Long Term for Success in the

Management of Patients with

Schizophrenia
Beyond Symptoms Control

Prof. Afaf Hamed Khalil

Professor of Psychiatry
MD, FR, psych., FAPA
Ain Shams University

Schizophrenia is a common and

Chronic Disorder
Affect 1% of the population.
Long time course of illness.
Most affected group (15-35) years.
It ranks as leading cause of years of life
lost due to disability and premature
mortality.
It is an expensive disorder with high
economic burden.

SCHIOPHRENIA
Is a devasting illness that strikes at
some of the most advanced functions
of human brain.
It is characterized by a diverse array of
clinical symptoms.

SCHIZOPHRENIA

(a serious public health problem)

of people with schizophrenia
are not receiving appropriate care
Source: World Health Organization

of people with untreated schizophrenia

are in developing countries
Effective treatments are available:
Should be acceptable to patients, families and society
More effective in the early stages
Care can be with active family and community involvement

Costs of Schizophrenia
Direct costs:
Transfer of money for resources
consumed
Hospitalization, residential care, social
care
Pharmacotherapy (chronic course)
Comorbidity (mood, sub. Abuse)

3rd highest for YLD* among

neuropsychiatric conditions
1. Unipolar major depression

7.

Parkinsons disease

2. Bipolar disorder

8.

Multiple sclerosis

3. Schizophrenia

9.

Drug use

4. Epilepsy

10.

PTSD

5. Alcoholism

11.

OCD

6. Dementia

12.

Panic disorder

* YLD = years of life with a

disability

Murray CL, Lopez AD, editors. The global burden of disease.

Cambridge, Massachusetts: Harvard University Press, 1996

Costs of Schizophrenia
Indirect costs:
Are those borne by the society?
Lost productivity & severe functional
impairment .
Social welfare.
Quality of life.
Lost productivity of family members caring for
the patient.
Comorbidity, mortality, intangible cost

DALY:

20,000

1,500

All causes

15,000
1,000
Schizophrenia
10,000
500
5,000

1990

2000

2010

2020

DALYs: all causes (millions)

DALYs: schizophrenia (thousands)

Predicted increase in disease burden 19902020

Murray CL, Lopez AD, editors. The global burden of disease.

Cambridge, Massachusetts: Harvard University Press, 1996

IMPACT OF SCHIZOPHRENIC SYMPTOMS

ON OVERALL FUNCTIONING

Positive symptoms:
delusions
hallucinations
disorganized speech
catatonia

Cognitive
symptoms:

Social

Work

attention
memory
executive functions
(eg, abstraction)

Occupational

Negative
symptoms:
affective flattening
alogia
avolition
anhedonia

Interpersonal
Mood symptoms:

Selfcare

dysphoria
suicidality
helplessness
QOL 2

Therapeutic Goals
Regain
functioning
Improve
quality of life
Maintain stability
Effective relapse prevention
Prevention of non-compliance
)Weiden.P.J, 2007(

Therapeutic Goals in Schizophrenia

Goal I
Onset of schizophrenia: +ve

(10-20%.)

-ve

(50-60%)

+ve & -ve

( 20-30%)

Recognition of prodromal
symptoms
Rapid control
of positive symptoms
alleviate patient distress

Management of co-morbid
,affective symptoms
substance abuse

Establishment of a
therapeutic alliance'
initiate a positive relationship
between patient and
healthcare services

Prevention of
cognitive dysfunctions
Montogomery.S.A, Zwiten.B.B
Eur.Neuropsychopharmacol 2007

Problems Hinder Achieving Goal I

A. Delayed recognition
Symptoms (Delusion, Hallucination, Bizzar
behavior, attributed to Jinn, sorcery, envy, evil
eye)

Stigma
Resort to native healers
El Islam 1980, El Qureshi 1998, El Habib 2001 and Khebl 2002

Problems Hinder Achieving Goal I

B- Non response or partial response

1. Variable remission rates

A substantial percent of sufferers of

schizophrenia derive little or no benefit
from antipsychotic medications.

30-50%

of

patients

are

partially

responsive.
(Cont.)

Therapeutic Goals in
Schizophrenia
Goal II
Maintaining remission.
Effective prevention of relapse.
Prevention of non-compliance.

Problems Hinder Achieving

Goal II
None Compliance
None compliance with oral medication

50% after one year.

75% after two year.

Medication compliance is poor in

patients with Schizophrenia
Nearly two-thirds of schizophrenia patients
have compliance problems
41% Compliant

39%
Non- compliant

20%
Partially compliant

Coldham EL, et al. Acta Psychiatr Scand 2002;106:28690

Factors Affecting Outcome

PATIENT FACTORS
Medical comorbidities;
Substance abuse;
Cognitive capacity;
Illness insight;
Medication adherence;
Cultural issues;
Employment;
Personal relationship;
Coping skills

PHARMACOLOGICAL FACTORS
Broad efficient antipsychotics
Minimal side effect
Easy drug schedule

PHYSICIAN FACTORS
Ability to educate patient and
family;
Treatment expertise;
Knowledge of rehabilitation
resources;
Understanding of treatment
goals;
Clinic convenience

SOCIAL FACTORS
General shortage of
appropriate community
resources;
Stigmatization and
misunderstanding of
psychiatric illness;
Red tape

Direction Of Adherence Influence

Toward adherence

Toward nonadherence

Perceived benefits of medication

Symptom relief

Acknowledgement of some
relief

Does not report any day-to-day

relief

Prevention

Fearful of relapses
Medication prevents future
relapse

Does not fear relapse

Medication unrelated to
relapse

Life goals

Reports that medication

would heip achieve life goals

Feels that medication interferes

with life goals

Current
functional status

Acknowledges presence of
problem
Relieves that medications are
still necessary

Does not Acknowledge any

problem needing treatment
Reports that problem no longer
active or in need of treatment

)Weiden.P.J, 2007(

Non Adherence Problems

Relapse rate
With oral medication
50% within 1 year
60% within 2 years
75% within 3 years
82% within 5 years
With depot medication
25-30% (CAA)
Relapse rate

1/3
Fully
adherent

1/3
Partially
adherent

1/3
completely
nonadherent

5 times higher in nonadherent patients (Velligan D.I, 2007)

Oehl m,et al. Acta Psychiatr Scand. 2000, 102 (407):83-86
Peter Weiden et al. Assessment and treatment selection for revolving door in patients withh schizophrenia, Psychiatric quarterly, vol 68, no 4 winter 1997

Most Patient With Schizophrenia

Are Only Partially Compliant
Unsatisfactory compliance
Satisfactory
Compliance

Noncompliance
Few or no
meds taken

0%

)Henderson.D.C, 2003(

Partial compliance

Adherence to prescribed regimen

of 80%-70%<
meds taken

100%

Impact of Partial Adherence

Full recovery
Impact on illness

Loss of confidence
Incomplete
recovery
Symptom
exacerbation

Impact on Patient

Demoralization
Loss of job
Family discord

Rehospitalization
Relapse
Danger to
self/other

Duration of missed doses

Poor adherence is a major predictor of outcome in

schizophrenia and is correlated with the following
negative outcomes.
Relapse; Rehospitalization; Longer readmissions
(Henderson. D.C, 2003)

Partial Adherence Nearly Doubles The

Risk Of Hospitalization

Hospitalization
nearlydouble

%
of
patients
hospitalized

(n=327)

(n=1710)

MedicationGap

(n=1166)
(n=1122)

Kane JM. J Clin Psychiatry 2006; 67 (5):9-14 Review of treatment that can ameliorate nonadherence in
patients with schizophrenia.

Why are patients non-adherent?

Factors associated with non-adherence include:
Poor insight (refusal of treatment) 2,3
Negative attitude 3
Discontinuation of treatment
Taking medication = sickness
Stopping medication = being well
Substance abuse 4
Inadequate discharge planning/after care environment 4
Poor therapeutic alliance 4
Lack of psychoeducation
Linden M, et al. Schizophr Bull 2001;27(4):58596
Kozuki Y, et al. West J Nurs Res 2003;25(1):5774
Irregularities in treatment
Perkins DO. J Clin Psychiatry 2002;63:11218
Side effects
Lacro JP, et al. J Clin Psychiatry 2002;63:892909
1

Robinson D, et al. Schizophr Res 2002;57:20919

Problems Hinder Achieving Goal II

Distressing side effects: Neuroleptic induced dysphoria and
extrapyramidal

side

effects

(EPS,

including NMS);
Sexual dysfunction, weight gain, CVS
side effects, sedation
C- Medical comorbidity

Non-adherence to therapy =
relapse
Year*

Relapse
rate (%)

Patients still at
risk at end of year

16.2

80

53.7

39

63.1

22

74.7

81.9

*Year(s) since previous episode

First-episode schizophrenia
patients (n=104)

Robinson D, et al. Arch Gen Psychiatry 1999;56:2417

Consequences of relapse
Increased long term morbidity
Increased likelihood of exhibiting more
deterioration
Increased

likelihood

treatment refractory

of

becoming

Many Factors Can Affect Adherence To

Medication
Impaired CF
Poor insight
&
symptom
profile

Inadequate
discharge
planning

Shorter
illness
duration

Adherence
To
Treatment
Substance
abuse
Therapeutic
alliance
Oehl M, et al. Acta Psychiatr Scand 2000;102(Suppl. 407):836

Many Factors Can Affect Adherence To

Medication
Accessibilit
y
To drug
Attitude
To drugs

Drug
formulation

)Henderson.D.C, 2003(

Complicated

Adherence
To
Treatment

regimen

Side effects
profile

Symptoms
exacerbation

Medication
Nonadherence

Relapse

Consequence of relapse
Aggressive and destructive behavior
Impaired self care
Increase risk of hospitalization
Increase risk of suicide
Severe disruption of life
Psycho-social & financial cost
Increased long term morbidity & more deterioration & treatment
refractory
)Weiden.P.J, 2007(

Consequences of relapse
Relapses are accompanied by several
major negative consequences
Aggressive and destructive behaviour
Impaired self care
Increase risk of hospitalization
Increase risk of suicide
Severe disruption of life
Psycho-social & financial cost

But It Is Not Just Rehospitalization

Patients with
drug holidays of
at least 30 days
have a 4.2*
times higher
risk of suicide
attempts

*95% CI: 1.7-10.1, after controlling for age and gender.

Herings RMC, Erkens JA. The PHARMO Institute, The Netherlands; Submitted to BMJ.

Therapeutic Goals in
Schizophrenia
Goal III
Maintaining Phase
(Improve outcome)

Drug + Social alliance

Rehabilitation to optimize function (work).

Maximization of quality of life, IP relation.
Improve quality of life.
Integration to the community (Better outcome
in our countries).

Problems hinder Achieving Goal

III
Pseudo integration.
No Intermediate services
No community services

Schizophrenia: Outcome
From Birchwood M et al.Br. J. Psychiatry1998;172
Breier Am. J. Psychiatry 1994;151

Prodrome
Level of functioning

Remission
Response
Partial response
First episode

Chronic relapse
Relapse

Critical Period
Age

Early Treatment Intervention

Reduced morbidity
More rapid recovery
Better prognosis
Preservation of psychosocial skills
Preservation of family and social
supports
Decreased need for hospitalisation

Pathogenetic hypotheses
of schizophrenia
Cause of schizophrenia = unknown!
Neurodevelopmental hypothesis:
Toxic/genetic insults of neurons
Poor neuronal migration during fetal brain
development
Inadequate synaptogenesis/neuronal inputs

Neurodegenerative hypothesis:
Glutamatergic excitotoxicity

Dopaminergic hypothesis:
4 dopaminergic pathways
Target of neuroleptics/antipsychotics

Schizophrenia Core
Symptoms
Psychotic

Deficit

Cognitive

Positive
Symptoms

Negative
Symptoms

Cognitive
Dysfunction

Schizophrenia Core
Symptoms
Psychotic

Positive
Symptoms

Hyper activity of D2 in
mesolimbic pathway
Delusion
Hallucinations
Conceptual
disorganization
Hostility and

Hostility
Buckley P.F., Stahl S.M. (2007): Acta Psychiatr
Scand, and
115: 93100.

Schizophrenia Core
Symptoms
Affective flattening
Alogia
Avolition
Anhedonia

Deficit
1yr core ve sx

A spontaneity
Negative
Symptoms

2yr ve sx
To +ve
To EPS

To Affective sx
s

Schizophrenia Core
Symptoms
Deficit

Negative
Symptoms
Increased 5HT2a in
mesocortical area
Hypodopaminerga in DLPFC
Adrenergic dysfunction

Dysfunction
Communication
Socialization
Capacity for
pleasure
Motivation

Wong A.H.C. and Van Tol H.H.M. (2003): Neuroscience and Biobehavioral Reviews 27, 26
Murphy B.P., et al. (2006): Schizophrenia Research 88 525.

Schizophrenia Core
Symptoms

Cognitive
Stable over time
May precede onset
Cognitive
Independent of psychotic sx
Dysfunction
Predictor of functional
outcome
Indicator of maladaptive
social function
Harvey P.D. and McClure M.M., 2006: Drugs; 66 (11): 1465-1473

Schizophrenia Core
Symptoms
Working memory
Sustained attention

Cognitive

Executive function
Problem solving
Verbal skills
Reasoning

Cognitive
Dysfunction

Schizophrenia Core
Symptoms
Molecular alteration in
DLPFC

Cognitive

Hypodopaminergic in
mesocortical areas
D1 and D5
Central cholinergic
dysfunction

Cognitive
Dysfunction

Altered glutamate
Altered GABA transmission
in DLPFC

Ferreri F., Agbokou C., Gauthier S. (2006): J Psychiatry Neurosci;31(6):369-76.

To Understand the Therapeutic

Intervention of this Devasting
Illness
WE HAVE

To highlight possible theories that explain

schizophrenia.

To identify the neuro chemical dysfunction

which underly the diverse 3 clusters of sx.

To understand the molecular targets and

mechanism of action of current and future
drugs.

Symptoms May Match To Malfunctioning

Brain Circuits
Mesolimbic
Positive
symptoms

Ventromedial
Prefrontal
cortex

Affective
symptoms

Aggressive
symptoms

Cognitive
symptoms

Dorsolateral
prefrontal cortex

Orbitofrontal
cortex
)Conlry.R, 2007(

Mesocortical
/prefrontal
cortex
Nucleus
Negative
accumbens
symptoms
reward circuits

Amygdala

Dopamine

Therapeutic Pharmacological
Targets in Schizophrenia
Dopamine
Dopaminergic Pathways in the Brain
Mesocortical
Pathway

Nigrostriatal
Pathway

Hypoactivity: Negative
and Cognitive Symptoms

Tuberoinfundibular Pathway
Adapted from Kandel et al., eds. Principles of Neural Science.
Norwalk, CT: Appleton & Lange; 1991:854.

Mesolimbic
Pathway
Hyperactivity:
Positive Symptoms

Therapeutic Pharmacological Targets in Schizophrenia

Dopamine

Hyperdopamineric in subcortical
mesolimbic pathways

D2 receptors

D2 like receptors (D3 &

to mesolimbic a
Mechanism of action of Restricted
APs
- D4 Clozapine
- Blockage
- Dissociation

- D3 Amisulpride

- Partial agonism

- D3 Remoxipride

Possible Relations to
Dopamine-Binding Affinity

High binding affinity (Tight D2 binding)

lead to DA receptor up regulation and
Increase risk of relapse long term.

Intermediate or low binding affinity

(loose D2 binding)
Less potential for up regulation and low
risk of relapse.

Therapeutic Pharmacological Targets in Schizophrenia

Dopamine
Mechanism of action of APs
Dissociation (Fast OFF)
Dynamic process of binding
EPS, PRL
e.g. Quetiapine, Clozapine

racek et al., (2006): CNS Drugs; 20 (5): 389-409.

Relative Binding of
Antipsychotics
To D2 Receptors

K at D2 (nM)

100

10

Quetiapine
Clozapine

Loose

Olanzapine
Sertindole

Intermediate
Dopamine K (1.5nM)

Risperidone
Ziprasidone
Chlorpromazine
Haloperidol
Fluphenazine

0.1

Tight

Therapeutic Pharmacological Targets in Schizophrenia

Dopamine
Mechanism of action of APs
Partial agonism
e.g. Aripiprazole

kman T.R., et al. (2006): CNS & Neurological Disorders - Drug Targets, 5

Therapeutic Pharmacological Targets in Schizophrenia

Dopamine
Hypodopamineria
in mesocortical
D1 receptors*
D1 like
receptors (D5)*
*: Future drug
target
Werkman T.R., et al. (2006): CNS &
Neurological Disorders - Drug
Targets, 5, 3-23.

a)

Nigrostriatal

b)

Mesolimbic

c)

Mesocortical

d)

Tubuloinfundibular

Therapeutic Pharmacological Targets in Schizophrenia

Serotonin
5HT2a receptors density in PFC
leads to release of dopamine in
PFC
(-ve and cognitive sx)
5HT1a (-ve sx, mood sx)*
? Indirect action on DA
5H2c (+ve ss.)*
?? 5HT6 and 5HT7 ??
Marek G. and Merchant K. (2005): The Journal of the American Society
for Experimental NeuroTherapeutics. Vol. 2, 579589.

Therapeutic Pharmacological Targets in Schizophrenia

Glutamenergic function
Glutamate mediated excitatory
neurotransmission through the NMDA & AMPA
receptor.
Altered glutamate neurotransmission.
NMDA antagonists (Ketamine & PCP)
psychosis NMDA agonist improve cognition.
N.B.
Excessive Glutamate during development leads
to: excitatoxic damage to hippocampus, cortical
neurons which result in abnormal pruning of
glutametergic innervations during development

D.R. et al., (2006): Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 617

Therapeutic Pharmacological Targets in Schizophrenia

Adenosinergic transmission
(purinergic hypothesis)

Adenosin agonists have properties similar

to dopamine agonists.

adenosin D1

Adenosin modulate glutamate

N.B. Allopurinal used as a combined agent

for treatment of cognitive dysfunction.

D.R. et al., (2006): Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 617

Therapeutic Pharmacological Targets in Schizophrenia

Cortical cholinergic function

Acetyl choline is important for neuro
modulation of cognitive process.
Anomalies in cholinergic pathway in
schizophrenia.
Combined
therapy with cognitive
enhances (Donepezil, rivastigmine,
galantamine)
N.B. not evidence based

Ferreri F., Agbokou C., Gauthier S. (2006): J Psychiatry Neurosci;31(6

Therapeutic Pharmacological Targets in Schizophrenia

Muscarinic receptors
Muscarinic receptors may reduce
D2 mediated side effects.
Decrease number of M1
receptors and N7* receptors.
GABA transmission *
Reduced synthesis and reuptake of
GABA in DLPFC D1.

Wong A.H.C. and Van Tol H.H.M. (2003): Neuroscience and Biobehavioral Reviews 27, 26

Therapeutic Pharmacological Targets in Schizophrenia

Adrenergic receptors

1 & 2 adrenoreceptor agonists

improve cognition.

NE

improve
attention,
concentration
and
social
function.

Harvey P.D. and McClure M.M., 2006: Drugs; 66 (11): 1465-1473

Miyamoto S. et al., (2003): Molecular Interventions, Volume 3, Issue

Therapeutic Pharmacological Targets in Schizophrenia

Other Therapeutic Targets

Histamine (modafinil)
Sigma receptors
Substance P.
Endorphins (naltrexone)
NK 3 &
Canabinoid receptors* (CB1)
Neurotensin*

Marek G. and Merchant K. (2005): The Journal of the American

Society for Experimental NeuroTherapeutics. Vol. 2, 579589.

Typical Antipsychotics
Greater affinity for D2 receptors in nigrostriatal
system.
Effective

for

positive

symptoms

schizophrenia.
Limited effects on negative symptoms.
Limited effects on cognitive dysfunction.
Limited affective symptoms

of

Typical Antipsychotics
Sedation, cognitive dysfunction.
Prominent extrapyramidal side effects.
Associated with poor compliance.
Associated with frequent relapse
Poor overall outcome.
Low price? Lead to increased costs.

Atypical Antipsychotics

Induce

neuronal

plasticity

and

synaptic remodeling in the PFC and

hippocampus.

Normalize glutametergic dysfunction

and

prevent

further

structural

anomalies.

Induce neuroplastic changes through

NGF & BDNF

Horacek et al., (2006): CNS Drugs; 20 (5): 389-409.

Typical Antipsychotic

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Atypical Antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Essence of Atypicality
Less
Tardive
Dyskinesia

Fewer
EPS

Atypical
Antipsychotic

Fewer
-ve
Symptoms

Better
Cognitive

Less
Non
Compliance

Less
Dysphoria

Atypical Antipsychotics
Reduce preferentially the firing of mesolimbic
dopaminergic neurons.
They

have

little

effect

on

nigrostriatal

dopaminergic neurons.
They are potent 5 HT2 antagonists.
They have a high 5 HT2/D2 ratio.

Enhance glutaminergic pathway to frontal cortex.

Atypical Antipsychotics
They have better extrapyramidal side
effects profile.
They improve positive symptoms.
They are effective for negative symptoms.

Why Using Atypical

Antipsychotics?
Preserve cognitive functions.
Associated with better compliance.
Associated with better quality of life.
Optimizing the integrity of schizophrenic
patients to the community.
!! Cost effective.

Efficacy of atypicals extends beyond

positive symptoms of disease

Positive Negative Cognitive

Affective

Conventional
antipsychotics
Atypical
antipsychotics
Stahl M.S. 2002: Psychopharmacology of antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Neuroprotective Role

Antipsychotic drugs stimulates resilience and

trophic promoting factors.
Some APD inhibit glutamate activity.
Some medications are able to stimulate the actual
production of new cells through neurogenesis.
In recent years mood stabilizers, such as lithium
with antidepressants, have been shown to
stimulate neurogenesis in the dentate gyrus of the
hippocampus and the olfactory bulb.
Atypical antipsychotics are also able to promote
neurogenesis in a way that contributes to a
putative neuroprotective effect.

Manjl and Dunan, 2001: Psychopharmacol Bult.; 35(2):5-49

Potential Clinical implications of

receptor activities of anti
D2 antagonism

Positive symptoms efficacy, EPS,

endocrine effects

HT2A antagonism-5

Negative symptom efficacy, reduced

EPS

High 5-HT2A/D2
affinity ration

Antipsychotic efficacy reduced EPS

(compared to D2 antagonism alone)

HT1A agonism-5

Antidepressant and anxiolytic activity,

improved cognition, reduced EPS

HT1D antagonism-5

Depressive symptom efficacy

HT2C antagonism-5

Positive symptom efficacy, weight gain

Potential Clinical implications of

receptor activities of antipsychotic
Mixed 5-HT/NE
neuroal reuptake
inhibition

Antidepressant and anxiolytic

activity

1 antagonism

Sedation, postural hypotension,

sexual dysfunction, weight gain

H1 antagonism

Sedation, weight gain

M1 antagonism

Memory impairment, Gl
symptoms

Optimizing and Maximizing

Atypical Antipsychotic Therapy

Managing side effects

Sedation
H1

Antagonism

Antagonism

Benefit

restraints
Control violent behavior
Security measures

Management =

dose

Bedtime administration

Postural
hypotention

Reflex
tachycardia
Management

1 antagonism

Slowly movement
Beta blockers

Sexual side
effects

= 1 Antagonism
D2 Antagonism
PRL

Management

= Dose
Bromocryptin
Switch to another AP

EPS

= D2 Antagonism

Management

= Anticholinergic drugs
Switch to another AP

Cognitive impairment = M1 Antagonism

Management

= Dose

GIT symptoms

= M1 Antagonism

Blood dyscriasis
Seizures

Weight gain
(H1 & 1) antagonism
5HT2c affinity
Dysregulation of leptin

Metabolic complication (DM)

Weight gain
Prolactin can cause insulin resistant state
Novel antipsychotic, drugs exacerbate existing
disease or predisease
Use of concomitant medication? such as valproic
acid may also increase the risk of weight gain
and diabetes
Wirshing 2001

Management of weight gain and

metabolic problems
Nutritional counseling
Exercise
Drugs which decrease absorption of glucose
Life style changes
Switch to another drug with no weight gain in
metabolic problems

Prevention of unwanted
pharmacokinetic interaction
1A2 interaction
Inhibition (Fluvaxamine) Olanzapine,
Clozapine

Induction (grape fruit)

Olanzapine,

Ciprofloxacine Clozapine
Smoking

Prevention of unwanted
pharmacokinetic interaction
2D6 interaction
Inhibition (Fluoexetine), Paroxetine)
Risperidone, Olanzapine, Clozapine

Prevention of unwanted
pharmacokinetic interaction
3A4 Inhibition
(Fluvoxamine, Erythromycine,
antifungal, ketoconazol)
Clozapine
Ziprasidone
Quetiapine

Treating Schizophrenic Patients

in a Real World
Patient factors
Age,

gender,

ethnicity,

education,

employment, marital status, life style (diet,

exercise; leisure time), habits (smoking,
caffeine), Substance (psychoactive, OC drug)
belief system, personality, coping skills.

Treating Schizophrenic Patients

in a Real World
Physician factors
Commitment to patient
Patient, family, education
Psychotherapy
Team approach
Expertise in conducting drug treatment
Proper diagnosis
Selection of drug
Avoid drug interaction
Know patient tolerability profile
Give drug adequate duration, regular visits
Screen for side effect, document response, enhance
compliance

Conclusion
Atypical antipsychotic medications:
Improve psychopathology.
Enhance patients adherence to treatment.
Improve outcome.

Conclusion
Psychiatrists

can

share

by giving

their

patients safe, tolerable and effective drugs.

Can share by giving their patients psychoeducation.
Alliance and family intervention.

Protecting the Brain is a Long term

Investment
Successive relapse lead to deterioration and
.worsen disability
Every further relapse is associated with a 15%
.decrease in likelihood to achieve remission
or 7 relapse are enough to loss the brain of the 6
.patient
Early start of long acting antipsychotic is
recommended for suspected revolving door
.patients

Do Antipsychotic Drugs Change

?Brain Structure
Atypical anti-psychotic release the brain from its
aberrant wiring, and reengage the patient in a
.cognitive dialogue with the real world
APD reestablishes a richer fabric of neuronal
connectivity, increased number of synapses and
changes in the proportions and properties of
.them
.APD prevent the backward loss of connections
McGiashan, 2006: Schizophrenia Bulletin 2006 32(4):609-613
Harrison, 1999: Schizophrenia Research 40: 87-89

Behavioral and Cognitive

Intervention
.New computerized cognitive exercises
Help patient to learn new mechanisms
.for adaptive function
Bridge the gap between cognitive and
.real world function
Hopefully

may

alleviate cognitive
.dysfunction

Harvey P.D. and McClure M.M., 2006: Drugs; 66 (11): 1465-1473

Drugs in Pipelines
Targets
.Alpha adrenoreceptor agonist
.Alpha 7 nicotinic agonist
.Canabinoid receptors
Catechol O methyl transferase
inhibitors

Drugs in Pipelines
(Phase 2, 3)
Name

Action

Company

Bifeprunox

Partial D2 & 5HTT1a

agonist

Wyeth & Solvay

Asenaprine
Iloperidon
Ocaperidone

5HT2a antagonist
and D2 partial
agonist

Organon & Pfizer

etc

Paliperidon

5HT2a antagonist
and D2 partial
agonist

Jhonson &
Jhonson etc

Talnetant

NK3 receptor
antagonist

GSK

Problems Hinder Achieving Goal I

B- Non response or partial response
2. Some drugs have little or no effect on all
dimensions of psychopathology.
3. Potentially worsening of cognitive function.

Negative symptoms and neuro-cognitive defects are

poorly treated by typical antipsychotics.

Quetiapine is as effective as
risperidone
in improving cognitive function
Pearson
correlation

Risperidone
Quetiapine

Fleischhacker W.W. and Widschwendter C.G. (2006): Current Opinion in Psychiatry, 19:12
Harvey et al 2005

Quetiapine improves verbal fluency:

patients with first episode of schizophrenia
Functional magnetic resonance imaging (fMRI)

Drug-nave

Seroquel-treated

Patients with schizophrenia; Seroquel treatment:

mean duration 5.7 months; mean dose 364 mg/day
fMRI session conducted during overt verbal fluency task

Jones et al 2004
Meisenzahl E.M. et al., (2006):
Eur Arch Psychiatry Clin
Neurosci, 256:522531.

Prolactin levels in men and women

treated with quetiapine or risperidone
Prolactin
levels
(ng/mL)

Risperidone
Quetiapine

***

***p<0.001 vs risperidone

***

Meyer J.M. 2007: J Clin Psychiatry 68:suppl. 1: 28-33

Knegtering et al 2004

Lower levels of sexual dysfunction

Patients
(%)

*
**

(n=49)
*p=0.05; **p=0.01 vs risperidone

(n=44)
Knegtering et al 2004

Long-term weight change with

Quetiapine and olanzapine
Mean
weight
change
from
baseline
(kg)

Quetiapine monotherapy
(n=43)

12

12

10

10

0
0

12

52

Time (weeks)

Olanzapine 15 mg/day
(n=69)

104

26

52

Time (weeks)

Brecher et al 2005; Nemeroff 1997

Low striatal D2 receptor occupancy

predicts reduced risk of EPS
Haloperidol 13 mg (n=6)
Risperidone 8 mg (n=6)
Olanzapine 18 mg (n=6)
Risperidone 3 mg (n=5)

Quetiapine

600 mg (n=3)

Clozapine

475 mg (n=4)

20

EPS

40
60
80
D2 receptor occupancy rate (%)

100

Kasper et al 1999
Tandon R., Targum S.D., Nasrallah H.A., Ross R. (2006): Journal of Psychiatric Practice Vol. 12, No. 6, 348-363.

Quetiapine 400-800 mg/day: most frequent

dose range in psychoses
Pooled OLE data from patients treated with
Quetiapine for up to 1 year
Patientsa
(%)

Mean dose of Seroquel (mg/day)

n=1085
a
With schizophrenia, schizoaffective disorder or bipolar disorder
Adapted from Arvanitis & Rak 1997; Data on file (S118) - Astra Zeneca

Still There are unmet

needs in the
management of
SCHIZOPHRENIA

Still There are unmet

needs in the
management of
SCHIZOPHRENIA

We know that there are unmet

needs in the management of
SCHIZOPHRENIA
Which can be fulfilled in the
future
But until that time we can use
effective, safe antipsychotics