Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21A) pptx

19
Psychotropic
drugs
SYNOPSIS
Advances
in
drug treatment
have
revolutionised
the
practice
of
psychiatry
over
the
past
six
decades.
Drugs provide
a
degree
of
stability
and
control
in the
lives
of
those
suffering
from

schizophrenia,
a
chronic
debilitating
illness
with
impact
so
profound that
it
accounts
for
2-3%
of UK
national
health
spending.
Similarly,
the
impact
of
medication
in
alleviating
the
burden
on
individuals,
their
families

and
society
of
depression,
which
has a
lifetime
prevalence
of up to I in 6 of the
population,
is
substantial.
Psychotropic
drugs
greatly
improve
the
prognosis
of
other
common
conditions
such
as
anxiety
disorders,
attention
deficit/hyperactivity
disorder
and

bipolar
affective
disorder.
In
this
chapter
the
following drug
groups
are
considered
Antidepressants
Antipsychotics
('neuroleptics')
Mood
stabilisers
Drugs
for
anxiety
and
sleep
disorders
Drugs
for
Alzheimer's
dementia
Drugs
for
attention
deficit/hyperactivity

disorder
Writing
prescriptions
is
easy,
understanding
people
is
hard.
(Franz
Kafka,
1883-1924)
In
1940 psychotropic medication
was
limited
to
chloral
hydrate, barbiturates
and
amphetamine.
By
contrast,
the
modern-day formulary lists almost
100
psychotropic drugs, with
efficacious
treatment avail-
able

for the
vast
majority
of
psychiatric diagnoses
and in all
phases
of
life.
Psychotropic medication
has
been
a key
factor
in
accelerating
the
closure
of
Victorian
'asylums' such that the psychiatric inpatient
population
is now a
tiny
fraction
of its
1954 peak
of
148,000
in

England
and
Wales.
DIAGNOSTIC
ISSUES
Older classifications
of
psychiatric disorder divided
diseases into
'psychoses'
and
'neuroses'.
The
term
'psychosis'
is
still widely used
to
describe
a
severe
mental illness with
the
presence
of
hallucinations,
delusions
or
extreme abnormalities
of

behaviour
including marked overactivity, retardation
and
catatonia,
usually accompanied
by a
lack
of
insight.
Psychotic
disorders
therefore include
schizophrenia,
severe forms
of
depression
and
mania. Psychosis
may
also
be due to
illicit substances
or
organic con-
ditions. Clinical features
of
schizophrenia
may be
subdivided into 'positive symptoms', which include
hallucinations, delusions

and
thought disorder
and
'negative symptoms' such
as
apathy, flattening
of
affect
and
poverty
of
speech.
Disorders that would
formerly
have been grouped
under
'neuroses'
include depression
in the
absence
of
psychotic symptoms, anxiety disorders (e.g. panic
disorder, generalised anxiety disorder, obsessive-
compulsive disorder, phobias
and
post-traumatic
stress disorder), eating disorders (e.g. anorexia
nervosa
and
bulimia nervosa)

and
sleep disorders.
367
19
PSYCHOTROPIC
DRUGS
Also
falling
within
the
scope
of
modern psychia-
tric
diagnostic systems
are
organic mental disorders
(e.g.
dementia
in
Alzheimer's disease), disorders
due to
substance misuse (e.g. alcohol
and
opiate
dependence—see Chapter 10), personality disorders,
disorders
of
childhood
and

adolescence (e.g. attention
deficit/hyperactivity
disorder, Tourette's syndrome)
and
mental retardation (learning disabilities).
DRUG
THERAPY
IN
RELATION
TO
PSYCHOLOGICALTREATMENT
No
account
of
drug
treatment
strategies
for
psy-
chiatric
illness would
be
complete without consi-
deration
of
psychological therapies. Psychotherapy
is
broad
in
content, ranging

from
simple counselling
and
'supportive psychotherapy' sessions through
ongoing
formal
psychoanalysis
to
newer techniques
such
as
cognitive behavioural therapy.
As
a
general
rule,
psychotic
illnesses
(e.g. schizo-
phrenia, mania
and
depressive psychosis) require
drugs
as
first-line
treatment,
with
psychothera-
peutic approaches limited
to an

adjunctive
role,
for
instance
in
promoting drug compliance, improving
family
relationships
and
helping individuals cope
with distressing symptoms.
By
contrast,
for
non-
psychotic
depression
and
anxiety disorders such
as
panic
disorder
and
obsessive-compulsive disorder,
forms
of
psychotherapy
are
available which
provide

alternative
first-line
treatment
to
medication.
The
choice
between drugs
and
psychotherapy depends
on
treatment availability, previous history
of
response, patient
preference
and the
ability
of the
patient
to
work appropriately
with
the
chosen
therapy.
In
many cases there
is
scope
to use

drugs
and
psychotherapy
in
combination.
Taking
depression
as an
example,
an
extensive
evidence
base exists
for the
efficacy
of
several
forms
of
psychotherapy. These include cognitive therapy
(in
which individuals
identify
faulty
views
and
negative
automatic thoughts
and
attempt

to
replace
them
with ways
of
thinking less likely
to
lead
to
depression),
interpersonal therapy (which focuses
on
relationships, roles
and
losses),
brief
dynamic
psychotherapy
(a
time-limited version
of
traditional
psychoanalysis)
and
cognitive analytical therapy
(another
well structured time-limited therapy which
combines
the
best points

of
cognitive therapy
and
traditional analysis).
Finally,
it
must
be
stressed that
all
doctors
who
prescribe
psychotropic drugs engage
in a
'thera-
peutic
relationship' with their patients.
A
depressed
person whose doctor
is
empathic, supportive
and
appears
to
believe
in the
efficacy
of the

drug
prescribed
is
more likely
both
to
take
the
medica-
tion
and to
adopt
a
mindset that might actually
make
him or her
feel
better than
if the
doctor
seemed
aloof
and
ambivalent about
the
value
of
psychotropic
drugs. Remembering that placebo
response rates

of
30-40%
are
common
in
double-
blind trials
of
antidepressants,
we
should never
underestimate
the
importance
of our
'therapeutic
relationship' with
the
patient
in
enhancing
the
pharmacological
efficacy
of the
drugs
we
use.
Antidepressant
drugs

Antidepressants
can be
broadly divided into
four
main
classes
(Table
19.1),
tricydics
(TCA,
named
after
their three ring structure),
selective
serotonin
reuptake
inhibitors
(SSRIs),
monoamine
oxidase
inhibi-
tors
(MAOIs),
and
novel
compounds
some
of
which
are

related
to
TCAs
or
SSRIs.
Clinicians
who
wish
to
have
a
working knowledge
of
antidepressants
would
be
advised
to be
familiar
with
the use of at
least
one
drug
from
each
of the
four
main categories
tabulated.

A
more thorough knowledge base would
demand awareness
of
differences
between individual
TCAs
and of the
distinct characteristics
of the
novel
compounds. Since antidepressants
are
largely similar
in
their therapeutic
efficacy,
awareness
of
profiles
of
unwanted
effects
is of
particular importance.
An
alternative categorisation
of
antidepressants
is

based solely
on
mechanism
of
action (Fig. 19.1).
The
majority
of
antidepressants, including TCAs,
SSRIs
and
related compounds
are
reuptake
inhibitors.
Certain
novel
agents including trazodone
and
mirtazapine
are
receptor
blockers
while MAOIs
are
enzyme
inhibitors.
The
first
TCAs (imipramine

and
amitriptyline)
and
MAOIs
appeared
between
1957
and
1961
(Fig.
19.1).
The
MAOIs were developed
from
anti-
tuberculosis
agents which
had
been noted
to
elevate
mood. Independently, imipramine
was
synthesised
from
the
antipsychotic drug chlorpro-
mazine
and
found

to
have antidepressant rather
than
antipsychotic properties. Over
the
next
25
368
A
N Tl D E P RE SS AN T
DRUGS
19
TABLE
19.1
Classification
of
antidepressants
Tricyclics
Selective
serotonin
reuptake
inhibitors
Monoamine
oxidase
inhibitors
Dothiepin (dosulepin)
Amitriptyline
Lofepramine
Clomipramine
Imipramine

Trimipramine
Doxepin
Nortriptyline
Protriptyline
Desipramine
Fluoxetine
Paroxetine
Sertraline
Citalopram*
Fluvoxamine
Phenelzine
Isocarboxazid
Tranylcypromine
Moclobemide
(RIMA)
Novel
compounds
Mainly
noradrenergic
Mainly
serotonergic
Reboxetine
(NaRI) Trazodone
Nefazodone
Mixed
Venlafaxine
(SNRI)
Mirtazapine
(NaSSA)
Milnacipran (SNRI)

Within
each
class
or
subclass
drugs
are
listed
in
order
of
frequency
of
prescription
in the
United Kingdom (1997 data). Abbreviations;
RIMA—reversible
inhibitor
of
monoamine oxidase; NaRI—noradrenaline reuptake
inhibitor;
SNRI—serotonin
and
noradrenaline reuptake
inhibitor;
NaSSA—noradrenaline
and
specific
serotonergic antidepressant.
*

Citalopram
is a
racemic
mixture
of S and R
isomers.The antidepressant activity
of
citalopram
appears
to
reside
in the
S-isomer.
Escitalopram
the
pure
S-isomer,
may
offer clinical benefits over existing preparations.
Trazodone,
nefazodone
and
mirtazapine
have
been
classed
as
'receptor blocking'
antidepressants
based

on
their
antagonism
of
postsynaptic
serotonin
receptors
(trazodone,
nefazodone)
and
presynaptic
2
-receptors
(trazodone,
mirtazapine). Nefazodone
has
additional
weak
SSRI
activity.
fl Not
available
in the
United Kingdom.
years
the TCA
class enlarged
to
more than
10

agents
with heterogeneous pharmacological
profiles
and
further
modifications
of the
original three ring
structure
gave rise
to the
related (but pharmaco-
logically
distinct) antidepressant trazodone.
In
the
1980s
an
entirely
new
class
of
antidepres-
sant arrived with
the
SSRIs,
firstly
fluvoxamine
immediately followed
by

fluoxetine
(Prozac).
Within
10
years,
the
SSRI
class accounted
for
half
of
anti-
depressant prescriptions
in the
United Kingdom.
Further
developments
in the
evolution
of the
anti-
depressants have been novel compounds such
as
venlafaxine,
reboxetine, nefazodone
and
mirtaza-
pine,
and a
reversible monoamine oxidase inhibitor,

moclobemide.
Mechanism
of
action
The
monoamine
hypothesis
proposes that,
in
depres-
sion, there
is
deficiency
of the
neurotransmitters
noradrenaline
and
serotonin
in the
brain which
can
be
altered
by
antidepressants.
Drugs that
affect
depression
can
modify

amine storage, release,
or
uptake (Fig. 19.2). Thus
the
concentration
of
amines
in
nerve endings and/or
at
postsynaptic receptors
is
enhanced.
In
support
of the
monoamine hypo-
thesis
are the
findings that amfetamines, which
release
presynaptic noradrenaline
and
dopamine
from
stores
and
prevent their reuptake, have
a
weak

antidepressant
effect,
whilst
the
antihypertensive
agent
reserpine, which prevents normal noradrena-
line storage, causes depression,
as
does experimental
depletion
of the
serotonin
precursor tryptophan.
The
importance
of
serotonin
is
further
illustrated
by
the
finding that depressed patients
may
exhibit
down-regulation
of
some postsynaptic serotonin
receptors.

Specific
serotonin reuptake inhibitors,
as the
class name
implies,
act
predominantly
by
prevent-
ing
serotonin reuptake
and
have more limited
effects
on
noradrenaline reuptake.
Tricyclic
antidepressants
in
general inhibit noradrenaline reuptake,
but
effects
on
serotonin reuptake vary widely; desipra-
mine
and
protriptyline have minimal potential
for
raising
serotonin

concentrations, whereas clomi-
pramine possesses
a
greater propensity
for
blocking
serotonin reuptake than
for
noradrenaline.
The
369
19
PSYCHOTROPIC
DRUGS
Reuptake inhibitors
1950s
1960s
1970s
1980s
1990s
Tricyclics
Amitriptyline
Imipramine
Predominantly
noradrenergic
TCAs
Desipramine
Predominantly
seratonergic TCAs
Clomipramine

SSRIs
Fluoxetine
Paroxetine
SNRIs
Venlafaxine
NaRls
Reboxetine
Receptor
blockers
Mianserin
Trazodone
Nefazodone
Mirtazapine
Enzyme
inhibitors
Monoamine Oxidase
Inhibitors
Phenelzine
RIMAs
Moclobemide
Key-Drugs
classes
in
boxed,
shaded fields represent
the
three major antidepressants
groups,
tricyclics
(TCAs),

selective serotonin reuptake
inhibitors
(SSRIs)
and
monoamine oxidase
inhibitors.
Novel
compounds
are
left unboxed.
NaRI-noradrenaline
reuptake
inhibitor
SNRI-serotonin
and
noradrenaline reuptake
inhibitor
RIMA-reversible
inhibitor
of
monoamine
oxidase
*-Mianserin
is
rarely used
due to
associations
with
aplastic anaemia
t-Nefazodone

is
both
a
reuptake
inhibitor
and
receptor
blocker
Fig. 19.1
Flow
chart
of the
evolution
of
antidepressant
drugs
and
classification
by
mechanism
of
action.
novel compound venlafaxine
is
capable
of
exerting
powerful
inhibition
of

reuptake
of
both trans-
mitters,
noradrenergic activity
appearing
at
doses
greater
than
200
mg/day. Mirtazapine also achieves
an
increase
in
noradrenergic
and
serotonergic neuro-
transmission,
but
through
antagonism
of
presynap-
tic
a
2
-autoreceptors (receptors that mediate negative
feedback
for

transmitter release, i.e.
an
autoinhibi-
tory feedback system). Nefazodone
has
properties
of
weak serotonin reuptake inhibition
but
addi-
tionally
has
complex
but
principally antagonist
effects
on
postsynaptic serotonin receptors,
a
property
it
shares with trazodone.
MAOIs
increase
the
availability
of
noradrenaline
and
serotonin

by
preventing their destruction
by
the
monoamine oxidase type
A
enzyme
in the
presynaptic terminal.
The
older MAOIs, phenelzine,
tranylcypromine
and
isocarboxazid, bind irreversibly
to
monamine oxidase enzyme
by
forming
strong
(covalent)
bonds.
The
enzyme
is
thus
rendered
permanently
ineffective
such that amine metabolising
activity

can be
restored only
by
production
of
fresh
enzyme, which takes weeks. These MAOI
are
thus
called
hit and run
drugs
as
their
effects
greatly
outlast their detectable presence
in the
body.
But
how do
changes
in
monoamine transmitter
levels
produce
an
eventual elevation
of
mood?

Raised
neurotransmitter concentrations produce
immediate alterations
in
postsynaptic receptor
activation, leading
to
changes
in
second messenger
(intracellular)
systems
and to
gradual modifications
in
cellular protein expression. Antidepressants
increase
a
cyclic
AMP
response-element binding
(CREB)
protein which
in
turn
is
involved
in
370
ANTIDEPRESS

ANT
DRUGS
19
Physiological
processes
at the
synapse:
1.
When
an
electrical
signal
reaches
the
presynaptic
terminal,
presynaptic
amine
vesicles
fuse
with
the
neuronal
membrane
and
release
their
contents
into
the

synaptic
cleft.
2.
Amines
in the
synaptic
cleft
bind
to
postsynaptic
receptors
to
produce
a
post
synaptic
response.
3.
Amines
may be
removed
from
the
synaptic
cleft
by
reuptake
into
the
presynaptic

neuron.
4.
The
monoamine
oxidase
enzyme
breaks
down
presynaptic
amines.
Effects
of
antidepressants:
A.
Tricyclics
prevent
presynaptic
reuptake
of the
amines
nonadrenaline
and
serotonin
B.
SSRIs
predominantly
block
reuptake
of
serotonin.

C.
MAOIs
reduce
the
activity
of
monoamine
oxidase
in
breaking
down
presynaptic
amines
(leaving
more
available
for
release
into
the
presynaptic
cleft).
D.
Some
antidepressants
(e.g.
nefazodone)
block
postsynaptic
receptors

directly.
Fig. 19.2 Mechanism
of
action
of
antidepressant drugs
at the
synapse.
regulating
the
transcription
of
genes that influence
survival
of
other proteins including brain derived
neurotrophic
factor
(BDNF)
which exerts
effects
on
neuronal
growth.
The
role
of
BDNF
in
depression

is
supported
by the
observation that stress both
reduces
its
expression
and
impairs neurogenesis.
While
the
monoamine hypothesis
of
depression
is
conceptually straightforward,
it is in
reality
it
is an
oversimplification
of a
complicated picture.
Other systems that
are
implicated
in the
aetiology
of
depression (and which provide potential targets

for
drug therapy) include
the
hypothalamopituitary-
thyroid axis
and the
hypothalamopituitary-adrenal
axis
(HPA).
The
finding that
50% of
depressed
patients have elevated plasma cortisol concentra-
tions constitutes evidence that depression
may be
associated
with
increased
HPA
drive.
Drugs
with similar modes
of
action
to
antidepres-
sants
find
other uses

in
medicine. Amfebutamone/
buproprion inhibits reuptake
of
both dopamine
and
noradrenaline
and was
originally developed
and
used
as an
antidepressant;
it is now
used
to
assist
smoking cessation (see
p.
178). Sibutramine, licenced
as
an
anorectic agent,
is a
serotonin
and
noradrenaline
reuptake
inhibitor (see
p.

697). Despite
its
similarity
of
action
to
venlafaxine
and
evidence
of an
anti-
depressant
effect
from
animal studies, sibutramine
has yet to be
recognised
as
effective
for
depression.
PHARMACOKINETICS
The
antidepressants listed
in
Table 19.1
are
generally well absorbed
after
oral administration.

Steady-state plasma concentrations
of
TCAs show
great
individual variation
but
correlate with thera-
peutic
effect.
Measurement
of
plasma concentration
can
be
useful
especially where there
is
apparent
failure
of
response (though
it is
often
not
available).
371
19
PSYCHOTROPIC
DRUGS
Antidepressants

in
general
are
inactivated princi-
pally
by
metabolism
by
hepatic cytochrome P450
enzymes (see
p.
112).
Of the
many isoenzymes iden-
tified,
the
most important
in
antidepressant
metabolism
are
Cytochrome
P450
(CYP)
2D6
(Table
19.2a)
and CYP 3A4
(Table
19.2b). Other important

P450
enzymes
are CYP 1A2
(inhibited
by the
SSRI
fluvoxamine,
induced
by
cigarette smoking, sub-
strates include
caffeine
and the
atypical antipsychotics
clozapine
and
olanzapine)
and the CYP 2C
group
(inhibition
by
fluvoxamine
and
fluoxetine, involved
in
breakdown
of
moclobemide). Sometimes several
CYP
enzymes

are
capable
of
mediating
the
same
metabolic
step.
For
example
at
least
six
isoenzymes,
including
CYP
2D6,
3A4 and 2C9 can
mediate
the
desmethylation
of the
SSRI
sertraline
to its
major
metabolite.
Several
of
these drugs produce active meta-

bolites which prolong their action (e.g. fluoxetine
is
TABLE
1
9.2A Psychotropic (and
selected
other)
drugs
known
to be CYP 2D6
substrates
and
inhibitors
CYP
2D6
inhibitors
Antidepressants
Paroxetine
Fluoxetine
CYP
2D6
substrates
Antidepressants
Paroxetine
Fluoxetine
Citalopram
Sertraline
Venlafaxine*
Amitriptyline
Clomipramine

Desipramine
Imipramine
Nortriptyline
Antipsychotics
Chlorpromazine
Haloperidol
Thioridazine
Zuclopenthixol
Perphenazine
Risperidone
Miscellaneous
Dexfenfluramine
Opioids
Codeine
Hydrocodeine
Dihydrocodeine
Tramadolol
Ethyl
Morphine
Tenamfetamine
('Ecstasy')
Bupropion
-blockers
Propanolol
Metoprolol
Timolol
Bufaralol
A
substrate
is a

substance
that
is
acted
upon
and
changed
by an
enzyme.
An
enzyme
inducer
accelerates
metabolism
of
co-prescribed
drugs which
are
substrates
of the
same
enzyme,
reducing
their
effect.
An
enzyme
inhibitor
retards metabolism
of

co-prescribed
drugs,
increasing
their
effects
(see Chapter
7,
Metabolism).
Competition
between
drugs
that
are
substrates
for
the
same
enzyme
may
retard
their
metabolism,
increase
plasma
concentration
and
lead
to
enhanced
therapeutic

or
adverse
effects.
*CYP
2D6 is
involved only
in the
breakdown
of
venlafaxine
to its
active
metabolite
and
implications
of 2D6
interactions
are of
limited
significance.
metabolised
to
norfluoxetine,
t
1
/
2
200 h). The
meta-
bolic

products
of
certain TCAs
are
antidepressants
in
their
own
right, e.g. nortriptyline
(from
ami-
triptyline), desipramine
(from
lofepramine)
and
imipramine
(from
clomipramine).
Half-lives
of
TCAs
lie
generally
in the
range
of
15
h
(imipramine)
to 100 h

(protriptyline)
and
those
for
SSRIs
from
15 h
(fluvoxamine)
to 72 h
(fluoxetine).
Around
7% of the
Caucasian population have
very
limited
CYP 2D6
enzyme activity. Such 'poor
metabolisers'
may
find
standard doses
of
tricyclic
antidepressants intolerable
and it is
often
worth
starting
at a
very

low
dose.
If the
drug
is
then
tolerated, plasma concentration assay
may to
confirm
the
suspicion that
the
patient
is a
poor
metaboliser.
TABLE
I9.2B
Psychotropic (and selected
other)
drugs
known
to be CYP 3A4
substrates, inhibitors
and
inducers
CYP 3A4
inhibitors
Antidepressants
Nefazodone

Fluoxetine
CYP 3A4
substrates
Antidepressants
Anxiolytics,
hypnotics
and
antipsychotics
Fluoxetine
Sertraline
Amitriptyline
Imipramine
Nortriptyline
Trazodone*
Alprazolam
Buspirone
Diazepam
Midazolam
Triazolam
Zopiclone
Haloperidol
Quetiapine
Sertindole
CYP 3A4
inducers
Antidepressant
St.
John's
Wort
Other

drugs
Cimetidine
Erythromycin
Ketoconazole
(and
grapefruit
juice)
Miscellaneous
Buprenorphine
Carbamazepine
Cortisol
Dexamethasone
Methadone
Testosterone
Calcium
channel
blockers
Diltiazem
Nifedipine
Amlodipine
Other
drugs
Amiodarone
Omeprazole
Oral contraceptives
Simvastatin
Miscellaneous
Carbamazepine
Phenobarbital
Phenytoin

*
mCPP,
the
active metabolite
of
trazodone,
is a CYP 2D6
substrate;
observe
for
unwanted
effects
when trazodone
is co-
administered
with
the 2D6
inhibitors fluoxetine
or
paroxetine.
372
19
THERAPEUTIC
EFFICACY
Provided antidepressant drugs
are
prescribed
at
an
adequate dose

and
taken regularly, 60-70%
of
patients with moderate
or
severe depression should
respond within
3-4
weeks. Meta-analyses have
shown little evidence that
any
particular drug
or
class
of
antidepressant
is
more
efficacious
than
others,
but
there
are
four
possible exceptions
to
this
general
statement.

•
Small trials have
suggested
that
the
SNRI
agent
venlafaxine,
in
high dose
(> 150
mg/day)
may
have greater
efficacy
than other antidepressants.
•
Amitriptyline
appears
to be
slightly more
effective
than other TCAs
and
also SSRIs
but
this
advantage
is
compromised

by its
poor
tolerability
relative
to
more modern agents.
• The
older MAOIs (e.g.
phenelzine)
may be
more
effective
than other classes
in
'atypical'
depression,
a
form
of
depressive illness where
mood reactivity
is
preserved,
lack
of
energy
may
be
extreme
and

biological
features
are the
opposite
of the
normal syndrome i.e. excess
sleep
and
appetite with weight gain.
•
Evidence suggests that
in
patients hospitalised
with
severe
depression, TCAs
as a
class
(also
venlafaxine)
may be
slightly more
effective
than
either
SSRIs
or
MAOIs.
SELECTION
An

antidepressant should
be
selected
to
match
individual
patients'
requirements, such
as the
need
or
otherwise
for a
sedative
effect
or the
avoidance
of
antimuscarinic
effects
(especially
in the
elderly).
In
the
absence
of
special
factors
the

choice rests
on
tolerability,
safety
in
overdose
and
likelihood
of an
effective
dose being reached.
SSRIs,
lofepramine,
mirtazapine,
nefazodone,
reboxetine
and
venlafaxine
are
highlighted
as
best
fulfilling
these needs.
MODE
OF USE
The
action
of
TCAs

in
ameliorating mood
is
usually
absent
in the
first
2
weeks
of
therapy
and at
least
4
weeks must elapse
to
constitute
an
adequate trial.
Where
a
minimal response
is
noted
in
this period,
it
is
reasonable
to

extend
the
trial
to 6
weeks
to see
ANTIDEPRESSANT
DRUGS
if
further benefit
is
achieved.
By
contrast,
patients
may
experience unwanted drug
effects
imme-
diately
on
starting treatment (and they should
be
warned),
but
such symptoms
often
diminish with
time. Titrating
from

a
generally tolerable starting
dose, e.g. amitriptyline
30-75
mg/day
(25-50
mg/
day for
imipramine), with weekly increments
to
a
recognised 'minimum therapeutic' dose, usually
around
125
mg/day (140
mg/day
for
lofepramine)
lessens
the
impact
of
adverse symptoms
before
a
degree
of
tolerance (and therapeutic benefit)
develops.
Low

starting doses
are
particularly
important
for
elderly patients. Only when
the
drug
has
reached
the
minimum therapeutic dose
and
been taken
for at
least
4
weeks
can the
test
of
response
or
nonresponse
be
considered adequate.
Some
patients
do
achieve response

or
remission
at
subtherapeutic
doses,
for
reasons
of
drug kinetics
and
individual metabolism,
the
self-limiting nature
of
depression
or by a
placebo
effect
(reinforced
by
the
experience
of
side
effects
suggesting
that
the
drug must
be

having some
action).
TCAs
are
given either
in
divided doses
or, for
the
more sedative compounds,
as a
single evening
dose.
SSRIs
have advantages over
tricyclics
in
simplicity
of
introduction
and
use. Dose titration
is
often
unnecessary since
the
minimum therapeutic dose
can
usually
be

tolerated
as a
starting
dose. Divided
doses
are not
required
and
administration
is by a
single morning
or
evening dose. Evidence suggests
that patients commencing treatment
on
SSRIs
are
more
likely
to
reach
an
effective
dose than those
starting
on
TCAs.
The
novel compounds nefazodone
and

trazodone
usually require titration
to a
minimum therapeutic
dose
of at
least
200
mg/day. Response
to
reboxetine,
venlafaxine
and
mirtazapine
may
occur
at the
starting
dose
but
some dose
titration is
commonly required.
Venlafaxine
is
licensed
for
treatment-resistant
de-
pression

by
gradual
titration
from
75 to 375
mg/day.
There
is
some need
for
dose
titration
when using
MAOIs
although recommended starting doses (e.g.
phenelzine
15 mg
t.d.s.)
may be
effective.
Unlike other
drug classes, reduction
to a
lower maintenance dose
is
recommended
after
a
response
is

achieved.
373
19
PSYCHOTROPIC
DRUGS
CHANGING
AND
STOPPING
ANTIDEPRESSANTS
When
an
antidepressant
fails
through
lack
of
efficacy
despite
an
adequate trial
or due to
unacceptable side
effects,
it is
generally advisable
to
change
to a
drug
of

a
different
class.
For a
patient
who
does
not
respond
to
an
SSRI
it is
logical
to try a TCA or a
novel compound
such
as
venlafaxine,
reboxetine
or
mirtazapine.
Any
of
these
options
may
offer
a
greater increase

in
synaptic noradrenaline than
the
ineffective
SSRI.
There
is
also evidence
to
suggest that patients
failing
on one
SSRI
may
respond
to a
different
drug within
the
class,
an
approach which
is
particularly
useful
where other antidepressant classes have been
un-
successful
previously,
are

contraindicated,
or
have
characteristics
which
the
patient
or
doctor
feel
are
undesirable.
For
example,
a
patient
who is
keen
to
avoid
putting
on
weight
may
prefer
to try a
second
SSRI
after
an

initial
failure
than
to
switch
to a TCA or
MAOI
since both
of
these classes commonly cause
weight gain. Awareness
of
differences
between drugs
within
a
class
may
also
be
helpful,
e.g.
the
greater
serotonergic enhancing
effects
of
clomipramine
compared
to

other
tricyclics
may be
advantageous
in
a
patient
who
cannot tolerate
any
other drug class.
When changing between
SSRIs
and/or
TCAs doses
should
be
reduced progressively over
2-4
weeks.
Where
a new
drug
is to be
introduced
it
should
be
'cross-tapered' i.e.
the

dose
gradually increased
as
that
of the
substituted drug
is
reduced. Changes
to
or
from
MAOIs must
be
handled
with
great caution
due to the
dangers
of
interactions between anti-
depressant classes (see below).
Therefore
MAOIs
cannot
safely
be
introduced within
2
weeks
of

stop-
ping paroxetine, sertraline
or
tricyclics
(3
weeks
for
imipramine
and
clomipramine; combination
of
the
latter with tranylcypramine
is
particularly
dangerous),
and not
until
5
weeks
after
stopping
fluoxetine,
the
active metabolite
of
which
has a
very
long

t
l
/
2
(9
days).
Similarly,
TCAs
and
SSRIs
should
not
be
introduced until
2-3
weeks have elapsed
from
discontinuation
of
MAOI
(as
these
are
irreversible
inhibitors,
see p.
370).
No
washout period
is

required
when
using
the
reversible monoamine oxidase
inhibitor moclobemide.
When
a
patient achieves remission,
the
antidepres-
sant should
be
continued
for at
least
9
months
at the
dose which returned mood
to
normal. Premature
dose reduction
or
withdrawal
is
associated with
increased risk
of
relapse.

In
cases
where
three
or
more depressive episodes have occurred, evidence
suggests that long-term continuation
of an
anti-
depressant
offers
protection,
as
further
relapse
is
almost
inevitable
in the
next three years.
When ceasing
use of an
antidepressant,
the
dose
should
be
reduced over
at
least

6
weeks
to
avoid
a
discontinuation syndrome (symptoms include
anxiety,
agitation, nausea
and
mood swings). Dis-
continuation
of
SSRIs
and
venlafaxine
are
asso-
ciated
additionally
with
dizziness, electric shock-
like
sensations
and
paraesthesia. Short-acting drugs
that
do not
produce active metabolites
are
most

likely
to
cause such problems. Paroxetine
in
particular
is
associated with severe withdrawal symptoms
including
bad
dreams, paraesthesia
and
dizziness
(which
can be
misdiagnosed
as
labyrinthitis).
AUGMENTATION
Augmentation, i.e.
the
addition
of
another drug,
is
used
to
enhance
the
effects
of

standard antidepres-
sants
when
two or
more have successively
failed
to
alleviate
depressive symptoms despite treatment
at an
adequate dose
for an
adequate time.
The
therapeutic
efficacy
of new
agents, e.g. venlafaxine,
has
provided clinicians with
further
options which
now
tend
to be
employed
before
augmentation
but
the

following
may be
used.
The
most common
is
augmentation
is
with
the
mood stabiliser
lithium
carbonate.
Indeed,
lithium
may
be
effective
as
monotherapy
for
depression
but is not
preferred
because
of its
adverse
effect
profile
and

need
for
plasma concentration monitoring.
Its
prescription
in
combination with antidepressants that have
failed
to
produce remission
is
more usual
and
evidence
suggests that
up to 50% of
patients
who
have not:
responded
to
standard antidepressants
can
respond
after
lithium augmentation. Addition
of
lithium
requires
careful

titration of the
plasma concentration
up to the
therapeutic range, with periodic checks
thereafter
and
monitoring
for
toxicity
(see
p.
389).
Thyroid hormones also
aid
antidepressant action.
Guidance points
to the
combination
of
tri-
iodotyronine
(T
3
)
and
TCAs
as
being most
effective
374

19
(but
effects
of
lofepramine
may be
augmented
by
levothyroxine
to the
extent that co-administration
should
be
avoided).
The
amino acid isomer
L-
tryptophan,
a
precursor
of
serotonin,
may
also
augment
but
such
use is
restricted
to

hospital
specialists
who
must monitor haematological
function
(it is
associated
with
an
eosinophilia/
myalgia syndrome though this
may
have been
due
to
an
impurity rather
than
the
L-tryptophan
itself).
The
(3-adrenoceptor
blocker
pindolol
can
augment
the
action
of

SSRIs.
Pindolol
may act by
binding
to
a
serotonin autoreceptor
and
thus
interfere with
a
homeostatic
mechanism which acts
to
reduce sero-
tonin concentrations
after
the
initial elevation
by
SSRI
action.
None
of
these augmentation strategies
is
ideal,
since they either require plasma monitoring (lithium,
tryptophan, tri-iodothyronine), expose
the

patient
to
potential
toxicity
(lithium, tryptophan)
or
have
only
a
moderate evidence base
for
efficacy
(tri-
iodothyronine, pindolol).
OTHER
INDICATIONS
FOR
ANTIDEPRESSANTS
Antidepressants
may
benefit
most
forms
of
anxiety
disorder,
including panic disorder, generalised
anxiety
disorder, post-traumatic stress disorder,
obsessive-compulsive disorder

and
social phobia
(see
p.
393).
SSRIs
are
effective
in
milder cases
of the
eating
disorder
bulimia
nervosa,
particularly fluoxetine
(in
higher
doses
than
are
required
for
depression). This
effect
is
independent
of
that
on

depression (which
may
co-exist)
and may
therefore involve action
on
transmitter systems other than those involved
in
modulating depression. Antidepressants appear
to
be
ineffective
in
anorexia nervosa.
ADVERSE
EFFECTS
As
most antidepressants have similar therapeutic
efficacy,
the
decision regarding which drug
to
select
often
rests
on
adverse
effect
profiles
and

potential
to
cause
toxicity.
Tricyclic antidepressants
The
commonest unwanted
effects
are
those
of the
antimuscarinic
action,
i.e.
dry
mouth (predisposing
ANTI
DEPRESSANT
DRUGS
to
tooth decay), blurred vision
and
difficulty
with accommodation, raised intraocular pressure
(glaucoma
may be
precipitated), bladder neck
obstruction (may lead
to
urinary retention

in
older
males).
Patients
may
also experience: postural hypo-
tension
(through
inhibition
of
a-adrenoceptors)
which
is
often
a
limiting
factor
in
their utility
in the
elderly,
interference with sexual
function,
weight
gain (through blockade
of
histamine
H
1
receptors),

prolongation
of the QT
interval
of the ECG
which
predisposes
to
cardiac arrhythmias especially
in
overdose
(use
of
TCAs
after
myocardial
infarction
is
contraindicated).
Some
TCAs (especially trimipramine
and
ami-
triptyline)
are
heavily sedating through
a
combination
of
antihistaminergic
and

a-adrenergic blocking
actions.
This presents special problems
to
those
whose lives involve driving vehicles
or
performing
skilled
tasks.
In
selected patients, sedation
may be
beneficial,
e.g.
a
severely depressed person
who has
a
disrupted sleep pattern
or
marked agitation.
It
is
essential
to
remember that there
is
great
heterogeneity

in
adverse
effect
profiles
between
TCAs.
Imipramine
and
lofepramine cause relatively
little
sedation
and
lofepramine
is
associated with
milder antimuscarinic
effects
(but
is
contraindicated
in
patients with severe liver disease).
Overdose.
Depression
is a
risk
factor
for
both
parasuicide

and
completed suicide,
and
TCAs
are
commonly taken
by
those
who
deliberately
self-
harm.
Dothiepin
(dosulepin)
and
amitriptyline
are
particularly
toxic
in
overdose, being responsible
for
up to 300
deaths
per
year
in the UK
despite
the
many alternative antidepressants that

are
available.
Lofepramine
is at
least
15
times less likely
to
cause
death
from
overdose; clomipramine
and
imipramine
occupy
intermediate positions.
Clinical
features
of
overdose
reflect
the
pharma-
cology
of
TCAs. Antimuscarinic
effects
result
in
warm,

dry
skin
from
vasodilatation
and
inhibition
of
sweating, blurred vision
from
paralysis
of
accom-
modation, pupillary dilatation
and
urinary retention.
Consciousness
is
commonly dulled
and
respira-
tion depression
and
hypothermia
may
develop.
Neurological signs include hyperreflexia,
myo-
clonus
and
divergent strabismus. Extensor plantar

responses
may
accompany lesser degrees
of
impaired
375
19
PSYCHOTROPIC DRUGS
consciousness
and
provide scope
for
diagnostic
confusion,
e.g.
with structural brain damage. Con-
vulsions
occur
in a
proportion
of
patients.
Halluci-
nations
and
delirium
occur
during recovery
of
consciousness,

often
accompanied
by a
character-
istic
plucking
at
bedclothes.
Sinus tachycardia
(due
to
vagal blockade)
is a
common feature
but
abnormalities
of
cardiac
conduction accompany moderate
to
severe intoxi-
cation
and may
proceed
to
dangerous tachy-
or
bradyarrhythmias.
Hypotension
may

result
from
a
combination
of
cardiac arrhythmia, reduced
myocardial contractility
and
dilatation
of
venous
capacitance
vessels.
Supportive treatment
suffices
for the
majority
of
cases.
Activated charcoal
by
mouth
is
indicated
to
prevent
further
absorption
from
the

alimentary
tract
and may be
given
to the
conscious
patient
in
the
home prior
to
transfer
to
hospital. Convulsions
are
less likely
if
unnecessary stimuli
are
avoided
but
severe
or
frequent
seizures
often
preceed cardiac
arrhythmias
and
arrest,

and
their suppression with
diazepam
is
important.
The
temptation
to
treat
cardiac
arrhythmias ought
to be
resisted
if
cardiac
output
and
tissue perfusion
are
adequate. Correc-
tion
of
hypoxia with oxygen
and
acidosis
by
i.v.
infusion
of
sodium bicarbonate

are
reasonable
first
measures
and
usually
suffice.
Reboxetine
is not
structurally related
to
tricyclic
agents
and
acts predominantly
by
noradrenergic
reuptake inhibition. Antimuscarinic
effects
trouble
only
a
minority
of
patients,
postural
hypotension
may
occur
and

impotence
in
males.
It is
relatively
safe
in
overdose.
Selective serotonin
reuptake
inhibitors
SSRIs
have
a
range
of
unwanted
effects
including
nausea, anorexia, dizziness, gastrointestinal disturb-
ance,
agitation, akathisia (motor restlessness)
and
anorgasmia
(failure
to
experience
an
orgasm). They
lack

direct
sedative
effect,
an
advantage
in
patients
who
need
to
drive vehicles.
SSRIs
can
disrupt
the
pattern
of
sleep with increased awakenings,
transient reduction
in the
amount
of REM and in-
creased
REM
latency
but
eventually sleep improves
due to
elevation
of

mood.
This class
of
antidepres-
sant does
not
cause
the
problems
of
postural hypo-
tension,
antimuscarinic
or
antihistaminergic
effects
seen with
TCAs.
Their
use is not
associated with
weight
gain
and
conversely
they
may
induce
weight loss through their anorectic
effects.

SSRIs
are
relatively
safe
in
overdose.
The
serotonin syndrome
is a
rare
but
dangerous
complication
of
SSRIs
and
features
restlessness,
tremor,
shivering
and
myoclonus possibly leading
on
to
convulsions, coma
and
death.
Risk
is
increased

by
co-administration with drugs that enhance
serotonin transmission, especially MAOIs,
the
anti-
migraine
drug
sumatriptan
and St.
John's
Wort.
Note.
When
SSRIs
are
compared with
TCAs
for
patients
who
discontinue therapy
(a
surrogate end-
point
for
tolerability), most meta-analyses show
a
slight
benefit
in

favour
of
SSRIs.
Comparisons
which exclude TCAs with
the
most prominent anti-
muscarinic
effects
(amitriptyline
and
imipramine)
show either marginal
benefits
in
favour
of
SSRIs
or
no
difference
between
the
groups.
It is
noteworthy
that
despite
their
pronounced

adverse
effects,
amitriptyline
and
imipramine tend
to be
selected
as
'standard'
TCAs
against which
SSRIs
are
compared.
Lofepramine,
the
second most prescribed
TCA
in the UK and the one TCA
which causes little
sedation,
has few
antimuscarinic
effects
and is
as
safe
as
SSRIs
in

overdose
is; it
under-represented
in
meta-analyses
Novel
compounds
Venlafaxine
produces some unwanted
effects
that
resemble
those
of
SSRIs
with
a
higher incidence
of
nausea. Sustained hypertension
(due
to
blockade
of
noradrenaline reuptake)
is a
problem
in a
small
percentage

of
patients
at
high dose
and
blood
pressure
should
be
monitored when
> 200
mg/day
is
taken.
Nefazodone
lacks antimuscarinic
effects
but may
cause
postural hypotension
and
abdominal discom-
fort.
It
appears
to
improve sleep quality
and
seems
not to

interfere
with sexual
function.
Mirtazapine also
has
benefits
in
rarely being asso-
ciated
with sexual dysfunction
and in
improving
376
19
sleep
independent
of
mood
but
like TCAs
it may
cause
unwanted sedation
and
weight gain.
Trazodone
has
structural similarities with TCAs
but
probably acts

by
antagonism
of
postsynaptic
serotonin receptors
and
presynaptic a-adrenoceptors.
It
is an
option
for
depressed patients where heavy
sedation
is
required. Trazodone also
has the
advan-
tages
of
lacking antimuscarinic
effects
and
being
relatively
safe
in
overdose. Males should
be
warned
of

the
possibility
of
priapism
(painful
penile
erections), attributable
to the
drug's
blockade
of
oCj-adrenoceptors.
Monoamine
oxidase
inhibitors
Adverse
effects
include postural hypotension (espe-
cially
in the
elderly)
and
dizziness. Less common
are
headache, irritability, apathy, insomnia,
fatigue,
ataxia,
gastrointestinal disturbances including
dry
mouth

and
constipation, sexual dysfunction
(especially
anorgasmia), blurred vision,
difficult
micturition, sweating, peripheral oedema, tremu-
lousness,
restlessness
and
hyperthermia. Appetite
may
increase inappropriately, causing weight gain.
INTERACTIONS
Antidepressant
use
offers
considerable scope
for an
adverse interaction with other
drugs
through
both pharmacodynamic
and
pharmakokinetic
mechanisms.
It is
therefore prudent always
to
check
specific

sources
for a
possibly unwanted outcome
whenever
a new
drug
is
added
or
removed
to a
prescription list that includes
an
antidepressant.
TCAs
and
SSRIs
Pharmacodynamic
interactions.
Many TCAs cause
sedation
and
therefore
co-prescription with other
sedative agents such
as
opioid analgesics, antihista-
mines, anxiolytics, hypnotics
and
alcohol

may
lead
to
excessive drowsiness
and
daytime somnolence.
The
majority
of
TCAs
can
have undesirable cardio-
vascular
effects,
in
particular
prolongation
of the
QT
interval.
A
similar risk
of QT
prolongation arises
with many other cardiovascular drugs including
amiodarone, disopyramide, procainamide, propa-
ANTI
DE
PRESSANT
DRUGS

fenone,
quinidine,
terfenadine,
also
psychotropic
agents such
as
pimozide, sertindole
and
thiorida-
zine. Their
use in
combination with TCAs known
to
prolong
QT
enhances
the
risk
of
ventricular
arrhythmias (for
further
discussion
see p.
509).
The
combination
of
thioridazine with

any
such
TCA is
thought
to be
particularly dangerous
and is
formally
contraindicated.
TCAs potentiate
the
effects
of
catecholamines
and
other
sympathomimetics
but
not
2
-receptor agonists used
in
asthma. Even
the
small
amounts
of
adrenaline
or
noradrenaline

in
dental local anaesthetics
may
produce
a
serious rise
in
blood pressure.
Both
TCAs
and
SSRIs
may
cause central nerv-
ous
system toxicity
if
co-prescribed with
the
dopaminergic
drugs
entacapone
and
selegiline
(for
Parkinson's disease).
SSRIs
increase
the
risk

of
toxicity
(the serotonin syndrome) when combined
with other drugs which upregulate serotonin
transmission, e.g.
the
5HT
]
antagonist sumatriptan
(antimigraine)
and the
anti-obesity drug sibutramine
(see
p.
697).
Tricyclics
and
SSRIs
can
lower
the
convulsion
threshold making epilepsy more
difficult
to
control
by
anti-epilepsy drugs
and
lengthening seizure time

in
electroconvulsive therapy.
The
situation
is
further
complicated
by the
ability
of
carbamazepine
to
accelerate
(induce)
the
metabolism
of
antidepres-
sants
and
inhibition
of
carbamazepine metabolism
by
certain antidepressants (below).
Pharmacokinetic
interactions.
TCAs
and
SSRIs

are
metabolised extensively
by
cytochrome
P450
enzymes
and
adding, changing
or
stopping anti-
depressants
to a
drug regimen
can
have important
consequences.
Potential
interactions through
the
cytochrome
P450
CYP 2D6 and CYP 3A4
enzymes
can be
noted
from
Tables 19.2a
and
19.2b.
The

combination
of
drugs that
are
substrates
of the
same enzyme
creates
potential
for
competitive inhibition
of
their
metabolism
with
unexpected elevation
of
plasma
concentration. Similarly, potent inhibitors, e.g.
fluoxetine
and
paroxetine (CYP 2D6), fluoxetine
and
nefazodone (CYP 3A4)
and
fluvoxamine
(CYP
1A2),
may
cause

adverse
effects
by
reducing
meta-
bolic
breakdown
of
co-prescribed drugs that
are
used
in
standard doses. Antidepressants
are
commonly
prescribed
with
antipsychotics
in a
depressive
377
19
PSYCHOTROPIC
DRUGS
psychosis.
Some combinations
may
have
an un-
expected adverse outcome unless anticipatory dose

adjustment
is
made, e.g. paroxetine
+
thioridazine
(CYP
2D6),
fluoxetine
+
sertindole (CYP 3A4)
and
fluvoxamine
+
olanzapine (CYP 1A2)
but
others,
e.g.
fluoxetine
+
quetiapine (CYP 3A4) appear
to be
of
less
significance.
An
interaction
of
particular
importance
involves

zuclopenthixol acetate
used
rapidly
to
tranquillise psychotic patients
who are
also
receiving
fluoxetine
or
paroxetine
and an
oral
antipsychotic (see
p.
363). Inhibition
of
zuclopenthixol
metabolism (CYP 2D6)
by
fluoxetine
or
paroxetine,
and
exacerbated
by
competition
from
another anti-
psychotic

CYP 2D6
substrate,
can
provoke serious
over-sedation
and
respiratory
depression.
Epilepsy
is a
common co-morbid illness
in
patients
who
have both psychiatric illness
and
learning disabilities.
The
necessary combination
of
the
anti-epilepsy drug carbamazepine,
a CYP 3A4
enzyme inducer, with
a CYP 3A4
inhibiting
SSRI
antidepressant then calls
for
particularly

careful
increment
in
drug
doses
supported
by
monitoring
of
plasma carbamazepine concentration.
Depression
and
hypertension
are
both common
conditions such that some co-morbidity
is
inevitable,
and
panic disorder
is
epidemiologically associated
with hypertension. Co-prescription
of an
enzyme-
inhibiting antidepressant with
a
-adrenoceptor
blocker (metoprolol,
CYP

2D6)
or
with
a
calcium
antagonist (diltiazem, amlodipine,
CYP
3A4)
may
exaggerate antihypertensive
effects.
P450
enzyme inhibition
by
SSRIs
may
also
augment
effects
of
alcohol, tramadol, methadone,
terfenadine
(danger
of
cardiac arrhythmia), -caine
anaesthetics
and
theophylline.
Monoamine
oxidase

inhibitors
Hypertensive reactions. Many sympathomimetic
substances
can
cause highly dangerous hypertensive
reactions
if
taken
by
patients using
MAO
inhibitors.
Patients taking MAOIs
are
vulnerable
for two
reasons.
Firstly,
since MAOIs cause
an
increase
in
catecholamine stores
in
adrenergic
and
dopaminer-
gic
nerve endings, there
is

potentiation
of
sympa-
thomimetics that
act
indirectly
by
releasing stored
nor
adrenaline. Secondly, patients taking
a
mono-
amine oxidase inhibitor
are
deprived
of the
protec-
tion
of the MAO
enzyme present
in
large
quantities
in
the gut
wall
and
liver. Thus orally administered
sympathomimetics that would normally
be

inacti-
vated
by
this enzyme
can be
absorbed
in
much
greater
quantities. Note that potentiation
of
admin-
istered adrenaline, noradrenaline
and
isoprenaline
is
not to be
expected since these substances
are
chiefly
destroyed
by
catechol-O-methyltransferase
in the
blood
and
liver.
Symptoms
and
treatment

of
hypertensive
crisis.
Symptoms include
a
severe, sudden throbbing
headache
with
slow palpitation, flushing, visual
disturbance, nausea, vomiting
and
severe hyper-
tension.
If
headache occurs without
hypertension
it
may
be due to
histamine release.
The
hypertension
is due
both
to
vasoconstriction
from
activation
of
oc-

adrenoceptors
and to
increased cardiac output
consequent
on
activation
of
cardiac
(3-adrenoceptoi's.
The
mechanism
is
thus similar
to
that
of the
episodic hypertension
in a
patient with phaeochro-
mocytoma.
The
rational
and
effective
treatment
is
an
a-adrenoceptor blocker (phentolamine,
5 mg
i.v.)

and a
(3-blocker
may be
later added
in
case
of
excessive
tachycadia.
Patient education.
It is
essential
to
warn patients
taking
MAOIs
not to use
over-the-counter med-
ication,
as
many
simple
remedies
sold
direct
to
the
public, such
as
those

for
nasal congestion,
coughs
and
colds, will contain sympathomimetics
(ephedrine, phenylpropanolamine). Patients must
receive
detailed instructions about their diet
and be
made aware
of the
need
to
avoid
the
many
foods
containing substantial amounts
of
sympathomime-
tics, most commonly tyramine, which acts
by
releasing
tissue-stored noradrenaline.
For
example,
degradation
of
the
protein

'casein'
by
resident bacteria
in
well matured cheese
can
produce tyramine
from
the
amino acid tyrosine, hence
use of the
term 'cheese
reaction'
to
describe provocation
of a
hypertensive
crisis
by
orally administered sympathomimetics.
Stale
foods also present
a
danger, since
any
food
subjected
to
autolysis
or

microbial decomposition
during
preparation
or
storage
may
contain
pressor
amines resulting
from
decarboxylation
of
amino
acids.
Moclobemide
offers
the
dual advantages
of
selective
MAO-A inhibition which theoretically
378
19
The
following
foods
are
capable
of
producing dangerous

hypertensive effects:
•
cheese,
especially
if
well matured
• red
wines (especially
Chianti)
and
some
white
wines;
and
some beer
(non-
or
low-alcohol varieties contain
variable
but
generally
low
amounts
of
tyramine)
yeast
extracts
(Marmite,
Oxo,
Bovril)

some
pickled herrings
broad
bean pods
(contain
dopa,
a
precursor
of
adrenaline)
over-ripe
bananas,
avocados,
figs
game
stale
foods
fermented bean curds including
soy
sauce
fermented
sausage
(e.g. salami), shrimp
paste
flavoured
textured
vegetable
protein
(Vegemite).
This

list
may be
incomplete
and any
partially decomposed
food
may
cause
a
reaction. Milk
and
yoghurt
appear
safe.
should avoid
the
'cheese'
reaction
by
sparing
the
intestinal MAO, which
is
mainly MAO-B,
and by
being
a
competitive, reversible inhibitor. Whereas
the
irreversible inhibitors inactivate

the MAO
enzyme
and can
therefore
continue
to
cause dangerous
interactions
in the 2-5
weeks
after
withdrawal,
until more enzyme
can be
synthesised, reversible
MAO
inhibition
is
incomplete except during peak
plasma concentrations. Since
the
inhibition
is
competitive, tyramine
can
then displace
the
inhibitor
from
the

active site
of the MAO
enzyme.
Consequently there
are
less dietary restrictions
for
patients using moclobemide
but
hypertensive
reactions
have been reported.
Interactions with other drugs.
The
mechanisms
of
many
of the
following interactions
are
obscure
and
some
are
probably
due to
inhibition
of
drug meta-
bolising enzymes other than

MAO as
MAOIs
are
not
entirely selective
in
their action.
Effects
last
for
weeks
after
stopping
a
MAOI.
Reactions
can be
very
severe
and
even
fatal.
Antidepressants:
Combination with tricyclic anti-
depressants
has the
potential
to
precipiate hyper-
tensive crisis complicated

by
hyperreflexia, rigidity
and
hyperpyrexia. MAOI-SSRI combinations
may
provoke
the
life-threatening 'serotonin syndrome'
(p.
376).
Strict rules apply regarding washout
periods when switching between MAOIs
and
other
ANTI
DE
PRESS
ANT
DRUGS
drugs (see 'Changing antidepressants', above).
Very
occasionally, MAOIs
are
co-prescribed with other
antidepressants
but
since many combinations
are
highly dangerous, such practice should
be

reserved
for
specialists only
and
then
as a
last resort.
Narcotic
analgesics:
with co-prescribed
pethidine
respiratory
depression, restlessness, even coma,
and
hypo-
or
hypertension
may
result (probably
due to
inhibition
of its
hepatic demethylation). Interaction
with other
opioids
occurs
but is
milder. Other drugs
which cause minor interactions with MAOIs include
antiepileptics

(convulsion
threshold
lowered),
dopa-
minergic drugs
(e.g.
selegeline [MAO
B
inhibitor]
may
cause dyskinesias),
antihypertensives
and
antidiabetes
drugs (metformin
and
sulponylureas
potentiated). Concomitant
use
with amfebutanone/
bupropion (smoking cessation), sibutramine (weight
reduction),
and
5HT
1
-agonists (migraine)
should
be
avoided. Because
of the use of

numerous drugs
during
and
around surgery,
an
MAOI
is
best
withdrawn
2
weeks
before,
if
practicable.
Overdose with MAOIs
can
cause hypomania,
coma
and
hypotension
or
hypertension. General
measures
are
used
as
appropriate with minimal
administration
of
drugs: chlorpromazine

for
rest-
lessness
and
excitement; phentolamine
for
hyper-
tension,
no
vasopressor drugs
for
hypotension,
because
of
risk
of
hypertension
(use
posture
and
plasma volume expansion).
ST
JOHN'S
WORT
Many
patients with mild
to
moderate depression
are
aware

of the
potential
benefits
of the
herbal
remedy
St.
John's
Wort
(Hypericum
perforatum).
The
active
ingredients
in the
hypericum extract have
yet
to
be
identified
and
their mode
of
action
is
unclear,
although
it has
been postulated that several
of the

known mechanisms
of
existing antidepressants
are
incorporated (inhibition
of
monoamine reuptake
and the
monoamine oxidase enzyme,
as
well
as
a
stimulation
of
GABA
receptors). Much
of the
original research into
the
efficacy
of St.
John's
Wort
was
performed
in
Germany where
its use is
well established. Several direct comparisons with

tricyclic
antidepressants have shown equivalent
rates
of
response
but
these studies should
be
interpreted with caution since many trials
failed
to
379
19
PSYCHOTROPIC
DRUGS
use
standardised ratings
for
depressive symptoms,
patients
tended
to
receive tricyclic regimes below
the
minimum therapeutic dose
and
sometimes
received hypericum
in
doses above

the
maximum
recommended
in
commercially available prepara-
tions.
A
large multicentre trial
found
only limited
evidence
of
benefit
for St.
John's
Wort
over placebo
in
significant
major
depression.
1
Despite these reservations, there
is
certainly
a
small
proportion
of
patients

who
when presented
with
all the
available
facts,
express
a
strong
desire
to
take only
St.
John's
Wort,
perhaps
from
a
prefer-
ence
for
herbally derived compounds over conven-
tional medicine.
For
patients with mild depression,
it is
reasonable
on
existing
evidence

to go
along
with this
preference
rather than
to
destroy
the
therapeutic alliance
and
risk prescribing
a
standard
antidepressant which will
not be
taken.
Use of St.
John's
Wort
is
complicated
by the
lack
of
standardisation
of the
ingredients. Those
who
wish
to

take
St.
John's
Wort
should
be
made
aware
that
it may
cause
dry
mouth, dizziness,
sedation, gastrointestinal disturbance
and
confusion.
Importantly also,
it
induces hepatic
P450
enzymes
(CYP
1A2 and CYP
3A4)
with
the
result that
the
plasma
concentration

and
therapeutic
efficacy
of
warfarin,
oral contraceptives, some anticonvulsants,
antipsychotics
and HIV
protease/reverse
transcriptase
inhibitors
are
reduced. Concomitant
use of
trypto-
phan
and St
John's
Wort
may
cause serotonergic
effects
including nausea
and
agitation.
ELECTROCONVULSIVE
THERAPY
Electroconvulsive
therapy
(ECT)

involves
the
passage
of a
small electric charge across
the
brain
by
electrodes applied
to the
frontotemporal aspects
of
the
scalp with
the aim of
inducing
a
tonic-clonic
seizure.
Reference
to it is
made here principally
to
indicate
its
place
in
therapy.
ECT
requires

the
patient
to be
receiving
a
general anaesthetic, carrying
the
small risks equivalent
to
those associated with
general
anaesthesia
in
minor surgical operations.
It
may
cause memory
deficits
although this
is
generally transient.
For
these
reasons
as
well
as the
1
Shelton
R C et al

2001
Effectiveness
of St.
John's Wort
in
major
depression.
A
randomised control trial. Journal
of the
American
Medical Association
285:1978-1986
relative
ease
of use of
antidepressant drugs,
ECT is
usually reserved
for
psychiatric illness where
pharmacological
treatments have been
unsuccessful
or
where
the
potential
for
rapid improvement

characteristic
of ECT
treatment
is
important. This
may
arise where patients
are in
acute danger
from
their
mental state,
for
instance
the
severely depressed
patient
who has
stopped eating
or
drinking.
Modern-day
ECT is a
safe
and
effective
alternative
to
pharmacological treatment
and

remains
a
first-
line option
in
clinical circumstances where rapid,
response
is
desired, when
it can be
life-saving.
Antipsychotics
CLASSIFICATION
Originally tested
as an
antihistamine
and
then pro-
posed
as a
drug
for
combating helminth infections,
chlorpromazine
emerged
as an
effective
treatment
for
psychotic

illness
in the
1950s. Chlorpromazine-like
drugs were originally termed 'neurolep tics'
or
'major
tranquillisers'
but the
class adopted
the
name 'anti-
psychotics'
as
over
20
compounds
were
brought
to
market
during
the
next
30
years.
Classification
is by
chemical structure (e.g.
phenothiazines,
butyrophe-

nones).
Within
the
large phenothiazine group,
compounds
are
divided
into three
types
on the
basis
of the
side chain since these tend
to
predict
adverse
effect
profiles
(Table 19.3).
The
continuing search
for
greater
efficacy
and
better tolerability
led
researchers
and
clinicians

to
reinvestigate
dozapine,
a
drug which
was
originally
licenced
in the
1960s
but
subsequently withdrawn
because
of
serious haematological
effects.
Clozapine
appeared
to
offer
greater
effectiveness
in
treatment-
resistant schizophrenia,
to
have
efficacy
against nega-
tive

in
addition
to
positive psychiatric symptoms
(see
Table 19.4),
and to be
less
likely
to
cause extra-
pyramidal motor symptoms.
It
regained
its
licence
in
the
early 1990s
with
strict requirements
on
dose titration
and
haematological monitoring.
The
renewed interest
in
clozapine
and its

unusual
efficacy
and
tolerability stimulated researchers
to
examine
similar 'atypical' antipsychotic drugs.
Thus
the
most important distinction
in
modern-
day
classification
of
antipsychotic drugs
is
between
380
19
the
classical
(typical) agents such
as
chlorproma-
zine, haloperidol
and
zuclopenthixol,
and the
atypical

antipsychotics, which include clozapine,
and now
risperidone, olanzapine
and
quetiapine.
These latter
are
'atypical'
in
their mode
of
action,
effects
on
experimental animals
(lack
of
extra-
pyramidal motor symptoms
in
rats)
and
adverse
effect
profiles.
Categorisation
of
atypical agents
by
their chemical structure

is of
limited
value
clinically
as
they
are
very heterogenous.
A
classification
by
receptor
binding
profiles
is
likely
to
emerge with
growing evidence
on the
clinical importance
of
their actions
on
inter-related transmitter
systems.
INDICATIONS
Antipsychotic drugs
are
used

for the
prophylaxis
and
acute treatment
of
psychotic illnesses including
schizophrenia
and
psychoses associated
with
depression
and
mania.
They also have
an
important role
as an
alternative
or
adjunct
to
benzodiazepines
in the
TABLE
1 9.3
Antipsychotic drugs
Atypical
Classical
antipsychotics*
antipsychotics

Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Amisulpride**
Zotepine
Sertindole***
Phenothiazines
Type
1
Type
2
Type
3
Butyrophenones
Substituted
benzamide
Thioxanthines
Others
Chlorpromazine
Promazine
Thioridazine
f If
Pericyazine
Trifluoperazine
Prochlorperazine
Fluphenazine
Haloperidol
Benperidol

Sulpiride**
If
Flupentixol
Zuclopenthixol
Pimozide
Loxapine
* No
recognised classification system exists
for
atypical
antipsychotics.Tentative
terms
based
on
receptor
binding
profiles
have
been applied
to
certain
drug
groupings,
for
example'broad
spectrum atypicals'
for
clozapine, olanzapine
and
quetiapine,

whilst
risperidone
and
ziprasidone
have
been described
as
'high
affinity
serotonin-dopamine
antagonists'.
**
Amisulpride
and
sulpiride
are
structurally
related.
***
Sertindole
is
available only
on a
named
patient
basis.
f
Licenced indications
for
thioridazine

were
severely
restricted
in
2000
after
evidence
emerged
of
cardiovascular
toxicity.
fl In
some classifications
thioridazine
and
sulpiride
are
considered
to be
'atypical'
due to
their
low
propensity
to
cause
extrapyramidal
adverse effects.
ANTI
PSYCHOTICS

management
of the
acutely disturbed
patient,
both
for
tranquillisation
and
sedation. Antipsychotics have
been used short-term
in
severe anxiety
but are now
given only
as a
last resort. Certain antipsychotics
have
an
antidepressant
effect
which
is
distinct
from
their ability
to
treat
the
psychosis associated with
depression

but use as
antidepressants
is
difficult
to
justify
given
the
many pharmacological options
now
available
for
treating
depression.
Antipsycho-
tics
have also proved
useful
in the tic
disorder
Tourette's syndrome
and for
recurrent self-harming
behaviour.
The
threshold
for
seeking specialist involvement
in
starting antipsychotics

is
much lower than that
when initiating antidepressant drugs. This
reflects
the
complexity
of
diagnosis
of
psychotic illness,
its
chronicity,
the
increased likelihood
of
poor
compliance without appropriate support
and the
potential toxicity
of
antipsychotic agents.
MECHANISM
OF
ACTION
Historically
the
beneficial
effects
of
classical anti-

psychotic agents were explained
by
their action
on
brain
pathways
in
which
dopamine
is the
neuro-
transmitter. Dopaminergic pathways include
the
tuberoinfunibular
pathway (moderating prolactin
release
from
the
hypothalamus),
the
nigrostriatal
pathway (involved
in
motor control
and
deficient
in
Parkinson's
Disease)
and the

mesolimbic pathway,
which
runs
from
the
ventrotegmental area
via the
nucleus accumbens
to the
prefrontal cortex (Fig. 19.3)
(and
is
overactive
in
psychotic illness according
to
the
dopamine hypothesis
of
schizophrenia). Five
dopamine receptor types
are
identified.
D
1
- and D
5
-
receptor
activation increases intracellular

cyclic
AMP
concentrations whereas activation
of D
2
, D
3
and D
4
subtypes
has the
opposite
effect.
Since
all
classical
antipsychotic agents shared
an
ability
substantially
to
block D
2
-receptors, their
effects
in
ameliorating psychosis were ascribed
to
preventing
activation

of
these receptors. Thus
it was
postulated
that
the key
deficit
in
schizophrenia
was
increased
dopaminergic
activity,
brought about
by a
rise
in
the
number
of
brain dopamine D
2
-receptors,
or
receptor supersensitivity,
or
excess availability
of
dopamine
for

D
2
-receptor activation
from
over-
production
or
reduced destruction through enzyme
deficiency.
381