Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man

Rationale: The time-course of the pupillary light reflex response is determined by the successive activation of the parasympathetic and sympathetic innervations of the iris, the latency and the amplitude reflecting parasympathetic and the recovery time mainly sympathetic activity. Objective: To compare the effects of single doses of three antidepressants (venlafaxine: serotonin/noradrenaline reuptake inhibitor, paroxetine: selective serotonin reuptake inhibitor, and desipramine: tricyclic antidepressant) on resting pupil diameter and the pupillary light reflex response. Methods: Fifteen healthy male volunteers participated in five weekly sessions, each of which was associated with one treatment (venlafaxine 75 mg or 150 mg, paroxetine 20 mg, desipramine 100 mg, or placebo) according to a double-blind, double-dummy, balanced, cross-over design. An infrared binocular television pupillometer was used for the recording of the resting pupil diameter and the pupillary light reflex in darkness, in previously dark-adapted eyes. Resting pupil diameter in darkness was recorded before and after treatment. The pupillary light reflex was elicited after treatment, with six light flashes (green, 565 nm peak wavelength) of 200 ms duration and of incremental illuminance (measured in the plane of the cornea): 3.0 × 10–3, 8.5 × 10–3, 2.5 × 10–2, 7.0 × 10–2, 0.18, 0.43 mW cm−2. The parameters studied were: latency, amplitude and 75% recovery time. Results: Analyses of variance followed by post hoc tests (least significant difference test or Dunnett’s test; P < 0.05) revealed that both doses of venlafaxine produced a significant increase in resting pupil diameter, decrease in amplitude and shortening of the 75% recovery time of the light reflex response; venlafaxine 150 mg prolonged the latency, while the other treatments had no significant effects. Conclusions: The increase in resting pupil diameter could be indicative of parasympathetic inhibition and/or sympathetic activation. The shortening of the recovery time of the light reflex response is consistent with sympathetic potentiation resulting from noradrenaline uptake blockade in the iris. The prolongation of the latency and decrease of the amplitude of the light reflex response are indicative of a parasympatholytic effect of venlafaxine. However, as venlafaxine has negligible affinity for muscarinic cholinoceptors, this effect cannot be attributed to the blockade of cholinoceptors in the iris. A possible explanation for this finding is that it reflects a central rather than a peripheral effect of the drug: the blockade of noradrenaline uptake in the brain could lead to the potentiation of the noradrenergic inhibition of central parasympathetic (Edinger-Westphal) neurones. These results demonstrate the ability of therapeutically relevant single doses of venlafaxine to potentiate noradrenergic responses in man, consistent with the blockade of noradrenaline uptake.