Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21B) docx

19
PSYCHOTROPIC DRUGS
The
reality
is
more complex since
the
receptor
binding
profile
of
clozapine
and the
newer atypical
antipsychotic agents suggests that D
2
-receptor
blockade
is not
essential
for
antipsychotic
effect.
The
atypical drugs
act on
numerous receptors
and
modulate several interacting transmitter systems.
Clozapine
is a

highly
effective
antipsychotic.
It has
little
affinity
for the
D
2
-receptor compared with
classical
drugs
but
binds more avidly
to
other
dopamine subtypes
(e.g.
D
1
, D
3
and
D
4
).
It
blocks
muscarinic acetylcholine
receptors,

as do
certain
classical
agents (e.g. thioridazine),
a
property which
may
reduce
the
experience
of
extrapyramidal
effects.
Clozapine binds more readily
as an
antagonist
at
a
2
-adrenoceptors
than
the
classical drugs
and
also
blocks
histamine
and
serotonin receptors
(5HT

2
and
others).
The
newer atypical psychotropics vary widely
in
their receptor binding
profiles.
Olanzapine
and
quetiapine bear resemblance
to the
profile
of
cloza-
pine
in
that their therapeutic
effects
appear
to
derive
from
action
on
different
receptors
and
transmitter
systems.

All
atypicals
(except
amisulpride) exhibit
greater
antagonism
of
5HT
2
-receptors than
D
2
-
receptors
compared with
the
classical agents.
Atypical drugs that
do
antagonise
dopamine
D
2
-
receptors appear
to
have
affinity
for
those

in the
Fig. 19.3
Sagittal
brain
section
illustrating
dopaminergic
pathways.
I.
Mesolimbic pathway
(overactive
in
psychotic
illness
according
to
the
dopamine
hypothesis
of
schizophrenia).VTA=
ventrotegmental
area.
2.
Nigrostriatal
pathway
(involved
in
motor
control,

underactive
in
Parkinson's
Disease
and
associated
with
extrapyramidal
motor
symptoms).
3.
Tuberoinfundibular pathway
(inhibits
prolactin
release
from
the
hypothalamus).
mesolimbic system (producing antipsychotic
effect)
rather than
the
nigrostriatal system (associated with
unwanted motor
effects).
In
contrast
to
classical
antipsychotics, risperidone shares with clozapine

an
ability antagonise a
2
-adrenoceptors,
a
property
which
may
have utility
in the
treatment
of
schizo-
phrenia
and is
seen
as an
area
of
interest
for
developing
new
drugs.
PHARMACOKINETICS
Like
antidepressants, antipsychotics
are
well
absorbed

and
distributed
after
oral
administration.
In
situations where very rapid
relief
of
symptoms
or
disturbed
behaviour
is
required, faster uptake
into plasma
can be
achieved through
the
intramus-
cular
route. Again
in
common with antidepressants,
antipsychotics
are
mainly metabolised
by
cyto-
chrome

P450
isoenzymes
in the
liver,
e.g.
CYP 2D6
(zuclopenthixol, risperidone
[Table
19.2a]),
CYP 3A4
(sertindole
[Table
19.2b]),
CYP 1A2
(olanzapine,
clozapine).
Metabolism
of
some compounds
is
parti-
cularly
complex (e.g. chlorpromazine, haloperidol),
involving more than
one
main pathway, utilising
several
P450
enzymes
or

resulting
in the
production
of
many inactive metabolites. Antipsychotic plasma
levels
can be
increased
or
decreased
by co-
prescription
of
drugs which
are
inhibitors,
inducers
or
substrates
of the
same isozyme. Amisulpride
is
an
exception
to the
general
rule
as it is
eliminated
by the

kidneys without hepatic metabolism.
Examples
of
plasma half-lives
for
antipsychotics
include quetiapine
7 h,
clozapine
12 h,
haloperidol
18
h and
olazapine
33 h.
Depot intramuscular
injec-
tions
are
available
from
which drug
is
released over
2-4
weeks.
EFFICACY
Symptoms
in
schizophrenia

are
defined
as
positive
and
negative
(Table
19.4). Whilst
a
classical anti-
psychotic drug should provide adequate treatment
of
positive
symptoms including hallucinations
and
delusions
in at
least
60% of
cases, patients
are
often
left
with
unresolved
negative symptoms
such
as
apathy,
flattening

of
affect
and
alogia. Evidence
suggests that clozapine
and the
newer atypicals
have
a
significant
advantage over classical drugs
against negative symptoms. Clozapine
has a
382
19
ANTI
PSYCHOTI
CS
further
advantage over
all
other antipsychotics,
whether classical
or
atypical,
in
that
it may be
effective
when other antipsychotics prescribed

at
adequate doses have
failed
or are not
tolerated.
Schizophrenia
often
runs
a
chronic relapsing
and
remitting course. Less than one-quarter
of
patients
who
experience
a
psychotic
episode
and are
diag-
nosed
as
having schizophrenia succeed
in
avoiding
further
episodes. Nevertheless, taking antipsychotics
as
prophylaxis

significantly
reduces
the
likelihood
of
relapse.
MODE
OF USE
Since
the
potency (therapeutic
efficacy
in
relation
to
weight)
of
antipsychotic agents varies markedly
between compounds,
it is
useful
to
think
of the
effective
antipsychotic dose
of
classical agents
in
terms

of
''chlorpromazine
equivalents'
(see
Table
19.5).
For
example,
haloperidol
has a
relatively high anti-
psychotic potency, such that
2-3 mg is
equivalent
to
chlorpromazine
100 mg,
whereas
sulpiride
200 mg
(low
potency)
is
required
for the
same antipsychotic
effect.
Patients
who are
'neuroleptic naive' (i.e. have

never previously taken
any
antipsychotic agent)
should start
at the
lowest available dosage, such
as
haloperidol
0.5
mg/day
or
chlorpromazine
25 mg/
day,
in
case
the
patient
is
particularly susceptible
to
adverse
effects,
especially extrapyramidal motor
symptoms. Conservative starting doses
are
also
recommended
in the
elderly

and for
patients with
learning disabilities
who may
require antipsychotics
for
psychosis
or
severe behavioural disturbance.
The
dose
can be
titrated
up at
intervals, until
the
desired
effect
in
treating psychotic symptoms,
calming
disturbed
behaviour
or
effecting
sedation
is
achieved.
The
interval depends

on the
context,
with
the
urgency
of the
situation
and
previous
use of
antipsychotics being
factors
which would
accelerate
the
upward titration.
An
important issue
is
that
the
longer
a
psychosis
is
left
untreated
the
less favourable
is the

outcome; thus drug treatment
should
be
instigated
as
soon
as an
adequate period
of
assessment
has
allowed
a
provisional diagnosis
to
be
established.
For
each antipsychotic agent there
is a
licensed
maximum dose;
for
example
up to
1000
mg of
chlorpromazine/day
may be
given under

the
United Kingdom licence. Prescribing beyond
the
licensed
maximum dose requires specialist consent.
When
two
antipsychotics
are
co-prescribed,
the
maximum antipsychotic dose should
not
exceed
1000
mg of
chlorpromazine equivalents/day except
under specialist supervision.
For
some antipsycho-
tics
the
licenced maximum dose
is
considerably less
than 1000
mg of
chlorpromazine equivalents/day.
For
instance,

the
licenced maximum dose
of
thioridazine
was
reduced
to 600
mg/day
following
concerns about
its
cardiovascular
toxicity.
Note
TABLE
19.4 Symptoms
of
schizophrenia
Positive
symptoms
Negative
symptoms
Hallucinations,
most
commonly
auditory
(i.e.
voices)
in the 3rd
person,

which
patients
may
find
threatening.The
voices
may
also give
commands.Visual
hallucinations
are
rare.
Delusions,
most
commonly
persecutory.'Passivity
phenomena'
include delusions
of
thought
broadcasting,
thought
insertion
or
thought
withdrawal,
made
actions,
impulses
or

feelings.
Bizarre
behaviours
including
agitation,
sexual
disinhibition,
repetitive
behaviour,
wearing
of
striking
but
inappropriate
clothing.
Thought
disorder
manifest
by
failure
in the
organisation
of
speech
such
that
it
drifts
away
from

the
point
(tangentiality),
never
reaches
the
point
(circumstantiality),
moves
from
one
topic
to
the
next
illogically
(loosened
associations,
knight's
move
thinking),
breaks
off
abruptly
only
to
continue
on an
unrelated
topic

(derailment)
or
moves
from
one
topic
to the
next
on the
basis
of a pun or
words
which
sound
similar
(clang association).
Affective
flattening
manifest
by
unchanging
facial
expression
with
lack
of
communication
through
expression,
poor

eye
contact,
lack
of
responsiveness,
psychomotor
slowing
Alogia
(literally'absence
of
words'
manifesting clinically
as a
lack
of
spontaneous speech
(poverty
of
speech).
Anhedonia
(inability
to
derive
pleasure
from
any
activity)
and
Associality
(narrowing

of
repertoire
of
interests
and
impaired
relationships)
Apathy
IAvolution
involving lack
of
energy, lack
of
motivation
to
work,
participate
in
activities
or
initiate
any
goal-directed
behaviour,
and
poor
personal hygiene.
Attention
problems
involving

an
inability
to
focus
on any
one
issue
or
engage
fully
with
communication.
383
19
PSYCHOTROPIC
DRUGS
that plasma electrolytes
and an ECG
should
be
checked
on
introducing
or
increasing
the
dose
of
thioridazine
and

that
an ECG
should
be
seen
before
prescribing pimozide
and
sertindole.
Prescription
of
atypical antipsychotics
follows
similar
rules
to
those
for
classical drugs, starting
at
low
doses
in
neuroleptic naive patients. Whereas
there
is a
wide
range
of
effective

doses
for
many
classical
agents (e.g. chlorpromazine
25-1000
mg/
day),
much narrower ranges have been
defined
for
atypical
agents
(Table
19.5).
While classical anti-
psychotics
are
licenced
for the
management
of
acutely disturbed behaviour
as
well
as for
schizo-
phrenia, atypical agents
are
generally licenced only

for
the
latter indication, although that
for
risperi-
done
is
broader.
For
most atypical agents used
in
schizophrenia,
a
brief
period
of
dose
titration
by
protocol
up to a
stated lowest therapeutic dose
is
usual, e.g. risperidone
4
mg/day, quetiapine
300
mg/day. Dose increases
are
indicated where

there
is no
response
after
2
weeks
and
these
may be
repeated until
the
maximum licenced dose
is
achieved.
Clozapine
may be
initiated only under specialist
supervision
and
only
after
two
other antipsychotic
agents have
failed
through
lack
of
efficacy
or

adverse
effects.
Additionally, leucocyte count moni-
toring
is
mandatory (danger
of
agranulocytosis)
and
blood pressure checking
is
required (for hypo-
tensive
effect).
Patients
are
most vulnerable
to
agranulocytosis
on
initiation
of
therapy with
75% of
cases
occurring
in the
first
18
weeks.

The
dose
titration
schedule must
be
followed
strictly, starting
with clozapine 12.5
mg
nocte
and
working
up
over
a
period
of
four
weeks
to a
target therapeutic dose
of
450
mg/day.
Alternative administration
strategies
in
acute
use of
antipsychotics

Some
of the
antipsychotics
are
available
as
intra-
muscular
injections
for
patients
who are
unable
or
unwilling
to
swallow tablets
(as is
common
in
psychosis
or
severe behavioural disturbance).
Halo-
peridol
is
most
often
used
for

these indications
on
psychiatric inpatient wards (chlorpromazine i.m.
being
restricted
due to
hypotension
and
skin
nodule
formation).
Olanzapine
may be
given i.m.
for
acute behavioural disturbance
in
schizophrenia.
This drug
is
also presented
as a
Velotab' which
dissolves
rapidly
on
contact
with
the
tongue

allow-
ing
drug
to be
absorbed despite
lack
of
cooperation
from
a
disturbed patient.
Long-acting
(depot)
injections
Haloperidol,
zudopenthixol,
fluphenazine,
flupentixol
and
pipothiazine
are
available
as
depot intramuscular
injections
for
maintenance treatment
of
patients
with schizophrenia

and
other chronic psychotic
disorders. Provided
the
patient
is
willing
to
agree
to
have depot injections, usually
by a
community
psychiatric nurse
at
intervals
of 2-4
weeks,
the
need
to
take tablets
two or
three times
a day is
removed.
Poor compliance with oral medication
is the
most
common cause

of
admission
to
hospital
with
a
relapse
of
schizophrenia.
A
reduced initial dose
of
the
depot medication should
be
given, with
a
review
for
unwanted
effects
after
5-10 days.
Rapid
tranquillisation
Rapid
tranquillisation protocols have been devised
for
patients
who are

severely disturbed
and
violent
or
potentially violent
and
have
not
responded
to
nonpharmacological approaches.
The
risks
from
administering psychotropic drugs (e.g. cardiac
arrhythmia
with high-dose antipsychotics)
may
greatly
outweigh
the
risk
of
leaving
the
patient
untreated, including physical trauma
and the
consequences
of

over-stressing
the
cardiovascular
system.
A
benzodiazepine, e.g.
lomzepam
1-2 mg
i.v. (into
a
large vein)
failing
which i.m. (dilute
with
an
equal
volume
of
water
or
physiological saline)
is the
first
option
if the
patient
is not
already receiving
an
antipsychotic drug. Patients requiring rapid

tranquillisation
are
commonly taking antipsycho-
tics
for
established illness
and an
additional anti-
psychotic
may
then
be
used
if the
patient
has not
received
an
adequate dose; otherwise
a
benzo-
diazepine should given.
Haloperidol
2-10
mg
i.m.
is
currently
preferred
for

rapid tranquillisation,
but
new
protocols
may
evolve with
the
development
of
atypical antipsychotics that
can be
given i.m. When
i.m.
antipsychotic
or
benzodiazepine
tranquilliser
is
given
as an
emergency, pulse, blood pressure,
384
19
ANTI
PS YC
HOTI
CS
temperature
and
respiration should

be
monitored,
and
pulse oximetry (oxygen saturation)
if
con-
sciousness
is
lost.
When
at
least
two
doses
of
haloperidol
i.m.
fail
to
produce
the
desired result, zuclopenthixol
acetate
i.m.
is an
alternative. This heavily sedating
drug usually produces
a
calming
effect

within
2
h,
persisting
for 2-3
days
if
used
at
appropriate
dose. Zuclopenthixol acetate
should
never
be
prescribed
to the
neuroleptic naive. Patients must
be
observed with
the
utmost care following admin-
istration. Some will require
a
second dose within
1-2
days.
Amylobarbitone
and
paraldehyde have
a

role
in
emergencies when antipsychotic
and
benzodiazepine
options have been exhausted.
ADVERSE
EFFECTS
(see
Table
19.5)
Active
psychotic illnesses
often
cause patients
to
have poor insight into their condition; unwanted
drug
effects
can
compromise already
fragile
com-
pliance
and
lead
to
avoidable relapse.
Classical
antipsychotics

It
is
rare
for any
patient taking classical anti-
psychotic
agents completely
to
escape their adverse
effects.
Thus
it is
essential
to
discuss with patients
the
possibility
of
unwanted
effects
and
regularly
to
review
this
aspect
of
their care.
Extrapyramidal
symptoms.

All
classical
anti-
psychotics
are
capable
of
producing these
effects
because they
act by
blocking dopamine receptors
in
the
nigrostriatal pathway.
The
result
is
that some
75%
of
patients experience extrapyramidal symptoms
which
may
appear shortly
after
starting
the
drug
or

increasing
its
dose (acute
effects),
or
some time
after
a
particular dose level
has
been established (tardive
effects,
see p.
387).
Acute
extrapyramidal
symptoms.
Dystonias
are
manifest
as
abnormal movements
of the
tongue
and
facial
muscles with
fixed
postures
and

spasm,
including torticollis
and
bizarre
eye
movements
('oculogyric
crisis').
Parkinsonian
symptoms
result
in the
classical
triad
of
bradykinesia,
rigidity
and
tremor.
Both
dystonias
and
parkinsonian symptoms
are
believed
to
result
from
a
shift

in
favour
of
cholinergic
rather than dopaminergic neurotrans-
mission
in the
nigrostriatal
pathway
(see
p.
422).
Anticholinergic
agents,
e.g.
procyclidine, orphe-
nadrine
or
benztropine, restore
the
balance
in
fav-
our of
dopaminergic transmission
but are
liable
to
provoke
antimuscarinic

effects
(dry mouth, urine
retention, constipation, exacerbation
of
glaucoma
and
confusion)
and
they
offer
no
relief
for
tardive
dyskinesia, which
may
even worsen. They should
be
used only
in
response
to
clear
dystonic
or
parkinsonian symptoms rather than
for
prophyl-
axis.
Benzodiazepines, with their general inhibitory

effects,
are an
alternative.
Thioridazine
and
related
Type
2
phenothiazines
are
less likely
to
provoke
extrapyramidal
effects
as
they also block cholinergic
transmission (but patients
may
suffer
antimusca-
rinic
effects).
Note
that
confusion
from
anticholiner-
gic
effects

may
mimic
or
complicate schizophrenic
thought disorder.
Akathisia
is a
state
of
motor
and
psychological
restlessness,
in
which patients exhibit persistent
foot
tapping, moving
of
legs repetitively
and
being
unable
to
settle
or
relax.
A
strong association
has
been noted between

its
presence
in
treated schizo-
phrenics
and
subsequent suicide.
A
(3-adrenoceptor
blocker
is the
best treatment, although anticholiner-
gic
agents
may be
effective
where akathisia coexists
with dystonias
and
parkinsonian symptoms.
Differ-
entiating symptoms
of
psychotic illness
from
adverse drug
effects
is
often
difficult:

drug-induced
akathisia
may be
mistaken
for
agitation
induced
by
psychosis.
Tardive
dyskinesia
affects
about
25% of
patients
taking
classical antipsychotic drugs,
the
risk
increasing with length
of
exposure.
It was
formerly
thought
to be a
consequence
of
up-regulation
or

supersensitivity
of
dopamine receptors.
A
preferred
explanation
is
that tardive dyskinesia
is a
conse-
quence
of
oxidative damage
after
neuroleptic-
induced increases
in
glutamate transmission. Patients
display
a
spectrum
of
abnormal movements
from
minor tongue protusion, lip-smacking, rotational
tongue movements
and
facial
grimacing, choreo-
athetoid movements

of the
head
and
neck
and
even
to
twisting
and
gyrating
of the
whole
body.
It is
less
likely
to
remit
on
stopping
the
causative agent than
385
19
PSYCHOTROPIC
DRUGS
TABLE
19.5
Relative
frequency

of
selected adverse effects
of
antipsychotic
drugs
Drug
Classical
Chlorpromazine
Thioridazine
Trifluoperazine
Haloperidol
Sulpiride
Zuclopenthixol
Atypical
Clozapine**
Olanzapine
Quetiapine
Risperidone
Amisulpride
CPZ
Equiv
Dose
100mg
50
mg
5mg
3
mg
200 mg
25

mg
Min
eff.
dose
(/day)
300
mg
5-1 0 mg
300
mg
4mg
800 mg
Max
dose
(/day)
1
000 mg
300
mg*
50
mg
30
mg
2400
mg
150mg
Max
dose
(/day)
900 mg

20 mg
750 mg
I6mg
1
200 mg
Structure
Type
1
Phenothiazine
Type
2
Phenothiazine
Type
3
Phenothiazine
Butyrophenone
Substituted
benzamide
Thioxanthene
Dibenzodiazepine
Theinobenzodiazepine
Dibenzothiazepine
Benzisoxazole
Substituted
benzamide
++
+
+++
+++
+

++
++
+++
+
+
+
++
+++
+++
+++
+++
+++
+++
++
+++
++
++
+
++
+
+++
+
+
+
+
+
+
+
+
+

+++
+++
+
+
++
+
+
+++
++
+
+
+
++
++
+++
+++
+
+
+
+
+++
+
+
+
+
+++
++
+++
+
Key:

CPZ
equiv
dose
=
Chlorpromazine
equivalent
dose.This
concept
is of
value
in
comparing
the
potency
of
classical
antipsychotics.
Dose
ranges
are not
specified
as
they
are
extremely
wide
and
drugs
are
normally

titrated
up
from
low
starting
doses (e.g.
Chlorpromazine
25 mg
or
equivalent)
until
an
adequate
antipsychotic
effect
is
achieved
or the
maximum
dose
reached.The
Chlorpromazine
equivalent
dose
concept
is of
less
value
for
atypical

antipsychotics
since
minimum
effective
doses (Min. eff. dose)
and
narrower
therapeutic
ranges have
been
defined.
Maximum
dose
(Max.
dose)
can be
exceeded
only
under
specialist
supervision.
* The
maximum
recommended
dose
of
thioradazine
was
reduced
to 300

mg/day
(or 600
mg/day
in
hospitalised
patients)
following
concerns
about
QT
prolongation
and
risk
of
fatal
cardiac
arrhythmias
at
higher
doses.
** A
dose
of
clozapine
50 mg is
considered
equivalent
to
Chlorpromazine
100 mg.

1f
Lower
doses
of
amisulpride
(e.g.
100
mg/day)
are
indicated
for
patients
with
negative
symptoms
of
schizophrenia
only.
are
simple dystonias
and
parkinsonian symptoms.
Any
anticholinergic agent should
be
withdrawn
immediately.
Reduction
of the
dose

of
classical anti-
psychotic
is
often
advised
but
psychotic symptoms
may
then worsen
or be
'unmasked'. Alternatively,
an
atypical antipsychotic
can
provide rapid
improvement whilst retaining control
of
psychotic
symptoms.
Atypical
drugs, particularly
at
high doses,
can
yet
cause extrapyramidal
effects
and
this strategy

is not
always
helpful.
If the
classical antipsychotic
is
simply continued, tardive dyskinesia remits
spontaneously
in
around
30% of
patients within
a
year
but
since
the
condition
is
difficult
to
tolerate,
patients
may be
keen
to try
other medications, even
where evidence suggests that
the
success rates

for
remission
are
limited. These include vitamin
E,
benzodiazepines,
(3-blockers, bromocriptine
and
tetrabenazine. Clozapine, which does
not
appear
to
cause tardive dyskinesia,
may be
used
in
severe
cases where continuing antipsychotic treatment
is
required
and
symptoms have
not
responded
to
other medication strategies.
Cardiovascular
effects.
Postural hypotension
may

result
from
blockade
of
oc-adrenoceptors;
it is
dose-related. Prolongation
of the QT
interval
in the
cardiac
cycle
may
rarely lead
to
ventricular arrhyth-
mias
and
sudden death (but particular warnings
and
constraints apply
to the use of
thioridazine
and
pimozide).
Prolactin elevation. Classical antipsychotics raise
plasma prolactin concentrations
by
their blocking
action

on
dopamine receptors
in the
tuberoinfundi-
bular pathway (Fig. 19.3
and p.
711)
and can
cause
386
19
ANTIPSYCH
OTI CS
gynaecomastia
and
galactorrhoea
in
both sexes,
and
menstrual disturbances.
A
change
to an
atypical
agent
such
as
quetiapine
or
olanzapine

(but
not
risperidone
or
amisulpride) should minimise these
effects.
If
continuation
of the
existing classical
antipsychotic
is
obligatory,
a
dopamine
agonist
such
as
bromocriptine
or
amantadine
may be
beneficial.
Sedation.
In the
acute treatment
of
psychotic
illness
this

may be a
highly desirable property
but it
may
be
unwelcome
as the
patient seeks
to
resume
work, study
or
relationships.
Classical antipsychotics
may
also
be
associated
with:
•
weight gain
(a
problem with almost
all
classical
antipsychotics with
the
exception
of
loxapine,

most pronounced
with
fluphenazine
and
flupentixol)
•
seizures
(chlorpromazine
and
thioridazine
are
especially likely
to
lower
the
convulsion threshold)
•
interference
with
temperature regulation
(hypothermia
or
hyperthermia, especially
in the
elderly)
•
skin problems
(phenothiazines, particularly
chlorpromazine,
may

provoke photosensitivity
necessitating advice about limiting exposure
to
sunlight. Rashes
and
urticaria
may
also
occur)
•
sexual dysfunction
(ejaculatory
problems through
a-adrenoceptor blockade)
•
retinal pigmentation
(chlorpromazine, thioridazine,
vision
is
affected
if
dose
is
prolonged
and
high)
•
corneal
and
lens opacities

•
blood
dyscmsias
(agranulocytosis
and
leucopenia)
•
osteoporosis
(associated
with
prolactin elevation)
•
jaundice
(including cholestatic).
Atypical
antipsychotics
Atypical
drugs
can
provoke
a
range
of
adverse
effects
that
is
similar
to
that

of the
classical anti-
psychotics
but is
generally lesser
in
degree (with
exceptions).
The
following
are the
main
differences.
Atypical
antpipsychotics provoke
fewer extra-
pyramidal
effects
(less blockade
of
dopamine
D
2
-
receptors
in the
nigrostriatal pathway). Neverthe-
less, extrapyramidal
effects
are

seen, notably
with
high
dose
of
risperidone
(8-12
mg per
day)
and
olanzapine
(> 20
mg/day).
Clozapine
and
olanzapine
are the
most likely
of
the
atypical agents
to
cause
anticholinergic (anti-
muscarinic)
effects.
They
are
more likely
than

other
atypicals
to
cause
weight gain
(glucose tolerance
may
be
impaired
and
should
be
monitored
in
susceptible individuals)
and are
second only
to
quetiapine
in
their
sedative
effects.
Sexual dysfunction
and
skin problems
are
rare with atypical anti-
psychotics. Risperidone
and

amisulpride
are as
likely
as
classical antipsychotics
to
raise prolactin
concentrations
and
cause
galactorrhoea.
Clozapine
warrants
further
mention, given
its
value
for
patients
with
treatment-resistant schizo-
phrenia
or
severe treatment-related extrapyramidal
symptoms.
It may
cause postural hypotension
and
tachycardia,
and

provoke seizures
in
3-5%
of
patients
at
doses above
600
mg/day. Most important
is the
risk
of
agranulocytosis
in up to 2% of
patients
(compared
with 0.2%
in
classical antipsychotics).
When clozapine
was
first
licenced without require-
ments
for
regular white count monitoring,
the
haematological problems caused appreciable morta-
lity.
Thanks

to
strict monitoring, there have been
no
recorded deaths
from
agranulocytosis since clozapine
was
reintroduced
in the
United Kingdom,
and
internationally
the
death rate among
the
small
minority
who
develop agranulocytosis
is now
less
than
1 in
1000.
Neuroleptic
malignant
syndrome
The
syndrome
may

develop
in up to 1% of
patients
using
antipsychotics
and is
more
prevalent
at
high doses.
The
elderly,
and
those with organic
brain
disease,
hyperthyroidism
or
dehydration
are
thought
to be
most susceptible. Clinical
features
include:
•
fever
•
confusion
or

fluctuating consciousness
•
rigidity
of
muscles which
may
become severe
•
autonomic instability
manifest
by
labile blood
pressure
•
tachycardia
•
urinary incontinence
or
retention.
Raised
plasma creatine kinase concentration
and
white
cell
count
are
suggestive (but
not
conclusive)
of

neuroleptic
malignant
syndrome.
There
is
some
clinical
overlap
with
the
'serotonin syndrome' (see
387
19
PSYCHOTROPIC
DRUGS
p.
376)
and
concomitant
use of
SSRI
antidepressants
(or
possibly
TCAs)
with antipsychotics
may
increase
risk.
It

is
essential
to
discontinue
the
antipsychotic
when
the
syndrome
is
suspected
and to be
ready
to
transfer
the
patient
to a
medical ward
for
rehydra-
tion. Benzodiazepines
are
indicated
for
sedation
and
their transquillising
effect
may be

useful
where
active
psychosis
has to be
left
untreated. Dopamine
agonists (bromocriptine, dantrolene)
are
beneficial
in
some cases. There
is
also evidence
to
support
a
role
for
electroconvulsive therapy
in
treatment
of
neuroleptic malignant syndrome. Even when
recognised
and
treated,
the
condition carries
a

mortality
of
12-15%,
through cardiac arrhythmia,
rhabdomyolysis
or
respiratory
failure.
The
condition
usually lasts
for 5-7
days
after
the
antipsychotic
is
stopped
but may
continue longer
when
a
depot
preparation
has
been used. Fortunately
those
who
survive
tend

to
have
no
long lasting physical
effects
from
their ordeal.
CLASSICAL
VERSUS
ATYPICAL
ANTIPSYCHOTICS
As
atypical antipsychotics have become established
as
alternatives
to
classical agents, clinicians
are
presented
with
the
dilemma
as to
which
should
be
their
first
choice
in

patients
with
schizophrenia
and
psychotic
illnesses,
and
indeed
whether there
is
sufficient
justification
to
transfer
a
patient stabilised
on a
classical agent over
to an
atypical.
Atypical
antipsychotics
may
have advantages
in
three areas. First, they appear
to be
better tolerated,
2
in

particular being less likely than classical agents
to
induce extrapyramidal
effects
and
hyperprolac-
2
Whilst
the
advantages
of
atypicals over classical
antipsychotics
may
seem clear cut,
one
analysis
using
only
trials
where doses
of
classical antipsychotics were
at or
below
a
dose
of
haloperidol
12

mg/day
or
equivalent (now
regarded
as the
upper limit
for
optimised
use of
these
agents)
produced rather
different
results. Although
the
atypicals
retained their advantage
in
causing extrapyramidal
side
effects
less
frequently,
overall tolerability
and
efficacy
appeared
to be
similar. Geddes
J et al

2000
Atypical
antipsychotics
in the
treatment
of
schizophrenia: systematic
overview
and
meta-regression analysis.
British
Medical
Journal
321:
1371-1376.
tinaemia (with gynaecomastia
and
galactorrhoea),
although
these
latter remain common with risperi-
done
and
amisulpride. Improved tolerance
is
reflected
in
better compliance with taking atypical agents,
so
lessening

the
chance
of
psychosis being untreated
with
the
likelihood
of
relapse once remission
has
been achieved. Secondly, atypical antipsychotics
are
more
efficacious
against
the
negative symptoms
of
schizophrenia which
are
particularly debilitating
in
chronic
illness.
Thirdly, clozapine (but
not the
newer atypicals)
is
more
effective

than classical agents
for
resistant
schizophrenia.
Atypical
antipsychotics
are
significantly more
expensive than classical drugs.
In
some countries
this will
be the
overriding argument
for
retaining
classical
agents
as
first
choice drugs
in
schizoph-
renia.
Additionally,
if a
patient
is
successfully main-
tained

on a
classical antipsychotic,
transfer
to an
atypical
agent
is
difficult
to
justify.
Where
a
classical
antipsychotic
is not
achieving optimal results
or
causes unwanted
effects,
a
more persuasive case
for
change
to an
atypical
can be
made.
But
economic analysis must take into account
factors

beyond
the
crude cost
of
drugs.
If
atypical
antipsychotics truly cause
fewer
distressing
extra-
pyramidal symptoms
and
improve compliance,
they
may
prevent relapse
of
psychotic illness
and
protect
patients against lasting damage
from
periods
of
untreated psychosis. Greater
effective-
ness
in
treating negative symptoms would

afford
patients with schizophrenia more opportunity
of
re-integrating
into
the
community
and to
make
positive contributions
to
society rather than
the
alternative
of
long-term institutionalisation. Such
factors
alleviate
the
cost burden
of
psychotic illness
on
society,
and
must
form
part
of the
overall

accounting between classical
and
atypical drugs
as
first
line treatment.
Mood
stabilisers
In
bipolar
affective
disorder patients
suffer
episodes
of
mania, hypomania
and
depression, classically
with periods
of
normal mood
in
between.
Manic
episodes
involve greatly elevated mood,
often
interspersed with periods
of
irritability

or
undue
388
MOOD
STABILISERS
11
excitement, accompanied
by
biological symptoms
(increased
energy, restlessness, decreased need
for
sleep, increased
sex
drive), loss
of
social inhibitions,
irresponsible behaviour
and
grandiosity. Psychotic
features
may be
present, particularly disordered
thinking manifested
by
grandiose delusions
and
'flight
of
ideas'

(acceleration
of the
pattern
of
thought with rapid speech).
Hypomania
is a
less
dramatic
and
dangerous presentation
but
retains
the
features
of
elation
or
irritability
and the
biolo-
gical
symptoms, abnormalities
in
speech being
limited
to
increased talkativeness
and in
social

conduct
to
overfamiliarity
and
mild recklessness.
Depressive
episodes
may
include
any of the
depres-
sive symptoms described
before
and may
include
psychotic
features.
Lithium
salts were known anecdotally
to
have
beneficial
psychotropic
effects
as
long
ago as the
middle
of the
19th

century
but
scientific
evidence
of
their
efficacy
followed
a
serendipitous discovery.
In
1949,
during
a
search
for
biologically active
substances
in
mania, urine
from
manic patients
was
injected
into
guinea pigs.
The
animals appeared
to
be

affected
by the
accompanying large amounts
of
urea
and it was
postulated that administration
of
urate would exacerbate manic
effects.
Lithium
urate, which
is
highly soluble,
was
selected
to
conduct investigations into urate
toxicity.
It was
found
to be
sedative
and to
protect against manic
urine
toxicity.
Lithium carbonate
was
tried

in
manic
patients,
was
found
to be
effective
in the
acute state
and, later,
to
prevent recurrent attacks.
3
Lithium
salts
are
ineffective
for
prophylaxis
of
bipolar
affective
disorder
in
around
35% of
patients
and
cause several unwanted
effects.

The
search
for
alternatives
has
produced drugs that
are
more
familiar
as
anticonvulsants, notably carbamazepine
and
sodium valproate,
and
possibly lamotrigine.
LITHIUM
The
mode
of
action
is not
fully
understood.
The
main
effect
of
lithium
is
probably

to
inhibit hydro-
lysis
of
inositol phosphate,
so
reducing
the
recycling
of
free
inositol
for
synthesis
of
phosphatidylino-
3
Cade
J F.
1970
The
story
of
lithium.
In: Ayd F J,
Blackwell
B
(eds)
Biological
psychiatry. Lippincott, Philadelphia.

sitides.
These intracellular molecules
are
part
of the
transmembrane signalling system that
is
important
in
regulating intracellullar calcium
ion
concentra-
tion, which subsequently
affects
neurotransmitter
release.
Other putative mechanisms involve
the
cyclic
AMP
'second
messenger' system
and
mono-
aminergic
and
cholinergic neurotransmitters.
Pharmacokinetics.
Knowledge
of

pharmacokinetics
of
lithium
is
important
for
successful
use
since
the
therapeutic plasma concentration
is
close
to the
toxic
concentration (low therapeutic index). Lithium
is
a
small
ion
that, given orally,
is
rapidly absorbed
throughout
the
gut.
High peak plasma concentra-
tions
are
avoided

by
using
sustained-release
formu-
lations which deliver
the
peak plasma lithium
concentrations
in
about
5 h. At
first
lithium
is
distributed throughout
the
extracellular water
but
with continued administration
it
enters
the
cells
and is
eventually distributed throughout
the
total
body water
with
a

somewhat
higher concentration
in
brain, bones
and
thyroid gland.
The
apparent
volume
of
distribution
is
about
50 1 in a 70 kg
person (whose total body water
is
about
40 1)
which
is
compatible with
the
above. Lithium
is
easily
dialysable
from
the
blood
but the

concentration
gradient
from
cell
to
blood
is not
great
and the
intracellular
concentration (which determines toxi-
city)
falls
slowly. Lithium enters cells about
as
readily
as
does sodium
but
does
not
leave
as
readily
(mechanism uncertain). Being
a
metallic
ion it is not
metabolised,
nor is it

bound
to
plasma proteins.
Only
the
kidneys eliminate lithium.
Like
sodium,
it
is
filtered
by the
glomerulus
and 80% is
reabsorbed
by the
proximal tubule
but it is not
reabsorbed
by
the
distal tubule. Intake
of
sodium
and
water
are
the
principal determinants
of its

elimination.
In
sodium
deficiency
lithium
is
retained
in the
body,
thus concomitant
use of a
diuretic
can
reduce lithium
clearance
by as
much
as 50% and
precipitate toxi-
city.
Sodium chloride
and
water
are
used
to
treat
lithium
toxicity.
With

chronic
use the
plasma t
l
/
2
of
lithium
is
15-30
h.
Lithium
is
usually given 12-hourly
to
avoid unnecessary
fluctuation
(peak
and
trough
concentrations)
and
maintain
a
plasma concentra-
tion just below
the
toxic
level.
A

steady-state
plasma concentration will
be
attained
after
about
5-6
days
(i.e.
5 x
t
l
/
2
)
in
patients with normal renal
389
19
PSYCHOTROPIC
DRUGS
function.
Old
people
and
patients with impaired
renal
function
will have
a

longer
t
l
/
2
so
that steady
state will
be
reached later
and
dose
increments
must
be
adjusted accordingly.
Indications
and
use.
Lithium carbonate
is
effective
treatment
in > 75% of
episodes
of
acute mania
or
hypomania.
Because

its
therapeutic action takes
2-3
weeks
to
develop,
lithium
is
generally
used
in
com-
bination with
a
benzodiazepine such
as
lorazepam
or
diazepam
(or
with
an
antipsychotic agent where
there
are
also psychotic
features).
For
prophylaxis,
lithium

is
indicated when there
have been
two
episodes
of
mood disturbance
in
two
years,
although
in
some cases
it is
advisable
to
continue with prophylactic
use
after
one
severe
episode. When
an
adequate dose
of
lithium
is
taken consistently,
around
65% of

patients
achieve
improved control
of
their illness.
Patients
who
start lithium only
to
discontinue
it
within
two
years have
a
significantly poorer
outcome than matched patients
who are not
given
any
pharmacological prophylaxis.
The
existence
of
this
'rebound
effect'
dictates
that
persistence

with
long-term treatment
is of
great importance.
Lithium
is
also used
to
augment
the
action
of
antidepressants
in
treatment-resistant
depression
(see
p.
375).
Pharmaceutics.
It is
important
for any
patient
to
adhere
to the
same pharmaceutical brand,
as the
dose

of
lithium
ion
(Li
+
)
delivered
by
each tablet depends
on
the
pharmaceutical preparation.
For
example,
each
Camcolit
250 mg
tablet contains
6.8
mmol, each
Liskonium
450 mg
tablet contains 12.2 mmol
and
each
Priadel
200 mg
tablet contains
5.4
mmol

of
Li
+
.
Thus
the
proprietary name must
be
stated
on the
prescription. Some patients cannot tolerate slow-
release preparations because release
of
lithium
ions
distally
in the
intestine causes diarrhoea; they
may
be
better served
by the
liquid preparation, lithium
citrate, which
is
absorbed proximally. Patients
who
are
naive
to

lithium should
be
started
at the
lowest
dose
of the
preparation selected.
Any
change
in
preparation
demands
the
same precautions
as
does
initiation
of
therapy.
Monitoring.
The
difference
between therapeutic
and
toxic
doses
is
narrow
and

therapy must
be
guided
by
monitoring
of the
plasma concentration
once
a
steady state
is
reached. Increments
are
made
at
weekly
intervals
until
the
concentration
lies within
the
required range
of
0.4-1
mmol/1
(maintenance
at the
lower level
is

preferred
for
elderly patients).
The
timing
of
blood
sampling
is
important.
By
convention
a
blood sample
is
taken
prior
to the
morning dose,
as
close
as
possible
to
12
h
after
the
evening dose. When
the

therapeutic
range
is
reached,
the
plasma concentration should
be
checked every three months. Likewise,
for
toxicity
monitoring,
thyroid
function (especially
in
women)
and
renal
function
(plasma creatinine
and
electrolytes)
should
be
measured
before
initiation
and
every
3
months

during
therapy.
Patient
education about
the
role
of
lithium
in
the
prophylaxis
of
bipolar
affective
disorder
and
discussion
of the
pros
and
cons
of
taking
the
drug
are
particularly important
to
encourage compliance
with therapy; treatment cards, information

leaflets
and
where appropriate, video material
are
used.
Adverse
effects.
Lithium
is
associated with three
categories
of
adverse
effects.
•
Those experienced
at
plasma
concentrations
within
the
therapeutic
range
(see above) include
fine
tremor (especially involving
the
fingers;
if
this

is
difficult
to
tolerate
a
(3-blocker
may
benefit),
constipation, polyuria
and
polydipsia
(due
to
loss
of
concentrating ability
by the
distal
renal tubules), metallic
taste
in the
mouth,
weight gain, oedema, goitre, hypothyroidism,
acne,
rash, diabetes insipidus
and
cardiac
arrhythmias. There
can
also

be
mild cognitive
and
memory impairment.
•
Signs
of
intoxication,
associated with plasma
concentrations
greater
than
1.5
mmol/1
are
mainly gastrointestinal (diarrhoea, anorexia,
vomiting)
and
neurological (blurred vision,
muscle weakness,
drowsiness,
sluggishness
and
coarse
tremor, leading
on to
giddiness,
ataxia
and
dysarthria).

•
Frank
toxicity,
due to
severe overdosage
or
rapid
reduction
in
renal clearance, usually associated
with plasma concentration greater than
2
mmol/1,
constitutes
an
acute medical
emergency.
Hyperreflexia, hyperextension
of
390
19
limbs, convulsions, toxic psychoses, syncope,
oliguria, coma
and
even death
may
result
if
treatment
is not

instigated urgently.
Overdose
is
treated
by use of
i.v.
fluid
to
maintain
a
good
urine
output guided
by
frequent measure-
ment
of
plasma electrolytes
and
osmolality. Hyper-
natraemia
indicates
probable
diabetes
insipidus
and
isotonic dextrose should then
be
used until
plasma sodium concentration

and
osmolality become
normal. Isotonic saline
forms
part
of the
fluid
regimen (but overuse
may
result
in
hypernatrae-
mia)
and
potassium supplement will
be
required.
Haemodialysis
is
effective
but may
have
to be
repeated
frequently
as
plasma concentration
rises
after
acute reduction (due

to
equilibration
as
lithium
leaves cells
and
also
by
continued absorption
from
sustained-release formulations).
Interactions. Several types
of
drug interfere with
lithium
excretion
by the
renal tubules, causing
the
plasma concentration
to
rise. These include
diuretics (thiazides more than loop type),
ACE
inhibitors
and
angiotensin-11
antagonists,
and
non-

steroidal
anti-inflammatory analgesics. Theophylline
and
sodium-containing antacids reduce plasma
lithium concentration.
The
effects
can be
important
because lithium
has
such
a low
therapeutic ratio.
Diltiazem,
verapamil, carbamazepine
and
pheny-
toin
may
cause neurotoxicity without
affecting
the
plasma lithium. Concomitant
use of
thioridazine
should
be
avoided
as

ventricular arrhythmias
may
result.
Carbamazepine
Carbamazepine
is
licenced
as an
alternative
to
lithium
for
prophylaxis
of
bipolar
affective
dis-
order,
although
clinical
trial evidence
is
actually
stronger
to
support
its use in the
treatment
of
acute

mania.
Carbamazepine appears
to be
more
effective
than
lithium
for
rapidly cycling bipolar
disorders,
i.e.
with recurrent
swift
transitions
from
mania
to
depression.
It is
also
effective
in
combination with
lithium.
Its
mode
of
action
is
thought

to
involve
agonism
of
inhibitory
GABA
transmission
at the
GABA-benzodiazepine
receptor complex (see also
Epilepsy,
p.
417).
MOOD
STABILISERS
Valproic
acid
Valproic
acid
is the
drug
of
first
choice
for
prophylaxis
of
bipolar
affective
disorder

in the
United States, despite
the
lack
of
robust clinical trial
evidence
in
support
of
this indication.
But
treat-
ment with valproic acid
is
easy
to
initiate (especially
compared
to
lithium),
it is
well tolerated
and its
use
appears likely
to
extend
if the
evidence-base

expands.
As the
semisodium
salt,
valproic acid
is
licenced
for use in the
treatment
of
acute mania
unresponsive
to
lithium. (Note:
sodium
valproate,
see
p.
420,
is
unlicenced
for
this indication.)
Treatment
with carbamazepine
or
valproic acid
appears
not to be
associated with

the
'rebound
effect'
of
relapse into manic symptoms that
may
accompany
early withdrawal
of
lithium therapy.
Other
drugs
Evidence
is
emerging regarding
the
efficacy
of
lamotrigine
in
prophylaxis
of
bipolar
affective
disorder
and
treatment
of
bipolar depression. Other
drugs which have been used

in
augmentation
of
existing
agents
include
the
anticonvulsant
gaba-
pentin,
the
benzodiazepine clonazepam,
and the
calcium
channel blocking agents verapamil
and
nimodipine.
Drugs
used
in
anxiety
and
sleep disorders
The
disability
and
health
costs caused
by
anxiety

disorders
are
comparable
to
those
of
other common
medical
conditions such
as
diabetes, arthritis
or
hypertension. People with anxiety disorders expe-
rience
impaired physical
and
role functioning, more
work days lost
due to
illness, increased impairment
at
work
and
high
use of
health services.
Our
under-
standing
of the

nature
of
anxiety
has
increased
greatly
from
advances
in
research
in
psychology
and
neuroscience.
It is now
possible
to
distinguish
different
types
of
anxiety with distinct biological
and
cognitive symptoms. Clear criteria have been
accepted
for the
diagnosis
of
various anxiety
disorders.

The
last decade
has
seen developments
391
11
PSYCHOTROPIC DRUGS
in
both drug
and
psychological therapies such that
a
range
of
treatment options
can be
tailored
to
individual patients
and
their condition.
The
GABA
A
-
benzodiazepine
receptor
complex
This subject
is

central
to any
discussion
of
anxiety
and its
treatment.
Gamma
aminobutyric
acid
(GABA)
is
probably
the
most important inhibitory trans-
mitter
in the
central nervous system.
GABAergic
neurones
are
distributed widely
in the CNS but are
virtually
absent outside
the
brain
and the
spinal
cord.

GABA
controls
the
state
of
excitability
in
all
brain areas
and the
balance between excitatory
inputs (mostly glutamatergic)
and the
inhibitory
GABAergic
activity determines
the
prevailing level
of
neuronal activity.
If the
balance swings
in
favour
of
GABA,
then sedation, amnesia, muscle relaxation
and
ataxia
appear

and
nervousness
and
anxiety
are
reduced.
The
mildest reduction
of
GABAergic
activity elicits arousal, anxiety, restlessness, insomnia
and
exaggerated reactivity.
When
GABA
binds
with
the
GABA
A
-benzodia-
zepine receptor complex,
the
permeability
of the
central pore
of the
receptor
to
chloride ions increases,

allowing more ions into
the
neurone
and
decreasing
excitability.
Classical benzodiazepines
(BDZs)
in
clinical
use
enhance
the
effectiveness
of
GABA
by
lowering
the
concentration
of
GABA
required
for
opening
the
channel,
so
enabling
the

GABAergic
circuits
to
produce
a
larger inhibitory
effect
(Fig.
19.4).
These drugs
are
agonists
at the
receptor
and
there
is an
antagonist
(flumazenil) which prevents
agonists
from
binding
at the
receptor site
and
enhancing
GABA
function.
Drugs that
act as

agonists
at
this receptor
are
used mostly
but not
exclusively
in
sleep
and
anxiety disorders. Benzodiazepines (see
later)
have
hypnotic, sedative, anxiolytic, anticonvulsant
and
(central)
muscle relaxant actions. They
form
a
sig-
nificant
but not the
only part
of
available pharma-
cological
treatments,
as the
following account will
illustrate.

Fig. 19.4
Schematic
representation
of the
GABA
A
-
benzodiazepine
(B2D) receptor complex.
Note
that
drugs
that
bind
to the
benzodiazepine (B2D)
receptor
site
do not
open
the
chloride
channel
directly
but
rather
augment
the
capacity
of

GABA
to do so.
Conversely agents
such
as the
barbiturates
at
lower
doses
enhance
GABA action
but at
higher
doses
act
directly
to
open
the
chloride channel.
Classification
of
anxiety
disorders
The
diagnostic criteria
of
DSM-IV (Diagnostic
and
Statistical

Manual)
or ICD 10
(International Classi-
fication
of
Disease)
are
generally used. Both divide
anxiety
into
a
series
of
sub-syndromes with clear
operational criteria
to
assist
in
distinguishing them.
At
any one
time many patients
may
have symp-
toms
of
more than
one
syndrome
but

making
the
primary
diagnosis
is
important
as
this markedly
influences
the
choice
of
treatment.
The key
features
of
each anxiety disorder
are
given below, with
a
practical description
of the
preferred
choice
of
medication,
its
dose
and
duration.

PANIC
DISORDER
The
main
feature
is
recurrent, unexpected panic
attacks.
These
are
discrete periods
of
intense
fear
accompanied
by
characteristic physical symptoms
such
as
skipping
or
pounding heart, sweating,
hot
flushes
or
chills, trembling/shaking, breathing
difficulties,
chest pain, nausea, diarrhoea
and
other

gastrointestinal symptoms, dizziness
or
light-
headedness.
The
first
panic attack
often
occurs
392
CLASSIFICATION
OF
ANXIETY
DISORDERS
19
without warning
but may
subsequently become
associated with
specific
situations
e.g.
in a
crowded
shop, driving. Anticipatory anxiety
and
avoidance
behaviour develop
in
response

to
this chain
of
events.
The
condition must
be
distinguished
from
alcohol
withdrawal,
caffeinism,
hyperthyroidism
and
(rarely)
phaeochromocytoma.
Patients
experiencing panic attacks
often
do not
know what
is
happening
to
them,
and
because
the
symptoms
are

similar
to
those
of
cardiovascular,
respiratory
or
neurological
conditions,
often
present
to
nonpsychiatric services
e.g.
casualty depart-
ments,
family
doctors, medical specialists, where
they
may
either
be
extensively investigated
or
given reassurance that there
is
nothing wrong.
A
carefully
taken history reduces

the
likelihood
of
this
occurrence.
Treatment.
The
choice lies between
a
fast-acting
benzodiazepine such
as
alprazolam
(1-3
mg/day
p.o.)
and a
drug with delayed
efficacy
but
fewer
problems
of
withdrawal such
as a
TCA, e.g.
clomipramine
(100-250
mg/day
p.o.)

or an
SSRI,
e.g.
paroxetine
(20-50
mg/day
p.o.).
The
different
time course
of
these
two
classes
of
agent
in
panic disorder
is
depicted
in
Fig.
19.5
(see also
Tables
19.5
and
19.6).
Benzodiazepines rapidly reduce panic
frequency

and
severity
and
continue
to be
effective
for
months;
significant
tolerance
to the
therapeutic action
is
uncommon.
On
withdrawal
of the
benzodiazepine,
even
when
it is
gradual, increased symptoms
of
anxiety
and
panic attacks
may
occur, reaching
a
maximum

when
the
final
dose
is
stopped.
Indeed,
about
20% of
patients
find
they
are
unable
to
with-
draw
and
remain long-term
on a
benzodiazepine.
Fig. 19.5
Schematic
representation
of the
time
course
of
panic
treatments.

Antidepressants (both
SSRIs
and
TCAs)
have
a
slower
onset
of
action
and,
indeed,
may
induce
an
initial increase
in
both anxiety
and
panic
frequency,
such
that
a
patient
may
discontinue medication,
even
after
a

single
dose. This provoking reaction
usually lasts
for
only
2-3
weeks
after
which panic
frequency
and
severity improve
but
patients need
help
to
stay
on
treatment over this period.
The
doctor
needs
to
give
a
clear
explanation
of the
likely
course

of
events
and the
antidepressant should
be
started
at
half
the
usual initial
dose
to
reduce
the
likelihood
of
exacerbation. Where
the
exacerbation
is
particularly
of
anxiety,
a
short course
of a
long-
acting
benzodiazepine
can

provide
benefit.
The
dose
of
antidepressant required
to
treat panic
dis-
order
is
generally
as
high
or
higher than that
for
depression
and
maximal
benefit
may not
emerge
for
8-12
weeks. Patients should
therefore
receive
as
high

a
dose
as can be
tolerated
for
this length
of
time.
If
there
is no
response
to
adequate
trial
of an
SSRI,
followed
by a
TCA,
the
MAOI,
phenelzine
should
be
used
at
doses
of up to 90
mg/d.

MAOIs
tend
to
produce less exacerbation
at the
beginning
of
treatment than
the
other antidepressants
but
can
increase anxiety
and
panics
in
more sensitive
individuals.
SOCIAL
ANXIETY
DISORDER
The
essential
feature
of
social phobia
is a
marked
and
persistent

fear
of
performance situations
when
patients
feel
they will
be the
centre
of
attention
and
will
do
something humiliating
or
embarrassing.
The
situations that provoke
this
fear
can be
quite
specific,
for
example public speaking,
or be of a
much more generalised nature involving
fear
of

most social interactions,
for
example initiating
or
maintaining conversations, participating
in
small
groups, dating, speaking
to
anyone
in
authority.
Exposure
to the
feared
situation almost invariably
provokes anxiety with similar symptoms
to
those
experienced
by
patients with panic attacks
but
some
seem
to be
particularly prominent
and
difficult
i.e.

blushing, tremor, sweating
and a
feeling
of
'drying
up'
when speaking.
Treatment.
The
drugs with established
efficacy
are the
SSRI,
paroxetine,
the
MAOI,
phenelzine
and
393
19
PSYCHOTROPIC
DRUGS
TABLE
19.5
Relative
effectiveness
of
pharmacological
treatments
for

anxiety
disorders
Benzodiazepine
SSRI
TCA
Panic
disorder
++ +++ +++
Social
phobia
+ ++ +
(social
anxiety disorder)
Generalised
anxiety disorder
++ ++ ++
Obsessive-compulsive
disorder
-/+ ++ ++
(Clomipramine)
Post-traumatic
stress
disorder
+ ++ +
Acute
stress
reaction
++
Other
MAOI

++
MAOI++
Venlafaxine++
MAOI+
Buspirone++
Addition
of
antipsychotics
TABLE
19.6
Properties
of
anti-anxiety
drugs
Benzodiazepines
Buspirone
Onset
Initial
worsening
of
symptoms
Withdrawal
symptoms
Acute
Chronic
Abuse
potential
Interactions
with
alcohol

Adverse
effects
Sedation
Amnesia
Cardiovascular
Gastrointestinal
Sexual
Depression
Relative
safety
in
overdose
fast
no
yes
(~30%)
?yes(~10%)
low
marked
yes
yes
no
no
no
sometimes
yes
slow
rarely
no
no

zero
slight
no
no
no
slight
no
no
yes
Antidepressants
SSRIs
TCAs
slow
sometimes
(especially
panic)
sometimes
no
zero
no
no
no
yes
yes
no
yes
slow
sometimes
no
zero

some
TCAs
mild
yes
no
no
no
no
the
RIMA,
moclobemide
in the
same doses
as for
depression. These achieve equivalent degrees
of
improvement; phenelzine
has a
slightly
faster
onset
of
action
but
produces more adverse
effects.
Some
benzodiazepines
and
other

SSRIs
are
reported
to
provide
benefit
but
evidence
for
their therapeutic
efficacy
is
less
conclusive. $-adrenoceptor blockers
continue
to be
widely used despite their having
no
proven
efficacy
in
social phobia.
But
they have
a
place
in the
treatment
of
specific performance

anxiety
in,
e.g. musicians,
when
management
of the
tremor
is
crucial.
The
duration
of
treatment
is as for
depression
or
longer,
for
this
can be a
lifelong
condition.
POST-TRAUMATIC
STRESS
DISORDER
(PTSD)
Symptoms characteristically
follow
exposure
to an

extreme
traumatic stressor event. These include
persistent re-experiencing
of the
traumatic
event,
persistent avoidance
of
stimuli associated
with
the
trauma
and
numbing
of
general responsiveness,
and
persistent symptoms
of
increased arousal.
In
taking
a
history
the
association with
the
event
is
usually

obvious. PTSD
is
differentiated
from
acute
stress
disorder (below)
by its
persistence—the
symptoms
of the
latter resolve within about
4
weeks.
Depression quite commonly coexists with
PTSD
and
should
be
enquired
for in the
history.
Treatment
is
poorly researched; there have been
few
properly controlled trials
and
almost
all

open
trials
have been conducted
on
small numbers
of
patients long
after
the
causative incident.
The
wide
range
of
drugs that
has
been reported
to
provide
some
benefit
includes benzodiazepines, TCAs
and
MAOIs;
paroxetine
(SSRI)
(20-50
mg/day
p.o.)
is

now
licenced
for
this indication
in the UK. The
preferred
treatment immediately following
the
394
CLASSIFICATION
OF
ANXIETY
DISORDERS
19
incident should probably
be a
short course
of a
benzodiazepine
to
promote sleep
and
help
minimise mental rehearsal
of the
trauma that
may
lead
to its
perpetuation. Long-term therapy appears

to be
indicated
at
doses
in the
same range
as for
other anxiety disorders.
ACUTE
STRESS
DISORDER/
ADJUSTMENT
DISORDER
Acute stress disorder
is
anxiety
in
response
to a
recent extreme stress. Although
in
some respects
it
is
a
normal
and
understandable reaction
to an
event,

the
problems associated with
it are not
only
the
severe distress
the
anxiety causes
but
also
the
risk
that
it may
evolve into
a
more persistent state.
Treatment.
A
benzodiazepine used
for a
short time
is the
preferred
approach
for
treating overwhelm-
ing
anxiety that
needs

to be
brought
rapidly
under
control.
It
particularly relieves
the
accompanying
anxiety
and
sleep disturbance.
A
drug with
a
slow
onset
of
action such
as
oxazepam
(60-120
mg/day
p.o.)
causes less dependence
and
withdrawal,
and
is
preferred

to
those that enter
the
brain rapidly,
e.g.
diazepam, lorazepam. Some patients
find
it
hard
to
discontinue
the
benzodiazepine,
so its use
should
be
reserved
for
those
in
whom extreme
distress
disrupts normal coping strategies.
GENERALISED
ANXIETY
DISORDER
(GAD)
The
essential
feature

of
this condition
is
chronic
anxiety
and
worry.
To the
nonsufferer
the
focus
of
the
worry
often
seems
to be
trivial,
e.g.
getting
the
housework done
or
being late
for
appointments,
but to the
patient
it is
insurmountable.

The
anxiety
is
often
associated with other symptoms, which
include
restlessness,
difficulty
in
concentrating,
irritability,
muscle tension
and
sleep disturbance.
The
course
of the
disorder
is
typically chronic with
exacerbations
at
times
of
stress
and is
often
asso-
ciated
with depression.

Its
chronic nature with
worsening
at
times
of
stress helps
to
distinguish
GAD
from
anxiety
in the
form
of
episodic panic
attacks
with associated anticipatory anxiety (panic
disorder).
Hyperthyroidism
and
caffeinism
should
also
be
excluded.
Treatment.
Historically
benzodiazepines
have been

seen
as the
most
effective
treatment
for GAD for
they rapidly reduce anxiety
and
improve sleep
and
somatic
symptoms. Consequently patients
like
taking
them
but the
chronic nature
of GAD
raises issues
of
duration
of
treatment, tolerance, dependence
and
withdrawal reactions.
Buspirone
is
structurally unrelated
to
other anxio-

lytics
and was the
first
nonbenzodiazepine
to
demonstrate
efficacy
in
GAD.
Its
mode
of
action
is
unclear, although
we
know
it
suppresses
5HT
neurotransmission through
a
selective activation
of
the
inhibitory presynaptic 5HTl
A
-reactor. Buspirone
has a
t

1
/
2
of 7 h, and is
metabolised
in the
liver;
it has
an
active metabolite that
may
accumulate over
weeks.
Twice
daily
dosing
is
suitable, with
the
usual
range being
15-30 mg/d
p.o., maximum
45
mg/d.
Buspirone
is
generally less
effective
and

slower
in
action than benzodiazepines
and
does
not
improve
sleep;
it
does
not
benefit
benzodiazepine
withdrawal symptoms.
The
advantages
are
that
it
does
not
seem
to
cause dependence
or
withdrawal
reactions
and
does
not

interact with alcohol.
It
appears
to be
less
effective
in
patients
who
have
previously received benzodiazepines
and is
there-
fore
probably best used
in
benzodiazepine naive
patients.
A
disadvantage
is
that
useful
anxiolytic
effect
is
delayed
for 2 or
more weeks.
Adverse

effects
can
include dizziness, headache,
nervousness, excitement, nausea, tachycardia
and
drowsiness.
Paroxetine
(SSRI)
and
venlafaxine
(SNRI)
are
effective
(and
are
licenced
for GAD in the
UK),
and
TCAs
have also been
shown
to
give
benefit.
These
drugs have
a
slower onset
of

action than benzodia-
zepines,
are
less well tolerated
but
cause
fewer
problems
of
dependence
and on
withdrawal.
A
delayed
response
in GAD is not as
critical
as
with acute situational anxiety.
A
sensible approach
(especially
in
benzodiazepine naive patients)
is to
start
with
buspirone
for 6-8
weeks,

at
least
30 mg
day
increasing over
2-3
weeks
to
minimise
unwanted actions; patients should
be
warned
not to
expect
an
immediate
benefit.
Those
who do not
respond
should
receive
an
antidepressant
(SSRI
or
venlafaxine)
for 6-8
weeks
at

full
therapeutic dose.
There
remain some patients, including those with
a
395
I9
PSYCHOTROPIC
DRUGS
long history
of
benzodiazepine
use,
who yet
fail
to
respond.
A
benzodiazepine
may be the
only
medication that provides
relief
for
such resistant
cases,
and can be
used
as the
sole treatment.

The
duration
of
therapy
depends
on the
nature
of
the
underlying illness.
If
symptoms
are
inter-
mittent,
i.e.
triggered
by
anxiety-provoking situa-
tions,
then intermittent
use of a
benzodiazepine
(for
a few
weeks)
may be
sufficient.
More typically
GAD

requires treatment over
6-8
months
with
gradual withdrawal
of
medication
thereafter.
This
may
suffice
but
some patients experience severe,
unremitting anxiety
and the
best resort
is to
chronic
maintenance treatment with
a
benzodiazepine
(analogous
to
long-term drug
use in
epilepsy). Such
clinically
supervised benzodiazepine
use is
justified

because, without treatment, patients
often
derive
comfort
from
the
most widely accessible, easily
available anxiolytic, alcohol.
Specific
phobia
A
specific
phobia
is a
fear
of a
circumscribed
object
or
situation,
for
instance
fear
of
spiders,
fear
of
flying.
The
diagnosis

is not
usually
in
doubt.
A
course
of
treatment
by a
trained therapist, involv-
ing
graded exposure
to the
feared
stimulus
is the
treatment
of
choice
and can be
very
effective.
By its
nature such therapy generates severe anxiety
and a
benzodiazepine
may
permit patients
fully
to

engage
in
therapy.
Obsessive-compulsive
disorder
(OCD)
Obsessive-compulsive disorder
has two
main com-
ponents:
• the
repetition
of
acts
or
thoughts which
are
involuntary, recognised
by the
sufferer
to be
generated
by
their
own
brain
but are not in
keeping
with their usual thought processes,
morals

or
values,
and are
therefore
very
distressing
and
•
anxiety provoked
by the
occurrence
of
such acts
or
thoughts.
OCD on its own
often
starts
in
late adolescence
and
has a
chronic
and
pervasive course unless treated.
OCD
starting later
on in
life
is

often
associated
with
affective
or
anxiety disorders. Symptoms
often
abate
briefly
if the
individual
is
taken
to a new
environment.
Treatments
are
cognitive behavioural therapy
and
an
SSRI
or
clomipramine
(i.e.
an
antidepressant
that enhances serotonergic
function),
used
at

higher
doses
and for
much longer periods than
for
depres-
sive disorders. Neuroleptics, atypical antipsychotics
in
low
dose
and
benzodiazepines
can be
used
successfully
to
augment
the
SSRIs
if
they
are not
wholly
effective,
especially
in
patients with tics
(habitual,
repeated contraction
of

certain muscles).
Psychosurgery
is
still occasionally used
for
severe
and
treatment resistant cases. Interestingly,
the
brain pathways targeted
by the
surgeon
are
those
that show abnormalities
in
neuroimaging
(PET)
studies
of
OCD, i.e.
the
basal ganglia/orbitofrontal
pathways.
GENERAL
COMMENTS
ON
DRUG
TREATMENT
FORANXIETY

DISORDERS
The
effective
dose
of
antidepressant
for
anxiety
is
generally
higher
than that
for
antidepressant
effect
and
takes
longer
for
improvements
to be
seen
(at
least
4-8
weeks compared
to 2-3
weeks
for
depression).

The
patient
should
be
maintained
on as
high
a
dose
as can be
tolerated
for at
least
8
weeks
before
changing
a
medication. Educating
the
patient
is
crucial
to
obtaining cooperation.
The
duration
of
treatment
is

often
a
controversial
issue. Anxiety disorders (apart
from
the
self-
limiting acute stress reaction)
are
chronic conditions
and may
require treatment
for as
long
as
that used
in
depression.
In a
first
episode,
patients
may
need
medication
for at
least
6
months, withdrawing over
a

further
4-8
weeks
if
they
are
well. Those with
recurrent illness
may
need treatment
for 1-2
years
to
enable them
to
learn
and put
into place psycho-
logical
approaches
to
their problems.
In
many cases
the
illnesses
are
lifelong
and
chronic maintenance

396