Blue Genes and the Mechanism of Action of Antidepressants
Issue: Antidepressants may work by triggering a molecular cascade starting with the interaction of monoamines with their receptors and culminating in the up- and down-regulation of critical genes. Neurotransmitter receptor synthesis may be decreased, whereas neurotrophic factors such as brain-derived neurotrophic factor may be increased, leading to an antidepressant response.
| All antidepressants increase
neurotransmission for one or more of the
monoamines--serotonin, norepinephrine, or dopamine.1
One problem with the monoamine hypothesis is that the
timing of antidepressant effects on neurotransmitters is
generally faster (within minutes) than the timing of the
antidepressant effects on mood (reaching maximal effect
in days to weeks).1 One theory to explain the
ultimate mechanism of delayed therapeutic action of
antidepressants is the "neurotransmitter receptor
hypothesis of antidepressant action," which proposes
that antidepressants, no matter what their initial
actions on receptors and enzymes, eventually cause a
desensitization or "down-regulation" of key
neurotransmitter receptors in a time course consistent
with the delayed onset of antidepressant action of these
drugs (Figure 1).1 This time course coincides
with other events, including how long it takes for a
patient to become tolerant to the side effects of
antidepressants. Thus, desensitization of some
neurotransmitter receptors may lead to the delayed
therapeutic actions of antidepressants, whereas
desensitization of other neurotransmitter receptors may
lead to the decrease of side effects over time. The monoamine hypothesis of antidepressant action on gene expression proposes that antidepressants, no matter what their initial actions on receptors and enzymes, eventually cause critical genes (i.e., "blue genes") to be activated or inactivated. As already mentioned, some of these are clearly the genes that code for neurotransmitter receptors. Others may be related to neurotrophic factors, such as brain-derived neurotrophic factor (BDNF),2 as discussed in last month's Brainstorms.3 The genetic expression of such neurotrophic factors may be regulated in part by monoaminergic neurotransmission and stress. |
Delayed actions of
antidepressants may not only explain the long-lasting
therapeutic action of antidepressants, but they may also
explain why some patients fail to respond to
antidepressants, since it is possible that in such
patients the initial pharmacologic actions are not
translated into the required delayed pharmacologic and
genetic actions. Knowing the biological basis for
treatment nonresponse may lead to the development of a
greatly needed advance in the pharmacotherapy of
depression, namely, an effective treatment for refractory
or nonresponding depressed patients. The absence of
neurotrophic factors in depression may also explain why,
over time and with multiple recurrent episodes, the brain
appears to be more likely to relapse into another bout of
depression and become more resistant to antidepressant
treatments. Also, if one understands the key
pharmacologic events that are linked to the therapeutic
actions of the drugs, it may be possible to accelerate
these events with drugs in the future. If so, it could
lead to another highly desired advance in the
pharmacotherapy of depression, namely, a rapid-onset
antidepressant. In summary, all antidepressants have a common action on monoamine neurotransmitters: they boost monoamine neurotransmission, leading to changes in gene expression in the neurons targeted by the monoamines. This change includes desensitization of neurotransmitter receptors, leading to both therapeutic actions and tolerance to side effects. Although antidepressants are classified on the basis of those actions on neurotransmitter receptors and enzymes that are immediate, attention is increasingly being paid to how these initial and immediate actions translate into delayed actions. |
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Brainstorms aims to provide updates of novel concepts emerging from the neurosciences that have relevance to practitioners. From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego. |
REFERENCES 1. Stahl SM. Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge University Press. In press. 2. Duman RF, Heninger CR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54:597-606 3. Stahl SM. Blue genes and the monoamine hypothesis of depression [Brainstorms]. J Clin Psychiatry 2000;61:77-78 |