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THE MONOAMINE-DEFICIENCY HYPOTHESIS
The noradrenergic and serotonergic systems originate deep in the brain and fan out over almost the entire brain, suggesting a system capable of modulating many areas of feeling, thinking, and behaving. The early antidepressants blocked the reuptake of norepinephrine and serotonin by the presynaptic neuron. The immediate effects of this pharmacologic action are to increase the availability of norepinephrine and serotonin in the synapse and to increase stimulation of the postsynaptic neuron. Inhibitors of the enzyme monoamine oxidase were also discovered to have antidepressant properties. This enzyme catabolizes norepinephrine and serotonin in their respective presynaptic neurons, and such inhibition could be expected to increase the availability of neurotransmitters. These discoveries led to a major theory of depression known as the monoamine-deficiency hypothesis. Numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal fluid, as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably. However, a newly discovered form of the enzyme tryptophan hydroxylase, designated TPH-2, is specific to the brain15 and could explain why previous postmortem studies of total enzyme activity did not show differences in tryptophan hydroxylase activity between patients with depression and controls.16 A recent positron-emission tomographic study using a ligand for brain monoamine oxidase showed a 30% increase of the enzyme in a subgroup of patients with depression.17 A study measuring differences in monoamine metabolites between the internal jugular vein and the brachial artery showed lower production by the brain of norepinephrine metabolites in patients with depression than in controls.18 The monoamine-deficiency hypothesis continues to stimulate research whenever a new technical window into the brain is opened.
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