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Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial

  • Wayne C. Drevets
    Affiliations
    Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Maura L. Furey
    Correspondence
    Address correspondence to Maura L. Furey, Ph.D., Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Building 15K, Room 201, Bethesda, MD 20892
    Affiliations
    Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
    Search for articles by this author

      Background

      We previously reported that intravenous (IV) scopolamine administration produced rapid and robust antidepressant effects in a sample consisting of both unipolar and bipolar depressives. The present study aimed to replicate this finding in an independent sample limited to unipolar depressives.

      Methods

      Outpatients with major depressive disorder (MDD; n = 23; 22 were included in analyses) participated in a double-blind, placebo-controlled, crossover trial. Subjects were randomized into either a P/S or S/P sequence (P = block of three placebo sessions; S = block of three scopolamine sessions; [4.0 μg/kg IV]). Sessions occurred 3 to 5 days apart, such that time spent in each block lasted 1.5 to 2 weeks and the interval between blocks was 3 to 5 days. The Montgomery-Asberg Depression Rating Scale (MADRS) served as the primary outcome measure.

      Results

      Following the initial block, the group receiving scopolamine first (S/P) showed a 32% reduction in MADRS scores (p < .001), which exceeded the corresponding change of 6.5% under placebo (P/S; p = .009), confirming the a-priori hypothesis. Improvement was significant at the first evaluation that followed scopolamine administration (p = .011). In Block 2, the P/S group showed a 53% reduction in MADRS scores (p = .001) following scopolamine versus placebo, whereas 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 because of side effects.

      Conclusions

      These results replicate previous finding that scopolamine produces a rapid and robust antidepressant response.

      Key Words

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      References

        • Pacher P.
        • Kecskemeti V.
        Trends in the development of new antidepressants.
        Curr Med Chem. 2004; 11: 925-943
        • Furey M.L.
        • Drevets W.C.
        Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial.
        Arch Gen Psychiatry. 2006; 63: 1121-1129
      1. Diagnostic and Statistical Manual of Mental Disorders.
        4th ed. American Psychiatric Association, Washington, DC2000
        • Khan A.
        • Khan S.R.
        • Shankles E.B.
        • Polissar N.L.
        Relative sensitivity of the Montgomery-Asberg depression rating scale, the Hamilton depression rating scale and the clinical global impressions rating scale in antidepressant clinical trials.
        Int Clin Psychopharmacol. 2002; 17: 281-285
        • Hamilton M.
        The assessment of anxiety states by rating.
        Br J Med Psychol. 1959; 32: 50-55
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: Reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • McNair D.M.
        • Lorr M.
        • Droppleman L.F.
        EITS Manual for the Profile of Mood States.
        Educational and Industrial Testing Service, San Diego, CA1971
        • Nierenberg A.A.
        • DeCecco L.M.
        Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: A focus on treatment-resistant depression.
        J Clin Psychiatry. 2001; 62: 5-9
        • Berger M.
        • Riemann D.
        • Hochli D.
        • Spiegel R.
        The cholinergic rapid eye movement sleep induction test with RS-86.
        Arch Gen Psychiatry. 1989; 46: 421-428
        • Browne R.G.
        Effects of antidepressants and anticholinergics in a mouse “behavioral despair” test.
        Eur J Pharmacol. 1979; 58: 331-334
        • Comings D.E.
        • Wu S.
        • Rostamkhani M.
        • McGue M.
        • Iacono W.G.
        • MacMurray J.P.
        Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women.
        Am J Med Genet. 2002; 114: 527-529
        • Dilsaver S.C.
        Pathophysiology of “cholinoceptor supersensitivity” in affective disorders.
        Biol Psychiatry. 1986; 21: 813-829
        • Gillin J.C.
        • Sutton L.
        • Ruiz C.
        • Darko D.
        • Golshan S.
        • Risch S.C.
        • et al.
        The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.
        Biol Psychiatry. 1991; 30: 157-169
        • Janowsky D.S.
        • El-Yousef M.K.
        • Davis J.M.
        • Sekerke H.J.
        A cholinergic-adrenergic hypothesis of mania and depression.
        Lancet. 1972; 2: 632-635
        • Janowsky D.S.
        • Overstreet D.H.
        The Role of Acetylcholine Mechanisms in Mood Disorders.
        Raven, New York1995
        • Riemann D.
        • Hohagen F.
        • Krieger S.
        • Gann H.
        • Muller W.E.
        • Olbrich R.
        • et al.
        Cholinergic REM induction test: Muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia.
        J Psychiatr Res. 1994; 28: 195-210
        • Risch S.C.
        • Kalin N.H.
        • Janowsky D.S.
        Cholinergic challenges in affective illness: Behavioral and neuroendocrine correlates.
        J Clin Psychopharmacol. 1981; 1: 186-192
        • Wang J.C.
        • Hinrichs A.L.
        • Stock H.
        • Budde J.
        • Allen R.
        • Bertelsen S.
        • et al.
        Evidence of common and specific genetic effects: Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.
        Hum Mol Genet. 2004; 13: 1903-1911
        • Nestler EJH S.E.
        Regulation of gene expression.
        in: Davis K.L. Charney D. Coyle J.T.NemeroffC. Neuropsychopharmacology the Fifth Generation of Progress. Lippincott Williams & Wilkins, Philadelphia2002: 217-228
        • Liu H.F.
        • Zhou W.H.
        • Xie X.H.
        • Cao J.L.
        • Gu J.
        • Yang G.D.
        [Muscarinic receptors modulate the mRNA expression of NMDA receptors in brainstem and the release of glutamate in periaqueductal grey during morphine withdrawal in rats].
        Sheng Li Xue Bao. 2004; 56: 95-100
        • Rami A.
        • Ausmeir F.
        • Winckler J.
        • Krieglstein J.
        Differential effects of scopolamine on neuronal survival in ischemia and glutamate neurotoxicity: Relationships to the excessive vulnerability of the dorsoseptal hippocampus.
        J Chem Neuroanat. 1997; 13: 201-208
        • Krystal J.H.
        • Sanacora G.
        • Blumberg H.
        • Anand A.
        • Charney D.S.
        • Marek G.
        • et al.
        Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments.
        Mol Psychiatry. 2002; 7: S71-S80
        • Paul I.A.
        • Skolnick P.
        Glutamate and depression: Clinical and preclinical studies.
        Ann NY Acad Sci. 2003; 1003: 250-272
        • Skolnick P.
        • Layer R.T.
        • Popik P.
        • Nowak G.
        • Paul I.A.
        • Trullas R.
        Adaptation of N-methyl-d-aspartate (NMDA) receptors following antidepressant treatment: Implications for the pharmacotherapy of depression.
        Pharmacopsychiatry. 1996; 29: 23-26
        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • et al.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • Chen C.
        • Hardy M.
        • Zhang J.
        • Lahoste G.J.
        • Bazan N.G.
        Altered NMDA receptor trafficking contributes to sleep deprivation-induced hippocampal synaptic and cognitive impairments.
        Biochem Biophys Res Commun. 2006; 340: 435-440
        • McDermott C.M.
        • Hardy M.N.
        • Bazan N.G.
        • Magee J.C.
        Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus.
        J Physiol. 2006; 570: 553-565
        • Raeder E.A.
        • Stys A.
        • Cohen R.J.
        Effect of low-dose scopolamine on autonomic control of the heart.
        Ann Noninvasive Electrocardiol. 1997; 2: 236-241
        • Sunderland T.
        • Tariot P.N.
        • Cohen R.M.
        • Weingartner H.
        • Mueller III, E.A.
        • Murphy D.L.
        Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls.
        Arch Gen Psychiatry. 1987; 44: 418-426
        • Vitiello B.
        • Martin A.
        • Hill J.
        • Mack C.
        • Molchan S.
        • Martinez R.
        • et al.
        Cognitive and behavioral effects of cholinergic, dopaminergic, and serotonergic blockade in humans.
        Neuropsychopharmacology. 1997; 16: 15-24
        • Carney R.M.
        • Freedland K.E.
        • Veith R.C.
        Depression, the autonomic nervous system, and coronary heart disease.
        Psychosom Med. 2005; 67: S29-S33
        • Udupa K.
        • Sathyaprabha T.N.
        • Thirthalli J.
        • Kishore K.R.
        • Raju T.R.
        • Gangadhar B.N.
        Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation.
        J Affect Disord. 2007; 104: 231-236
        • Furey M.L.
        • Pietrini P.
        • Haxby J.V.
        • Drevets W.C.
        Selective effects of cholinergic modulation on task performance during selective attention.
        Neuropsychopharmacology. 2008; 33: 913-923
        • Thase M.E.
        • Entsuah A.R.
        • Rudolph R.L.
        Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors.
        Br J Psychiatry. 2001; 178: 234-241
        • Khan A.
        • Brodhead A.E.
        • Kolts R.L.
        • Brown W.A.
        Severity of depressive symptoms and response to antidepressants and placebo in antidepressant trials.
        J Psychiatr Res. 2005; 39: 145-150
        • Newhouse P.A.
        • Sunderland T.
        • Tariot P.N.
        • Weingartner H.
        • Thompson K.
        • Mellow A.M.
        • et al.
        The effects of acute scopolamine in geriatric depression.
        Arch Gen Psychiatry. 1988; 45: 906-912
        • Ebert U.
        • Grossmann M.
        • Oertel R.
        • Gramatte T.
        • Kirch W.
        Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers.
        J Clin Pharmacol. 2001; 41: 51-60
        • Bagby R.M.
        • Ryder A.G.
        • Cristi C.
        Psychosocial and clinical predictors of response to pharmacotherapy for depression.
        J Psychiatry Neurosci. 2002; 27: 250-257
        • Kupfer D.J.
        • Spiker D.G.
        Refractory depression: Prediction of non-response by clinical indicators.
        J Clin Psychiatry. 1981; 42: 307-312
        • Sackeim H.A.
        The definition and meaning of treatment-resistant depression.
        J Clin Psychiatry. 2001; 62: 10-17
        • Klein D.N.
        • Schatzberg A.F.
        • McCullough J.P.
        • Dowling F.
        • Goodman D.
        • Howland R.H.
        • et al.
        Age of onset in chronic major depression: Relation to demographic and clinical variables, family history, and treatment response.
        J Affect Disord. 1999; 55: 149-157