Breakdown inhibitors take a different approach to elevating synaptic neurotransmitter levels. Rather than blocking reuptake (which traps neurotransmitter in the synapse), they block the enzymes that destroy the neurotransmitter, raising overall tissue levels.
Monoamine oxidase inhibitors (MAOIs) are the prototype. Monoamine oxidase exists in two isoforms — MAO-A and MAO-B — that degrade dopamine, norepinephrine, and serotonin to varying degrees. Inhibiting MAO raises levels of all three monoamines. The MAOIs were among the first effective antidepressants, discovered serendipitously in the 1950s when tuberculosis patients on the antitubercular drug iproniazid showed mood elevation.
Classical MAOIs — phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan) — are non-selective and irreversible. They work, often dramatically, in treatment-resistant depression and atypical depression. But they carry two serious risks. First, hypertensive crisis from tyramine ingestion: dietary tyramine (in aged cheeses, cured meats, fermented foods, fava beans, certain wines) is normally degraded by intestinal MAO; with MAO inhibited, tyramine is absorbed systemically and triggers massive sympathetic activation and dangerous blood pressure spikes. Second, serotonin syndrome when combined with other serotonergic drugs.
These restrictions have largely sidelined classical MAOIs in modern psychiatry, but they remain occasionally useful in carefully selected patients with treatment-resistant depression who can adhere to the dietary restrictions. Selegiline (transdermal patch) is a selective MAO-B inhibitor at low doses (used for Parkinson's disease) that loses selectivity at the doses needed for depression. The transdermal route bypasses first-pass intestinal MAO inhibition, partially reducing the tyramine risk.
Cholinesterase inhibitors use the same strategy on a different neurotransmitter. Acetylcholinesterase is the enzyme that breaks down acetylcholine at the synapse. Block it, and acetylcholine accumulates. Donepezil, rivastigmine, and galantamine are cholinesterase inhibitors used in Alzheimer's disease. They preserve the dwindling acetylcholine supply from the dying basal forebrain, modestly slowing cognitive decline. The benefit is real but typically measured in months to a year of additional function — meaningful, but not curative.
Cholinesterase inhibitors also have intriguing applications outside Alzheimer's. Rivastigmine is used for Parkinson's disease dementia and Lewy body dementia. Physostigmine, a tertiary amine that crosses the blood-brain barrier, can be used acutely to reverse central anticholinergic toxicity from drugs like atropine, scopolamine, or accidental ingestion of anticholinergic plants. Pyridostigmine, a non-CNS-crossing cholinesterase inhibitor, is used in myasthenia gravis to enhance neuromuscular transmission.
COMT inhibitors — entacapone, tolcapone, opicapone — block catechol-O-methyltransferase, the secondary enzyme that breaks down catecholamines. In Parkinson's disease, COMT inhibitors are used alongside levodopa to extend its half-life and reduce off-time fluctuations.
Hold the strategy. Step 5 of the synaptic cycle is breakdown. Inhibit the enzyme, and neurotransmitter persists. The trade-off is that you also alter the metabolism of dietary or other substrates, which is where the clinical risks come in.