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Scopolamine has been used in multiple forms (patches, tablets, nasal sprays, and IV)  for nausea, sea-sickness, and even depression.  It is a muscarinic acetylcholine receptor antagonist agent.

In 2006, Maura Fury, Ph.D. of the National Institutes of Mental Health treated anxiety and depression with I.V. Scopolamine with rapid results.Antidepressant-Efficacy-of-the-Antimuscarinic-drug-scopolamineDownload

In the trial they evaluated the role of the cholinergic
system in cognitive symptoms of depression and unexpectedly
observed rapid reductions in depression severity
following the administration of the antimuscarinic drug
scopolamine hydrobromide (4 μg/kg intravenously) compared
with placebo (P=.002) In this trial, 9 patients with treatment resistant depression and anxiety received infusions and had significant repsonses,

The cholinergic system is one of the neurotransmitter systems implicated in the pathophysiologic mechanism of mood disorders. Increasing cholinergic activity using physostigmine (an anticholinesterase inhibitor) provides a challenge uniquely capable of exacerbating depressive symptom in currently depressed patients with MDD and inducing depressive symptoms
in currently manic patients with Bipolar disorder.

The cholinergic system also is implicated in depression by evidence showing that polysomnographic responses to muscarinic receptor agonists and neuroendocrine and pupillary responses to cholinomimetics are exaggerated in depressed patients and that some muscarinic receptor gene polymorphisms are associated with an elevated incidence of depression. Elevated cholinergic function thus was hypothesized to participate in
the pathogenesis of mood disorders.Associations-of-acetylcholinesterase-activity-with-depression-and-anxiety-symptoms-among-adolescents-growing-up-near-pesticide-spray-sites-ScienceDirectDownload

In fact it has been noted that children growing up near sites of cholinergic pesticides have an increase rate of depression as the article above discusses.

A follow up study using Scopolamine was accomplished with 23 patinets and demonstrated rapid antidepressant and anti-anxiety effects with IV Scopolamine:Replication-of-Scopolamine’s-Antidepressant-Efficacy-in-Major-Depressive-Disorder-a-Randomized-Placebo-Controlled-Clinical-TrialDownload

In the study, 23 subjects were treated. Here are the results:

Results—Following the initial block the group receiving scopolamine first (S/P) showed a 32 percent reduction in MADRS scores (p<0.001) which exceeded the corresponding change of 6.5 percent under placebo (P/S) (p=0.009), confirming the a priori hypothesis. Improvement was
significant at the first evaluation that followed scopolamine administration (p=0.011). In block 2 the P/S group showed a 53 percent reduction in MADRS scores (p=0.001) following scopolamine versus placebo, while the reduction seen in S/P subjects who received scopolamine during block 1
persisted as they received placebo during block 2. Scopolamine induced drowsiness, blurred vision, dry mouth, light-headedness and reduced blood pressure, which were sufficiently well tolerated that no subject dropped out due to side effects.

The trial included Bipolar disorder and depressed patients and used a protocol of 4 mcg/kg over 15 minutes protocol. No patients dropped out.Patient improved within 3-5 days of the infusion. The improvement in the study lasted well over two weeks.

Moreover, the delay in the onset of the antidepressant response until well after the resolution of anticholinergic side effects appears compatible with an effect on transcription of “late response” genes or synaptic plasticity, rather than a direct action on muscarinic receptors.

One effect scopolamine shares with other somatic antidepressant treatments involves the modulation of N-methyl-D-aspartate receptor (NMDAR) function. Blocking muscarinic receptors via scopolamine administration reduces mRNA concentrations for NMDAR types
1A and 2A in the rat brain in vivo and protects hippocampal neurons from glutamatemediated neurotoxicity in vitro . Chronic administration of antidepressant drugs from various classes and repeated electroconvulsive shock reduce cortical NMDAR function ), and treatments associated with a rapid onset of antidepressant effects either exert direct
NMDAR antagonist effects (ketamine) or induce NMDR internalization (sleepdeprivation)). Taken together with evidence that abnormal glutamatergic transmission is involved in the pathophysiology of depression, these data suggest the hypothesis that scopolamine’s effect on NMDAR function plays a role in its antidepressant action.

Another possible mechanism that merits consideration is scopolamine’s paradoxical effect of enhancing parasympathetic autonomic outflow when administered in the low dose range that encompasses the doses used in this study.

While it remains unclear whether the effect of scopolamine (at 4.0
ug/kg iv) on parasympathetic activity plays any role in the antidepressant response, it is noteworthy that the pathophysiology of depression is associated with a reduction in the parasympathetic-to-sympathetic balance. Decreasing parasympathetic tone improves depression.

Side effects during the infusion:

  • Blurry vision
  • Dry Mouth
  • Lowered Blood pressure
  • Nausea
  • Some confusion for two hours may occur but no delirium

Small but statistically significant antidepressant effects were observed the day following the administration of scopolamine 0.4 mg i.m., which would have a bioavailability similar to that of about 2 ug/kg i.v.

In 2012, researchers in Iran led by Danial Khajavi, M.D.,
compared 40 patients with MDD randomly assigned to either
oral scopolamine plus citalopram or citalopram plus placebo.
Augmentation with scopolamine was significantly more
effective than placebo, with 65 percent of patients receiving
scopolamine showing higher rates of response at week 4 and
remission at week 6 than patients receiving placebo.

Oral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study:

Danial Khajavi, MD; Mehdi Farokhnia, MD; Amirhossein Modabbernia, MD; Mandana Ashrafi, MD; Seyed-Hesammedin Abbasi, MD; Mina Tabrizi, MD; and Shahin Akhondzadeh, PhD

Objective:To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram.

Method:In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18–55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n=20) or placebo (n=20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥50% decrease in HDRS score; remission, as HDRS score ≤7.

Results: Augmentation with scopolamine was significantly more effective than placebo (F1,38=5.831, P=.021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P=.027, P=.004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group.

Conclusions: Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder.

General information regarding Treatment resistant Depression :Treatment-of-MDD-Treatment-ResistantDownload

Carlos Zarate also did a review on Scopolamine for depression therapy:Antidepressant-Efficacy-of-the-Antimuscarinic-drug-scopolamine-1Download

They 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 scopolamineinduced
changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.

Interest in the muscarinic cholinergic system in mood disorders stemmed initially from evidence suggesting that hyper-sensitivity of the cholinergic system plays a role in the pathophysiology of depression. 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 symptoms and reversing manic symptoms in manic subjects with bipolar disorder (BD) . The neuroendocrine and pupillary responses to physostigmine) also were abnormally increased in depressed individuals. The muscarinic cholinergic receptor system specifically was implicated by
evidence showing that polysomnographic responses to selective muscarinic agonists were exaggerated in depressed versus control samples, suggesting that muscarinic receptor supersensitivity exists in depressed individuals

The muscarinic receptor system, variation in the type 2 muscarinic (M2) cholinergic receptor gene (CHRM2) was associated with an elevated incidence or severity of unipolar depression and with abnormal
reductions in M2 receptor binding in bipolar depression.

Some abnormalities in cholinergic receptor function in mood disorders showed sex effects. For example, sex differences manifested in the baseline and cholinergically stimulated plasma hormone measures that differed between depressed and control samples, suggesting that heightened cholinergic sensitivity exists preferentially in premenopausal females with
MDD . Comings et al. found that genetic variation in CHRM2 gene (A/T
1890) was associated with MDD specifically in female subjects. In rodents, estrogen enhanced choline acetyltransferase activity and acetylcholine release , and M2 receptor stimulation mediated the estrogen-induced enhancement of N-methyl-D-aspartate receptor (NMDAR) function (24). These observations complement evidence reviewed
below that women are more likely than men to show an antidepressant response to scopolamine.

Putative animal models of depression also supported a role for elevated muscarinic cholinergic function. Flinders Sensitive Line rats, bred selectively for increased sensitivity of muscarinic receptors, showed putative behavioral analogs of depression such as lethargy,
reductions in self-stimulation, and increased behavioral despair in the forced swim test in response to agents that increase central cholinergic function . Moreover, antimuscarinic agents (including scopolamine) produced antidepressant-like effects by reducing the
behavioral despair induced via this test.

The timing of the antidepresant effects was after the third day of the infusion.


Scopolamine conceivably may alter synaptic plasticity or gene expression through a variety of direct or indirect mechanisms. In addition to producing antagonist effects at muscarinic receptors, scopolamine acutely increases acetylcholine release (via inhibi tion of releasecontrolling
muscarinic autoreceptors) and thereby increases cholinergic effects on nicotinic receptor systems to an extent that conceivably may contribute to antidepressant or antiinflammatory
effects. In addition, changes in muscarinic tone specifically have been
shown to affect other depression relevant systems, including the central dopamine serotonin, and neuropeptide Y transmitter systems and the innate immune system. Thus,
the antidepressant mechanism(s) of scopolamine potentially may involve a variety of systems.
One effect of scopolamine that is shared by some other somatic antidepressant treatments involves modulation of NMDAR function. The NMDAR gene expression is enhanced by muscarinic receptor stimulation in at least some brain structures , and thus, the elevated
muscarinic receptor sensitivity identified in mood disorders may contribute to an elevation in NMDAR transmission. Blocking muscarinic receptors via scopolamine administration reduces messenger RNA concentrations for NMDAR types 1A and 2A in the rat brain in vivo and protects hippocampal neurons from glutamate-mediated neurotoxicity
in vitro . Chronic administration of TCAs and repeated electroconvulsive shock reduce cortical NMDAR function, and treatments associated with a rapid onset of antidepressant effects exert direct NMDAR antagonist effects (ketamine) or induce NMDAR internalization (sleep deprivation) . Given evidence that abnormal glutamatergic transmission is involved in the pathophysiology of depression, these datasuggest that scopolamine’s effect on reducing NMDAR gene expression may play a role in
its antidepressant action.The-Role-of-the-Medial-Habenula-Cholinergic-System-in-Addiction-and-Emotion-Associated-BehaviorsDownloadScopolamine-Produces-Larger-Antidepressant-and-Antianxiety-Effects-in-Women-Than-in-MenDownload

In the above article, women have a more robust response to scopolamine than men do.

When comparing the baseline block to study end, the blockgender interaction (F¼12.6, p¼0.001) 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 bottom line: Scopolamine offers another route of treatment for depression and anxiety. We offer IV Scopolamine infusions at NOVA Health as well as scopolamine /Beta Blocker oral treatment dor dperession add on therapy and anxiety.

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