Dissociative experiences among Kenyan youth in the Nairobi metropolitan area: Associations with psychosis risk symptoms.

Major depressive disorder is a highly prevalent psychiatric disorder affecting 3.8% of the population globally. Antidepressants of various classes are the first-line treatment. Commonly used antidepressants are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin modulators and atypical antidepressants. SSRIs like sertraline (SER) and escitalopram (ESC) inhibit the presynaptic reuptake of serotonin specifically, whereas SNRIs like duloxetine (DUL) inhibit reuptake of both norepinephrine and serotonin, resulting in their antidepressant effects. Tricyclic antidepressants (TCAs), such as amitriptyline (AT), were one of the first-generation drugs and brought about their therapeutic effect by inhibiting monoamine reuptake. However, they fell out of favour because of their adverse side effects due to their action on the cholinergic and histaminergic systems. Bupropion (BUP) is considered an atypical antidepressant because it shows dual norepinephrine-dopamine reuptake inhibition without the commonly observed side effects seen with SSRIs and SNRIs. Ketamine (KET) is a new-age rapid-acting antidepressant that was recently FDA-approved. Its mechanisms of action are still being delineated, although it is primarily an -methyl--aspartate (NMDA) receptor antagonist. Aside from these conventional targets, antidepressants also target several other proteins and engage a wide array of downstream signalling cascades to bring about their effects. This provides innumerable possible therapeutic targets that could be further investigated for clinical efficacy. One such target is the cholinergic system, particularly acetylcholinesterase (AChE). AChE helps regulate the levels of acetylcholine (ACh), which is essential for maintaining euthymia, as explained in the cholinergic-adrenergic hypothesis put forward by Janowsky et al. Following this, several studies showed that exogenous administration of acetylcholinesterase inhibitors (AChEIs) induces depression in human subjects as well as rodent models. However, there is only limited investigation into whether antidepressants can affect AChE activity. Chronic administration of the SSRI fluoxetine increased hippocampal AChE activity in mice, along with an antidepressant-like effect in the tail suspension test. Similarly, chronic reboxetine (a selective noradrenaline [NA] reuptake inhibitor) administration in depressed rats restored the AChE activity in the hippocampus and the frontal cortex. However, whether this is a direct or downstream effect is yet to be clarified. Müller et al. found that fluoxetine, SER and AT inhibited AChE and butyrylcholinesterase (BuChE) activities in human serum and erythrocyte membranes at micromolar concentrations. However, these studies are mostly restricted to the effects on peripheral AChE activity.