A8 Major depression (monoamines, altered plasticity)

Topic

Monoaminergic neurotransmission—such as that involving serotonin—normally supports mood regulation. In major depression, monoaminergic neurotransmission exhibits a functional deficit that impairs the brain's ability to regulate mood normally. This deficit is precisely what antidepressants aim to correct directly; however, as will be discussed later, correcting monoaminergic neurotransmission alone is insufficient to produce immediate clinical improvement.

In major depression, this monoaminergic neurotransmission deficit co-occurs with a second alteration: chronic stress keeps the hypothalamic-pituitary-adrenal (HPA) axis in a state of sustained hyperactivity, and this sustained HPA axis hyperactivity raises cortisol levels in the body.

Elevated cortisol suppresses the production of a brain-derived neurotrophic factor that the hippocampus requires for two distinct processes: first, this factor is necessary for hippocampal neurogenesis—that is, the generation of new neurons within the hippocampus; second, the same factor is required to maintain the effective learning rate associated with synaptic plasticity—specifically, the speed at which synaptic connections adjust in response to experience. The greater the suppression of this brain-derived neurotrophic factor, the lower both hippocampal neurogenesis and the effective learning rate of synaptic plasticity become.

This combined reduction in hippocampal neurogenesis and the effective learning rate of synaptic plasticity ultimately reduces the gain of the reward circuit—that is, the circuit's responsiveness to pleasurable stimuli. The lower the reward circuit's gain, the more pronounced the person's anhedonia—the inability to experience pleasure that characterizes major depression. This explains why the therapeutic response to antidepressants follows a characteristic latency curve rather than appearing immediately: although antidepressants relatively quickly correct the deficit in monoaminergic neurotransmission, the clinical effect only manifests after the effective learning rate associated with synaptic plasticity and hippocampal neurogenesis is also restored—processes both dependent on the same brain-derived neurotrophic factor that elevated cortisol had suppressed. Restoring monoaminergic neurotransmission alone, without also restoring this plasticity, is insufficient to reverse the reduced gain of the reward circuit or the resulting anhedonia.

ID:4290