Elsevier

Biological Psychiatry

Volume 73, Issue 12, 15 June 2013, Pages 1156-1163
Biological Psychiatry

Review
Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review

https://doi.org/10.1016/j.biopsych.2012.09.031Get rights and content

The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine’s pharmacokinetic properties and an emerging literature that characterizes scopolamine’s effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.

Section snippets

Muscarinic Cholinergic Antagonists in the Treatment of Mood Disorders

Interest in the muscarinic cholinergic system in mood disorders stemmed initially from evidence suggesting that hypersensitivity of the cholinergic system plays a role in the pathophysiology of depression (6). Researchers showed that increasing cholinergic activity using the anticholinesterase inhibitor, physostigmine, provided a challenge uniquely capable both of exacerbating depressive symptoms in currently depressed subjects with major depressive disorder (MDD) and inducing depressive

Pilot Dose-Finding Study Suggests Rapid Antidepressant Response to Scopolamine

In a pilot study designed to evaluate the role of the muscarinic system in the cognitive symptoms associated with depression, Furey and Drevets (31) observed a rapid and robust antidepressant response to scopolamine. We specifically aimed to investigate whether the impairments of selective attention manifest in depressed subjects would improve under antimuscarinic challenge. Muscarinic cholinergic mechanisms facilitate the processing of sensory information and play a major role in selective

Randomized Controlled Trial Confirms Rapid Antidepressant Response to Scopolamine

In a double-blind, placebo-controlled, crossover clinical trial (n = 18), depressed subjects with MDD (n = 9) or BD (n = 9) underwent multiple sessions in which they received 15-minute IV infusions of placebo (P) or scopolamine (S) (4.0 μg/kg) (31). Following a single-blind placebo lead-in, participants entered either a P/S sequence or a S/P sequence, where P was a series of three placebo sessions and S was a series of three scopolamine sessions. The sessions were separated by 3 to 5 days.

Replication in Independent Sample

These findings were replicated in an independent sample limited to depressed subjects with recurrent MDD (43). Twenty-three depressed subjects were randomized into the study, of whom 22 were included in the analysis (one dropped out before receiving scopolamine). Using the double-blind, placebo-controlled, crossover design described above, subjects were randomized into either a P/S (n = 11) or S/P (n = 11) sequence. Upon completion of the first block, the group receiving scopolamine first (S/P)

Sex Effects in the Response to Scopolamine

In a third study, we assessed sex differences in antidepressant response to scopolamine (44). A total of 52 (male [n = 21] and female [n = 31]) outpatients meeting criteria for recurrent MDD or BD participated using the same experimental design. The sample included the 18 subjects from our initial study, the 22 subjects from the replication study, and 12 newly studied subjects. The treatment group×block interaction was significant in male subjects (p = .043) and female subjects (p<.001)

Adverse and Side Effects

Compared with placebo, scopolamine administration resulted in higher rates of drowsiness, blurred vision, dry mouth, and light-headedness, but these effects were sufficiently transient (resolving within 2 to 4 hours) and well tolerated that no subject dropped out due to a side effect. No medically serious adverse event was encountered; in particular, no subject developed delirium, psychosis, overt confusion, clinically significant cardiovascular effects, or treatment-emergent suicidal ideation.

Timing of Onset of Scopolamine’s Antidepressant Effects

Although we established that scopolamine’s antidepressant action was evident by 3 days after administration, no ratings were obtained between the initial infusion and the first follow-up evaluation (days 3–5). Nevertheless, those participants who observed an improvement in their depression severity generally reported relief from their depressive symptoms on the first morning after scopolamine infusion (i.e., within 24 hours of drug exposure). In contrast, no improvement in mood was evident

Effect Size of the Antidepressant Response

The Cohen’s d values for the within-group comparisons of scopolamine versus placebo for blocks 1 and 2 were 2.2 and 3.4 in our first study and 1.2 and 1.7 in our replication study, respectively. These effect sizes compared favorably with those typically observed in antidepressant treatment studies, which ranged from .5 to 1.1 in moderately and severely depressed cases, respectively (49) (the participants in our studies manifested depression severity in the moderate-to-severe range).

Most of the

Duration of Antidepressant Effect: Potential Benefits of Repeated Administration

The antidepressant response persisted beyond the final scopolamine administration by at least several weeks. In individuals who received scopolamine during block 1, the improvement seen during drug administration persisted, as they received placebo during block 2, indicating the antidepressant effects persisted at least 10 to 14 days after the final scopolamine administration 31, 43. This carryover effect was confirmed by demonstrating that depression ratings did not differ between the S/P and

Preliminary Observations Using Scopolamine in Treatment-Resistant Depression

Within the study samples described above, 11 participants met criteria for treatment-resistant depression (Supplement 1). Preliminary data suggest that previous nonresponse to conventional antidepressants may not predict nonresponse to scopolamine. While confirmation in a larger sample of treatment-resistant subjects is critical, these observations are compatible with pharmacological and gene expression data indicating that the therapeutic mechanism of scopolamine differs from that of SSRIs.

Previous Literature Using Other Antimuscarinics in Depression

Of treatments reported to produce antidepressant responses within 1 week, namely electroconvulsive therapy (ECT), high-dose tricyclic antidepressant administration, total sleep deprivation, and ketamine, both ECT and high-dose tricyclic antidepressants are associated with potent antimuscarinic effects. Electroconvulsive therapy is routinely preceded by administration of the antimuscarinic agent, atropine, to reduce salivation and stabilize autonomic responses. Whether atropine contributes to

Possible Mechanisms of Action Underlying Scopolamine’s Antidepressant Effect

Although scopolamine’s antidepressant efficacy appears consistent with the hypothesis that hypersensitivity of the cholinergic system plays a central role in the pathophysiology of mood disorders (6), the latency of the antidepressant response and its persistence well after scopolamine’s clearance from plasma (elimination half-life = 2–4 hours) suggests a mechanism beyond the direct pharmacological actions on muscarinic receptors. The delayed onset and persistence of response until well beyond

Limitations of the Extant Data

The antidepressant efficacy of scopolamine (4.0 μg/kg IV) awaits replication by an independent laboratory. The generalizability of our findings is limited by the relatively small sample size studied to date (n = 52), the inclusion of both unipolar and bipolar depressives, and the exclusion of cigarette smokers and individuals under age 18 or over age 55. Our studies also were limited to outpatients and included a disproportionately high number of subjects who were naïve to antidepressant

Conclusions

The studies reviewed here provide evidence that scopolamine (4.0 μg/kg IV) exerts rapid and robust antidepressant effects. Scopolamine was well tolerated at this dose, particularly since it was pulsed at semiweekly intervals so that the problematical antimuscarinic effects associated with daily use (e.g., constipation, urinary retention) were rare. Future studies are needed to independently replicate these findings and to examine whether a comparable antidepressant response can be achieved when

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