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Scopolamine and Ketamine: Evidence of Convergence?

      Recent findings have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the muscarinic acetylcholine receptor antagonist scopolamine have rapid antidepressant effects in depressed individuals (
      • Berman R.M.
      • Cappiello A.
      • Anand A.
      • Oren D.A.
      • Heninger G.R.
      • Charney D.S.
      • Krystal J.H.
      Antidepressant effects of ketamine in depressed patients.
      ,
      • Zarate Jr, C.A.
      • Singh J.B.
      • Carlson P.J.
      • Brutsche N.E.
      • Ameli R.
      • Luckenbaugh D.A.
      • et al.
      A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
      ,
      • Furey M.L.
      • Drevets W.C.
      Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial.
      ). Patients resistant to other treatments reported alleviation of core major depression symptoms following infusion of low-dose ketamine or scopolamine, with effects lingering for longer than 2 weeks in some patients. The rapid efficacy of these compounds is in striking contrast to traditional antidepressants, which target the monoamine system and exert mood-elevating effects only after repeated administration (typically several weeks to months). Because there is an urgent need for antidepressants that exert therapeutic effects within hours or days after administration, preclinical studies have started to elucidate the mechanism of how ketamine can trigger a fast-acting antidepressant response (
      • Autry A.E.
      • Adachi M.
      • Nosyreva E.
      • Na E.S.
      • Los M.F.
      • Cheng P.F.
      • et al.
      NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
      ,
      • Li N.
      • Lee B.
      • Liu R.J.
      • Banasr M.
      • Dwyer J.M.
      • Iwata M.
      • et al.
      mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
      ). Despite initial progress, it remains unclear whether ketamine can exert long-term effects (beyond 1–2 weeks) and, if so, how such an effect can be maintained. It is also unknown how scopolamine triggers a rapid antidepressant effect and whether this effect has any commonalities with the effect of ketamine. In the current issue of Biological Psychiatry, two articles begin to address these questions.
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