THERAPEUTIC

STRATEGIES

DRUG DISCOVERY

TODAY

Treatment

of

first-episode

schizophrenia:

pharmacological

and

neurobiological

aspects

Alkomiet

Hasan

*

,

Thomas

Wobrock,

Daniela

Reich-Erkelenz,

Peter

Falkai

Department

of

Psychiatry

and

Psychotherapy,

Georg

August

University

Go¨ttingen,

Von-Siebold-Strasse

5,

D-37075

Go¨ttingen,

Germany

The

treatment

and

understanding

of

first-episode

schi-

zophrenia

belongs

to

the

greatest

challenges

in

clinical

psychiatry

and

psychiatric

research.

Antipsychotic

drugs

revolutionised

the

therapy

of

schizophrenia

since

their

first

introduction

in

the

1950s.

However,

there

are

still

unsolved

questions

about

an

evidence-based

and

improved

treatment

of

first-episode

patients,

which

neurobiological

and

clinical

studies

can

help

answering.

Section

editors

:

Diana

Kristensen

–

Department

of

Psychiatry,

Hvidovre

University

Hospital,

Brøndby,

Copenhagen,

Denmark

Mikkel

Myatt

–

Psykiatrisk

Center

Glostrup,

Copenhagen

University,

Glostrup,

Copenhagen,

Denmark

Introduction

Schizophrenia

is

still

the

most

serious

psychiatric

condition

affecting

all

areas

of

the

patient’s

life

and

leading

in

most

cases

to

a

chronic

disease

course.

Therefore,

the

development

of

effective

therapeutic

strategies,

especially

in

the

beginning

of

the

disease,

is

one

of

the

most

important

challenges

in

psychiatric

research.

However,

most

of

the

available

antipsy-

chotic

drugs

for

the

treatment

of

schizophrenia

have

not

been

investigated

to

a

great

extent

in

first-episode

schizo-

phrenia

patients:

even

today,

only

unsatisfying

evidence

exists

about

the

arrangement

of

a

conclusive

therapy

with

the

currently

available

antipsychotic

drugs.

This

short-review

will

focus

on

the

currently

available

and

evidence-based

treatment

strategies

in

first-episode

schizo-

phrenia

and

will

address

problems

in

transferring

findings

from

chronically

ill

to

first-episode

patients.

Furthermore,

we

will

provide

some

treatment

recommendations

according

to

the

recent

national

and

international

guidelines

and

discuss

new

treatment

options

which

might

become

available

for

future

clinical

use.

Diagnosis

and

disease

course

Research

on

first-episode

schizophrenia

patients

raises

the

question

about

how

to

exactly

define

the

first-episode.

In

most

studies

and

in

clinical

practice,

the

beginning

of

the

first-episode

is

defined

by

the

onset

of

the

first

prominent,

long-lasting

psychotic

symptoms

identifiable

by

the

patient

or

outsiders

[

1,2

].

However,

the

definition

of

first-episode

schizo-

phrenia

varies

and

overlaps

with

other

terms

like

recent-

onset

schizophrenia:

this

may

explain

diagnostic

uncertainties

and

variable

findings

in

clinical

and

experimental

trials.

Furthermore,

the

duration

of

the

untreated

illness

(DUI,

time

from

the

onset

of

non-specific

symptoms

till

treatment)

and

duration

of

the

untreated

psychosis

(DUP,

time

from

the

first

onset

of

productive

psychotic

symptoms

till

treatment)

represent

important

aspects

in

treatment

prognosis.

Different

studies

reveal

long

DUIs

(mean:

more

than

4.5

years)

and

DUPs

(mean:

more

than

2

years)

before

a

first-episode

schizophrenia

is

diagnosed

[

2–4

].

A

prolonged

DUI/DUP

is

associated

with

a

poorer

outcome

of

the

first-episode

schizo-

phrenia,

a

less

complete

recovery

and

an

increased

risk

for

a

relapse

[

5

].

A

short

duration

of

DUP

was

found

to

be

Drug

Discovery

Today:

Therapeutic

Strategies

Vol.

8,

No.

1–2

2011

Editors-in-Chief
Raymond

Baker

–

formerly

University

of

Southampton,

UK

and

Merck

Sharp

&

Dohme,

UK

Eliot

Ohlstein

–

GlaxoSmithKline,

USA

Treatment

of

schizophrenia

*Corresponding

author:

A.

Hasan

(

[e-mail]

),

(

[e-mail]

)

1740-6773/$

ß

2011

Elsevier

Ltd.

All

rights

reserved.

DOI:

10.1016/j.ddstr.2011.09.003

31

associated

with

a

better

response

to

antipsychotic

treatment

in

meta-analyses

and

systematic

reviews

[

6

].

Therefore,

one

key

feature

of

a

modern

and

successful

treatment

of

first-

episode

schizophrenia

is

to

shorten

the

time

between

symp-

tom

onset

and

diagnosis

and

to

start

antipsychotic

treatment

as

soon

as

the

diagnosis

of

first-episode

schizophrenia

is

confirmed

[

5

].

The

question,

whether

to

treat

patients

during

the

prodromal

phase

before

explicitly

diagnosing

a

first-epi-

sode

schizophrenia

or

not

is

subject

of

ongoing

discussions

(see

[

7,8

]).

However,

because

of

low

transition

rates

(below

20%

[

9

])

and

only

few

randomized

clinical

trials,

currently

no

specific

evidence-based

treatment

for

the

prodromal

phase

can

be

recommended.

First-generation

antipsychotics

or

second-generation

antipsychotics?

Since

the

first

introduction

of

antipsychotic

drugs,

a

magni-

tude

of

randomized

clinical

trials

provided

strong

evidence

for

their

efficacy

in

the

treatment

of

psychotic

symptoms

in

first-episode

and

multi-episode

schizophrenia

patients

(for

detailed

reviews

see

[

5,10

]).

With

regard

to

the

side

effect

profile

and

the

date

of

the

commercial

launch,

first-genera-

tion

antipsychotics

(FGAs,

‘old

antipsychotics’)

are

still

dif-

ferentiated

from

second-generation

antipsychotics

(SGAs,

‘new

antipsychotics’).

High-potency

FGAs

were

mainly

intro-

duced

in

the

1960s

and

1970s

and

act

predominately

as

dopamine-D2-receptor

antagonists.

This

D2-receptor

antag-

onism

is

responsible

for

the

neurological

side-effects

of

the

FGAs.

Clozapine

was

introduced

in

1972

and

was

the

first

SGA,

characterized

by

less

neurological

side-effects

than

the

known

FGAs.

From

the

early

1990s

till

today,

19

different

so-

called

SGAs

have

been

internationally

launched.

These

SGAs

are

characterized

by

a

heterogeneous

receptor

profile

(D2-

antagonism,

D4-antagonism,

5HT-agonism/antagonism

(on

different

subtypes),

mACh-Antagonims),

heterogeneous

effi-

cacy

and

a

heterogeneous

spectrum

of

side-effects.

Today,

this

classification

into

FGAs

and

SGAs

and

the

generalisation

of

receptor-binding

profile,

efficacy

and

side-

effects

within

each

group

must

be

considered

as

critical,

because

neither

SGAs

nor

FGAs

represent

a

homogenous

class

[

11

].

The

situation

is

further

complicated

by

the

important

fact

that

only

few

studies

compared

the

efficacy

of

the

FGAs

and

SGAs

in

the

treatment

of

first-episode

schizophrenia

patients

in

double-blinded

randomized

clinical

trials

with

a

satisfy-

ingly

large

sample

size.

From

1999

to

2011,

five

different

randomized

clinical

trials

with

a

large

sample

size

compared

FGAs

(haloperidol)

and

SGAs

(olanzapine

or

clozapine

or

risperidone)

and

these

studies

did

not

reveal

a

statistically

significant

difference

of

efficacy

[

12–16

].

In

2008,

the

first

head-to-head

comparison

between

FGAs

(haloperidol)

and

SGAs

(amisulpiride,

ziprasi-

done,

quetiapine,

olanzapine)

was

published

(EUFEST-Study

[

17

]),

showing

no

differences

concerning

efficacy

expressed

as

treatment

discontinuation.

These

findings

were

confirmed

in

a

recent

meta-analysis

including

150

double-blind

rando-

mized

clinical

trials

with

21,533

participants

revealing

no

efficacy

differences

between

FGAs

(haloperidol)

and

different

SGAs

[

11

].

Currently,

short-term

trials

could

not

detect

any

difference

of

efficacy

in

psychotic

symptom

reduction

between

FGAs

(especially

haloperidol)

and

SGAs,

whereas

some

few

long-term

trials

indicate

that

SGAs

might

be

super-

ior

to

FGAs

with

regard

to

relapse

prevention

[

10

].

However,

if

FGAs

and

SGAs

do

show

the

same

efficacy

in

the

treatment

of

positive

symptoms,

which

antipsychotic

class

should

be

used

for

the

treatment

of

first-episode

schizo-

phrenia?

Paradigms

are

changing

and

bit

by

bit

the

side-

effects

are

attached

greater

significance.

First-episode

schizo-

phrenia

patients

usually

are

young

patients

who

might

need

a

long-term

treatment

and

it

is

evident

that

side-effects

are

one

important

reason

for

treatment

discontinuation

and

non-

adherence

[

5,18

].

Side-effects

Antipsychotic

drugs

are

a

heterogeneous

drug

class

and

each

antipsychotic

has

its

individual

side-effect

profile.

A

wide

range

of

side-effects

has

been

described

elsewhere

[

5,10

],

but

in

summary

four

big

groups

of

side-effects

[

10,18

]

with

particular

importance

for

young

patients

are

emerging:

1.

Neurological

side

effects

(extrapyramidal

side-effects;

tard-

ive

dyskinesia,

acute

dystonia,

akathisia).

2.

Metabolic

side

effects

(weight

gain,

induction

of

diabetes,

hyperlipidemia).

3.

Prolactine

elevation

and

sexual

dysfunction.

4.

Cardiovascular

side-effects

(ECG-abnormalities,

QTc-pro-

longation,

tachycardia,

orthostatic

hypotension).

It

should

be

noticed

that

first-episode

patients

are

much

more

sensitive

to

the

various

side-effects

of

antipsychotic

drugs

than

multi-episode

schizophrenia

patients

[

5

].

Schizo-

phrenia

patients

in

general

have

an

illness-independent

risk

for

developing

a

metabolic

syndrome

[

19

]

and

untreated

first-

episode

patients

show

an

increased

amount

of

intra-abdom-

inal

fat

in

comparison

to

matched

healthy

controls

[

20

].

High-potency

FGAs

(like

haloperidol)

and

some

SGAs

(especially

risperidone/paliperidone,

but

other

SGAs,

too)

carry

the

risk

to

induce

neurological-side

effects,

whereupon

the

risk

for

such

side

effects

is

increased

following

a

treatment

with

FGA

in

first-episode

schizophrenia

patients

[

17

].

Both,

FGAs

and

SGAs

could

induce

weight-gain

and

a

metabolic

syndrome

[

21

],

but

certain

SGAs

(clozapine,

olanzapine,

que-

tiapine,

risperidone)

are

linked

to

the

highest

risk

of

this

side-

effect

[

5,10,17

].

Prolactine

elevation

is

associated

with

high-

potency

FGAs

and

some

SGAs

(especially

amisulpride

and

risperidone/paliperidone)

[

5,10,22

].

Last

but

not

least,

Drug

Discovery

Today:

Therapeutic

Strategies

|

Treatment

of

schizophrenia

Vol.

8,

No.

1–2

2011

32

www.drugdiscoverytoday.com

cardiovascular

side-effects

should

be

considered

when

using

antipsychotic

drugs.

All

antipsychotic

drugs

are

more

or

less

linked

to

cardiovascular

side

effects

[

5

].

Certain

SGAs

are

associated

with

a

significant

QTc

prolongation

(sertindole,

ziprasidone)

or

the

risk

of

inducing

a

myocarditis

(clozapine)

[

10,23

].

How

to

treat

psychotic

symptoms

in

first-episode

schizophrenia

patients?

Data

from

large

controlled

trials

comparing

the

efficacy

in

first-episode

schizophrenia

patients

are

still

lacking.

Because

of

practical

reasons

(easy

and

fast

inclusion

into

studies),

most

clinical

trials

have

been

conducted

in

chronically

ill

schizophrenia

patients.

Besides

the

development

of

new

therapeutic

agents,

the

established

antipsychotic

drugs

have

to

be

investigated

and

to

be

compared

in

additional

clinical

trials

with

a

large

number

of

first-episode

patients.

Today,

the

findings

from

multi-episode

patients

are

transferred

to

first-

episode

patients

and

the

findings

of

one

antipsychotic

drug

to

another

one.

Such

results

have

to

be

regarded

with

a

critical

eye.

Recent

publications

indicate

that

there

are

fundamental

neurobiological

differences

between

first-episode

and

multi-

episode

schizophrenia

patients

and

as

stated

before,

antipsy-

chotics

are

a

very

heterogeneous

group

and

therefore

difficult

to

compare.

First

of

all,

an

optimal

and

evidence

based

antipsychotic

treatment

of

first-episode

schizophrenia

should

follow

national

or

international

guidelines

[

5,10

].

Secondly,

each

patient

should

receive

an

individual

treatment

addressing

the

individual’s

risk

profile

for

side-effects,

the

individual’s

symp-

tomatology

and

the

individual’s

clinical

and

social

needs

[

11,24

].

Thirdly,

for

being

more

responsive

to

antipsychotic

treatment,

first-episode

schizophrenia

patients

have

an

increased

risk

to

develop

side-effects

[

10

].

Therefore,

they

should

be

treated

with

dosages

at

the

lower

end

of

the

standard

dose

range

[

10

].

Finally,

one

of

the

most

important

reasons

for

treatment

resistance

and

relapse

in

early

schizo-

phrenia

is

non-adherence

to

antipsychotic

medication

[

5

].

Therefore,

adherence

should

be

discussed

with

the

patient

(psychoeducation)

and

ensured

by

therapeutic

drug

monitor-

ing,

if

necessary.

Long-acting

formulations

of

antipsychotics

(FGAs

and

SGAs)

could

help

to

improve

adherence

and

to

reduce

the

relapse

rate

and

should

be

offered

to

patients

with

non-adherence.

Is

there

a

pharmacological

treatment

of

negative

symptoms?

Patients

with

a

first-episode

usually

present

positive

symp-

toms

at

their

first

contact

with

professional

healthcare.

Dur-

ing

the

disease

course,

negative

symptoms,

such

as

withdrawal

from

social

life,

apathy

and

anhedonia,

are

likely

to

occur.

A

couple

of

years

ago,

companies

claimed

an

improved

efficacy

of

SGAs

for

the

treatment

of

negative

symptoms

[

11

]

and

raised

hope

for

new

treatment

options.

However,

FGAs

and

SGAs

show

similar

efficacy

in

the

treat-

ment

of

negative

symptoms

by

both

only

slightly

improving

them

[

11,17,18

].

The

recently

published

recommendations

from

the

Schizophrenia

Patient

Outcomes

Research

Team

(PORT)

are

more

reserved

stating

an

‘insufficient

level

of

evidence

to

support

a

treatment

recommendation

for

any

pharmacological

treatment

of

negative

symptoms

in

schizo-

phrenia’

[

10

].

Implications

from

neuroscientific

research

Experimental

studies

indicate

pathophysiological

and

struc-

tural

changes

in

the

brain

of

schizophrenia

patients.

A

‘toxic’,

maybe

neurodegenerative

effect

of

psychosis

and

relapse

is

discussed

based

on

the

enhanced

symptom

severity,

the

reduced

neurocognitive

ability

and

the

reduced

drug

sensi-

tivity

in

multiple-episode

schizophrenia

patients

[

25

].

A

large

body

of

work

has

been

published

dealing

with

the

neurobiol-

ogy

of

the

disease

course

in

schizophrenia

and

we

would

like

to

introduce

three

recently

published

studies

to

the

reader.

One

longitudinal

MRI

study

(first

MRI

was

recorded

during

the

first-episode

with

a

consecutive

mean

follow-up

of

7

years)

revealed

that

antipsychotics

(no

matter

if

FGAs

or

SGAs)

have

a

significant

impact

on

brain

tissue

loss

over

time,

which

is

related

to

findings

from

animal

studies

in

macaque

monkeys

[

26

].

The

same

group

published

another

very

interesting

longitudinal

study

indicating

that

some

schizophrenia

patients

show

an

accelerated

and

progressive

decrement

in

brain

tissue

volume

compared

to

healthy

con-

trols

[

27

].

The

authors

investigated

first-episode

schizophre-

nia

patients

who

have

been

followed

up

to

18

years

and

found

the

greatest

volume

losses

during

the

early

stages

of

the

illness

[

27

].

Finally,

in

a

cross-sectional

proof-of-principle

study

we

showed

that

cortical

plasticity

is

affected

in

multiple-episode

schizophrenia

patients,

but

not

in

recent-onset

schizophre-

nia

patients

with

only

one

psychotic

episode

[

28

].

Summing

up,

there

is

neurobiological

evidence

for

a

dys-

functional

neuroplasticity

and

impaired

structural

integrity

during

the

disease

course

of

schizophrenia.

Today,

antipsy-

chotic

treatment

does

not

account

for

such

differences

between

first-episode

and

chronically

ill

schizophrenia

patients.

However,

new

antipsychotic

drugs

are

under

way

and

plasticity

modulating

therapies

might

provide

an

inno-

vative

treatment

option.

New

treatment

options

The

dopamine

hypothesis

of

schizophrenia

‘has

been

one

of

the

most

enduring

ideas

in

psychiatry’

[

29

],

but

many

other

neurotransmitters

and

neuromodulators

(glutamate,

acetyl-

choline,

endogenous

cannabinoid)

are

likely

to

be

involved

in

its

pathophysiology.

Therefore,

new

antipsychotic

drugs,

which

do

not

follow

the

pharmacological

principle

of

dopa-

mine/5-HT

2

antagonism

[

30

],

are

designed

to

target

other

Vol.

8,

No.

1–2

2011

Drug

Discovery

Today:

Therapeutic

Strategies

|

Treatment

of

schizophrenia

www.drugdiscoverytoday.com

33

receptor

systems

(especially

the

glutamate

and

acetylcholine

system).

A

detailed

overview

about

new

therapeutic

agents

is

published

elsewhere

[

31

].

Promising

novel

agents

are

LY-

404039,

a

metabotropic

glutamate

receptor

2/3

agonist

[

32

],

AVE1625,

a

cannabinoid-1-receptor

agonist

[

33

]

and

NS14492,

a

high-affinity

a

(7)nAChR-selective

partial

agonist

[

34

].

Furthermore,

phosphodiesterase

10A

(PDA10A)

inhibitors

are

discussed

to

provide

efficacy

in

the

treatment

of

schizo-

phrenia

[

35

].

Other

new

therapeutic

principles

are

the

mod-

ulation

of

5-HT(7)

receptors

[

36

]

or

of

dopamine

receptor

interacting

proteins,

like

NCS-1

[

37

].

These

agents

already

are

or

have

to

be

investigated

in

future

animal

studies/pre-clin-

ical-

and

clinical

trials.

In

schizophrenia

patients,

add

on

treatment

with

polyun-

saturated

fatty

acids

(e.g.

omega-3

or

omega-6

fatty

acids)

have

been

investigated

with

regard

to

their

efficacy

for

symp-

tom

reduction.

However,

an

important

meta-analysis

(Cochrane

review)

including

eight

different

studies

revealed

inconclusive

results

[

38

].

Therefore,

there

is

currently

not

enough

evidence

to

support

general

treatment

recommenda-

tions

with

polyunsaturated

fatty

acids.

Interestingly,

a

recently

published

double-blind,

placebo

controlled

randomized

clinical

trial

explored

the

efficacy

of

omega-3

fatty

acids

in

prodromal

patients.

This

study

found

that

omega-3

fatty

acids

reduce

the

risk

of

progression

to

psychotic

disorder

in

ultra-high-risk

prodromal

patients

[

39

].

In

conclusion,

omega-3

fatty

acids

may

be

a

promising

ther-

apeutic

option

in

future,

but

further

studies

need

to

confirm

these

preliminary

findings.

In

chronically

ill

patients,

treatment

approaches

to

enhance

neuroplasticity

were

shown

to

be

promising

in

small

proof-of

principle

studies

and

clinical

trials.

We

performed

a

sham-controlled

clinical

trial

to

investigate

the

influence

of

exercise

on

cognition

and

brain

volume

in

chronic

schizo-

phrenia.

Exercise

resulted

in

a

significant

increase

of

hippo-

campal

volume

(mean:

15%),

in

an

increase

of

hippocampal

n-acetyl-aspartate

(a

marker

for

neuronal

integrity)

and

in

an

improved

performance

in

verbal

and

spatial

working

memory

[

40

].

Weekly

intravenous

recombinant

erythropoietin

(EPO)

halts

the

progressive

cortical

atrophy

in

chronic

schizophre-

nia

and

improves

attention

and

memory

functions

[

41

].

Molecular

and

cell

studies

support

these

findings,

because

EPO

is

known

to

stimulate

axonal

sprouting,

synaptogenesis

and

to

modulate

synaptic

plasticity

[

42

].

Finally,

low

frequency

transcranial

magnetic

stimulation

(TMS)

is

proved

to

be

effective

and

is

therefore

recommended

for

the

treatment

of

refractory

auditory

hallucinations

[

10

].

In

summary,

modulation

of

neuroplasticity

might

be

pro-

mising

for

the

future

treatment

of

schizophrenia.

Especially,

transcranial

non-invasive

brain

stimulation

techniques,

like

TMS

or

transcranial

direct

current

stimulation

(tDCS),

have

to

be

further

investigated

and

tested

for

possible

application

in

schizophrenia.

However,

all

new

antipsychotic

drugs

and

treatment

strategies

have

to

be

proven

in

first-episode

patients,

because

till

today

all

studies

have

been

conducted

in

chronically

ill

patients.

Conclusions

Schizophrenia

is

a

disorder

with

a

heterogeneous

symptoma-

tology

presenting

a

wide

array

of

symptoms:

positive

symp-

toms,

negative

symptoms,

cognitive

impairments,

affective

symptoms,

suicidality

and

many

more.

There

are

clinical

and

neurobiological

differences

between

the

early

course,

the

first-episode

and

the

chronic

illness.

Therefore,

hoping

for

one

magic

bullet

for

all

disease

stages

and

all

symptom

complexes

is

highly

unrealistic.

In

the

future,

new

treatment

strategies

apart

from

dopamine

antagonists

and

5HT-receptor

modulating

drugs

are

needed.

Today,

a

modern

and

evidence-

based

treatment

of

first-episode

schizophrenia

should

follow

the

recommendations

of

national

and

international

guide-

lines

with

particular

emphasis

on

the

side-effects

of

antipsy-

chotics.

Furthermore,

it

should

be

remembered

that

the

currently

available

antipsychotics

are

powerful

drugs

in

the

treatment

of

positive

symptoms

and

relapse

prevention,

but

have

only

little

effects

on

negative

and

affective

symptoms.

First-episode

schizophrenia

patients

display

prominent

differences

in

symptomatology,

response

to

antipsychotic

treatment,

sensitivity

to

drug

side-effects

and

in

the

under-

lying

neurobiology.

Therefore,

the

knowledge

transfer

from

the

findings

in

chronically

ill

patients

to

first-episode

patients

should

be

regarded

with

caution.

More

baseline

studies

and

longitudinal

follow-up

studies

are

needed

to

extend

the

knowledge

about

the

neurobiology

and

the

disease

course

of

schizophrenia

patients.

Larger

well-designed

double-

blinded

randomized

trials

with

head-to-head

comparisons

of

the

available

antipsychotic

drugs

in

first-episode

are

also

needed

to

improve

the

treatment

and

to

allow

more

evi-

dence-based

recommendations.

Antipsychotics

have

revolutionised

the

treatment

of

schi-

zophrenia

after

their

introduction

in

the

1950s.

They

are

the

greatest

achievement

in

psychiatry

and

they

improved

the

treatment,

the

quality

of

life

and

the

disease

prognosis

of

schizophrenia

patients.

Now

it

is

time

to

take

the

next

step

towards

further

therapeutic

improvements

and

we

have

a

legitimate

hope

that

in

future

there

will

be

new

treatment

options

available.

Conflicts

of

interest

A.

Hasan

was

invited

to

scientific

congresses

by

Astra

Zeneca

and

Lundbeck.

T.

Wobrock

was

a

member

of

a

speaker

bureau

for

Alpine

Biomed,

AstraZeneca,

Eli

Lilly,

Essex,

Janssen

Cilag;

has

accepted

paid

speaking

engagements

in

industry-spon-

sored

symposia

from

Alpine

Biomed,

AstraZeneca,

Bristol

Myers

Squibb,

Eli

Lilly,

Janssen

Cilag,

Lundbeck,

Sanofi-Aventis

Drug

Discovery

Today:

Therapeutic

Strategies

|

Treatment

of

schizophrenia

Vol.

8,

No.

1–2

2011

34

www.drugdiscoverytoday.com

and

Pfizer,

and

travel

or

hospitality

not

related

to

a

speaking

engagement

from

AstraZeneca,

Bristol-Myers-Squibb,

Eli

Lilly,

Janssen

Cilag,

and

Sanofi-Synthelabo;

and

has

received

a

research

grant

from

AstraZeneca.

D.

Reich-Erkelenz

reports

no

conflicts

of

interest.

P.

Falkai

was

honorary

speaker

for

Janssen-Cilag,

Astra-Zeneca,

Lilly,

BMS,

Lundbeck,

Pfizer,

Bayer

Vital,

SKB,

Wyeth,

Essex

and

during

the

last

two

years,

but

not

presently,

he

was

member

of

the

advisory

boards

of

Janssen-

Cilag,

Astra-Zeneca,

Lilly

and

Lundbeck.

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Vol.

8,

No.

1–2

2011

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