novel antypsychotics

2. Novel Antipsychotics
Prof. Hani Hamed Dessoki, M.D.Psychiatry
Acting Dean, Faculty of Nursing
Prof. Psychiatry
Founder of Psychiatry Depart., Beni Suef University
Supervisor of Psychiatry Depart., El-Fayoum University
Treasurer of Egyptian Psychiatric Association
APA member
2019

3. Cognitive
benefits
Low EPS, TD
Affordable
No adverse
long-term health
consequences
Efficacious for
positive and
negative symptoms
What Constitutes an Ideal Antipsychotic
Mood-stabilizing
properties
Weight
Neutral
Improved
function and
quality of life
Ideal
antipsychotic

4. Aripiprazole
A Novel Anti Psychotic

8. NOT FOR PROMOTIONAL USE
Dopamine Hypothesis
of Schizophrenia
Inoue and Nakata. Jpn J Pharmacol. 2001;86:376; Sesack and Carr. Physiol Behav. 2002;77:513.
Hypoactivity:
Negative symptoms
Cognitive impairment
Hyperactivity:
Positive symptoms
Nigrostriatal
pathway
(part of EP system)
Tuberoinfundibular pathway
(inhibits prolactin release)
Mesocortical
pathway
Mesolimbic
pathway

9. NOT FOR PROMOTIONAL USE
Schizophrenia Core Symptoms
Psychotic Deficit Cognitive
Positive
Symptoms
Mesolimbic pathway
Negative
Symptoms
DLPC &VMPFC
Cognitive
Dysfunction
DLPFC
Affective
VMPFC

12. 12
Age (years)
6030 40 502010
Function
Good
Poor
Premorbid
Prodromal
Progression
Stable
Relapsing
Course of illness
Theoretical Model
Lieberman, JA
Premorbid : the period before a person first
shows clear symptoms ‘a little unusual’, ‘different’
Prodromal phase : the earliest
presentation of schizophrenia
Chronic phase : periodic relapses and
remissions -> periodic hospitalization
Onset phase (first break) : when
psychotic symptoms are first clearly noticed

15. Recent Changes In Classification
& Diagnosis Of Schizophrenia
• In 2013 the Diagnostic and Statistical Manual
of Mental Disorders 5th edition (DSM-V)
changed the method of classification to bring
all these categories under a single heading:
schizophrenia.
• According to the American Psychiatric
Association (APA), the decision to eliminate
these various subtypes was based on

16. • The conclusion they had "limited diagnostic
stability, low reliability, and poor validity." It
was concluded that they did not help to
provide better treatment or to predict how
patients would respond to treatment.
Recent Changes In Classification
& Diagnosis Of Schizophrenia

17. Recent Changes In Classification
& Diagnosis Of Schizophrenia
Two other important changes were made to
the diagnostic criteria in 2013.
• One was the removal of the requirement for
a person to experience bizarre delusions and
to hear two or more voices talking during an
auditory hallucination to receive a positive
diagnosis.

18. Recent Changes In Classification
& Diagnosis Of Schizophrenia
• The second was that, to receive a diagnosis, a
person must have at least one of the
following symptoms:
• hallucinations
• delusions
• disorganized speech

20. ’30s ’50s ’60s ’70s ’80s ’90s ’00 ’02
ECT
Chlorpromazine
Haloperidol
Fluphenazine
Thioridazine
Loxapine
Perphenazine
First-generation
antipsychotics
Second-generation
antipsychotics
Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Next-generation
Developments in Medical Treatments
for Psychotic Disorders
ECT = electroconvulsive therapy. Kapur and Remington. Ann Rev Med. 2001;52:503.
Worrel et al. Am J Health Syst Pharm. 2000;57:238.

21. D2
pure D2 blocker
H1
M1
D2
1
conventional
antipsychotic
drug

22. 5HT2A
D2
SDA
5HT7
5HT6
5HT3
5HT2C
5HT1D
5HT1A
M1
H1
1
2
SRI
NRI
D1
D3D4
5HT2A
D2
atypical
antipsychotic

24. Aripiprazole
Dopamine System Stabilizer
• Partial agonist at D2 receptors:
-Functional antagonist under conditions of
dopamine hyperactivity
-Functional agonist in conditions of dopamine
hypoactivity
• Presynaptic Dopamine autoreceptor partial
agonist

25. This mixture of agonist actions at D2-dopamine
receptors is consistent with the hypothesis that
aripiprazole has ‘functionally selective’
actions.
The ‘functional-selectivity’ hypothesis proposes that
a mixture of agonist/partial agonist/antagonist
actions are likely.
Smart Drug

26. Serotonergic Receptors
5‐HT2 receptor stimulation 5‐HT3 receptor stimulation
• Agitation
• Insomnia
• Sexual dysfunction
• Satiation
-5‐HT2A receptor normally works to inhibit
(brake) the release of the neurotransmitter
dopamine.
So, 5-HT2A antagonism – suppression of EPS
• Nausea
• Diarrhea
• Headache
• 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite
effect is on glutamate).
So, 5-HT1A agonism – effects on cognitive symptoms, suppression of EPS
5-HT2A antagonism – suppression of EPS

27. DA
D1
D2
Caudate/putamen
Normal function
Sunstantia nigra
pars
compacta
5-HT2A
-
5-HT
Raphe
Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Nigrostriatal tract

33. PET Analysis of D2R Occupancy
in Normal Healthy Male Volunteers
0
20
40
60
80
100
0.5 1 2 10 30
Caudate
Putamen
Aripiprazole dose (mg/d)
D2occupancy(%)
n= 3 3 3 2 4
No EPS even at >80% occupancy
Yokoi et al. Neuropsychopharmacology. 2002;27:248.

34. Aripiprazole binding to three
different receptors: D2, 5HT1A, 5HT2A

35. Partial Agonism at
5-HT1AReceptors: Clinical
Implications
• 5-HT1A partial agonists have been associated
with:
-Improvement in negative and cognitive
symptoms.
-Benefits for mood and anxiety symptoms.
-Decreased rates of EPS.
Millan. J Pharmacol Exp Ther. 2000;295:853.
Roth et al. Clin Neurosci Res. 2003;3:108.

36. Antagonism at 5-HT2A Receptors:
Po Clinical Implications
• 5-HT2A receptor antagonists modulate
dopaminergic activity and are associated
with:
-Decreased liability for EPS
-Amelioration of negative symptoms
-Improvements in cognition
• 5-HT2A receptor antagonists enhance
therapeutic responses to selective
serotonin reuptake inhibitors in patients
with major depression
Roth et al. Clin Neurosci Res. 2003;3:108.
Roth and Shapiro. Expert Opin Ther Targets. 2001;5:685.
Marek et al. Neuropsychopharmacology. 2003;28:402.

38. Dopamine Partial Agonism
• Aripiprazole is the first dopamine partial agonist
approved by the FDA for the treatment of
schizophrenia:
-Efficacy against positive and negative
symptoms.
-Minimal EPS.
-No elevation of prolactin levels.
-Minimal (if any) weight gain.

39. Aripiprazole Switch Study:
Study Design, Duration, and Inclusion
Criteria
• Design
-Multicenter, randomized, Open-label
-Parallel group
• Duration: 8 weeks
• Inclusion criteria
-Stable dose for at least 1 month prior to randomization
-No hospitalizations for acute exacerbations within
2 months of randomization
Casey et al. Psychopharmacology (Berl). 2003;166:391.

40. Change In Body Weight Following
Switch To Aripiprazole
-3
-2
-1
0
1
From olanzapine From risperidone From haloperidol
Meanchangeinweight(kg)
*
†
*P<0.001; †P=0.077. LOCF analysis.
Casey et al. Psychopharmacology Berl. 2003;166:391.
n= 169 106 14

41. Aripiprazole Switch Study:
Change in Serum Prolactin Following
Switch to Aripiprazole
-40
-30
-20
-10
0
From olanzapine From risperidone From haloperidol
Meanchangein
prolactin(ng/mL)
*
*
†
n= 171 108 15
*P0.01; †P0.05. LOCF analysis.
Casey et al. Psychopharmacology. 2003;166:391.

42. • 26-week, open-label design
• Aripiprazole 30 mg vs olanzapine 10-15 mg
• Diagnosis: schizophrenia or schizoaffective disorder
• Patients (N=255)
– Age 18-65 years
– Stable psychosis (not hospitalized for exacerbation
of symptoms for 2 months prior to randomization)
• Prior medication: stable dose of a first-generation
antipsychotic, risperidone, or quetiapine for 1 month
Cornblatt et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185.
Neurocognitive Function Trial:
Aripiprazole vs Olanzapine

43. Secondary Verbal Memory
• Ability to acquire, store, and retrieve
verbal information for more than a few minutes
• Plays an important role in activities of daily
living, employment, and general functioning
Addington and Addington. Schizophr Res. 2000;44:47.
Green et al. Schizophr Bull. 2000;26:119.

44. Neurocognitive
Function Trial: Improvement in
Secondary Verbal Memory
*P<0.05 vs baseline.
Based on the California Verbal Learning Test; LOCF analysis.
Cornblatt et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Week 8 Week 26
Aripiprazole (n=76) Olanzapine (n=93)
*
*
EffectSize
P<0.05P<0.05

45. Neurocognitive Function Trial:
Incidence of Significant Weight Gain
0
5
10
15
20
25
30
35
40
4 weeks 8 weeks 26 weeks LOCF
Incidence(%)
Aripiprazole
Olanzapine
n= 71 79 65 82 47 60 107 111
*
*
*Significantly greater than aripiprazole, P≤0.01.
Clinically significant weight gain is defined as ≥7% from baseline.
Data on file, Otsuka America Pharmaceutical, Inc.

46. BETA: Study Design
1649 patients enrolled
1-14 days screening and washout
Single antipsychotic agent
(no prior exposure)
chosen by investigator
Dosed by labeling guidelines
Safety Control (n=304)Aripiprazole (n=1295)
Starting dose = 15 mg/d
Dose range = 10-30 mg/d
65.0%
Completed
56.9%
Completed
1599 patients randomized
8-week open-label treatment
4:1 ratio
Data on file, Otsuka America Pharmaceutical, Inc.

47. BETA: Preference of Medication for
Individual Drugs by Week
0
10
20
30
40
50
60
70
Week 1 Week 2 Week 4 Week 8 End point
%ofpatients
Aripiprazole
Ziprasidone
Risperidone
Quetiapine
Olanzapine
Others
Weekly assessments: OC analysis; end point assessment: LOCF analysis (patient samples:
aripiprazole = 1214, ziprasidone = 99, risperidone = 49, quetiapine = 47, olanzapine = 29,
others = 21).
*Relative to prior antipsychotic medication.
Data on file, Otsuka America Pharmaceutical, Inc.
Percent of Patients Responding “Much Better”*

48. These data do not imply direct comparison among agents.
Data for aripiprazole, ziprasidone, risperidone, quetiapine, and olanzapine from US labels.
Clinically Significant (7%)
Weight Gain During Antipsychotic
Treatment from US Labels
0
5
10
15
20
25
30
35
Placebo
A
ripiprazole
Placebo
Ziprasidone
Placebo
R
isperidone
PlaceboQ
uetiapine
Placebo
O
lanzapine
Incidence(%)
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35

49. Incidence of Cardiovascular Adverse
Effects: Long-Term Trials
 26-week comparison with Olanzapine:
-Mean QTc interval reduction of 4.61
msec (Aripiprazole) and mean increase of
1.35 msec (Olanzapine)
Stock et al. Int J Neuropsychopharmacol. 2002;5(suppl
1):S186.
Pigott et al. J Clin Psychiatry. 2003;64:1048.
Data on file, Otsuka America Pharmaceutical, Inc.

50. Aripiprazole 26-Week Trial:
Effects on Lipids
-14
-12
-10
-8
-6
-4
-2
0
2
4
Total
cholesterol
LDL HDL Triglycerides
Placebo
Aripiprazole
n = 83 80 82 74 83 80 91 93
Baseline = 177 191 102 113 47 47 143 161
Medianchange
frombaseline(mg/dL)
Fasted plasma samples. LOCF analysis.
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
Pigott et al. J Clin Psych. 2003;64:1048.

51. Aripiprazole 26-Week Trial: Change
From Baseline in Fasting Glucose
Levels
0
2
4
6
8
Placebo Aripiprazole
Changefrombaselinein
glucoseconcentration
(mg/dL)
n= 92 93
LOCF analysis.
Pigott et al. J Clin Psychiatry. 2003;64:1048.

52. Aripiprazole Safety And Tolerability
Summary
 As expected from its pharmacologic profile,
aripiprazole is safe and well tolerated
-Favorable EPS profile
-No increase in plasma prolactin
-Relatively low rates of somnolence
-No clinically relevant QTc or orthostatic effects

53. Aripiprazole Safety And Tolerability:
Summary
-Minimal effects on weight
-No significant effect on lipids and glucose vs
placebo
-Adverse effects that do occur in the short term
with aripiprazole are generally mild and
transient
 Favorable safety and tolerability profile of
aripiprazole contributes to its overall
effectiveness

54. How to switch into Aripipracare
From high-potency antipsychotic
• High-potency antipsychotic:
– Relatively higher D2 blockade, have a weaker affinity
with other receptor (H1, adrenergic, muscarine) than
low-potency antipsychotic
• Successful switching:
– Be careful of overlapping period
– Minimum 2~3 weeks are needed for preventing D2
withdrawal symptom
• mild & stable patients,
– 1~2 week of overlapping period & 2 weeks of
down –titration period
• severe & high dosage patients,
– overlapping for 2~3 weeks are needed

57. Potential Mechanism of Anti- Depressant
Effects
 Precise mechanism unknown.
 - May be related to high affinity for
serotonergic over dopaminergic receptors.
 - Downregulation of 5HT2A receptors.
 - Increase 5HT1A in PFC….increase Da.
 - Rapid dissociation fromD2: less dysphoria
 - Action on neurotensin, glu., BDNF..?
 - Action on 5HT6,7 ?
 - Action on 5HT2C
 - Role of “NET” for “Nor-quetiapine”.

58. Potential Mechanism of Anti- Depressant
Effect
May be related to high affinity for
serotonergic over dopaminergic receptors.

59. FDA Approved APs in MDD

61. THE LANCET
Efficacy, safety, and tolerability of
augmentation pharmacotherapy with
aripiprazole for treatment-resistant
depression in late life:
A randomised, double-blind, placebo-controlled trial at three centres in the
USA and Canada to test the efficacy and safety of aripiprazole augmentation
for adults aged older than 60 years with treatment-resistant depression
(Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15).
Patients who did not achieve remission during a pre-trial with venlafaxine
extended-release (150–300 mg/day) were randomly assigned (1:1) to the
addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or
placebo for 12 weeks.
Published:September27,2015

62. Reduction in depressive symptoms
during augmentation with Aripiprazole

63. Pimavanserin
• Pimavanserin (Nuplazid, Acadia Pharmaceuticals),
a novel antipsychotic, when added to standard
treatment with an antidepressant, showed
"statistically significant and clinically relevant"
improvement in symptoms for patients with
resistant major depressive disorder (MDD).
News > Medscape Medical News > Psychiatry News
Megan Brooks
September 27, 2019

64. Pimavanserin
• As reported by Medscape Medical News,
pimavanserin is already approved for the
treatment of hallucinations and delusions in
patients with Parkinson disease psychosis.
• Although most antipsychotics bind
to dopamine, acetylcholine, histamine, and 5-
HT2A receptors, pimavanserin targets only 5-
HT2A receptors.

67. Respridone & Aripirazole are The

69. Drug Developer Description Targeted Indication(s) Expected Pricing
Strategy
Anticipated U.S.
Launch Date
Atypical Antipsychotics
ALKS 3831 Alkermes Fixed-dose
combination of mu-
opioid receptor
antagonist
(samidorphan) and
atypical antipsychotic
(olanzapine)
Schizophrenia (acute
exacerbations or stable
disease)
Priced at premium to
olanzapine (Zyprexa,
Lilly)
Third quarter of 2019
AVN-211 Avineuro
Pharmaceuticals
5-HT6 receptor
antagonist
Cognitive impairments
associated with
schizophrenia
Undetermined Undetermined
ITI-007 Intra-Cellular
Therapies
5-HT2A receptor
antagonist
Acute and residual
schizophrenia
Priced at premium to
currently marketed oral
antipsychotics
First half of 2018
Promising Compounds in Clinical Development for the Treatment
of Schizophrenia in Adults

70. MIN-101 Minerva
Neurosciences
5-HT2A and sigma-2
receptor antagonist
Schizophrenia Priced at premium to
currently marketed oral
antipsychotics
2019
RBP-7000 Indivior Sustained-release
risperidone
Schizophrenia (acute or
maintenance treatment)
Priced at premium to
Risperdal Consta
(Janssen)
Fourth quarter of 2017
Risperidone
implant Braeburn
Pharmaceuticals
Six-month,
nonbiodegradable,
drug-eluting stent
Schizophrenia
(maintenance
treatment)
Priced at 15% premium
to annual cost of
therapy with Risperdal
Consta
Second quarter of 2018
Risperidone ISM Rovi
Pharmaceutical
Laboratories
Once-monthly IM
formulation based on
ISM delivery system
Schizophrenia or
schizoaffective disorder
Priced at premium to
Risperdal Consta
Fourth quarter of 2019

71. Hyperammonemia Agent
Sodium
benzoate
(NaBen) SyneuR
x International
(Taiwan) Corp.
D-amino acid
oxidase inhibitor
•Pediatric
schizophrenia
•Refractory
schizophrenia
(in combination
with clozapine)
•Adjunctive
therapy for
schizophrenia in
adults
Undetermined Undetermined