Clinical Pharmacology and Therapeutics

CHAPTER 20
MOOD DISORDERS
● Depressive illnesses and antidepressants 116
● Lithium, tryptophan and St John’s wort 121
● Special groups 122
DEPRESSIVE ILLNESSES AND
ANTIDEPRESSANTS
Many forms of depression are recognized clinically and most
respond well to drugs. From a biochemical viewpoint, there
are probably different types of depression (which do not correspond
predictably to clinical variants) depending on which
neurotransmitter is involved, and these may respond differently
to different drugs.
PATHOPHYSIOLOGY: INSIGHTS FROM
ANTIDEPRESSANT DRUG ACTIONS
The monoamine theory of mood is mainly based on evidence
from the actions of drugs.
1. Reserpine, which depletes neuronal stores of noradrenaline
(NA) and 5-hydroxytryptamine (5HT) and α-methyltyrosine,
which inhibits NA synthesis, cause depression.
2. Tricyclic antidepressants (TCA) of the amitriptyline type
(which raise the synaptic concentration of NA and 5HT)
are antidepressant.
3. Monoamine oxidase inhibitors (MAOIs, which increase
total brain NA and 5HT) are antidepressant.
On the basis of these actions, it was suggested that depression
could be due to a cerebral deficiency of monoamines. One difficulty
with this theory is that amfetamine and cocaine, which
act like tricyclic drugs in raising the synaptic NA content, are
not antidepressive, although they do alter mood. Even worse,
the tricyclic antidepressants block amine reuptake from synapses
within one or two hours of administration, but take from ten
days to four weeks to alleviate depression. Such a long timecourse
suggests a resetting of postsynaptic or presynaptic
receptor sensitivity.
Another theory of depression is the serotonin-only hypothesis.
This theory emphasizes the role of 5HT and downplays that of
NA in the causation of depression, and is backed by the effectiveness
of the selective serotonin reuptake inhibitors, or SSRI
class of drugs, in the treatment of depression. However, it also
does not explain the delay in onset of the clinical effect of
antidepressant drugs, including the SSRIs, and again receptor
resetting has to be invoked. Also, many strands of evidence suggest
that NA does indeed have an important role in depression.
The permissive hypothesis of mania/depression suggests
that the control of emotional behaviour results from a balance
between NA and 5HT. According to this theory, both the
manic phase and the depressive phase of bipolar disorder are
characterized by low central 5HT function. Evidence suggests
that brain 5HT systems dampen or inhibit a range of functions
involving other neurotransmitters. Mood disorders result from
the removal of the serotonin damper. This hypothesis postulates
that low levels of 5HT permit abnormal levels of NA to
cause depression or mania. If 5HT cannot control NA and NA
falls to abnormally low levels, the patient becomes depressed.
On the other hand, if the level of 5HT falls and the level of
NA becomes abnormally high, the patient becomes manic.
According to this hypothesis, antidepressant drugs are effective
to the degree that they restore the ability of 5HT to control
NA, thus restoring the critical balance that controls emotional
behaviour. A recently available class of antidepressant drugs,
serotonin-noradrenaline reuptake inhibitors (SNRI), work by
selectively blocking reuptake of both NA and 5HT, thereby
increasing levels of both monoamines. The SNRIs have very
little affinity for other postsynaptic receptor sites and are therefore
less likely to produce some of the side effects associated
with TCA.
Dysregulation of the hypothalamic–pituitary–adrenal axis
is a common biological marker of depression and the value of
antiglucocorticoid drugs is under investigation.
GENERAL PRINCIPLES OF MANAGEMENT
Depression is common, but under-diagnosed. It can be recognized
during routine consultations, but additional time may
be needed. Genetic and social factors are often relevant. Drug
treatment is not usually appropriate at the mild end of the
severity range. Drugs are used in more severe depression,
especially if it has melancholic (‘endogenous’) features. Even
if depression is attributable to external factors (‘exogenous’),