pharmacotherapy of psychosis and schizophrenia in youth · 2017. 12. 5. · 1 pharmacotherapy of...
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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
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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
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Antipsychotics with FDA-approved pediatric indications
For the treatment of
Bipolar I Schizophrenia “Irritability”
risperidone: age 10-17 13-17 5-16
aripiprazole: age 10-17 13-17 6-17
quetiapine: age 10-17 13-17
olanzapine: age 13-17 13-17 (2nd line)
Risperidone vs. placebo (N=160, age 13-17) (Haas et al., 2009)
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Risperidone vs. placebo: acute efficacy (Haas et al., 2009)
PANSS PANSS+ PANSS-
d d d
1-3 mg 0.70 0.51 0.58
4-6 mg 0.70 0.58 0.61
Aripiprazole vs. placebo (age 13-17) (Findling et al., 2008)
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Aripiprazole vs. placebo: acute efficacy (Findling et al., 2008)
PANSS PANSS+ PANSS-
d d d
10 mg 0.29 0.34 0.25
30 mg 0.40 0.42 0.20
Lurasidone in adolescents with schizophrenia (Goldman et al 2017)
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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
4
Completed 12 months
3
Completed 12 months
7
Completed 12 months
13 Withdrew Early
6 Adverse Events
4 Weight Gain
1 Akathisia
2 Insomnia
4 Inadequate Response
2 Noncompliant
1 Consent withdrawn
17 Withdrew Early
7 Adverse Events
5 Weight Gain
1 Gynecomastia
1 Suicidality
5 Inadequate Response
3 Noncompliant
2 Consent withdrawn
10 Withdrew Early
4 Adverse Events
2 Weight Gain
1 Sedation
1 Other
3 Inadequate Response
1 Noncompliant
2 Consent withdrawn
Final mean daily dose
molindone 59.87
(range: 10-140 mg)
olanzapine 11.35
(range: 2.5-20 mg)
risperidone 2.8
(range: 0.5-6 mg)
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Acute treatment response rateResponse defined as CGI-I of 1 or 2 AND current PANSS ≤ 80% baseline.
Stricter response also required completion of acute phase. No statistically significant differences.
0
10
20
30
40
50
60
Per
cen
t S
ub
ject
s
Molindone Olanzapine Risperidone
TEOSS: 52-week survival plot(Findling et al., 2010)
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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 805 75% 8.4%
Olanzapine 382 74% 7.6%
Quetiapine 260 71% 8.8%
Aripiprazole 173 76% 7.2%
Ziprasidone 125 73% 9.9%
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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)
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Dopamine receptors
� G protein-coupled
� D1 and D5
� Activate adenylate cyclase� increase intracelluar cAMP
� D2, D3, D4
� Inhibit adenylate cyclase� decrease intracelluar cAMP
DOPAMINE BRAIN PROJECTIONS
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Receptor binding affinity (Ki) (Correll 2011)
CPZ HAL RISP QUE OLA ARI CLO
D2 2.0 2.6 3.8 770 20 0.7 210
5-HT1A 3115 1800 190 300 610 5.5 160
5-HT2A 8.0 61 0.15 31 1.5 8.7 2.6
α1 2.6 17 2.7 8.1 44 26 6.8
H1 0.2 260 5.2 19 0.08 30 3.1
M1 25 >103 >103 120 2.5 6780 1.4
New antipsychotics• Lurasidone
• D2/D3 antagonist
• 5HT2A antagonist
• Low affinity for H1
• Cariprazine
• D2/D3 partial agonist and 5HT1A antagonist
• High affinity for D3
• Brexpiprazole
• D2 partial agonist
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Antipsychotic dose equivalency
Chlorpromazine 100 mgHaloperidol 2 mgRisperidone 2 mgPaliperidone 3 mgQuetiapine 75 mgOlanzapine 5 mgAripiprazole 7.5 mg
Antipsychotic dosage (mg/day)
Starting dose Usual therapeutic range
ARI 2-5 10-30
RISP 0.5-1 1-6
QUE 50 150-750
OLA 5 5-20
CPZ 25-50 50-300
HAL 0.5-1 1-6
CLO 12.5 50-600
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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 (t1/2=72 h)
� Titration in 3-5 days
� Then, every 10-14 days
Safety concerns
� Extrapyramidal effects
� Akathisia
� Tardive dyskinesia
� Neuroleptic malignant syndrome
� Metabolic syndrome
� Hyperprolactinemia
� Sedation � cognition
� Cardiovascular
� Hematological
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Weight changes during treatment in adults (Casey 2005)
Antipsychotics and weight N=338; mean 10.6 wks (Correll et al. 2009)
8,5
6,15,3
4,4
0,20
1
2
3
4
5
6
7
8
9
olanzapine quetiapine risperidone aripiprazole none
mean weight gain (kg)
15
-30-20-10
0102030405060
BM
I Per
cen
tile
Ch
ang
e
Molindone Olanzapine Risperidone
BMI change in the TEOSS patients(Sikich et al. 2008)
Metabolic syndrome
• Obesity
• Hypertension
• Hypetriglyceridemia
• Low HDL cholesterol
• Hyperglycemia
[3 or more]
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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
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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
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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)
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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)
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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
�1000-1499 mild neutropenia
�500-999 moderate neutropenia*
�<500 severe neutropenia*
*Discontinue clozapine!
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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
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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)
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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 26+8
� 1991-2005 (up to 14 years of treatment)
� Repeated brain MRIs (2-5 scans/pt)
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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
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