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