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Antidepressants in palliative care |
The following article has been reprinted from the newsletter
of the NSW Society of Palliative Medicine, with the kind permission of its
management and the author.
In the palliative care population antidepressants have many uses. Principally
they are prescribed as anti-depressants and co-analgesics, but they may
also be given as sedative/hypnotics, anxiolytics or anti-panic agents.
Before discussing the use of antidepressants, it is appropriate to comment
on the difficulty of diagnosing depression in the medically ill. Sad feelings
are an acknowledged part of physical illness, especially when the illness
is irreversible. However, dysphoria in itself is not sufficient for the
diagnosis of depression. The vegetative symptoms of depression, eg. lethargy
and anorexia, often occur as part of illness and if these are not particularly
disproportionate, the clinician is forced to rely upon the psychic symptoms
of depression; particularly anhedonia (or loss of interest). Also, most
patients, unless in continuous pain, will retain a variable affective response
and respond positively to humour and intimacy, good news, or some pleasant
event. If the affect is unreactive and anhedonia is pervasive for more than
two weeks, a diagnosis of major depression is likely.
The frequency of this diagnosis amongst the medically ill is estimated at
around 8-20%, depending on methodology. The diagnosis is missed in 30-50%
of these patients. If there is significant doubt, a trial of treatment should
be instituted. Given that a diagnosis of major depression is made, the choice
of pharmacological management is broad, bearing in mind that psychological
and social strategies are also important.
Amongst the antidepressants available, all are of equal efficacy at adequate
dose, being 60-70% efficacious in major depression over a four week period.
All have a delayed onset of clinical effect and are less efficacious in
"minor" or "neurotic/reactive depression". However all
agents are not equal in their accessory function and the choice will be
dictated by the other functions that the medications are to serve and the
side effect profile of each agent.
Tricyclic antidepressants (TCAs):
eg. amitriptyline, doxepin, desipramine
In the medically ill, lower doses are usually required; 100-125 mg daily
is usually enough. If the drug is prescribed only as a co-analgesic, 50-75
mg is adequate. The starting dose is always small and the dose gradually
built up. These agents have a long half life and can be given once a day
as a nocte dose minimising day time side effects and assisting with sleep.
All block re-uptake of monoamines (serotonin, nor-adrenalin or both) in
the CNS.
The adverse effects (see table) include: sedation (sometimes useful in an
agitated or sleepless patient), anticholinergic effects (eg. dry mouth,
constipation, confusion), orthostatic hypotension, cardiovascular toxicity
(quinidine like effects, hypotension in cardiac failure, arrhythmias in
overdose) and some drug interactions (eg. cimetidine increases the blood
levels of TCAs).
Obviously in the palliative care population, these drugs will not always
be suitable. A drug with significant anticholinergic effects will exacerbate
constipation secondary to opiate analgesics and will easily tip a seriously
medically ill patient into confusion.
Additionally, imipramine has been widely validated as useful in panic disorder
and can be helpful in the treatment of frequent panic attacks even in the
absence of depression.
At times, doses of a sedative tricyclic are prescribed when a sedative and
anxiolytic action is desired and benzodiazepines would be appropriate.
Agents indicated * are significant serotinergic re-uptake blockers. This
is thought to be important in the co-analgesic role of these drugs.
| Table 1: Side effects profile
of commonly used tricyclic antidepressants | | Agent | Sedation
| Anticholinergic | Hypotension |
| Amitriptyline ** | ++++ | ++++ | ++++
| | Imipramine ** | +++ | +++ | +++
| | Clomipramine ** | +++ | +++ | +++
| | Doxepin * | +++ | ++ | ++
| | Nortriptyline | ++ | ++ | +
| | Desipramine | + | + | +
|
Tetracyclic antidepressants
Mianserin is the only example currently available. A dose of 60-80 mg
daily is usually efficacious in the medically ill. A single night-time dose
is preferred as sedative side effects are great.
Mianserin is serotonergic and therefore co-analgesic activity is
predicted. There is little anti-cholinergic activity and mianserin
is not cardio-toxic, making it useful in the medically ill and the elderly.
Many active, ambulant patients, however, would find the sedation unacceptable.
Mono-amine Oxidase Inhibitors
These agents are thought to be equal to the TCAs in efficacy in major depression
and to be superior in "atypical" and "minor depression"
where anxiety may be a prominent feature.
Phenelzine (45-90 mg/day in divided doses) may be either "stimulating"
or "sedating" in its effect and has documented anti-panic activity.
Tranylcypromine (30-60 mg per day in divided doses weighted towards the
morning) is usually stimulating, having some amphetamine-like activity.
These agents bind irreversibly to mono-amine oxidase and therefore the possibility
of drug and food interactions can continue for up to two weeks after cessation
of these drugs.
Patients who may, therefore, need relatively urgent surgery, eg. patients
with visceral cancers and threatened obstruction, would be unsuitable because
of possible drug interactions with anaesthetic agents.
The drug and food interactions of these agents are their most dramatic adverse
effects and usually the greatest disincentive to prescribe. A hypertensive
crisis can be precipitated by interactions with sympathomimetics and other
catecholamine agonists and with tyramine containing foods (unfortunate in
patients with anorexia and decreasing food preferences). Narcotics are potentiated.
Whereas pethidine in combination is dangerous, morphine and codeine tend
to be safe if lower doses of these opioids are used.
Other adverse effects include orthostatic hypotension is some patients and
occasional gastrointestinal discomfort and myoclonus. Anticholinergic side
effects are minimal.
Whereas these drugs make physicians very anxious, they are generally well
tolerated by patients and therefore have a definite place given proper precautions,
an educated patient and family, or the controlled setting of inpatient care.
Tranylcypromine, in particular, can be very useful in the depressed, anergic,
seriously ill patient.
Specific Serotonergic Re-uptake Inhibitors
Currently the agents available are fluoxetine, paroxetine and sertraline.
Flouxetine has a very long half-life and is usually given at a dose of 20
mg/day but can be given second daily in the circumstances of significant
liver dysfunction or a small, wasted patient. Fluoxetine is as effective
as the tricyclics in major depression, although it is not helpful as a sedative
hypnotic and its role as a co-analgesic is not yet clear despite its Serotonergic
properties.
Although mostly well tolerated in the medically ill, adverse effects do
occur. Frequently, a subjective agitation will make this unsuitable in anxious
patients. In these patients it should therefore be coupled with a benzodiazepine
or another agent should be used. Some nausea and anorexia is obviously a
worry in a population concurrently at risk for this. Insomnia is also a
common complaint although palliative patients may well be using other sedative
medication already. Headache may be complained of and this drug also has
some extrapyramidal side effects which, given the dopaminergic sensitivity
of those with HIV encephalopathy, make it unsuitable for many patients with
advanced AIDS.
Fluoxetine is safe in overdose and initial claims of particular worsening
of suicidal behaviour seem not to have been substantiated.
Reversible Inhibitors of Mono-amine Oxidase A (RIMA's)
Mono-amine oxidase A preferentially metabolises serotonin and nor-adrenalin.
The only agent available, Moclobemide, has been demonstrated to have efficacy
equal to the TCAs in major depression and may also be efficacious in "minor"
and "atypical" depression. No co-analgesic role has been identified
for this agent.
In contrast to the traditional antidepressants, it is 90% renally excreted
and is therefore useful in patients who have advanced hepatic disease. It
has few adverse effects and is usually well tolerated. If complaints are
made, they are usually of nausea, insomnia and some increase in anxiety.
In contrast to the traditional, irreversible, non-selective MAOIs, no dietary
restrictions are warranted and drug interactions are minimal, tending not
to be clinically significant. Pethidine, however, would still be best avoided.
Moclobemide is also safe in overdose.
Lithium
Occasionally a palliative care physician may encounter a patient who is
prescribed lithium for either adjunctive treatment of a resistant
depression or for prophylaxis of bipolar disorder. The risk of lithium toxicity
in the seriously medically ill is great and a psychiatric opinion re the
fragility of the patient's illness should be sought. Patients with a limited
prognosis may be expected to be managed without lithium. Maintenance would
require strict attention to fluid balance, and frequent monitoring of serum
lithium levels.
Summary
All antidepressant drugs have a place in the palliative care population
and the rational use of these agents is predicted upon a knowledge of their
diverse indications and actions.
Dr. Melissa Corr, liaison psychiatrist, Royal Prince Alfred Hospital, Sydney
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