There can be variation in the licensing of
different medicines containing the same drug.
Oral solution
CAUTIONARY AND ADVISORY LABELS 10
▶Li-Liquid (Rosemont Pharmaceuticals Ltd)
Lithium citrate 101.8 mg per 1 ml Li-Liquid 509mg/5ml oral
solution | 150 ml P £5.79 DT = £5.79
Lithium citrate 203.6 mg per 1 ml Li-Liquid 1.018g/5ml oral
solution | 150 ml P £17.49 DT = £11.58
▶Priadel (lithium citrate) (Essential Pharma M)
Lithium citrate 104 mg per 1 ml Priadel 520mg/5ml liquid sugar-
free | 150 ml P £6.73 DT = £6.73
3.4 Depression
Antidepressant drugs
Overview
Antidepressant drugs are effective for treating moderate to
severe depression associated with psychomotor and
physiological changes such as loss of appetite and sleep
disturbance; improvement in sleep is usually the first benefit
of therapy. Ideally, patients with moderate to severe
depression should be treated with psychological therapy in
addition to drug therapy. Antidepressant drugs are also
effective for dysthymia (lower grade chronic depression
(typically of at least 2 years duration)).
Antidepressant drugs should not be used routinely in mild
depression, and psychological therapy should be considered
initially; however, a trial of antidepressant therapy may be
considered in cases refractory to psychological treatments or
in those associated with psychosocial or medical problems.
Drug treatment of mild depression may also be considered in
patients with a history of moderate or severe depression.
Choice
The major classes of antidepressant drugs include the
tricyclic and related antidepressants, the selective serotonin
re-uptake inhibitors (SSRIs), and the monoamine oxidase
inhibitors (MAOIs). A number of antidepressant drugs
cannot be accommodated easily into this classification.
There is little to choose between the different classes of
antidepressant drugs in terms of efficacy, so choice should be
based on the individual patient’s requirements, including
the presence of concomitant disease, existing therapy,
suicide risk, and previous response to antidepressant
therapy. Since there may be an interval of 2 weeks before the
antidepressant action takes place, electroconvulsive
treatment may be required in severe depression when delay
is hazardous or intolerable. During the first few weeks of
treatment, there is an increased potential for agitation,
anxiety, and suicidal ideation.
SSRIs are better tolerated and are safer in overdose than
other classes of antidepressants and should be considered
first-line for treating depression. In patients with unstable
angina or who have had a recent myocardial infarction,
sertraline p. 385 has been shown to be safe.
Tricyclic antidepressants have similar efficacy to SSRIs but
are more likely to be discontinued because of side-effects;
toxicity in overdosage is also a problem. SSRIs are less
sedating and have fewer antimuscarinic and cardiotoxic
effects than tricyclic antidepressants.
MAOIs have dangerous interactions with some foods and
drugs, and should be reserved for use by specialists.
Although anxiety is often present in depressive illness
(and may be the presenting symptom), the use of an
antipsychotic or an anxiolytic may mask the true diagnosis.
Anxiolytics or antipsychotic drugs should therefore be used
with caution in depression but they are useful adjuncts in
agitated patients. Augmenting antidepressants with
antipsychotics under specialist supervision may also be
necessary in patients who have depression with psychotic
symptoms.
St John’s wort (Hypericum perforatum) is a popular herbal
remedy on sale to the public for treating mild depression. It
should not be prescribed or recommended for depression
because St John’s wort can induce drug metabolising
enzymes and a number of important interactions with
conventional drugs, including conventional antidepressants,
have been identified. Furthermore, the amount of active
ingredient varies between different preparations of St John’s
wort and switching from one to another can change the
degree of enzyme induction. If a patient stops taking St
John’s wort, the concentration of interacting drugs may
increase, leading to toxicity.
Management
Patients should be reviewed every 1–2 weeks at the start of
antidepressant treatment. Treatment should be continued
for at least 4 weeks (6 weeks in the elderly) before
considering whether to switch antidepressant due to lack of
efficacy. In cases of partial response, continue for a further
2–4 weeks (elderly patients may take longer to respond).
Following remission, antidepressant treatment should be
continued at the same dose for at least 6 months (about
12 months in the elderly), or for at least 12 months in
patients receiving treatment for generalised anxiety disorder
(as the likelihood of relapse is high). Patients with a history
of recurrent depression should receive maintenance
treatment for at least 2 years.
Hyponatraemia and antidepressant therapy
Hyponatraemia (usually in the elderly and possibly due to
inappropriate secretion of antidiuretic hormone) has been
associated with all types of antidepressants; however, it has
been reported more frequently with SSRIs than with other
antidepressants. Hyponatraemia should be considered in all
patients who develop drowsiness, confusion, or convulsions
while taking an antidepressant.
Suicidal behaviour and antidepressant therapy
The use of antidepressants has been linked with suicidal
thoughts and behaviour; children, young adults, and
patients with a history of suicidal behaviour are particularly
at risk. Where necessary patients should be monitored for
suicidal behaviour, self-harm, or hostility, particularly at the
beginning of treatment or if the dose is changed.
Serotonin syndrome
Serotonin syndrome or serotonin toxicity is a relatively
uncommon adverse drug reaction caused by excessive
central and peripheral serotonergic activity. Onset of
symptoms, which range from mild to lifethreatening, can
Nervous system
occur within hours or days following the initiation, dose
escalation, or overdose of a serotonergic drug, the addition
of a new serotonergic drug, or the replacement of one
serotonergic drug by another without allowing a long
enough washout period in-between, particularly when the
first drug is an irreversible MAOI or a drug with a long half-
life. Severe toxicity, which is a medical emergency, usually
occurs with a combination of serotonergic drugs, one of
which is generally an MAOI.
The characteristic symptoms of serotonin syndrome fall
into 3 main areas, although features from each group may
not be seen in all patients—neuromuscular hyperactivity
(such as tremor, hyperreflexia, clonus, myoclonus, rigidity),
autonomic dysfunction (tachycardia, blood pressure
changes, hyperthermia, diaphoresis, shivering, diarrhoea),
and altered mental state (agitation, confusion, mania).
Treatment consists of withdrawal of the serotonergic
medication and supportive care; specialist advice should be
sought.
Failure to respond
Failure to respond to initial treatment with an SSRI may
require an increase in the dose, or switching to a different
SSRI or mirtazapine p. 389. Other second-line choices
include lofepramine p. 395, moclobemide p. 380, and
reboxetine p. 381. Other tricyclic antidepressants and
venlafaxine p. 386 should be considered for more severe
forms of depression; irreversible MAOIs should only be
prescribed by specialists. Failure to respond to a second
antidepressant may require the addition of another
antidepressant of a different class, or use of an augmenting
agent (such as lithium, aripiprazole p. 413 [unlicensed],
olanzapine p. 416 [unlicensed], quetiapine p. 419, or
risperidone p. 421 [unlicensed]), but such adjunctive
treatment should be initiated only by doctors with special
experience of these combinations. Electroconvulsive therapy
may be initiated in severe refractory depression.
Anxiety disorders and obsessive-compulsive disorder
Management of acute anxiety generally involves the use of a
benzodiazepine or buspirone hydrochloride p. 358. For
chronic anxiety (of longer than 4 weeks’ duration) it may be
appropriate to use an antidepressant. Combined therapy
with a benzodiazepine may be required until the
antidepressant takes effect. Patients with generalised anxiety
disorder, a form of chronic anxiety, should be offered
psychological treatment before initiating an antidepressant.
If drug treatment is needed, an SSRI such as escitalopram
p. 382, paroxetine p. 384, or sertraline p. 385 [unlicensed],
can be used. Duloxetine p. 385 and venlafaxine p. 386
(serotonin and noradrenaline reuptake inhibitors) are also
recommended for the treatment of generalised anxiety
disorder; if the patient cannot tolerate SSRIs or serotonin
and noradrenaline reuptake inhibitors (or if treatment has
failed to control symptoms), pregabalin p. 341 can be
considered.
Panic disorder, obsessive-compulsive disorder, post-
traumatic stress disorder, and phobic states such as social
anxiety disorder are treated with SSRIs. Clomipramine
hydrochloride p. 391 or imipramine hydrochloride p. 394 can
be used second-line in panic disorder [unlicensed];
clomipramine hydrochloride can also be used second-line for
obsessive-compulsive disorder. Moclobemide p. 380 is
licensed for the treatment of social anxiety disorder.
Tricyclic and related antidepressant drugs
Choice
Tricyclic and related antidepressants block the re-uptake of
both serotonin and noradrenaline, although to different
extents. For example, clomipramine hydrochloride is more
selective for serotonergic transmission, and imipramine
hydrochloride is more selective for noradrenergic
Nervous system
transmission. Tricyclic and related antidepressant drugs can
be roughly divided into those with additional sedative
properties and those that are less sedating. Agitated and
anxious patients tend to respond best to the sedative
compounds, whereas withdrawn and apathetic patients will
often obtain most benefit from the less sedating ones. Those
with sedative properties include amitriptyline hydrochloride
p. 390, clomipramine hydrochloride, dosulepin
hydrochloride p. 392, doxepin p. 393, mianserin
hydrochloride p. 389, trazodone hydrochloride p. 388, and
trimipramine p. 396. Those with less sedative properties
include imipramine hydrochloride, lofepramine p. 395, and
nortriptyline p. 395.
Tricyclic and related antidepressants also have varying
degrees of antimuscarinic side-effects and cardiotoxicity in
overdosage, which may be important in individual patients.
Lofepramine has a lower incidence of side-effects and is less
dangerous in overdosage but is infrequently associated with
hepatic toxicity. Imipramine hydrochloride is also well
established, but has more marked antimuscarinic side-
effects than other tricyclic and related antidepressants.
Amitriptyline hydrochloride and dosulepin hydrochloride
are effective but they are particularly dangerous in
overdosage and are not recommended for the treatment of
depression; dosulepin hydrochloride should be initiated by a
specialist.
Dosage
About 10 to 20% of patients fail to respond to tricyclic and
related antidepressant drugs and inadequate dosage may
account for some of these failures. It is important to use
doses that are sufficiently high for effective treatment but
not so high as to cause toxic effects. Low doses should be
used for initial treatment in the elderly. In most patients the
long half-life of tricyclic antidepressant drugs allows once-
daily administration, usually at night; the use of modified-
release preparations is therefore unnecessary.
Some tricyclic antidepressants are used in the
management of panic and other anxiety disorders. Some
tricyclic antidepressants may also have a role in some forms
of neuralgia and in nocturnal enuresis in children.
Children and adolescents
Studies have shown that tricyclic antidepressants are not
effective for treating depression in children.
Considerations in the elderly
The use of tricyclic antidepressants in elderly patients is
potentially inappropriate (STOPP criteria):
. if prescribed in those with dementia, narrow angle
glaucoma, cardiac conduction abnormalities, prostatism,
or history of urinary retention (risk of worsening these
conditions);
. if initiated as first-line antidepressant treatment (higher
risk of adverse drug reactions than with SSRIs or SNRIs).
For further information, see STOPP/START criteria in
Prescribing in the elderly p. 33.
Monoamine-oxidase inhibitors
Monoamine-oxidase inhibitors are used much less
frequently than tricyclic and related antidepressants, or
SSRIs and related antidepressants because of the dangers of
dietary and drug interactions and the fact that it is easier to
prescribe MAOIs when tricyclic antidepressants have been
unsuccessful than vice versa.
Tranylcypromine p. 380 has a greater stimulant action than
phenelzine p. 380 or isocarboxazid p. 379 and is more likely
to cause a hypertensive crisis. Isocarboxazid and phenelzine
are more likely to cause hepatotoxicity than
tranylcypromine.
Moclobemide should be reserved as a second line
treatment.
Phobic patients and depressed patients with atypical,
hypochondriacal, or hysterical features are said to respond
best to MAOIs. However, MAOIs should be tried in any
patients who are refractory to treatment with other
antidepressants as there is occasionally a dramatic response.
Response to treatment may be delayed for 3 weeks or more
and may take an additional 1 or 2 weeks to become maximal.
Interactions
Other antidepressants should not be started for 2 weeks after
treatment with MAOIs has been stopped (3 weeks if starting
clomipramine or imipramine). Conversely, an MAOI should
not be started until:
. at least 2 weeks after a previous MAOI has been stopped
(then started at a reduced dose)
. at least 7–14 days after a tricyclic or related antidepressant
(3 weeks in the case of clomipramine or imipramine) has
been stopped
. at least a week after an SSRI or related antidepressant (at
least 5 weeks in the case of fluoxetine) has been stopped
Other antidepressant drugs
The thioxanthene flupentixol p. 403 (Fluanxol ®) has
antidepressant properties when given by mouth in low
doses. Flupentixol is also used for the treatment of
psychoses.
Vortioxetine p. 397, an antidepressant thought to directly
modulate serotonergic receptor activity and inhibit the re-
uptake of serotonin, is recommended in patients whose
condition has responded inadequately to 2 antidepressants
within the current episode.
Tryptophan is licensed for use in treatment-resistant
depression, used as monotherapy and as an adjunct to other
antidepressant drugs; it should be initiated by hospital
specialists.
Other drugs used for Depression Lithium carbonate, p. 375
. Lithium citrate, p. 376
ANTIDEPRESSANTS › MELATONIN RECEPTOR
AGONISTS
PDF pages 398, 399, 400
