Lecture1 Chile SGAs PDF

1
Sydney-Santiago 2015
Professor Tim Lambert

BSc MBBS PhD FRANZCP
Professor and Head of Psychiatry

Concord Medical School, University of
Sydney
Schizophrenia Treatments and Outcomes
Research
SYDNEY MEDICAL SCHOOL
Director, ccCHIP clinical programmes
Node leader CPC: Schizophrenia and
medical comorbidities; Complex Systems
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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
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3
Centres of Excellence for Relapse Prevention
CENTRES OF EXCELLENCE FOR RELAPSE PREVENTION
Seminar 1:
’Atypical’CERP CERP
antipsychotics
Centre of Excellence for Relapse Prevention
Focus on Schizophrenia Centre of Excellence for Relapse Prevention
Focus on Schizophrenia
1. The 3 swirls convey fluidity and movement. 2. Humanistic approach. Each circle and curve represents
The ellipse shape represents a centre of excellence from a person while the central circle represents the centre of
which knowledge is shared and disseminated. excellence. This icon symbolizes a group of people coming
together to share information.
FOR RE
CERP
CE
EN LA
LL P
4a. Existing colouration
E
SE
NTRE OF EXC
PRE

VENTION
CE
CERP
4b. Red colouration
CERP
3. A global icon. The circles and lines represents a network 4. The circle within the centre of the letter C represents
from which knowledge is shared and disseminated. excellence within the field of Schizophrenia.
lecture1_chile_SGAs.key - 6 July 2015

4
Context/background
The future of medicine 5

5
COMPLEXITY
The illnesses; the patient; the health system
COMORBIDITIES CHRONICITY
Multiple systems, pathologies Dynamic
SEVERITY
Mensuration;domain spans; interactions
FUNCTION/OUTCOME
Biological; social; psychological;
multidimensional
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Clinical imperatives
• Arguably, the three main areas that require increased
clinical and research focus and attention in psychosis are
the following:
Relapse Medical Treatment

Prevention comorbidity refractory
Phase of illness
Early Relapsing Stable

basis of schizophrenia 7
7 treatment
Optimised Functional outcomes 5
2 3
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en
m
Vocation /
at
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social role
tre
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gic
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Social and family
olo
cia
functioning
ac
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re
m
at
ar
m
ph
Behavioural
en
ho
ts
yc
1
Ps
Suicidality
Symptom factors
(Positive, negative, cognitive, affective, excited)
Optimised Psychopharmacological treatment foundation 4
Discussed further in lecture 3
Antipsychotic development 8
8 phases
FGAs SGAs
orals then orals then
depots LANAs
4 LA-SGA
3 SGA ('atypicals')
2 long-acting FGA ('depots')
1 FGA ('typicals')
1950 1960 1970 1980 1990 2000 2010
FGA=First Generation Antipsychotic; SGA= Second-generation antipsychotic; LANA=Long-Acting Novel

Antipsychotic
Dopamine blockers 9
•All these drugs share a common

pharmacology - they block post-
synaptic 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

10
10
Dopamine systems
• 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
Overactivity of DA Striatal DAergic

in these systems are
projections associated with
thought to be movement
associated with disorders, and
positive some cognitive
Mesolimbic symptoms Basal function
Hypofunction of DA acts as the

PFC (possibly PRIF
through underactive (neurohormone).
D1 mediated Affected by DA
circuits) underlies blockade by low
negative, Ki antipsychotics
Mesocortical cognitive, some Pituitary
mood symptoms.

12
Overactivity of DA Overactivity
Striatal DAergic
in these
projections
of systems
DA inare
associated with
thought to be these
movement
positive projections
some cognitive
Mesolimbic symptoms Basal thought
function to be
associated
Hypofunction of with positive
DA acts as the
PFCMesolimbic
(possibly PRIF
through underactive symptoms
(neurohormone).
mood symptoms.

13


PFC (possibly PRIF
mood symptoms.

14

Striatal
Hypofunction of
DAergic DA acts as the
PFC (possibly systems are PRIF
through underactive associated (neurohormone).
D1 mediated with Affected by DA
circuits) underlies movement blockade by low
Mesocortical cognitive, some disorders,
Pituitary
and
mood symptoms. some
cognitive
function
Basal

15


PFC (possibly PRIF
mood symptoms.

16

Hypofunction of
symptoms PFC (possibly
function
Mesolimbic Basal
through
underactive D1
Hypofunction of mediated
DA acts as the
PFC (possibly PRIFcircuits)
underlies
negative,
cognitive, some
Mesocortical cognitive, some mood
Pituitary
mood symptoms. symptoms.
Mesocortical
Basal

17


PFC (possibly PRIF
mood symptoms.

18

Pituitary Hypofunction of DA acts as the

PFC (possibly PRIF
DA acts as the PRIF D1 mediated Affected by DA
(neurohormone). negative, Ki antipsychotics
Affected by DA blockade
Mesocortical cognitive,bysome Pituitary
mood symptoms.
low Ki antipsychotics

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FGAs or SGAs?
19
Problems associated with 20

20 FGAs
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
NIDS 21
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Mental
Neuroleptic side effect Negative symptom
function
Vigilance Drowsiness, somnolence Attentional impairment
Reduced speed of thinking   Alogia 
Concentration difficulties  Poverty of speech 
Cognition “Narrowing of mind”   
“Fuzzy head”
Apathy 
Avolition, apathy 
Conation Lack of energy 
Diminished sense of purpose
“Weak, tired”
Flat affect  Affective blunting 
Affectivity Indifference Restricted affect
Lack of feeling 
Emotionality Dysphoria  Diminished emotional range
“Dead inside”
Anhedonia, asociality 
Anhedonia 
Curbing of interest 
Motivation Reduced drive 
Diminished social drive 
Reduced initiative
Diminished curiosity
Lewander, 1994.

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Proposed advantages of SGAs
• 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:
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• 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
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• 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)

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• 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)
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On the other hand….
• ‘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
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SGAs: evidence and uptake policy
• 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, 391–392.

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LMIC and policy re SGAs
• 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.
• “Chile’s 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 30
Magnitude descriptors
Effect size
Test
Statistic
Small Medium Large
Correlation r 0.1 0.3 0.5
t-test Cohen’s d 0.2 0.5 0.8
Multiple regression f2 0.02 0.15 0.35
ANCOVA/MANCOVA Partial η2 < .06 .06 < .14 0.14

Drug update
continued
Targets and initiating 31

31
Table. Using atypical antipsychotic therapy in schizophrenia

Agent Near-maximal effective dose* Comments on initiating therapy
Oral
Amisulpride (Solian Tablets 200 mg/day Low dose may activate a patient; addition of a benzodiazepine
and Solution) 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, >400 mg/day† Requires slow titration (in approved centres only)
CloSyn, Clozaril)
Olanzapine (Zyprexa) >16 mg/day† Can cause sedation
May be increased to full dose quickly in the management of
acute relapse
Quetiapine (Seroquel) 150 to 600 mg/day Causes sedation, but can be initiated to maximal doses
reasonably quickly in acute relapse
Risperidone (Risperdal) 4 mg/day Can cause initial hypotension, which suggests dose should be
built up over 3+ days in some patients
Injectable
Risperidone, long acting 50 mg/two weekly Requires antipsychotic cover (oral or previous depot) for three
(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 medications requires careful monitoring
From:Lambert T. Atypical antipsychotics in schizophrenia: a guide for GPs. (2006). Medicines Today. 7(1):
consumers and carers can be downloaded room may provide an efficient method of of adherence, outcomes, mental state, and
55-58; * Davis & Chen. J Clin Psychopharm 2004;24:192-208
from www.psychiatry.unimelb.edu.au/ identifying issues that are of immediate physical health status so that the risks and
open/ diabetes_consensus.) The principles importance to the patient. An example is benefits are balanced. For most patients
outlined in the consensus statement are the Liverpool University Neuroleptic Side with schizophrenia, treatment is long term,
consonant with those proposed by the Effect Rating Scale (LUNSERS), which can and forming an enduring relationship
RACGP.23 be completed in about three minutes.24-25 with a GP will enhance the possibility of
However, many side effects are not simply recovery by maximising the potential of
What about side effects? attributable to antipsychotics: psychotropic treatment. MT
It is important to enquire about common polypharmacy is common in mental health
side effects of antipsychotics because these settings and contributes substantially to A list of references is available on request
have an impact on quality of life and daily side effects such as weight gain and seda- to the editorial office.
function and, subsequently, adherence to tion. Polypharmacy should be avoided
treatment. Sedation, weight gain, akathisia, whenever clinically possible. DECLARATION OF INTEREST: Associate Professor
and sexual side effects often cause much Lambert has been a member of advisory boards for
distress. Patients may experience long-term Conclusion Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, Sanofi,
extrapyramidal side effects, such as tardive GPs care for a substantial proportion of Novartis and Faulding. He has received funding for
dyskinesia, but they might not complain patients with schizophrenia, and many unrestricted research from Eli Lilly, Novartis, Janssen-
of these spontaneously. atypical antipsychotics are now available Cilag, Bristol-Myers Squibb, Pfizer and AstraZeneca,
Many GPs have limited time to investi- for treating this illness. Selecting medica- and travel assistance to attend meetings from Eli Lilly,
Average doses in real world

gate side effects in depth. Self-report sched- tions and maintaining patients on these Novartis, Janssen-Cilag and Bristol-Myers Squibb. 32
32
58 MedicineToday 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.)
Average doses in real world 33

33
SGA Dose (mg/d)1 ~400mg CPZe (TL) ~400mg CPZe (SL)
Olanzapine 18.1 17.6 12

Risperidone 4.1 4.1 3.2
Risperidone LAI2 46 q2 50 q2 -
Clozapine 418 400 480
Quetiapine 511 600 240
Amisulpride 650* 400 -
Aripiprazole 19.1* 10^ 16
Asenapine - 12 16
Paliperidone - 9 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 al’s
values are here for comparison and do raise a number of questions.

converta© 34
34
http://www.addat.com/converta/index.html#/converta
35
Mechanisms
35
Efficacy and Consequences 36

36
Potential clinical
Mechanisms Potential consequences
efficacy
EPS  
D 2R ↑ Negative symptoms  
↓ positive symptoms
antagonism ↑ Cognitive symptoms
↑ PRL
↓ positive symptoms  
D2R partial Little or no EPS  
↓ negative symptoms  
agonism Behavioral activation
↓ cognitive deficits
DA and NE ↓ negative symptoms  

release in the ↓ cognitive deficits   Behavioral activation
PFC ↓ depressive symptoms
ACh release in
↓ cognitive deficits ?
the PFC
Miyamoto S, et al (2005). Mol Psychiatry, 10(1), 79-104

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Potential clinical Potential

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

38
Potential clinical Potential

Mechanisms
efficacy consequences
Muscarinic R ↓ psychotic symptoms   [See withdrawal

agonism ↓ cognitive deficits section - CRS]
↓ positive symptoms  
↓ negative symptoms   Apoptosis /
Glutamate modulation
↓ cognitive deficits   neurodegeneration
↓ illness progression
FGA affinities1 39
39
Receptor TRZ HP FF CPZ FPT

5-HT1A
5-HT2A
5-HT2C
D1
D2
D3
D4
α2A
α2B
α2C
α1A
Ki Affinity
α1B <1 Very strong
1 Strong
M1 10 Moderate
M4 100 Mild
1,000 Very weak

H1 10,000 Negligible
1 Roth BL, et al. (2004). Nat Rev Drug Discov, 3, 359–364.

SGA affinities 40
40
Receptor ZIP QUET RIS ARI OLZ CLOZ AMI

5-HT1A
5-HT2A
5-HT2C
D1
D2
D3
D4
α2A
α2B
α2C
α1A
α1B
M1
M4
H1
1 Roth BL, et al. (2004). Nat Rev Drug Discov, 3, 359–364.
Balancing the equation 41

41
Source: Universal Antipsychotic Converter © Addat Pty Ltd 2001-2008
42
42
Use of pharmacological parameters
• 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

we’re likely to see emerge or to improve post-
switching
• It helps us to understand pharmacodynamic interactions

that might express themselves as DDIs, or peculiar non-
linearities in efficacy or side effects.
• Let’s 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 Adrenergic Serotinergic

Postural
Blurred vision Weight Gain Parkinsonism Affective
hypotension
Reflex
Dry mouth Drowsiness Akathisia Weight gain
tachycardia
Drive Sexual
Constipation Sedation Dystonia
reduction function
Urinary
?Hypotension Dyskinesia Headache
retention
Decreased Hyperprolactin
Insomnia
sweating aemia
Glaucoma
?NIDS
hazard
Dysmnesis
Speech block
Delirium
NIDS = neuroleptic induced deficit syndrome
45
EPS
45

Types of (common) NIEPS 46
46
Type Comment
Four components: rigidity, bradykinesia,
Parkinsonism tremor, postural stability.
± bradyphrenia
Three components: subjective (feelings of
Acute
Akathisia inner restlessness), objective (motor signs);
akathisic distress (subjective)
Twisting, pulling or squeezing; involuntary,
Dystonia
often within 96 hrs of Rx; variable sustain
Two broad co-occuring subtypes: choreic;
Dyskinesia athetoid (snake-like); may blend with t.
akathisia and t. dystonia
Tardive
Dystonia This sometimes conceptualised as a dyskinetic
variant
Akathisia
Consequences of EPS 47
47
• Even in the era of SGAs, neuroleptic-induced extrapyramidal disorders (NIEPS)

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

48
• With both FGAs

and some SGAs
once 80% of D2
receptors are
D2 Receptor Occupancy
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.

EPS: agents are not equal
49
49
• Rates of EPS with FGAs

Acute EPS Antipsychotic are up to 65%1
• Rates with SGAs have
RIS, AMI, ZIP, OLZ, fallen substantially but are
Dose dependent
FGAs not equal among agents2
• Tardive phenomena have
also fallen to <20% of
Flat ~ low CLOZ, QUET, ARI 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.
TD: FGA vs SGA

50
50
• There are only two RIS HP OLZ

RCTs of annualised TD
incidence (AFAIK)1,2
• 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
Moderators/effectors of EPS 51
51
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 ?
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.
Tight/loose binding 53
53
Seeman, P. et al. (1999). Am J Psychiatry, 156(6), 876-884.
SDA and EPS: hypothesis 54

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.

EPS: effect of intrinsic 55
55 activity
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
57
Mouth and Tongue: Pre
•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
60
Mouth and tongue: post
• The lingual tremor with

superimposed chorea has
substantially diminished.
• Both stigma and discomfort
are reduced
60

61
Hands
61
Poly-antipsychotics: FGAs 62
62
Mono-therapy: SGA 63
63
Monotherapy after 12 weeks

Resource: EPS CD 64
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
Resource: GATES
65
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
O12. TORTICOLLIS / RETROCOLLIS / ANTEROCOLLIS

Is torticollis or retrocollis or anterocollis (ie dystonia) present?
No 0
Yes 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 patient’s report and any existing clinical knowledge, rate the acuteness of
the dystonia.
No neck dystonia 0
Acute neck dystonia 1
Persistent/chronic/tardive neck dystonia 2
Definite acute on chronic dystonia 3
Using the GATES: Parkinsonian

Unsure 4
66
66
rigidity
O13. Do the movements appear to be dyskinetic (ie athetotic movements)?
No 0
Yes 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 can’t 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:
“I’m going to take my hands away. When I do, let your arms fall to your sides naturally – don’t
help them fall”.
A normal response is a quick fall with a clear slap or bounce.

Normal free fall with slap and 0
Fall slowed slightly less rebound 1
Fall slowed, no rebound 2
Marked slowing, no slap at all 3
Arms fall as though through glue 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 patient’s 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 Left Right
Normal 0 0
Slight stiffness and resistance 1 1
Moderate stiffness and resistance 2 2
General Akathisia Tardive phenomena & Extrapyramidal rating Schedule – OBJective – v6.5 – © T Lambert 1999

Using the GATES: Objective 67
Akathisia
GATES v6.5 - Akathisia abstracted items
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 doesn’t take a step off this spot (more marked cases).
None 0
Just noticeable 1
Mild 2
Moderate 3
Frequent and gross 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 0
Oscillates, walks a pace or two 1
Walks around the room 2
Paces 3
Urgently paces or leaves room 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

Prolactin sparing; Similar profile to QUET and
PRL CLOZ5
69

Neurohormone effects of DA 70
70 antagonism
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 71
71
antagonism
• 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 72
72 side effects
Gynecomastia 5%
Galactorrhoea 7%
Loss libido 50%
Orgasm Disorder 18%
SFX Erectile dys. 23%
Ejeculation dys. 23%
Menstrual disorder 75%
Amenhorrhoea 35%
?
Osteporosis
0 20 40 60 80

73
Variable hyperPRL risks
No or minimal PRL PRL increase above the Higher

increase norm (dose dependent)
Risk
Olanzapine Paliperidone
Ziprasidone Amisulpride (all doses)
Clozapine Risperidone (all doses)
Quetiapine FGAs (all doses)
Lower
Aripiprazole Zotepine (from 100mg)
Side eﬀects 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
74
PRL: FGAs and SGAs
• 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
75
PRL: background1
• 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
76
PRL: treatment
• 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
Common antipsychotic SFX 78

78
Muscarinic Histamine Dopamine Adrenergic Serotinergic

Postural
Blurred vision Weight Gain Parkinsonism Affective
hypotension
Reflex
Dry mouth Drowsiness Akathisia Weight gain
tachycardia
Sexual
Constipation Sedation Dystonia Drive reduction
function
Urinary
?Hypotension Dyskinesia Headache
retention
Decreased Hyperprolactin
Insomnia
sweating aemia
Glaucoma
NIDS
hazard
Dysmnesis
Speech block
Delirium
NIDS = neuroleptic induced deficit syndrome

NIDS 79
79
Mental function Neuroleptic side effect Negative symptom

Vigilance Drowsiness, somnolence Attentional impairment
Reduced speed of thinking   Alogia 
Concentration difficulties  Poverty of speech 
Cognition
“Narrowing of mind”   
“Fuzzy head”
Apathy  Avolition, apathy 
Conation Lack of energy  Diminished sense of
“Weak, tired” purpose
Flat affect  Affective blunting 
Affectivity
Indifference Restricted affect
Lack of feeling 
Diminished emotional
Emotionality Dysphoria 
range
“Dead inside”
Anhedonia, asociality 
Anhedonia 
Curbing of interest 
Motivation Reduced drive 
Diminished social drive 
Reduced initiative
Diminished curiosity
Lewander, 1994; NIDS=Neuroleptic Induced Deficit Syndrome
80
80
Patients and sedation
• 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.
81
81
Cognitive deficits:FGA=SGA😞
• 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), 43–57.

82
Dealing with poor

adherence:
SGA-LAIs*
Slides for this section extracted from the CERP
education programme
82 *Second generation Long-acting Injectable antipsychotics
83
83
Adherence in psychosis
• 80% of patients with
schizophrenia are non-
adherent 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
•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
84
84
SGA adherence
• 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
Relapses contribute to psychosocial decline, perhaps
secondary to worsening pos/neg symptoms
© Tim Lambert 2009-2015
Nonadherence: 86
86 consequences
Psychological consequences include:

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

Requiring more involuntary treatment
Longer hospital stays if nonadherent pre-
admission
Fracturing the gossamer-like social
connections re-established after previous
relapses
Greater direct and indirect costs (service,
community, patient, family)

88
Bedtime reading 88
SGA-LAIs: different vehicles

89
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
Need for crossover

Target FGA-LAI Delivery
oral adjunct AP
FGAs
Fluphenazine Oil-based Moderate
Haloperidol Oil-based Moderate
Flupenthixol/
Oil-based Moderate
zuclopenthixol
SGAs
RLAI Microspheres High
OLAI Crystal Nil/minimal loading
PALI Crystal Nil/Minimal loading
ALAI Crystal Nil/minimal loading
Lambert T and Taylor D (2010) in Haddad et al, op.cit
90
90
Benefits of SGA-LAIs
• 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
91
FGA-LAI release kinetics
• 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
92
FGA-LAI Kinetics
• 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
94
Plasma-dose levels
• Reduced peak to
trough (less side
effects)
• Mean plasma
levels towards
the lower side
(hypofrontal
targeting)
CERP Workshop
Pharmacokinetic profile of PLAI initiation 95

95 regimen compared to oral paliperidone ER
•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
Median 5
[PLAI]
(ng/ 3
mL) 0
2
5
2
0
1
5
1 Oral 6 mg paliperidone ER
0 Oral 12 mg paliperidone ER
Paliperidone palmitate
5
Estimated oral 6 mg steady-state
Estimated oral12 mg steady-state

0
1 8 1 2 2 3
5 Time (day) 2 9
Invega® Sustenna 6
® Product Information
CERP Workshop
Median plasma concentration-time 96

96 profiles, by treatment
1 4 8 15 22 36 50 64 78 92
35
(paliperidone or active moiety)
30
Plasma concentration ng/mL
25
20
15
10
RLAI (+ oral risperidone*) RLAI injections
5 Paliperidone palmitate (+ oral placebo*) Paliperidone palmitate injections
0
1 4 8 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;35:218–226

CERP Workshop

Time to steady state: OLAI 97
97
Mean ±SD olanzapine plasma concentrations; 405 mg/q4 in LOBE patients 1
100
80
Olanzapine (ng/ml)
60
40
20
0
0 4 8 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
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 in the next
seminar….
99
Centres of Excellence for Relapse Prevention
Seminar 1:
’Atypical’CERP CERP
antipsychotics
Focus on Schizophrenia Centre of Excellence for Relapse Prevention
1. The 3 swirls convey fluidity and movement. 2. Humanistic approach. Each circle and curve represents
The ellipse shape represents a centre of excellence from a person while the central circle represents the centre of
which knowledge is shared and disseminated. excellence. This icon symbolizes a group of people coming
together to share information.
FOR RE
CERP
CE
EN LA
LL P
4a. Existing colouration
E
SE
NTRE OF EXC
PRE

VENTION
CE
CERP
4b. Red colouration
CERP
3. A global icon. The circles and lines represents a network 4. The circle within the centre of the letter C represents
from which knowledge is shared and disseminated. excellence within the field of Schizophrenia.

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1

Professor Tim Lambert

Professor and Head of Psychiatry

› 10:30 - 12:00 Atypical antipsychotics

› 12:00 - 13:00 Discussion

› 14:00 - 16:00 Cardiometabolic effects and sleep

› 16:30-18:30 Clinical evaluation and monitoring

Centre of Excellence for Relapse Prevention

lecture1_chile_SGAs.key - 6 July 2015

The future of medicine 5

Relapse Medical Treatment

Early Relapsing Stable

lecture1_chile_SGAs.key - 6 July 2015

Optimised Functional outcomes 5

Optimised Psychopharmacological treatment foundation 4

Discussed further in lecture 3

2 long-acting FGA ('depots')

1950 1960 1970 1980 1990 2000 2010

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

•All these drugs share a common

lecture1_chile_SGAs.key - 6 July 2015

• FGAs (aka conventional or 'typical'

DAergic areas of interest 11

Overactivity of DA Striatal DAergic

Hypofunction of DA acts as the

DAergic areas of interest 12

lecture1_chile_SGAs.key - 6 July 2015

Overactivity of DA Striatal DAergic

Hypofunction of DA acts as the

DAergic areas of interest 14

Overactivity of DA Striatal DAergic

DAergic areas of interest 15

Overactivity of DA Striatal DAergic

Hypofunction of DA acts as the

lecture1_chile_SGAs.key - 6 July 2015

Overactivity of DA Striatal DAergic

DAergic areas of interest 17

Overactivity of DA Striatal DAergic

Hypofunction of DA acts as the

DAergic areas of interest 18

Overactivity of DA Striatal DAergic

Pituitary Hypofunction of DA acts as the

lecture1_chile_SGAs.key - 6 July 2015

Problems associated with 20

Poor efficiency (50% success rate; low remission)

Potential worsening of cognition (NIDS)

Specific problems related to polypharmacy and high doses

Link to (self-medicating) substance abuse

FGA= First generation antipsychotic (typicals)

lecture1_chile_SGAs.key - 6 July 2015

• When comparing SGAs to FGAs there is a

• Improved therapeutic effect in some treatment-resistant

• Reduction of suicidality within schizophrenia.12

lecture1_chile_SGAs.key - 6 July 2015

• For those that have been sufficiently

• ‘If efficacy differences are a “myth,” it is

• In an editorial published in the British Journal of

lecture1_chile_SGAs.key - 6 July 2015

• LMiCs that are able to manufacture or import cheaper generic atypical

• “Chile’s experience indicates that an LMiC that implemented policies

124 studies of SGAs vs FGAs; 18 studies of SGAs

Correlation r 0.1 0.3 0.5

t-test Cohen’s d 0.2 0.5 0.8

› 10:30 - 12:00 Atypical antipsychotics  

› 12:00 - 13:00 Discussion  

DA and NE ↓ negative symptoms  

Muscarinic R ↓ psychotic symptoms   [See withdrawal