Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Abstract

Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 mg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group  block interaction (F ¼ 21.0, po0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F ¼ 8.4, p ¼ 0.006). The treatment group  block interaction was also significant in males (F ¼ 3.8, p ¼ 0.043) and females (F ¼ 35.6, po0.001) separately. A block  gender interaction (F ¼ 7.4, p ¼ 0.009) indicated that the response magnitude was larger in women. The treatment  block interaction was significant for the HAM-A across gender (F ¼ 12.0, po0.001), and was significant for females (F ¼ 24.9, po0.001) but not for males (F ¼ 1.3, p ¼ 0.30). When comparing the baseline block to study end, the block  gender interaction (F ¼ 12.6, p ¼ 0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.

The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing

“…Of note, however, a compound with a melatonin agonist action has shown some promise in clinical studies (Green, 2011;Sansone and Sansone, 2011). Some investigators have reported an AD-like effect of scopolamine in humans (Furey and Drevets, 2006;Drevets and Furey, 2010;Furey et al, 2010), although other articles have reported negative effects (Howland, 2009). In addition, the positive studies used an atypical treatment design, with scopolamine being given intravenously over 3 consecutive days (Furey and Drevets, 2006;Drevets and Furey, 2010;Furey et al, 2010).…”

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

“…While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6)(7)(8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9)(10)(11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12)(13)(14)(15)(16)(17)(18)(19).…”

Possible directions for the discovery of new antidepressant

“…So, for example, the combination of scopolamine (which has recently been shown to have antidepressant activity and presumably works via muscarinic receptor blockade 28 ) with exercise (which may act via serotonergic and opioid pathways) may target 3 different neurotransmitter systems. This would presumably be preferable to combining a selective serotonin reuptake inhibitor (SSRI) with exercise, which also may have an action on serotonin.…”