sign in sign up
<<
Home , Scopolamine

Isr J Psychiatry - Vol. 58 - No 1 (2021) as a Potential Treatment Option in Major Depressive Disorder - A Literature Review

Dusan Kolar, MD, MSc, PhD, FRCPC

Department of Psychiatry, Queen’s University, Mood Disorders Research and Treatment Service, Kingston, Ontario, Canada

as selective serotonin reuptake inhibitors (SSRIs) and Abstract serotonin norepinephrine reuptake inhibitors (SNRIs), are currently used as first-line pharmacological treat- Introduction: Slow onset response to ments for major depressive disorder (MDD). Despite the and partial response is a common problem in mood availability of a comprehensive list of antidepressants, disorders psychiatry. There is an ongoing need for rapid- approximately 50% of the patients on an acting antidepressants, particularly after introducing regimen experience non-response to treatment (3, 4). in the treatment of depression. Scopolamine Furthermore, the mood elevating effects of antidepres- may have promise as an antidepressant. sant medication is often delayed (5). It is recommended Methods: The author conducted a literature review to that the patient be treated for at least six weeks with identify available treatment trials of scopolamine in the adequate dosage of the given antidepressant before unipolar and bipolar depression in PubMed, the Cochrane considering making changes to the treatment (5). Partial database, Ovid Medline and Google Scholar. to no response to treatment with antidepressants and delayed onset of action indicate that there is a need for Results: There have been eight treatment trials of the development of novel and improved medications scopolamine in MDD and bipolar depression. Seven for the treatment of depression. Many studies in recent studies confirmed significant antidepressant effects years have recognised two different classes of with of scopolamine used as monotherapy and as an rapid and robust antidepressant effects. These drugs augmentation. There was only one negative trial where are ketamine, which is a non-competitive glutamate scopolamine had only limited antidepressant effects, and NMDA receptor antagonist, and scopolamine, which this trial included patients with most severe depression. is a non-selective muscarinic receptor Conclusions: Most of available treatment trials of antagonist (6, 7). Janowsky and colleagues (8) were the scopolamine have confirmed rapid onset of antidepressant first to propose the -adrenergic hypothesis of effects in unipolar and bipolar depression. Scopolamine mania and depression. They suggested that mania is the may be used as an alternative treatment option to result of high adrenergic activity, whereas depression is ketamine in patients with treatment resistant depression. a state characterized by high cholinergic activity when compared with adrenergic activity. An evidence that increased cholinergic activity can induce depression came from reports which indicated that administration of cholinergic and acetyl- inhibitors lead to severe depression (9). Introduction Scopolamine is a tertiary amine plant which Major depressive disorder is a common disorder affecting acts as a muscarinic cholinergic receptor antagonist more than 264 million people worldwide (1). The World (10). A decrease in cholinergic activity via scopolamine Health Organization classifies depression as the leading administration may produce excitement and euphoriant cause of disability and as a significant contributor to effects in higher doses (10). Scopolamine’s mechanism of the global burden of disease (2). Antidepressants, such action is thought to stem from the convergent activation

Address for Correspondence: Dr. Dusan Kolar, Associate Professor, Department of Psychiatry, Queen’s University, Mood Disorders Research and Treatment Service, 752 King Street West, K7L4X3, Kingston, Ontario, Canada [email protected]

48 Dusan Kolar of synaptic plasticity and synaptogenesis, with effects on Authors reported that the depressed group had a small glutamatergic activity occurring via antagonistic effects but statistically significant antidepressant response as a at muscarinic receptors (11). result of scopolamine administration. After the second In the last few decades, a number of studies have been dose of scopolamine, the group of depressed patients conducted in order to test scopolamine’s showed improvements in depression when compared effects and how it impacts mood. In the era of searching with the baseline as measured by the Profile of Mood for rapid onset of treatment action in major depressive States questionnaire (mean(SD), 20.9± 13.7 units vs 24.5 disorder it is worth exploring the potential therapeutic ±16, p < 0.04, t = 2.40, df = 10) (13). use of scopolamine in depression. The pilot study conducted by Furey and Drevets (7) in The goal of this paper is to review all published treat- 2006 intended to assess the contribution of the cholinergic ment studies on scopolamine use in major depressive system on the cognitive symptoms in patients with depres- disorder. sion. This study came up with an unforeseen observation that scopolamine administration resulted in a decrease in depression severity. Eight currently depressed patients Methods took part in this study (5 MDD and 3 BD patients). It This was a literature review of the electronic database was determined that after three intravenous infusions of in PubMed, the Cochrane database, Ovid Medline and scopolamine 4.0 µg/kg, five patients exhibited an MADRS Google Scholar of all studies using the keywords “sco- score reduction of 50%, whereas the three remaining polamine in depression” (unipolar and bipolar) and patients remitted to the non-depressed range (MADRS “scopolamine as rapid acting antidepressants” from 1970 score < 10) (7). A double-blind, randomized, placebo- and 2020. We searched for randomized controlled trials, controlled crossover study was conducted in order to non-randomized controlled prospective studies and further evaluate the antidepressant response to scopol- meta-analyses. amine. A total of 18 depressed patients were included (9 MDD and 9 BD patients). The patients were assigned to one of the two groups, with one group of patients set Results to receive an intravenous infusion of saline placebo (3 We found eight treatment trials on using scopolamine sessions) followed by 4.0 µg/kg intravenous infusion of in major depressive disorder. The result of these trials is scopolamine (3 sessions), whereas the other group would summarized in chronological order and then presented receive 4.0 µg/kg intravenous infusion of scopolamine (3 in Table 1. sessions) followed by an intravenous infusion of saline Newhouse and colleagues’ (12) double-blind study from placebo (3 sessions). MADRS and HARS scores were 1988 investigated the role of central cholinergic nervous used in order to assess the antidepressant and antianxiety system in geriatric depression. Nine elderly patients (age response. Significant improvements in depressive and range: 62 to 78 years) who met the DSM-III criteria for anxiety symptoms were observed in the evaluation after major depression were administered one of the following scopolamine administration in both unipolar and bipolar each day for five days: intravenous scopolamine (0.1, 0.25. depressed patients, while such a response was not noted and 0.5 mg), 1 mg of oral , or placebo. The in placebo group. Furthermore, patients reported rapid patients were evaluated at 0, 60, and 120 minutes following improvement in clinical symptoms in the evening or the administration using a modified Brief Psychiatric Rating morning after the scopolamine administration. It should be Scale (BPRS). This study did not demonstrate any statisti- noted that all the patients had at least a 25%-50% decrease cally significant improvements in mood and depression in MADRS score (7). following the administration of scopolamine. Drevets and Furey conducted another study in 2010 The study performed by Gillin and colleagues (13), with the goal of replicating their results from an earlier published in 1991, investigated the effects of scopolamine study conducted in 2006 that demonstrated rapid anti- on mood and sleep. The subjects were administered 0.4 effects following intravenous scopolamine mg of scopolamine intramuscularly for three consecutive administration (14). This time, however, the study was nights. A total of 10 depressed (9 MDD and 1 BD) and limited to only patients with unipolar depression. A total 10 control subjects were enrolled in this study, with 8 of of 22 patients were included in this study with one group the depressed subjects having a history of alcoholism. of patients set to receive placebo infusions followed by

49 Scopolamine in Major Depressive Disorder

Table 1. Medications Sample size(n)/ Dosage/Route of Author Diagnosis administration Outcome Adverse Effects Comments Newhouse n=9 (MDD) 0.1, 0.25, and 0.5 mg There were no statistically significant High dose (0.5 mg) of Elderly patients et al., 1988 of scopolamine (IV) improvements in mood and scopolamine lead to between the ages and 1mg lorazepam measures of depression in any of the reduction in vigilance, of 62 to 78 years old (oral) scopolamine groups. attention, word free were used in this recall, immediate study. learning, and consistency. Anxiety and restlessness were also reported. Gillin et al., n=20 (9 MDD, 1 0.4 mg of The depressed group had a One depressed 8/10 depressed 1991 BP, and 10 healthy scopolamine (IM) small but statistically significant patient was patients had a history comparison antidepressant response when removed from the of abuse. subjects) compared with the baseline as a study due to mild result of scopolamine administration. confusion following first scopolamine administration. Furey & Study 1: n=8 (5 Study 1: 2.0, 3.0, Study 1: The investigators Patients in both of the Follow-up studies Drevets, MDD and 3 BD) and 4.0 µg/kg of unexpectedly established a studies experienced were conducted 2006 scopolamine (IV) statistically significant decrease in confusion following based on this study Study 2: n=18 (9 depression when compared with the the administration of MDD and 9 BP) Study 2: 4.0 µg/kg of baseline following the administration scopolamine. scopolamine (IV) of 4.0 µg/kg of scopolamine.

Study 2: Significant improvements in depression and anxiety symptoms were recorded following the 4.0 µg/kg intravenous infusions of scopolamine. Drevets & n= 22 (MDD) 4.0 µg/kg of A significant improvement in Heart rate and blood N/A Furey, 2010 scopolamine (IV) depressive symptoms (as measured pressure decreased by MADRS) was recorded after following scopolamine scopolamine administration vs administration. No placebo. other major adverse effects were reported. Furey et al., n=52 (MDD and 4.0 µg/kg of Significant improvements in Men reported fatigue 40 of the 52 patients 2010 BD) scopolamine (IV) depressive symptoms were again more frequently than enrolled were from recorded for both men and women, women under both the 2006 and 2010 although women had a greater scopolamine and trials. response to scopolamine. placebo conditions. Furey et al., n=51 (37 MDD and 4.0 µg/kg of The discriminant function analysis No adverse effects N/A 2012 14 BD) scopolamine (IV) successfully identified over were reported. 85% of the unipolar and bipolar depressed patients as responders or non-responders to scopolamine treatment. Khajavi et n=40 (MDD) 20 patients Higher rates of response and Scopolamine group N/A al., 2012 received 1 mg/d remission were recorded in patients patients reported the of scopolamine + in the group where scopolamine was following symptoms: citalopram while included. dry mouth, blurred other 20 patients vision, and . received placebo + citalopram. Park et al., n=23 (MDD) 4.0 µg/kg of Scopolamine administration did not Minor side effects Newhouse et al., 2019 scopolamine (IV) lead to significant antidepressant or such as dry mouth, 1988, and Park et anxiolytic effects when compared , blurred al., 2018, are two with the placebo. vision, drowsiness, studies that are not and nervousness were in line with the other reported. reported studies as they show no antidepressant effect of scopolamine.

50 Dusan Kolar

4.0 µg/kg intravenous infusions of scopolamine, or the unipolar and bipolar depressed patients as responders or other way around. Infusions were administered within non-responders to scopolamine treatment (16). 3 to 5 days apart. The primary outcome measure was A randomized controlled trial performed by Khajavi determined using MADRS. Significant improvements and colleagues (17) examined the efficacy and safety of in MADRS scores were recorded following the 4.0 µg/kg oral scopolamine augmentation in patients with MDD. A intravenous infusions of scopolamine when compared total of 40 patients were enrolled; the patients were split with the placebo. The group that received the placebo into two groups of twenty with each group receiving either first had a 53% reduction in MADRS scores following scopolamine plus citalopram or placebo plus citalopram. the shift to scopolamine regiment, while the group that Patients in the group receiving scopolamine had an average received scopolamine first recorded a 32% reduction in of 73.8% reduction in their HDRS score, while the group MADRS scores after scopolamine administration. These receiving the placebo had an average of 59.3% reduction in results have once again shown that scopolamine offers a their HDRS score. Furthermore, 65% of patients assigned rapid and potent relief of symptoms to patients suffering to the scopolamine-augmented schedule achieved remis- from depression (14). sion, whereas this was the case with only 20% of patients’ Previous studies have shown that scopolamine produces receiving citalopram alone. It is also important to note that a robust and rapid antidepressant response in both gen- this study assessed the side effects of scopolamine. Although ders, but it is known that some antidepressants generate dizziness, , and dry mouth were more com- different responses based on gender. The study by Furey mon in the group receiving scopolamine, nonetheless no et al. (15) examined whether scopolamine administration serious adverse effects were noted in this study. Overall, this leads to different antidepressant response magnitudes in study illustrates that incorporating oral scopolamine to the males and females. A total of 52 patients (31 women and antidepressant regiment is an effective and safe approach 21 men) participated in this study. The results show that to achieving high remissions rates in patients with severe both men and women have a rapid antidepressant response to moderate MDD (17). after scopolamine administration, although women had a Park and colleagues (18) conducted a randomized, greater response to scopolamine (71%) when compared placebo-controlled, crossover trial which included a total with men (38%). A rapid antianxiety response after sco- of 23 medication-free patients with MDD and all of them polamine administration was found solely in females, had scored ≥20 on the MADRS prior to the initiation of whereas males did not exhibit significant improvement the study. Firstly, the patients were given a single placebo in anxiety scores (15). lead-in, followed by two blocks of three 4 μg/kg intrave- After reporting that scopolamine administration pro- nous infusions of scopolamine or placebo. The primary duces rapid and robust antidepressant response in their and secondary outcomes were measured with MADRS studies from 2006 and 2010, Furey and colleagues (16) and Hamilton Anxiety Rating Scale (HARS) respec- conducted another study in order to find out whether tively. The results of this trial indicate that scopolamine self-reported mood ratings can be used as a predictor of administration did not lead to significant antidepressant the antidepressant response in depressed patients. Fifty- or anxiolytic effects when compared with the placebo. one patients participated in this study with each of them It should be noted that Park and colleagues mention meeting the DSM-IV criteria for major depressive disor- that these findings are not in line with previous studies der (n=37) or bipolar disorder (n=14). A total of seven that tested the antidepressant effects of scopolamine. infusions were conducted, with all the patients receiving One possible explanation for this may be the fact that placebo saline solution in the first session. Self-assessments average MADRS scores of the patients entering the trial of mood were measured using Visual Analog Scales (VOS) were between 23 and 30 in the previous studies. On the and the Profile of Mood States (POMS) while the antide- other hand, the average MADRS scores of patients in the pressant response was determined by measuring the change current study were 33. Furthermore, the patients in the in MADRS from baseline to the end of the study. In the current study could have been more treatment-resistant discriminant function analysis, the combination of seven when compared with patients in previous scopolamine behavioral measures in MDD subjects and four behavioral studies. Nevertheless, the findings by Park and colleagues variables in bipolar subjects were found as predictors of (18) indicate that scopolamine may have only limited treatment response or non-response. The discriminant or no significant antidepressant effects in patients that function analysis successfully identified over 85% of all suffer from more severe forms of depression.

51 Scopolamine in Major Depressive Disorder

in this population of patients with more severe forms Discussion of depression is not yet established due to the limited Ketamine has recently become a model of rapid act- number of trials. ing antidepressants and a possible treatment option for The safety profile and tolerability of scopolamine is patients with treatment resistant depression. It is hard to favorable. Besides dizziness, blurred vision and dry mouth say if ketamine effects in major depressive disorder could no other side effects were noted, and there were no par- be called antidepressant effects or just simply transient ticularly serious adverse effects in treatment trials (16). euphoriant effects. The research team conducted by Allan Unfortunately, there was no any follow-up on patients Schatzberg had demonstrated that ketamine’s antidepres- included in the eight available treatment trails, and thus sant may be related to intrinsic there is no data on long-term outcomes of patients treated receptor properties of ketamine as naltrexone with scopolamine. Future studies should obviously con- significantly blocks antidepressant effects of ketamine sider a somewhat longer duration of treatment, possibly (19). Ketamine is a well-known of abuse and longer some maintenance and follow-up on treatment outcomes. use of this compound may have an addictive potential Similarities in the mechanism of action and effects as chronic administration may contribute to developing between ketamine and scopolamine are subject of many tolerance (19-21). On the other hand, the long-term use debates. Park and colleagues used magnetoencephalog- of medication which has never been tested raphy (MEG) and measured plasma brain-derived neu- for a long-term administration may be associated with rotrophic factor (BDNF) concentrations before and after some unknown long-term negative consequences, such treatment with scopolamine (18). These neurophysiological as cognitive impairments and neurotoxicity associated markers concentrations tend to change in the case of with chronic ketamine use (22, 23). ketamine administration. The results of this study illus- In the context of these concerns about ketamine, con- trate that MEG and BDNF levels showed no association sidering other non-chemical, natural products with rapid with scopolamine administration. These findings would antidepressant effects, such as scopolamine, is supposed suggest that scopolamine and ketamine do not utilise to be a more convenient, safer and overall more benign similar neurobiological effects (drug effects). The authors option for treatment resistant depression, particularly if were not able to test the hypothesis that scopolamine and longer treatment is required. ketamine have a shared mechanism of action due to the The adrenergic-cholinergic imbalance hypothesis was lack of clinical efficacy (18). first proposed in 1972 by Janowsky and colleagues (8) However, the results of study performed by Wohleb and as a mechanism underlying major depressive disorder. colleagues (24) have demonstrated that the rapid-acting It was determined that increased cholinergic activity antidepressant effects of scopolamine, like ketamine anti- exacerbates depressive symptoms, whereas decreased depressant response, are also associated with increased cholinergic activity leads to a reduction in depressive glutamate transmission and synapse formation. symptoms. The exploratory genome-wide association analysis of More recent research indicates that central cholinergic response to ketamine and polygenic analysis of response pathways may play a role in the regulation of both mood to scopolamine revealed that genetic variants associated and cognition. Studies conducted on animal and human with ketamine response accounted for ~6% of the vari- models have shown that alteration of cholinergic activity ance in scopolamine response. This suggests a modest may be directly tied to the development of depressive potential genetic overlap in antidepressant response to symptoms (9). ketamine and scopolamine (25). Seven treatment trials have demonstrated rapid thera- Even if a hypothesis of an increased glutamate trans- peutic effects of scopolamine in depression both as mono- mission and activation of synaptic plasticity and synap- therapy and augmentation. Only one study conducted togenesis proposed by Wohleb and colleagues (24) and by Park and colleagues (18) indicate that scopolamine Duman et al. (11) as one of the assumed scopolamine’s administration did not lead to significant antidepressant mechanism of action, the absence of opioid effects might or anxiolytic effects in patients with severe depression. make scopolamine less effective than ketamine in most They concluded that scopolamine had modest effects severe cases of depression. The absence of any severe type or no significant effects in patients with more severe of adverse effects, though, could be a reason for using and refractory depression. The efficacy of scopolamine scopolamine alternatively with ketamine in patients with

52 Dusan Kolar

treatment resistant depression, particularly for those 13. Gillin JC, Sutton L, Ruiz C, et al. The effects of scopolamine on sleep and where a rapid treatment response is required. mood in depressed patients with a history of alcoholism and a normal comparison group. Biol Psychiatry 1991; 30: 157-169. 14. Drevets WC, Furey ML. Replication of scopolamine’s antidepressant References efficacy in major depressive disorder: A randomized, placebo-controlled 1. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, clinical trial. Biol Psychiatry 2010; 67: 432-438. prevalence, and years lived with disability for 354 diseases and injuries 15. Furey ML, Khanna A, Hoffman EM, et al. Scopolamine produces for 195 countries and territories, 1990–2017: A systematic analysis for larger antidepressant and antianxiety effects in women than in men. the Global Burden of Disease Study 2017. Lancet 2018; 392: 1789-1858. Neuropsychopharmacol 2010; 35: 2479-2488. 2. World Health Organization. Depression and other mental health 16. Furey ML, Nugent AC, Speer AM, et al. Baseline mood-state measures disorders: Global health estimates, 2017. https://apps.who.int/iris/ as predictors of antidepressant response to scopolamine. Psychiatry bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf Res 2012; 196: 62-67. 3. Trivedi MH, Rush AJ, Wisniewski, et al. Evaluation of outcomes with 17. Khajavi D, Farokhnia M, Modabbernia A, et al. Oral scopolamine citalopram for depression using measurement-based care in STAR* D: augmentation in moderate to severe major depressive disorder: A Implications for clinical practice. Am J of Psychiatry 2006; 163: 28-40. randomized, double-blind, placebo-controlled study. J Clin Psychiatry 4. Connolly KR, Thase ME. If at first you don’t succeed. Drugs 2011; 71: 43-64. 2012; 73: 1428-1433. 5. Richelson E. of antidepressants. Mayo Clin Proc 2001; 18. Park L, Furey M, Nugent AC, et al. Neurophysiological changes 76: 511-527. associated with antidepressant response to ketamine not observed in a negative trial of scopolamine in major depressive disorder. Int J 6. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl- Neuropsychopharmacol 2019; 22: 10-18. D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856-864. 19. Williams NR Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 7. Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic 2018; 175:1205-1215. drug scopolamine: A randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 2006; 63: 1121-1129. 20. Freedman R. Further investigation of ketamine. Am J Psychiatry 2016;173:761-762. 8. Janowsky DS, El-Yousef MK, Davis JM, et al. A cholinergic adrenergic hypothesis of depression and mania. Lancet 1972; 632-635. 21. Kolar D. Addictive potential of novel treatments for refractory depression 9. Janowsky DS, Overstreet DH, Nurnberger Jr JI. Is cholinergic sensitivity and anxiety. Neropsychiatr Dis Treat 2018; 14: 1513-1519. a genetic marker for the affective disorders? Am J Med Genet 1994; 54: 22. Chaki S. Beyond ketamine: New approaches to the development of safer 335-344. antidepressants. Curr Neuropharmacol 2017; 15: 963-976. 10. Radhakrishnan R, Field C. Cholinergic antagonists. In Whalen K, editor. 23. Zhu W, Ding Z, Zhang Y, et al. Risks associated with misuse of ketamine Lippincott Illustrated Reviews in Pharmacology, 7th Edition, 2018. as a rapid-acting antidepressant. Neurosci Bull 2016; 32: 557-564. 11. Duman RS, Aghajanian GK, Sanacora G, et al. Synaptic plasticity and 24. Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular depression: New insights from stress and rapid-acting antidepressants. mechanisms of rapid-acting antidepressants ketamine and scopolamine. Nat Med 2016; 22: 238-249. Curr Neuropharmacol 2017; 15: 11-20. 12. Newhouse PA, Sunderland T, Tariot PN, et al. The effects of acute 25. Guo W, Machado-Vieira R, Matthew S, et al. Exploratory genome-wide scopolamine in geriatric depression. Arch Gen Psychiatry 1988; 45: association analysis of response to ketamine and a polygenic analysis of 906-912. response to scopolamine in depression. Transl Psychiatry 2018; 8: 2-8.

53