Published in: Int J Mol Sci. 2018 Sep 23;19(10). pii: E2888. doi: 10.3390/ijms19102888.
Ketamine may decrease suicidal thoughts
The mechanism of action of ketamine in the treatment of suicidal patients involves several pathways but, first of all, the glutamatergic system seems to play a pivotal role. In fact, it has been suggested that a glutamate neurotransmission dysregulation may be the basis of suicidal ideation, and since keatmine modulates glutamate neurotransmission one can hypothesize that ketamine may relieve suicidal thoughts. Of course, this has yet to be supported by research.
Though there is robust evidence that ketamine may offer significant short-term benefits to many individuals suffering from possibly fatal mood disorders due to high suicide risk, this treatment has not yet undergone the test of multiple large-scale trials to determine the durability and safety of long-term treatment. Only Grunebaum et al. found that a significant anti-suicidal effect was maintained for up to 6 weeks when combined with optimized pharmacotherapy, but there is a lack of studies that evaluated the ketamine effect on suicidal ideation after 6 weeks.
A closer look at suicidal behavior
From an ethological and psychobiological point of view, suicidal behavior can be seen as a complicated process in which genetic, neurobiological, environmental and psychological factors come together to develop the final outcome. However, how these factors interact with each other represents an issue so entangled that it is actually extremely difficult to predict who would commit a complete suicide and when. Indeed, A recent meta-analysis on suicide risk reported that 95% of high-risk patients (i.e., displaying multiple suicide-related characteristics defining a high propensity to suicidal mortality) usually do not attempt suicide, whereas 50% of low-risk patients do, thus confirming the complexity of suicidal behavior processes.
Recent research breaks down suicidal behavior into its chronological parts: the ideation, the planning, the attempt/attempts, and the complete suicide. Each phase may have a different duration and intensity, and, although suicidal attempts cannot chronologically precede ideation, they do not always follow it as expected, since suicidal ideas are not always followed by suicidal attempts. However, even if suicidal ideation should be manifest, it has been demonstrated in several studies that clinical interventions may not be efficacious. A lot of studies have reported high rates of persistence of suicidal ideation in people diagnosed with psychiatric disorders, despite adequate treatments. For example: in first-episode psychosis patients, 33% report moderately stable and 7% moderately increasing persistent suicidal ideation over two years; 6.3% of patients with diagnosed depression may experience high suicidal ideation despite 4 months of treatment; 14% of bipolar disorder patients endure suicidal ideation over 6 months of treatment; and lastly, even after hospitalization due to acute attempts or acute ideation, suicidal thoughts have been demonstrated to persist in adolescent patients even after 12 months following discharge from treatment. Anyway, some studies suggest there are possible predictors of suicide, even if ideation is not completely expressed. For instance, Köhler-Forsberg and colleagues have reported that suicide may be predicted by higher baseline depression scores in bipolar patients with persistent ideation. Furthermore, suicide attempts may be considered a significant risk factor for possible completed suicide.
Some theories of suicide
Modern theories try to converge multiple levels of analysis, such as neurobiological (i.e., dysfunctions in the hypothalamic-pituitary axis, abnormal noradrenergic/serotonergic/dopaminergic/glutamatergic neurotransmissions, neuroinflammatory dysregulation) and sociological hypotheses (i.e., the relationship between the individual personality and social/environmental stressful factors), in order to develop and integrated model aiming at finding a “biosignature” of suicide.
Moreover, an extensive family-based genetic study analyzing those who attempted suicide switched the attention from “classical” serotonergic-related pathways to the involvement of GABA and glutamate neurotransmission in suicidal behaviors. Indeed, Sokolowski et al. found that GRIN2B (a glutamate NMDA receptor subunit gene) and ODC1 (a gene coding for ornithine decarboxylase, a rate-limiting enzyme on the polyamine synthesis pathway) seem to be associated with severe suicide attempts, as well as with serious physical assault in childhood and adolescence, which in turn increase the risk of suicide attempts, thereby configuring a gene-by-environment interaction. Finally, according to a diathesis-stress model, recent evidence points out that early stressful life events may increase the diathesis for suicidal behaviors both by provoking epigenetic and neurological changes (e.g., on serotonin neurotransmission, opioids, oxytocin, and HPA axis) and impacting on neurobiological correlates underlying character traits that have been associated with susceptibility to suicide risk (such as impulsivity, emotional dysregulation, poor attachment, chronic pessimism, impaired cognition).
Ketamine works on multiple receptors
Ketamine is a non-selective NMDA receptor antagonist acting at opened channels, but several studies have identified multiple receptor interactions of ketamine, such as with opioid sigma and mu receptors, serotonin 5HT3 receptors, muscarinic receptors, α7 nicotinic acetylcholine receptors, and cathecolamines transporters, localizing the principal sites of action of this compound in PFC and hippocampal brain areas. The numerous ketamine actions on neurotransmitters and selected brain areas may help explain its antidepressant and potentially anti-suicidal properties.
Furthermore, part of how ketamine may achieve rapid antidepressant and potentially anti-suicidal effects is by activating two transductional processes that have been regarded as fundamental: the GSK3 and the BDNF pathways. Also, ketamine action on mTOR-dependent pathways may further contribute to its rapid effects.
Concerning clinical trials, the results of recent reviews demonstrate a remarkable and fast efficacy of ketamine and esketamine (within 24 h in more than half of the patients, and with benefits observed for up to 1 week) in reducing suicidal ideation in patients with major depressive disorder (MDD or unipolar depression), bipolar depression, cancer or other conditions.
Given the controversial literature reports on the major antidepressant effects of the administration of single isomers of ketamine rather than the racemic mixture, recent studies have focused on the possible administration of S-ketamine (esketamine, which is considered the most active and less damaging isomer) by intranasal administration. The administration of intranasal esketamine (84 mg) has been demonstrated to induce early antidepressant effects (within 4 h), rapidly diminishing (up to a week) with scarce side effects (mostly dissociation, dizziness, and headache), and a peculiar action on suicidal thoughts, which rapidly decrease within 4 h from administration. However, these effects do not persist significantly after 24 h.
More research is needed
Despite the potential benefits of ketamine as a “crisis” treatment of a subjects with high suicide risk, there are still several concerns on its use and the main may be the potential abuse of this compound and the lacking of multiple large-scale trials to determine the durability and safety of long-term ketamine treatment