Scopolamine and Depression: A Role for Muscarinic Antagonism?

Abstract

Depressive disorders have, for a sizeable extent, proven resilient to pharmacotherapy. Established drugs such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs) often provide inadequate symptom relief and sometimes fail altogether. Recently, interest in antidepressant effects of scopolamine, a non-selective muscarinic acetylcholine receptor (mAChR) antagonist, has arisen. Initial evidence suggests that scopolamine provides relatively rapid and long-lasting symptom alleviation for unipolar and bipolar depressed patients. At the same time, side effects of medical dosages appear mild and transient in nature. The aim of the present review is to tentatively discuss the antidepressant potential of scopolamine and to outline putative neurobiological pathways. Clearly, mAChR antagonism provides an intriguing novel therapeutical approach for treating depressive disorders.

Antimuscarinic Use in Females With Overactive Bladder Syndrome Increases the Risk of Depressive Disorder: A 3‐Year Follow‐up Study

“…Nevertheless, several studies reported an opposite view on this issue . They found that a nonselective antimuscarinic (scopolamine) may contribute to a short‐term antidepressant response because the M 2 muscarinic receptor was supposed to be associated with depressive disorder …”

Circuits Regulating Pleasure and Happiness in Bipolar Disorder

“…Direct evidence for an anticholinergic drug-induced switch to (hypo)mania is missing, but anticholinergic drug-induced antidepressant effects are well-known (Hasselmann, 2014; Van Enkhuizen et al, 2015). Moreover, many findings in humans and animal studies indicate an association between cholinergic hyperactivity and bipolar depression (Van Enkhuizen et al, 2015).…”

Criticisms of drugs in early development for the treatment of depression: what can be improved?

“…Interestingly, NMDA antagonists (e.g., ketamine) may also promote neuroplasticity by modulating neurotrophic pathways (e.g., brain-derived neurotrophic factor [BDNF]) or mammalian target of rapamycin expression, leading to neuronal recovery and enhanced resilience [48]. A recent study [49] has investigated the effect of antidepressants on the response to stress.…”

“…MDD is also characterized by an increase in central cholinergic activity relative to noradrenergic tone; muscarinic acetylcholine receptor (mAChR) antagonists may also decrease glutamatergic excitotoxicity by off-target effects on NMDA receptors [48]. Scopolamine, a mAChR antagonist, enhances neuropeptide Y (NPY) levels in the hippocampus by upregulating NPY receptor mRNA expression [52].…”

“…Unwanted anticholinergic side effects including dry mouth, blurred vision and dizziness were almost two times higher than in the placebo group. Moreover, the fact that reduction of brain mAChR is associated with many severe psychiatric conditions such as Alzheimer's dementia, Parkinson's disease and schizophrenia is also a concern [48].…”