Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment‐resistant depression

the REAL‐ESK Study Group, Giovanni Martinotti, Bernardo Dell'Osso, Giorgio Di Lorenzo, Giuseppe Maina, Alessandro Bertolino, Massimo Clerici, Stefano Barlati, Gianluca Rosso, Marco Di Nicola, Matteo Marcatili, Giacomo d'Andrea, Clara Cavallotto, Stefania Chiappini, Sergio De Filippis, Giuseppe Nicolò, Pasquale De Fazio, Ileana Andriola, Raffaella Zanardi, Domenica NuciforaStefania Di Mauro, Roberta Bassetti, Mauro Pettorruso, Roger S. McIntyre, Stefano L. Sensi, Massimo di Giannantonio, Antonio Vita, Giulia Baldacci, Sandro Belletti, Antonello Bellomo, Beatrice Benatti, Matteo Carminati, Rosalba Carullo, Domenico de Berardis, Renato de Filippis, Roberto Delle Chiaie, Francesco di Carlo, Gilberto Di Petta, Alessandro Galluzzo, Valentina Giorgelli, Ginevra Lombardozzi, Vassilis Martiadis, Chiara Mattei, Alessio Mosca, Cinzia Niolu, Miriam Olivola, Mauro Percudani, Maria Pepe, Eros Rossi, Maria Ilaria Scardigli, Filippo Tatì

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Background: Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first‐line therapeutic options, resulting in treatment‐resistant bipolar depression (B‐TRD). Esketamine, the S‐enantiomer of ketamine, has recently been approved for treatment‐resistant depression (TRD), but no data are available on its use in B‐TRD. Objectives: To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B‐TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B‐TRD, focusing on the average risk of an affective switch. Methods: Thirty‐five B‐TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery‐Asberg Depression Rating Scale/MADRS, Hamilton‐depression scale/HAM‐D, Hamilton‐anxiety scale/HAM‐A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up. Results: A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B‐TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B‐TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment‐emergent affective switch. Conclusions: Our results supported the effectiveness and tolerability of esketamine in a real‐world population of subjects with B‐TRD. The low risk of manic switch in B‐TRD patients confirmed the safety of this treatment.
Original languageEnglish
Pages (from-to)233-244
Number of pages12
JournalBipolar Disorders
Issue number3
Early online date13 Jan 2023
Publication statusPublished - 18 Jan 2023


  • bipolar depression
  • esketamine
  • glutamate
  • mood disorders
  • pharmacological treatment
  • rapid‐acting antidepressant
  • real‐world study
  • TRD
  • treatment‐resistant depression
  • real-world study
  • rapid-acting antidepressant
  • treatment-resistant depression


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