In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are clomipramine and to a lesser extent its dechlorinated analogue imipramine, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives), clomipramine cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of clomipramine, suggesting that its blockade of the α1-adrenergic receptor is strong enough to overcome the stimulatory effects on the α1-adrenergic receptor of its NET inhibition. Serotonergic activity
Clomipramine is a very strong SRI. Its affinity for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were imipramine, amitriptyline, and dosulepin (dothiepin), with Ki values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition, clomipramine has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100–200 mg/day).
Balance
Providing balance, when moving or stationary, is also a central function of the ear. The ear facilitates two types of balance: static balance, which allows a person to feel the effects of gravity, and dynamic balance, which allows a person to sense acceleration. Static balance is provided by two ventricles, the utricle and the saccule. Cells lining the walls of these ventricles contain fine filaments, and the cells are covered with a fine gelatinous layer. Each cell has 50–70 small filaments, and one large filament, the kinocilium. Within the gelatinous layer lie otoliths, tiny formations of calcium carbonate. When a person moves, these otoliths shift position. This shift alters the positions of the filaments, which opens ion channels within the cell membranes, creating depolarisation and an action potential that is transmitted to the brain along the vestibulocochlear nerve.Dynamic balance is provided through the three semicircular canals. These three canals are orthogonal (at right angles) to each other. At the end of each canal is a slight enlargement, known as the ampulla, which contains numerous cells with filaments in a central area called the cupula. The fluid in these canals rotates according to the momentum of the head. When a person changes acceleration, the inertia of the fluid changes. This affects the pressure on the cupula, and results in the opening of ion channels. This causes depolarisation, which is passed as a signal to the brain along the vestibulocochlear nerve. Dynamic balance also helps maintain eye tracking when moving, via the vestibulo–ocular reflex.