Ketamine infusions for depression – augmenting the results with Scopolamine infusions | Northern Virginia Ketamine Infusion Center Fairfax, Virginia

NOVA Health Recovery Ketamine Infusion Center Fairfax, Virginia

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                     Scopolamine and Ketamine as Rapid Acting Antidepressants 

Approximately one-third of patients with Major depressive disorder (MDD) fail to respond to first-line antidepressants. There is a need for rapid acting antidepressants. Two different classes of rapid acting antidepressants include ketamine, a non-competitive antagonist at the glutamate N-methyl-D-aspartate (NMDA) receptor and scopolamine, a non-selective acetylcholine muscarinic receptor antagonist. Scopolamine has demonstrated rapid antidepressant effects in MDD and bipolar patients

Scopolamine is derived from Brugmansia, a flowering plant in the family of Solanaceae. The common name is Angel’s Trumpets. These plants are rich in alkaloids, in particular scopolamine, which in excess can cause amnesia, delirium, and anticholinergic syndrome. 

By Paul K from Sydney – Brugmansia bicolor, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=17868322 

The pursuit of rapid acting antidepressant research led to research of scopolamine infusions and intramuscular scopolamine injections for depression: 

1991: Gillin administered intramuscular scopolamine for depression, with resulting improvement of depression but with a statistical non-significant effect. 

2006: Drevets and Furey did several randomized double-blind trials demonstrating that depressed and bipolar patients had rapid antidepressant effects based on improvements in the MADRS score (Montgomery-Asberg Depression Rating Scale) by three days after the infusion. The effect was such that 2/3 of patients had marked improvement in depression with half having remission of depression. The treatment effect lasted over two weeks. 

Key Papers regarding scopolamine are listed below: 

Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010;67:432–8. 

Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121–9. 

Furey ML, Khanna A, Hoffman EM, Drevets WC. Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology. 2010;35:2479–88

Furey ML, Nugent AC, Speer AM, et al. Baseline mood-state measures as predictors of antidepressant response to scopolamine. Psychiatry Res. 2012;196:62–7. 

Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA Jr. Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. JAMA Psychiatry. 2013;70:280–90

Khajavi D, Farokhnia M, Modabbernia A, et al. Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73:1428–33. 

Ketamine has a robust antidepressant effect, especially when added to existing antidepressant treatment. One study augmenting escitalopram (Celexa) with a single ketamine infusion demonstrated a 92% response rate (vs 51% without ketamine) and a depression remission rate of 76% (versus 14% without ketamine). Scopolamine affects similar mechanisms of action as does ketamine in reducing depression and anxiety. 

The study by Furey and Drevets in 2006 demonstrated that three scopolamine infusions 3-5 days apart at 4mcg/kg IV over twenty minutes demonstrated robust antidepressant and antianxiety effects of scopolamine IV.  

How does this work? 

Tricyclic antidepressants do have antimuscarinic effects but also have a lot of side effects. Part of their efficacy in depression may be the anticholinergic effects that they have. Amitriptyline has a large occupancy of serotonergic receptor sites at traditional dosing and may explain why it is more efficacious than SSRI’s. 

The dosing administration of scopolamine was determined by EEG effects in healthy volunteers. In this study, 10 volunteers were modeled with 0.5 mg IV scopolamine hydrobromide over 10 minutes. IM availability was only 57%. The 0.5 mg IV dose over 15 minutes represented the ideal dosing based on EEG outcomes. 

The 2006 Furey and Drevets study utilized 15-minute infusions of scopolamine hydrobromide every 3-5 days for three sessions at 2.0, 3.0, and 4 mcg/kg dosing.  The best results were at 4 mcg/kg dosing over 15 minutes resulting in a 50% decrease in the MADRS depression scoring by the fourth infusion. Two sets of study designs were done, and they demonstrated rapid improvement of depression and thus suggested hyperactivity of the cholinergic system as the cause of depression in some cases. There was no real effect on cognition by the infusions in terms of delirium or memory-related issues. The effect size of the infusions was larger than traditional antidepressant studies and the scopolamine infusions results in prolonged effects. Further studies reproduced the antidepressant effect of scopolamine infusions. 

Because there is a delay before the onset of the antidepressant effect of scopolamine, it is felt there is gene transcription rather than a direct effect on the muscarinic receptors that makes it work. There are also areas in the brain that the NMDA receptor expression is regulated by muscarinic receptor stimulation (I,e, NMDAR types 1A and Type 2A) The efficacy of scopolamine may also be due to its interaction at a specific type of Muscarinic receptor (I.e. M3) as another study did not show glycopyrrolate and biperidin to be antidepressant even though they are anti-muscarinic. 

Recent studies have demonstrated that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. Ketamine and scopolamine both have effects by increasing extracellular glutamate, elevating BDNFactivation mTORC1, and increasing the number of synapses (synaptogenesis) in the prefrontal cortex (PFC). Scopolamine and ketamine both antagonize inhibitory interneurons in the LFC to promote the antidepressant responses. Both NMDA and muscarinic acetylcholine receptor antagonism on the interneurons of the PFC are targets of rapid antidepressant agents. Increased synapse number and function in the PFC in response to ketamine or scopolamine reverses the pathophysiology associated with stress and depression which result in synaptic dysfunction. Changes in gene expression and synaptic plasticity are key features to scopolamine and ketamine’s effect on depression as reviewed in Zarate and Drevets 2013. The basis for the synaptic plasticity also involves mTORC1 activation and the production of proteins such as BDNF, which promotes dendritic spine formation. In depression and stress, there is a destruction of dendritic spines. 

. 

  • Alterations of signaling pathways and neuroplasticity correlate with behavior changes and mood elevation with the use of ketamine and scopolamine. Chronic stress destroys synaptogenesis and dendritic spines
  • The volume and connectivity of the subgenual PFC and cingulate cortex is decreased in depressed individuals and there is a reduction in cell body size as well as a loss of synapses in the dorsolateral PFC. This results in a functional dysconnectivity in the brain of depressed individuals. There is also a dysregulation of genetic functioning as well in genes related to glutamate signaling. 
  • A region of interest in MDD is the hippocampus (HPC), which plays a key role in cognitive functions such as spatial and declarative memory and anxiety, as well as in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. HPC volume is reduced in depressed individuals and antidepressant therapy has been shown to reverse this stress-induced atrophy
  • There is a decreased number and length of apical dendrites in CA3 pyramidal neurons of the HPC and reduced synaptic connectivity in response to chronic stress in models of depression. Chronic stress destroys neural networks in the brain. 
  • Animal models demonstrate reduced length and branching of the apical dendrites in the PFC in response to chronic stress. Also seen are dendritic branching changes and decreased spine density in depression. In Ketamine and scopolamine treatment, pyramidal neurons in the PFC show enhanced number and function of dendritic spines (link
  • The amygdala, a subcortical structure involved in emotional memory formation and retrieval, has primarily been studied for its role in fear conditioning and memory. The amygdala exhibits a dysfunctional activity profile in individuals suffering from depression and anxiety. 
  • Depression should be considered a system-wide disorder, but the PFC is important as it receives and sends substantial projections throughout the brain to both cortical and subcortical regions that have been implicated in depression. 
  • Scopolamine and ketamine work through stimulation of mTORC1 signaling which promotes protein formation and synaptic spine formation. Synaptic spines are depleted in depression and stress. Rapamycin blocks mTORC1 and its use blocks ketamine and scopolamine’s behavioral and synaptic actions. Thus, mTorC1 is critical to the antidepressant actions of ketamine and scopolamine
  • The key event for mTORC1 activation is extracellular glutamate being released in the PFC 
  • Acute NMDA and muscarinic acetycholine (mACH) receptor antagonism are what produces the rapid glutamate burst in the PFC.  
  • Interneurons releasing the inhibitory neurotransmitter γ-aminobutyric acid (GABA) play an important role in mediating glutamate release from pyramidal cells which utilize mostly excitatory glutamate as the neurotransmitter. The interneurons tonically inhibit the glutamate burst. Ketamine and scopolamine turn off this interneuron to allow for the glutamate burst. 
  • Ketamine and scopolamine antagonize specific receptor subtypes on inhibitory interneurons that lead to disinhibition of glutamatergic pyramidal neurons causing a subsequent glutamate burst in the PFC – Ketamine and scopolamine turn off the interneuron so that the synapse can fire its glutamate burst 
  • An infusion of scopolamine increases extracellular glutamate in the striatum 
  • Despite the role of acetylcholine as a critical neuromodulator recent studies show that mACh receptors in the PFC may not have a prominent role in the direct excitation of cortical pyramidal neurons 
  • Evidence indicates that M1-ACh receptors modulate both cortical pyramidal and interneuron activity. Specific interaction by scopolamine with the M1-ACH is what makes it effective. 
  • Glutamate elevation requires low levels of Ketamine (10 mg/kg or less) and scopolamine (25 mcg/kg) 
  • The increased glutamate burst resulting from ketamine and scopolamine in the PFC leads to AMPA receptor activation and inward calcium currents to ultimately produce BDNF (Brain Derived Neurotrophic Factor
  • BDNF is released into the synapse to activate TRkB (tyrosine kinase B) which activates AKT and mTORC1 inside the postsynaptic neuron. 
  • This leads to protein production, increase dendritic spines, increased synaptogenesis and less depression = neuroplasticity 
  • mice lacking M1- or M2-ACh receptor do not show antidepressant responses following scopolamine treatment 
  • Link 2 
  • Does oral scopolamine work for depression? There is research regarding this as well as a double-blind randomized trial that enrolled 20 patients and used scopolamine 0.5 mg with citalopram (20-40 mg) for 6 weeks which showed a 74% reduction in the HAM-D (a depression ranking system) scores with scopolamine and citalopram combination treatment versus the citalopram-only group having a 59% decrease in depression. Likewise, the scopolamine augmentation was faster and seen by day 4. Oral scopolamine also can be added to a beta blocker to help with anxious depression as well. 

Key Points: 

  • Infusions of Scopolamine can be useful in the context of ketamine infusions as a rapid acting antidepressant 
  • Scopolamine results in the production of synapses and neuroplasticity through a similar mechanism that ketamine works. 
  • The infusions of scopolamine are shorter and have no psychomimetic effect and can be used prior to ketamine infusions with excellent effect as they are anti-emetic, anti-anxiety, and antidepressant in nature. 
  • At NOVA Health Recovery Ketamine Infusion Center in Alexandria, Virginia, we treat patients with anxious depression, general anxiety, and bipolar disorder with scopolamine and ketamine infusions to maximize recovery. Contact us today at 703-844-0184 or here
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NOVA Health Recovery is a Ketamine Treatment Center in Fairfax, Virginia (Northern Virginia Ketamine) that specializes in the treatment of depression, anxiety, bipolar disorder, OCD, and chronic pain such as CRPS, cluster headaches, and fibromyalgia using Ketamine therapies, both infusion and home-based ketamine nasal spray and oral tablets. We also offer addiction treatment services with Suboxone, Vivitrol, and Sublocade therapies for opiate addiction as well as alcohol treatment regimens. Contact us at 703-844-0184 or at this link: NOVA Health Recovery Ketamine Infusion Center Near me Ketamine Infusion 

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