Quetiapine XR provides advantages over the immediate release formulation for patients and clinicians. It allows for once-daily dosing, simplifies titration, and facilitates reaching therapeutic doses earlier through an initial higher dose. This makes adherence more likely. Studies also found Quetiapine XR had a better tolerability profile with less sedation and orthostatic hypotension compared to the immediate release formulation. Quetiapine more broadly has benefits for treating depression, psychosis, and behavioral symptoms associated with various neurological conditions due its antidepressant, antipsychotic, and sleep promoting effects with a low risk of side effects.

1. “Quetiazic”
(Extended Release Quetiapine)
in Clinical Neurological Practice
Dr.Tarek Asaad
Prof. of Psychiatry, Ain Shams University
Director of Psychophysiology & Sleep Unit
Chief Editor : Current Psychiatry ME Journal
Secretary of Cross Cultural Psychiatry Center

3. Agenda & Objectives
• Disclosure.
• Mechanism of action of Quetiazic.
• From Pharmacology to clinical practice?
• Advantages of Quetiapine XR > IR ?
• Role of Quetiazic in Neurology :
A-General Overview
B-Examples : 1-Parkinsonism
2-Dementia
3-Stroke
4-MS

4. Quetiapine molecule
• An atypical antipsychotic
developed as an
improvement from first
generation
antipsychotics.
• Quetiapine IR: FDA
Approved 1997
• Quetiapine XR: FDA
approved 2007

5. Quetiapine: mechanism of
action..
Quetiapine is a
dopamine, serotonin,
and adrenergic
antagonist, and a
potent antihistamine
with clinically negligible
anticholinergic
properties.
Guzman, F. "Mechanism of action of quetiapine".
Psychopharmacology Institute. Retrieved 20 January

6. Why is “Quetiapine” considered “The
Clever Molecule” ?
• It has low affinity to D2 receptors,SO:
1-It binds to D2 receptor (60-80%), thus,
producing the therapeutic anti-psychotic effect.
2-It rapidly dissociates from the receptor
( because of the low affinity), thus NOT reaching
>80% blockade, that is why it has no EPS
The “Rapid Dissociation” or “Hit & Run “ Theory

7. Hit & Run Mechanism of “Quetiapine”
D2 affinity < 60% block 60-80 % block > 80% block Example
1-No affinity YES
No anti-
psychotic
effect
NO
No AP effect
NO
No EPS
Non-AP
psychotropics
2-Low-
moderate
affinity
NO YES
Therapeutic
AP effect
NO
No EPS side
effect
Quetiapine
3-High
affinity
NO YES
Therapeutic
AP effect
YES
EPS Side
effects
Typical &
some
Atypical APs

8. Quetiapine: Different drugs at different
doses…….
Stahl, S. 2008. “StahFs Essential Psychopharmacolo
Neuroscientific Basis and Practical Applications”.

9. Dose –Response Relation
A-1 H NE D2 Cinical
<100mgs +++ +++ ++ - ? -sed./PH
-AD effect ?
100-300
mgs
+++ +++ ++++ + or - ? -No more sed / PH
-AD effect
>300 mgs +++ +++ ++++ +++ -No more Sed./PH
-AD effect ?
-Anti-agitation ?
-Anti--psychotic

10. Quetiapine Paradox ?
Alpha 1 Histamine NE
Reuptake
Clinical effect
Low doses <
100 mgs
+++ +++ ++ -Sedation ,
postural
hypotension
(Adverse effect)
-Starting AD
effect ?
Higher doses +++
(SAME)
(SATURATED)
+++
(SAME)
(SATURATED)
++++ -No more
sedation or
postural
hypotension
-maybe
improvement of
retardation?
-AD effect?

11. Approved Indications of “Quetiapine”
• Acute & maintenance schizophrenia.
• Bipolar : acute mania.
• Bipolar : depression.
• Bipolar : maintenance
• Psychosis in adolescents
• Adjuvant X monotherapy ? in MDD
• GAD (Canada) ?

12. Quetiapine: FDA Approvals
• 2007 – approved for treatment of
schizophrenia.
• 2007 – approved as maintenance
treatment for schizophrenia.
• 2008 – approved for bipolar
depression and bipolar mania.
• 2009 – approved as add-on treatment
of major depressive disorder.
• 2004 – approved for acute mania as
mono-therapy or combination.
• 2006 – approved for bipolar depression.
• 2008 – approved for bipolar maintenance.
Quetiapine
IR
Quetiapine
XR

13. Quetiapine: off-label indications
• Sleep promoting drug
• Agitation
• Substance abuse
• GAD (generalized anxiety
disorder) (Canada)
• Borderline personality disorder
• Parkinson's disease psychosis

14. Quetiapine : off-label indications
• 23.3% of Quetiapine prescriptions are for 25
mgs, which is not indicated except for titration
period!, meaning that it is mainly for “Off-label”
indication!
• In 2010, quetiapine was the 5th biggest selling
drug (6.8 billion$), and a penalty of 520$was
paid for “Off-label” uses!
• CBC News 15/4/2014 : Quetiapine is the known
“Sleeping Pill” for prisoners in Canada!
• Low dose quetiapine : Pace in Therapy: Health
News & Evidence, 11/4/2014 : Cntroversies!?

15. Quetiapine: Hypnotic & anxiolytic drug
at 25-50 mg……….
• High affinity to H1
receptors.
Stahl, S. 2008. “StahFs Essential Psychopharmacolo
Neuroscientific Basis and Practical Applications”.

16. Quetiapine: Antidepressant drug at 300
mg…..
Triple effect on different neurotransmission pathways
Dopaminergic
pathway
5HT2A antagonist
5HT1A partial agonist
5HT2c
α2 antagonist
5HT6 antagonist
Serotonin transporter
Noradrenaline
pathway
5HT2C antagonist
NET antagonist
5HT6 antagonist
α2 antagonist
Serotonergic
pathway
5HT7 antagonist
α2 antagonist
Serotonin transporter
inhibition
Stahl, S. 2008. “StahFs Essential Psychopharmacolo
Neuroscientific Basis and Practical Applications”.

17. FDA-Approved APs for
“Depression”
FDA-Approved
AP
Unipolar
depression
Bipolar depression Mechanisms
Quetiapine Yes (Add on) Yes (Monotherapy) NET,5HT1A,2A,2c,
5HT7,….
Aripiprazole
Bexipiprazole
Yes(Add on) No Da &5HT1A PA,
5HT7
Olanzapine Yes (Combined
with Fluoxetine)
Yes (Combined with
Fluoxetine)
5HT2c, others?
Lurazidone Not yet Yes (Monotherapy) 5HT1A PA, 5HT7,
Alpha2..?

18. Quetiapine: Practical market is far away from
approved indications………. WHY????
• The issue of “Compliance”
o More treatment adherence = more
likelihood for remission
o Titration policy may hinder
compliance.
o Initial dose is away from the
therapeutic dose.
• The issue of “Efficacy”
o Quetiapine IR is most of the time
under dosing.
• The issue of “Tolerability”
o Sedation , postural hypotension &
weight gain.

19. QUETIAPINE
THE LONG-ACTING VERSION

20. What is quetiapine XR?
Quetiapine XR is released from the hard core over the course of a 20 hour
period
Hydrated Gel Layer
Water Channel Hard Core
Hydration & Gel Formation

21. ADVANTAGES OF “Quetiapine XR”
• The issue of “compliance” ?
- More treatment adherence = more likelihood
for remission
- Titration policy may hinder compliance ?
• The issue of “tolerability”?
- Sedation , postural hypotension..?

22. Q & A : Quetiapine XR
Q1-Why is better efficacy expected with
Quetiapine XR > IR ?
A1-For two main reasons :
a-More likelihood to reach optimal dose in
schizophrenia (500-800) early
( Quetiapine usually under-dosed? why?)
b-More adherence (easy once dosing)

23. Q & A : Quetiapine XR
Q2-Is there a difference in pharmaco-kinetics
between Quetiapine XR & IR ?
A2-
IR XR
1-T max 1 hour –peak 6 hours-dome
2-Dose-Level
Curve Non-linear Linear
3-T ½ , Absorption,
Elimination SAME SAME

24. Quetiapine XR vs IR:
pharmacokinetics in Humans
Plasmaconcentration(ng/mL)
300 mg Quetiapine XR
300 mg Quetiapine IR
Time (hr)
200
400
600
800
1000
0
0 5 10 15 20 25
-tmax longer with quetiapine XR
(6 hours vs 1 hour)
-Quetiapine XR released
gradually over a 20-hour
period compared with rapid
release and elimination
with quetiapine IR
-Quetiapine XR once daily has
linear dose-proportional
pharmacokinetics up to 800
mg
-No change in t1/2, overall
absorption or elimination
pathways from the body
-AUC similar for both
Css
max (geometric mean; fasted
patients) were:
AstraZeneca; Study 118 data on file

25. Q & A : Quetiapine XR
Q3-Is there difference in side effect profile
between Quetiapine IR & XR , regarding
sedation, postural hypotension, Wt gain? Why ?
A3-Initial sedation & postural hypotension is less
with XR ,probably with less Weight gain?, but no
evidence of a difference in other adverse effects
( i.e.less “peak-dose”related AEs)

26. Incidence and Time to Onset of Adverse Events*
of Special Interest
3 (2.4)
9.0
1 (0.8)
3.0
1 (0.9)
4.0
2 (1.8)
3.5
1 (0.8)
24.0
Tachycardia
Incidence, n (%)
Median time to onset (days)
0 (0)
—
0 (0)
—
0 (0)
—
0 (0)
—
0 (0)
—
Syncope
Incidence, n (%)
Median time to onset (days)
2 (1.6)
7.0
1 (0.8)
13.0
0 (0)
—
0 (0)
—
0 (0)
—
Orthostatic hypotension
Incidence, n (%)
Median time to onset (days)
7 (5.7)
4.0
8 (6.6)
2.0
10 (8.8)
4.0
6 (5.3)
12.5
1 (0.8)
2.0
Dizziness
Incidence, n (%)
Median time to onset (days)
2 (1.7)
12.5
PBO
(n=118)
9 (7.3)
2.0
14 (11.6)
2.5
10 (8.8)
2.0
8 (7.1)
3.0
Somnolence
Incidence, n (%)
Median time to onset (days)
800 mg
(n=121)
600 mg
(n=113)
400 mg
(n=113)
Quetiapine
IR 400 mg
(n=123)
QuetiapineXR
*MedDRA preferred terms
Study 132

27. Change in Weight
Study 132
18.411.121.117.36.6>7% increase in weight (%)
87
1.8
90
1.9
91
2.1
82
1.3
76
0.5
OC safety population, nb
Mean change from
baseline (kg)
7.8
115
0.5
PBO
(n=118)
14.48.517.414.7>7% increase in weight (%)
118
1.4
117
1.5
110
1.8
110
1.1
Safety population, na
Mean change from
baseline (kg)
800 mg
(n=121)
600 mg
(n=113)
400 mg
(n=113)
QuetiapineI
R 400 mg
(n=123)
Quetiapinel XR
aNumber of patients with non-missing observations; bOC, observed cases: number
of patients with assessment at randomization and at the last visit (Day 42)

28. Tolerability profile
0,00%
5,00%
10,00%
15,00%
20,00%
25,00%
sedation Orthostatic hypotension
Pooled Safety
Population
Meulien et al Poster Presented at the 16th European Congress of Psychiatry, Nice, France, 5-9 April ´08.
IR 600 mg(n=86) XR 600 mg (n=310) XR 800 mg (n=323) Placebo(n=314)

29. Clinical Rationale for Development
of Quetiapine XR
To provide physicians and patients with enhanced
convenience of use and potentially improve
adherence by:
SINGLE DOSE--Once-daily dosing
SIMPLE TITRATION--Simplifying dose titration
SATISFACTORY INITIAL DOSE--Initiating therapy at a
higher dose
SPEED OF REACHING THERAPEUTIC DOSE--Reaching
therapeutic dose range as early as possible

30. Quetipine in Neurological Practice

31. Quetiapine for Neurological patients
• Advantages of Quetiapine in treatment of
depression associated with neurological
disorders :
1-In addition to its AD effect, it can control
associated behavioral symptoms.
2-It can control sleep problems without he need
to give a sedative or hypnotic.
3-It lacks the troublesome side effects of AD drugs
(e.g.SSRIs), like anhedonia, GIT upsets & sexual
dysfunction

32. Quetiapine for Neurological patients
• Advantages of Quetiapine for control of
“Psychosis” associated with neurological
disorders”:
1-It gives good control at low doses.
2-It has a sleep promoting effect.
3-It lacks the common EPS side effect
observed with other AP drugs.
4-It has good cognitive profile.

33. Quetiapine improves verbal fluency:
Patients with schizophrenia; Quetiapine treatment:
mean duration 5.7 months; mean dose 364 mg/day
fMRI session conducted during overt verbal fluency task
Drug-naïve Quetiapine-treated
Functional magnetic resonance imaging (fMRI)
Jones HM et al. Biol Psychiatry 2004; 56: 938-942.

34. Benefit of “Quetiapine” in :Parkinsonism
BENEFIT EVIDENCE COMMENT
1-Psychosis,
associated with
Parkinsonism
1-Targum et al, J Clin Psychopharmacology, 2000
2-Jorge et al, J Movement Disorders, 2004
3-Fernandez et al, Int J Neuroscience, 2009
3-Shotbolt et al, Therapeutic Advances in
Neurological Disorders,2010
Psychosis = up to
40%, visual
hallucinations are
common/ might be
related to
medications?
2-Cognitive
functions,
Depression,
Anxiety…
1-Jorge et al, J Movement Disorders, 2004
2-Weiintraub et al, Neuropsychiatric & cognitive
changes in Parkinsonism, Cambridge University
Press, 2013
Improvement in
recall
3-Parkonism-
related sleep
disorders
1-Juri et al, clin Neuropharmacol, 2005
2-Dopadoc Parkinsonism International, july 2011
Low dosed used
4-Drug-induced
Dyskinesia ?
Katzenschager et al, J Neurol, Neurosurg &
Psychitry, 2003
Low dose used :
25,50 mgs

35. Illustrating Example
“Quetiapine improves psychotic symptoms &
cognition in Parkinsonism”
( Jorge et al , J Movement Disorders, 2004)
• 23 elderly included after failure of clozapine,
olanzapine or risperidone
• Dose of Quetiapine ranged from 12.5-400 mgs
(Average = 62.5 mgs), for 24 weeks
• Results :
1-Improvement in Brief Psychiatric Rating Scale &
Neuropsychiatric Inventory (BPRS/NPI)
2-No decline in Unified PD Rating Scale
3-Significant improvement in recall

36. Pimavanserin : A New Hope for
Parkinsonism-associated Psychosis!?
Are There Other Options?
• 5HT2A-inverse agonist, Phase III clinical trial
• The 1st,to be indicated specifically for psychosis
associated with Parkinsonism by FDA , 2013…
• Da Maagd (11/12/2015, P&T Community) :
Treatment options for non-motoric Parkinsonian
symptoms? Role of Quetiapine?
• A common HCV infection may lead to
Parkinsonism & Neuropsychiatric symptoms:
(J Neurology,24/12/2015) !?

37. Benefit of “Quetiapine” in : Dementia
• Treatment of BPSD, as agitation, psychosis &
depression
( Despite the “Blackbox” warning, physicians
highly use AAP, as quetiapine in patients with
dementia : Archives of Neurology, july,2011) !
• Ongoing research on the low dose Quetiapine
for insomnia in Alzheimer’s Disease :
-University of Vermont : National Center for
Research Resources NCRR
-Contact : Sally.analom@vt mednet.org

38. Vascular Risk with Quetiapine in the Elderly
• Quetiapine associated with moderately lower risk of
CV events than Olanzapine & Risperidone
( Comparative risk of cerebro-vascular events in
community dwelling older adults using risperidone,
olanzapine & quetiapine : a multiple propensity score
adjusted retrospective cohort study, Challenger et al,
Drugs.Aging, 2012
• Other studies did not show conclusive differences :
Leyton et al, Psychopharmacology, 2005 / Shin et al,
Psychopharmacology, 2013 / Pasternak et al , risk of
acute major cardiovascular events, cohort study in
Denmark, CNS Drugs, 2014…..

39. Benefit of “Quetiapine” in : Stroke
• Delusional Disorder with Delusions of
Parasitosis & Jealousy after Stroke :
Treatment with Quetiapine & Sertraline
(Blasco-Fontecilla et al Clin Psychoph, 2005)
• Quetiapine for Hypersexuality & Delusional
Jealousy after Stroke
(Chae et al, J Clin Psychpharmacology, june
2006)
• Role in Sleep, PSD, agitation…..

40. Benefit of “Quetiapine” in :MS
• Apart from its value in depression, agitation & sleep, it
has a possible role in the patho-physiology of MS !?
EVIDENCE :
1-Quetiapine enhances oligo-dendrocytic regeneration &
myelin repair after Cuprizone-induced demyelination
(Zhang et al, Sch Res, 2012)
2-Quetiapine is protective against auto-immune mediated
demyelination, by inhibiting T-cell proliferation (Mei et al,
PLoS One,2012)
3-Quetiapine for treatment of MS : focus on myelin repair
(Zhornisky et al, CNS Neurosc.Ther.,2013)
4-Remyelination Strategies in MS ( Luessi t al,Exp Rev Neu
Therapeutics, 2014)

42. Administration
• Once Daily dose on
empty stomach.
• Don’t score the
tablet.

43. Packages
30 tab.
75 L.E.
30 tab.
150 L.E.
30 tab.
195 L.E. 30 tab.
225 L.E.
50
mg 150
mg
300
mg 400
mg

44. Your patient
worth it