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Scopolamine As a Potential Treatment Option in Major Depressive Disorder - a Literature Review

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Scopolamine As a Potential Treatment Option in Major Depressive Disorder - a Literature Review Isr J Psychiatry - Vol. 58 - No 1 (2021) Scopolamine 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 antidepressants 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 antidepressant acting antidepressants, particularly after introducing regimen experience non-response to treatment (3, 4). ketamine 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 drugs 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 acetylcholine 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 cholinergic-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 agonists and acetyl- cholinesterase inhibitors lead to severe depression (9). INTRODUCTION Scopolamine is a tertiary amine plant alkaloid 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 anticholinergic 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 lorazepam, 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 depressant 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
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