Clinical Pharmacology and Therapeutics

120 MOOD DISORDERS
Lofepramine – less sedative, and with less cardiac toxicity,
but occasionally hepatotoxic.
Mirtazapine – increases noradrenergic and serotonergic
neurotransmission via central α 2 adrenoceptors. The
increased release of 5HT stimulates 5HT 1 receptors, whilst
5HT 2 and 5HT 3 receptors are blocked. H 1 receptors are
also blocked. This combination of actions appears to be
associated with antidepressant activity, anxiolytic and
sedative effects. Reported adverse effects include increased
appetite, weight gain, drowsiness, dry mouth and (rarely)
blood dyscrasias.
Drug interactions
These include the following:
• antagonism of anti-epileptics;
• potentiation of sedation with alcohol and other central
depressants;
• antihypertensives and diuretics increase orthostatic
hypotension;
• hypertension and cardiac dysrhythmias with adrenaline,
noradrenaline and ephedrine.
MONOAMINE OXIDASE INHIBITORS (MAOIs)
These drugs were little used for many years because of their
toxicity, and particularly potentially lethal food and drug interactions
causing hypertensive crises. Non-selective MAOIs
should only be prescribed by specialists who are experienced
in their use. They can be effective in some forms of refractory
depression and anxiety states, for which they are generally
reserved. The introduction of moclobemide, a reversible selective
MAO-A inhibitor, may lead to more widespread use of this
therapeutic class.
Tranylcypromine is the most hazardous MAOI because of
its stimulant activity. The non-selective MAOIs of choice are
phenelzine and isocarboxazid.
Uses
These include the following:
1. MAOIs can be used alone or (with close psychiatric
supervision) with a TCA, in depression which has not
responded to TCAs alone;
2. in phobic anxiety and depression with anxiety;
3. in patients with anxiety who have agoraphobia, panic
attacks or multiple somatic symptoms;
4. hypochondria and hysterical symptoms may respond well;
5. for atypical depression with biological features such as
hypersomnia, lethargy and hyperphagia.
Adverse effects
1. Common effects include orthostatic hypotension, weight
gain, sexual dysfunction, headache and aggravation of
migraine, insomnia, anticholinergic actions and oedema.
2. Rare and potentially fatal effects include hypertensive
crisis and 5HT syndrome, psychotic reactions,
hepatocellular necrosis, peripheral neuropathy and
convulsions.
3. Stopping a MAOI is more likely to produce a withdrawal
syndrome than is the case with tricyclics. The syndrome
includes agitation, restlessness, panic attacks and
insomnia.
Contraindications
These include the following:
• liver failure;
• cerebrovascular disease;
• phaeochromocytoma;
• porphyria;
• epilepsy.
Drug interactions
Many important interactions occur with MAOI. A treatment
card for patients should be carried at all times, which describes
precautions and lists some of the foods to be avoided. The
interactions are as follows:
• hypertensive and hyperthermic reactions sufficient to
cause fatal subarachnoid haemorrhage, particularly with
tranylcypromine. Such serious reactions are precipitated
by amines, including indirectly acting sympathomimetic
agents such as tyramine (in cheese), dopamine (in broad
bean pods and formed from levodopa), amines formed
from any fermentation process (e.g. in yoghurt, beer,
wine), phenylephrine (including that administered as
nosedrops and in cold remedies), ephedrine, amfetamine
(all can give hypertensive reactions), other amines,
pethidine (excitement, hyperthermia), levodopa
(hypertension) and tricyclic, tetracyclic and bicyclic
antidepressants (excitement, hyperpyrexia). Buspirone
should not be used with MAOIs. Hypertensive crisis may
be treated with α-adrenoceptor blockade analogous to
medical treatment of patients with phaeochromocytoma
(see Chapter 40). Interactions of this type are much less
likely to occur with moclobemide, as its MAO inhibition
is reversible, competitive and selective for MAO-A, so that
MAO-B is free to deaminate biogenic amines;
• failure to metabolize drugs that are normally oxidized,
including opioids, benzodiazepines, alcohol (reactions
with alcoholic drinks occur mainly because of their
tyramine content). These drugs will have an exaggerated
and prolonged effect;
• enhanced effects of oral hypoglycaemic agents, anaesthetics,
suxamethonium, caffeine and anticholinergics (including
benzhexol and similar anti-Parkinsonian drugs);
• antagonism of anti-epileptics;
• enhanced hypotension with antihypertensives;
• central nervous system (CNS) excitation and hypertension
with oxypertine (an antipsychotic) and tetrabenazine (used
for chorea);
• increased CNS toxicity with triptans (5HT 1 agonists) and
with sibutramine.