Kathryn R. Cullen, MD

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide an understanding of the treatment modalities for the management of nonsuicidal self-injury (NSSI) in adolescents.

At the end of this CE activity, participants should be able to:

• Describe the evidence-based behavioral interventions that are used in the management of NSSI;

• Appreciate the current status of knowledge on somatic treatments for NSSI behavior; and

• Discuss the recommendations for future research on treatment development.

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Kathryn R. Cullen, MD, reports that she has received research support in the form of Grant R61AT009995 Identifying Biological Signatures of N-acetylcysteine for Nonsuicidal Self-Injury in Adolescents from the National Center for Complementary and Integratvie Health.

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Non-suicidal self-injury (NSSI), or the deliberate act of self-inflicted damage to one’s body without suicidal intent, is a maladaptive and potentially habitual behavior that often serves to relieve strong negative feelings. NSSI typically emerges in adolescence. The average prevalence of NSSI behavior in adolescents is 18%, while 7% of adolescents potentially qualify for the diagnosis of NSSI disorder as proposed in the DSM-5.

 NSSI is associated with multiple psychiatric disorders including depression, anxiety, substance use, eating disorders, personality disorders, and developmental disorders; it can also occur in the absence of any psychiatric disorder.

“Mary” is a 15-year-old high school student with no previous psychiatric history who was brought to the emergency department (ED) by her parents because of self-inflicted lacerations on her arms. During the assessment, Mary revealed to the physician that she had been cutting herself one to two times a week for several months.

In the past year, Mary had experienced episodes of intense sadness and anxiety. She had learned about self-cutting through social media outlets; she also said her peers were using this strategy to manage stress. Mary reported that cutting served to numb her feelings and described it as “the only thing that helps.” Mary reported that about 8 months ago, she had thoughts of wanting to die and took 5 pills from the medicine cabinet; the next morning she woke up feeling fine and told no one about this incident until now. She denied any current suicide attempts, but reported occasionally wishing that she had not been born.

While suicidal behavior and NSSI are separate phenomena, they commonly co-occur. In fact, NSSI is a strong predictor for suicide attempts. Therefore, effective treatment of NSSI represents an avenue for preventing suicide, the second leading cause of death among adolescents. Previous empirical treatment reviews that have summarized ­behavioral and pharmacological interventions for NSSI have largely focused on adults. Since adolescence is a notable period both for onset of NSSI and for brain development, it represents a critical time for adequate treatment of NSSI. Here, we review the available evidence for treatments of NSSI, focusing on studies that include children, adolescents, and young adults (

Although CBT has not been directly tested as a treatment for adolescent NSSI, two large randomized controlled trials (RCTs) that evaluated CBT as an adjunct treatment to SSRIs for treating depression in adolescents examined change in NSSI as a secondary outcome.

 Neither found that the addition of CBT reduced NSSI frequency in these adolescents.

Dialectical behavioral therapy (DBT) is a CBT-based intervention that was originally designed for adults with chronic suicidal behavior.

 DBT includes individual and group components and teaches skills including distress tolerance, emotion regulation, mindfulness, and interpersonal effectiveness. A robust literature supports the use of DBT in adults with self-harm behaviors (both suicide attempts and NSSI). Study results show that DBT is helpful in reducing NSSI in adolescents and college students.

 Furthermore, randomized controlled trials comprising adolescents and college students have confirmed efficacy of DBT in reducing NSSI and suicide attempts in youth.

Mentalization-based treatment (MBT) promotes the understanding of mental states underlying behavior for self and others. A recent RCT reported that MBT was more effective in reducing NSSI in adolescents with NSSI compared with treatment as usual.

Findings from preliminary research suggest that therapy involving the expressive arts, such as voice movement therapy, may have some promise for reducing NSSI in youth, but these approaches remain understudied.

In summary, the efficacy of several behavioral intervention for addressing NSSI in youth have been explored and tested to date. At present, DBT has the strongest evidence base as a well-established, empirically supported treatment for reducing both NSSI and suicide attempts in adolescents.

Somatic treatments: pharmacological and neuromodulation approaches

There are currently no somatic treatments that have approval from the Food and Drug Administration for the specific treatment of NSSI. Therefore, in the following paragraphs, all discussion of potential effects on NSSI behavior by somatic treatments refers to off-label use of these agents.

Antidepressants are commonly used in the treatment of adolescents with NSSI because this behavior often occurs in the context of depression and anxiety symptoms. However, no studies have formally tested if antidepressants reduce NSSI frequency in adolescents. Moreover, combination treatment using SSRIs and CBT has not been shown to help with NSSI.

 One case report noted improvement in NSSI behavior with fluoxetine treatment in an adolescent with intellectual disability in whom a trial of naltrexone had previously failed.

 Despite their common use in neurotypical adolescents with NSSI, there is currently limited evidence to support antidepressant medication efficacy for reducing NSSI specifically.

Opioid antagonists have been investigated as an intervention for NSSI, with the idea of blocking endogenous opioids generated by and reinforcing the behavior. To date, research has focused primarily on adult patients with developmental disorders. However, there are some reports of opioid antagonist use in adolescents with neurodevelopmental disorders. One case series reported that treatment with naltrexone was associated with reduced NSSI behaviors in 3 of 6 male adolescents with profound intellectual disability.

 Two single-subject, placebo-controlled, crossover-design studies added to the evidence that opiate blockade may be useful for decreasing NSSI in youth with developmental disabilities.

 However, there have been no studies in the past two decades on opioid antagonists in adolescents or neurotypical adolescents with NSSI.

Lithium is a mainstay for treating bipolar disorder and is known for its anti-suicide effect in patients with mood disorders. A meta-analysis of 48 RCTs (including adults and children) suggested that lithium is more effective than placebo in reducing the number of suicides, overall mortality, and self-harm in patients with unipolar depression.

However, to date no studies have investigated the role of lithium in treating NSSI in adolescents.

In addition to their use for treating psychotic disorders, atypical antipsychotics have been prescribed off-label with increasing frequency to children and adolescents to address non-psychotic problems. Some studies indicate utility of these medications in reducing NSSI in youth. A placebo-controlled RCT that examined adolescents and adults (mean age=22 years) with borderline personality disorder found that aripiprazole treatment was associated with fewer NSSI episodes than placebo.

 A retrospective chart review found that ziprasidone treatment was associated with lower NSSI frequency in 16 female adolescents.

 In two case studies (consisting of 3 non-psychotic adolescents), clozapine treatment was associated with a reduction in NSSI behaviors.

 However, the adverse effects of atypical antipsychotics limit their broad use for treating NSSI in adolescents.

Given the wide-spread problem of NSSI in adolescents, interventions that are safe and broadly accessible are needed. Off-label use of N-acetylcysteine (NAC), an inexpensive and widely-available nutritional supplement, has shown treatment potential in multiple psychiatric disorders.

 NAC is a precursor in the formation of glutathione (GSH), the primary antioxidant in the brain, which suggests its potential to confer neuroprotection. NAC also modulates glutamate and dopamine receptors that play a role in motivation and reward, therefore it has relevance in the treatment of habitual behaviors.

An 8-week open-label study showed that an oral NAC was associated with reduced frequency of NSSI, decreased depressive symptoms, and global psychopathology.

 However, there are no results from placebo-controlled RCTs for NAC in adolescents with NSSI.

Neuromodulation approaches such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) may have a role in the treatment of self-harm behaviors. ECT is known to have an important anti-suicide effect, and case reports have suggested its ability to reduce aggression and self-mutilation in adolescents with autism spectrum disorders and intellectual disability.

 There is no research on non-invasive neuromodulation such as TMS for the treatment of NSSI; this may represent an important avenue for future research.

Auricular acupuncture involves stimulation of acupuncture points on the external surface of the ears. Nine adolescents on an inpatient unit with depression and NSSI were administered auricular acupuncture bilaterally at five ear sites for five days per week for three weeks.

 The treatment was well tolerated, and a reduction in NSSI and internalization of anger was seen.

In the ED, Mary’s injuries were treated with topical ointment. The emergency physician disclosed the past suicide attempt to Mary’s parents and engaged the family in a detailed safety plan (eg, removal of access to sharps in the home, locking up home medications). Mary was discharged to home with referrals to an adolescent DBT program and to a child psychiatrist for further assessment of depression and anxiety.

NSSI is a highly prevalent problem in youth and represents an important risk factor for later suicide attempts. Early and effective treatment is therefore critical for suicide prevention. Because of ongoing neurodevelopment during adolescence, this represents an especially important time for effective intervention, as these developmental processes likely:

• Play a role in disease vulnerability;

• Contribute to how adolescents respond to different interventions; and

• Enhance brain plasticity, potentially allowing maximal impact from interventions.

While some evidence is available to support interventions for adolescents with NSSI, the field stands in need of significant advancement in multiple areas.

The next steps in treatment development for adolescents with NSSI (both behavioral and pharmacological approaches) should incorporate:

• Larger samples and rigorous, unbiased study designs with improvement of NSSI symptoms as the primary outcome;

• An experimental medicine approach to identify not only whether a treatment works but also how it works, providing the basis for optimization based on biological effects; and

• A personalized medicine approach, to discover for whom each treatment is most suitable based on patient factors such as demographic, clinical and biological characteristics, patient preferences. and available community resources.

Meanwhile, as the field awaits new research to provide improved, evidence-based intervention options, how to we treat adolescents in our offices who present with NSSI?

Information should be drawn from the patient, the family, and the available literature to select the best treatment path. While currently DBT has the strongest evidence as an intervention for NSSI in adolescents, research on other psychotherapies (both individual and family) and somatic (eg, medication, nutritional supplements, neuromodulation) interventions are emerging. Comorbid psychiatric conditions must be assessed and treated, and psychosocial issues, including family dynamics, must be addressed. Healthy connections within supportive networks (eg, family, friends, teachers, coaches, etc.) can play a key role in restoring and maintaining the health and safety of children and adolescents. The final ingredients that a clinician can offer when caring for youth with NSSI include instilling hope, modeling resilience to setbacks, and maintaining the goal of full remission and restoration of healthy brain and behavioral development.

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Dr Elmaghraby, is a Child and Adolescent Psychiatry Fellow, Mayo Clinic, Rochester, MN. Dr Nobari is a Child and Adolescent Psychiatry Fellow, University of California, Davis, CA. Dr Cullen is Associate Professor and Division Director of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, MD.

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 Zetterqvist M, Lundh L-G, DahlstrÃ¶m O, Svedin CG. Prevalence and function of non-suicidal self-injury (NSSI) in a community sample of adolescents, using suggested DSM-5 criteria for a potential NSSI disorder. 

 Brent DA, Emslie GJ, Clarke GN, et al. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study. 

 Goodyer I, Dubicka B, Wilkinson P, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. 

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 Goldstein TR, Axelson DA, Birmaher B, Brent D A. Dialectical behavior therapy for adolescents with bipolar disorder: a 1-year open trial. J Am Acad Child Adolesc Psychiatry. 2007;46:820-830.

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 Mehlum L, et al. Dialectical behavior therapy compared with enhanced usual care for adolescents with repeated suicidal and self-harming behavior: outcomes over a one-year follow-up. J Am Acad Child Adolesc Psychiatry. 2016;55:295-300.

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 Rossouw TI, Fonagy P. Mentalization-based treatment for self-harm in adolescents: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012;51:1304-1313.

 Martin S, et al. Voice movement therapy: evaluation of a group-based expressive arts therapy for nonsuicidal self-injury in young adults. 

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Articles

This CME article provides an understanding of the treatment modalities for the management of nonsuicidal self-injury (NSSI) in adolescents.

Treatment of Non-Suicidal Self-Injurious Behavior in Adolescents

The number of prescriptions for antipsychotic treatment of teenagers has increased sharply in office-based medical practice.

 Adolescents with psychotic symptoms frequently present for clinical evaluation, and early-onset schizophrenia spectrum disorders (onset of psychotic symptoms before the age of 18 years) represent an important consideration in the differential diagnosis in these youths. The onset of schizophrenia occurs by the age of 19 in nearly 40% of male patients and 23% of female patients.

 Although childhood-onset schizophrenia (onset of psychotic symptoms before age 13) is rare,

 the incidence of schizophrenia rises sharply and steadily after the onset of puberty.

 Since a longer duration of untreated psychosis may be a predictor of poor outcomes in first-episode psychosis, early and appropriate treatment is crucial.

The goals of antipsychotic treatment for psychotic episodes are amelioration of acute symptoms; main- tenance of treatment effect; and functional recovery in terms of academics, peer relations, and family life. Although antipsychotic medications remain the cornerstone of treatment for early-onset schizophrenia spectrum disorders, most teenagers require multiple treatment strategies to facilitate rehabilitation, including individual supportive therapy, family psychoeducation, and special classroom placement. These interventions help prevent relapse, enhance treatment adherence, and address deficits in social skills. In addition, once acute psychotic symptoms have resolved, comorbid conditions (eg, substance use) must be addressed, as well as other psychosocial factors that contribute to psychiatric morbidity.

The atypical antipsychotics, which differ from typical antipsychotics because of a decrease in associated extrapyramidal symptoms (EPS), have now become the standard treatment for youth with early-onset schizophrenia spectrum disorders.

 For years now, these medications have been given to younger people without specific FDA approval for pediatric populations, and clinicians have provided off-label prescriptions drawing from clinical experience using these medications successfully in adults. However, 3 recently completed double-blind, randomized controlled clin- ical trials reporting the use of risperidone, olanzapine, and aripiprazole for early-onset schizophrenia spectrum disorders in teenagers have demonstrated effectiveness relative to placebo.

 As a result of these studies, risperidone and aripiprazole now have a formal indication for the treatment of psychotic symptoms in adolescents with schizophrenia. Several important adverse effects are common with the use of atypical antipsychotics including sedation, metabolic abnormalities, elevated prolactin levels, and movement disorders.

This article reviews the available efficacy and safety data for each atypical antipsychotic. A discussion of the considerations involved in choosing an atypical antipsychotic for this population follows (

The first atypical antipsychotic to be approved by the FDA, clozapine is known for its exceptional efficacy and for its considerable associated adverse effects. Although clozapine is not approved for use in pediatric patients, early studies of this medication in youths with early-onset schizophrenia spectrum disorders suggested that it is effective in that group.

 Because it is associated with risks of neutropenia and agranulocytosis, treatment with clozapine is reserved for children and adolescents with treatment-resistant schizophrenia.

 Two initial open-label trials of clozapine treatment in youths demonstrated efficacy with mean dosages of 370 mg/d

The first randomized controlled trial of clozapine in pediatric patients compared clozapine with haloperidol in adolescent inpatients with treatment-refractory schizophrenia.

 In this study, initial dosages were based on weight and ranged from 6.25 to 25 mg/d, and were titrated every 3 days by 1 or 2 times the initial dose. The final mean dosage was 176 mg/d. The investigators reported that although clozapine was superior in efficacy to haloperidol, it was associated with adverse effects including neutropenia, which required 1 patient to discontinue the study. Other notable adverse effects observed in patients taking clozapine included hypotension and dizziness, sialorrhea, seizures, and myocarditis.

Risperidone was the first atypical antipsychotic to be released as a first-line agent in the United States and will soon be available in generic form. The most frequently prescribed antipsychotic agent for children and adolescents, risperidone has now been approved by the FDA for the treatment of schizophrenia in adolescents as well as for autistic spectrum disorders in children. After it was introduced in the United States in 1993, early studies using this medication in children and adolescents with early-onset schizophrenia spectrum disorders suggested that risperidone is effective in reducing psychotic symptoms in this group but that it is associated with adverse effects including moderate weight gain, mild sedation, and dose-related EPS.

 In the study by Armenteros and colleagues,

 10 adolescents with schizophrenia were treated for 6 weeks beginning with 1 mg bid and increasing by 1 mg to a maximum daily dose of 10 mg. Six of the patients showed significant reduction of symptoms overall, and although adverse motor effects developed in 5 patients, the medication was thought to be generally well-tolerated.

Efficacy of risperidone for the treatment of schizophrenia in adolescents has now been established. Haas and colleagues

 studied 160 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of treatment with risperidone (1 to 3 mg/d or 4 to 6 mg/d) or placebo. At the end of the study, improvements in treatment outcomes (eg, Positive and Negative Syndrome Scale [PANSS] total, positive and negative symptom subscale scores) were significantly greater in both risperidone groups than in those who received placebo, and there were few observed differences in efficacy between the active treatment groups. However, the higher-dose group had a greater incidence of EPS and dizziness than the lower-dose group.

Overall, the findings indicate that risperidone is effective in the treatment of early-onset schizophrenia spectrum disorders in adolescents, although it is associated with risks of adverse effects such as movement disorders (possibly at an increased rate compared with adults),

 and significant weight gain. Although prolactin elevation has been repeatedly described for youths treated with risperidone, the available data do not suggest that these changes interfere with development in puberty.

The next atypical antipsychotic introduced in the United States was olanzapine. Pharmacokinetic data for olanzapine use in adolescents suggest that its effect on metabolism is similar to that in adults.

 Initial studies assessing the use of olanzapine in youth focused on treatment-resistant schizophrenia. In addition, a growing body of research, including case series,

has investigated the use of olanzapine as a first-line treatment option for youth with early-onset schizophrenia spectrum dis- orders. The findings suggest that olanzapine is effective in reducing symptoms in adolescents with these disorders and that it is associated with a low incidence of adverse motor effects.

In a recently completed 6-week, randomized placebo-controlled trial of adolescents with schizophrenia (N = 107), Kryzhanovskaya and colleagues

 found olanzapine to be superior to placebo in reducing symptom ratings (ie, overall psychopathology, positive and negative symptoms). In this study, olanzapine was started at 2.5 or 5 mg/d. The titration schedule was flexible, with a final mean dosage of 11.1 mg/d achieved between 4 and 6 weeks. However, patients gained an average of 4.3 kg during this short-term trial, and continued weight gain was observed in patients who enrolled in the 6-month, open-label extension phase. Indeed, among the atypical antipsychotics, olanzapine seems to be associated with a greater risk of weight gain, which limits its practical use. For example, the NIMH Data Safety Monitoring Board stopped enrollment in the olanzapine arm of the Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study after an interim analysis revealed alarming levels of weight gain and metabolic changes in children treated with olanzapine.

 Although the findings of a recent study indicated that orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets, the weight gain still remained in excess of what was seen for youth treated with risperidone.

After quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997, several stud- ies assessing its use in pediatric populations have been conducted. Early data suggested that it is a helpful and well-tolerated medication for children and adolescents with a variety of psychiatric disorders.

 In the first open-label study that assessed the use of quetiapine in adolescents with psychotic disorders, McConville and colleagues

 demonstrated efficacy and tolerability in a 23-day trial in which 10 adolescents with psychotic disorders were given quetiapine 25 mg bid, with upward titration to 400 mg bid by day 20. The investigators found the drug to be well-tolerated and reported an average mean weight gain of 1.5 kg. Pharmacokinetic studies were also undertaken and showed that adolescents and adults have similar metabolism of this medication.

In an open-label extension of this trial, patients were treated with a physician's choice flexible dose titration, with ending dosages ranging from 300 to 800 mg/d. The investigators reported a significant decrease in psychotic symptoms, as well as a nonsignificant increase in weight after 6 weeks.

 conducted an open-label, 6-week trial using quetiapine to treat psychotic disorders in children and adolescents with an average final treatment dosage of 467 mg/d. They found the drug to be well-tolerated, with the exception of weight gain of 4.1 kg on average.

Randomized controlled data supporting the use of quetiapine in teenagers with schizophrenia are not yet available. Other adverse effects noted in the use of quetiapine include sedation, hypotension, and dizziness. Studies have suggested that the incidence of treatment-emergent movement disorders in adult patients given a daily dose ranging from 50 to 750 mg does not differ from that seen with placebo.

Ziprasidone was approved for use in the United States in 2001 for the treatment of schizophrenia in adults; it now also has an indication for adult bipolar mania. Efficacy and tolerability have been demonstrated in pediatric patients with Tourette syndrome

 but there are few data regarding its use in children and adolescents with early-onset schizophrenia spectrum disorders. Single-dose pharmacokinetics and the safety of ziprasidone in children and adolescents have been examined in an open-label study that reported findings that were comparable to those in adults.

 Prompted by concerns about QT prolongation from the adult trials, prospective data have been generated in children and adolescents, which suggested that long-term treatment with low-dose (40 mg) ziprasidone led to prolongation of the QT interval by 28 ± 28 milliseconds.

 Cardiac monitoring according to guidelines recommended by the American Heart Association is advised.

The most recent atypical antipsychotic to become available in the United States is aripiprazole, a high-affinity partial dopamine D

 Large-scale, pivotal trials with aripiprazole for adults with chronic schizophrenia have consistently shown efficacy, with relatively minor adverse effects on body weight, metabolic parameters, prolactin levels, and sedation.

Since aripiprazole is newer in the United States, there are fewer data that assess this drug in young patients. However, one randomized controlled trial has recently been completed, which led to the approval of aripiprazole in the treatment of adolescents with schizophrenia. Robb and colleagues

 studied 300 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of active treatment with fixed dosages of aripiprazole (10 or 30 mg/d) or placebo. More than 85% of patients completed the 6-week study. At the end of the study, both the 10 mg and 30 mg doses showed significant differences from placebo on the PANSS total score and several secondary end points. Across treatment outcome measures, however, efficacy tended to be greater at 30 mg than at 10 mg, with earlier evidence of statistical separation from placebo and numerically greater improvements from baseline.

The majority of spontaneously reported adverse effects were EPS, including akathisia and somnolence, which were rated as either mild or moderate in severity.

 Mean change in weight from baseline was minimal (10 mg, no change; 30 mg, 0.2 kg; placebo, 20.8 kg). Also, a mean decrease in prolactin levels from baseline to end of study was observed in all treatment groups (10 mg, 212 ng/ mL; 30 mg, 217 ng/mL; placebo, 29 ng/mL). These data suggest that the incidence of weight gain and hyperprolactinemia is likely to be minimal in youths receiving aripiprazole.

Clinicians can now begin to draw from emerging data to guide them in the choice of atypical antipsychotics for teenagers with early-onset schizophrenia spectrum disorders. A recent open-label, randomized comparison between olanzapine (mean dosage, 8.2 mg/d) and risperidone (mean dosage, 1.6 mg/d) in 25 children with early-onset schizophrenia spectrum disorders found that both medications were comparably efficacious in decreasing symptoms, and both were associated with a similar number of adverse effects, the most important being weight gain.

 Olanzapine had a nonsignificantly lower dropout rate. A recent chart review noted increased EPS in risperidone versus olanzapine and quetiapine.

Efficacy and tolerability of risperidone, olanzapine, and haloperidol were compared in youths with psychosis in a randomized controlled comparative trial.

 In this study, all treatments led to a significant reduction of psychotic symptoms. Olanzapine showed the greatest efficacy followed by risperidone and then haloperidol. As expected, the primary adverse effects were sedation, EPS, and weight gain.

The sparsity of controlled trial data on the comparative effectiveness and safety of the atypical antipsychotics in adolescents represents a significant gap in our current knowledge. Only the TEOSS study funded by NIMH has directly compared first-line treatment with risperidone and olanzapine versus a first-generation antipsychotic (molindone) in a large group of adolescents with schizophrenia spectrum disorders.

 However, data from this study are still unavailable. In the face of limited comparative efficacy data, the choice of antipsychotics for teenage patients with early-onset schizophrenia spectrum disorders depends largely on consideration of what is known about the adverse effect profile for each medication.

Since a substantial number of patients do not respond to first-line medication, considerable research has been devoted to assessing options for managing patients with treatment-resistant schizophrenia, defined as failure of 2 or more first-line antipsychotics. These studies have focused on clozapine and olanzapine. An early retrospective study found olanzapine to be an effective substitute for clozapine in adolescents with treatment-resistant schizophrenia

; however, in an open-label comparison in a similar population, Kumra and colleagues

 observed that olanzapine was effective but inferior in efficacy to clozapine.

More recently, an open-label study found olanzapine to cause sustained improvement over 1 year in 8 of 9 children with treatment-resistant schizophrenia.

 Two double-blind, randomized trials that compared clozapine with olanzapine for youths with treatment-resistant schizophrenia have now been published. In the first, Shaw and colleagues

 reported that clozapine (mean final dosage, 327 mg/d) was significantly superior in efficacy to olanzapine (mean final dosage, 19.1 mg/d) after 8 weeks, although olanzapine was associated with fewer adverse effects. A recent 12-week, randomized, double-blind comparison between clozapine and high-dose olanzapine in refractory early-onset schizophrenia showed that clozapine (mean final dosage, 403.1 mg/d) was superior to olanzapine (mean final dosage, 26.2 mg/d) in reducing psychosis and negative symptoms, but both medications were associated with significant weight gain and related metabolic abnormalities.

 These findings suggest that clozapine remains the agent of choice in treatment-resistant schizophrenia, despite its significant risks.

In the treatment of adolescents, it is important to consider potential developmental differences of this group that may impact course and treatment response. Compared with adult-onset schizophrenia, naturalistic data suggest that the course of illness is more severe in early-onset illness.

 Study findings have suggested that youth treated with antipsychotic medications may be more sensitive to EPS.

 In addition, olanzapine may be more sedating in children and adolescents compared with adults.

 In light of recent data that suggest that risperidone may have adverse effects on spatial working memory in adults with first-episode schizophrenia, the long-term safety of atypical antipsychotics on the developing brain needs to be clarified.

A growing body of research assessing the use of atypical antipsychotics in adolescents with early-onset schizophrenia spectrum disorders suggests that medications are effective in reducing symptoms and improving function. Although these medications are associated with a lower incidence of adverse motor effects compared with typical antipsychotics, the atypical antipsychotics are associated with a number of important adverse effects including sedation and metabolic abnormalities. Furthermore, increasing evidence suggests that because of developmental differences, adolescents may be especially vulnerable to a whole range of adverse effects. While a limited data set is available that suggests some differences between atypical antipsychotics in terms of their adverse-effect profiles, additional comparative studies of the efficacy and tolerability of atypical antipsychotics are needed to inform the clinician's choice of initial antipsychotic.

Of the adverse effects associated with atypical antipsychotics, metabolic effects may be the most significant problem. Weight gain is of primary importance for teenagers: it contributes to subjective distress and nonadherence and has long-term medical consequences.

 The atypical antipsychotics share a class warning for hyperglycemia and, thus, symptoms of diabetes and fasting blood sugars need to be monitored.

Given that patients with schizophrenia are approximately twice as likely as the general population to die of cardiovascular disease,

 and that most of them will require long-term therapy, their physical health must be safeguarded. At the same time, because longer duration of untreated psychosis may predict poorer long-term outcomes in first-episode psychosis, physicians are compelled to treat early and aggressively to improve outcomes for their young patients with early-onset schizophrenia spectrum disorders.

Fortunately, considerable research has been devoted in recent years to begin to characterize the mechanism of these problems, which will hopefully guide interventions to decrease adverse effects. A recent study by Klein and colleagues

 demonstrated reduced weight gain in adolescents treated with olanzapine while taking metformin, but further research is needed to guide clinicians in managing these difficulties.

In conjunction with medication management of youths with early- onset schizophrenia spectrum disorders, it is important to keep in mind the social contextual issues that commonly occur in this population. There is often confusion and fear in the family regarding the nature of the illness and presenting symptoms that may delay treatment seeking. Shock and denial regarding the diagnosis commonly emerge during the early treatment phase. Since treatment noncompliance or discontinuation is a significant concern, early psychoeducation and support is crucial.

In addition, since response to currently available treatments remains suboptimal for many teenagers with schizophrenia, it is important to examine whether the use of adjunctive psychosocial treatments improves outcome.

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The number of prescriptions for antipsychotic treatment of teenagers has increased sharply in office-based medical practice. Adolescents with psychotic symptoms frequently present for clinical evaluation, and early-onset schizophrenia spectrum disorders (onset of psychotic symptoms before the age of 18 years) represent an important consideration in the differential diagnosis in these youths

Kathryn R. Cullen, MD

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