Eight Core Principles for Treating Psychosis in Adolescents. Sanjiv Kumra MD. Off-Label Use. Psychosis/Schizophrenia in U.S. Children/Adolescents

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1 Off-Label Use Eight Core Principles for Treating Psychosis in Adolescents Sanjiv Kumra MD Some of the medications described in this presentation constitute off-label use Objectives At the conclusion of this session, participants should be able to: Appreciate how to take a developmental informed approach to treatment. Recognize importance of involving family in the treatment plan. Understand current evidence-based interventions to treat psychosis in youth. Psychosis/Schizophrenia in U.S. Children/Adolescents Schizophrenia affects 1 Estimated 1.% of adults Schizophrenic illness before adulthood 2 Very early onset occurs before age 13 Early onset occurs before age 18 Approximately 3% of patients with schizophrenia experience the onset of their illness by age 18 years 2 1 Findling RL et al. (21), Psychotic Disorders in Children and Adolescents. Thousand Oaks, Calif: Sage Publications Inc., pp16-28; 2 American Academy of Child and Adolescent Psychiatry (AACAP) (21), J Am Acad Child Adolesc Psychiatry 4(7 suppl):4s-23s Longitudinal Course Premorbid dysfunction Prodrome Acute phase of illness Premorbid Dysfunction Evident during even the 1st years of life Delayed motor milestones Speech and language deficits/delays Shy, withdrawn, timid, sensitive Attentional impairments Masi G et al. (26), CNS Drugs 2(1): ; Jones PB, Tarrant CJ (2), Eur Arch Psychiatry Clin Neurosci 25(6): ; Nicolson R et al. (2), Am J Psychiatry 157(5):

2 Prodrome Course and Outcome Precedes the onset of syndromal expression Is associated with declines in baseline functioning Worsening school performance Emerging cognitive and social deficits Disorganized behavior Unusual thought content Deterioration in self-care High levels of depression and anxiety An earlier onset of schizophrenia is associated with a worse long-term prognosis Major observations from follow-up studies High likelihood of relapse Moderate educational and occupational impairment School failure Premorbid function, negative symptoms, degree of recovery best predictors of long-term outcome Masi G et al. (26), CNS Drugs 2(1): ; White T et al. (26), Biol Psychiatry 6(5): Kyriakopoulos and Frangou (27), International Review of Psychiatry Case Presentation 17 year old refugee with psychosis and intermittent medication adherence: Multiple hospitalizations and patient has dropped out of school x 1 year Lack of therapeutic alliance Poor insight, language barriers, negative peer influence Cultural remedy: prayer + evidence based treatment = success Psychosocial History Predisposing factors: prenatal stress, adverse childhood experiences, immigration, low SES, cannabis misuse Presenting symptoms include somatic and religious delusions, agitation, catatonia, disorganized behavior, negative symptoms Developmental issues Perpetuating factors Key factors: Treatment History Significant cognitive limitations Pre-contemplation phase Reason for taking medication: It makes me think clearly Mother has limited knowledge regarding her son s illness Focus of the treatment plan has been to find the right antipsychotic medication Schizophrenia in Youth Associated with a more insidious onset in comparison to adult schizophrenia Symptoms depend on age, developmental stage, cultural background and cognitive ability Signs/symptoms Distortion of reality Auditory hallucinations, less well-formed delusions Negative symptoms Flat or inappropriate affect Disorganization American Psychiatric Association (APA) (2), Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.: American Psychiatric Publishing, Inc.; AACAP (21), J Am Acad Child Adolesc Psychiatry 4(7 suppl):4s-23s 2

3 Differential Diagnosis Psychiatric illnesses Mood disorders Psychosis Negative symptoms (depression) Anxiety disorders (PTSD, OCD, GAD) Pervasive developmental disorders (PDD) ADHD/disruptive behavior disorders Sleep disorders Dissociative disorders Drug abuse disorders/intoxication General medical conditions Findling RL et al. (21), Psychotic Disorders in Children and Adolescents. Thousand Oaks, Calif: Sage Publications Inc., pp16-28; White T et al. (26), Biol Psychiatry 6(5): Genetics Schizophrenia is a highly genetic disorder with heritability of about 8% Increased familial aggregation of for childhood onset schizophrenia compared to controls and later-onset cases Higher risk for schizophrenia Higher risk for schizophrenia spectrum disorders Asarnow RF et al. (21), Arch Gen Psychiatry 58(6): ; Lichtermann D et al. (2), Eur Arch Psychiatry Clin Neurosci 25(6):31-31; Nicolson R et al. (23), Am J Psychiatry 16(3): Cognitive function General intellectual ability Executive function, working memory, attention Motor function Verbal memory and learning Oie M, Rund BR (1999), Am J Psychiatry 156(8): ; Fagerlund B et al. (26), Schizophr Res 85(1-3):3-39; White T et al. (26), Biol Psychiatry 6(5): Adolescent Schizophrenia and Substance Abuse Common comorbidity in adults Adolescents with schizophrenia appear to be at high risk Earlier age at onset is associated with cannabis use Comorbid substance use may be associated with: Higher family histories of substance use More frequent suicide attempts Barnes TR et al. (26), Br J Psychiatry 188: ; Shoval G et al. (27), Compr Psychiatry 48(1):1-7; Westermeyer J (26), Am J Addict 15(5): Goals in Treatment of Psychotic Youth Symptom amelioration Acute Maintenance Side effects Adherence Adaptive function Academic Social skills Familial Goals in Treatment of Psychotic Youth (Cont.) Successful treatment of an acute psychotic episode, particularly the disorganized behavior associated with positive symptoms is essential for minimizing the compounding effects of derterioration in social and academic function AACAP (21), J Am Acad Child Adolesc Psychiatry 4(7 suppl):4s-23s AACAP (21), J Am Acad Child Adolesc Psychiatry 4(7 suppl):4s-23s 3

4 Treatment Modalities Psychopharmacology Psychosocial treatments Family interventions Social skills training Cognitive remediation Special education Classroom placement Treatment for comorbidities Substance abuse Young Patients Are Different Efficacy Adverse events Pharmacokinetics Neuroontology Differences due to brain maturation Dystonia (%) Incidence of EPS as a Function of Age EPS (%) Age (Year) Age (Year) Akathisia (%) No Prophylaxis (N=135) Prophylaxis (N=8) p<.1; p<.5; Keepers GA et al. (1983), Arch Gen Psychiatry 4(1): Age (Year) Parkinsonism (%) Age (Year) Loxapine (Loxitane)/Haloperidol (Haldol): Adverse Events Percent Haloperidol Loxapine EPS Pool D et al. (1976), Curr Ther Res Clin Exp 19(1):99-14 Sedation Thiothixene (Navane) vs. Thioridazine (Mellaril) Trial: Side Effects Antipsychotic Studies in Pediatric Schizophrenia: Major findings % of Patients Extrapyramidal Side Effects Thiothixene Orthostasis Thioridazine Sedation Moderate effect size reduction in overall psychopathology observed across placebocontrolled studies Early separation from placebo by second week of treatment Higher than expected rates of placebo response High rates of adverse side effects Prolactin elevation, weight gain, extrapyramidal symptoms Quality of life? Realmuto GM et al. (1984), Am J Psychiatry 141(3):

5 (Risperdal) vs. : Patients/Methods vs. : Patient Disposition 6-week trial Ages with schizophrenia (mean = 15.6) 12 males 58 females 3-arm study 1-3 mg/day (N=55) 4-6 mg/day (N=51) (N=54) (N=54) Completed: 67% Discontinued due to: Adverse event: 4% Insufficient response: 24% Withdrawal of consent: 4% Other: 2% Randomized (N=16) (N=55) Completed: 82% Discontinued due to: Adverse event: 5% Insufficient response: 5% Ineligible to continue: 2% Withdrawal of consent: 5% (N=51) Completed: 86% Discontinued due to: Adverse event: 8% Insufficient response: 2% Withdrawal of consent: 2% Other: 2% Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the American Psychiatric Association (APA), NR516. San Diego: May Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May Improvement vs. : Efficacy Least Square Mean Change at Endpoint From Baseline in PANSS Total Scores Baseline (±SD) PANSS Total: Mean Change From Baseline (1.3) (11.) (11.9) -2.7 p<.1 vs. placebo; PANSS = Positive and Negative Syndrome Scale; pooled SD = 15.6; Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May vs. : Efficacy Least Square Mean Change From Baseline at Endpoint in PANSS Total Score Over Time Mean ±SE mg 4-6 mg Day 8 Day 15 Day 29 Baseline Endpoint Time p<.1 vs. placebo; p<.5; p<.1; p<.1; PANSS = Positive and Negative Syndrome Scale; pooled SD = 15.6; Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May vs. : Efficacy Clinical Response Rates (% of Patients With Reduction in PANSS Total Score of 2% From Baseline to Endpoint) Patients (%) p<.1 vs. placebo; Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May vs. : Efficacy Change in PANSS Factor Scores for Positive and Negative Symptoms From Baseline to Endpoint (ITT LOCF Population) Dose (N=54) (N=5) PANSS Positive Symptoms Score Baseline, mean (±SD) 26.8 (5.2) 26.5 (5.1) 25.7 (4.1) Change from baseline, mean (±SD) -3. (6.3) -6.3 (6.5) -6.5 (5.4) p-value (minus placebo) <.1 <.1 Difference of LS means (±SE) -3.6 (1.) -4.1 (1.1) 95% CI (-5.6; -1.5) (-6.2; -2.) PANSS Negative Symptoms Score Baseline, mean (±SD) 23. (4.7) 24.1 (4.8) 23.7 (4.3) Change from baseline, mean (±SD) -1.9 (4.3) -5.4 (6.1) -4.9 (4.9) p-value (minus placebo) <.1.2 Difference of LS means (±SE) -3.2 (.9) -2.8 (.9) 95% CI (-4.8; -1.5) (-4.5; -1.1) p<.1 vs. placebo; Pairwise comparison; Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May

6 vs. : Tolerability (N=54) Dose (N=55) (N=51) Total AEs, N (%) Most common AEs ( 5%) 29 (54) 41 (75) 39 (76) Somnolence 2 (4) 13 (24) 6 (12) Extrapyramidal disorder 2 (4) 5 (9) 8 (16) Headache 1 (19) 7 (13) 5 (1) Agitation 4 (7) 8 (15) 4 (8) Dizziness 1 (2) 4 (7) 7 (14) Tremor 3 (6) 6 (11) 5 (1) Hypertonia 4 (7) 3 (5) 7 (14) Hyperkinesia 3 (6) 4 (7) 5 (1) Insomnia 5 (9) 4 (7) 4 (8) Anxiety 4 (7) 3 (6) Pharyngitis 2 (4) 3 (5) 2 (4) Saliva increased 1 (2) 5 (1) Tachycardia 3 (6) 3 (5) 2 (4) Nausea 4 (7) 1 (2) 3 (6) Vomiting 4 (7) 2 (4) 2 (4) AE = adverse event; Haas M et al. (27), Poster Presented at the 16th Annual Meeting of the APA, NR516. San Diego: May Aripiprazole (Abilify) vs. : Patients/Methods 6-week trial Age with schizophrenia (mean = 15.5) 57% males 43% females 3-arm study Aripiprazole 1 mg/day (N=1) Achieved by day 5 Aripiprazole 3 mg/day (N=12) Achieved by day 11 (N=1) Mean baseline PANSS = 94.5 Mean baseline CGI-S = 4.6 Robb AS et al. (27), Presented at the 16th Annual Meeting of the APA, NR742. San Diego: May 19-24; Findling RL et al. (27), Presented at the 16th Annual Meeting of the APA, NR741. San Diego: May Aripiprazole vs. : Efficacy Primary Endpoint: PANSS Total Score (LOCF) PANSS Total Aripiprazole 1 mg Aripiprazole 3 mg p<.5; p<.1; Baseline PANSS total score = 94.5; Robb AS et al. (27), Presented at the 16th Annual Meeting of the APA, NR742. San Diego: May PANSS Positive Aripiprazole vs. : Efficacy -2-4 PANSS Positive Score (LOCF) -6-8 Aripiprazole 1 mg PANSS Negative Aripiprazole 3 mg PANSS Negative Score (LOCF) p<.5; p<.1; p<.5 (ARI 1mg vs. ; Baseline PANSS positive score = 22.8; Baseline PANSS negative score = 25.3; Robb AS et al. (27), Presented at the 16th Annual Meeting of the APA, NR742. San Diego: May CGI-I Score Aripiprazole vs. : Efficacy CGI-Improvement Score (LOCF) Aripiprazole 1 mg CGI-S Score Aripiprazole 3 mg CGI- Severity Score (LOCF) p<.5; p<.1; Baseline CGI-S score = 4.6; Robb AS et al. (27), Presented at the 16th Annual Meeting of the APA, NR742. San Diego: May Aripiprazole (ARI) vs. : Tolerability Patient Disposition (%) ARI 1 mg (%) ARI 3 mg (%) Randomized Discontinued 1 (1) 16 (16) 18 (18) Adverse event 2 (2) 7 (7) 4 (4) Lack of efficacy 1 (1) 5 (5) 1 (1) Withdrew consent 5 (5) 4 (4) 12 (12) Lost to follow-up 1 (1) () () Other 1 (1) () 1 (1) Completed 9 (9) 84 (84) 84 (82) SAS = 1.9; BARS =.1; AIMS =.2; Findling RL et al. (27), Presented at the 16th Annual Meeting of the APA, NR741. San Diego: May

7 Aripiprazole vs. : Tolerability Simpson-Angus, Barnes Akathisia and Abnormal Involuntary Movement Scales CGI-S Score Aripiprazole 1 mg SAS BARS AIMS Aripiprazole 3 mg p<.5; Baseline score: SAS = 1.9; BARS =.1; AIMS =.2; Findling RL et al. (27), Presented at the 16th Annual Meeting of the APA, NR741. San Diego: May Aripiprazole vs. : Tolerability Incidence of Clinically Significant Weight Gain (>7% Increase from Baseline) % Patients Aripiprazole Aripiprazole 1 mg 3 mg 1 mg vs. ; p=.37 3 mg vs. ; p=.13 Mean Change From Baseline (kg) Change in Body Weight Aripiprazole Aripiprazole 1 mg 3 mg p<.5; Findling RL et al. (27), Presented at the 16th Annual Meeting of the APA, NR741. San Diego: May vs. : Patients/Methods vs. : Efficacy 6-week trial Ages years with schizophrenia (mean = 16.1) 75 males 32 females 2-arm study mg/day (N=72) Mean dose was 11.1 mg/day (N=35) LS Mean Change Visitwise BPRS-C Score (MMRM) Week of Treatment p=.2 p=.4 p=.23 p=.1 p=.15 LS Mean Changes in Secondary Efficacy Measures Efficacy Measures (N=72) (N=35) p-value PANSS Total Positive Negative CGI-S CGI-I <.1 Kryzhanovskaya L et al. (25), Presented at the 44th Annual Meeting of the American College of Neuropsychopharmacology. Waikoloa, HI: Dec N=71; Only patients with both baseline and postbaseline measures; Mean at endpoint; Kryzhanovskaya L et al. (28), J American Academy of Child and Adolescent Psychiatry vs. : Tolerability Treatment-Emergent Adverse Events (TEAE) TEAE N (%) N (%) p-value Patients with 1 TESS 61 (84.7) 24 (68.6).74 Patients with no TESS 11 (15.3) 11 (31.4) Weight increased 22 (3.6) 3 (8.6).14 Somnolence 17 (23.6) 1 (2.86).6 Headache 12 (16.7) 2 (5.7).138 Increased appetite 12 (16.7) 3 (8.6).376 Sedation 11 (15.3) 2 (5.7).214 Dizziness 6 (8.3) 1 (2.9).423 Nasopharyngitis 4 (5.6) 2 (5.7) 1. Pain in extremity 4 (5.6) 1 (2.9) 1. Schizophrenia 4 (5.6) 7 (2.).37 Vomiting 4 (5.6) 4 (11.4).434 Fisher s exact test; Refers to an exacerbation of schizophrenic symptoms; TESS = Treatment Emergent Symptom Scale; Kryzhanovskaya L et al. (25), Presented at the 44th Annual Meeting of the American College of Neuropsychopharmacology. Waikoloa, HI: Dec vs. : Tolerability Weight Change From Baseline to Endpoint Baseline Mean (SD) Change to Endpoint Mean (SD) Baseline Mean (SD) Change to Endpoint Mean (SD) p-value Weight (kg) 67. (13.3) 4.3 (3.3) 68.9 (16.9).1 (2.8) <.1 Body mass index 23.5 (4.6) 1.5 (1.2) 24. (6.1).4 (1.1) <.1 Treatment-Emergent Weight Gain (Anytime During Treatment) N (%) N (%) p-value Weight 7% of baseline 33 (45.8) 5 (14.7).2 p-values derived from Type III Sum of Squares from an analysis of variance (ANOVA): Model = Country Therapy; Frequencies were analyzed using Fisher s exact test; Kryzhanovskaya L et al. (25), Presented at the 44th Annual Meeting of the American College of Neuropsychopharmacology. Waikoloa, HI: Dec

8 Long-Term Open Label 19 received treatment Ages 6-15 (1.5) Childhood-onset DSM-IV schizophrenia Open label treatment for up to 1 year 14/19 completed 1 switched to clozapine All patients experience weight gain 4 discontinued for weight gain Ross RG et al. (23), J Child Adolesc Psychopharmacol 13(3):31-39 TEOSS Patient Selection Criteria Inclusion criteria Diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder Between ages 8-19 Currently experiencing positive psychotic symptoms of at least moderate intensity Premorbid IQ >65 Exclusion criteria Current major depression Adequate trial or intolerance to any study treatment On current antidepressant or mood stabilizer for <4 weeks TEOSS = Treatment of Early Onset Schizophrenia Spectrum Disorders; McClellan J et al. (27), J Am Acad Child Adolesc Psychiatry 46(8): TEOSS Study: Design Double-blind, 3-armed comparison of:,.5-6 mg, target 3 mg, mg, target 12.5 mg Molindone (Moban), 1-14 mg, target 65 mg Molindone arm also got.5 mg benztropine (Cogentin), SGAs got placebo Flexible dose Acute treatment phase is 8 weeks Clinician defined responders asked to continue blinded treatment for a full year Antidepressants and mood stabilizers permitted if on stable dose for 4 weeks or after 8 weeks of antipsychotic treatment McClellan J et al. (27), J Am Acad Child Adolesc Psychiatry 46(8): TEOSS Demographic Information Demographics of the Early-Onset Schizophrenia Spectrum Disorders Schizo- Schizo- Demographics, phrenia affective Total No. (%) (N=79) (N=4) (N=119) p Sex Male 49 (62) 29 (72.5) 78 (66) 2 =1.29, p=.256 Female 3 (38) 11 (27.5) 41 (34) Age range, years (18) 7 (17.5) 21 (18) t=.4, p= (52) 24 (6) 65 (54) (3) 9 (22.5) 33 (28) Frazier JA et al. (27), J Am Acad Child Adolesc Psychiatry 46(8): Discontinuation of Arm in TEOSS November 25 DSMB reviewed a planned interim analysis including weight gain and outcome data DSMB concluded that assignment of additional patients to olanzapine therapy would not be justified New patients only randomized to molindone or risperidone Patients on olanzapine already could continue All patients who had gained more than 7% of baseline body weight were reviewed by PIs to determine whether treatment response justified continued study participation McClellan J et al. ( 27), J Am Acad Child Adolesc Psychiatry 46(8): Clozapine (Clozaril) in Schizophrenia 21 youths with childhood-onset, treatment resistant schizophrenia Mean age = 14 years 6-week parallel design Haloperidol vs. clozapine Flexible dosing Clozapine superior to haloperidol in symptom reduction 1/3 treated with clozapine had to discontinue due to hematological or neurological side effects Kumra S et al. (1996), Arch Gen Psychiatry 53(12):

9 Clozapine vs. Haloperidol in Childhood-Onset Schizophrenia Haloperidol (N=11) Clozapine (N=1) 4 p=.4 p=.2 p=.2 p=.1 p= BPRS BHS SANS SAPS CGAS BPRS = Brief Psychiatric Rating Scale; BHS = Bunney-Hamburg Psychosis Rating Scale; SANS/SAPS = Schedule for Assessment of Negative/Positive Symptoms; CGAS = Children s Global Assessment Scale; Kumra S et al. (1996), Arch Gen Psychiatry 53(12): Scores Clozapine vs. (Zyprexa): Patients/Methods 12-week trial with no drug washout Treatment resistant ages 1-18 years 18 received clozapine (mean = 43 mg/day) 21 received olanzapine (mean = 26.2 mg/day) Kumra S et al. (28), Biol Psychiatry 63: Clozapine vs. (Zyprexa): Efficacy Significantly greater proportion of adolescents treated with clozapine (12 of 18, 66%) met responder criteria as compared with adolescents treated with olanzapine (7 of 21, 33%), p=.4 Reduction in symptom score changes between the two groups was similar Significant treatment condition x time interaction (p=.2) for reduction in negative symptoms favoring clozapine Kumra S et al. (28), Biol Psychiatry 63: Clozapine vs. : Tolerability Serious adverse events: Neutropenia Constipation Excessive weight gain and impaired glucose tolerance Weight gain 5 of 39 (13%) of study participants (3 clozapine, 2 olanzapine) gained > 7% of their baseline body weight by study endpoint Kumra S et al. (28), Biol Psychiatry 63: Conclusions Choice of medication is up to the clinician Variable course observed in terms of symptom improvement Higher doses may be more effective than lower doses in terms of achieving faster symptom control Weight gain and metabolic factors are an important consideration for the prescribing physician 9