Chapter 12

Experimental Pharmacologic Approaches

fortheReductionofSuicidalIdeation
and Behavior

ElizabethD.Ballard,EricaM.Richards,DawnF.Ionescu,
MarkJ.Niciu,JenniferVandeVoortandCarlosA.ZarateJr

Abstract Treatment of the suicidal patient is limited by existing antidepressant

medications,whichcantakeweeksforanadequateresponse.Newtreatment
approachesassociatedwithrapidreductionofacutesuicideriskaregreatlyneeded.
Experimental therapeutics—including intravenous ketamine andscopolamine—
haverapid,robust,andrelativelysustainedreductionsinsuicidalthoughtswithin
minutestohoursofadministration.Thesefindingshavethepotentialtotransform
emergenttreatmentoftheacutelysuicidalpatientandimplicatetheglutamatergic
and muscarinic system in the development of suicidal thoughts and behaviors.
Otherputativetargetsforantisuicidalinterventionincludethethyroidandpuri-
nergic system, the latter involving the impulsive/aggressive suicide endophenotype.
Benefits of research involving rapid-acting therapeutics include smaller sample
sizes,shortlengthofclinicaltrials,andassuredcompliancewithstudyinterven-
tions.Thisapproachalsopermitstheevaluationofpossiblebiomarkersofresponse
andrelapsetobeincorporatedintoclinicaltrialdesigntomorerapidlyidentify
neurobiological correlates of suiciderisk.

Eachyear,anestimated1,000,000individualsworldwide,and30,000inAmerica
alone,diebysuicide(CentersforDiseaseControlandPrevention2013).Clinically,
over420,000individualsseektreatmentforsuicidalthoughtsorbehaviorinU.S.
emergencydepartmentseachyear(Tingetal.2012).Consequently,suicidalidea-
tionisacommonpresentationinpsychiatricpracticewithpotentiallyfatalconse-
quences;50%ofpsychiatristshavehadapatientdiebysuicide(Ruskinetal. 2004).
Unfortunately, few psychopharmacologic approaches have been consistently
associatedwithareductioninsuicidalbehavior(Mathewsetal.2013)andonlyone
psychiatric medication, clozapine, has Food and Drug Administration(FDA)
approvalforsuicidalbehaviorinpatientswithschizophrenia.Existingantidepres-
santmediations,whichalsomaybeusedtotreatdepressedsuicidalindividuals,can
takeweekstotakeeffect.Thisdelayinimprovementofsuicidalideationplaces

E.D.BallardE.M.RichardsD.F.IonescuM.J.NiciuJ.V.VoortC.A.ZarateJr(&)
· · · · ·
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program,
NationalInstituteofMentalHealth,NationalInstitutesofHealth,Bethesda,MD20892,USA
e-mail:zaratec@mail.nih.gov

© Springer International Publishing Switzerland 2014 209

K.E. Cannon and T.J. Hudzik (eds.), Suicide: Phenomenology and Neurobiology,
DOI 10.1007/978-3-319-09964-4_12
210 E.D. Ballard etal.

individualsatriskforsuicidalbehavior(Jicketal.2004).Therefore,inadditionto
theFDAapprovedpsychopharmacologicmedications,thereisagreatneedfornew
approachesthatareassociatedwithrapidreductionofacutesuiciderisk.

12.1 Obstacles to Suicide Research

Thereareanumberofobstaclestosuicideresearch,whichcanbecomeevenmore
intransigentinthedevelopmentandevaluationofnovelcompounds.First,deathby
suicideisalowbaseratephenomenonevenamongpatientswithmajorpsychiatric
disorderslikemajordepressivedisorder,bipolardisorder,andschizophrenia.Since
extremelylargesamplesizeswouldberequiredtodetectchangesindeathby
suicide,mostclinicaltrialsusesuicideideationorattemptsasprimaryoutcomes.
Patients who contemplate and attempt suicide—but live—may be clinically dif-
ferentfromthoseindividualswhodiebysuicide(DeJongetal.2010),whichcreates
asignificantlimitationinsuicideresearchandagainatteststotheneedforlarge
samplesizes.Second,thetimingofaclinicaltrialinrelationtothesuicidalthoughts
orbehaviorcanbeproblematic,asattemptsmaybeimpulsivewithlittlecontem-
plationbeforehand.Bythetimearesearcherisabletoidentify,contact,andfully
consentaparticipant,the“suicidalcrisis”maybeoveroralreadytreatedinan
emergencysetting.Lastly,ethicalconcernsinherentinclinicaltreatmentresearch
withsuicidalindividualsarenumerous,includingthecapacitytoconsentwhilea
patientissuicidal,thepotentialtodoharmiftreatmentiswithheldinaplacebo-
controlled study, safety monitoring throughout the trial (including emergency
coverage)andcriteriaforstudywithdrawal(Pearsonetal.2001).Asaresult,most
oftheneurobiologicalliteratureonsuicideriskisconductedwithparticipantswho
haveattemptedsuicideintheirlifetimeandrarelyproximaltotheeventitself.
Nonetheless,consideringtheimpactofsuicidalbehavioronpatients,cliniciansand
communities,clinicaltrialswithpatientsatacuteriskareessential.Thefollowing
chapterdetailspotentialneurobiologicaltargetsinsuicidalpatientsanddescribes
newprogressinexperimentaltherapeuticswiththehopethatfaster,moreeffica- cious
interventions can bedeveloped.

12.2 ANewResearchModeltoDevelopandEvaluate
Rapid-ActingTreatmentsforDepressionandSuicidal
Ideation

Theevaluationoftreatmentsforsuicidalpatientsandidentificationofbiomarkersof
treatment response have been limited by existing pharmacologic interventions.
Treatment response may take weeks-to-months with standard antidepressants,
which is inadequate for the urgent need to treat suicidal thoughts andbehavior
12Experimental Pharmacologic Approaches for the Reduction… 211

immediately in emergency settings. Furthermore, to detect a

treatmenteffectonsuicidalbehaviors,follow-upobservationwouldneedtolastwel
lbeyondthedurationofmostclinicaltrialsinordertocapturesufficientevents.Conseq
uently,ascertainingtreatmenteffectsandpotentialresponsebiomarkersforconventi
onalantidepressants(oftencitedastheprimarytreatmentsforsuicidalbehavior)islen
gthy,costly,andrequiresmanyparticipants.Incontrast,newexperimentaltherapeut
ics—includingintravenousinfusionswithketamineandscopolamine—have rapid,
robust, and relatively sustained antidepressant
effectsinmajordepression(Zarateetal.2012,2013b;Murroughetal.2013).Thebenefi
tsofthisresearch model or paradigm include smaller sample sizes, decreasedcosts
fromlonger trials, and assured compliance unlike with daily
oralmedications,whichaddressessomeoftheethicalobstaclestoresearchwithsuicid
alindividuals.Fur-thermore,thisparadigmallowsevaluationofpossiblebiomarkerso
fresponseandrelapse to be incorporated into clinical trial design.
Specifically,exploratorybio-markersoftreatmentresponse,suchasneuroimaging,p
eripheralbloodmarkers,genomics,andproteomicscanbeassessedbefore,duringan
daftertheadminis-tration of the experimental compound; the
post-administrationevaluationthenoccurs on a time scale of hours-to-days
instead
ofweeks-to-months.Treatmentresponsebiomarkersmaythenbevalidatedinlarg
ertrialsand,inaniterativeprocess,leadtoenrichmentstrategiesforfuturedrugscree
ninganddevelopment(forafulldiscussionofthisprocess,pleaseseeZarateetal.(2013
a);Niciu(2014)).Within this paradigm, the treatment of the suicidal
patientwarrantsspecificconsideration,astheprimaryoutcomeofinterestshiftsawayf
romsuicidalbehaviortosuicidalthoughts.Ifanintravenousantidepressantcompoun
dhaseffectswithinanhour,itisimprobabletoseeanobservableeffectonsuicidalbe
havior(s)inahighlysupervisedresearchsetting.Inotherwords,sincesuicideattempt
sarerel-ativelyrare,itisnotpossibletodemonstrateashort-termimpactonsuicid
albehaviorintheresearchenvironment.Further,whilesuicidalideationisassociated
withlatersuicideattemptanddeath(Baca-Garciaetal.2011),itisnotanappro-priatep
roxyforsuicidalbehavior,duetotheclinicaldifferencesbetweenideatorsandattempte
rs(DeJongetal.2010;Smithetal.2010;Borgesetal.2010).Instead,inevaluatingrapid
-actingantidepressants,trajectoriesofsuicidalideationareassessedusingsuchmea
suresastheScaleforSuicidalIdeation(SSI)(Becketal.1979), Montgomery-Asberg
Depression Rating Scale
(MADRS)(MontgomeryandAsberg1979),andColumbia-SuicideSeverityRatingScal
e(C-SSRS)(Posneretal.2011)whicharesensitivetochangeovershortperiodsoftime.W
hileindividualswhocontemplatesuicidemaydifferfromthosewhoattempt(DeJonget
al.2010),arobust antisuicidal effect of rapid-acting antidepressants
onthesestandardizedmeasuresentailsfewerparticipantsand/ormorerapidthrough
putinacontrolled
(typicallyinpatient)milieu.Sucharesearchmodelmayminimizeriskassociatedwithp
articipationwithexperimentaltrials,includinglesstimeoffofmediationsortraditional
clinical treatment and closer observation during the experimental phase.
212 E.D. Ballard etal.

12.3 Potential Targets for SuicidalBehavior

Putativetargetsinthedevelopmentofpharmacologicapproachestothetreatmentof
suicidalthoughtsandbehavioraredisplayedinFig.12.1.Thereareseveralotherin-
depthanalysesoftheneurobiologyofsuicide(Ernstetal.2009;MannandCurrier
2010),includingarecentreviewfromourgroup(Mathewsetal.2013).Themostres
earchedpotentialtargetsinclude:(1)theserotonergicsystemaslowerseroto- nergic
functioning and lower 5-hydroxyindoleacetic acid (HIAAA) levelshave
beenfoundinthecerebrospinalfluid(CSF)ofindividualswhodiebysuicide
(Asbergetal.1976;Nordstrometal.1994;Mannetal.1995);(2)thehypotha-
lamic-pituitary-adrenal(HPA)axis,whichmaybeaffectedbyepigeneticinfluences
relatedtoearlylifestress(Tureckietal.2012)and;(3)otherhormonalsystems,
including low cholesterol and high testosterone, which are associated with
increasedsuicideattempts(Kunugietal.1997;Sher2012).
Whilehistoricallyunderstudiedinthesuicideresearchliterature,theglutama-
tergicsystemhasreceivedgreatattentioninthepasttwodecadesintheetiology,
pathogenesis,pathophysiology,andtreatmentofmajormooddisorders(Sanacora
etal.2008;Zarateetal.2006).Inthelargereal-worldmajordepressivedisorder
effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression
(STAR*D), treatment-emergent suicidal ideation, was associated with single
nucleotidepolymorphismsforGRIA3andGRIK2,whosegenesencodeionotropic
glutamatereceptors(Lajeetal.2007).Similarassociationswerefoundinthe
MunichAntidepressantResponseSignature(MARS)trial(Menkeetal.2008).
AlterationsinN-methyl-D-aspartate(NMDA)receptorfunctionhavealsobeen
foundinindividualswhodiedbysuicide(Nowaketal.1995).Suchfindingshave led
to the investigation of glutamate-based compounds such as ketamine in the
treatmentofdepressionandsuicidalideation.Table12.1depictsclinicalcom-
poundsimplicatedinthetreatmentofsuicidalthoughtsandbehaviors.

12.3.1 Endophenotypes of SuicidalBehavior

Duetotheheterogeneityinmolecularpathwaysandclinicalpresentationsassoci-
ated with suicide, an endophenotypic approach may be beneficial for identifying
treatment targets. An endophenotype represents an intermediary step fromgenes-to-
clinicalphenotype,whichcansimplifyintermediateplayersinmultifactorialdis-
orders and identify mediators/moderators underpinning complex clinical presenta-
tions (Gottesman and Gould 2003). Several proposed suicide-salient
endophenotypes,usingcriteriasetforwardbyGottesmanandGould(2003),include
impulsive and aggressive traits, early onset of major depression, neurocognitive
dysfunction(includingexecutivefunctioningandimpaireddecision-making),and
cortisolresponsetopsychosocialstress(Mannetal.2009;Courtetetal.2011).
Otherproposedcandidateendophenotypesforsuicidalbehaviorwithrelativelyless
12Experimental Pharmacologic Approaches for the Reduction… 213

Serotonin
Neurotransmitters HPA Axis
StressSystems CellG-Proteins
Signaling
Norepinephrine Polyamines PLC
Dopamine Cytokines PKC
Glutamate Testosterone PKA
GABA Lipid Metabolism CREB
Opioid Epigenetics BDNF andTrk-B
Acetylcholine CognitiveAlterations receptor

Fig.12.1Putativetargetsintheneurobiologyofsuicide.Adaptedfrom:(Mathewsetal.2013).
BDNF brain-derived neurotrophic factor; CREB cyclic AMP-response element binding protein;
GABA gamma-aminobutyric acid; HPA hypothalamic-pituitary-adrenal; PLC Phospholipase C;
PKC Protein Kinase C; PKA Protein Kinase A; Trk tyrosine kinasereceptor

research evidence are dysfunctional serotonergic neurotransmission, second-mes-

senger systems aberrations, and traits consistent with borderline personality disor-
der,includingaffectivedysregulationanddifficultiesininterpersonalrelationships.
Eachoftheseconstructscouldbeusedtoidentifytreatmenttargetsforexperimental
therapeuticsforsuicidalbehavior,withallopurinolasacaseexamplediscussedin the
followingsection.

12.3.2 Purinergic System and Allopurinol

The purinergic system has been implicated in the impulsive and aggressive
behavior associated with mania (Machado-Vieira 2012) and has therefore been
targeted in drug development. Purinergic metabolism is involved in the
regulation of neurotransmitters (ATP and adenosine) and affects
sleep,motoractivity,appetite, cognition, and social interaction
(Machado-Vieira2012). An adenosine antagonist, caffeine is also a GABA
receptor antagonist and phosphodiesterase inhibitor; excessive consumption
is associated with irritability, anxiety, tachycardia, and increased blood
pressure (presumably via its effects on GABA). In contrast, increased
caffeine consumption has been linked with a lower risk of death by suicide
(Lucasetal. 2014). The end product of purinergic metabolism is uric acid, which
has been positively associated with increased drive/motivation, disinhibition,
hyperthymia, and irritable temperament (Lorenzietal. 2010). As a syndrome
model,Lesch-Nyhan Disease is a congenital disorder associated with the
over- production of uric acid associated with increased de novo purine synthesis
and deficient salvage of purine bases. Among the characteristics associated with
this disorder is intense self-injurious behavior, including self-biting and
self-hitting
214 E.D. Ballard etal.

Table 12.1 Psychiatric Medications with AntiSuicidal Evidence

Drug Target Findings
Clozapine Dopamine receptors (D1-4), serotonin Anti-aggressive effects, antipsychotic
receptors (1A, 2A, 2C), adrenergic and mood stabilizing effects, close
receptors, histamine (H1) receptors, clinical monitoring (Hennen and
muscarinic (M2) receptors Baldessarini.2005;Frogleyetal.2012)
FDA approved for suicidal behavior in
patients with schizophrenia
Lithium cAMP mediated signal transduction; Mood stabilizing and anti-depressant
CREB activation; BDNF; PI cascade; effects; thought to also target
PKC inhibition; GSK-3 inhibition; impulsivity and aggression (oral
Bcl-2 expression formulation) (Quiroz et al. 2010;
McCarthy et al. 2010)
Ketamine NMDA receptor antagonist; mTOR Rapid antidepressant and antisuicidal
activation; eEF2 de-suppression; effects(0.1–0.5mg/kgIV)(Kavalali
BDNF production/release; Arc; 2012)
GSK-3 inhibition
TRH HPT axis Rapid anti depressant effect (IV)
and antisuicidal effects (IT)
(Callahanetal.1997; Bonnin et al.
2010)
Scopolamine Muscarinic receptor antagonist; Rapid antidepressant effects (IV);
NMDA receptor expression; mTOR decreased suicidal ideation
activation (Fureyand Drevets 2006; Drevets and
Furey 2010)
Allopurinol Xanthine oxidase inhibitor: decreased Efficacy in bipolar mania; may reduce
purines and free radicals impulsivity associated with suicidal
behavior (Machado-Vieiraetal.2002;
Sperlagh et al.2012)
Adapted from: (Mathews et al. 2013)
Arc activity-regulated cytoskeletal associated protein; Bcl-2 B-cell lymphoma 2; BDNF brain-
derivedneurotrophicfactor;cAMPcyclicadenosinemonophosphate;CREBcAMPresponse
elementbindingprotein;eEFeukaryoticelongationfactor;GSK-3glycogensynthasekinase3;
HPThypothalamic-pituitary-thyroid;IVintravenous;ITintrathecal;mTORmammaliantargetof
rapamycin;NMDAN-methyl-D-aspartate;PIphosphatidylinositide;PKCproteinkinaseC;TRH
thyrotropin releasinghormone

(Torresetal.2012). Therefore, the purinergic system may be a potential target for

suicidal/self-injurious behaviors and a model for the study of impulsivity.
Allopurinol is axanthine oxidase inhibitor, which decreases production of uric
acid, superoxide, and hydrogen peroxide and is widely used as a treatment for
gout. Because of its role in the purinergic system, it has been proposed as a
possible treatment for acute mania. In a randomized placebo-controlled trial of
180 bipolar I patients in a current manic episode, adjunctive allopurinol to lithium
was associated with greater Young Mania Rating Scale (YMRS) (Young et al.
1978) score reductions when compared to adjunctive dipyridamole, another agent
that regulates purine metabolism, plus lithium, or lithium plus placebo
(Machado-Vieira et al. 2008). Similar results were found in a randomized
clinical trial of lithium,
12Experimental Pharmacologic Approaches for the Reduction… 215

haloperidol, and allopurinol compared to lithium, haloperidol, and placebo

(Akhondzadeh et al. 2006). While the relationship of allopurinol to suicidal
behavior has yet to be evaluated, it has a theoretical therapeutic role for patients
with high impulsivity and aggression.

12.3.3 Ketamine

There cent interesting lutamatergic pathways in depression has been led by

promising results with subanesthetic doses of the non-competitive N-methyl-D-
aspartate receptor antagonist ketamine.Originally used clinically as a
dissociative anesthetic and analgesic, recent research on ketamine’s rapid and
potent antidepressant properties has opened promising venues for future
development of treatments for acutely suicidal patients
(Zarateetal.2006,2013b;Murroughetal. 2013). After initial reports as an
antidepressant, an open-labelsinglesub anesthetic infusion of ketamine
(0.5mg/kg given intravenously over 40 min) in 33 major depressive disorder
(MDD) patients decreased suicidal ideation (as assessed by the decreased mean
SSI) immediately following infusion, which continued over the next 4h. Suicide
items from the MADRS, Hamilton Depression Rating Scale (HDRS) (Hamilton
1960), and Beck Depression Inventory (BDI) (Beck and Bea-
mesderfer1974),as well as indicators of anxiety and hopelessness also
significantly decreased over the same time period (Diaz Granados et al. 2010).
Analogous reductions in suicidal ideation were further demonstrated in a
double-blind, placebo-controlled study of the glutamatergic modulator riluzole or
placebo following a single open-label ketamine infusion in treatment-resistant
unipolar depression (Ibrahimetal.2012). Similarly, in a double-blind,
randomized, cross over study of 15 participants with bipolar I or II depression,
suicidal ideation (assessed bythe MADRS) significantly improved within 40 min
after a single infusion of ketamine (Zarateetal.2006). A comparable decrease in
suicidal ideation was demonstrated 24h after ketamine infusion in 25
participants with treatment-resistant depression (Price et al. 2009), a finding
which has been replicated in a trial of ketamine compared to midazolam
(Price et al.2014). A subset of the participants (n=9) received multiple
infusions over 12 days, and the anti suicidal effects were main- tained. Similar
results have been found in a study involving patients in India with
treatment-resistant depression (Thakurta et al. 2012). When collapsing across
multiple ketamine clinical trials,the effect of ketamine on suicidal ideation is
independent of its effect on depression and anxiety (Ballardetal. InPress).
Several case reports and naturalistic studies have also hinted how ketamine could
Be used with suicidal patients in clinical practice. In a naturalistic study,14
depressed patients in the emergency department with active suicidal
ideation received low-dose ketamine(0.2mg/kg intravenous push) and were
followed for up to 10 days (Larkin and Beautrais 2011). Improvements in suicidal
ideation were demonstrated over the 10day so follow-up. A case report in an
urgent out patient psychiatric clinic described the use of ketamine in a patient
with depression and
216 E.D. Ballard etal.

Suicidal ideation, intent, and plan (Zigman and Blier 2013). The patient was
offered the option of ketamine or psychiatric hospitalization/electroconvulsive
therapy (ECT). After opting for ketamine,suicidal ideation resolved within
30min and improvements in depressive symptoms were maintained at 8 days
post-infusion. Suicidal thoughts had not returned after a month post-infusion.
Lastly, in a letter to the editor, a palliative care team advocated the clinical use of
ketamine for termi- nally ill patients with suicidal ideation, depression, and
anxiety, reporting a 20 year track record of using a combination of ketamine and
narcotics at acceptable/tolerable doses (Thangathurai and Mogos 2011).
These antidepressanteffectsofketaminearelikelymediatedbyenhancedsyn-
apticplasticityinkeybraincircuits,e.g.prefrontalcortexandhippocampus(Du-
manandAghajanian2012).Potentialcellularandmolecularmechanismsforthese
effects include presynaptic glutamate release increasing α-amino-3-hydroxy-5-
methylisoxazole-4-propionate(AMPA)/NMDAreceptorthroughput,theactivation/
phosphorylation of mammalian target of rapamycin (mTOR), and GSK-3 inhibi-
tion.Eukaryoticelongationfactor(eEF2),atranslationrepressor,maybedeacti-
vatedthroughketamine-mediatedblockadeofNMDAreceptors,whichthenleads to
reductions in eEF2 phosphorylation and de-suppression of rapid dendritic protein
translationsuchasincreasedbrain-derivedneurotrophicfactor(BDNF)releasein
thehippocampus(KavalaliandMonteggia2012).Cytoskeleton-associatedproteins
(Arc)mayalsobeactivatedbyketamine,leadingtodynamicchangesintheactin
cytoskeletonandremodelingofdendriticspines.Therefore,theantisuicidaleffects
ofketaminemayberelatedtoanyorallofthesecellularandmoleculartargets.
Whiletheantisuicidaleffectsofketamineappearpromising,thereremainseveral
cautionary tales. First, in an open-label trial of subanesthetic intravenous ketamine
in10patientswithtreatment-refractoryobsessive-compulsivedisorder(OCD),two
patientsreportedpassivesuicidalideation,worseninganxiety,anddysphoriaat1
daypost-infusioninpreviouslynon-syndromaldepressionatthetimeofinfusion
(Niciuetal.2013).Theauthorshypothesizethatthedelayed-onsetsuicidalideation
mayberelatedto:(1)worseningobsessionalandfree-floatinganxietyandpsy-
chomotor agitation post-infusion, (2) the interaction of ketamine-related acute
dysphoria with existing psychiatric comorbidities, or (3) ketamine-induceddere-
alization/depersonalization, activating past vulnerabilities (both patients had
extensivetraumahistories).Consequently,off-labeluseofketamineisnotindicated at
this time for individuals with substantial psychiatric comorbidities and past
trauma.Ifketamineisusedinanon-researchsetting,closefollow-upintheperi-
infusion period ismandatory.
Anotherconcernwithketamineadministrationispsychotomimeticordissocia-
tiveadverseeffects.Consequently,differentopportunitiesforNMDAreceptor
modulationhavebeenexplored.AZD6765/lanicemine,aproprietarylow-trapping
NMDA receptor antagonist, was administered to inpatients with treatment-resistant
depression in a double-blind, placebo-controlled, proof-of-concept study, and
demonstratedabrief(80–110min)antidepressanteffect(Zarateetal.2013a;
Mathews et al. 2013). Albeit less potent, this compound was not associatedwith
dissociative,psychotomimetic,orothereffectsseenwithketamine;infact,neither
12Experimental Pharmacologic Approaches for the Reduction… 217

cliniciansnorpatientscouldcorrectlyguesswhetherthepatienthadbeenadmin-
isteredthestudydrugorplacebo.Aplacebo-controlledtrialhasdemonstratedthatrep
eatedinfusionsofAZD6765isassociatedwithmaintainedmoodimprovements
(Sanacoraetal.2013;Smithetal.2010).CompoundssuchasAZD6765,whichare
abletoreplicatetherapidantidepressantandanxiolyticeffectsofketaminewithout
psychogenicexperienceswouldbeexceptionallyusefulinclinicalpractice.

12.3.4 Scopolamine

Scopolaminehydrobromideisamuscariniccholinergicreceptorantagonist,which
mayalsohaveantisuicidaleffectsviaitseffectsofmultifariouspathways:musca-
rinicneurotransmissionandglutamatergicneurotransmission(leadingtodown-
stream mTOR phosphorylation/activation) (Voleti et al. 2013). Scopolamine has
been shown to have rapid antidepressant effects in recurrent MDD and bipolar
depressionwhenadministeredintravenously(4mcg/kg)(FureyandDrevets2006).
Antidepressantresponsetoscopolaminehasbeenassociatedwithactivationinthe
bilateralmiddleoccipitalcortexduringemotionalvisualstimuliprocessing(Furey
etal.2013),potentiallyidentifyingabiomarkerfortreatmentresponse.Inadouble
blind,placebo-controlled,crossovertrial,scopolaminewasassociatedwith a
reductiononthesuicidalideationitemontheMADRS(DrevetsandFurey2010).
Furtherprospectiveinvestigationofscopolamine’sputativeantisuicidalproperties is
criticallyneeded.

12.3.5 Thyrotropin-ReleasingHormone

Thyrotropin-releasinghormone(TRH)isahypothalamictripeptidethatregulates the
hypothalamic-pituitary-thyroid axis by stimulating the production and release of
thyroidstimulatinghormone(TSH)fromthepituitary.Thegreatestconcentrationof
TRHreceptorsisintheamygdalaandhippocampuswithlowerdensitiesinthe
cortex,diencephalon,andbasalganglia(Manakeretal.1986).Resultsonthe
efficacyoforalandintravenousTRHinmajormooddisordershavebeenmixed
(Callahanetal.1997)andmaybelimitedbyinadequateblood-brainbarrierpen-
etrationandextremelyshorthalf-life(Marangelletal.1997).Inapilotstudyof
lumbarintrathecalTRHinjectionineightpatientswithtreatment-resistantdepres-
sion,therewasareductionofdepressionandsuicidalideationwithin1dayof
administration (Marangell et al. 1997). Similar results were demonstrated after
intravenousandintrathecaladministrationofTRHtotwopatientswithtreatment-
resistantbipolarIIdisorder(Callahanetal.1997).Thesefindingsinsmallcohorts
havenotbeenreplicated,butnoveldeliveryrouteswithincreasedCNSpenetrance,
e.g.intranasaladministration,mayrevitalizeTRHresearchindepressiveillnesses.
 218 E.D. Ballard etal.

12.4 Future Directions

Withtheriseofrapid-actingantidepressantresearch,psychiatryispoisedfornovel, mechanistically
distinct treatments for depression and suicidal ideation. While
muchofthesuicideresearchliteraturehasfocusedonalterationsinserotonergic and HPA functioning,
new findings implicate the glutamatergic, muscarinic,and
thyroidhormonalsystems.Inaddition,theimpulsive/aggressiveendophenotype
mayalsobeapotentialtargetforexperimentalinterventiondevelopment,especially
withhigh-risksuicidalpatientswithsubstanceusedisordersandborderlineper-
sonalitydisorder.Currentresearchonketamineandscopolaminemayfurtherour understanding of
underlying neurobiological processes as an enrichment strategy to
developmoretargetedtreatments.ConsistentwiththeNIMH’sResearchDomain
Criteria(RDoC)initiative,whichwillemphasizeconstructs/dimensionsofobser-
vablebehaviorandneurobiologicalmeasures,furtherresearchmustalsoevaluate
thesecompoundsoutsidethecontextoftraditionaldiagnosticcategoriesandinreal- world settings to
evaluate how they perform with community samples. Further-
more,sincetheliteratureontheimpulsive/aggressiveendophenotypeisrobust,the
evaluationofsubstancessuchasketamineinindividualswithimpulsiveand/or aggressive tendencies
is warranted to determine possible antisuicidal and self- injuriousefficacy.
Asstatedintheintroductiontothischapter,ourworkwithrapid-actinganti- depressants has
necessitated a focus on suicidal ideation, rather than suicidal
behavior,asourprimaryoutcome.Thisfocuscouldsignificantlyimpacttheclinical
careofemergentsuicidalideation,e.g.emergencydepartments.Theabilityto reduce suicidal
thoughts within hours instead of days-to-weeks could facilitatea
short-termreductioninsuicideriskandprecluderecidivismandfrequentpsychi-
atrichospitalizations(therebycuttinglong-termhealthcosts).Suchtreatmentpro- vides time to
both connect the patient with more comprehensive long-term resources, such as regular
psychopharmacological follow-up and therapeutic resources (such as Cognitive Behavioral
Therapy or Dialectical Behavioral Ther-
apy)toallowsuchinterventionstotakeeffect.Albeitdifficulttoassessprospec-
tivelyduetoitslowincidence,futurestudieswillneedtoevaluatetherelationship between
suicide-related biomarkers and subsequent suicide attempt(s) and/or death to truly impact
publichealth.