Lecture1 Chile SGAs

1
Sydney-Santiago 2015
Professor Tim Lambert
BSc MBBS PhD FRANZCP
SYDNEY MEDICAL SCHOOL
Professor and Head of Psychiatry

Concord Medical School, University of
Sydney
Schizophrenia Treatments and Outcomes
Research
Director, ccCHIP clinical programmes
Node leader CPC: Schizophrenia and
medical comorbidities; Complex Systems
2
Lecture timetable
10:30 - 12:00 Atypical antipsychotics
12:00 - 13:00 Discussion
14:00 - 16:00 Cardiometabolic effects and sleep
disorders in (medicated) psychotic patients
coffee
16:30-18:30 Clinical evaluation and monitoring
of people with severe mental disorder.
Go
2
Centres of Excellence for Relapse Prevention

CENTRES OF EXCELLENCE FOR RELAPSE PREVENTION
Seminar 1:
AtypicalCERP
antipsychotics
CERP
Centre of Excellence for Relapse Prevention
Focus on Schizophrenia
1. The 3 swirls convey fluidity and movement.

The ellipse shape represents a centre of excellence from
which knowledge is shared and disseminated.
2. Humanistic approach. Each circle and curve represents
a person while the central circle represents the centre of
excellence. This icon symbolizes a group of people coming
together to share information.
LL
CE
EN
FOR RE
LA
P
SE
4a. Existing colouration
VENTION
PRE
NTRE OF EXC
CE
E
CERP
CERP

4b. Red colouration
CERP

3. A global icon. The circles and lines represents a network

from which knowledge is shared and disseminated.
4. The circle within the centre of the letter C represents

excellence within the field of Schizophrenia.
lecture1_chile_SGAs.key - 6 July 2015
Context/background
The future of medicine
COMPLEXITY
The illnesses; the patient; the health system
COMORBIDITIES
Multiple systems, pathologies
CHRONICITY
Dynamic
SEVERITY
Mensuration;domain spans; interactions
FUNCTION/OUTCOME
Biological; social; psychological;
multidimensional
Clinical imperatives
6
6
Arguably, the three main areas that require increased
clinical and research focus and attention in psychosis are

the following:
Relapse
Prevention
Medical
comorbidity
Treatment
refractory
Phase of illness
Early
Relapsing
Stable
basis of schizophrenia
treatment
Optimised Functional outcomes
so
tre
al
gic
ho
yc
Vocation /
social role
Ps
at
m
en
olo
ac
re
lt
ph
ar
m
at
cia
Social and family

functioning
ho
Ps
ts
yc
en
Behavioural
1
Suicidality
Symptom factors
(Positive, negative, cognitive, affective, excited)
Optimised Psychopharmacological treatment foundation
Discussed further in lecture 3
Antipsychotic development
phases
FGAs
orals then
depots
SGAs
orals then
LANAs
4 LA-SGA
3
long-acting FGA ('depots')

FGA ('typicals')
1
1950
SGA ('atypicals')
1960
1970
1980
1990
2000
2010
FGA=First Generation Antipsychotic; SGA= Second-generation antipsychotic; LANA=Long-Acting Novel

Antipsychotic
Dopamine blockers
All these
drugs share a common

pharmacology - they block postsynaptic D2 receptors and, more
variably, a variety of other
receptor types.
Reviewing dopamine circuits generates
an heuristic model of the relationship

of dopamine biology to therapeutic and
toxic effects of antipsychotics
Dopamine systems
10
10
FGAs (aka conventional or 'typical'
antipsychotics) block the action of

dopamine-2 receptors (D2R) throughout ALL
of the brain.
They do not discriminate between the brain
regions, blocking frontal, basal, pituitary, as
well as limbic dopaminergic systems.
This is said to be in contrast to the 'atypical'
antipsychotics (see below).
DAergic areas of interest
11
11
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
12
12
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFCMesolimbic
(possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Overactivity
Striatal DAergic
of systems
DA inare
associated with
movement
these
disorders, and
projections
some cognitive
function to be
thought
associated
DA acts
as the
with
positive
PRIF
symptoms
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
13
13
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
14
14
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Striatal
DAergic
systems are
associated
with
movement
disorders,
and
Pituitary
some
cognitive
function
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Basal
15
15
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
16
16
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Pituitary
Striatal DAergic
systems are
associated with
movement
disorders, and
Hypofunction of
some cognitive
PFC (possibly
function
through
underactive D1
mediated
DA acts
as the
PRIFcircuits)
(neurohormone).
underlies
Affected
by DA
negative,
blockade by low
cognitive, some
Ki antipsychotics
mood
symptoms.
Mesocortical
Basal
17
17
Mesolimbic
Mesocortical
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Hypofunction of
PFC (possibly
through underactive
D1 mediated
circuits) underlies
negative,
cognitive, some
mood symptoms.
Basal
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
18
18
Mesolimbic
Overactivity of DA
in these
projections
thought to be
associated with
positive
symptoms
Basal
Pituitary
Hypofunction of
PFC (possibly
through underactive
D1 mediated
DA acts as the PRIF
circuits) underlies
(neurohormone). negative,
Affected
by DA blockade
cognitive,by
some
Mesocortical
mood symptoms.
low Ki antipsychotics
Striatal DAergic
systems are
associated with
movement
disorders, and
some cognitive
function
DA acts as the
PRIF
(neurohormone).
Affected by DA
blockade by low
Ki antipsychotics
Pituitary
19
FGAs or SGAs?
19
Problems associated with

FGAs
20
20
Problem area
Poor efficiency (50% success rate; low remission)
Little, no, or negative effects on dimensions other than positive symptoms
(i.e. negative, cognitive, affective, aggressive)
Potential worsening of cognition (NIDS)
Many potentially severe side effects (risks) with reduced benefits (directly
contributing to reduced adherence)
Specific problems related to polypharmacy and high doses
Link to (self-medicating) substance abuse
FGA= First generation antipsychotic (typicals)
Based on: Lambert & Castle. Med J Australia (2003) 178(9 Suppl): S57-61
21
NIDS
21
Mental
function
Neuroleptic side effect
Negative symptom
Vigilance
Drowsiness, somnolence
Attentional impairment
Cognition
Reduced speed of thinking

Concentration difficulties
Narrowing of mind
Fuzzy head
Alogia
Poverty of speech
Conation
Apathy
Lack of energy
Weak, tired
Avolition, apathy
Diminished sense of purpose
Affectivity
Flat affect
Indifference
Affective blunting
Restricted affect
Emotionality
Lack of feeling
Dysphoria
Dead inside
Diminished emotional range
Motivation
Anhedonia
Reduced drive
Reduced initiative
Anhedonia, asociality
Curbing of interest
Diminished social drive
Diminished curiosity
Lewander, 1994.
22
Proposed advantages of SGAs
22
When comparing SGAs to FGAs there is a
tendency to conflate clozapine with other

SGAs.
This may inflate effectiveness for domains
such as positive symptoms, aggression,
suicidality, and mood1.
With this caveat, the perceived/reported
advantages of SGAs over FGAs include the
following:
23
23
Improved therapeutic effect in some treatment-resistant

patients (mainly clozapine).2
Improved therapeutic effect on negative symptoms,3-5
and neurocognitive deficits.6,7
Reductions in aggression and hostility.8-10

Modifying depression within schizophrenia.11
Reduced potential to cause acute extrapyramidal side
effects (EPS; e.g, akathisia, dystonia, parkinsonism)
and
reduced potential to cause longer-term EPS (eg,

tardive dystonia, tardive dyskinesia, tardive akathisia).13
1 Marder, S. R. et al. Schizophr Bull 28, 5-16 (2002). 2 Wahlbeck, K.et al Am J Psychiatry 156, 990-999 (1999). 3
Moller, H. J Int Clin Psychopharmacol 13 Suppl 3, S43-7 (1998). 4 Moller, H. J. CNS Drugs 17, 793-823 (2003). 5
Corrigan, P. W.,et al Schizophr Res 63, 97-101 (2003). 6 Harvey, P. D. & Keefe, R. S. Am J Psychiatry 158, 176-184
(2001). 7 Keefe, R. S.,et al Schizophr Bull 25, 201-222 (1999). 8 Keck, P. Eet al J Clin Psychiatry 61 Suppl 3, 4-9
(2000). 9 Spivak, B., et al. J Clin Psychiatry 64, 755-760 (2003). 10 Essock, S. M., et al ,Arch Gen Psychiatry 57,
987-994 (2000). 11 Siris, S. G. Am J Psychiatry 157, 1379-1389 (2000).
24
24
Reduction of suicidality within schizophrenia.12

Reduced potential to elevate prolactin levels with the
exception of risperidone and amisulpride, in some
cases 14
Improvement in psychosocial function5

Enhancement of QoL15-18
Better overall tolerability19
Better subjective wellbeing experienced by patients20
Reduced relapse rates21
12 Meltzer, H. Y. et al. Arch Gen Psychiatry 60, 82-91 (2003). 13 Caroff, S. N.,et al, J Clin Psychiatry 63 Suppl 4, 12-19
(2002). 14 Dickson, R. A. & Glazer, W. M. Schizophr Res 35 Suppl, S75-86 (1999). 15 Cook, P. E., et al, Can J
Psychiatry 47, 870-874 (2002).16 Voruganti, L. et al. Schizophr Res 43, 135-145 (2000). 17 Voruganti, L. N. P., et al,
Journal of Psychiatry and Neuroscience 22, 267-274 (1997).18 Lambert, M. & Naber, D. CNS Drugs 18 Suppl 2, 5-17;
discussion 41-3 (2004).
19 Naber, D. & Karow, European Neuropsychopharmacology. 11, S391-6 (2001). 20 Naber, D. et al, Schizophr Res 50,
79-88 (2001). 21 Leucht, S. et al. Am J Psychiatry 160, 1209-1222 (2003). 22 Bagnall, A. M. et al. Health Technol
Assess 7, 1-193 (2003)
25
25
For those that have been sufficiently

examined, many have modest effect sizes
and most are yet to be confirmed through
appropriate meta-analyses and further
research22.
However, proven or otherwise, there is wide

acceptance of their potential benefits by many
psychiatrists, sufferers, and their carers and
families.
19 Naber, D. & Karow, European Neuropsychopharmacology. 11, S391-6 (2001). 20 Naber, D. et al, Schizophr Res 50,
79-88 (2001). 21 Leucht, S. et al. Am J Psychiatry 160, 1209-1222 (2003). 22 Bagnall, A. M. et al. Health Technol
Assess 7, 1-193 (2003)
26
On the other hand.
26
If efficacy differences are a myth, it is

a myth that reduces costs. Because
there are qualitative and quantitative
adverse effect and efficacy differences
among SGAs, we believe that most
guidelines that group SGAs as a
homogeneous class are imprecise.
Davis et al, 2003
27
SGAs: evidence and uptake policy
27
In an editorial published in the British Journal of

psychiatry (2006), the authors wrote:
Rich countries develop and evaluate the new drugs, and these same
nations are the first focus of the initial decades of marketing. As the
battle of the companies is fought out in high-income countries,
clouds of dust from marketing obscure the view. Unless effects are
dramatic, it takes decades for the dust to settle. . . . During this
period many in the lower-income countries have to observe the
battle from afar and they are forced to use older drugs. . . .
Evidence-based practice is the judicious use of the best available
evidence in patient care or policy making . . . , by the time drugs
are widely accessible in lower-income nations, the best available
evidence may well be better in these poor countries than was the
case when the drugs were first marketed in rich nations. [1]
1. Adams, C.E.; Tharyan, P.; Coutinho, E.S.; & Stroup, T.S. (2006) The schizophrenia drug-treatment paradox:
Pharmacological treatment based on best possible evidence may be hardest to practice in high-income
countries. British Journal of psychiatry, 189, 391392.
28
LMIC and policy re SGAs
28
Horvitz-Lennon et al1 assessed the quality of the scientific
evidence available to policymakers in Chile, a middle-income

country.
Minimal LMiC-specific scientific evidence to inform policy analyses

exists. What exists is heavily biased.
Only 4 studies existed and SFX including CMRFs were not considered
sufficiently.
LMiCs that are able to manufacture or import cheaper generic atypical

drugs have readily embraced them.
Chiles experience indicates that an LMiC that implemented policies
when evidence from higher-income countries strongly favored atypical

drugs responded to new evidence to the contrary, but not forcefully
enough to counter pressure from advocates or market forces.
Horvitz-Lennon, M., Iyer, N., & Minoletti, A. (2013). Do Low- and Middle-Income Countries Learn from the
Experience of High-Income Countries? Lessons from the Use of Atypical Antipsychotics for Treatment of
Schizophrenia. International Journal of Mental Health, 42(1), 33-50.
Meta-analysis1
29
124 studies of SGAs vs FGAs; 18 studies of SGAs
Effect size in each study (solid circles) for 10 drugs, with better second-generation antipsychotic efficacy
indicated by positive effect sizes. The mean effect size of each drug is indicated by a short horizontal bar.
1. Davis JM, et al. Arch Gen Psychiatry. 2003;60:553-564.
Meta-analysis1
Test
Effect size
Statistic
30
Magnitude descriptors
Small
Medium
Large
Correlation
0.1
0.3
0.5
t-test
Cohens d
0.2
0.5
0.8
Multiple regression
f2
0.02
0.15
0.35
ANCOVA/MANCOVA
Partial 2
< .06
.06 < .14
0.14
Drug update
continued
31
Targets and initiating
31
Table. Using atypical antipsychotic therapy in schizophrenia

Agent
Near-maximal effective dose*
Comments on initiating therapy
Amisulpride (Solian Tablets

and Solution)
200 mg/day
Low dose may activate a patient; addition of a benzodiazepine

may be helpful in the first two weeks
Aripiprazole (Abilify)
10 mg/day
Activation and other initiation side effects suggest that addition

of a benzodiazepine may be useful in the first five to 10 days
Clozapine (Clopine,
CloSyn, Clozaril)
>400 mg/day
Requires slow titration (in approved centres only)
Olanzapine (Zyprexa)
>16 mg/day
Can cause sedation

May be increased to full dose quickly in the management of
Quetiapine (Seroquel)
150 to 600 mg/day
Risperidone (Risperdal)
4 mg/day
Can cause initial hypotension, which suggests dose should be

built up over 3+ days in some patients
50 mg/two weekly
Requires antipsychotic cover (oral or previous depot) for three
Oral
acute relapse
Causes sedation, but can be initiated to maximal doses
reasonably quickly in acute relapse
Injectable
Risperidone, long acting
(Risperdal Consta)
to six weeks until a steady state is reached
* Based on reference 18. The near-maximal effective dose is the threshold dose necessary to produce all or almost all the clinical responses for each drug. These values are not
inconsistent with maintenance doses for patients with multiepisode schizophrenia.
Upper limit not yet clearly defined.
practical advice for professionals and for ules that a patient can fill out in the waiting
From:Lambert T. Atypical antipsychotics in schizophrenia: a guide for GPs.
consumers and carers can be downloaded room may provide an efficient method of
55-58; * Davis & Chen. J Clin Psychopharm 2004;24:192-208
from www.psychiatry.unimelb.edu.au/ identifying issues that are of immediate
open/ diabetes_consensus.) The principles importance to the patient. An example is
outlined in the consensus statement are the Liverpool University Neuroleptic Side
consonant with those proposed by the Effect Rating Scale (LUNSERS), which can
RACGP.23
be completed in about three minutes.24-25
However, many side effects are not simply
What about side effects?
attributable to antipsychotics: psychotropic
It is important to enquire about common polypharmacy is common in mental health
side effects of antipsychotics because these settings and contributes substantially to
have an impact on quality of life and daily side effects such as weight gain and sedafunction and, subsequently, adherence to tion. Polypharmacy should be avoided
treatment. Sedation, weight gain, akathisia, whenever clinically possible.
and sexual side effects often cause much
distress. Patients may experience long-term Conclusion
extrapyramidal side effects, such as tardive GPs care for a substantial proportion of
dyskinesia, but they might not complain patients with schizophrenia, and many
of these spontaneously.
atypical antipsychotics are now available
Many GPs have limited time to investi- for treating this illness. Selecting medicagate side effects in depth. Self-report sched- tions and maintaining patients on these
32
medications requires careful monitoring

(2006). Medicines Today. 7(1):
of adherence, outcomes, mental state, and
physical health status so that the risks and
benefits are balanced. For most patients
with schizophrenia, treatment is long term,
and forming an enduring relationship
with a GP will enhance the possibility of
recovery by maximising the potential of
treatment.
MT
A list of references is available on request
to the editorial office.
DECLARATION OF INTEREST: Associate Professor
Lambert has been a member of advisory boards for
Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, Sanofi,
Novartis and Faulding. He has received funding for
unrestricted research from Eli Lilly, Novartis, JanssenCilag, Bristol-Myers Squibb, Pfizer and AstraZeneca,
and travel assistance to attend meetings from Eli Lilly,
Novartis, Janssen-Cilag and Bristol-Myers Squibb.
Average doses in real world
58
MedicineToday
32
January 2006, Volume 7, Number 1
SGA
Dose (mg/d)1
Olanzapine
18.1
Risperidone
4.1
Clozapine
418
Quetiapine
511
Amisulpride
650*
Aripiprazole
19.1*
Risperidone
LAI2
46 q2
1. SGA doses from audit of adult community patients in Victoria with schizophrenia (2005); 2 Average q2 dose
IM from HIC, IMS, and audit data (2006); * doses may be supra Maximal Effective Dose (MED) proposed by
Davis and Chen (op cit.)
33
Average doses in real world

SGA
Dose (mg/d)1
~400mg CPZe (TL)
Olanzapine
18.1
17.6
12
Risperidone
4.1
4.1
3.2
Risperidone LAI2
46 q2
50 q2
Clozapine
418
400
480
240
33
~400mg CPZe (SL)
Quetiapine
511
600
Amisulpride
650*
400
Aripiprazole
19.1*
10^
16
Asenapine
12
16
Paliperidone
4.8
PLAI
100 q4
Ziprasidone
160
64
SGA doses from audit of adult community patients in Victoria with schizophrenia (2005); 2 Average q2 dose IM
from HIC, IMS, and audit data (2006); * doses may be supra Maximal Effective Dose (MED) proposed by
Davis and Chen (op cit.)^ partial dopamine agonist; equivalence is approximate from practice. Leucht et als
values are here for comparison and do raise a number of questions.
converta
http://www.addat.com/converta/index.html#/converta
34
34
35
Mechanisms
35
Efficacy and Consequences
36
36
Mechanisms
Potential clinical
efficacy
Potential consequences
D 2R
antagonism
positive symptoms
EPS
Negative symptoms
Cognitive symptoms
PRL
D2R partial
agonism
positive symptoms
negative symptoms
cognitive deficits
Little or no EPS
Behavioral activation
DA and NE
release in the
PFC
negative symptoms
cognitive deficits
depressive symptoms
Behavioral activation
ACh release in
the PFC
cognitive deficits
Miyamoto S, et al (2005). Mol Psychiatry, 10(1), 79-104
37

37
Mechanisms
Potential clinical
efficacy
Potential
consequences
5-HT2A antagonism
negative symptoms
EPS
5-HT1A partial
agonism
negative symptoms
cognitive symptoms
anxiety symptoms
depressive
symptoms
??? activation
Muscarinic R
antagonism
EPS
Anticholinergic
symptoms e.g. dry
mouth, constipation
tachycardia, cognitive
38

38
Mechanisms
Potential clinical
efficacy
Potential
consequences
Muscarinic R
agonism
psychotic symptoms
cognitive deficits
[See withdrawal
section - CRS]
Glutamate modulation
positive symptoms
negative symptoms
cognitive deficits
illness progression
Apoptosis /
neurodegeneration
39
FGA affinities1
39
Receptor
TRZ
HP
FF
CPZ
FPT
5-HT1A
5-HT2A
5-HT2C
D1
D2
D3
D4
2A
2B
2C
1A
1B
M1
M4
H1
Ki
Affinity
<1
Very strong
Strong
10
Moderate
100
Mild
1,000
Very weak
10,000
Negligible
1 Roth BL, et al. (2004). Nat Rev Drug Discov, 3, 359364.
40
SGA affinities
40
Receptor
ZIP
QUET
RIS
ARI
OLZ
CLOZ
AMI
5-HT1A
5-HT2A
5-HT2C
D1
D2
D3
D4
2A
2B
2C
1A
1B
M1
M4
H1
1 Roth BL, et al. (2004). Nat Rev Drug Discov, 3, 359364.
Balancing the equation
41
41
Source: Universal Antipsychotic Converter Addat Pty Ltd 2001-2008
42
Use of pharmacological parameters
42
From the above this will allow us to predict problems
with switching (mismatch on both sides of the equation)
It will also allow us a priori to guesstimate side-effects

were likely to see emerge or to improve postswitching
It helps us to understand pharmacodynamic interactions

that might express themselves as DDIs, or peculiar nonlinearities in efficacy or side effects.
Lets examine some clear winners and losers in the side

effects domain for SGAs.
43
Risks (Safety)
Risks
43
Common antipsychotic SFX
44
44
Muscarinic
Histamine
Dopamine
Blurred vision
Weight Gain
Parkinsonism
Dry mouth
Drowsiness
Akathisia
Constipation
Sedation
Dystonia
Urinary
?Hypotension Dyskinesia
retention
Decreased
Hyperprolactin
sweating
aemia
Glaucoma
?NIDS
hazard
Dysmnesis
Speech block
Delirium
Adrenergic Serotinergic
Postural
hypotension
Reflex
tachycardia
Drive
reduction
Affective
Weight gain
Sexual
function
Headache
Insomnia
NIDS = neuroleptic induced deficit syndrome
45
EPS
45
Types of (common) NIEPS
46
46
Type
Comment
Parkinsonism
Four components: rigidity, bradykinesia,

tremor, postural stability.
bradyphrenia
Akathisia
Three components: subjective (feelings of

inner restlessness), objective (motor signs);
akathisic distress (subjective)
Dystonia
Twisting, pulling or squeezing; involuntary,

often within 96 hrs of Rx; variable sustain
Dyskinesia
Two broad co-occuring subtypes: choreic;

athetoid (snake-like); may blend with t.
akathisia and t. dystonia
Acute
Tardive
Dystonia
Akathisia
Consequences of EPS
47
Even in the era of SGAs, neuroleptic-induced extrapyramidal disorders (NIEPS)

remain a significant public health risk.
Consequences of EPS include:
Behavioural disturbances
suicidality,
homicidal urges
Social withdrawal
Akinetic phenomena
Link to persistent dyskinetic and other tardive phenomena
agitation,
Misdiagnosis and misapprehension of symptoms
Stigma
Poor quality of life
EPS should not be acceptable in modern pharmacotherapy
EPS and D2r occupancy
D2 Receptor Occupancy
47
Patient non-adherence
48
This sometimes conceptualised as a dyskinetic

variant
48
With both FGAs

and some SGAs
once 80% of D2
receptors are
occupied in BG,
parkinsonism
will follow.
This sets the upper

threshold of the SGA
reference range
Kapur, S., et al (2000). Relationship between dopamine D(2) occupancy, clinical response, and side effects: a
double-blind PET study of first-episode schizophrenia. Am J Psychiatry, 157(4), 514-520.; Seeman, P. &
Tallerico, T. (1998). Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine
to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry, 3(2), 123-134.
49
EPS: agents are not equal
49
Acute EPS
Antipsychotic
Dose dependent
RIS, AMI, ZIP, OLZ,

FGAs
Flat ~ low
CLOZ, QUET, ARI
Rates of EPS with FGAs

are up to 65%1
Rates with SGAs have

fallen substantially but are
not equal among agents2
Tardive phenomena have

also fallen to <20% of
FGAs but have not
disappeared3
1 Iqbal et al (2007) CNS Spectr. 2007;12(9 Suppl 14):1-16; 2 Weiden, P. J. (2007). EPS profiles: the atypical
antipsychotics are not all the same. J Psychiatr Pract, 13(1), 13-24; 3 Correll, C. U., Leucht, S., & Kane, J. M.
(2004). Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review
of 1-year studies. Am J Psychiatry, 161(3), 414-425.
50
TD: FGA vs SGA
50
There are only two
RCTs of annualised TD
incidence (AFAIK)1,2
RIS
HP
OLZ
Note that the rate is
very much lower in the

SGAs
Open studies for other
SGAs show similar

trends (e.g. ARI 0.2%)3
1 Beasley CM,, et al. Br J Psychiatry. 1999;174:23-30.; 2 Correll CU,et al. Am J Psychiatry.

2004;161:414-25. 3 Swainston Harrison T, Perry CM. Drugs. 2004;64:1715-1736
51
Moderators/effectors of EPS
Modulator
SGA
M1 antagonism
CLOZ, OLZ
5HT2A antagonism
RIS, ZIP, OLZ, CLOZ, QUET, ARI
D1-D2 links
?NDM-CLOZ
5HT1A agonism
ARI, ZIP
Fast-off
CLOZ, QUET
Pre-synaptic D3/D2
AMI
Partial DA agonists (PDA)
ARI, NDM-CLOZ
Neuropeptides
51
AMI=Amusulpride; ARI=Aripiprazole; CLOZ=Clozapine; OLZ=Olanzapine; QUET=Quetiapine;

RIS=Risperidone; ZIP=Ziprasidone; NDM-CLOZ= N-desmethyl Clozapine
EPS and D2r occupancy
52
52
However, the
fast-off
antipsychotics
are usually
unable to
compete with
DA for D2R
sites
Leads to low
EPS as DA
throughput is
OK
Kapur, S., et al (2000). Relationship between dopamine D(2) occupancy, clinical response, and side effects: a
double-blind PET study of first-episode schizophrenia. Am J Psychiatry, 157(4), 514-520.; Seeman, P. &
Tallerico, T. (1998). Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine
to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry, 3(2), 123-134.
53
Tight/loose binding
53
Seeman, P. et al. (1999). Am J Psychiatry, 156(6), 876-884.
54
SDA and EPS: hypothesis
54
Serotonin modulation pushes the

curve to the right
Yamada, Y., et al. (2002). Prediction and assessment of extrapyramidal side effects induced by risperidone
based on dopamine D(2) receptor occupancy. Synapse, 46(1), 32-37.; Kapur, S. & Remington, G. (1996).
Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry, 153(4), 466-476.
55
EPS: effect of intrinsic

activity
55
Intrinsic activity
decreases the DA
antagonistic
effects
Based on: Yokoi, F., et al. (2002). Neuropsychopharmacology, 27(2), 248-259. Net effective occupancy
imputed from Shapiro, D. A., et al. (2003). Aripiprazole, a novel atypical antipsychotic drug with a unique
and robust pharmacology. Neuropsychopharmacology, 28(8), 1400-1411.
56
Example Movements - TD:
Oro-buccal
56
Mouth and Tongue: Pre
57
In the next video, the degree of lingual
movements (composite hyperkinetic

movements) were socially embarrassing to
the patient and affected his speech.
He shows lingual tremor, dyskinesia, and
some mild jaw dystonia to the left
57
Poly-antipsychotics: FGAs
58
58
Mono-therapy: SGA
59
Monotherapy after 12 weeks
59
Mouth and tongue: post
60
The lingual tremor with
superimposed chorea has

substantially diminished.
Both stigma and discomfort
are reduced
60
61
Hands
61
Poly-antipsychotics: FGAs
62
Mono-therapy: SGA
63
62
63
Monotherapy after 12 weeks
64
Resource: EPS CD
64
All 1st to 3rd year BMRI trainees may

acquire a CD from Trudy (as a disk image).
Only works on Win and pre-intel

Macs sorry may update to
modern language in next year.
oGATES 6.5
Page 6 of
65
Resource: GATES
65
Structured interview to
generate standard scores
(BAS, AIMS, AS, etc).
Training occurs when demand is
sufficient. Concord training will be in

July.
General Akathisia Tardive phenomena & Extrapyramidal rating Schedule OBJective v6.5 T Lambert 1999
oGATES 6.5
Page 7 of
O12. TORTICOLLIS / RETROCOLLIS / ANTEROCOLLIS

Is torticollis or retrocollis or anterocollis (ie dystonia) present?
No
Yes
0
1
ES11. ACUTENESS OF NECK DYSTONIA

If neck dystonic movements are found, ask the patient:
Have these [movements] started recently or been present for more than a few weeks?
Examiner: Based on the patients report and any existing clinical knowledge, rate the acuteness of
the dystonia.
No neck dystonia
Acute neck dystonia
Persistent/chronic/tardive neck dystonia
Definite acute on chronic dystonia
Unsure
0
1
2
3
4
Using the GATES: Parkinsonian

rigidity
O13. Do the movements appear to be dyskinetic (ie athetotic movements)?
66
No
Yes
66
0
1
O20. ARM DROPPING.

Both the patient and the examiner raise their arms to shoulder height and then, on the command, let
them drop to their sides. If the patient cant relax, stand behind and ask the patient to raise their
arms to shoulder height. Support their arms at the level of the mid forearm or elbow joint. Tell the
patient:
Im going to take my hands away. When I do, let your arms fall to your sides naturally dont
help them fall.
A normal response is a quick fall with a clear slap or bounce.
Normal free fall with slap and
Fall slowed slightly less rebound
Fall slowed, no rebound
Marked slowing, no slap at all
Arms fall as though through glue
0
1
2
3
4
[The patient may require to be distracted in order to relax. Asking the patient to make their limbs go
floppy, like a rag doll, sometimes helps].
021. PASSIVE SHOULDER MOVEMENTS

Examiner: Grasp the patients elbow and hand. The elbow is flexed at 90. Do the following to the
flexed arm.
Abduct it; adduct it; Externally and internally rotate it; Flex it; Extend it; shake the whole limb like a
floppy rag doll, ensuring that the shoulder joint is able to move and rotate freely.
Repeat for the other shoulder.
Shoulder stiffness
Normal
Slight stiffness and resistance
Moderate stiffness and resistance
Left
0
1
2
Right
0
1
2
General Akathisia Tardive phenomena & Extrapyramidal rating Schedule OBJective v6.5 T Lambert 1999
oGATES 6.5
Page 8 of
Using the GATES: Objective

Akathisia
GATES v6.5 - Akathisia abstracted items
67
67
OBJECTIVE AKATHISIA
Examiner: You may later return to any of the items below and recode them if new phenomena
appear during the course of the examination. If you noticed any of these movements during the
preamble or, if completed, during the subjective questionnaire, please indicate below.
O1. ROCKING FROM FOOT TO FOOT/ WALKING ON THE SPOT
Examiner: watch the person for knee jiggling or other signs of restlessness which may occur
despite the soles of the feet remaining steady (milder cases). The patient may march on the spot
but doesnt take a step off this spot (more marked cases).
None
Just noticeable
Mild
Moderate
Frequent and gross
0
1
2
3
4
O2. INABILITY TO REMAIN STANDING ON THE SPOT.

Examiner: The patient may appear to step off the spot, shuffle a little, walk around the spot or
frankly pace the room, or even leave. This item is usually accompanied to some degree by
movements in the previous item (O1).
None
Oscillates, walks a pace or two
Walks around the room
Paces
Urgently paces or leaves room
0
1
2
3
4
DURATION OF AKATHISIC MOVEMENTS

This item (O3) is completed following item O75 (ie. at the conclusion of the examination).
Remember to observe for Akathisic motor movements throughout the interview.
GATES v6.5 - Akathisia abstracted items
Resources: Akathisia DVD
68
68
69
Prolactin
Target
Risk potential
PRL
Prolactin sparing; Similar profile to QUET and

CLOZ5
69
Neurohormone effects of DA
antagonism
70
70
Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: structure, function and regulation of
secretion. Physiol Rev 2000; 80: 1523-31.; Gudelsky GA. Tuberoinfundibular dopamine neurons
and the regulation of prolactin secretion. Psychoneuroendocrinology 1981; 6: 3-16
Neurohormone effects of DA
antagonism
71
71
Stimulating factors: Serotonin

5HT1A, 5HT2A; oestrogens;
(TRH, CCK; GABA)
Inhibiting factors:
Dopamine; (Ach;GAP)
DA acts as a neurohormone
(prolactin-release inhibiting
factor) to prevent the release
of prolactin by binding to DA
receptors.
Tight blocking of D2 receptors

leads to hyperprolactinaemia
Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: structure, function and regulation of secretion. Physiol Rev
2000; 80: 1523-31.; Gudelsky GA. Tuberoinfundibular dopamine neurons and the regulation of prolactin
secretion. Psychoneuroendocrinology 1981; 6: 3-16
Hyperprolactinaemia
side effects
72
5%
Gynecomastia
7%
Galactorrhoea
50%
Loss libido
18%
Orgasm Disorder
SFX
72
Erectile dys.
23%
Ejeculation dys.
23%
75%
Menstrual disorder
Amenhorrhoea
35%
Osteporosis
0
20
40
60
80
73
Variable hyperPRL risks

No or minimal PRL PRL increase above the
increase
norm (dose dependent)
Olanzapine
Higher
Risk
Paliperidone
Ziprasidone
Amisulpride (all doses)
Clozapine
Risperidone (all doses)
Quetiapine
FGAs (all doses)
Aripiprazole
Zotepine (from 100mg)
Lower
Side eects commonly seen are:
Gynecomastia (3-6%); Loss of libido (40-60%); Orgasm disorder

(15-20%); Erectility dysfunctions (20-25%); Ejaculation
dysfunctions (20-25%); Galactorrhoea (5-10%); Menstrual
disorders (70-80%); Amenhorrhoea (20-50 %); osteoporosis (?%)
73
74
PRL: FGAs and SGAs
74
Data from five preclinical
studies1 involving 1,648

patients indicated that the
PRL-sparing SGA
aripiprazole increased
prolactin levels above the
upper limit of normal in
only 1.8% of patients,
compared to substantial
increases in prolactin levels
with either haloperidol
(FGA) or risperidone (SGA;
54 and 89%, respectively).
1 Abou-Gharbia N, et al. Meta-analysis of prolactin effects with aripiprazole. Schizophr Res

2003;60:350.
75
PRL: background1
75
Prolactin sparing: ARI,ZIP,CLOZ,OLZ,QUET

Prolactin raising: FGAs, RIS, AMI, ?PALI
60% female, 40% male had elevated PRL levels on PRL-raising drugs
Direct (PRL) and indirect (hypogonadism) effects
HyperPRL may be symptomatic or asymptomatic
In the young, these consequences may play an over-determined role
in discontinuation (and nonadherence)2
Amenorrhoea for 1 year should be investigated

Consider early detection by both lab work and a direct sfx history for
medications which are PRL-raising
1 Haddad, P. M. & Wieck, A. (2004). Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical

features and management. Drugs, 64(20), 2291-2314. 2 Kelly DL, Conley RR. Sexuality and schizophrenia:
a review. Schizophr Bull. 2004;30:767-779.
76
PRL: treatment
76
The option for dose reduction carries appreciable risk of relapse
in the current era where SGA doses are often optimal. FGA doses
may, however, still be too high, and gradual reduction is possible
Switching, or first-line prescribing of a PRL-sparing agent has

preventative potential - an arguably better option
Haddad, P. M. & Wieck, A. (2004). Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical

features and management. Drugs, 64(20), 2291-2314. Note: ALAI is probably PRL-sparing; ? OLAI
77
Cognitive
77
78
Common antipsychotic SFX

78
Muscarinic
Histamine
Dopamine
Blurred vision
Weight Gain
Parkinsonism
Dry mouth
Drowsiness
Akathisia
Constipation
Sedation
Dystonia
Urinary
retention
Decreased
sweating
Glaucoma
hazard
Dysmnesis
Speech block
Delirium
?Hypotension
Adrenergic
Serotinergic
Postural
hypotension
Reflex
tachycardia
Drive reduction
Affective
Weight gain
Sexual
function
Dyskinesia
Headache
Hyperprolactin
aemia
Insomnia
NIDS
NIDS = neuroleptic induced deficit syndrome
79
NIDS
79
Mental function
Neuroleptic side effect
Negative symptom
Vigilance
Drowsiness, somnolence
Reduced speed of thinking
Concentration difficulties
Narrowing of mind
Fuzzy head
Apathy
Lack of energy
Weak, tired
Flat affect
Indifference
Lack of feeling
Dysphoria
Dead inside
Attentional impairment
Alogia
Poverty of speech
Cognition
Conation
Affectivity
Emotionality
Motivation
Anhedonia
Reduced drive
Reduced initiative
Avolition, apathy
Diminished sense of
purpose
Affective blunting
Restricted affect
Diminished emotional
range
Anhedonia, asociality
Curbing of interest
Diminished social drive
Diminished curiosity
Lewander, 1994; NIDS=Neuroleptic Induced Deficit Syndrome
Patients and sedation
80
80
Patients often worry about sedation and the other
psychic cluster UKU side effects, more so than other

SFX 1,4
Patients rank concern as sedation > weight > EPS5
Doctors may not hear the patients complaints and
often underestimate their importance to the patient2
Past and present side effects are a major cause of later

non-adherence3, as the disjunction in communication
styles leads to a sense of diminished therapeutic
relationship (a major predictor of non-adherence)
1 Hofer, A. et al. (2002). J Clin Psychiatry, 63(1), 49-53.; 2 Seale et al. Social science & medicine (2007). 65 (4)
pp. 698-711; 3 Lambert, M. et al. (2004). Eur Psychiatry, 19(7), 415-422.; 4 Angermeyer, M. C. et al. (2001).
Psychol Med, 31(3), 509-517.; 5 Angermeyer, M. C. et al. (1999). Psychiatr Prax, 26(4), 171-174.
Cognitive deficits:FGA=SGA
81
81
Cognition is a significant focus as a treatment target in schizophrenia.

Typically, neither first- nor second-generation antipsychotics have a
clinically meaningful beneficial effect on cognition in schizophrenia.
There is a gap between the beneficial effects of second-generation antipsychotics observed in animal studies
using tests of very specific behavioral abilities and the modest to negligible effects in global
neuropsychological function seen in clinical studies that remains to be fully understood.
There is a need for greater validation of standardized neuropsychological batteries (i.e., the Measurement
and Treatment Research to Improve Cognition in Schizophrenia program) as an approach for assessing
cognitive outcomes in comparison to other approaches rooted in cognitive neuroscience.
Other valid methodologies for evaluating cognitive treatment effects, such as those grounded in
translational neuroscience, have not been utilized frequently or effectively.
For future research and drug development, a translational/biomarker approach may be more effective.
Significant hurdles to obtaining an indication for cognitive enhancement include validation of functional
outcome measures and understanding the time and psychosocial supports needed for cognitive changes to
translate into improved community function.
Developing approaches for using cognitive profiles and pharmacogenetics to individualize treatment
selection are promising strategies for potential advancement in this area.
Hill, S. K., Bishop, J. R., Palumbo, D., & Sweeney, J. A. (2010). Effect of second-generation antipsychotics
on cognition: current issues and future challenges. Expert Review of Neurotherapeutics, 10(1), 4357.
82
Dealing with poor

adherence:
SGA-LAIs*
Slides for this section extracted from the CERP
education programme
*Second generation Long-acting Injectable antipsychotics
82
Adherence in psychosis
83
80% of patients with

schizophrenia are nonadherent at some stage of
1
their illness
Adherence is dynamic - 67% of

patients will be non-adherent
from time to time during any
2
one 12 month period
About a quarter become

partially adherent within 14
3
days
83
On any day, the median
nonadherence rate is about

4
50%
1 Corrigan, P. W. et al. (1990). Hosp Community Psychiatry, 41(11), 1203-1211. 2 Williams CL et al. 1999. Med
Care, 37(4 Suppl Lilly), AS81-6.; 3 Velligan et al(2003) op. Cit.; 4 Oehl, M. et al. (2000). Acta Psychiatrica
Scandinavica, Supplementum, 102(407), 83-86
SGA adherence
84
84
A three month study of discharged patients1. All pts in
possession of medication at start with future adherence

defined as 80% of prescribed dose
25% missed doses in first 10-14 days.
At 3 months 25% rehospitalised; 12% jailed/homeless
Self-report: 55% said fully

adherent
MPR: 40% (only 9% took all
doses in the 3 month period)
Blood levels: 23%
BUT.up to 90+% of
doctors believe their pts are
adherent at various times
1 Velligan, D. I., et al(2003). Psychiatric Services, 54(5), 665-667.; 2 Byerly et al quoted in Marder SR.
(2003). The Journal of clinical psychiatry, 64 Suppl 16, 3-9.
85
Relapse: consequences
85
Having more intense psychotic symptoms when

admitted after poor adherence
Neurobiological damage is thought to accrue in
association with positive symptom relapses
Each relapse results in increasingly longer times to
remission
Tim Lambert 2009-2015
Relapses contribute to psychosocial decline, perhaps

secondary to worsening pos/neg symptoms
86
Nonadherence:
consequences
86
Psychological consequences include:

demoralisation,
hopelessness,
poor self-esteem,
increasing isolation (1 and 2)
disruption to family
suicide risk (4x)
87
Nonadherence:
consequences
87
Social consequences include:

Requiring more involuntary treatment
Longer hospital stays if nonadherent preadmission
Fracturing the gossamer-like social
connections re-established after previous
relapses
Greater direct and indirect costs (service,
community, patient, family)
Bedtime reading
88
SGA-LAIs: different vehicles
89
88
89
The FGA-LAIs are all oil-based. The current and forthcoming SGA-LAIs (LANAs) no longer rely on
the older oil paradigm
RLAI is an interim delivery formulation, being based on microsphere technology whilst those that
follow are based on crystal technology
Target FGA-LAI
Fluphenazine
Haloperidol
Flupenthixol/
zuclopenthixol
RLAI
OLAI
PALI
ALAI
Delivery
Need for crossover

oral adjunct AP
FGAs
Oil-based
Oil-based
Moderate
Moderate
Oil-based
Moderate
SGAs
Microspheres
Crystal
Crystal
Crystal
High
Nil/minimal loading
Nil/Minimal loading
Nil/minimal loading
Lambert T and Taylor D (2010) in Haddad et al, op.cit
Benefits of SGA-LAIs
90
90
Arguably the main benefit of SGA-LAIs has been in

the ability to control the kinetics (or at least
understand the release probabilities better)
There are also the advantages of the SGA class (low

EPS)
As ALL antipsychotic prescribing should be dynamic
and personalised, some SGA-LAIs allow for easier

joint decision-making with patient when the dosing is
adjusted (below)
91
FGA-LAI release kinetics
91
Note the fatty acid tail is lipophilic and the AP head is
hydrophilic; once the head is out of the oily FGA-LAI, it is

hydrolysed to the free antipsychotic
Source: The Lundbeck Education Program on FGA-LAI Antipsychotics CD-ROM Addat Pty Ltd
92
FGA-LAI Kinetics
92
Real world and computer
models agree that steady

state occurs in ~2-3
months.
However, elimination is NOT

reciprocal. Many patients
develop fibrotic lumps and
FGA-LAI becomes loculated.
apparent half-lives have
been recorded as long as

3-6 months with18 month
elimination times
Source: The Lundbeck Education Program on FGA-LAI Antipsychotics Tim Lambert 1999
93
Microsphere action
93
The very different mode of action should be contrasted

against that seen for the depot FGAs (oil-based).
94
Plasma-dose levels
94
Reduced peak to
trough (less side
effects)
Mean plasma
levels towards
the lower side
(hypofrontal
targeting)
CERP Workshop
Pharmacokinetic profile of PLAI initiation

regimen compared to oral paliperidone ER
95
95
Median pharmacokinetic profiles for paliperidone for 5 weeks following
paliperidone palmitate administration using the recommended initiation regimen

compared to the administration of an oral modified-release tablet (6 mg or 12
mg)
4
0
3
5
Median
[PLAI]
(ng/
mL)
3
0
2
5
2
0
1
5
Oral 6 mg paliperidone ER
Oral 12 mg paliperidone ER
Paliperidone palmitate
Estimated oral 6 mg steady-state
Estimated oral12 mg steady-state
1
0
5
0
1
1
5
Time (day)
2
2
2
3
Product Information
9
6
Invega Sustenna
CERP Workshop
Median plasma concentration-time

profiles, by treatment
96
96
1 4
15
22
36
50
64
78
92
Plasma concentration ng/mL

(paliperidone or active moiety)
35
30
25
20
15
10
5
RLAI (+ oral risperidone*)
RLAI injections
Paliperidone palmitate (+ oral placebo*)
Paliperidone palmitate injections
0
1 4
15
22
36
50
64
78
92
Time (days)
*Oral risperidone received for first three weeks and then again at dose change (ie not given for the duration of trial)
RLAI, risperidone long-acting injectable; from study PALM-PSY-3006
Pandina et al. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:218226
CERP Workshop
Time to steady state: OLAI
97
97
Mean SD olanzapine plasma concentrations; 405 mg/q4 in LOBE patients 1

100
Olanzapine (ng/ml)
80
60
40
20
0
12
16
20
24
Time after first injection (weeks)

FDA website (accessed 11.16.2008): http://www.fda.gov/OHRMS/DOCKETS/ac/08/slides/
2008-4338s-Lilly-Core-Backup.ppt
CERP Workshop
98
SGAs and cardiometabolic risk

One of the main problems of all generations of
antipsychotics has been their link to obesity, insulin

resistance, dyslipidaemia and so on
We will discuss aspects of this area

seminar.
in the next
99
Centres of Excellence for Relapse Prevention

Seminar 1:
AtypicalCERP
antipsychotics
CERP
1. The 3 swirls convey fluidity and movement.

The ellipse shape represents a centre of excellence from
which knowledge is shared and disseminated.
2. Humanistic approach. Each circle and curve represents
a person while the central circle represents the centre of
excellence. This icon symbolizes a group of people coming
together to share information.
LL
CE
EN
FOR RE
LA
P
SE
4a. Existing colouration
VENTION
PRE
NTRE OF EXC
CE
E
98
CERP
CERP

4b. Red colouration
CERP

3. A global icon. The circles and lines represents a network

from which knowledge is shared and disseminated.
4. The circle within the centre of the letter C represents

excellence within the field of Schizophrenia.

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SYDNEY MEDICAL SCHOOL

Professor and Head of Psychiatry

Centres of Excellence for Relapse Prevention

Centre of Excellence for Relapse Prevention

Centre of Excellence for Relapse Prevention

1. The 3 swirls convey fluidity and movement.

4a. Existing colouration

Centre of Excellence for Relapse Prevention

4b. Red colouration

Centre of Excellence for Relapse Prevention

3. A global icon. The circles and lines represents a network

4. The circle within the centre of the letter C represents

lecture1_chile_SGAs.key - 6 July 2015

The future of medicine

The illnesses; the patient; the health system

Multiple systems, pathologies

Mensuration;domain spans; interactions

Arguably, the three main areas that require increased

clinical and research focus and attention in psychosis are

lecture1_chile_SGAs.key - 6 July 2015

Optimised Functional outcomes

Social and family

Discussed further in lecture 3

long-acting FGA ('depots')

FGA=First Generation Antipsychotic; SGA= Second-generation antipsychotic; LANA=Long-Acting Novel

drugs share a common

an heuristic model of the relationship

lecture1_chile_SGAs.key - 6 July 2015

FGAs (aka conventional or 'typical'

antipsychotics) block the action of

DAergic areas of interest

DAergic areas of interest

lecture1_chile_SGAs.key - 6 July 2015

DAergic areas of interest

DAergic areas of interest

DAergic areas of interest

lecture1_chile_SGAs.key - 6 July 2015

DAergic areas of interest

DAergic areas of interest

DAergic areas of interest

lecture1_chile_SGAs.key - 6 July 2015

Problems associated with

Neuroleptic side effect

Reduced speed of thinking

Diminished emotional range

lecture1_chile_SGAs.key - 6 July 2015

Proposed advantages of SGAs

When comparing SGAs to FGAs there is a

tendency to conflate clozapine with other

Proposed advantages of SGAs

Improved therapeutic effect in some treatment-resistant

Reductions in aggression and hostility.8-10

reduced potential to cause longer-term EPS (eg,

Proposed advantages of SGAs

Reduction of suicidality within schizophrenia.12

Improvement in psychosocial function5

lecture1_chile_SGAs.key - 6 July 2015

Proposed advantages of SGAs

For those that have been sufficiently

However, proven or otherwise, there is wide

On the other hand.

If efficacy differences are a myth, it is

SGAs: evidence and uptake policy