A Textbook of Clinical Pharmacology and Therapeutics

●Depressive illnesses and antidepressants 116

●Lithium, tryptophan and St John’s wort 121

●Special groups 122

CHAPTER 20

MOOD DISORDERS

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 corres-
pond predictably to clinical variants) depending on which
neurotransmitter is involved, and these may respond differ-
ently 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 dif-
ficulty with this theory is that amfetamineandcocaine, 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 time-
course 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 effect-
iveness 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 sug-

gest 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 postu-

lates 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 effect-

ive 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 there-

fore 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 recog-

nized 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’),