ReviewAntidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review
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
References (75)
- et al.
Antidepressant effects of ketamine in depressed patients
Biol Psychiatry
(2000) - et al.
Therapeutic use of sleep deprivation in depression
Sleep Med Rev
(2002) - et al.
Sleep deprivation accelerates the response to nortriptyline
Prog Neuropsychopharmacol Biol Psychiatry
(1993) - et al.
Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder
Biol Psychiatry
(2009) - et al.
A cholinergic-adrenergic hypothesis of mania and depression
Lancet
(1972) - et al.
Retroactive amnesia induced in chicks by the proline analog L-baikiain, without EEG seizures or depression
Physiol Behav
(1978) - et al.
Behavioral, physiological, and neuroendocrine responses to arecoline in normal twins and "well state" bipolar patients
Psychiatry Res
(1983) Pathophysiology of "cholinoceptor supersensitivity" in affective disorders
Biol Psychiatry
(1986)- et al.
Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: Sex differences between major depressives and matched control subjects
Psychiatry Res
(1999) - et al.
Muscarinic supersensitivity: A possible model for the sleep disturbance of primary depression?
Psychiatry Res
(1979)