Resiliency of monoaminergic systems: the 80% rule and its relevance to drug development

Monoaminergic systems have long been implicated in the pathophysiology and/or the therapeutics of mood disorders. These are old systems on the phylogenic scale, which has allowed their in-depth studies in the rodent brain with the results being extrapolated to humans with striking consistency. Mother Nature has built-in mechanisms in these systems to maintain their homeostasis. Indeed, they exert such important roles in the brain within the animal kingdom, including nonhuman primates and humans, and the maintenance of their normal function plays a crucial role in survival. The level of redundancy appears to be of the order of 80%, meaning that alterations of various parameters controlling the function of these system has to reach an approximate threshold of 80% change before a net change in transmission can occur. This is highly relevant to human therapeutics because it implies that there should not be a linear relationship between interference with a monoaminergic neuronal element, such as reuptake transporter, and a clinical phenomenon. Some examples are given here. In Parkinson’s disease, patients begin to show motor symptoms when there is an approximate loss of 80% of dopamine neurons in the substantia nigra (Agid, et al., 1987). These neurons give rise to the dopaminergic innervation of the striatum, which plays a crucial role in motor function. Consistent with the above-mentioned figure, 80% of striatal dopamine type 2 receptors need to be blocked by antipsychotic medications to lead to extrapyramidal symptoms. In Alzheimer’s disease, approximately 75% of the cholinergic neurons in the basal forebrain are lost when symptoms (Farde et al., 1992) appear (McGeer, et al., 1984). These neurons provide the cholinergic innervation to the cerebral cortex. Acetylcholine is generally not thought of as a monoamine, such as serotonin (5-HT), noradrenaline (NE) or dopamine, but it has a single quaternary amine (a positively charged nitrogen atom with three methyl groups). Approximately, 70–80% of monoamine oxidase (MAO) need to be inhibited before an antidepressant action can occur with inhibitors of this enzyme (Zimmer, 1990). This was determined from MAO-B inhibition and the decrease of 3,4-dihydroxyphenyl-ethylene glycol in the blood to assess MAO-A inhibition. Finally, the minimal effective doses of the serotonin reuptake inhibitors (SRIs) produce an 80% occupancy of 5-HT transporters (5-HTTs) in the human brain, as measured by positron emission tomography (PET; Meyer, et al., 2004). Experimental results in the rodent brain are consistent with the above observations. In the NE system, approximately 90% of NE neurons need to be lesioned before attenuating the effect of the stimulation of the NE pathway on postsynaptic neuron firing in the hippocampus (Curet and de Montigny, 1988). In the 5-HT system, an approximate 80% decrease in tissue 5-HT content leaves extracellular 5-HT levels unaltered in the rat striatum (Kirby, et al., 1995). In the dopamine system, extracellular levels are maintained until 80% of control tissue content is eliminated (Castaneda, et al., 1990). Why is this relevant to current drug development? Because selective 5-HT, NE or dopamine agents can produce an antidepressant action on their own, it is generally accepted that the combination of at least two effects can produce a greater therapeutic effect. This is supported by the effectiveness of augmentation or combination strategies in patients not responding to a selective agent (Blier, 2006). In the case of the dual 5-HT/NE reuptake inhibitors, venlafaxine and duloxetine, biochemical data are consistent in showing their potent action on the 5-HT transporter (Turcotte, et al., 2001; Vincent, et al., 2004; Blier, et al., 2007). With concentration or dose increments, the NE transporters (NETs) are progressively inhibited. Regarding NET inhibition, the main issue is at what dose(s) or concentration(s) are NETs inhibited to an extent that significantly impacts overall NE transmission? In the case of venlafaxine, 75 mg/day produces the above mentioned 80% occupancy of the 5-HTT, which corresponds to its minimal effective dose in depression (Meyer, et al., 2004). Similarly, the minimal Editorial

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