prognosis, the earlier it presents.16–19 Within this framework, early-onset psychosis (EOP) has received particular attention as it provides on the one hand a unique opportu- nity to explore the aberrant neurodevelopmental origins of the condition and on the other hand, potential opportunities to affect its long-term course. Despite research into the phenomenol- ogy, epidemiology, pathophysiology and treat- ment options in EOP, there are several challenges that clinicians face in the assessment and manage- ment of children and young people presenting

Dilemmas in the treatment of early-onset first-episode psychosis Daniel Hayes and Marinos Kyriakopoulos

Abstract: Early-onset first-episode psychosis (EOP) is a severe mental disorder that can pose a number of challenges to clinicians, young people and their families. Its assessment and differentiation from other neurodevelopmental and mental health conditions may at times be difficult, its treatment may not always lead to optimal outcomes and can be associated with significant side effects, and its long-term course and prognosis seem to be less favourable compared with the adult-onset disorder. In this paper, we discuss some dilemmas associated with the evaluation and management of EOP and propose approaches that can be used in the clinical decision-making process. A detailed and well-informed assessment of psychotic symptoms and comorbidities, a systematic approach to treatment with minimum possible medication doses and close monitoring of its effectiveness and adverse effects, and multidimensional interventions taking into consideration risks and expectations associated with EOP, are paramount in the achievement of the most favourable outcomes for affected children and young people.

Keywords: adolescents, antipsychotics, children, first episode, psychosis, schizophrenia, treatment

Received: 6 December 2017; revised manuscript accepted: 26 February 2018

Correspondence to: Daniel Hayes National and Specialist Bethlem Adolescent Unit, Bethlem Royal Hospital, Child and Adolescent Mental Health Clinical Academic Group, South London and the Maudsley NHS Foundation Trust, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK daniel.hayes@slam. nhs.uk

Marinos Kyriakopoulos National and Specialist Acorn Lodge Inpatient Children’s Unit, South London and the Maudsley NHS Foundation Trust, London, UK

Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Icahn School of Medicine at Mount Sinai, New York, USA

Review

Therapeutic Advances in Psychopharmacology 8(8)

232 journals.sagepub.com/home/tpp

with psychotic symptoms for the first time. In this paper, we will discuss some of the dilemmas related to the treatment of psychosis presenting for the first time in children and adolescents and ways to navigate through these (Table 1).

Dilemma number 1: what are we treating? The assessment of psychotic disorders can be complicated, and its challenges can be exacer- bated by the precocious onset of these conditions. Psychosis presenting in childhood and adoles- cence, whilst to a large extent characterized by the same combination of symptoms as with the adult- onset disorder, can manifest in ways that are more easily subject to alternative diagnostic formula- tions. Only a small percentage of psychosis cases are manifest before adulthood,20,21 and presenta- tions can be complicated by comorbidities22 which may both serve as vulnerability for the evo- lution of the disorder, but also alter its clinical picture. Furthermore, EOP is often characterized by a more protean presentation, which can be harder to differentiate from combinations of neu- rodevelopmental (e.g. autism spectrum disor- ders) with mental health conditions (e.g. anxiety or mood disorders).7,23 In addition, given the rel- ative infrequency of psychosis in adolescents and the extreme rarity in children, more comprehen- sive physical investigations need to be under- taken, depending on the age at onset and clinical presentation, in order to exclude neuropsychiatric complications of physical conditions.7 The nature of psychotic experiences in childhood and adoles- cence is also subject to differences of interpreta- tion, with evidence of childhood hallucinatory experiences frequently indexing emotional and conduct problems rather than a psychotic disor- der.24 The prevalence of unusual experiences in clinical populations of this age group has been identified as very high. In a recent study, direct evaluation through self report of psychotic-like symptoms experienced by children and adoles- cents attending community mental health clinics was found to reach 68%, with 60% of these being associated with distress or impairment.25 Finally, the multiple routes into psychosis, affected both by genetic liability26 and psychosocial adversity and abuse27 may not always provide a good pointer towards EOP as they are not unique to psychosis, also being associated with a wide range of brain changes and mental and behavioural dis- orders with commonly adolescent onset.28–30 The interaction between brain maturational processes, environmental insults and proneness to mental

illness are more likely to give mixed or hard-to- deconstruct clinical presentations in this age when EOP incidence gradually reaches its peak.

Unravelling this diagnostic dilemma is crucial because the provision of early, robust and effec- tive treatment relies on accurate diagnosis. When diagnostic clarity does occur, there is evidence of good diagnostic stability over time for early-onset schizophrenia,31,32 and bipolar disorder32 but not as good for psychosis associated with other condi- tions, for example, depressive disorder.32 It is therefore very important to avoid premature diag- nostic foreclosure in the face of uncertainty. The evolution of psychosis does go through stages; functional impairment in the prodrome can be interpreted as affective disorder, or even a mani- festation of normal adolescence, and a detailed developing assessment and staged approach to treatment interventions are warranted. Careful consideration of developmental history and envi- ronmental circumstances, characterization of psy- chotic symptoms, comprehensive evaluation for mood and anxiety disorders, exclusion of organic conditions and substance misuse, and conclusion about the degree of impairment associated with psychotic symptoms are likely to facilitate the diagnostic formulation. A balance between indis- criminate classification of psychotic symptoms as a psychotic disorder and reluctance to give the diagnosis needs to be maintained. In early-onset cases, the accurate characterization of the young person’s difficulties, and a narrower approach to psychosis as a disorder to include a more severe and impairing combination of psychotic symp- toms is likely to be the most appropriate, clini- cally, to identify evidence-based interventions.

Dilemma number 2: how do we treat? In children and young people, once the diagnosis of psychosis is made, second-generation antipsy- chotics (SGAs) are generally recommended.33 Although the choice of treatment is hampered by some limitations in evidence base, both first- and second-generation antipsychotics are of estab- lished and comparable efficacy in psychosis but differ in their side-effect profile.34,35 Use of SGAs is almost ubiquitous, but perhaps needs to be rebalanced in context of patient discussion about acceptability of side effects, both in the short and longer term, given the likelihood of necessity for continuing treatment. First-generation antipsy- chotics are generally to be avoided due to their side-effect profile, in particular, high incidence of

D Hayes and M Kyriakopoulos

journals.sagepub.com/home/tpp 233

movement disorders, including tardive dyskine- sia.36 The safety of antipsychotics in childhood and adolescence remains a key area of clinical uncertainty, and risk/benefit analysis, mostly favouring their use in severe mental illness, needs to be undertaken in all cases.35 The choice of antipsychotic is to a large extent determined by its side-effect profile. Of all the SGAs, olanzapine is associated with more weight gain and metabolic side effects, so when this choice is made, it needs to be discussed with young people and their fami- lies.33 Most clinicians would not prescribe olan- zapine routinely as first line in EOP. Additional treatments may also be prescribed to target comorbid conditions, for example, mood stabilis- ers in presentations with a bipolar affective com- ponent or selective serotonin reuptake inhibitors for comorbid anxiety and depression. There are a growing number of trials in this population reflecting the importance of generating a child- specific evidence base for prescribing antipsy- chotics. To that end, international initiatives to set standards and optimise the methodological and practical aspects of research in children, such as the Standards for Research in Children (STaR Child Health) and the Child and Adolescent Psychiatry Trials Network (CAPTN) group have been developed.37,38

The only antipsychotic which seems to be more efficacious compared with the rest of the SGAs is clozapine.39–41 Although its superiority in meta- analyses of adult samples has recently been a sub- ject of debate,42,43 it was also argued that trials including children and young people need to be considered separately.44 The evidence base on clozapine in this age group is very limited and clo- zapine trials are generally difficult to conduct due to the small number of cases that can potentially be included in them. Clozapine remains an underused drug across the lifespan40,45 that results in treatment-resistant cases going through repeated cycling through pharmacopoeia rather than having clozapine tried. This is likely due to barriers to acceptability, and whilst risk issues can be a concern for patients and families, profes- sional difficulties also compromise its use with many child and adolescent psychiatrists being wary of the drug due to unfamiliarity outside of inpatient units. This situation may also be per- petuated by lack of resources to initiate clozapine in the community in this population and services not being set up to manage the monitoring pro- cesses required. However, in cases not respond- ing to alternative SGAs, clinicians should become

more comfortable considering this option as the majority of EOP patients who are eventually pre- scribed clozapine appear to have a favourable clinical outcome.40

In this younger age group, the principle of cau- tious initiation and gradual increase of the dose of antipsychotic is clinically applied, but needs to be balanced against the risk of delayed or inadequate treatment.46 Whilst the principle of ‘start low, go slow’ is widely employed, young people are not uniquely responsive to the beneficial effects of medication, but rather sensitive to side effects that can impair tolerability and compliance.47 The decision about when an antipsychotic is con- sidered to not be effective has also been subject to investigation, with some evidence suggesting that this may be concluded as early as 2–3 weeks into treatment with an adequate dose of the drug.48,49 However, taking the current guidelines into account, it is important to consider that early dis- continuation may affect eventual classification of cases as treatment resistant,50 which is likely to have implications for clozapine use. In addition to the absence of clear treatment response, there can also be uncertainty in relation to suboptimal response, problems with tolerability or a combi- nation of the two. Although these challenges apply similarly to some extent to adults, ongoing lack of capacity or competence in children and young people make such discussions with the wider family more complicated. Alongside clini- cal judgement and close physical health monitor- ing, the use of rating scales to quantify the young person’s improvement and side effects are likely to assist with these decisions.7,51

Alternative forms of administration, for example, long-acting injectable (LAI) medication, have a role in the management of young people when there are concerns about nonadherence, but some- times clarity about the necessity for using such interventions only becomes apparent in retrospect. Nonadherence certainly is an issue with adoles- cents, not just with regard to psychotropic medica- tion,52 but also for other diseases requiring long-term pharmacological intervention e.g. diabe- tes53 or epilepsy.54 This may be embedded in developmental processes around autonomy and control,55 and difficulties accepting long-term con- sequences of current difficulties.56 Nevertheless, when LAIs are considered for EOP, due to serious adherence issues and significant risks associated with the young people’s clinical presentation, care- ful monitoring is warranted due to almost

Therapeutic Advances in Psychopharmacology 8(8)

234 journals.sagepub.com/home/tpp

complete lack of trial evidence in this age group. It is encouraging that, in adult studies, LAIs were similar to oral antipsychotics regarding the fre- quency of treatment discontinuation due to adverse events and serious adverse events. However, their use was associated with significantly more akinesia, low-density lipoprotein cholesterol changes and anxiety but also, interestingly, with significantly lower prolactin change.57

Treatment with antipsychotics in schizophrenia spectrum disorders is usually long term. No clear evidence exists about when it may be safe to reduce the dose or discontinue medication following the first episode of EOP and, from a practical perspec- tive, such approaches may only be discussed in the case of full remission for a very considerable amount of time. Under these circumstances, potential reduction of medication needs to be very gradual and be accompanied with very close moni- toring of its outcome. With the first signs of clinical deterioration, medication needs to be reinstated as

previously, to avoid another episode of psychosis. The development of side effects may also trigger discussions about medication discontinuation or switching to an alternative antipsychotic. Only one study to date58 has investigated antipsychotic with- drawal in adolescents with schizophrenia using a double-blind placebo-control randomized design. In this study, patients were cross titrated and stabi- lized from their antipsychotic treatment to ari- piprazole, and then randomized to aripiprazole or placebo in a 52-week double-blind maintenance phase. Compared with placebo, active treatment was associated with a significantly longer time to exacerbation of psychotic symptoms or impending relapse, lower rates of serious or severe adverse events, lower rate of discontinuation due to serious or severe adverse events, and similar or lower inci- dences of extrapyramidal symptoms, weight gain, and somnolence.

Although antipsychotic medication is the first-line treatment for EOP, psychological interventions

Table 1. Dilemmas in the treatment of early-onset first episode psychosis.

(1) What are we treating?

(a) Early-onset psychotic disorder is rare but psychotic symptoms are frequent.

(b) Frequent comorbidity and atypical presentation can complicate diagnosis.

(c) Developmental and environmental factors are very relevant.

(d) ‘Narrower’ approach to psychosis as a disorder is recommended.

(2) How do we treat?

(a) Second-generation antipsychotics are the treatment of choice.

(b) Side-effect profile guides treatment choice, given the similar effectiveness of different SGAs.

(c) Cautious initiation and gradual increase of the dose of antipsychotic should be applied.

(d) Clozapine should be considered in treatment-resistant cases.

(e) Long-term treatment is likely to be needed.

(f) Psychological interventions should be offered.

(3) What should we expect from treatment?

(a) Resolution of symptoms should be the aim of treatment but prognosis is poorer compared with adult-onset cases.

(b) Treatment of comorbidities is an important aspect of long-term management.

(c) Suicide prevention is paramount.

(d) Adverse effects of medication should be minimized.

SGAs, second-generation antipsychotics.

D Hayes and M Kyriakopoulos

journals.sagepub.com/home/tpp 235

also have a role to play in its management. Psychological therapies need to be adapted for children and adolescents with psychosis.33 These adaptations take into consideration cognitive, social, psychological and practical aspects specific to their age. From a practical perspective, com- pared with mood and anxiety disorders, young people with EOP seek psychological support less often and their engagement may not be as good. They need a flexible and creative approach; one that adapts to their understanding and the lan- guage they use about their experiences. The evi- dence base for psychological therapies specific to adolescent psychosis is very limited and there is practically no evidence for their use in children. Cognitive remediation therapy (CRT) seems to be beneficial for improving cognitive ability in EOP59– 61 and also psychosocial functioning59 with the lat- ter also being shown to improve by a combination of cognitive behavioural therapy (CBT) and fam- ily intervention in a small pilot study.62 Studies focusing on EOP that examined therapy effects on psychotic symptoms have reported negative results.59,61,62 More research on psychological interventions in this age group is needed.

Dilemma number 3: what should we expect from treatment? The majority of EOP patients will have further episodes of illness and long-term difficulties. Having at least one further episode requiring hos- pitalization was reported to reach 83% of adoles- cents with schizophrenia over a period of more than 10 years63 with the majority of the sample also having at least moderate educational and occupational impairment and serious social disa- bility. Two studies that followed up childhood- onset patients over a period of 42 years18,64 also reported poor outcomes, with half of them being found to have continuous symptoms, 25% to be in partial remission and less than a sixth showing a favourable outcome. More than 70% did not graduate from school and were unemployed at the time of follow up.18 Two age cut-off points delineating worse prognosis, as assessed by num- ber of days in first admission, percentage of patients with more than one admission, average number of days in hospital and number of admis- sions per illness year, seem to be around 17 and 12 years, with patients having earlier onset being more affected.17

As in all other clinical conditions, the aim of treat- ment in EOP should always be for symptom

resolution, with a return to premorbid levels of functioning. However, this can be difficult to achieve in the context of increased severity and poorer prognosis associated with earlier onset,65 so there is an imperative to ensure all remediable issues are dealt with, in terms of prompt effective treatment in multiple modalities.33 Within EOP, poorer premorbid functioning in childhood, the severity of negative symptoms at baseline and the duration of untreated psychosis are all associated with a worse outcome.66 Inferior treatment response to antipsychotic medication has also been associated with comorbid autism spectrum disorders.67 Even in the event of a good response to treatment, EOP has a significant impact on young people. The recovery model68 has had a significant influence on mental health policy and provision, and whilst its tenets are applicable to young people with EOP, it is important to acknowledge that despite symptomatic recovery, young people are on a chronologically determined trajectory through educational attainments and social transitions that they cannot step out of, in the context of an episode of illness, and return to at the same point, rather than behind similarly aged peers.

A particular concern in relation to long-term management in EOP is suicide. Suicide rates for people with schizophrenia are elevated compared with the general population, with an estimated lifetime risk of approximately 5%.69 The strongest associations with later suicide include being young and male, and experiencing a greater bur- den of illness. In early-onset cases, suicide rates may be much higher; a study following up 61 patients over a period of at least 11 years70 identi- fied 9 patients dying of suicide (14.7%) with this being particularly elevated in males (6/28; 21.4%). Considering the possibility of this devas- tating outcome is directly relevant to risk manage- ment in EOP, further emphasizing the necessity for effective treatment for psychosis, including the use of clozapine71 as a specific suicide-reduc- tion strategy.

Taking into account the increased susceptibility of young people to adverse side effects of medica- tion, a not uncommon clinical dilemma emerges when a good clinical response is associated with a side-effect profile that has significant biological or psychosocial implications, such as excessive weight gain, sexual dysfunction or sedation. From the clinician’s point of view, altering established and effective medication regimes can generate

Therapeutic Advances in Psychopharmacology 8(8)

236 journals.sagepub.com/home/tpp

understandable anxiety with regard to risk of relapse. However, given the likelihood for the necessity for long-term treatment, efforts should be made to establish the minimum effective dose, or to switch young people to medication with less propensity to cause side effects of particular sali- ence to them. This not only affects the young per- son’s quality of life, physical health and long-term morbidity and mortality, but increases the chances of treatment compliance, which is a significant concern in adolescent-onset psychotic disorders, as mentioned above.

Significant dilemmas associated with long-term expectations from treatment also emerge in rela- tion to the management of comorbid conditions. Comorbidities may include neurodevelopmental disorders, like autism spectrum disorders, which affect the clinical presentation of young people with psychosis in remission and will require active management of associated impairment on its own right.7 Psychosis in young people is also highly comorbid with depressive and anxiety disorders69 which can be harder to identify as they may be considered to be part of the psychosis phenome- nology or represent medication side effects and are therefore left untreated. Low expectations of full recovery may affect clinicians’ motivation to diagnose additional conditions and therefore miss the opportunity to implement evidence-based interventions which are likely to significantly improve the clinical progress of the young person. Finally, substance misuse, frequently preceding or coexisting with psychosis,72,73 can influence not only the aetiological conceptualization of young people’s symptomatology, but also lower the expectations of recovery and lead to subopti- mal treatments of both conditions.

Conclusion First-episode EOP is a severe mental health condition which requires timely specialist inter- vention. Although our understanding of the sig- nificance of psychotic symptoms in clinical and nonclinical populations and our conceptualiza- tion of EOP and its overlap with other conditions have significantly evolved in the last few decades, its treatment remains to a large extent subopti- mal. Its clinical presentation and management can be associated with significant difficulties, giv- ing rise to dilemmas both for the treating clinician and the young person and their family. Better characterization of its phenomenology, identifica- tion and application of the most favourable

treatment strategies, and realistic but also well informed expectations are likely to result in the achievement of the best possible clinical out- comes, and assist in the young person reaching their full potential. Further research targeting improved medication effectiveness, optimal use of current treatment options, evaluation of treat- ment failure, side-effect reduction and the devel- opment of psychosocial interventions in children and young people with EOP is urgently needed.

Funding This research received no specific grant from any funding agency in the public, commercial, or not- for-profit sectors.

Conflict of interest statement The authors declare that there is no conflict of interest.

References 1. American Psychiatric Association DSM-5 Task

Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Association, 2013.

2. World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization, 1992.

3. Biedermann F and Fleischhacker WW. Psychotic disorders in DSM-5 and ICD-11. CNS Spectr 2016; 21: 349–354.

4. Jääskeläinen E, Juola T, Korpela H, et al. Epidemiology of psychotic depression - systematic review and meta-analysis. Psychol Med. Epub ahead of print 12 September 2017. DOI: 10.1017/S0033291717002501.

5. Smith LM, Johns LC and Mitchell R. Characterizing the experience of auditory verbal hallucinations and accompanying delusions in individuals with a diagnosis of bipolar disorder: a systematic review. Bipolar Disord 2017; 19: 417–433.

6. Van Nierop M, Van Os J, Gunther N, et al. Phenotypically continuous with clinical psychosis, discontinuous in need for care: evidence for an extended psychosis phenotype. Schizophr Bull 2012; 38: 231–238.

7. Pina-Camacho L, Parellada M and Kyriakopoulos M. Autism spectrum disorders and schizophrenia: boundaries and uncertainties. BJPsych Advances 2016; 22: 316–324.

D Hayes and M Kyriakopoulos

journals.sagepub.com/home/tpp 237

8. Balaratnasingam S and Janca A. Normal personality, personality disorder and psychosis: current views and future perspectives. Curr Opin Psychiatry 2015; 28: 30–34.

9. Bebbington P and Freeman D. Transdiagnostic extension of delusions: schizophrenia and beyond. Schizophr Bull 2017; 43: 273–282.

10. Rössler W, Hengartner MP, Angst J, et al. Linking substance use with symptoms of subclinical psychosis in a community cohort over 30 years. Addiction 2012; 107: 1174–1184.

11. Rössler W, Ajdacic-Gross V, Müller M, et al. Assessing sub-clinical psychosis phenotypes in the general population–a multidimensional approach. Schizophr Res 2015; 161: 194–201.

12. Van Os J, Linscott RJ, Myin-Germeys I, et al. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med 2009; 39: 179–195.

13. Jonas KG and Markon KE. A model of psychosis and its relationship with impairment. Soc Psychiatry Psychiatr Epidemiol 2013; 48: 1367– 1375.

14. Stewart SL and Baiden P. An exploratory study of the factors associated with medication nonadherence among youth in adult mental health facilities in Ontario, Canada. Psychiatry Res 2013; 207: 212–217.

15. Kaushik A, Kostaki E and Kyriakopoulos M. The stigma of mental illness in children and adolescents: a systematic review. Psychiatry Res 2016; 243: 469–494.

16. Kyriakopoulos M and Frangou S. Pathophysiology of early onset schizophrenia. Int Rev Psychiatry 2007; 19: 315–324.

17. Rabinowitz J, Levine SZ and Häfner H. A population based elaboration of the role of age of onset on the course of schizophrenia. Schizophr Res 2006; 88: 96–101.

18. Remschmidt H, Martin M, Fleischhaker C, et al. Forty-two-years later: the outcome of childhood- onset schizophrenia. J Neural Transm (Vienna) 2007; 114: 505–512.

19. Schmidt M, Blanz B, Dippe A, et al. Course of patients diagnosed as having schizophrenia during first episode occurring under age 18 years. Eur Arch Psychiatry Clin Neurosci 1995; 245: 93–100.

20. Amminger GP, Henry LP, Harrigan SM, et al. Outcome in early-onset schizophrenia revisited: findings from the Early Psychosis Prevention and

Intervention Centre long-term follow-up study. Schizophr Res 2011; 131: 112–119.

21. Cannon M, Jones P, Huttunen MO, et al. School performance in Finnish children and later development of schizophrenia: a population- based longitudinal study. Arch Gen Psychiatry 1999; 56: 457–463.

22. Stentebjerg-Olesen M, Pagsberg AK, Fink-Jensen A, et al. Clinical characteristics and predictors of outcome of schizophrenia-spectrum psychosis in children and adolescents: a systematic review. J Child Adolesc Psychopharmacol 2016; 26: 410–427.

23. Kyriakopoulos M, Stringaris A, Manolesou S, et al. Determination of psychosis-related clinical profiles in children with autism spectrum disorders using latent class analysis. Eur Child Adolesc Psychiatry 2015; 24: 301–307.

24. Garralda ME. Research into hallucinations and psychotic-like symptoms in children: implications for child psychiatric practice. Br J Psychiatry 2016; 208: 4–6.

25. Gin K, Banerjea P, Abbott C, et al. Childhood unusual experiences in community Child and Adolescent Mental Health Services in South East London: prevalence and impact. Schizophr Res. Epub ahead of print 2 September 2017. DOI: 10.1016/j.schres.2017.08.046.

26. Serretti A and Fabbri C. Shared genetics among major psychiatric disorders. Lancet 2013; 38: 1339–1341.

27. Ajnakina O, Trotta A, Oakley-Hannibal E, et al. Impact of childhood adversities on specific symptom dimensions in first-episode psychosis. Psychol Med 2016; 46: 317–326.

28. Jaffee SR. Child maltreatment and risk for psychopathology in childhood and adulthood. Annu Rev Clin Psychol 2017; 13: 525–551.

29. Teicher MH and Samson JA. Annual research review: enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry 2016; 57: 241–266.

30. Van der Kolk B. Commentary: the devastating effects of ignoring child maltreatment in psychiatry–a commentary on Teicher and Samson 2016. J Child Psychol Psychiatry 2016; 57: 267–270.

31. Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: diagnostic stability and predictive validity. Am J Psychiatry 2000; 157: 1652–1659.

32. Castro-Fornieles J, Baeza I, De la Serna E, et al.Two-year diagnostic stability in early-onset

Therapeutic Advances in Psychopharmacology 8(8)

238 journals.sagepub.com/home/tpp

first-episode psychosis. J Child Psychol Psychiatry 2011; 52: 1089–1098.

33. National Institute of Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management, https:// www.nice.org.uk/guidance/cg155/resources/ psychosis-and-schizophrenia-in-children-and- young-people-recognition-and-management- pdf-35109632980933. (2013, accessed 29 November 2017).

34. Pagsberg AK, Tarp S, Glintborg D, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: a systematic review and network meta- analysis. J Am Acad Child Adolesc Psychiatry 2017; 56: 191–202.

35. Schneider C, Taylor D, Zalsman G, et al. Antipsychotics use in children and adolescents: an on-going challenge in clinical practice. J Psychopharmacol 2014; 28: 615–623.

36. Factor SA, Lang AE and Weiner WJ (eds) The pharmacology of typical and atypical antipsychotics. Chapter 4. In: Remington G and Kapur S (eds) Drug Induced Movement Disorders, 2nd ed. Wiley-Blackwell 2005, pp. 55–71.

37. Klassen TP, Hartling L, Hamm M, et al. StaR Child Health: an initiative for RCTs in children. Lancet 2009; 374: 1310–1312.

38. March JS, Silva SG, Compton S, et al. The Child and Adolescent Psychiatry Trials Network (CAPTN). J Am Acad Child Adolesc Psychiatry 2004; 43: 515–518.

39. Schneider C, Corrigall R, Hayes D, et al. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia. Eur Psychiatry 2014; 29: 1–10.

40. Schneider C, Papachristou E, Wimberley T, et al. Clozapine use in childhood and adolescent schizophrenia: a nationwide population-based study. Eur Neuropsychopharmacol 2015; 25: 857–863.

41. Thomas KL, Jiang Y and McCombs JS. Clozapine revisited: impact of clozapine vs olanzapine on health care use by schizophrenia patients on Medicaid. Ann Clin Psychiatry 2015; 27: 90–99.

42. Samara MT, Dold M, Gianatsi M, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry 2016; 73: 199–210.

43. Siskind D, McCartney L, Goldschlager R, , et al.Clozapine v. first- and second-generation

antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2016; 209: 385–392.

44. Samara M and Leucht S. Clozapine in treatment- resistant schizophrenia. Br J Psychiatry 2017; 210: 299.

45. Bachmann CJ, Aagaard L, Bernardo M, et al. International trends in clozapine use: a study in 17 countries. Acta Psychiatr Scand 2017; 136: 37–51.

46. Schimmelmann BG, Schmidt SJ, Carbon M, et al. Treatment of adolescents with early-onset schizophrenia spectrum disorders: in search of a rational, evidence-informed approach. Curr Opin Psychiatry 2013; 26: 219–230.

47. Correll C. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry 2008; 47: 9–20

48. Samara MT, Leucht C, Leeflang MM, et al. Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry 2015; 172: 617–629.

49. Stentebjerg-Olesen M, Ganocy SJ, Findling RL, et al. Early response or nonresponse at week 2 and week 3 predict ultimate response or nonresponse in adolescents with schizophrenia treated with olanzapine: results from a 6-week randomized, placebo-controlled trial. Eur Child Adolesc Psychiatry 2015; 24: 1485–1496.

50. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on diagnosis and terminology. Am J Psychiatry 2017; 174: 216–229.

51. Kyriakopoulos M, Garcia R, Menounou A, et al. RCPsych CAP Faculty report: what specialist child and adolescent psychiatrists need to know and do about the physical health of children and adolescents, http://www.rcpsych.ac.uk/pdf/ FRCAP02.pdf (2015, accessed 1 November 2017).

52. Häge A, Weymann L, Bliznak L, et al. Non- adherence to psychotropic medication among adolescents - a systematic review of the literature. Z Kinder Jugendpsychiatr Psychother. Epub ahead of print 1 December 2016. DOI: 10.1024/1422– 4917/a000505.

53. Gonzalez JS, Tanenbaum ML and Commissariat PV. Psychosocial factors in medication adherence and diabetes self-management: implications

D Hayes and M Kyriakopoulos

journals.sagepub.com/home/tpp 239

for research and practice. Am Psychol 2016; 71: 539–551.

54. Nabbout R, Camfield CS, Andrade DM, et al. Treatment issues for children with epilepsy transitioning to adult care. Epilepsy Behav 2017; 69: 153–160.

55. Eccles JS, Midgley C, Wigfield A, et al. Development during adolescence: the impact of stage-environment fit on young adolescents’ experiences in schools and in families. Am. Psychol 1993; 48: 90–101.

56. Michaud PA, Suris JC and Viner R. The adolescent with a chronic condition. Part II: healthcare provision. Arch Dis Child 2004; 89: 943–949.

57. Misawa F, Kishimoto T, Hagi K, et al. Safety and tolerability of long-acting injectable versus oral antipsychotics: a meta-analysis of randomized controlled studies comparing the same antipsychotics. Schizophr Res 2016; 176: 220–230.

58. Correll CU, Kohegyi E, Zhao C, et al. Oral aripiprazole as maintenance treatment in adolescent schizophrenia: results from a 52-week, randomized, placebo-controlled withdrawal study. J Am Acad Child Adolesc Psychiatry 2017; 56: 784–792.

59. Puig O, Penadés R, Baeza I, et al. Cognitive remediation therapy in adolescents with early- onset schizophrenia: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry 2014; 53: 859–868.

60. Ueland T and Rund BR. A controlled randomized treatment study: the effects of a cognitive remediation program on adolescents with early onset psychosis. Acta Psychiatr Scand 2004; 109: 70–74.

61. Ueland T and Rund BR. Cognitive remediation for adolescents with early onset psychosis: a 1-year follow-up study. Acta Psychiatr Scand 2005; 111: 193–201.

62. Browning S, Corrigall R, Garety P, et al. Psychological interventions for adolescent psychosis: a pilot controlled trial in routine care. Eur Psychiatry 2013; 28: 423–426.

63. Lay B, Blanz B, Hartmann M, et al. The psychosocial outcome of adolescent-onset

schizophrenia: a 12-year followup. Schizophr Bull 2000; 26: 801–816.

64. Eggers C and Bunk D. The long-term course of childhood-onset schizophrenia: a 42-year followup. Schizophr Bull 1997; 23: 105–117.

65. Clemmensen L, Vernal DL and Steinhausen HC. A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry 2012; 12: 150.

66. Díaz-Caneja CM, Pina-Camacho L, Rodríguez- Quiroga A, et al. Predictors of outcome in early-onset psychosis: a systematic review. NPJ Schizophr 2015; 1: 14005.

67. Downs JM, Lechler S, Dean H, et al. The association between comorbid autism spectrum disorders and antipsychotic treatment failure in early-onset psychosis: a historical cohort study using electronic health records. J Clin Psychiatry 2017; 78: e1233–e1241.

68. Leamy M, Bird V, Le Boutillier C, et al. Conceptual framework for personal recovery in mental health: systematic review and narrative synthesis. Br J Psychiatry 2011; 199: 445–452.

69. Hor K and Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010; 24: 81–90.

70. Krausz M, Müller-Thomsen T and Haasen C. Suicide among schizophrenic adolescents in the long-term course of illness. Psychopathology 1995; 28: 95–103.

71. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 82–91.

72. Conrad AM, Lewin TJ, Sly KA, et al. Utility of risk-status for predicting psychosis and related outcomes: evaluation of a 10-year cohort of presenters to a specialized early psychosis community mental health service. Psychiatry Res 2017; 247: 336–344.

73. Hodgins S, Larm P and Westerman J. Individuals developing schizophrenia are hidden among adolescent substance misusers. Psychol Med 2016; 46: 3041–3050.

Visit SAGE journals online journals.sagepub.com/ home/tpp

SAGE journals