The selective serotonin reuptake inhibitors, or SSRIs, are a class of antidepressants often used in the treatment of depression. SSRIs work by increasing the level of availability of the neurotransmitter serotonin in the synaptic cleft. Their pharmacological action achieves this by blocking the reuptake of serotonin and norepinephrine. The monoamine theory of depression, which proposes that depression results from a depletion in the levels of serotonin, norepinephrine, and/ or dopamine in the central nervous system, supports the proposed mechanism of action of SSRI antidepressants.
When SSRIs are used as treatment, they become pharmacologically active at their molecular sites of action almost immediately. Their action, which blocks the re-uptake of serotonin and norepinephrine by the monoamine transporter SERT, causes an increase in neurotransmitter availability at the synaptic cleft. However, the antidepressant effects of SSRIs are generally not seen until 2 to 4 weeks of continuous treatment, thus limiting the monoamine theory of depression. Ultimately there is a discrepancy between immediate inhibition of serotonin reuptake and clinical effects. Why are the clinical symptoms of depression not alleviated immediately after treatment by an SSRI?
One of the 14 subtypes of serotonin receptor, the 5-HT1A receptor, works as an auto-receptor that inhibits serotonergic activity. In simpler terms, this means that a 5HT1A receptor stimulated by the presence of the neurotransmitter serotonin inhibits the firing of serotonergic neurons. These 5HT1A receptors are expressed in the somato-dendritic region of a serotonergic (5-HT) neuron; here they act as inhibitory auto-receptors.
An SSRI works by blocking the monoamine transporter protein SERT, which transports serotonin from synaptic spaces into presynaptic neurons. Thus, an SSRI causes an increased availability of serotonin in the synaptic space. This increase in serotonin levels downregulates 5HT1A receptors present on serotonergic neurons. This means that there are fewer 5HT1A receptors present. Downregulation is controlled by genomic mechanisms, hence the reduction of 5HT1A receptors occurs over a period of weeks, and is not immediate. This explains the discrepancy of the monoamine theory of depression previously discussed.
The serotonergic neuron is now disinhibited since there are fewer 5HT1A receptors expressed in the somato-dendritic region. Consequently, the firing rate of the serotonin-sensitive neuron increases. This in turn increases serotonin release to the synaptic space, which stimulates postsynaptic serotonin receptors.
To summarise, the monoamine theory of depression hypothesises that depression may result from a depletion in the levels of serotonin in the CNS. Treatment by an SSRI increases the concentration of serotonin in the synaptic cleft by blocking the SERT monoamine transporter. This decrease in serotonin degradation results in the down-regulation of the inhibitory auto receptor 5-HT (type 1A). A reduction in the presence of 5-HT1A receptors means that the serotonergic neuron is disinhibited, and hence neurotransmission by the serotonin-sensitive neuron increases. Ultimately, 2-4 weeks is required to alleviate clinical symptoms of depression since down-regulation of the 5-HT1A receptor is mediated by genomic processes. Although serotonin levels may increase immediately after administration of an SSRI, this is not the case for the 5-HT1A receptor.
The Science of Mental Illness 