Ketamine and suicidal ideation in depression: Jumping the gun?

Pharmacological Research 99 (2015) 23–35

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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Ketamine and suicidal ideation in depression: Jumping the gun? R. Rajkumar a,b,c , J. Fam d , E.Y.M. Yeo a,b,c , G.S. Dawe a,b,c,∗ a

Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore c Singapore Institute for Neurotechnology (SINAPSE), Singapore d Department of Psychological Medicine, National University Health System, National University of Singapore, Singapore b

a r t i c l e

i n f o

Article history: Received 2 April 2015 Received in revised form 5 May 2015 Accepted 6 May 2015 Available online 15 May 2015 Chemical compounds studied in this article: Ketamine (PubChem CID: 3821) S-Ketamine (PubChem CID: 182137) R-Ketamine (PubChem CID: 644025) Fenfluramine (PubChem CID: 3337) Riluzole (PubChem CID: 5070) Lanicemine (PubChem CID: 3038485) Dexamethasone (PubChem CID: 5743) Clozapine (PubChem CID: 2818) Quetiapine (PubChem CID: 5002) Lithium (PubChem CID: 3028194).

a b s t r a c t Depression and suicide are known to be intricately entwined but the neurobiological basis underlying this association is yet to be understood. Ketamine is an N-methyl d-aspartate (NMDA) receptor antagonist used for induction and maintenance of general anaesthesia but paradoxically its euphoric effects lead to its classification under drugs of abuse. The serendipitous finding of rapid-onset antidepressant action of subanaesthetic dosing with ketamine by intravenous infusion has sparked many preclinical and clinical investigations. A remarkable suppression of suicidal ideation was also reported in depressed patients. This review focuses on the clinical trials on ketamine that reported remedial effects in suicidal ideation in depression and addresses also the molecular mechanisms underlying the antidepressant and psychotomimetic actions of ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine encourages its use in the management of suicidal ideation that could avert emergent self-harm or suicide. Finally, the need for neuroimaging studies in suicidal patients to identify the brain region specific and temporal effects of ketamine, and the possibility of employing ketamine as an experimental tool in rodent-based studies to study the mechanisms underlying suicidal behaviour are highlighted. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Ketamine NMDA receptor antagonist Subanaesthetic dose Depression Rapid-onset antidepressant Suicidal ideation

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Antidepressant mechanisms of ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Psychotomimetic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Ketamine and suicidal ideation in clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Pharmacological management of suicidal ideation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Neurobiology of suicide/suicidal ideation: is there a scope for ketamine? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Abbreviations: Glu, glutamate; Gln, glutamine; HP, hippocampus; PFC, prefrontal cortex. ∗ Corresponding author at: Department of Pharmacology, Yong Loo Lin School of Medicine, Centre for Life Sciences, Level 5, 28 Medical Drive, National University of Singapore, Singapore 117456, Singapore. Tel.: +65 6516 8864. E-mail address: gavin [email protected] (G.S. Dawe). http://dx.doi.org/10.1016/j.phrs.2015.05.003 1043-6618/© 2015 Elsevier Ltd. All rights reserved.

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R. Rajkumar et al. / Pharmacological Research 99 (2015) 23–35

1. Introduction The latest edition of the Diagnostic and Statistical Manual of Mental Disorders, DSM-5, states that suicidal tendency is a common manifestation of many psychiatric conditions, especially depressive disorders [1], rendering patients susceptible to take inappropriate, but indeed, preventable fatal decisions [2,3]. For example, suicidal tendency is 20–30 times higher in patients with bipolar disorder than in the general population [4]. The delay in onset of clinical antidepressant efficacy observed with both pharmacotherapy and electroconvulsive therapy further increases the risk [5–7]. Suicide is not however an inevitable and integral component of depression but rather involves complex and poorly understood neurobiological mechanisms closely associated with, but likely separable from, depression. Curbing suicidal ideation would be the ideal strategy to avert the emergent self-harm responsible for the major proportion of deaths that are associated with depressive disorder. Here we draw attention to the potential for utilisation of ketamine, a dissociative anaesthetic and N-methyl d-aspartate (NMDA) receptor antagonist, which has attracted interest as a potential novel antidepressant strategy beyond the well accepted doctrine based on serotonin. A rapid-onset antidepressant effect was observed in patients with major depression who received intravenous infusion of subanaesthetic dose of ketamine over 40 min [8]. This unanticipated finding impelled many clinical investigations that reproduced the finding, as well as preclinical investigations that explored the underlying antidepressant mechanisms of ketamine especially in the past couple of years. More interestingly, rapid-onset antidepressant effects encompassed a remarkable suppression of suicidal ideation [8,9]. Further, one other group revealed reduction of suicidal ideation with ketamine even at lower doses when infused over a shorter duration [10,11]. The potential risks of ketamine and its association with liability for abuse may lead to reluctance to adopt ketamine for routine treatment of depression. However, in cases in which suicidal ideation threatens an imminent fatality, the delay in onset of clinical efficacy of conventional antidepressants may be life-threatening. Under such circumstances, evaluation of the potential risk-tobenefit ratio may justify a recourse to the more radical approach of using subanaesthetic dose intravenous ketamine. A number of recent reviews have explored the rapid-onset antidepressant effects of ketamine but its effect on suicidal ideation has received relatively little attention [12,13]. In this review, we showcase recent advances in neuropsychopharmacological investigations of ketamine in humans and rodents with an emphasis on the potential utility of ketamine in depressed patients with suicidal ideation.

2. Antidepressant mechanisms of ketamine The NMDA antagonism following administration of subanaesthetic doses of ketamine has both remedial (antidepressant) and adverse (psychotomimetic) consequences in humans and rodents [14–21]. Interestingly, lanicemine (AZD6765), an NMDA channel blocker with lower propensity to cause psychomimetic effects than ketamine, showed rapid-onset and sustained antidepressant effects [22]. The antidepressant mechanisms of ketamine involving various neurotransmitters, signalling pathways and neurotrophic factors that lead to synaptogenesis and plasticity effects have been extensively reviewed in the recent past [23–32]. A simplified version of the proposed mechanism that underlies the rapid-onset antidepressant action of ketamine is presented here based on preclinical investigations, which report that NMDA antagonism modulates downstream pathways in rodent brain, especially in prefrontal cortex and hippocampus (Fig. 1). Recent reports demonstrated some common neurochemical and molecular changes in

hippocampus and prefrontal cortex that perhaps underlie the antidepressant effect of ketamine. They are, inhibition of glycogen synthase kinase-3 (GSK-3) an enzyme involved in mTOR pathway [33], upregulation of glutamate levels, downregulation of Neuregulin 1 (NRG1)-ErbB4 signalling in a subset of pyramidal neurons, parvalbumin, 67-kDA isoform of glutamic acid decarboxylase (GAD67) and gamma-aminobutyric acid (GABA) [34,35], and reduction in the expression of interleukin (IL)-1␤ and IL-6 [36]. Other studies looked into the neurochemical changes in either of the structures separately. In the prefrontal cortex, antagonism of excitatory NMDA receptors by ketamine predominantly affects inhibitory interneurons resulting in increases in alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptormediated neurotransmission that activates a downstream pathway involving the mammalian target of rapamycin (mTOR) leading to increased synaptic signalling protein expression, spine density and synaptic activity via pp70S6K (a serine threonine kinase) and inhibitory 4E binding proteins (4E-BP) [15,37,38] (Fig. 1). A recent study proposed that increased protein synthesis via mTOR is mediated by antagonism of GluN2B-containing NMDARs in the PFC [39]. Further, an Akt-mediated phosphorylation of GSK-3␤ was reported to underlie the rapid-onset antidepressant effects of ketamine [40]. In the hippocampus, NMDA antagonism causes dephosphorylation of eukaryotic elongation factor 2 (eEF2K) leading to brain-derived neurotrophic factor (BDNF) upregulation and a consequent activation of its cognate tropomyosin-related kinase B (TrkB) receptor [41,42]. Phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) partly contributes to the BDNF upregulation [43]. Further, a downregulation of microRNA-206, a modulator of BDNF, due to ketamine treatment is reported to upregulate BDNF [44]. Upregulation of BDNF by one of these mechanisms, if not all, leads to synaptogenesis and remodelling by multiple downstream cascades, including the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway [45], transient receptor potential cation channel subfamily C (TRPC) activation [46], augmented actin [47] and tubulin [48] polymerisation, and via intracellular mTOR activation [49]. To date, detailed investigations of these two mechanisms, AMPA neurotransmission-mediated modulation of m-TOR and BDNF-mediated modulation of multiple of pathways including m-TOR, have largely been reported separately in the prefrontal cortex and hippocampus, respectively (Fig. 1). However, ketamine (10 mg/kg) increased the levels of both BDNF and mTOR in prefrontal cortex and hippocampus [50]. Chronic doses of a combination of ketamine and AMPA, at dose levels which were ineffective when given alone, displayed antidepressant effects that were associated with upregulation of BDNF, synapsin and mTOR in hippocampus [51]. Further studies are required to investigate the implication that the same AMPA–BDNF–mTOR antidepressant molecular mechanisms occur in both prefrontal cortex and hippocampus. Acute ketamine treatment (5–10 mg/kg) elevated the expression of ribosomal protein S6 (rpS6P), a signalling protein downstream of mTOR and p70S6K activation, in prelimbic and infralimbic prefrontal cortex, basolateral amygdala and nucleus accumbens core of rat [52]. A recent report suggested that the loss of parvalbumin interneurons in the prefrontal cortex contributes to the antidepressant-like (and propyschotic-like) effects of ketamine [53]. Isomers of ketamine are known to have differential antidepressant effects in animal models of depression. In juvenile mice exposed to neonatal dexamethasone, single dose of R-ketamine showed rapid-onset and long-lasting antidepressant effects compared to S-ketamine [54]. Despite the lack of direct evidence, the results of this preclinical study, which is in line with a clinical case report [55], tempts us to speculate that R-isoform may contribute to the rapid and long-standing antidepressant effects, while the S-isoform may mediate the psychotomimetic effects.


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Fig. 1. Schematic depiction of effects of ketamine in rodent brain published in the recent past. The NMDA antagonism following ketamine administration elicits triggering of a cascade of putative signalling mechanisms in prefrontal cortex (PFC) and hippocampus (HP) of the rodent brain that could result in rapid-onset antidepressant (orange arrows) and psychotomimetic effects (red arrows). The common mechanisms in PFC and HP include inhibition of glycogen synthase kianse-3 (GSK-3), down regulation of NRG1–ErbB4 signalling in a subset of pyramidal neurons, parvalbumin, GAD67, GABA, IL-1␤ and IL-6. In the PFC, ketamine treatment results in (1) an alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) dependent phosphorylation of mammalian target of rapamycin (mTOR) via Akt/extracellular regulated kinase (ERK) and involving pp70S6K (a serine threonine kinase) and inhibitory 4E binding proteins (4E-BP) causing an increase in expression of synaptic proteins, spine density and function, (2) increases in glutamate (Glu), glutamine (Gln) levels and augmented neuronal and glial energy metabolism, and (3) Akt mediated phosphorylation of GSK-3␤, all of which could underlie the quick-onset antidepressant effects. The mTOR activation may occur via inhibition of GluN2B-containing NMDARs in the PFC. In the HP, ketamine treatment has been show to cause inhibition of eukaryotic elongation factor kinase 2 (eEFK2) that activates BDNF expression and TrKB activation which in turn increases expression of synaptic proteins, spine density and function via mTOR, Ras-mitogen activated protein kinase (MAPK) and transient receptor potential cation channel subfamily C (TRPC). Ketamine mediated upregulation of BDNF is also partly mediated (dotted orange arrows) by both phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and downregulation of microRNA-206. Chronic treatment with ketamine and AMPA also activates BDNF pathway in HP. Ketamine treatment also increased mean neuronal firing and bursting in locus ceruleus (LC) and population activity in ventral tegmental area (VTA). These result in rapid-onset antidepressant effects. The psychotomimetic effects are proposed to rely on increased functional connectivity in the PFC and the HP-PFC connectivity. Further, central administration of GSK-3 inhibitors prevent the psychotomimetic effects of ketamine presenting a GSK-3 mechanism. (For interpretation of reference to color in this figure legend, the reader is referred to the web version of this article.)

Rodent brain regions that are influenced by ketamine have been identified by regional metabolic rate of glucose (rMRGlu) evaluation and pharmacological magnetic resonance imaging (phMRI). In unconscious rats, activation in frontal, hippocampal, cortical and limbic areas has been revealed [56,57]. In conscious rats, subanaesthetic doses of ketamine activated medial prefrontal, anterior and posterior cingulate, auditory, visual, entorhinal and retrosplenial cortices, hippocampus (CA1) and striatum [58]. A significant negative bold signal was observed in periaqueductal grey [58]. Further, an elevated GABA level was reported in the anterior cingulate cortex [59]. In the clinic, except for one initial contradictory report [60], a series of recent investigations consistently reported elevated serum BDNF in samples of frequent ketamine users [61], treatmentresistant major depression patients responding to ketamine treatment [62,63] and bipolar patients responding to ketamine [64]. Likewise, phMRI investigations on subanaesthetic doses of

ketamine in healthy volunteers showed activation in many regions of the brain including cingulate cortex (midline, supra, anterior and posterior aspects), prefrontal cortex (medial, ventrolateral and dorsolateral), thalamus, insula and anterior temporal lobe, and more interestingly, a decrease in blood oxygen level dependent (BOLD) signal in the subgenual cingulate cortex [14,65,66]. Metabolism increased in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices in patients with treatment resistant depression receiving ketamine. Clinical improvement inversely correlated with metabolic changes in right parahippocampal gyrus and temporoparietal cortex whereas improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) ratings directly correlated with change in metabolism in right superior and middle temporal gyri [67]. The effect of ketamine in various sub-regions of cingulate cortex is noteworthy since a positron emission tomography (PET) study showed that bipolar patients with the greatest rMRGlu under placebo in the subgenual

26


anterior cingulate displayed the highest degree of antidepressant outcome following ketamine administration [68]. These molecular, metabolic and region specific changes brought about by ketamine could contribute to the overall antidepressant effects. 3. Psychotomimetic effects The underlying molecular mechanisms triggering the psychotomimetic effects of ketamine appear to overlap with the mechanisms of rapid-onset antidepressant action. Subanaesthetic doses of ketamine are reported to increase amino acid (glutamate, GABA and glutamine) neurotransmitter cycling and neuronal and glial energy metabolism in the medial prefrontal cortex [69], due to the likely disinhibition of glutamatergic neurotransmission caused by NMDA antagonism on GABAergic interneurons [70,71]. This hyperglutamatergic state likely underlies the psychotomimetic effect. This is corroborated by a recent report, which shows that S-ketamine treatment caused increased functional connectivity within the prefrontal cortex, and between hippocampus and prefrontal cortex within 30 min [18]. On the contrary, an earlier report showed that ketamine augments synaptic inhibition in the hippocampus-medial prefrontal cortex pathway, which nevertheless is suggested to contribute towards the psychotomimetic effects [16]. A behavioural study in mice shows that intracerebroventricular injections of GSK-3 inhibitors attenuated locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficit effects of ketamine sparing its anaesthetic effects indicating the putative role of GSK-3 in the psychomimetic effects of ketamine [72]. The psychotomimetic effects of ketamine are also evident in human patients, where they are reported to be at least partly mediated by acute cortical gamma oscillations [73] and BOLD activation in the posterior cingulate; while a BOLD suppression in subgenual cingulate may underlie the dissociative effects [14]. However, it was recently shown that dissociative side effects of ketamine, but not its psychotomimetic effects correlated with antidepressant response on day 1 and day 7 after infusion, but contributed to only a fraction of the variance in the response [74]. Thus, while the psychotomimetic effects of ketamine may be separable from its anaesthetic effects by administration of different doses, it may not be possible to separate the antidepressant, dissociative and psychotomimetic effects by careful dosing. Studies in rodents, healthy humans and schizophrenic patients that have examined the effects of subanaesthetic doses of ketamine have proclaimed it as a drug-induced model of schizophrenia and/or psychosis. Ketamine (30 mg/kg) caused increases and decreases in metabolic activity in the prefrontal cortex and dorsal reticular thalamic nucleus, respectively, in mice that reflect its propensity to model schizophrenia [75]. Ketamine administered during four sessions (0.1–0.5 mg/kg) or two sessions (0.3 mg/kg) exacerbates the positive symptoms that were previously experienced in schizophrenic patients [76]. It may therefore be prudent to exercise caution in utilisation of ketamine in suicidal patients with schizophrenia or other predispositions to psychosis. However, for other patients with incipiently fatal suicidal ideation the potential benefits may outweigh the potential risks posed by the psychotomimetic effects. 4. Ketamine and suicidal ideation in clinical studies Clinical studies (Table 1), that support antisuicidal effects of ketamine, encompass (1) studies that explored antisuicidal effects as the primary outcome in depressed patients [10,11,77,78], (2) studies that primarily explored the antidepressant effects [8,79–81] and (3) discrete case reports [82] and a anecdotal report based on observation during many years of clinical practice [83].

Similar to other groups, Price et al. [84] noted that single infusion of ketamine shows significant antisuicidal effects (that could be sustained by repeated infusions) that were mediated by reduction in depression. A couple of case reports suggested the use of ketamine (at higher doses) as a prehospital sedative as observed from its tranquillising effect in suicidal patients [85,86]. Chronic thoughts of death were obliterated in one patient who received ketamine for treatment-resistant depression [87]. A number of other case reports indicated the beneficial effects of ketamine on patients with suicidal behaviour/ideation: at the dose level of 0.5 mg/kg (infused intravenously over 50 min) in treatment-resistant depression with alcohol and benzodiazepine dependence [88]; at a higher dose of 1.5 mg/kg (administered intramuscularly) in severe major depression [89]; at the dose level 0.5 mg/kg (infused intravenously over 50 min) administered twice, 34 days apart in treatmentresistant depression [90]; at the dose level of 0.5 mg/kg (infused intravenously over 50 min), administered 6 times in treatmentresistant depression [91]; ketamine and S-ketamine at the dose level of 0.5 and 0.25 mg/kg respectively (infused intravenously over 50 min) infused one week apart in one treatment-resistant major depression patient [55]; S-ketamine at the dose level of 0.5 mg/kg (infused intravenously over 40 min) in major depression with melancholic symptoms [92]; at the dose level of 0.5 mg/kg (infused intravenously over 40 min) for major depression with comorbid post-traumatic stress disorder [93]; at the dose level of 0.5 mg/kg (oral) in 2 patients with treatment-resistant depression [94] and at a dose level of 50 mg/kg over a day (5 intranasal 15 min apart) in a treatment-resistant depression patient [95]. Further, the risk of suicide was one of the reasons that warranted ketamine treatment (0.5 mg/kg infused intravenously over 40 min) in a patient who suffered severe chronic post-traumatic stress disorder (PTSD) and depression due to combat trauma [96]. A recent case report recommended an intramuscular administration of ketamine (0.5 mg/kg) for suicidal patients [97]. It is noteworthy that these patients had a history of suicidal ideation but the studies do not directly show a reduction in specific suicidal ideation scores. A recent study reported that intravenous ketamine rapidly suppresses suicidal cognition [98]. Although there are a number of suggestive case reports, there have to date been relatively few clinical trials on ketamine that incorporated assessment of suicide subscores. The trials that have been performed were not specifically designed to be powered to detect differences in 1-item suicide subscores (MADRS, HDRS and BDI). It is also important to note that clinical trials not specifically addressing suicidal ideation would invariably exclude highly suicidal subjects. The clinical trials reported thus far cannot conclusively determine whether ketamine is able to specifically target suicidal ideation. There is a need for clinical trials specifically designed to investigate whether there is a consistent preferential decrease in suicide symptom severity with respect to other depressive symptoms. Suicidal risk was an exclusion criteria in several other ketamine trials [9,29,99–103] and other reports argue against the notion that ketamine might alleviate suicidal ideation. A case report observed instances of delayed-onset suicidal ideation associated with ketamine infusion in two female patients who had other psychiatric conditions such as obsessive compulsive disorder, post-traumatic stress disorder and personality disorder comorbid with depression [104]. Interestingly, oral dosing of ketamine was devoid of antisuicidal effects in patients with depression and anxiety and receiving hospice care [105]. Moreover, ketamine abuse, which is frequently via the oral route, with or without history of alcohol or drug abuse is known to sometimes lead to suicidal deaths [106–109]. Ironically, a recent report on the effect of subanaesthetic dose of ketamine on treatment-resistant major or bipolar depression patients suggested that absence of a history of suicide attempt is associated with the durability of antidepressant response[110].


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Table 1 A synopsis of clinical investigations that reported effects of ketamine on suicidal ideation. Study details and diagnosis

Dose administration protocol

No. of patients

Suicide risk instrument

Findings

References

Single i.v. infusion (0.5 mg/kg) over 40 min

36

MADRS, QIDS-SR and BSS

[98]

Double-blind study on the antidepressant effect of ketamine in MD Placebo-controlled, double-blind crossover study in TRD Add-on trial of ketamine in TRBD


7

HDRS


18

HDRS


18

MADRS

Double-blind, crossover, placebo-controlled study on antidepressant efficacy in BD


15

MADRS, HDRS And BDI

SIcomposite scores were reduced in the ketamine group compared to midazolam (p = 0.02; corrected for multiple comparisons). 53% of ketamine-treated patients scored zero on all three explicit suicide measures at 24 h. The antisuicidal effects of ketamine were related to baseline suicidal cognition and non suicide related depressive symptoms. Significant (p = 0.02) reduction in the suicide item (uncorrected for multiple comparisons). Significant (p < 0.05) reduction in the suicide item (uncorrected for multiple comparisons). No significant (p > 0.05) reduction in the suicide item (corrected for multiple comparisons). One patient dropped out due to worsening of suicidal ideation. Significant (p < 0.001) reduction in the suicide item of the specified scales (uncorrected for multiple comparisons). Ketamine lowered suicidal ideation scores from 40 min and sustained till day 3 (MADRS), 40–80 min and day 2 (HDRS) and 40 min to day 2 and at day 10 (BDI).


19

MADRS, HAMD and SSI

[185]

Investigating of explicit and implicit measures of suicidality in TRD

Single or repeated i.v. infusion (0.5 mg/kg) over 40 min

26

MADRS

Study on suicidal ideation and depression scores in TRD


33

SSI, MADRS, HDRS and BDI

Investigation in MD patients with suicidal ideation in emergency department Single-centre, single-arm, pilot study on suicidal cognition in TRD


14

MADRS


27

SSI and HDRS

Study in TRD and anxiety patients receiving hospice care Study in TRD

Nightly oral flavoured solution (0.5 mg/kg) for 28 days Six i.v. infusions (0.5 mg/kg over 40 min) three times weekly over 12-day period

14

SRA

Baseline suicidal ideation and regional cerebral glucose metabolism (rCGM) in the infralimbic cortex were significantly (r = 0.59, p = 0.007) correlated. Reduction in suicidal ideation with ketamine infusion was significantly correlated with decreased rCGM (r = 0.54, p = 0.02) Significant (p < 0.001) reduction suicide item at 24 h post single infusion. With repeated infusions of ketamine the significant (p < 0.001) acute reductions in suicide item persisted for the 12-day treatment period (uncorrected for multiple comparisons in both cases). Significant (p < 0.001) reduction in the suicide item of the specified scales within 40 min and persisted up to 4 h approximately (corrected for multiple comparisons). Significant (p < 0.001) reduction in the suicide item after 40 min and persisted for 10 days (uncorrected for multiple comparisons). Significant (p < 0.001) reduction in scores (SSI) and suicide item (HDRS from 40 min to 230 min but not significant at day 1 (corrected for multiple comparisons). No effects on suicidal behaviour.

24

MADRS

Significant (p < 0.05) reduction in the suicide item suicidal ideation in the study group including non-responders to ketamine (uncorrected for multiple comparisons).

[81]

Randomised controlled trials Two-site double-blind trial on the antidepressant efficacy of ketamine in TRD

Open-labelled studies Identifying neural correlates of suicidal ideation and its reduction in depression in TRD

[8]

[9]

[79]

[80]

[84]

[75]

[11]

[78]

[105]

28


Table 1 (Continued ) Study details and diagnosis

Dose administration protocol

No. of patients

Suicide risk instrument

Findings

References

Study in MD

Twice weekly infusions (0.5 mg/kg over 100 min), until remission or 4 infusions Single i.v. infusion (0.5 mg/kg) over 40 min

10

SSI and SSF

Suppression of scores. SSI and SSF scores significantly correlated with MADRS scores.

[192]

133

HDRS, SSI, BDI and HARS

Reductions in the suicidal ideation was independent of reduction in depressive and anxiety symptoms.

[193]

Three or 6 infusions (0.5 mg/kg over 40 min)

28

BDI, HSRD, BPRS

[194]


52

MADRS, HDRS, HARS, BDI, SSI and YMRS

Reduction in suicide ideation (item 3 on HSRD) in 61% of the patients within 6 h after single infusion. (uncorrected for multiple comparisons). Mean score of all patients dropped and the effect persisted for 21 days in responders. Correlations between total BDI scores and HSRD suicidality score was modest but not significant. Increased suicidal ideation in 3 patients. Although the antidepressant effects of ketamine sustained for 4 weeks, no significant effects on suicide scores.

Data from 4 independent clinical trials on patients TRD (major and bipolar) Study in TRD (major and bipolar)

Antidepressant efficacy of ketamine infusion followed by riluzole or placebo in TRD patients with the family history of alcohol use disorder

[195]

Case reports Ketamine abuse in a bipolar patient (with cannabis/alcohol/ cocaine/ methamphetamine use disorder) Effect in acute depression

Intranasal (1–3 g/day) over a period of 5 years

1

1

Remission of depression mood and suicidal ideation within minutes of insufflation. Symptoms returned within several hours.

[196]

Two intramuscular injections (0.5 mg/kg)

2

HDRS

[97]

Effect in OCD, PTSD and MD patients Reduction of suicidal ideation in MD

Single i.v. infusion (0.5 mg/kg) over 40 min Single i.v. infusion (0.5 mg/kg) over 40 min

2

–

Suppression of suicidal ideation (scores were not reported). Delayed-onset suicidal ideation

1

–

[82]

Oral ketamine augmentation on chronic suicidality in TRD

Fortnightly oral flavoured solution dose of 100 mg/ml (initial dose of 0.5 mg/kg and increased by 0.5 mg/kg with each treatment)

2

MADRS

Marked reduction in suicidal ideation. Intense suicidal ideation was not observed in the subsequent 1 month. Reduction in the suicide item observed within 24 h and the reduction persisted with repeated treatments.

[104]

[94]

Grey rows indicate studies which showed no or worsening effect of ketamine. BD: bipolar depression; BDI: beck depression inventory; BPRS: brief psychiatric rating scale; BSS: beck scale for suicide ideation; HARS: Hamilton anxiety rating scale; HDRS: Hamilton depression rating scale; MADRS: Montgomery–Åsberg depression rating scale; OCD: obsessive-compulsive disorder; PTSD: posttraumatic stress disorder; QIDS-SR: quick index of depressive symptoms (self-report); SIcomposite : composite explicit suicide index; SRA: Suicide risk assessment (derived from Mini International Neuropsychiatric Interview English Version 5.0.0); SSI: scale for suicidal ideation; SSF: Suicide status form; TRD: treatment-resistant depression; TRBD: treatment-resistant bipolar depression, YMRS: Young mania rating scale.

5. Pharmacological management of suicidal ideation As mentioned before, suicidality is one of the most appalling symptoms in many severe psychiatric conditions [111]. Apart from depression, the other psychiatric condition which shares this symptom and contributes significantly to the number of suicides committed is schizophrenia [112]. However, pharmacotherapy of suicidal ideation/behaviour is still premature. The literature is limited to the use of (1) a mood stabiliser (lithium), in suicidality associated with mood disorders, (2) atypical antipsychotics (clozapine and quetiapine) when suicidality is associated with schizophrenia or schizoaffective disorders and sometimes depression, (3) SSRI antidepressants (fluoxetine and paroxetine) and finally, (4) anticonvulsants (divalproex or carbamazepine) [for

reviews see: 113,114,115]. Of note, reports on the SSRI antidepressants and anticonvulsants have been sparse and discouraging and hence they have not been discussed in this review. Clozapine, one of the clinically successful atypical antipsychotics for management of schizophrenia, has been reported to have antisuicidal effects especially in treatment-resistant schizophrenia [for reviews see: 116,117–119]. The antisuicidal effect of clozapine has become one of the key attributes that differentiates it from other antipsychotics [120]. Clozapine showed encouraging results in controlling suicidality in neurolepticresistant schizophrenia [121–123] in comparison to olanzapine [124] and clozapine has a promising impact on saving lives in this patient group at least as modelled on clinical data in the UK [125]. Reports indicate that clozapine has antisuicidal effects


in patients with schizophrenia or schizoaffective disorder [126] and the treatment reduces suicide risk, attempted suicide and rehospitalisation [127]. However, another study demonstrated no influence of clozapine on suicidal behaviour in treatmentresistant schizophrenia [128]. Further, several case studies have shown that clozapine causes suicidal ideation in patients with treatment-resistant/responsive schizophrenia [129–131] or after discontinuation [132]. Due to differences in methodologies, metaanalysis of the data is questionable and caution in interpretation of such data is recommended [133,134]. Quetiapine is another atypical antipsychotic, which has been shown to be antisuicidal by a few reports that have indicated antisuicidal effects in adolescent patients with bipolar and conduct disorder [135], agitated depression [136] and in children and adolescents with symptoms of adult bipolar disorders [137]. The case for use of quetiapine for suicidal ideation is not yet sufficiently established. Lithium, a mood stabiliser, is another interesting pharmacotherapeutic strategy. Although its mechanisms of action are poorly understood, lithium is known to reduce suicidal ideation. In the recent past, epidemiological studies have attempted to correlate lithium in drinking water and suicide prevalence [138,139]. Studies have revealed a marginal but notable decrease in suicide rates with increased levels of lithium in drinking water in Japanese males [140], in Japanese females [141] and significant effects in populations in Greece [142], Austria [143–145], and Texas [146], but no such effect in the east of England [147]. Systematic reviews and meta-analysis reports upheld the effectiveness of lithium in averting suicide, particularly associated with mood disorders [148–152]. Depression, being an integral component of many psychiatric conditions including schizophrenia, mood disorder and adjustment disorder, seems to be the prospective avenue to understand the mechanisms that underlie suicidal ideation/behaviour. This is substantiated by a report which showed that awareness of this psychiatric condition in schizophrenia at the baseline increased the risk of suicide that was mediated by depression and hopelessness levels [153]. Reports on antisuicidal effects of clozapine, quetiapine and lithium have not extensively and specifically focused on suicidal ideation associated with depression. Moreover, the mechanisms of the putative antisuicidal actions of clozapine, quetiapine and lithium are poorly understood. Clozapine is known to modulate various neurotransmitter systems (dopaminergic, serotonergic, cholinergic, GABAergic and glutamatergic), hormones, intracellular pathways and neurotrophic factors. It is speculated that the diversity in pharmacology of this drug may underlie the antisuicidal properties [113]. For quetiapine, the sleep-improving effects may underlie the antisuicidal property [154]. The propensity of lithium to reduce relapse of mood disorder is proposed as the underlying mechanism [148]. In recent years, the mechanisms of action of ketamine have become relatively clearer than for other putative antisuicidal drugs.

6. Neurobiology of suicide/suicidal ideation: is there a scope for ketamine? Post-mortem studies on brain samples from depressed suicide victims throw some light on the gene expression and resultant neurochemical changes that occur in different regions of the brain. A review of these studies, which report changes in the expression of receptors and signalling molecules that play a putative role in the antidepressant and antisuicidal effects of ketamine, could rationalise its use in suicidal ideation in depression. Depressed suicide subjects had reduced expression of extracellular regulated kinases (ERK) 1/2 and increased expression of mitogen activated protein kinase phosphatase 2 (MKP2) that may have possibly led to lesser activation of p44/42 mitogen activated protein (MAP) kinases [155].

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Catalytic activity of B-Raf, a Raf kinase that is one of the upstream activators of ERK-signalling pathway, was reduced in the prefrontal cortex and hippocampus of suicide victims with and without a history of depression [156]. Activities of Akt (protein kinase B) and p44/42 MAP kinases were attenuated in the occipital cortex of depressed suicides [157]. However, the activity of Akt (decreased) and GSK-3beta (increased) in the ventral prefrontal cortex is more an indicator of depression rather than suicide [158]. BDNF and TrkB mRNA levels in the prefrontal cortex and hippocampus of depressed suicide victims were significantly lower than the controls [159]. Furthermore, several independent risk alleles in the neurtrophic tyrosine kinase 2 NTRK2 gene is associated with suicide attempt in depressed patients [160]. These signalling molecules have been implicated in the preclinical rapid-onset antidepressant effects of ketamine (Fig. 1). Upregulations of GABAA receptor subunit alpha 5 in the prefrontal cortex and alpha 1 and beta 1 subunits in limbic system were evident [161,162]. Similar upregulation of GABAA alpha1 and beta3 subunits in the anterior cingulate and dorsolateral prefrontal cortex was also reported [163]. Among microRNAs downregulated and reorganised in the prefrontal cortex of depressed suicides [164], miRNA-34a was shown to be upregulated in hippocampus of mice treated with repeated anaesthetic doses of ketamine [165]. Although a study with a small sample size of 12 major depression subjects (of which 10 subjects were suicide victims), analysis of mTOR, its principle downstream signalling targets in the prefrontal cortex, showed corroborative evidence of deficits in mTOR-dependent translation initiation in major depressive disorder via the p70S6K/eIF4B pathway [166]. When attributing the NMDA-antagonistic effect of ketamine to depression and suicide, it is relevant to discuss the post-mortem reports that revealed derangements in glutamate neurotransmission. Increased glutamate levels were noted in the frontal cortex of bipolar and major depression subjects, especially, a marginal increase was noted in suicide victims [167]. Reduced expressions of NR2A and NR2B transcripts, GluR1 and GluR3 AMPA receptors in the perirhinal cortex of major depression subjects and, downregulation of GlruR1 in perirhinal, GluR2 in entorhinal and GluR3 in both perirhinal and entorhinal cortex in bipolar subjects reflect the disharmony in the glutamatergic neurotransmission in these areas that principally interact with hippocampus and prefrontal cortex [168]. Compensatory or basal changes in the glutamate neurotransmission were suggested to contribute to major depression as observed from lower mGluR5 binding (PET scan) in prefrontal and cingulate cortices, insula, thalamus and hippocampus in the major depression group and a decreased mGluR5 (but not mGluR1) expression (post-mortem brain tissue analysis) [169]. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD95 were noted in prefrontal cortex of 14 major depression subjects and it is notable that 10 of these subjects were suicide victims [170]. Likewise, the hippocampus of suicide victims had decreased potency of zinc and magnesium to inhibit [3H] MK-801 binding to NMDA receptors that were associated with increased NR2A and decreases in both the NR2B and PSD-95 subunit (of NMDA receptor) levels [171]. Furthermore, mGlu2/3 receptor was found to be upregulated in prefrontal cortex of 11 major depression subjects (7 of which were suicide victims) [172]. An increased [3 H]AMPA binding density was noted in anterior cingulate of major depression subjects [173]. A global downregulation of glutamine synthase, an enzyme which contributes to glutamate cycling, and glutamate receptor metabotropic 3 (GRM3) and upregulation of GABA receptor and AMPA receptor subunit genes were observed in the brains of depressed suicides [174]. Another interesting feature is the role of locus coeruleus in major depression that has been revealed by a couple of post-mortem studies. The immunoreactivity level of neuronal nitric oxide synthase, an intracellular mediator of glutamate receptor activation, was significantly lower and NR2C

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immunoreactivity was higher in locus coeruleus in depressed subjects, majority of which were suicide victims [175,176]. Analysis of glutamate transporters in hippocampus showed that expression of membrane transporters (SLC1A2 and SLC1A3) was diminished and vesicular transporter (SLC17A7) was increased in major depression subjects, with similar trends (but lacked statistical significance) in bipolar subjects. Again, 3 of the 6 bipolar patients and 7 of the 11 MDD subjects were suicide victims [177]. Thus, it is apparent that perturbed glutamatergic signalling is integral in the pathophysiology of depression and a majority of the subjects in the aforesaid post-mortem studies were indeed suicide victims. These studies allow us to consider the prospect of employing ketamine for the management of depression and suicidal behaviour. Having given importance to post-mortem studies, which appear to be the logical route to understand the neurobiology underlying depressed suicides, these studies do present a number of interpretational difficulties. Various factors may contribute to suicide, and the investigations carried out so far leave room for ambiguity over whether the finds are markers of depression, suicidality, impulsivity, aggression or stress. Even accepting the assumption that they were suicide markers, it would remain unclear whether they were state or vulnerability markers. The post-mortem changes are also confounded by various factors such as the means of suicide, the differences in method of harvest and processing, age, sex, race, family and medication history of the victim. With such caveats in drawing links between interpretations from post-mortem brain tissue analysis of suicide victims and neuromolecular changes in response to ketamine treatment, the other prospective avenue left with us is to study neurobiology of suicidal ideation especially in depressed patients. Analysis of cerebrospinal fluid of 64 medication free suicidal patients revealed augmented quinolinic acid levels compared to healthy controls, implying heightened glutamate neurotransmission [178], that might explain the use of ketamine in suicidal ideation. It is notable that no statistically significant difference was observed between the patient group with depression and those with disorders such as psychosis, anxiety and substance use as primary diagnosis. This indicates that elevated glutamate neurotransmission might be a common feature in patients with suicidal intent due to any underlying neuropsychiatric condition. Literature is limited on the region specific changes in the brain function in suicides that attempted to correlate suicidal ideation and functional changes in certain regions of frontal cortex. A PET study in major depression patients showed that regional cerebral glucose uptake was lower in ventral, medial and lateral prefrontal cortex in high lethality suicide attempters compared to the low lethality attempters and this effect was more prominent with fenfluramine challenge indicating the role of serotonergic system. Further, lower ventromedial prefrontal cortex activity was associated with higher suicidal intent and higher lethality suicide attempts [179]. Whereas the 5-HT1A binding in prefrontal cortex or raphe regions did not differ among major depression patient groups of suicide attempters and non-attempters [180], prefrontal cortex/midbrain SERT binding ratio was increased in depressed suicidal patients [181]. Further, fMRI studies in recurrent major depression and bipolar II depression implicate the striatalcortical midline circuit in suicidal ideation and that the functional connectivity in the posterior cingulate cortex is associated with suicidal ideation in unipolar but not in the bipolar II depression [182–184]. Investigation of ketamine-related changes in the aforesaid brain regions might provide some cognizance. In line with this view, a very recent study proposed the infralimbic cortex as a putative correlate of suicidal ideation based on a data from 19 treatment-resistant major depression patients in which a significant correlation between suicidal ideation scores and rMRGlu in the infralimbic cortex was noted. Further, the reduction of suicidal

ideation in response to ketamine treatment was correlated with decreased rMRGlu in the infralimbic cortex [185]. Data on the effects of ketamine on animal models of suicidetrait-related behaviour [186,187] will be valuable to identify the avenues to explore the molecular mechanisms that could underlie the antisuicidal effects. The lack of suicidal-trait in animals [187,188] has been the reason for reluctance in the development of animal models of suicide, which in turn is one of the principal reasons retarding identification of targets, ligands and understanding of suicidal ideation. Suicide is challenging to model in animals because it is a culmination of a myriad of factors ranging from human will, intent, impulsivity, aggression, hopelessness, perception and judgement, genetic predisposition, emotional development and social circumstance. Nevertheless, it has proved possible to devise animal models for other complex psychiatric conditions, such as depression and psychosis, with predictive validity that have accelerated drug discovery. If it does prove to be the case that ketamine suppresses suicidal ideation, the mechanisms of action of ketamine may offer a valuable window onto approaches to develop animal models of suicide with predictive validity. 7. Perspective The abrupt suppression of suicidal ideation in response to ketamine infusion is expected to provide a new route towards understanding suicidal ideation. Suicide and depression being intertwined with respect to their manifestation and neurobiological basis, timely pharmacological management of depression itself has been accepted as a tactic to control suicide. The studies on ketamine discussed above suggest some important inferences that could drive future investigations to confirm and understand the effects of ketamine on suicidal ideation in depression. With regards to informing potential strategies for therapeutic intervention, the literature points to the conclusions that (1) subanaesthetic dose (0.5 mg/kg) by intravenous infusion, typically over 40 min is effective in controlling suicidal ideation, (2) lowering the dose further (to 0.2–0.25 mg/kg) and infusion over a shorter duration (2–3 min) was effective in controlling suicidal tendencies in a small population; and (3) the antidepressant effect is generally short-lived, as substantiated by recent reviews and meta-analysis [189–191]. This warrants repeated infusions or subsequent use of other antidepressants for sustenance beyond 3–10 days but encourages the immediate use of ketamine to control suicidal ideation during the first presentation at the clinic. There also remain important limitations and issues that require further investigation: (1) the occurrence of antidepressant/antisuicidal and psychomimetic effects appear to be time-dependent and could be explained by regional influence of ketamine in the brain but further metabolomic and imaging-based investigations are required to reveal the spatial and temporal patterns of brain modulation/activation; (2) the effect of ketamine on suicidal ideation associated with psychiatric conditions other than depression has not been reported and requires further investigation; and (3) some case studies on ketamine showed no antisuicidal effects or even reported ketamine-associated suicidal tendency with use at higher and uncontrolled doses, or in individuals with comorbid psychiatric conditions and/or a history of alcohol or other kinds of drug abuse. It is also of worth mentioning that reports to date have focused on treatment-resistant depression and so less is known about the effects of ketamine on suicidal ideation early in the course of treatment-responsive depression. Investigations in suicidal patient groups with primary diagnosis of depression (major and bipolar), anxiety disorders and personality disorders need to be carried out to examine if the suppression of suicidal ideation is limited to treatment-resistant depression. The psychogenic effects of ketamine will however likely thwart clinical


trials in schizophrenic patients. fMRI evaluation of a larger group of ketamine-treated depressed patients subclassified as (1) patients with suicidal ideation (planners) and (2) patients who attempted suicide, assessed using appropriate scales, could identify the brain regions that respond to rapid intravenous subanaesthetic dose of ketamine and more importantly their role in with suppression of suicidal thoughts. Such thorough investigations on ketamine are obligatory to clarify the mechanisms of the suppression of suicidal ideation. In this scenario, potential biomarkers of the antidepressant and antisuicidal effects of ketamine will be very similar to the current read-outs employed in published trials on ketamine. Identification of specific biomarkers, perhaps, levels of BDNF, glutamate, other neurotransmitter metabolites in CSF or plasma, neurosteroid levels, or modulation of specific brain regions (recorded via electroencephalography or fMRI) in response to ketamine await confirmation from forthcoming clinical trials. With the current dismal lack of pharmacotherapeutic strategies to manage suicide, there is perhaps scope for the optimistic approach of focusing on ketamine as a candidate for controlling suicidal ideation associated with depression, if not comorbid with other psychiatric conditions. While trials on larger patient populations will be essential to confirm the effects, owing to the rapid but short-acting antidepressant characteristic of ketamine, the antisuicidal effects of ketamine could find application in emergency departments prior to other protracted antidepressant pharmacotherapy. Conflict of interest The authors declare no conflict of interest. References [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 5th ed., American Psychiatric Press, Arlington, VA, 2013. [2] C.A. Claassen, M.H. Trivedi, A.J. Rush, M.M. Husain, S. Zisook, E. Young, A. Leuchter, S.R. Wisniewski, G.K. Balasubramani, J. Alpert, Clinical differences among depressed patients with and without a history of suicide attempts: Findings from the star*d trial, J. Affect. Disord. 97 (2007) 77–84. [3] Z. Rihmer, P. Dome, X. Gonda, The role of general practitioners in prevention of depression-related suicides, Neuropsychopharmacol. Hung.: A Magyar Pszichofarmakologiai Egyesulet lapja = Off. J Hung. Assoc. Psychopharmacol. 14 (2012) 245–251. [4] M. Pompili, X. Gonda, G. Serafini, M. Innamorati, L. Sher, M. Amore, Z. Rihmer, P. Girardi, Epidemiology of suicide in bipolar disorders: a systematic review of the literature, Bipolar Disord. 15 (2013) 457–490. [5] K. Szanto, B.H. Mulsant, P. Houck, M.A. Dew, C.F. Reynolds 3rd., Occurrence and course of suicidality during short-term treatment of late-life depression, Arch. Gen. Psychiatry 60 (2003) 610–617. [6] H. Jick, J.A. Kaye, S.S. Jick, Antidepressants and the risk of suicidal behaviors, JAMA: J. Am. Med. Assoc. 292 (2004) 338–343. [7] C.H. Kellner, M. Fink, R. Knapp, G. Petrides, M. Husain, T. Rummans, M. Mueller, H. Bernstein, K. Rasmussen, K. O’Connor, G. Smith, A.J. Rush, M. Biggs, S. McClintock, S. Bailine, C. Malur, Relief of expressed suicidal intent by ECT: a consortium for research in ECT study, Am. J. Psychiatry 162 (2005) 977–982. [8] R.M. Berman, A. Cappiello, A. Anand, D.A. Oren, G.R. Heninger, D.S. Charney, J.H. Krystal, Antidepressant effects of ketamine in depressed patients, Biol. Psychiatry 47 (2000) 351–354. [9] C.A. Zarate Jr., J.B. Singh, P.J. Carlson, N.E. Brutsche, R. Ameli, D.A. Luckenbaugh, D.S. Charney, H.K. Manji, A randomized trial of an n-methyl-d-aspartate antagonist in treatment-resistant major depression, Arch. Gen. Psychiatry 63 (2006) 856–864. [10] G.L. Larkin, A.L. Beautrais, M. Lippmann, Rapid treatment of suicide states in the emergency department, Injury Prev. 16 (2010) A260. [11] G.L. Larkin, A.L. Beautrais, A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department, Int. J. Neuropsychopharmacol./Off. Sci. J. Collegium Int. Neuropsychopharmacol. 14 (2011) 1127–1131. [12] R.B. Price, S.J. Mathew, Does ketamine have anti-suicidal properties? Current status and future directions, CNS Drugs 29 (2015) 181–188. [13] L. Reinstatler, N.A. Youssef, Ketamine as a potential treatment for suicidal ideation: a systematic review of the literature, Drugs in R&D 15 (2015) 37–43. [14] J.F. Deakin, J. Lees, S. McKie, J.E. Hallak, S.R. Williams, S.M. Dursun, Glutamate and the neural basis of the subjective effects of ketamine: a pharmacomagnetic resonance imaging study, Arch. Gen. Psychiatry 65 (2008) 154–164.

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Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety.

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