Depression, III: Treatments

Antidepressant treatments are currently targeted to synaptic elements that regulate concentrations of serotonin and norepinephrine at the postsynaptic monoamine receptors. Drug development for mood disorders has relied heavily on this focus in the past; so heavily, in fact, that there is little mechanistic diversity among current antidepressant drugs. Recently, however, investigations into the mechanisms of antidepressant actions have focused on downstream intracellular elements that are modulated by chronic, but not acute, antidepressant administration, particularly the intracellular signaling pathways mediating cellular resilience and neuroplasticity. Two of these intracellular signaling pathways (involving the neuroprotective protein bcl-2 and brain-derived neurotrophic factor [BDNF]), altered by both antidepressants and mood stabilizers, are known to be neuroprotective and to mediate neurotrophic events. One pathway first involves signaling by growth factors (especially BDNF) through the intracellular enzymes ERK and RSK followed by CREB activation, leading ultimately to an increase in the transcription of bcl-2 (see Figure). A second pathway involves the activation of the G protein-related enzymes adenylate cyclase and protein kinase A, followed by CREB activation, leading subsequently to an increase in the expression of BDNF, one of the cellular growth factors. We already know that antidepressant treatment increases CREB phosphorylation (i.e., CREB activation) in the brain of rats. Antidepressants and ECT each increase the expression of BDNF. Chronic antidepressant treatment results in neurogenesis (i.e., new neuronal birth) in the hippocampus of rats (and presumably of humans). Lithium and valproate each increase the expression of bcl-2 at least in part through activation of the ERK-MAP intracellular cascade. Lithium is frankly neuroprotective in several animal models of neurodegeneration and actually increases gray matter volumes (possibly through reversal of illness-related atrophy) in patients with bipolar disorder. In addition, enhancement of neurotrophic pathways is apparent by both antidepressant and mood-stabilizing treatments. Thus, a potential novel target for treatment development in mood disorders will be medications with neurotrophic properties, some examples of which are under development currently, including phosphodiesterase (PDE4) inhibitors and AMPA receptor modulators (which increase BDNF expression).