New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality

ABSTRACT

Introduction

Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions.

Areas covered

To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24–25 January 2024 using strategies like (‘acute suicid*’[ti] OR ‘suicide crisis syndrome’ OR ‘acute suicidal affective disturbance’) AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and (‘acute suicid*’[ti] OR ‘suicide crisis syndrome’ OR ‘acute suicidal affective disturbance’) AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality.

Expert opinion

Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.

KEYWORDS:

• Suicide, completed
• suicide attempt
• suicidal ideation
• suicidality
• bipolar disorder
• drug treatment
• drug design
• glutamatergic transmission

Article highlights

• Bipolar disorder is associated with a higher risk of suicide among psychiatric disorders.

• Acute suicidal thinking or attempt may surge abruptly during the course of bipolar disorder.

• The use of ketamine in severe cases of depression with suicidal intent showed a reduction of suicidality and paved the way of a glutamatergic hypothesis of suicidal behavior.

• Currently, the assessment of acute suicidality is not adequately standardized and is not sought after in clinical studies.

• Combining basic and clinical science results, it appears that targeting the glutamatergic transmission could benefit people with bipolar disorder and acute suicidality.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

The authors are grateful to the Scientific Administration of the Bibliographic and Bibliometric Support Service, Fondazione Policlinico A. Gemelli IRCCS, in particular, Dr. Maria Pattuglia, and Ms. Mimma Ariano, Ms. Ales Casciaro, Ms. Teresa Prioreschi, and Ms. Susanna Rospo, Librarians of the Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, for rendering precious bibliographical material accessible.

Author contributions

G D Kotzalidis, F Fiaschè, and G Sani conceptualized the review, G D Kotzalidis, F Fiaschè, A Alcibiade, L Monti, and F Di Segni performed literature searches, G D Kotzalidis, F Fiaschè, A Alcibiade, F Di Segni and M Mazza provided the first draft, G D Kotzalidis, F Fiaschè, A Alcibiade, F Di Segni, and G Sani supervised the writing of the manuscript and provided the final draft. The final version of the manuscript has been read and approved by all named authors; no other persons meet criteria for authorship.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.