Esordio in età evolutiva : traiettoria incerta e diagnosi complessa Controversie nell’utilizzo di farmaci antipsicotici dell’Infanzia e Adolescenza LameziaTerme 21 Settembre 2018 Cosa fare quando il paziente non ha 18 anni? Esordio in età evolutiva : traiettoria incerta e diagnosi complessa Egea Sanna Clinica di Neuropsichiatra Infanzia e Adolescenza Dip. Scienze Biomediche Sez. Neuroscienze e Farmacologia Clinica Università degli Studi di Cagliari

Olfson et al. Arch Gen Psychiatry, 2012 In recent years, there has been a significant rise in the prevalence of use of antipsychotics in children and adolescents in the US. This reflects a global phenomenon, since this is also the case for the number of prescriptions for adults, but we should consider that the increase in children and adolescents has been 9-fold and 5-fold, respectively, as compared with a 2-fold increase in adult patients. Negli ultimi anni, c'è stato un aumento significativo della prevalenza dell'uso di antipsicotici nei bambini e negli adolescenti negli Stati Uniti. Ciò riflette un fenomeno globale, poiché questo è anche il caso per il numero di prescrizioni per gli adulti, ma dovremmo considerare che l'aumento di bambini e adolescenti è stato di 9 volte e di 5 volte, rispettivamente, rispetto a un doppio aumento nei pazienti adulti. Olfson et al. Arch Gen Psychiatry, 2012

Psychiatric diagnoses and off-label prescribing in children and adolescents receiving antipsychotics A second relevant fact is that most of the prescriptions for antipsychotics are for off-label indications. Thus, this study by Olfson and colleagues detected that more than 85% of the antipsychotic prescriptions were for off-label indications. Olfson et al. Arch Gen Psychiatry, 2012

Treatment of Young People With Antipsychotic Medications in the United States Olfson et al JAMA Psychiatry 2015

Psychiatric diagnoses and off-label prescribing in children and adolescents receiving antipsychotics Germany (2011) Similarly, data from the same study in Germany reported that the diagnoses most frequently associated with an antipsychotic prescription were hyperkinetic disorders and conduct disorders. This makes sense, of course, considering that these conditions are much more prevalent than psychotic disorders in this population. Nevertheless, they also point at an increasing use of antipsychotics for non-approved indications, which could be associated with increased risks. Psychiatric diagnoses in children and adolescents receiving at least one prescription for risperidone in 2011 (total number of patients 2525). The diagnoses listed on the Table may appear as main diagnoses or comorbidity. Each patient can carry more than one diagnosis. The data did not permit the authors to determinate as to which diagnosis was the indication for risperidone. Bachmann et al. Dtsch Arztebl Int, 2014

Gabriel , 7 anni Esame Psichico all’ingresso: Inviato in ricovero Marzo 2017 per rivalutazione: ADHD, ODD e Disabilità intellettiva lieve Esame Psichico all’ingresso: Sufficientemente curato e ben orientato nello spazio e nel tempo Mimica e gestualità varie Scarsamente disponibile al colloquio , Scarsa modulazione della voce Contatto oculare incostante Tensione ed irrequietezza motoria Moderata impulsività Affaticabile e facilmente distraibile Umore: moderatamente disforico Esame Neurologico: nella norma

Storia clinica: Da circa un anno di : Dall’età di due tre anni: Anamnesi personale: Convulsioni febbrili pregresse Da circa un anno di : Umore COSTANTEMENTE irritabile Frequenti crisi di aggressività fisica. Bassa autostima e sentimenti di inadeguatezza. Anedonia Interessi ripetitivi (matematica, fisica, astronomia) Dall’età di due tre anni: Stereotipie (flapping, saltelli) Alimentazione selettiva (cibi rossi) Numerose abbuffate diurne. Anedonia Iperattività ed impulsività Moderata labilità attentiva Marcate difficoltà di socializzazione con i pari  Familiarità per: ADHD, Depressione, Disturbo Bipolare, Epilessia e convulsioni febbrili

Valutazioni: Kiddie SADS-PL (Kid Schedule Affective Disorder and Schizophrenia-Present & Lifetime) ADHD ODD lieve, Depressione subclinica Cognitiva (WISC-IV): Ai limiti inferiori della NORMA ADOS (Autism Diagnostic Observation Schedule) ADI-R (Autism Diagnostic Interview-Revised): -Cut-off per D. Spettro autistico NON raggiunti Esami strumentali (RMN encefalo, EEG in veglia e sonno, ECG) e biochimici: -Nella norma

Ipotesi diagnostiche: Disturbo da deficit attentivo con iperattività Disturbo da Disregolazione dell’Umore Dirompente Disturbo Oppositivo-Provocatorio Disturbo Bipolare Disturbo Depressivo maggiore Disturbo dello Spettro Autistico Disturbo da deficit Attentivo con Iperattività Combinato di grado severo (ADHD-C , 314.01); Disturbo da Disregolazione dell’Umore Dirompente (DMDD, 296.99)

Alla dimissione (marzo 2017 ): Terapia farmacologica con Metilfenidato (Ritalin) 5 mg ore 08:00+ 5 mg ore 14:00 Intervento psicoeducativo domiciliare e scolastico rivolto ai genitori ed al bambino. La terapia con Ritalin determina moderato controllo della sintomatologia inattentiva e dell’ iperattività/impulsività. Aumento dell’ irritabilità Crisi di rabbia giornaliere con aggressività auto ed eterodiretta Marcato effetto rebound da fine dose

Lieve incremento ponderale Maggio 2017 Introduzione di terapia con Risperidone (Risperdal) sino alla posologia iniziale di 0.75 mg/die: Maggior controllo dell’irritabilita Diminuizione per frequenza ed intensità delle crisi di rabbia Maggior gestione dell’impulsività Permangono sintomi d’iperattività e inattenzione che tuttavia appaiono maggiormente gestibili e non sembrano compromettere ulteriormente il funzionamento globale del bambino Lieve incremento ponderale

JAACAP 2014 168 children, 6-12; 8.9 + 2.0 years Boys 77%, mean, IQ 97.1I 53% whites, 53% working parents, Basic: MPH (45 mg/day) + parent training Augmented : Basic + risperidone (1.9 mg/day)

Gadow et al. JAACAP 2014

Effect Size Differenza tra i cambiamenti dal baseline tra farmaco e placebo, diviso la media delle dev. standard (placebo e farmaco ad end point). L’effect size standardizza le unità di misura nei diversi studi. Baseline EndPoint Farmaco 38.5 + 5.8 25.5 + 4.2 Placebo 40.4 + 6.1 32.7 + 5.0 d= (38.5-25.5) - (40.4-32.7) = 13.0 -7.7 = ES 1.1 (4.2+5.0)/2 4,6 Secondo la definizione di Cohen, ES > 0.2 è considerato basso, ES > di 0.5 è considerato medio; oltre 0.8 è considerato alto

Method—Children (6-12 years; N=168) with severe physical aggression, ADHD, and cooccurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks. Results—Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p=.02, Cohen's d=0.27) and peer aggression (p=. 02, Cohen's d=0.32), but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at Week 9/endpoint (p=.008). Teacher ratings indicated greater reduction in ADHD severity (p=.02, Cohen's d =0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated impaired for at least one targeted disorder at Week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%). Conclusion—Augmented was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context-specific, and effect sizes ranged from small to moderate.

Gli antipsicotici nel bambino e nell’adolescente Controversie nell’utilizzo di farmaci antipsicotici dell’Infanzia e Adolescenza LameziaTerme 21 Settembre 2018 Gli antipsicotici nel bambino e nell’adolescente Egea Sanna Clinica di Neuropsichiatra Infanzia e Adolescenza Dip. Scienze Biomediche Sez. Neuroscienze e Farmacologia Clinica Università degli Studi di Cagliari Jean Dubuffet, Art Brut

Antipsicotici in età evolutiva Principi generali e meccanismi d’azione Principali utilizzi nella pratica clinica: Efficacia nei disturbi di condotta Efficacia nei disturbi dello spettro autistico Sicurezza e tollerabilità

Psychosis as a state of Aberrant Salience: A framework linking biology, phenomenology and pharmacology in Schizophrenia Kapur, AJP 2003 Dopamine as the “Wind of the Psychotic Fire” Dopamine as a mediator of Motivational Salience Bias in probabilistic reasoning Tendency to jump to conclusion Alteration in attributional style “Theory of mind”, perceptual alteration, magical thinking Dampering of aberrant Salience by antipsychotics “The voice actually said those words, but it does not bother me anymore” Tradurre!!

Meccanismo d’azione degli antipsicotici

Non Antipsicotici ma Bloccanti i recettori DA The Neuroscience-based Nomenclature (NbN), is available for free download on the iOS App Store and the Google Play Store.  Visit the website: ww.nbn2.com

Indication in psychosis EMA-approved indications for antipsychotics in children and adolescents Antipsychotic Indication in psychosis Other disorders FDA Chlorpromazine Schizophrenia and other psychoses ≥ 1 year Mania, agitation due to other causes, nausea-vomiting Severe hyperactivity and behavioural disorders in children 1-12 years., tetanus, nausea-vomiting Haloperidol Schizophrenia and other psychoses > 2 years Tourette, mania, other behavioural disorders (especially when associated wit hyperactivity and aggression). Schizophrenia, conduct disorders , severe hyperactivity, Tourette in children older than 3 and adults Clozapine Schizophrenia ≥ 16 years No Aripiprazole Schizophrenia ≥ 15 years Long-acting: adults Mania up to 12 weeks ≥ 13 years Schizophrenia ≥13, BD ≥ 10, irritability in ASD 6-17 years, Tourette 6-18 years Paliperidone Oral: schizophrenia ≥ 15 Schizophrenia ≥12 Risperidone No (in some European countries schizophrenia ≥ 15 years) Short-term treatment of aggressiveness in conduct disorder and intellectual disability 5-18 years Schizophrenia ≥13, BD ≥10, irritability in ASD 5-17 years Quetiapine Schizophrenia ≥13, mania ≥10 Olanzapine Schizophrenia and manic/mixed episodes ≥13. Second line because of side effects Asenapine Mania in adults (studies underway for children 10-17 years) Schizophrenia and mania in adults Amisulpride Contraindicated in children. Could be used in some adolescents ≥ 15-18 years Ziprasidone Severe manic/mixed episodes ≥ 10 years I have included in this Table the indications approved by the FDA and the EMA for the use antipsychotics in children and adolescents. I won’t go into detail, but what I wanted to highlight is the marked heterogeneity in the approved indications between continents and among drugs, which problably reflects the particular interests of some drug companies to get approvals.

Indication in psychosis EMA-approved indications for antipsychotics in children and adolescents Antipsychotic Indication in psychosis Other disorders FDA Chlorpromazine Schizophrenia and other psychoses ≥ 1 year Mania, agitation due to other causes, nausea-vomiting Severe hyperactivity and behavioural disorders in children 1-12 years., tetanus, nausea-vomiting Haloperidol Schizophrenia and other psychoses > 2 years Tourette, mania, other behavioural disorders (especially when associated wit hyperactivity and aggression). Schizophrenia, conduct disorders , severe hyperactivity, Tourette in children older than 3 and adults Clozapine Schizophrenia ≥ 16 years No Aripiprazole Schizophrenia ≥ 15 years Long-acting: adults Mania up to 12 weeks ≥ 13 years Schizophrenia ≥13, BD ≥ 10, irritability in ASD 6-17 years, Tourette 6-18 years Paliperidone Oral: schizophrenia ≥ 15 Schizophrenia ≥12 Risperidone No (in some European countries schizophrenia ≥ 15 years) Short-term treatment of aggressiveness in conduct disorder and intellectual disability 5-18 years Schizophrenia ≥13, BD ≥10, irritability in ASD 5-17 years Quetiapine Schizophrenia ≥13, mania ≥10 Olanzapine Schizophrenia and manic/mixed episodes ≥13. Second line because of side effects Asenapine Mania in adults (studies underway for children 10-17 years) Schizophrenia and mania in adults Amisulpride Contraindicated in children. Could be used in some adolescents ≥ 15-18 years Ziprasidone Severe manic/mixed episodes ≥ 10 years I have included in this Table the indications approved by the FDA and the EMA for the use antipsychotics in children and adolescents. I won’t go into detail, but what I wanted to highlight is the marked heterogeneity in the approved indications between continents and among drugs, which problably reflects the particular interests of some drug companies to get approvals.

Antipsicotici di seconda generazione Caratteristiche farmacodinamiche M1 5-HT2A 5-HT2A H1 5-HT1A α1 SDA Risperidone Paliperidone Ziprasidone α1 MARTA Clozapina Olanzapina Quetiapina α2 5-HT2C 5-HT3 D2 D2 5-HT6 D3 5-HT7 Multi-acting Receptor Targeted Antipsychotics 5-HT2A ANTAGONISTI SELETTIVI D2-D3 Amisulpride 5-HT1A AGONISTI DOPAMINERGICI PARZIALI Aripiprazolo D2 D2 D3 D3

Efficacy: numbers needed to treat 50 Numbers needed to treat = 100% / (percent improved on Drug – Percent improved on Placebo) Example: Numbers Needed to Treat = 100 / (75 – 25) = 100 / 50 = 2 Percentage of patients normalised 100 100 75 25 Active treatment Placebo

Mean Improvement in PANSS Total Score from 56-Wk RCTs in Pediatric Schizophrenia (13-17 Yrs) PBO ARI 10 30 mg mg PBO RIS 1-3 4-6 mg mg RIS 0.15-0.6 1.5-6 mg mg PBO QUE 600 800 mg mg PBO OLA 2,5-20 mg Cambiamento medio nel punteggio totale della PANSS Miglioramento Baseline PANSS 95.3 95.5 95.0 93.7 94.9 93.2 95.4 93.0 98.1 97.7 97.2 1. Kryzhanovskaya et altri 2009 2. Findling RL et altri 2008 3. Haas Met altri 2007 4. Findling RL et altri 2008 * p<0.05 vs placebo ** p<0.01 vs placebo ***p<0.001 vs placebo

“Response” rates in Schizophrenia: NNTs1-4=5-10 PBO OLA1 PBO ARI2 PBO RIS3 PBO QUE MOLRIS OLA5 OLA CLO6 OLA CLO7 Dose(mg/dl): 2,5-20 10-30 1-3 4-6 400-800 0,5-3 2,5-12,5 10-30 50-700 5-20 150-500 Duration: 6 weeks 6 weeks 6 weeks 8 weeks 12 weeks 1. Kryzhanovskaya et al. 2009 2. Findling RL e et al. 2008 3. Haas M et al. 2007 4. Finding RL et al, 2008 5. Sikich L et al. 2008 6. Kumra S et al. 2008 7. Shaw P et al. 2006

A Multiple-Center, Randomized, Double-Blind, Placebo-Controlled Study of Oral Aripiprazole for Treatment of Adolescents With Schizophrenia Findling et al. AJP 2008

METHOD: This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross-titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7-21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (≤52 weeks). The primary endpoint was time from randomization to exacerbation of psychotic symptoms/impending relapse. Safety and tolerability were assessed. RESULTS: Of 201 enrolled participants, 146 were randomized to aripiprazole (n = 98) or placebo (n = 48) in the double-blind maintenance phase. Treatment with aripiprazole was associated with a significantly longer time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio, 0.46 [95% CI = 0.24-0.88]; p = .016). Aripiprazole was associated with lower rates of serious treatment-emergent adverse events (TEAEs) versus placebo (3.1% versus 12.5%; p = .059) and severe TEAEs (2.0% versus 10.4%; p = .039). The rate of discontinuation due to TEAEs was lower with aripiprazole versus placebo (20.4% versus 39.6%, p = .014; number-needed-to-harm = 5.1). The incidences of extrapyramidal symptoms, weight gain, and somnolence were similar or lower with aripiprazole than with placebo, and no TEAEs related to elevated serum prolactin were reported. Based on Tanner staging, 27.6% of participants treated with aripiprazole and 16.7% of those who received placebo progressed one or two stages from baseline.

Efficacy of SGAs for the treatment of schizophrenia in young people As for SGAs, they seem to be more efficacious than placebo, both in low and high doses, as shown in this recent meta-analysis. Stafford et al., 2014. Plos One

ES in General (Adult) Psychiatry ADHD ES in General Medicine Aspirine for prevention cardiovascular disease 0.06 Antypertensive on long term mortality 0.11 Corticosteroids for asthma 0.54 Antypertensive for high blood pressure 0.55 Interferone for Chronic Hepatitis C 2.27 ES in General (Adult) Psychiatry SGA for schizophrenia (PANS) 0.51 SSRI for depression (HAMD) 0.32 SSRI/ Bdz for Panic 0.41 SSRI for OCD 0.44 ADHD Leucht et al.2012

Psychiatric diagnoses and off-label prescribing in children and adolescents receiving antipsychotics Germany (2011) Similarly, data from the same study in Germany reported that the diagnoses most frequently associated with an antipsychotic prescription were hyperkinetic disorders and conduct disorders. This makes sense, of course, considering that these conditions are much more prevalent than psychotic disorders in this population. Nevertheless, they also point at an increasing use of antipsychotics for non-approved indications, which could be associated with increased risks. Psychiatric diagnoses in children and adolescents receiving at least one prescription for risperidone in 2011 (total number of patients 2525). The diagnoses listed on the Table may appear as main diagnoses or comorbidity. Each patient can carry more than one diagnosis. The data did not permit the authors to determinate as to which diagnosis was the indication for risperidone. Bachmann et al. Dtsch Arztebl Int, 2014

SGAs in Bipolar disorder Zuddas et al. ENP 2011 ES: 0.8-1.2 NNT: 2.7- 5.3

SGAs in Pervasive Developmental Disorders ES: 0.6-1.3 NNT: 1.3-5.5 RAAP = Rating of Aggression Against People and/or Property Scale; ABC-I = Aberrant Behavior Checklist-Irritability; NCBRF = Nisonger Child Behavior Rating Form; Zuddas et al. ENP 2011

Effect size: 1.1 NNT: 1.6 Methods We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions — Improvement (CGI-I) scale at eight weeks. Results A total of 101 children (82 boys and 19 girls; mean [±SD] age, 8.8±2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7±2.9 kg, as compared with 0.8±2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P< 0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. Conclusions Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia. Effect size: 1.1 NNT: 1.6

Risperidone in children with autism and severe irritability Effect sizes RUPP Autism Network, NEJM, 2002, 347-314-321

SGA in Disruptive Behaviour Disorder - Conduct Disorder Zuddas et al. ENP 2011

ANTIPSYCHOTICS: 7 studies on RISP, 1 on QUET 2 included in meta-analysis (same as Cochrane’s) 242 subjects in total (average n = 48.4; age = 10.66 years)

Risperidone, compared with placebo Pringsheim et al CJP 2015 for conduct problems and aggression (ES: 0.72) In youth with low IQ and ODD, CD or DBD-NOS, with or without ADHD, for disruptive behaviour and aggression In youth with ODD, CD or DBD-NOS, with or without ADHD: ES: 0.60

No RCT DBPLC of other SGA ARIPIPRAZOLE Findling et al., (2009) small short 15-day open label study on CD (N = 23; aged 6–17 years; daily dose: 1–15 mg): effective in treating aggression Kuperman et al. (2011) 6 weeks open label intent-to-treat design study (N = 10, 1-20 mg/day): reduced physical aggression, verbal aggression, and aggression against objects and animals. Ercan et al. (2012) open label on ADHD + CD (N = 20 aged 6–16 years; mean daily dose: 8,55mg; 2,5–10 mg/day): effective in treating aggression OLANZAPINE Holzeret al., (2013) 10 weeks open label study on ADHD with DBD using OLANZAPINE + ATX: effective in reducing ADHD symptoms and overt aggressive behaviour Masi et al. (2006) retrospective study (N = 23 severe CD): reduced aggression at MOAS, impulsive affective aggression as predictor of better response

Safety issues: Frequent side effects of antipsychotics commonly used in children and adolescents As for safety issues, I’ve included this table not to review each antipsychotic separately but in order to highlight how the safety profiles of each antipsychotic differ. IACAPAP Textbook of Child and Adolescent Mental Health, 2012

Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents Correll CU, et al. JAMA 2009:302;1765–1773. All values refer to mean change from baseline (p value) Aripiprazole (n=41) Olanzapine (n=45) Quetiapine (n=36) Risperidone (n=135) Untreated (n=15) Weight (kg) 4.44 <0.001 8.54 <0.001 6.06 <0.001 5.34 <0.001 0.19 0.77 Fat mass (kg) 2.43 <0.001 4.12 <0.001 2.82 <0.001 2.45 <0.001 0.35 0.39 Waist (cm) 5.40 0.001 8.55 <0.001 5.27 <0.001 5.10 <0.001 0.70 0.40 Glucose (mg/dl) 0.54 0.76 3.14 0.02 2.64 0.12 1.14 0.26 0.69 0.81 The results from the SATIETY study also support that most antipsychotics are associated with significant changes in body composition during the first 3 months of treatment. However, olanzapine and quetiapine do seem to show a more adverse profile regarding glucose abnormalities. Caveat, results not controlled for normal development using percentiles (although it has been considered that 12 weeks is a period not long enough for detecting developmentally mediated changes). Adverse baseline-to-end-point changes reached statistical significance for olanzapine and quetiapine for total cholesterol, triglycerides, non- HDL cholesterol, and ratio of triglycerides to HDL cholesterol With risperidone, levels of tri- glycerides increased significantly. Meta- bolic baseline-to-end-point changes were not significant with aripiprazole With risperidone, doses greater than 1.5 mg/d were associated with sig- nificantly greater increases in weight, waist circumference, fat mass, and BMI z score. L’aumento di peso è spesso associato all’uso degli antipsicotici e può predisporre a disturbi alimentari, depressione, o disturbi coinvolgenti i sistemi cardiovascolare, endocrino, gastrointestinale, renale e polmonare, riducendo cosi l’aspettativa di vita dell’individuo (Ebbeling et al., 2002). L’aumento di peso inappropriato per età è di particolare preoccupazione in quanto tende a persistere anche in età adulta. L’eziopatogenesi dell’aumento di peso è ancora oggetto di discussione, probabilmente è determinato dalla potente azione di blocco degli SGA sui recettori della serotonina che può predisporre il paziente ad un maggiore aumento di peso rispetto agli FGA antagonisti-D2 (Allison 1999). Potenzialmente tutti gli SGA possono indurre un aumento di peso, tuttavia esistono delle differenze fra i singoli farmaci: l’olanzapina è il farmaco maggiormente associato al rischio di incremento ponderale, il risperidone e la quetiapina presentano un rischio intermedio e l’aripiprazolo è associato a un basso rischio (Correl, 2008).

Inverse relationship between age and incidence of EPS Parkinsonism Dystonia Akathisia In general, EPS seem to be more frequent in children and adolescents than in adults, although this does not seem to be the case of akathisia. This has been explained in the literature by the fact that slower titration regimes and lower target doses would be used in child and adolescent psychiatry, leading to a reduced risk of akathisia, as compared with young adults). Keepers GA et al. Arch Gen Psychiatry. 1983;40:1113-7.

1 Year Prolactin Change Prolactin (ng/mL) † 25.7 ng/mL = Hyperprolactinemia Prolactin (ng/mL) † The chart shows that after the initial increase in prolactin induced by risperidone, it usually tends to normalize. However, PRL levels are still higher with risperidone treatment than with aripiprazole or quetiapine. Overall group comparison p<0.0001 at all time points Wks Correll CU et al. ICOSR 2007

Basic Algorithm For Selection of Antipsychotics Begin with antipsychotic that causes the less side effects or no side effects feared by the patients Once a diagnosis is made and it has been decided that the optimal strategy is to start antipsychotic medication, the basic algorithm would be to start an antipsychotic that causes less severe side effects, considering the patient’s background medical state or the ones less feared by the patient or their parents. Considering this, I would recommend in the first place the use of aripiprazole, risperidone or ziprasidone, even if there are no know factors for diabetes. Because of the higher risk for metabolic side effects, olanzapine cannot be recommended as a first choice. The results in CATIE suggest quetiapine has a metabolic side effect profile that is closer to olanzapine than the others. I am of the opinion that we also cannot conclude from CATIE in the absence of cognition data, nor from various meta-analyses that have been done, that a typical agent is as effective as an atypical. Therefore, the choice of atypicals might begin with aripiprazole, risperidone or ziprasidone, even if there are no known risk factors for diabetes. Aripiprazole was not used in Phase One of CATIE*, but other evidence suggests its efficacy is equivalent to the non-olanzapine group** and its rate of metabolic side effects seems comparable to ziprasidone and risperidone. Risperidone does cause prolactin elevations which the other drugs do not, but the long term implications of this are not so clear, so it is not deemed a sufficient reason to rank it lower than aripiprazole or ziprasidone with regard to tolerability and safety.   If aripiprazole, risperidone, or ziprasidone is tolerated and the patient receives an adequate trial, but effectiveness is unsatisfactory, then consider olanzapine next because all of the others have comparable effectiveness to the first medication tried, and olanzapine may have greater effectiveness. It may be necessary to go up to doses as high as 30 mg/day. If olanzapine then is given in an adequate trial and produces an unsatisfactory outcome, there would have been two adequate antipsychotics trials and clozapine should be considered. If, on the other hand, aripiprazole, risperidone, or ziprasidone can not be given in an adequate trial due to lack of toleration, try one of the others. If neither is tolerated, try haloperidol or perphenazine, or quetiapine which have somewhat more serious side problems (movement disorders, less benefit for cognition, greater weight gain) though these problems may be of less concern than the metabolic issues with olanzapine. If these are not tolerated, try olanzapine. *Lieberman J et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. NEJM 2005;353(12):1209-1223. **Potkin SG et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry 2003;60:681-690. Commentary: Kelleher JB. Evidence-based mental health 2004;7(1):13. Full URL for accessing Osser’s Editor’s Comment in which an algorithm is proposed, based on CATIE and other studies: see http://www.cogentmedicine.com/index.cfm?fuseaction=abstract_printable&oid=36&fid=207&MID=16172203&BackLink=%2Findex%2Ecfm%3Ffuseaction%3Dabstract%26OID%3D36%26FID%3D207%26MID%3D16172203%26action%3Deditor%26start%3D1

Medical Risk Management Strategies in Antipsychotic-Treated Patients PREVENTION Treatment Initiation Healthy lifestyle counseling Healthy lifestyle intervention Start with lower-risk antipsychotic PRIMARY If Adverse Effect Is Present Healthy lifestyle counseling/intervention Consider changing to lower-risk antipsychotic Consider weight loss intervention SECONDARY So what can we do in this scenario to optimize the care of our patients? In the first place, apply primary prevention measures during the treatment initation. If adverse event is present…. If adverse effect progresses or becomes serious… Medical Risk Management Strategies Strategies for the management of adverse metabolic effects in patients taking antipsychotics can be categorized according to whether they are aimed at primary prevention, secondary prevention, or tertiary prevention. Primary preventative measures, instituted at the beginning of treatment, can include counseling regarding the benefits of a healthy lifestyle, intervention to achieve this goal, and the selection of a lower-risk antipsychotic as initial therapy. Secondary preventative measures are called for if a patient experiences an adverse metabolic effect. Such measures may include counseling and intervention to help the patient achieve a healthy lifestyle, switching to an antipsychotic associated with lower metabolic risk, and augmenting therapy with a weight-loss agent. Tertiary preventative measures, instituted if a pathologic effect is present, can again include counseling and intervention to help the patient achieve a healthy lifestyle, switching to a lower-risk antipsychotic, and augmenting therapy with a weight-loss agent. In addition, a targeted treatment should be added to address any abnormal values, and the patient should be referred to a specialist. Reference Correll CU, Harris JL, Pantaleon Moya RA, Frederickson AM, Kane JM, Manu P. Low-density lipoprotein cholesterol in patients treated with atypical antipsychotics: Missed targets and lost opportunities. Schizophrenia Res. 2007 April;92:103-107. If Adverse Effect Progresses/Serious Healthy lifestyle counseling/intervention Considering changing to lower-risk antipsychotic Add targeted treatment for pathological values Consider referral to specialist TERTIARY Correll CU. CNS Spectr. Vol 12. No 10 (Suppl 17), 2007: 12-20,35.

Ziprasidone (Zeldox®) Asenapine (Sycrest®) 5-HT1A receptor (Ki = 3.4 nM) (partial agonist) 5-HT1B receptor (Ki = 4.0 nM) (partial agonist) 5-HT1D receptor (Ki = 2.3 nM) 5-HT1E receptor (Ki = 360 nM) 5-HT1F receptor (Ki = >10,000 nM) (inactive) 5-HT2A receptor (Ki = 0.4 nM) 5-HT2B receptor (Ki = 27 nM) 5-HT2C receptor (Ki = 1.3 nM) 5-HT3 receptor (Ki = > 10,000 nM) (inactive) 5-HT4 receptor (Ki = > 10,000 nM) (inactive) 5-HT5A receptor (Ki = 291 nM) 5-HT6 receptor (Ki = 61 nM) 5-HT7 receptor (Ki = 6 nM) Recaptor Afffinity (pKi) Afffinity (Ki (nM)) 5-HT2C 10.5 0.03 5-HT2A 10.2 0.06 5-HT7 9.9 0.13 5-HT2B 9.8 0.16 α2B-Adrenergic 9.5  ? (~0.25) 5-HT6 0.25 D3 9.4 0.42 H1 9.0 1.0 D4 1.1 α1-Adrenergic 8.9 1.2 α2A-Adrenergic α2C-Adrenergic D2 1.3 D1 1.4 5-HT5A 8.8 1.6 5-HT1A 8.6 2.5 5-HT1B 8.4 4.0 H2 8.2 6.2 mACh < 5 8,128 Ziprasidone: elevata affinità per D2 e 5ht2 antagonista 5ht1a-1b agonista parziale D1 receptor (Ki = 525 nM) D2 receptor (Ki = 4.8 nM) D3 receptor (Ki = 7.2 nM) D4 receptor (Ki = 32 nM) D5 receptor (Ki = 152 nM) α1-adrenergic receptor (Ki = 11 nM) α2-adrenergic receptor (Ki = 260 nM) β1-adrenergic receptor (Ki = >10,000 nM) (inactive) H1 receptor (Ki = 50 nM) mACh receptors (Ki = >10,000 nM) (inactive) 5-HT transporter (Ki = 53 nM) (inhibitor) NE transporter (Ki = 48 nM) (inhibitor) DA transporter (Ki = >10,000 nM) (inactive)

Lurasidone Iloperidone Antagonist of α2C-adrenergic receptor (Ki = 10.8 nM) D2 receptor (Ki = 1.0 nM) 5-HT2A receptor (Ki = 0.5 nM) 5-HT7 receptor (Ki = 0.5 nM) partial agonist of the following sites:[5] 5-HT1A receptor (Ki = 6.8 nM) weak or negligible actions at the 5-HT 2c, α1-adrenergic,H1, and mACh receptors high (nM) affinity to serotonin 5HT2A (Ki 5,2 nM), dopamine D2 (6,3 nM) and D3 (7,1 nM), moderate affinity for dopamine D4 (25 nM), serotonin 5HT6 (43 nM), 5HT7 (22 nM noradrenaline a1 receptors (36 nM), low affinity for serotonin 5HT1A (168 nM), dopamine D1 and histamine H1 receptors

Il trattamento con entrambe le dosi di lurasidone o con olanzapina è stato associato a un miglioramento significativamente maggiore alla settimana 6 del punteggio totale PANSS, dei punteggi PANSE positivi e negativi alla sottoscala e del punteggio CGI-S rispetto al placebo. Non c'è stata differenza statisticamente significativa nel punteggio medio PANSS o nei punteggi di variazione CGI-S per i gruppi lurasidone rispetto al gruppo di olanzapina. Con responder definiti come quelli con un miglioramento di almeno il 20% sul PANSS, i tassi di risposta degli endpoint erano significativi rispetto al placebo solo per olanzapina. L'incidenza di acatisia era maggiore con 120 mg di lurasidone (22,9%) rispetto a 40 mg di lurasidone (11,8%), olanzapina (7,4%) o placebo (0,9%). La proporzione di pazienti con un aumento di peso ≥ 7% è stata del 5,9% per i gruppi lurasidone combinati, del 34,4% per il gruppo con olanzapina e del 7,0% per il gruppo placebo. Miglioramento prestazioni cognitive ai 6 mesi di trattamento nella fase a doppio cieco del Lurasidone rispetto al placebo ed alla quetiapina xr (rilascio prolungato) CONCLUSIONI: Il lurasidone era un trattamento efficace per i pazienti con schizofrenia acuta. Le valutazioni di sicurezza hanno indicato una maggiore frequenza di eventi avversi associati a 120 mg / die di lurasidone rispetto a 40 mg / die. JCAP 2017

Cariprazine Cariprazina: miglioramento sintomi negativi della schizofrenia Lancet 2017

Conclusioni e implicazioni cliniche In Età evolutiva: I farmaci D2 Bloccanti (antipsicotici) risultano maggiormente efficaci (e maggiormente utilizzati) per i disturbi non psicotici. L’efficacia dei diversi composti è in genere paragonabile: i criteri di scelta del farmaco si basano sugli specifici profili di sicurezza I farmaci psicotropi possono avere effetti indesiderati diversi da quelli osservati negli adulti. I dati di sicurezza nel lungo termine sono carenti e sono generalmente estrapolati da studi su adulti.

Recognition and management of psychosis and schizophrenia in children and young people: Summary of NICE guidance BMJ 2013 How to use oral antipsychotic medication Before starting antipsychotic medication, undertake and record the following baseline investigations: Weight and height (both plotted on a growth chart) Waist and hip circumference Pulse and blood pressure Fasting blood glucose, glycated haemoglobin (HbA1c),blood lipid profile, and prolactin levels Assessment of any movement disorders Assessment of nutritional status, diet, and level of physical activity.

Recognition and management of psychosis and schizophrenia in children and young people: Summary of NICE guidance BMJ 2013 How to use oral antipsychotic medication Monitor and record the following regularly and systematically throughout treatment, but especially during titration: Efficacy, including changes in symptoms and behaviour Side effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety) The emergence of movement disorders Weight, weekly for the first six weeks, then at 12 weeks, and then every six months (plotted on a growth chart) Height every six months (plotted on a growth chart) Waist and hip circumference every six months (plotted on a centile chart) Pulse and blood pressure (plotted on a centile chart) at 12 weeks and then every six months Fasting blood glucose, HbA1c, blood lipids, and prolactin levels at 12 weeks and then every six months Adherence Physical health.  

Grazie per l’attenzione Hyeronimus Bosch