involves both manic and depressive episodes in the same person and is a biologically
different disorder from a unipolar illness, which involves just the depression. Since
depression is a common and potentially life-threatening disorder, drug design of anti-
depressants has been an ongoing activity for many decades.
According to the classical amine hypothesis of antidepressant action,tricyclic anti-
depressant drugs (TCAs) elevate the mood of patients suffering from depression and
decrease the probability of suicide by interfering with the reuptake of NE or serotonin
(section 4.5). Secondary amines such as desipramine (4.69) or nortriptyline (4.70)
are potent inhibitors of NE uptake, whereas the tertiary amines imipramine (4.71),
amitriptyline (1.4), and doxepin (4.72) are more effective as serotonin uptake inhibitors.
According to this hypothesis, reuptake inhibition (i.e., blocking of the amine pump)
increases the concentration of the neurotransmitter in the synaptic gap and thus the
central adrenergic (or serotonergic) tone, resulting in mood elevation. Unfortunately,
this simple and attractive hypothesis cannot explain a number of facts:
- The latency period of weeks or even months that occurs between the initiation of
therapy and the antidepressant effect when tertiary tricyclics are used. Secondary
amines act faster, but in both cases, although elevated neurotransmitter levels
become rapidly apparent, the clinical improvement lags far behind. - Cocaine (4.73), the local anesthetic tropane alkaloid of coca leaves, is a potent NE
reuptake inhibitor but has no antidepressant activity.
The problem with the tricyclic-based neurotransmitter–receptor hypothesis of antide-
pressant activity is that it was based on observations in normal rat brain. Unfortunately,
there are few techniques suitable for in vivowork on human CNS receptors of
depressed patients. In addition, compounds related to dopaminergic and serotonergic
NEUROTRANSMITTERS AND THEIR RECEPTORS 237