Pharmacotherapy of psychosis and schizophrenia in youth

Transcription

1 Pharmacotherapy of psychosis and schizophrenia in youth Benedetto Vitiello Pavia, 2 December 2017 Disclosure Benedetto Vitiello, M.D. Professor of Child and Adolescent Neuropsychiatry University of Turin, Italy o I do not have any financial conflict of interest with the content of this presentation 1

2 Psychoses Affective Mania Depression Drug-induced Schizophrenia spectrum Brief psychotic disorder Schizophreniform disorder Schizophrenia Schizoaffective disorder Early Onset Schizophrenia (onset <18 y) Similarities with adult schizophrenia: Same phenomenology Same diagnostic criteria Similar biological features Progressive loss of cortical gray matter Antipsychotic drugs better than placebo clozapine better than other antipsychotics no evidence of atypicals are better than typicals 2

3 Antipsychotics with FDA-approved pediatric indications For the treatment of Bipolar I Schizophrenia Irritability risperidone: age aripiprazole: age quetiapine: age olanzapine: age (2 nd line) Risperidone vs. placebo (N=160, age 13-17) (Haas et al., 2009) 3

4 Risperidone vs. placebo: acute efficacy (Haas et al., 2009) PANSS PANSS+ PANSSd d d 1-3 mg mg Aripiprazole vs. placebo (age 13-17) (Findling et al., 2008) 4

5 Aripiprazole vs. placebo: acute efficacy (Findling et al., 2008) PANSS PANSS+ PANSSd d d 10 mg mg Lurasidone in adolescents with schizophrenia (Goldman et al 2017) 5

6 TEOSS: acute and chronic treatment (Sikich et al 2008) 119 RANDOMIZED 40 Treated with Molindone 35 Treated with Olanzapine 41 Treated with Risperidone 25 Completed Acute Molindone Trial 50% responded 17 Completed Acute Olanzapine Trial 34% responded 28 Completed Acute Risperidone Trial 46% responded 20 Entered Maintenance 13 Entered Maintenance 21 Entered Maintenance 13 Withdrew Early 6 Adverse Events 4 Weight Gain 1 Akathisia 2 Insomnia 4 Inadequate Response 2 Noncompliant 1 Consent withdrawn 10 Withdrew Early 4 Adverse Events 2 Weight Gain 1 Sedation 1 Other 3 Inadequate Response 1 Noncompliant 2 Consent withdrawn 17 Withdrew Early 7 Adverse Events 5 Weight Gain 1 Gynecomastia 1 Suicidality 5 Inadequate Response 3 Noncompliant 2 Consent withdrawn 7 Completed 12 months 3 Completed 12 months 4 Completed 12 months Final mean daily dose molindone olanzapine risperidone 2.8 (range: mg) (range: mg) (range: mg) 6

7 Acute treatment response rate Response defined as CGI-I of 1 or 2 AND currentpanss 80% baseline. Stricter response also required completion of acute phase. No statistically significant differences Percent Subjects Molindone Olanzapine Risperidone TEOSS: 52-week survival plot (Findling et al., 2010) 7

8 Can early antipsychotic treatment improve the prognosis of schizophrenia? Duration of untreated psychosis predicts outcome and is one of the malleable risk factors in schizophrenia (Harrigan et al., 2003) Prognosis depends on level of functioning at time of treatment There is functional decline (and gray matter loss) early in the illness Antipsychotics in 6-17 year olds with early onset schizophrenia: first 6 months (Olfson et al., 2011) N Discont. Hospital. Risperidone % 8.4% Olanzapine % 7.6% Quetiapine % 8.8% Aripiprazole % 7.2% Ziprasidone % 9.9% 8

9 After the first episode of schizophrenia The risk of recurrence of acute psychotic episode is estimated to be about: 30% at 6 months 40% at 1 y 80% at 2 y 85% at 3 y Antipsychotics in 6-17 year old early onset schizophrenia (Olfson et al., 2011) 9

10 Dopamine receptors G protein-coupled D 1 and D 5 Activate adenylate cyclase increase intracelluar camp D 2, D 3, D 4 Inhibit adenylate cyclase decrease intracelluar camp DOPAMINE BRAIN PROJECTIONS 10

11 Receptor binding affinity (Ki) (Correll 2011) CPZ HAL RISP QUE OLA ARI CLO D HT 1A HT 2A α H M 1 25 >10 3 > New antipsychotics Lurasidone D 2/ D 3 antagonist 5HT 2A antagonist Low affinity for H 1 Cariprazine D 2/ D 3 partial agonist and 5HT 1A antagonist High affinity for D 3 Brexpiprazole D 2 partial agonist 11

12 Antipsychotic dose equivalency Chlorpromazine Haloperidol Risperidone Paliperidone Quetiapine Olanzapine Aripiprazole 100 mg 2 mg 2 mg 3 mg 75 mg 5 mg 7.5 mg Antipsychotic dosage (mg/day) Starting dose Usual therapeutic range ARI RISP QUE OLA CPZ HAL CLO

13 When to increase the dose? If possible, increase dose slowly If needed, increase to the usual therapeutic range in 3-5 days Afterwards, timing of further increase depends on the half-life: Aripiprazole (t 1/2 =72 h) Titration in 3-5 days Then, every days Safety concerns Extrapyramidal effects Akathisia Tardive dyskinesia Neuroleptic malignant syndrome Metabolic syndrome Hyperprolactinemia Sedation cognition Cardiovascular Hematological 13

14 Weight changes during treatment in adults (Casey 2005) Antipsychotics and weight N=338; mean 10.6 wks (Correll et al. 2009) mean weight gain (kg) 8,5 6,1 5,3 4,4 0,2 olanzapine quetiapine risperidone aripiprazole none 14

15 BMI change in the TEOSS patients (Sikich et al. 2008) B M I P e rc e n tile C h a n g e Molindone Olanzapine Risperidone Metabolic syndrome Obesity Hypertension Hypetriglyceridemia Low HDL cholesterol Hyperglycemia [3 or more] 15

16 Metabolic syndrome: the precise mechanisms are still unclear Direct mechanism on appetite centers in hypothalamus Change in production of satiety signals (e.g., adiponectin) Does weight gain lead to insulin resistance? Is dyslipidemia possible without BMI increase? Monitoring recommendations Personal & family history (baseline) Physical activity, diet (baseline + each visit) Weight, BMI (baseline + each visit) BP, pulse (baseline, 3 mo., q 6 mo.) Fasting glucose & lipids (baseline, 3 mo., q 6 mo.) TSH (baseline, annually) Prolactin, if clinically indicated 16

17 Suggested routine monitoring At baseline: Personal & family medical history Height, weight, BMI Blood pressure, heart rate Possible presence of tremors, involuntary movements (AIMS) Fasting glucose, lipids, liver function, CBC If symptomatic: ECG, prolactin Suggested routine monitoring During titration: Presence of sedation Height, weight, BMI Blood pressure, heart rate Possible presence of tremors, involuntary movements (AIMS) If symptomatic: ECG, prolactin 17

18 Suggested routine monitoring At 3 and 6 months (and annually afterwards) Height, weight, BMI Blood pressure, heart rate Possible presence of tremors, involuntary movements (AIMS) Fasting glucose, lipids, liver function, If symptomatic: ECG, prolactin How to prevent and treat antipsychotic-induced metabolic abnormalities? Preferentially select agents with lower metabolic impact (e.g., aripiprazole) Dietary interventions caloric restriction Metformin (Topiramate: but it may have cognitive adverse effects) 18

19 Effects on QTc Absence of change in corrected QT interval in children and adolescents receiving antipsychotic treatment: A 12 month study (Alda et al. 2016) N=216 quetiapine, risperidone or olanzapine ECG at times: 0, 3, 6 and 12 months Result: no clinically significant ECG changes Clozapine As in adults, also in children, clozapine is the most effective antipsychotic Off-label use <18 y; use after 2 other antipsychotics have failed Start with very low dose (12.5 mg-25 mg/d) 19

20 Additional mandatory monitoring for clozapine CBC with ANC (>1,500 per ul) At baseline Weekly for first 6 months Every two weeks for the following 6 months Monthly afterwards Absolute neutrofil count (ANC per ul) >1500 normal mild neutropenia moderate neutropenia* <500 severe neutropenia* *Discontinue clozapine! 20

21 Possible toxicities of clozapine Neutropenia, agranulocytosis Orthostatic hypotension, bradycardia, syncope Myocarditis, cardiomyopathy Seizure Obesity, diabetes-2, hyperlipidemia Can early antipsychotic treatment improve the prognosis of schizophrenia? Duration of untreated psychosis predicts outcome and is one of the malleable risk factors in schizophrenia (Harrigan et al., 2003) Prognosis depends on level of functioning at time of treatment There is functional decline (and gray matter loss) early in the illness 21

22 Progressive brain volume loss in children with schizophrenia (Sporn et al., 2003) Chronic (17-27 mo) antipsychotic exposure and brain volume in macaque monkeys (N=6/group) (Dorph-Petersen et al., 2005) 22

23 8-week antipsychotic exposure and brain volume in rats (Vernon et al. 2011) Olanzapine or Haloperidol 6-8% decrease in whole brain volume 8-12% decrease in frontal cortex vs. control vehicle Long-term antipsychotic treatment and brain volume (Ho et al. 2011) Iowa Longitudinal Study: 211 pts with schizophrenia; age (up to 14 years of treatment) Repeated brain MRIs (2-5 scans/pt) 23

24 Total cerebral gray matter (Ho et al. 2011) p Time: <.001 Antipsychotic dose:.005 Illness severity:.04 Substance abuse:.39 Prompt and vigorous management of first episode schizophrenia Early recognition and diagnosis Early and consistent antipsychotic treatment Cognitive remediation Behavioral rehabilitation Social support Social skill training Avoidance of substance abuse Treatment of comorbid anxiety, depression, OCD 24