Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety☆
Introduction
Suicidal ideation is a frequent and potentially life-threatening indication for psychiatric emergency services (Ting et al., 2012). Over 38,000 Americans died by suicide in 2010 (Centers for Disease Control and Prevention, 2013b), and it is estimated that many of these individuals were currently depressed or had a history of an affective disorder (Centers for Disease Control and Prevention, 2013a, Conwell et al., 1996). Due to the known relationship between suicidal ideation and attempts/death (Baca-Garcia et al., 2011), effective interventions are a priority, as highlighted by the 2012 U.S. National Strategy for Suicide Prevention (U.S. Department of Health and Human Services, 2012). Unfortunately, few psychiatric medications have been shown to reduce suicidal ideation as compared to the anti-aggressive and anti-impulsive effects of lithium and clozapine (Frogley et al., 2012, Hennen and Baldessarini, 2005, Quiroz et al., 2010), which may be more suited to reducing suicide attempts than suicidal ideation. Additionally, available antidepressants may take weeks-to-months to achieve the desired effects. As a consequence, the 400,000 individuals who seek emergency treatment for suicidal thoughts and behavior each year often do not receive timely relief (Ting et al., 2012).
Novel, rapid-acting antidepressants hold great potential in the emergent treatment of suicidal patients. Ketamine is a glutamatergic, N-methyl-D-aspartate (NMDA) receptor antagonist that has rapid-acting antidepressant effects (Berman et al., 2000, Diazgranados et al., 2010b, Ibrahim et al., 2012, Zarate et al., 2006) in both unipolar and bipolar depressed patients. A single subanesthetic dose (0.5 mg/kg over 40 min) of ketamine has antidepressant efficacy within hours-to-days with concomitant reductions in suicidal ideation on a similar time frame. In an open label trial of patients with Major Depressive Disorder (MDD), symptoms including suicidal ideation, anxiety and hopeless thoughts dissipated after a single infusion (Diazgranados et al., 2010a). Ketamine has also been shown to reduce implicit measures of suicidal cognition in both single and repeated-dose paradigms (Price et al., 2009, Price et al., 2014). Naturalistic studies and case reports in emergency department settings have also demonstrated reduced suicidal ideation after ketamine infusion (Larkin and Beautrais, 2011, Zigman and Blier, 2013).
As the evidence base for ketamine's anti-suicidal properties continues to grow, a critical question emerges: how does ketamine reduce suicidal thoughts? Suicidal ideation has a demonstrated relationship to both depression and anxiety symptoms and diagnoses (Nock et al., 2010, Rappaport et al., 2014, Sareen et al., 2005). Since ketamine has been shown to reduce both depression and anxiety (Diazgranados et al., 2010b, Ibrahim et al., 2012, Irwin et al., 2013, Zarate et al., 2006), a simple explanation may be that ketamine reduces suicidal thoughts through its impact on these symptoms. In support of this perspective, a re-analysis of 9185 patients across several randomized clinical trials of fluoxetine and venlafaxine found that depression mediated the reductions in suicidal thoughts and behaviors in adults, but not adolescents (Gibbons et al., 2012). Similarly, a recent analysis of ketamine in patients with treatment-resistant depression found that reductions in depressive symptoms mediated the reductions in suicide ideation after infusion (Price et al., 2014).
However, not all suicidal ideation and behavior are explained by mood and anxiety symptoms alone. Many individuals think about, attempt and die by suicide outside the context of a depressive or anxious episode (Centers for Disease Control and Prevention, 2013a, Conwell et al., 1996). Furthermore, a meta-analyses of psychotherapy for depression has found inconclusive effects of these therapies on suicidal thoughts and behaviors (Cuijpers et al., 2013), leading to the development of suicide-focused psychotherapies, such as Cognitive Behavioral Therapy for Suicidal Patients (Brown et al., 2005b). It is possible that ketamine decreases suicidal thoughts independently from depression and anxiety. If ketamine is found to impact suicidal thoughts directly, this would have important implications for both the neurobiological profile of suicidal thoughts and the treatment of suicidal patients.
This analysis takes advantage of the history of ketamine research conducted by our group to evaluate the relationship between suicidal ideation, depression and anxiety in a sample of depressed patients. We hypothesized that reductions in suicidal ideation post-infusion would be independent of reductions in depression and anxiety symptoms. To this end, we evaluated changes in ideation post-infusion. We also evaluated the effect of ketamine on suicidal thoughts when controlling for depressive symptoms and anxiety symptoms. Lastly, we identified whether ketamine had an impact on two cognitive aspects of suicidal ideation: the wish to live and the wish to die.
Section snippets
Methods
Patient-level data was obtained from four independent, previously-published clinical trials, including one open-label trial and one ongoing mechanism of action clinical trial, investigating the use of ketamine in treatment-resistant MDD and bipolar disorder (BD) depression without psychotic features (Diazgranados et al., 2010b, Ibrahim et al., 2012, Zarate et al., 2006, Zarate et al., 2012). Patients 18–65 years old were admitted to the inpatient unit at the NIMH Mood and Anxiety Disorders
Results
A total of 133 patients were included in this analysis; 35 with Bipolar Disorder (19 Bipolar I and 16 Bipolar II in a depressive episode) and 98 with Major Depressive Disorder (MDD). 51% of the sample was male (n = 68), and mean age was 47.8 (SD = 12.3). At baseline (60 min before infusion), 61% of the sample (n = 81) reported any type of suicidal ideation (measured by a score > 0 on HAMD suicide item) and 40% (n = 53) reported a history of suicide attempts. Ideation at baseline was not
Discussion
In this post-hoc analysis of 133 patients in a depressive episode, ketamine was associated with reductions in suicidal ideation independent of reductions in depressive and anxiety symptoms. Furthermore, ketamine had an impact on increased wish to live and decreased wish to die, two cognitive aspects of suicidal ideation which have been shown to predict later death by suicide (Brown et al., 2005a). While changes in suicidal ideation, depression and anxiety were significantly correlated, the
Conclusion
Reductions in suicidal ideation following ketamine infusion are related to, but also independent of, reductions in depression and anxiety. As interventions for suicidal ideation are critically needed in psychiatry, findings suggest that evaluations of ketamine can be used to further investigate the neurobiology and best treatments for suicidal individuals.
Role of funding source
The National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) funded this study, but had no role in the study design or analysis.
Contributors
All authors contributed to manuscript writing or data analysis, and agreed to submit the final version for publication.
Dr. Ballard conceptualized the study design, completed and interpreted the statistical analysis, drafted the manuscript and edited the manuscript for intellectual content. She approved the final manuscript before submission.
Dr. Ionescu assisted in the conceptualization of the study design, assisted in the interpretation of the statistical analysis and edited the manuscript for
Conflict of interest
Dr. Furey is listed as a co-inventor on a patent application for the use of scopolamine in major depression and Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Drs. Furey and Zarate have assigned their rights in the patent to the U.S. Government but will share a percentage of any royalties that may be received by the Government. The remaining authors have no conflicts of interest to disclose, financial or otherwise.
Acknowledgments
Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (NCT00088699 and 04-M-0222) by a NARSAD Independent Investigator and by the Brain & Behavior Mood Disorders Research Award to CAZ.
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Presented as a Poster at the American Psychopathological Association, New York City, March 6–8, 2014.