REVIEW

Pharmacologic Approaches to Suicide Prevention

Sidney Zisook, M.D., Isabel Domingues, M.D., Jason Compton, M.D.

Suicide is a leading cause of death that is often preventable. reducing suicidal thoughts and behaviors, primarily among
This article reviews the role of medications in treating patients with mood disorders. Treatment guidelines focus
suicidal behavior and in preventing suicide. For an acute on the importance of optimizing treatment of the psychiatric
suicidal crisis, ketamine, and perhaps esketamine, are conditions known to be associated with suicide risk. For
emerging as important tools. For patients with chronic patients with these conditions, the authors recommend
suicidality, clozapine remains the only U.S. Food and Drug focusing on suicide as an independent treatment target and
Administration (FDA) approved antisuicidal medication, and using an enhanced medication management strategy that
its use is predominantly for patients with schizophrenia includes maintaining a supportive, nonjudgmental therapeutic
and schizoaffective disorder. An abundance of literature relationship; flexibility; collaboration; measurement-based
supports the use of lithium among patients with mood care; consideration of combining medications with
disorders, including those with major depressive disorder. nonpharmacologic, evidence-based strategies; and ongoing
Despite the black box warning regarding antidepressants safety planning.
and suicide risk among children, adolescents, and young
adults, antidepressants are widely used and remain helpful in Focus 2023; 21:137–144; doi: 10.1176/appi.focus.20220076

Suicide is a public health problem. The 12th leading cause of defined as death caused by self-directed injurious behavior
death in the United States, suicide led to the loss of almost with the intent to die. The term “suicidal behaviors” en-
46,000 U.S. lives in 2020. In the same year, another 1.2 compasses attempts and completed suicide.
million people in the United States attempted suicide, and Measuring actual rates of suicidal behaviors is challeng-
about 10% of U.S. adults had suicidal thoughts (1). Despite ing. Many ecological studies on pharmacological approaches
these sobering statistics, we know that many suicides can be to reduce suicide use suicide as the primary outcome. One
prevented. Several helpful approaches for individuals who problem with interpreting such studies is inconsistency in
are in distress or at risk for suicidal behavior are available. the methods of determining when a death is the result of
Brief interventions that provide tools for managing suicidal suicide. In the United States, decisions about whether deaths
crises and for reducing suicidal behaviors include safety are listed as suicides on death certificates are made by a
planning interventions, lethal means counseling, and crisis coroner or medical examiner. These decisions frequently
response planning. In addition, several evidence-based lack consistency and clarity, and laws and procedures for
therapies have been found to reduce suicidal ideation and guiding these decisions vary from state to state and even
behavior: cognitive-behavioral therapy–suicide prevention from county to county. Another problem is that ecological
(2), dialectical behavior therapy (3), collaborative manage- studies do not identify the presence or absence of important
ment and assessment of suicidality (4), attachment-based measures of interest (e.g., antidepressant treatment) at the
family therapy (5), and prolonged grief disorder therapy for level of individual persons, and they rely on indirect indices
survivors of suicide loss (6). This article focuses on the role of drug usage (sales or prescription rates). Therefore, un-
of medications in suicide prevention. identified intervening variables can lead to apparent, but
misleading, correlation with suicide rates (7, 8).
By contrast, most clinical trials do not measure actual
DEFINITIONS AND MEASURES
suicides, but rather suicidal ideation or attempts. Because
For purposes of this review, the terms “suicidal thoughts” suicide is uncommon in experimental treatment trials and in
and “suicidal ideation” are used interchangeably and are clinical practice, these studies rely on these suicide proxies,
divided into “passive” thoughts (wish to be dead, to disap- which may not be highly correlated with actual suicides (8,
pear, or to not wake up) and “active” thoughts (method, plan, 9). Of note, most individuals with suicidal ideation never
or intent to die by suicide). The term “suicide attempt” refers make an attempt, and at least 85%–90% of attempters do not
to nonfatal, self-directed, potentially injurious behavior with go on to suicide (10, 11). Moreover, most therapeutic trials
intent to die as a result of the behavior. The term “suicide” is involving patients with acute depression exclude those

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considered at high risk of suicidal behavior, and in most such clozapine versus olanzapine. Fewer clozapine-treated pa-
studies, suicidal thoughts or behaviors are not explicit out- tients attempted suicide; required hospitalizations or rescue
come measures but, instead, incidental adverse events, re- interventions to prevent suicide; or required concomitant
ported with uncertain reliability and accuracy. treatment with antidepressants, anxiolytics, or soporifics.
When explicit suicide outcome measures are used, they Overall, five clozapine-treated patients versus three
often are limited to single items on depression rating scales, olanzapine-treated patients died by suicide during the study.
such as item 10 on the Montgomery-Åsberg Depression Rating In addition to its strong evidence-base for reducing suicidal
Scale (MADRS) (12), item 3 on the Hamilton Depression Rating behavior of patients with schizophrenia or schizoaffective
Scale (13), item 12 on the Quick Inventory of Depressive disorder, some reports (21) have suggested clozapine may
Symptomatology (14), or item 9 on the Physician Health reduce intentional self-harm and overdoses among patients
Questionnaire (15). Validated scales that give more compre- with borderline personality disorder.
hensive and nuanced assessments of suicidal thoughts and Despite clozapine’s unique antisuicidal profile, it tends to
behaviors include the Sheehan–Suicidality Tracking Scale (16), be underutilized (22). This is in large part because of its
the Concise Health Risk Tracking scale (17), and the Scale for serious and burdensome side effect profile. Clozapine has
Suicide Ideation (18). In 2012, the U.S. Food and Drug Ad- five black box warnings: severe neutropenia; orthostatic
ministration (FDA) made the Columbia–Suicide Severity Rat- hypotension, bradycardia and syncope; seizures; myocarditis
ing Scale (C-SSRS) the preferred instrument—the gold and cardiomyopathy; and increased mortality among elderly
standard—for measuring suicidal ideation and behavior in patients with dementia-related psychosis. Compared with
clinical trials (19). Three versions of the C-SSRS are available other antipsychotics, clozapine has an increased risk of
for use in clinical practice. The lifetime/recent version allows blood dyscrasias, in particular agranulocytosis during the
practitioners to gather lifetime history of suicidality as well as first 18 weeks of treatment. After 1 year, this risk reduces to
any recent suicidal ideation or behavior. The since-last-visit that associated with most antipsychotics. Clozapine’s use is
version of the scale assesses suicidality since the patient’s last therefore reserved for people who have not responded to
visit. The screen version of the C-SSRS is a truncated form of two other antipsychotics, and it requires stringent blood
the full version. When used in conjunction with other suicide monitoring. This monitoring includes obtaining a complete
prevention measures, any of these relatively brief and validated blood count prior to initiating treatment, to ensure the
suicide scales can be used to help prevent suicidal behaviors. presence of a normal baseline absolute neutrophil count
Because few medication trials have focused on prevention (ANC) ($1500/mL) and to permit later comparisons. Weekly
of suicidal behaviors, the role of medications in suicide ANC monitoring is required during the first 6 months of
prevention remains elusive. Yet, in clinical practice, medi- treatment. If a patient’s ANC remains normal for the first
cations play a prominent role in helping to prevent suicide. 6 months, monitoring frequency may be reduced to every
This review addresses medications and classes of medica- 2 weeks for the next 6 months. If the ANC remains normal
tions that have data to support their use in suicide preven- for the second 6 months, ANC monitoring frequency may
tion: clozapine, lithium, ketamine or esketamine, and be reduced to once every 4 weeks thereafter. Other, more
antidepressants. The review ends with clinical guidelines for common adverse effects include neutropenia, constipation,
an integrative, multipronged approach for reducing suicide dizziness, drowsiness, hypersalivation, hypotension, tachy-
risk in clinical settings. cardia, and weight gain.
In 2015, the individual manufacturer patient registries
were consolidated by request of the FDA into a single shared
MEDICATIONS
patient registry (the Clozapine Risk Evaluation and Mitiga-
Clozapine tion Strategy [REMS] Registry). This program requires
Clozapine is an atypical antipsychotic medication used to health care professionals and pharmacies prescribing or
treat individuals who have schizophrenia or schizoaffective dispensing clozapine to be certified and trained in the pro-
disorder and have not responded to other antipsychotics. It gram; patients also must be enrolled and must adhere to the
is the only medication with a specific FDA indication for ANC monitoring requirements.
reducing risk of recurrent suicidal behavior among at-risk Clozapine’s niche in suicide prevention is in reducing risk
patients with schizophrenia or schizoaffective disorder. of recurrent suicidal behavior among patients with schizo-
The regulatory approval was largely based on results from phrenia or schizoaffective disorder who are judged to be at
the multicenter, randomized, double-blinded, 2-year Inter- chronic risk, as determined by their history and recent
national Suicide Prevention Trial (20). The trial compared clinical state, for experiencing suicidal behavior. Whether
clozapine with olanzapine among patients with schizo- clozapine reduces death by suicide among these patients has
phrenia and schizoaffective disorder who were at high risk not been established.
for suicide as determined by previous suicide attempts or
current suicidal ideation. Patients were seen weekly for Lithium
6 months and then biweekly for 18 months. Suicidal behavior An abundance of observational data and randomized con-
was significantly reduced among patients treated with trolled trials (RCTs) attest to lithium’s antisuicidal effects

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among patients with mood disorders. Observational studies (suicide attempt, interrupted attempt, hospitalization to
have the advantage of being able to capture large cohorts prevent suicide, and death from suicide). The trial was
over long periods. Baldessarini et al. (23) reviewed 33 studies stopped for futility after 519 veterans were randomly
published between 1970 and 2000. Results yielded threefold assigned, because no overall difference was found in re-
lower rates of suicide and reported attempts during long- peated suicide-related events between treatments. The au-
term lithium treatment than without it or after it was dis- thors concluded that adding lithium to existing medication
continued. Although greatly reduced, these rates remained regimens was unlikely to effectively prevent suicide-related
above those estimated for the general population. The au- events among patients undergoing active treatment for
thors concluded that evidence for substantial, if incomplete, mood disorders. Baldessarini and Tondo (28), however,
protection against suicide with lithium was supported by noted several limitations of the Veterans Affairs study (low
more compelling evidence than that for any other treatment concentrations of lithium, brief treatment exposure and high
for patients with mood disorders. drop-out rate, poor adherence to prescribed lithium or pla-
Subsequently, Goodwin et al. (24), in a study of a large, cebo, and the three suicides among participants receiving
population-based sample of 20,638 individuals (ages 14 years placebo compared with one suicide among those receiving
or older with at least one outpatient diagnosis of bipolar lithium—an important, albeit nonsignificant difference),
disorder and at least one filled prescription for lithium, leading them to conclude that this study did not provide
divalproex, or carbamazepine) found a risk of suicide at- evidence that lithium lacks antisuicidal effects.
tempt or suicide that was 1.5 to 3 times higher among those Despite the considerable evidence that lithium helps
treated with divalproex compared with those treated with prevent suicidal behaviors among patients with mood dis-
lithium. The investigators concluded: orders, as with clozapine, the use of lithium remains un-
derrepresented in clinical practice (29). This underuse may
This evidence of lower suicide risk during lithium treatment
should be viewed in light of the declining use of lithium by
be related to insufficient training of psychiatrists in the use
psychiatrists in the United States, particularly among re- of lithium, fear of toxicity, aggressive marketing of alterna-
cently trained psychiatrists. Many psychiatric residents have tive medications that are patentable and therefore more
no or limited experience prescribing lithium, largely a re- profitable, and the need to monitor blood levels and thyroid
flection of the enormous focus on the newer drugs in edu- and kidney function (30). Of particular concern is lithium’s
cational programs supported by the pharmaceutical industry. potential for nephrotoxicity, affecting tubular or glomerular
If lithium does have an antisuicidal effect not matched by
function. In tubular dysfunction, which is more common,
currently available alternatives, then current prescribing
patterns should be reevaluated. At the least, use of lithium to
the kidney’s ability to concentrate urine is reduced, and the
treat mood disorders should be an essential component of intraluminal lithium concentration can increase to toxic
training in psychiatry (24). levels. Monitoring for diabetes insipidus, the most common
renal complication of lithium therapy, is vital because it is
Another large, longitudinal cohort study, in a nationally initially reversible with lithium withdrawal but may become
representative U.K. sample of almost 7,000 patients diag- irreversible because of structural damage. Annual assess-
nosed as having bipolar disorder and prescribed lithium, ment of urine production, which should not exceed 4 liters
valproate, olanzapine, or quetiapine as a maintenance mood per day, is recommended. Clinical decision making will need
stabilizer treatment (25), showed that those taking lithium to take a balanced view of the likely benefits and harms of
had reduced self-harm and unintentional injury rates com- lithium for the individual patient.
pared with those prescribed any of the other drugs. Self- Lithium’s niche in suicide prevention is most likely for
harm rates were lower among patients taking lithium treatment of patients who have chronic or recurrent mood
compared with those taking valproate, olanzapine, or que- disorders and are considered at risk for persistent or inter-
tiapine; unintentional injury was lower with lithium com- mittent suicidal behaviors.
pared with valproate and quetiapine but not with olanzapine.
Although the suicide rate was lower among the lithium group, Ketamine
there were too few events to allow accurate estimates. Ketamine, a glutamatergic modulator and N-methyl-D-
Several RTCs also have attested to lithium’s antisuicidal aspartate receptor antagonist, is a versatile drug used in
effects. In a review of 48 RTCs of patients with mood dis- anesthesiology, pain management, and most recently, as
orders (26), those who received lithium were less likely to either monotherapy or adjunctive treatment for major de-
die by suicide (and had fewer deaths overall) than patients pressive disorder and treatment-resistant depression. Mul-
treated with placebo for both bipolar and unipolar depres- tiple double-blind, placebo-controlled, randomized trials
sion. One study that stands in sharp contrast to most others have established the rapid antidepressant efficacy of
was a large Veterans Affairs Cooperative Study RTC (27) subanesthetic-dose (0.5 mg/kg) ketamine administered in-
that enrolled veterans with bipolar disorder or depression travenously for treatment-resistant depression (31) and
who had survived a recent suicide-related event. Partici- bipolar depression (32). The rapidity of ketamine’s antide-
pants received lithium augmentation of usual care. The main pressant effects, together with its efficacy among patients
outcome was time to the first repeated suicide-related event not responding to conventional antidepressant treatment, has

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sparked interest in its potential as an antisuicide treatment FDA to treat adults who have treatment-resistant depression
(33). An RCT (34) comparing ketamine with midazolam, and depressive symptoms in adults diagnosed as having
among 57 patients with treatment-resistant depression, found major depressive disorder who experience suicidal thoughts
a rapid (within 24 hours postinfusion) reduction in suicidal or behaviors. Note that the second indication does not mean
ideation with ketamine but not with midazolam. A systematic esketamine is an approved treatment for suicide prevention.
review of RTCs on the effect of ketamine on suicidal ideation It is not known whether esketamine is safe and effective for
(35) reported on four RCTs and confirmed a rapid antisuicidal use in preventing suicide or in reducing suicidal thoughts or
ideation effect of ketamine (within 24–48 hours post- behaviors. It carries the same black box warning as other
administration), and that effect was at least partially inde- antidepressants regarding an increased risk of suicidal
pendent of effects on depressive symptoms. In a preliminary thoughts and behaviors among pediatric and young adult
study of longer-term effects (36), repeated doses of open- patients. A meta-analysis (38) of randomized, double-blind
label ketamine rapidly and robustly decreased suicidal ide- RCTs examining the effectiveness, tolerability, and safety of
ation among 14 pharmacologically treated outpatients with intranasal esketamine in treating major depressive disorder
treatment-resistant depression and stable suicidal thoughts; (three of the studies included only patients with treatment-
in two patients, this decrease was maintained for at least resistant depression) found intranasal esketamine to have an
3 months following the final ketamine infusion. Whether any ultra-rapid antidepressant effect (within hours), which
of these findings can be translated into a reduction in actual peaked at 24 hours and lasted for up to 28 days. Another
suicidal behavior has yet to be established. systematic review (39) found racemic ketamine to be more
Despite the excitement surrounding ketamine’s rapid and efficacious than esketamine. One RCT (40) found signifi-
robust antidepressant and antisuicidal effects, several pre- cantly greater improvement with intranasal esketamine than
cautions and limitations remain. For one, medical insurance with placebo on the MADRS item of suicidal thoughts at
companies usually cover ketamine’s FDA-approved use as an 4 hours postadministration, but not at 24 hours or at day 25.
anesthetic but do not cover its use for other purposes, such Another RCT (41) found no group differences in reducing
as in the treatment of psychiatric disorders; therefore, pa- the percentage of patients reporting suicidal ideation.
tients must independently pay hundreds of dollars a dose for After several preliminary studies suggested adjunctive
repeated ketamine infusions. The ideal frequency of treat- intranasal esketamine might be an effective antidepressant
ment with intravenous ketamine has not been established. for adults with major depressive disorder and active suicidal
With repeated intravenous dosing, ketamine has been ideation or behavior (42), two phase-3 RCTs, ASPIRE I and
demonstrated to reduce suicidality for#6 weeks but has not II, were conducted to further assess the efficacy and safety of
been shown to reduce risk for completed suicide. esketamine in treating patients who had depression and
Side effects of ketamine tend to be mild and short-lived. were at imminent risk of suicide. These trials of esketamine
Intravenous ketamine promotes dissociation in nearly three- among patients with major depressive disorder and active
quarters of patients treated for treatment-resistant depression. suicidal ideation or behavior were the first large-scale RCTs
Dissociation peaks within 40 minutes after ketamine admin- of patients considered at imminent risk of suicide. ASPIRE I
istration and resolves within 1–2 hours. Ketamine is associated showed a significant reduction in depression severity among
with increases in blood pressure and pulse rate among the esketamine plus oral antidepressant treatment group
10%–50% of patients treated. These effects usually resolve compared with the placebo plus oral antidepressant group
within 2–4 hours after drug administration. Patients should be 24 hours after the first treatment, with a notable increase in
monitored for at least 2 hours after treatment. The reported the antidepressant effect among patients with prior suicide
incidence of serious adverse events or persistent medical se- attempts or more severe depressive symptoms. Severity of
quelae in clinical trials is low; however, there is a paucity of data suicidal ideation showed improvement in both groups, but
concerning long-term safety. Moreover, ketamine is a known no significant difference was found between treatment
drug of abuse, which raises concern that repeated adminis- groups (43). ASPIRE II also showed significant reduction in
tration of the drug could entail liability for drug abuse (37). depression severity from baseline to 24 hours after the first
Ketamine’s niche in suicide prevention may be for treatment, which was greater for the esketamine plus oral
treatment of patients who are acutely suicidal in emergency antidepressant group than for the placebo plus oral antide-
rooms or inpatient settings. Although ketamine may not be pressant group. Differences were significant as soon as
the ideal medication for suicide prevention, its rapid and 4 hours after the first treatment and also 25 days later. Again,
robust action has spurred great interest among clinicians although both groups showed rapid reduction in suicidal
and researchers alike and has triggered a long overdue ideation and scores on behavior assessments, the difference
search for rapidly acting, well-tolerated, safe, and sustain- between the treatment groups was not significant (44).
able antisuicidal interventions. Common side effects of intranasal esketamine include
sedation, fainting, dizziness, spinning sensation, and anxiety.
Esketamine Dissociation also occurs. There also is a risk for abuse and for
Along with an oral antidepressant, intranasal esketamine, physical and psychological dependence. As with clozapine,
the S-enantiomer of ketamine racemate, is approved by the because of the risks for abuse and misuse, esketamine is only

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available through a restricted REMS program. Patients associated with antidepressant treatment (4%), compared
treated in outpatient health care settings (e.g., medical of- with placebo (2%), among children and adolescents. The
fices and clinics) must be enrolled in the REMS program, FDA therefore directed antidepressant manufacturers to
and esketamine can only be administered at health care revise the labeling and to alert health care providers and
settings certified in the program. Patients are required to patients about an increased risk of suicidality among chil-
wait in the facility for at least 2 hours after inhalation, which dren and adolescents who take antidepressants. In 2006, on
may provide an opportunity for psychotherapy focused on the basis of a second, expanded meta-analysis of 372 RCTs of
suicide prevention. antidepressants involving nearly 100,000 participants (54),
Intranasal esketamine’s niche in suicide prevention may the FDA extended the warning to include young adults up to
be as an adjunctive treatment for acutely suicidal patients, age 24. The analysis showed that the increased risk was
but this role remains unproven. Esketamine does not appear significant only among children and adolescents under age
to have as robust an antisuicidal ideation effect as intrave- 18; there was no evidence of increased risk among adults
nous ketamine. The long-term therapeutic effect and safety older than age 24, and among adults age 65 or older, anti-
of intranasal esketamine require further examination in depressants had a protective effect against development of
large-scale RCTs. suicidal ideation and behavior (54). The FDA recommended
prescribers advise patients about this risk and maintain close
Antidepressants contact after patients began the medication.
Although none of the standard antidepressants have been Although the warning was meant to increase safety, sev-
demonstrated in methodologically rigorous RCTs to de- eral studies have suggested unintended consequences (55,
crease suicidal behaviors, antidepressants remain a key tool 56), including decreased diagnosis of depression (57) and
in suicide prevention. Antidepressants not only have bene- reduced antidepressant usage (58). At the same time, suicide
ficial effects for depression, but also for a host of other rates have continued to climb. There remains a lively debate
conditions often associated with increased suicide risk, such on whether the black box warning has had an untoward
as panic disorder, generalized anxiety disorder, obsessive- effect on suicide rates (59). In any case, it is important to
compulsive disorder, posttraumatic stress disorder, and balance this modest risk of increased suicidal thoughts and
binge eating disorders. Several studies, including cohort attempts among children, adolescents, and young adults
studies (45) and large multisite open (46) and controlled (47, treated with antidepressants versus the risk of untreated or
48) trials have reported reductions in suicidal ideation with inadequately treated depression and to incorporate suicide
antidepressants, and, on a population level, large ecological prevention–informed management strategies as described in
studies (49–51) have shown associations with antidepressant the next section.
use and decreased suicidal behaviors. Perhaps the most
compelling data on the risk of suicide attempts after initia-
TREATING UNDERLYING PSYCHIATRIC
tion of antidepressants have come from a study by Simon and
CONDITIONS RELATED TO SUICIDE RISK
Savarino (52) that compared the time patterns of suicide
attempts among outpatients starting depression treatment At the individual clinician’s level, treating underlying psy-
with medication or psychotherapy. Outpatient claims data chiatric conditions related to suicide risk has long been
from a prepaid health plan were gathered to identify new recognized as the cornerstone treatment for suicidal be-
episodes of depression treatment beginning with an anti- haviors and suicide prevention. The list of such conditions is
depressant prescription in primary care (N570,368), an long, and many of these conditions benefit from evidence-
antidepressant prescription from a psychiatrist (N57,297), based or evidence-informed pharmacologic strategies.
or an initial psychotherapy visit (N554,123). In that study, These conditions include mood disorders (46, 47, 54), psy-
the overall risk of suicide attempts was highest in the months chotic disorders (48), neurocognitive disorders (60), anxiety
before starting treatment and declined after depression and sleep disorders (61, 62), and substance use disorders
treatment was started with either medication or psycho- (63). We caution that although some studies have found a
therapy. Yet, since 2004, all antidepressants have a black box reduction in the likelihood of suicide among patients with
warning indicating that they are associated with an in- anxiety and sleep disorders who were treated with benzo-
creased risk of suicidal thinking, feeling, and behavior among diazepines in concordance with treatment guidelines, for
young people. limited durations and with concomitant psychotherapy or
The initial 2004 black box warning was based on data antidepressants (61), other studies have suggested a positive
from 23 trials conducted in pharmaceutical company– association between benzodiazepine use and suicide risk. Of
supported programs evaluating antidepressant efficacy these high-risk conditions, mood disorders, particularly
among pediatric patients and on one large multicenter trial major depressive disorder, have been the most widely
(the Treatment for Adolescents with Depression Study) (53). studied and play the most prominent role in suicide pre-
Although there were no completed suicides in any of the vention efforts.
clinical trials evaluated, this meta-analysis (54) revealed a At least 10% of the time, however, no accompanying
modestly increased risk of suicidal thoughts and behaviors mental health condition can be ascertained at the time of the

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Box 1. General principles for optimizing clinical treatment for suicidal behavior and for preventing suicide

Acute Care for Patients in or Near a Suicidal Crisis (e.g., Stay Flexible
Patient With Mood Disorder Feeling Overwhelmed,
Hopeless, Expressing Plans and Intent, and Increase contact and provide safety nets during transitions or
Having Means) gaps in care as necessary.
Consider increasing modes of contact, such as telephone calls
Consider hospitalization or increased surveillance. or email between sessions as needed.
Consider intravenous ketamine or possibly intranasal
esketamine as an adjunctive to antidepressants for Incorporate other evidence-informed nonpharmacologic
short-term reduction in suicidal ideation among treatments for enhanced coping strategies, preventing fu-
patients with major depressive disorder and suicidal ture suicide attempts, and managing associated conditions.
ideation.
Keep in mind that although practice standards suggest Involve the patient’s family wherever possible.
electroconvulsive therapy (ECT) is a good choice for Have a safety plan. The safety plan intervention is a prioritized
at-risk patients with severe mood disorders, the evidence set of coping skills and support, developed in collaboration
for the effects of ECT on suicide death has been with the patient, and, ideally, a family member or other
inconsistent (63). support person (67). The plan includes individualized warning
signs, internal coping strategies, social contacts to distract
Chronic Care for Patients With a Psychiatric Condition That from suicidal thoughts, and social and professional support to
assist with resolving suicidal crises.
Increases Suicide Risk or Who Have Suicidal Thoughts or
Past Attempts Include means restriction and firearms safety.
Include reasons for living.
Consider clozapine to decrease risk of suicide among patients Continue monitoring the patient and updating the treatment.
with schizophrenia or schizoaffective disorder and suicidal
ideation or past suicide attempt(s). Special Considerations for Treating Depression
Consider lithium alone (for patients with bipolar disorder) or
in combination with another psychotropic agent (for Recognize that major depressive disorder is a chronic and
patients with unipolar depression or bipolar disorder) to recurrent (sometimes lifelong) illness, and that suicide risk
decrease the risk of suicide among patients with mood waxes and wanes in intensity over time among many
disorders. individuals with the disorder.
Closely monitor patients for changes in thoughts of suicide or
Treat Co-Occurring Psychiatric Disorders (Depression, Post- suicidal behaviors after antidepressant treatment has been
traumatic Stress Disorder, Addictive Disorders) With En- initiated or when the medication dosage is changed.
hanced Clinical Management Pay attention to the risk of overdose when prescribing
antidepressants for patients at risk for suicide, and limit the
Develop and maintain an open, honest, nonthreatening, amount of medication dispensed and refilled.
nonjudgmental, patient-centered, therapeutic Consider lithium augmentation of antidepressant treatment for
relationship. patients with a major or persistent depressive disorder in an
Maintain a collaborative approach: effort to reduce suicide risk.
With the patient. Update safety plans regularly and provide long-term monitoring
With other treating clinicians. even after remission, because suicidal thoughts and behaviors
With your team—“Never worry alone.” may wax and wane over time, independent of other symptoms.

suicide. Furthermore, even with the psychiatric condi- esketamine, electroconvulsive treatment) (68) for acute
tions associated with high risk for suicidal behavior, most risk and for chronic risk. The section on chronic risk in-
patients do not engage in it (64). Thus, many clinical in- cludes comments on the use of clozapine, lithium, and the
vestigators have argued that suicidal behaviors should be treatment of coexisting disorders. The key components of
defined as a separate diagnosis so they can be more readily what we call enhanced clinical management, are outlined,
identified and treated in clinical practice (64, 65). A cor- and the importance of including a collaborative, live,
ollary of suicidal behavior being defined as a separate safety plan (66, 67) is emphasized. Box 1 ends with special
disorder is to consider suicide risk as its own treatment considerations for treating depression.
target. Indeed, a common feature of all the evidence-based
psychotherapies is the focus on suicidal thoughts and
CONCLUSIONS
behaviors over and above co-occurring psychiatric con-
ditions (66). Another common feature is the incorporation Medications are not stand-alone treatments for suicidal be-
of a safety plan (67). These common features may be haviors. There is no single cause of suicide. Rather, sui-
equally applicable to optimizing pharmacological care to cidal thoughts and behaviors have multiple determinants.
treat suicidal behaviors or to prevent suicide. Box 1 enu- Similarly, there is no single approach to reducing suicidal
merates general principles of optimizing clinical care for ideation or behaviors that is suitable for all individuals and
suicidal behavior and for preventing suicide. Box 1 is or- situations. Fortunately, we have a growing list of evidence-
ganized into treatment interventions (setting, ketamine or based brief interventions, therapies, and medications in our

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toolkit. As part of a multipronged approach to suicide pre- 13. Hamilton M: A rating scale for depression. J Neurol Neurosurg
vention, medications can, and often do, play a prominent Psychiatry 1960; 23:56–62
14. Rush AJ, Trivedi MH, Ibrahim HM, et al: The 16-Item Quick In-
role. Determining whether and which medication makes
ventory of Depressive Symptomatology (QIDS), clinician rating
sense for an individual patient at risk for suicide requires (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in
careful weighing of the risks and benefits of the medication patients with chronic major depression. Biol Psychiatry 2003; 54:
as well as the risks and benefits of not using the medication. 573–583
When rapid reduction in suicidal thoughts and behaviors is 15. Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief
depression severity measure. J Gen Intern Med 2001; 16:606–613
needed, off-label ketamine and possibly esketamine may be
16. Sheehan DV, Giddens JM, Sheehan IS: Status update on the
considered, but the roles of these drugs in long-term man- Sheehan–Suicidality Tracking Scale (S-STS) 2014. Innov Clin
agement of suicidal behaviors remain to be determined. For Neurosci 2014; 11:93–140
longer-term management, both clozapine for schizophrenia 17. Trivedi MH, Wisniewski SR, Morris DW, et al: Concise Health
and schizoaffective disorder and lithium for mood disorders Risk Tracking scale: a brief self-report and clinician rating of
suicidal risk. J Clin Psychiatry 2011; 72:757–764
remain underutilized. Care management for patients with
18. Beck AT, Kovacs M, Weissman A, et al: Assessment of suicidal
psychiatric disorders associated with suicide risk, or for in- intention: the Scale for Suicide Ideation. J Consult Clin Psychol
dividuals with suicidal thoughts and behaviors but no un- 1979; 47:343–352
derlying psychiatric diagnosis, should always include a 19. Posner K, Oquendo MA, Gould M, et al: Columbia Classification
thorough assessment of lifetime and current suicidal Algorithm of Suicide Assessment (C-CASA): classification of sui-
cidal events in the FDA’s pediatric suicidal risk analysis of anti-
thoughts and behaviors and individualized risk and protec-
depressants. Am J Psychiatry 2007; 164:1035–1043
tive factors and a nonjudgmental, empathic, and collabora- 20. Meltzer HY, Alphs L, Green AI, et al: Clozapine treatment for
tive therapeutic relationship (69). When medications are suicidality in schizophrenia: International Suicide Prevention Trial
part of the treatment, we recommend the enhanced clinical (InterSePT). Arch Gen Psychiatry 2003; 60:82–91
management approach outlined in Box 1. 21. Rohde C, Polcwiartek C, Correll CU, et al: Real-world effective-
ness of clozapine for borderline personality disorder: results from
AUTHOR AND ARTICLE INFORMATION a 2-year mirror-image study. J Pers Disord 2018; 32:823–837
22. Baig AI, Bazargan-Hejazi S, Ebrahim G, et al: Clozapine pre-
Department of Psychiatry, University of California, San Diego, San Diego. scribing barriers in the management of treatment-resistant
Send correspondence to Dr. Zisook ([email protected]). schizophrenia: a systematic review. Medicine (Baltimore) 2021;
Dr. Zisook receives research support from COMPASS Pathways. The 100:e27694
other authors report no financial relationships with commercial 23. Baldessarini RJ, Tondo L, Hennen J: Lithium treatment and sui-
interests. cide risk in major affective disorders: update and new findings.
J Clin Psychiatry 2003; 64:44–52
REFERENCES 24. Goodwin FK, Fireman B, Simon GE, et al: Suicide risk in bipolar
1. Suicide. Alexandria, VA, Mental Health America, 2022. https:// disorder during treatment with lithium and divalproex. JAMA
www.mhanational.org/conditions/suicide 2003; 290:1467–1473
2. Stanley B, Brown G, Brent DA, et al: Cognitive-behavioral therapy for 25. Hayes JF, Pitman A, Marston L, et al: Self-harm, unintentional
suicide prevention (CBT-SP): treatment model, feasibility, and ac- injury, and suicide in bipolar disorder during maintenance mood
ceptability. J Am Acad Child Adolesc Psychiatry 2009; 48:1005–1013 stabilizer treatment: a UK population-based electronic health
3. DeCou CR, Comtois KA, Landes SJ: Dialectical behavior therapy is records study. JAMA Psychiatry 2016; 73:630–637
effective for the treatment of suicidal behavior: a meta-analysis. 26. Lewitzka U, Severus E, Bauer R, et al: The suicide prevention
Behav Ther 2019; 50:60–72 effect of lithium: more than 20 years of evidence—a narrative re-
4. Jobes DA, Comtois KA, Gutierrez PM, et al: A randomized con- view. Int J Bipolar Disord 2015; 3:32
trolled trial of the collaborative assessment and management of 27. Katz IR, Rogers MP, Lew R, et al: Lithium treatment in the pre-
suicidality versus enhanced care as usual with suicidal soldiers. vention of repeat suicide-related outcomes in veterans with major
Psychiatry 2017; 80:339–356 depression or bipolar disorder: a randomized clinical trial. JAMA
5. Diamond G, Diamond GM, Levy S: Attachment-based family Psychiatry 2022; 79:24–32
therapy: theory, clinical model, outcomes, and process research. 28. Baldessarini RJ, Tondo L: Testing for antisuicidal effects of lithium
J Affect Disord 2021; 294:286–295 treatment. JAMA Psychiatry 2022; 79:9–10
6. Zisook S, Shear MK, Reynolds CF, et al: Treatment of complicated 29. Bastiampillai T, Sharfstein SS, Allison S: Increasing the use of
grief in survivors of suicide loss: a HEAL Report. J Clin Psychiatry lithium and clozapine in US suicide prevention. JAMA Psychiatry
2018; 79:17m11592 2017; 74:423
7. Baldessarini RJ: Epidemiology of suicide: recent developments. 30. Young AH, Hammond JM: Lithium in mood disorders: in-
Epidemiol Psychiatr Sci 2020; 29:e71 creasing evidence base, declining use? Br J Psychiatry 2007;
8. Tondo L, Baldessarini RJ: Antisuicidal effects in mood disorders: 191:474–476
are they unique to lithium? Pharmacopsychiatry 2018; 51:177–188 31. Ibrahim L, Diazgranados N, Franco-Chaves J, et al: Course of im-
9. Paris J: Can we predict or prevent suicide? An update. Prev Med provement in depressive symptoms to a single intravenous infusion
2021; 152:106353 of ketamine vs add-on riluzole: results from a 4-week, double-blind,
10. Owens D, Horrocks J, House A: Fatal and non-fatal repetition of placebo-controlled study. Neuropsychopharmacology 2012; 37:
self-harm: systematic review. Br J Psychiatry 2002; 181:193–199 1526–1533
11. Suominen K, Isometsä E, Suokas J, et al: Completed suicide after a 32. Bahji A, Zarate CA, Vazquez GH: Ketamine for bipolar depression: a
suicide attempt: a 37-year follow-up study. Am J Psychiatry 2004; systematic review. Int J Neuropsychopharmacol 2021; 24:535–541
161:562–563 33. Price RB, Mathew SJ: Does ketamine have anti-suicidal proper-
12. Montgomery SA, Åsberg M: A new depression scale designed to be ties? Current status and future directions. CNS Drugs 2015; 29:
sensitive to change. Br J Psychiatry 1979; 134:382–389 181–188

Focus Vol. 21, No. 2, Spring 2023 focus.psychiatryonline.org 143

PHARMACOLOGIC APPROACHES TO SUICIDE PREVENTION

34. Price RB, Iosifescu DV, Murrough JW, et al: Effects of ketamine 50. Gibbons RD, Hur K, Bhaumik DK, et al: The relationship between
on explicit and implicit suicidal cognition: a randomized con- antidepressant prescription rates and rate of early adolescent
trolled trial in treatment-resistant depression. Depress Anxiety suicide. Am J Psychiatry 2006; 163:1898–1904
2014; 31:335–343 51. Baldessarini RJ, Tondo L, Strombom IM, et al: Ecological studies
35. Hochschild A, Grunebaum MF, Mann JJ: The rapid anti-suicidal of antidepressant treatment and suicidal risks. Harv Rev Psychia-
ideation effect of ketamine: a systematic review. Prev Med 2021; try 2007; 15:133–145
152:106524 52. Simon GE, Savarino J: Suicide attempts among patients starting
36. Ionescu DF, Swee MB, Pavone KJ, et al: Rapid and sustained re- depression treatment with medications or psychotherapy. Am J
ductions in current suicidal ideation following repeated doses of Psychiatry 2007; 164:1029–1034
intravenous ketamine: secondary analysis of an open-label study. 53. Emslie G, Kratochvil C, Vitiello B, et al: Treatment for Adolescents
J Clin Psychiatry 2016; 77:e719–e725 with Depression Study (TADS): safety results. J Am Acad Child
37. McIntyre RS, Rosenblat JD, Nemeroff CB, et al: Synthesizing the Adolesc Psychiatry 2006; 45:1440–1455
evidence for ketamine and esketamine in treatment-resistant de- 54. Stone M, Laughren T, Jones ML, et al: Risk of suicidality in clinical
pression: an international expert opinion on the available evidence trials of antidepressants in adults: analysis of proprietary data
and implementation. Am J Psychiatry 2021; 178:383–399 submitted to US Food and Drug Administration. BMJ 2009; 339:
38. An D, Wei C, Wang J, et al: Intranasal ketamine for depression in b2880
adults: a systematic review and meta-analysis of randomized, double- 55. Friedman RA: Antidepressants’ black-box warning—10 years later.
blind, placebo-controlled trials. Front Psychol 2021; 12:648691 N Engl J Med 2014; 371:1666–1668
39. Bahji A, Vazquez GH, Zarate CA Jr: Comparative efficacy of ra- 56. Valuck RJ, Libby AM, Orton HD, et al: Spillover effects on treat-
cemic ketamine and esketamine for depression: a systematic re- ment of adult depression in primary care after FDA advisory on
view and meta-analysis. J Affect Disord 2021; 278:542–555 risk of pediatric suicidality with SSRIs. Am J Psychiatry 2007; 164:
40. Canuso CM, Singh JB, Fedgchin M, et al: Efficacy and safety of 1198–1205
intranasal esketamine for the rapid reduction of symptoms of de- 57. Libby AM, Orton HD, Valuck RJ: Persisting decline in depression
pression and suicidality in patients at imminent risk for suicide: treatment after FDA warnings. Arch Gen Psychiatry 2009; 66:
results of a double-blind, randomized, placebo-controlled study. 633–639
Am J Psychiatry 2018; 175:620–630 58. Lu CY, Zhang F, Lakoma MD, et al: Changes in antidepressant
41. Popova V, Daly EJ, Trivedi M, et al: Efficacy and safety of flexibly use by young people and suicidal behavior after FDA warnings
dosed esketamine nasal spray combined with a newly initiated oral and media coverage: quasi-experimental study. BMJ 2014; 348:
antidepressant in treatment-resistant depression: a randomized g3596
double-blind active-controlled study. Am J Psychiatry 2019; 176: 59. Fornaro M, Anastasia A, Valchera A, et al: The FDA “black box”
428–438 warning on antidepressant suicide risk in young adults: more harm
42. Nikayin S, Sanacora G: Evaluating the role of ketamine/esketamine than benefits? Front Psychiatry 2019; 10:294
in the management of major depressive disorder with suicide risk. 60. Gorlyn M, Keilp J, Burke A, et al: Treatment-related improvement
CNS Drugs 2021; 35:1069–1079 in neuropsychological functioning in suicidal depressed patients:
43. Fu DJ, Ionescu DF, Li X, et al: Esketamine nasal spray for rapid paroxetine vs bupropion. Psychiatry Res 2015; 225:407–412
reduction of major depressive disorder symptoms in patients who 61. Miller BJ, McEvoy JP, McCall WV: Insomnia, suicidal ideation,
have active suicidal ideation with intent: double-blind, randomized and suicide attempts in the Clinical Antipsychotic Trials of In-
study (ASPIRE I). J Clin Psychiatry 2020; 81:19m13191 tervention Effectiveness. J Clin Psychiatry 2021; 82:20m13338
44. Ionescu DF, Fu DJ, Qiu X, et al: Esketamine nasal spray for rapid 62. Fawcett J: Treating impulsivity and anxiety in the suicidal patient.
reduction of depressive symptoms in patients with major depres- Ann N Y Acad Sci 2001; 932:94–102
sive disorder who have active suicide ideation with intent: results 63. Molero Y, Zetterqvist J, Binswanger IA, et al: Medications for
of a phase 3, double-blind, randomized study (ASPIRE II). Int J alcohol and opioid use disorders and risk of suicidal behavior,
Neuropsychopharmacol 2021; 24:22–31 accidental overdoses, and crime. Am J Psychiatry 2018; 175:
45. Mulder RT, Frampton CMA, Luty SE, et al: Eighteen months of 970–978
drug treatment for depression: predicting relapse and recovery. 64. Oquendo MA, Baca-Garcia E: Suicidal behavior disorder as a di-
J Affect Disord 2009; 114:263–270 agnostic entity in the DSM-5 classification system: advantages
46. Zisook S, Trivedi MH, Warden D, et al: Clinical correlates of the outweigh limitations. World Psychiatry 2014; 13:128–130
worsening or emergence of suicidal ideation during SSRI treat- 65. Fehling KB, Selby EA: Suicide in DSM-5: current evidence for the
ment of depression: an examination of citalopram in the STAR*D proposed suicide behavior disorder and other possible improve-
study. J Affect Disord 2009; 117:63–73 ments. Front Psychiatry 2020; 11:499980
47. Zisook S, Lesser IM, Lebowitz B, et al: Effect of antidepressant 66. Yager J, Feinstein RE: A common factors approach to psycho-
medication treatment on suicidal ideation and behavior in a ran- therapy with chronically suicidal patients: wrestling with the angel
domized trial: an exploratory report from the Combining Medi- of death. Psychiatry 2017; 80:207–220
cations to Enhance Depression Outcomes Study. J Clin Psychiatry 67. Stanley B, Brown GK: Safety planning intervention: a brief inter-
2011; 72:1322–1332 vention to mitigate suicide risk. Cogn Behavioral Practice 2012; 19:
48. Zisook S, Kasckow JW, Lanouette NM, et al: Augmentation with 256–264
citalopram for suicidal ideation in middle-aged and older 68. Wilkinson ST, Trujillo Diaz D, Rupp ZW, et al: Pharmacological
outpatients with schizophrenia and schizoaffective disorder who and somatic treatment effects on suicide in adults: a systematic
have subthreshold depressive symptoms: a randomized controlled review and meta‐analysis. Depress Anxiety 2022; 39:100–112
trial. J Clin Psychiatry 2010; 71:915–922 69. Weinberg I, Ronningstam E, Goldblatt MJ, et al: Strategies in
49. Gusmão R, Quintão S, McDaid D, et al: Antidepressant utilization treatment of suicidality: identification of common and treatment-
and suicide in Europe: an ecological multi-national study. PLoS specific interventions in empirically supported treatment manuals.
One 2013; 8:e66455 J Clin Psychiatry 2010; 71:699–706

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