preliminary data from randomized controlled trials have demonstrated that ketamine may rapidly and effectively control treatment - resistant depression , though the effects are transient.a small subset of studies has demonstrated similar results in the effects of ketamine on suicidal ideation.ketamine has potential as a rapid treatment for suicidal ideation and/or a possible model compound for future drug development .
for decades , ketamine has been recognized as an anesthetic by the medical and veterinary worlds .
it has long been used as an anesthetic for children   and is also occasionally used as an anesthetic for administration of electroconvulsive therapy ( ect ) to patients with high seizure thresholds .
only recently has it been utilized for the treatment of depression and suicidal ideation ( si ) .
first described by berman et  al . , ketamine has since been observed in several small randomized controlled trials to rapidly reduce depressive symptoms and si [ 411 ] .
several review papers and recommendations have been written regarding application of ketamine in treatment - resistant depression ( trd ) , as well as for depressive episodes of bipolar disorder , but few have directly addressed its usefulness for treating si . nonetheless , a recent post  hoc analysis of four studies found that ketamine has an impact on si that is independent of improvement in depression and anxiety .
therefore , the aim of the current review is to provide an overview of the data describing the clinical efficacy of ketamine in si .
there are no current studies that have examined ketamine for suicide attempts and suicidal behavior as outcomes .
the pubmed and cochrane databases were searched by the two authors ( l. r. and n. a. y. ) independently to select relevant studies published up to january 2015 , using combinations of the terms  ketamine ,   suicidal ideation ,   suicide ,   suicidal ,  and  suicidality . 
after all publications were obtained , the articles were individually reviewed and the following inclusion criteria were used for selection : the publication was in the english language ; the patients had si measured at baseline ; and the publication was in a peer - reviewed journal .
because only a limited number of studies directly assessed si , we included randomized controlled trials , open - label uncontrolled studies , and case series / reports .
a total of 41 articles were reviewed , and nine met our inclusion criteria ( fig .  1 ) .
a combination of relevant reference citations within the original nine publications and additional searches for necessary background information completed the total data collection.fig . 
1search strategy for the systematic review of ketamine as a treatment for suicidal ideation or suicidality search strategy for the systematic review of ketamine as a treatment for suicidal ideation or suicidality
a total of nine publications ( six studies and three case reports ) investigated the efficacy of ketamine for si [ 4 , 7 , 10 , 11 , 1317 ] .
three of these studies were randomized controlled trials [ 4 , 11 , 18 ] , three were open - label non - randomized studies [ 1517 ] , and three were case reports [ 10 , 13 , 14 ] .
similar to the findings of studies examining patients with trd , a reduction in si was seen as early as 40  min and lasted for an average of 3  days .
the results are summarized in table  1 and are discussed further below.table  1studies and cases of ketamine as treatment for suicidal ideation ( si)referencesdesign , sample sizepatient selectiontreatmentoutcome measuresresultsberman et  al .
rct crossover , n  =  8mdd0.5  mg / kg  iv or placebo over 40  minhdrs items related to sisi symptoms decreased during ketamine treatment ( p  =  0.02)price et  al .
open study , n  =  26trd0.5  mg / kg  iv over 40  minmadrs - siat 24  h , madrs - si scores were 01  ( n  =  8) , 23 
( n  =  3 ) , 4  ( n  =  2)subset : madrs - si score  4 ( n  =  13)diazgranados et  al .
open study , n  =  33mdd0.5  mg / kg  iv over 40  minssi , madrs , hdrs , bdiscores on all scales were decreased significantly between 40  min and 4  hlarkin and beautrais open study , n  =  14ed patients with si0.2  mg / kg  iv bolusmadrsscores decreased from 3.9 at baseline to 0.6 at 40  min ; the effect lasted for 10  dayszarate et  al .
rct crossover , n  =  15bipolar i or  ii disorder with current depressive episode0.5  mg / kg  iv over 40  minmadrs - si , hdrs , bdimadrs : lower si scores between 40  min and day  3hdrs : lower si scores between 4080  min and day  2bdi : lower si scores between 40  min , day  2 and day  10zigman and blier case reporttrd0.5  mg / kg  iv over 40  minclinical interviewsi score decreased from 9/10 to 0/10 ; the effect lasted for 8  daysharihar et  al .
case reports , n  =  2depression0.5  mg / kg  ivhdrscase  1 : hdrs score was decreased from 17 to 4 after 2  hcase  2 : hdrs score was decreased from 21 to 6 after 2  hde  gioannis and de  leo case reports , n  =  2trd , previous suicide attempts0.5  mg / kg oral suspension titrated upmadrs - sicase 1 : madrs - si score was decreased from 4/6 to 1/6 after 24  hcase 2 : madrs - si score was decreased from 4/6 to 2/6 after 24  hprice et  al .
double - blind rct , n  =  57 ( n  =  36 for ketamine)trd0.5  mg / kg  iv over 40  min versus midazolam 0.045  mg / kgbss , madrs - si , qids - sr , iatlower composite si scores after 24  h with ketamine versus midazolam ( p  =  0.01)no difference in iat score 
 bdi  beck depression inventory , bss  beck scale for suicide ideation , ed  emergency department , hdrs  hamilton depression rating scale , iat  implicit association test , iv  intravenous(ly ) , madrs - si  montgomery  sberg depression rating scale suicidal ideation item , mdd  major depressive disorder , qids - sr  quick inventory of depressive symptomatology  self report , rct  randomized controlled trial , ssi  scale for suicide ideation , trd  treatment - resistant depression studies and cases of ketamine as treatment for suicidal ideation ( si ) 
 bdi  beck depression inventory , bss  beck scale for suicide ideation , ed  emergency department , hdrs  hamilton depression rating scale , iat  implicit association test , iv  intravenous(ly ) , madrs - si  montgomery  sberg depression rating scale suicidal ideation item , mdd  major depressive disorder , qids - sr  quick inventory of depressive symptomatology  self report , rct  randomized controlled trial , ssi  scale for suicide ideation , trd  treatment - resistant depression in the first study , by berman et  al .
, depressive symptoms , as assessed by the hamilton depression rating scale ( hdrs ) , were measured before and after ketamine administration . as a secondary measure ,
an item - level analysis of the suicidality item on the hdrs was also performed .
although the specific scores on the suicidality item were not reported , the authors reported a statistically significant reduction ( p  =  0.02 ) between the baseline and final scores of suicidality . similarly , in their randomized controlled add - on trial , zarate et  al .   examined si as a secondary outcome , using the montgomery
sberg depression scale ( madrs ) , hdrs , and beck depression inventory ( bdi ) surveys .
there were significant reductions in suicidality item scores in the 15 participants included in the study , beginning at 40  min and lasting for 3  days on the madrs ( p  <  0.001 for all three rating scales ) .
the effects lasted for 2  days as assessed by the hdrs , and for up to 10  days as assessed by the bdi .
after the ketamine infusion , there was a statistically significant improvement in suicidality on the suicide items of all three rating scales .
an open - label study by price et  al . in 2009   examined the effects of ketamine on si , using the madrs suicidal ideation item ( madrs - si ) and implicit association test ( iat ) measurements .
a subset of 13 of them had significant baseline si ( madrs - si score 4 ) .
mg / kg intravenously over 40  min . among the 13 patients , 8 ( 62  % ) had an madrs - si score of 1 24  h postinfusion , 3 ( 23  % ) had a score of 23 , and two ( 15  % ) remained at or above an madrs - si score of 4 .
the overall average reduction in madrs - si scores was just over  2 ( p  <  0.001 ) . it is interesting to report the results unique to that study related to implicit measures of suicidality . in a separate subset of 12 patients ,
implicit measures were assessed using the iat , which assesses implicit suicidal associations and is a  behavioral measure of suicidal cognition . 
statistical analysis revealed that stronger implicit associations correlated with higher madrs - si scores , and the implicit measurements significantly decreased after the ketamine infusion ( p  =  0.003 ) . in another open - label study , 33 patients with trd currently experiencing a major depressive episode were given ketamine 0.5  mg / kg intravenously for specific observation of its effects on si .
si was measured on four surveys : the scale for suicide ideation ( ssi ) , madrs , hdrs , and bdi .
the authors specifically used the ssi to determine the presence of baseline suicidality , and they found that 10 of the 33 patients had significant ssi scores of > 4 . in this population , significant decreases in symptoms ( ssi scores of < 4 ) were seen beginning at 40  min in nine of the patients and at 80  min in the tenth one .
the average time to an ssi score of 0 for all 10 patients was 2  h. the improvement in their clinical symptoms lasted for up to 4  h. when the 33 patients were analyzed together , clinical improvement was seen across all four suicide scales from 40 to 230  min ( p  <  0.001 ) .
larkin and beautrais   followed 14 patients who presented with si to the emergency department ( ed ) .
the patients received an intravenous bolus of ketamine 0.2  mg / kg over 12  min .
after the infusion , they were followed for 10  days and their symptoms were measured using the madrs .
these patients saw significant improvements in their clinical symptoms , beginning at 40  min , with the madrs - si score decreasing from 3.9 to 0.6 .
the patients subjectively reported relief of si , which lasted for the 10  days that they were followed . in their case report
, zigman and blier   described how a single infusion of ketamine 0.5  mg / kg over 40  min stabilized a patient with trd and suicide intent with a plan .
the patient reported that the effect of ketamine lasted for 8  days , and she denied any return of si for the following month .
the first patient had a psychiatric history of obsessive  compulsive disorder and worsening depression , including suicidal thoughts .
he received ketamine 0.5  mg / kg intramuscularly after admission to the hospital for a suicide attempt .
his hdrs score changed from a baseline of 17 to 4 , 2  h after the ketamine treatment .
after the same dose of ketamine , his hdrs score changed from 21 to 6 .
the most recent case reports documented two patients with trd , chronic si , and multiple past suicide attempts .
for the first patient , his dose was titrated up to 3  mg / kg , where he attained a maximum response without side effects .
his baseline madrs - si score was 4/6 , and 24  h after the ketamine treatment , it had decreased to 1/6 .
the patient received a maximum dose of oral ketamine solution 1.5  mg / kg .
she achieved a change in her madrs - si score from 4/6 to 2/6 after 24  h , and the authors also reported that she had sustained clinical remission of si with monthly oral doses of ketamine .
the largest study to date included 57 patients with trd in a randomized double - blind placebo - controlled trial .
patients were randomized to receive either ketamine 0.5  mg / kg intravenously over 40  min or midazolam 0.045  mg / kg intravenously .
patients who were thought to be at imminent suicide risk were excluded from the study because of ethical considerations about using a placebo .
a total of 36 patients received ketamine , and 21 received midazolam . as in the previous study conducted by this group , the patients were assessed for explicit and implicit suicidality .
a combination of the beck scale for suicide ideation ( bss ) , madrs - si , and the quick inventory of depressive symptomatology - self report ( qids - sr ) comprised the explicit measurements in a measurement termed  si composite scores ,  while the iat looked at implicit associations .
the ketamine treatment group experienced a greater reduction in si composite scores than the placebo group ( p  =  0.01 ) .
in addition , 53  % of the treatment group scored 0 on explicit measures of suicide after 24  h , while only 24  % of the placebo group scored 0 ( p  =  0.03 ) .
when looking at implicit measures , the authors found no difference in the effect on implicit suicidality , based on the treatment after 24  h. they did note that the scores for one item on the iat ,  escape  =  me ,  decreased from baseline only in the ketamine group .
with an estimated prevalence of mood disorders ranging from 3.3 to 21.4  % and the substantially increased risk of suicide among patients with mood disorders , treatment is certainly warranted .
they include brain stimulation therapeutics , such as ect , and pharmacological intervention ( lithium , clozapine ) .
the efficacy of lithium in treating suicidality has been documented [ 20 , 21 ] and has recently been reviewed and pooled in a recent meta - analysis of 48 studies .
clozapine has also been shown to reduce suicide risk in patients with schizophrenia [ 23 , 24 ] . the limitations of both lithium and clozapine include a longer time to efficacy in this psychiatric emergency / urgency , compared with the early response to ketamine .
ketamine seems to be gaining substantial evidence as a pharmacological option for depression with a fast onset of action , but its long - term effects need further investigation . in addition , ketamine probably offers a faster onset of action in terms of si , but further work is certainly needed in this area .
given the risk of suicide and even the increasing rates of suicide in certain subgroups , such as soldiers and veterans [ 26 , 27 ] , there is an urgent need for faster therapeutics for si and trd .
importantly , suicidality and suicide pose a high global burden of patient suffering to families and society .
although several small - to - moderate sized studies , in addition to several reviews , have been published that have examined the efficacy of ketamine in trd , there are considerably fewer published data specifically examining ketamine in patients presenting with si .
notably , only three studies have directly examined si as the primary outcome [ 11 , 16 , 17 ] , while the rest examined si as the secondary outcome [ 4 , 15 , 18 ] , not including case reports .
the data so far show promising trends of ketamine being an effective and rapid treatment with minimal side effects .
pharmacologically , ketamine is an n - methyl - d - aspartate ( nmda ) receptor antagonist .
it has been used for anesthesia in the usa since the 1970s . at subanesthetic doses
this mechanism is relevant , as glutamate regulation and expression are altered in patients with major depressive disorder ( mdd ) .
studies have also demonstrated an abnormal glutamate  glutamine  gamma - aminobutyric acid cycle in patients with suicidality .
no other class of antidepressant medication works to modulate the glutamatergic system , and research continues into this , with the goal of characterizing the full mechanism of action of ketamine and perhaps developing other compounds that would have similar effects .
thus , even if the approval and marketing of ketamine as a rapid - acting antisuicidal and antidepressant medication is not realized , it could well be a prototype for development of other medication(s ) that retain the mechanism of action with more favorable qualities and a lesser adverse effect profile ( such as a longer duration of action or less or no addictive potential ) .
although the mechanisms explaining the antisuicidal effect and the nmda receptor antagonism of ketamine are still unclear , some of the initial evidence points to an anti - inflammatory action via the kynurenic acid pathway .
strong suggestions as to the causal relationship between inflammation and depression / suicidality has come from studies demonstrating that cytokines [ 30 , 31 ] and interferon-   induce depression and suicidality .
other recent studies have added to the notion of implicating brain immune activation in the pathogenesis of suicidality .
for instance , one study showed microglial activation of postmortem brain tissue in suicide victims .
another study found increased levels of the cytokine interleukin-6 in cerebrospinal fluid from patients who had attempted suicide .
higher levels of inflammatory markers have been shown in suicidal patients than in non - suicidal depressed patients [ 33 , 35 ] .
inflammation leads to production of both quinolinic acid ( an nmda agonist ) and kynurenic acid ( a nmda antagonist ) .
the correlation between quinolinic acid and suicide intent scale scores indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality .
small randomized controlled trials have demonstrated the efficacy of ketamine in rapidly treating patients with both trd and/or bipolar depression [ 4 , 8 , 9 , 11 , 1618 ] .
some studies have also examined suicide items as a secondary measure in their depression rating scales [ 4 , 7 ] . in total
, the studies examining ketamine and trd have nearly consistently demonstrated that ketamine provides relief from depressive and suicidal symptoms , starting at 40  min and lasting for as long as 5  days .
questions still remain as to the long - term effects of this treatment , how much should be administered and how often , any serious adverse effects , and the mechanism of action .
pharmacologically , ketamine has poor bioavailability and is best administered via injection . in their landmark study , berman et  al
.   found that a subanesthetic dose ( 0.5  mg / kg ) rapidly improved depressive symptoms .
most of the subsequent studies have delivered ketamine as a constant infusion for 40  min at a rate of 0.5  mg / kg .
others have examined its efficacy after multiple infusions and observed similar results [ 8 , 13 , 16 , 38 ] .
ketamine is considered to be a safe compound ; however , it is not without its side effects .
some studies have reported symptoms of dissociation and hallucinations , although these are usually transient [ 7 , 14 , 18 ] . a recent study of ketamine administration in 10  patients with obsessive 
notably , these patients had extensive psychiatric comorbidity , and these findings have not been duplicated .
the current literature refers to patients who have abused ketamine as a recreational drug . in this population ,
the long - term consequences have not been described , but it is clear that further studies are needed in this area .
the weaknesses of this review include possible bias in the way in which studies were selected for inclusion  including publication and selection bias .
the literature is limited on this topic , as we have noted in this review .
however , this review includes recent data from several randomized controlled trials , including one recent double - blind placebo - controlled trial .
it must also be noted that differences in patient populations were not explored among the papers cited in this review .
some aspects of the efficacy of ketamine may be dependent on patient age , race , gender , etc .
, as evidenced by the differences in effect sizes noted among the studies , even when they used the same dosages and the same measurement tools .
there are still several questions that need to be answered if standard clinical use of ketamine as an agent for treatment of si is to be definitively pursued .
further studies are needed to better identify the best dose and delivery method of ketamine .
studies should specifically be conducted to assess si as the primary , not secondary , outcome .
studies are also needed to further characterize the long - term benefits ( if any ) and the long - term risks / adverse effects , especially the abuse potential .
also , there are no data on prevention of suicide attempts or death by suicide . more information is also warranted to gain a better understanding of the mechanism of action of ketamine .
this information could provide guidance for further drug development , as well as further insight into the pathogenesis of suicidality . additionally , the exploration of compounds that function similarly to ketamine warrants attention .
one of these compounds may be scopolamine , an antagonist at cholinergic muscarinic receptor sites .
studies have demonstrated effective resolution of depressive symptoms within 3  days of treatment with scopolamine in some patients . also , the metabolite norketamine , which may be a possible player in the antidepressant and/or antisuicidal effect of ketamine [ 43 , 44 ] , deserves further research .
investigations into ketamine and other promising agents for emergent treatment of suicidality merit further research and replication in larger studies , in addition to further understanding of the mechanism of action .
it should be noted that although nmda antagonism has been proposed as the primary mechanism of action , some researchers have questioned that and raised the possibility that its stimulant action or opiate agonism might be more important than is currently appreciated .
there is early preliminary evidence not only for the antidepressant action but also for the rapid antisuicidal action of ketamine .
further research is needed to achieve better understanding of the mechanism of action and the most appropriate route of administration , to better define dosing , and to examine the long - term adverse effects ( including abuse potential ) and benefits of ketamine , while exploring potential similar medications that might provide better side effect profiles , or that are more easily administered , in larger double - blind randomized clinical trials .
 objectiveto review the published literature on the efficacy of ketamine for the treatment of suicidal ideation ( si).methodsthe pubmed and cochrane databases were searched up to january 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with si / suicidality . 
 searches were also conducted for relevant background material regarding the pharmacological function of ketamine.resultsnine publications ( six studies and three case reports ) met the search criteria for assessing si after administration of subanesthetic ketamine . 
 there were no studies examining the effect on suicide attempts or death by suicide . 
 each study demonstrated a rapid and clinically significant reduction in si , with results similar to previously described data on ketamine and treatment - resistant depression . 
 a total of 137 patients with si have been reported in the literature as receiving therapeutic ketamine . 
 seven studies delivered a dose of 0.5  mg / kg intravenously over 40  min , while one study administered a 0.2  mg / kg intravenous bolus and another study administered a liquid suspension . 
 the earliest significant results were seen after 40  min , and the longest results were observed up to 10  days postinfusion.conclusionconsistent with clinical research on ketamine as a rapid and effective treatment for depression , ketamine has shown early preliminary evidence of a reduction in depressive symptoms , as well as reducing si , with minimal short - term side effects . 
 additional studies are needed to further investigate its mechanism of action , long - term outcomes , and long - term adverse effects ( including abuse ) and benefits . 
 in addition , ketamine could potentially be used as a prototype for further development of rapid - acting antisuicidal medication with a practical route of administration and the most favorable risk / benefit ratio . 
Key Points
Introduction
Methods
Results
Discussion
Conclusion