C H A P T E R 2 1
Antidepressant agents
321
Caution should be used with TCAs in people with
pre-existing cardiovascular (CV) disorders
because of the
cardiac stimulatory effects of the drug
and with
any con-
dition that would be exacerbated by the anticholinergic
effects
, such as angle-closure glaucoma, urinary reten
tion, prostate hypertrophy, or GI or genitourinary (GU)
surgery. Care should also be taken with people with
mental health problems,
who may exhibit a worsening
of psychoses or paranoia
, and with manic–depressive
people,
who may shift to a manic stage.
There is a black
box warning on all of the TCAs bringing attention to
a risk of suicidality, especially in children and adoles
cents; caution should be used, and the amount of drug
dispensed at any given time should be limited with poten
tially suicidal people. In addition, caution is necessary
in people with a history of seizures
because the seizure
threshold may be decreased secondary to stimulation
of the receptor sites
and in elderly people. The presence
of hepatic or renal disease,
which could interfere with
metabolism and excretion of these drugs and lead to
toxic levels
, also necessitates caution and the need for a
lower dose of the drug.
Adverse effects
The adverse effects of TCAs are associated with the
effects of the drugs on the central nervous system (CNS)
and on the peripheral nervous system. Sedation, sleep dis
turbances, fatigue, hallucinations, disorientation, visual
disturbances, difficulty in concentrating, weakness,
ataxia and tremors may occur. Limited quantities of
tricyclic antidepressants should be prescribed at any
one time because their cardiovascular and epileptogenic
effects are dangerous in overdosage. In particular, over
dosage with dosulepin
(dothiepin)
and amitriptyline is
associated with a relatively high rate of fatality.
Use of TCAs may lead to GI anticholinergic effects,
such as dry mouth, constipation, nausea, vomiting,
anorexia, increased salivation, cramps and diarrhoea.
Resultant GU effects may include urinary retention and
hesitancy, loss of libido and changes in sexual func
tioning. CV effects such as orthostatic hypotension,
hypertension, arrhythmias, myocardial infarction,
angina, palpitations and stroke may also pose problems.
Miscellaneous reported effects include alopecia, weight
gain or loss, flushing, chills and nasal congestion.
These adverse effects may be intolerable to some
people, who then stop taking the particular TCA. Abrupt
cessation of all TCAs causes a withdrawal syndrome
characterised by nausea, headache, vertigo, malaise and
nightmares (see Box 21.2).
Antidepressant discontinuation syndrome may occur
within 5 days of stopping treatment with antidepressant
drugs; symptoms are usually mild and self-limiting
(lasting for 1–2 weeks), but in some cases may be
severe. Tricyclic antidepressants MAO inhibitors
and antidepressants with a shorter half-life, such as
paroxetine and venlafaxine, are associated with a
higher risk of discontinuation symptoms. The risk
of discontinuation symptoms is also increased if
the antidepressant is stopped suddenly after regular
administration for 8 weeks or more. Symptoms can also
occur after a reduction in dose or omission of a dose.
The dose should preferably be reduced gradually over
about 4 weeks (fluoxetine is an exception to this rule
due to its long half-life), or longer if discontinuation
symptoms emerge (up to 6 months in people who have
been on long-term maintenance treatment). Many
people will continue to have symptoms despite a slow
withdrawal. Antimuscarinic agents may assist with
tricyclic antidepressant withdrawal.
Source: New Zealand Formulary,
.
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BOX 21.2
Antidepressant discontinuation
syndrome
Prototype summary: Imipramine
Indications:
Relief of symptoms of depression;
enuresis in children older than 6 years; off-label
consideration—control of chronic pain.
Actions:
Inhibits presynaptic reuptake of
noradrenaline and serotonin; anticholinergic at
CNS and peripheral receptors; sedating.
Pharmacokinetics:
Route
Onset
Peak
Oral
Varies
2–4 hours
T
1/2
:
8 to 16 hours, metabolised in the liver, excreted
in the urine.
Adverse effects:
sedation, anticholinergic effects,
confusion, anxiety, orthostatic hypotension, dry
mouth, constipation, urinary retention, rash, bone
marrow depression.
Clinically important drug–drug interactions
If TCAs are given with cimetidine, fluoxetine or raniti
dine, an increase in TCA levels results, with an increase
in both therapeutic and adverse effects, especially
anticholinergic conditions. People should be monitored
closely, and appropriate dose reductions should be
made.
Other drug combinations may also pose problems.
The combination of TCAs and oral anticoagulants
leads to higher serum levels of the anticoagulants and
increased risk of bleeding. Blood tests should be done
frequently, and appropriate dose adjustments in the oral
anticoagulant should be made.
