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

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

3

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)

4

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)

5

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)

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

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1 Consent withdrawn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2 Consent withdrawn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2 Consent withdrawn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)

7

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)

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 805 75% 8.4%

Olanzapine 382 74% 7.6%

Quetiapine 260 71% 8.8%

Aripiprazole 173 76% 7.2%

Ziprasidone 125 73% 9.9%

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)

10

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

11

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

12

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

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 (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

14

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]

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

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

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)

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)

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

�1000-1499 mild neutropenia

�500-999 moderate neutropenia*

�<500 severe neutropenia*

*Discontinue clozapine!

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

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)

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 26+8

� 1991-2005 (up to 14 years of treatment)

� Repeated brain MRIs (2-5 scans/pt)

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