Abstract
For which patients does this guidance apply? These principles should be applied in clinical decision making for a broader group of patients than just those with expressed suicidal ideation. Suicide risk includes any patients with elevated risk, many of whom do not present with a chief complaint of suicidal ideation. Their risk may be identified by a recent suicide attempt, or by a family history of suicide along with current psychosocial stressors, or the patient facing a life transition or loss along with deterioration in clinical status. (See Suicide Risk Assessment in Chapter 6). At the broadest level, current clinical standards (including those of The Joint Commission which is based in the USA but accredits health systems in the USA and internationally) consider all patients being treated in behavioral healthcare settings (psychiatric inpatient and outpatient care, psychological therapy, substances use disorder treatment, etc.) as having potentially elevated suicide risk.
A Principles
It important to stay grounded in the data related to medications in the context of treating patients at risk for suicide.
These medication guidelines should be considered for more patients than just for those who are actively expressing suicidal ideation or plans, since longer term suicide risk can be improved with a comprehensive treatment plan that includes medications.
This chapter aims to address any confusion that may still exist among the public and even among prescribers, about the relative harm and benefits related to medications and suicide prevention/risk.
An overarching set of principles are presented to guide clinicians’ decision making related to medication use when suicide risk is elevated.
These principles include a framework that includes the clinical targets of both the patient’s primary psychiatric condition(s), as well as suicide risk as a separate and appropriate target of clinical intervention.
Medications such as lithium, clozapine, ketamine, and other medications with newer mechanisms of action with suicide risk-reducing potential, and antidepressants as a class are discussed in further detail with key clinical takeaways.
The relationship with you as an ongoing health provider in the patient’s life can be a powerfully protective factor for patients at risk for suicide. While discussing and/or prescribing medications, remember that your caring tone and compassionate communication, even during an otherwise more technical discussion of medications, can have a therapeutic effect.
B Overarching Approach to Medications for Patients with Suicide Risk
Medications Have a Role to Play in Preventing Suicide
To optimize outcomes with medications when caring for patients whose suicide risk has been identified, consider the following overarching principles:
1. For which patients does this guidance apply? These principles should be applied in clinical decision making for a broader group of patients than just those with expressed suicidal ideation. Suicide risk includes any patients with elevated risk, many of whom do not present with a chief complaint of suicidal ideation. Their risk may be identified by a recent suicide attempt, or by a family history of suicide along with current psychosocial stressors, or the patient facing a life transition or loss along with deterioration in clinical status. (See Suicide Risk Assessment in Chapter 6). At the broadest level, current clinical standards (including those of The Joint Commission which is based in the USA but accredits health systems in the USA and internationally) consider all patients being treated in behavioral healthcare settings (psychiatric inpatient and outpatient care, psychological therapy, substances use disorder treatment, etc.) as having potentially elevated suicide risk. In primary care and other non-behavioral health settings, any patient with a mental health concern or psychiatric condition (including substance use disorder) is considered appropriate for suicide screening. Thus, consideration of “patients at risk for suicide” should be broadened beyond just those with current ideation.
2. When considering medications, discuss with the patient the risks and benefits on both sides. Address the potential ramifications (risks and benefits) of not using medication, i.e., using non-pharmacological treatments or not treating the mental health condition, versus the risks and benefits of using medication, possibly in concert with therapy or another non-pharmacological treatment. Unaddressed severe major depressive disorder (TRD) for example, has known likely outcomes including disability, suffering, increased medical comorbidity, negative impacts on medical conditions such as cardiac, chronic pain and autoimmune conditions, and an elevated risk of suicide by as much as seven times, as well as 50% increased risk in non-suicide mortality compared with non-depressed people or when depression is in remission.1 In other words, the risks of not treating the condition or treating with only non-pharmacological modalities must be weighed against the risks of the treatment. And alternatives to a particular medication under consideration must also be discussed. This process of informed consent is good practice, and important to document from a medicolegal standpoint, as well as being truly useful for patients’ understanding and engagement in their treatment. The same approach considering the risks and benefits of a particular medication in relationship to suicide risk and prevention can be utilized, as outlined in Figure 9.1.
Figure 9.1 Suicide-specific informed consent model
The same process of weighing risks and benefits of treatment versus not using the treatment can be applied to suicide risk, as we are accustomed to doing related to the outcomes of a psychiatric illness (or any health condition).
3. Optimize medication(s) for the primary psychiatric condition(s). Per usual practice, this should include a baseline evaluation/diagnosis/assessment of the mental health condition(s), education about condition, prognosis, and treatment, regular follow-up, monitoring of and adjusting for side effects, use of clinical assessment, scales and instruments as appropriate to track changes in symptoms and overall improvement, and adjusting the treatment plan including medication as necessary to maximize improvement. For depression, aim for full remission to every extent possible; consider medication dose adjustment, augmentation strategies and referral to CBT or other forms of psychotherapy. Optimal results are often achieved with a combination of medications and therapy. Electroconvulsive therapy (ECT) and transcranial magnetic stimulation (rTMS has FDA approval for TRD) should be considered for treatment refractory patients with severe or psychotic depression and bipolar disorder. Both of these forms of treatment may also be helpful in reducing suicide risk.2, 3
4. Consider suicide risk as its own target of treatment. This includes consideration of all treatments and interventions with evidence for suicide risk reducing potential. (See pp. 116 and 226 for psychotherapies with evidence for preventing suicide and remember safety planning as a brief intervention with risk-reducing potential.) In terms of medications, consider these medications which have the most evidence for suicide risk reduction:
a. Lithium: One of the oldest treatments used in modern psychiatry, it has been and still is underutilized. Has suicide preventive effect in the long-term treatment of both depression and bipolar mood disorders.
b. Clozapine: Until 2020 Clozapine was the only medication with an FDA indication mentioning suicide risk, indicated for patients with schizophrenia; also underutilized.
c. Ketamine: Rapid reduction of depressive symptoms and suicidal ideation. Esketamine is FDA-approved with indications for adults with Treatment-Resistant Depression, and for depressive symptoms in adults with MDD with suicidal thoughts or actions.
d. Antidepressants: Antidepressants can be used judiciously and effectively to address depression and anxiety, and on a population level, suicide preventive effects are associated with increased population rates of antidepressant use.
5. Limit the quantity of medications dispensed during times of higher suicide risk. Since suicide risk is dynamic, there may be periods of time during a patient’s course when risk becomes more acute. During these periods it is important to stay more closely in communication with the patient and if possible, the patient’s family, and limit the quantity of each medication refill, especially for medications with a narrow therapeutic index.
6. Schedule meetings with the patient more frequently than usual. When a medication is being initiated, when the dose is being increased, and when medications are being tapered down, these are periods when not only risk of side effects is greater, but when underlying suicide risk can be perturbed by side effects such as anxiety, agitation or insomnia. Therefore these are important periods of time to see the patient more frequently, to communicate more closely, and to alert the patient when to contact you. Let the patient know how to reach you or the covering provider between visits.
7. During medication initiation or dosage changes, be sure to include the following in your communication with patients:
a. Permission to speak with family or other support person if necessary.
b. Consent to communicate with other health providers, e.g., therapist, primary care provider or psychiatrist.
c. Education about transition periods during treatment, what to expect in the short-term and goals for the longer term.
d. Encouragement and education about your goals for the treatment plan, ideas for next steps, offer the patient hope for improvement, remission, recovery.
8. Medication transitions are an excellent time to re-visit or initiate a patient’s Safety Plan (see Chapter 7 for Safety Planning).
Note: recommendations related to medications included in this book are not comprehensive. Please see Stahl Prescriber’s Guide for detailed prescribing guidance.4
C Lithium
A large body of evidence indicates that lithium decreases suicide in patients with affective disorders. Lithium has been suggested to have antisuicidal properties based on secondary analyses of RCTs, naturalistic studies, meta-analyses, and open-label treatment trials, likely related to and additionally independent of its mood-stabilizing effect.5–11 Because lithium is generally used in patients with affective disorders, the antisuicidal effects of lithium have not been evaluated in patients with other psychiatric conditions such as schizophrenia.
Summary of the data related to lithium’s impact on suicide:
1. Lithium is an effective mood stabilizer for bipolar disorder, and has effectiveness as an augmentation agent for unipolar depression. Stabilizing mood symptoms especially over the long term can contribute to suicide risk reduction.
2. Lithium has a large evidence base for having a protective effect against suicide drawn from more than 50 studies.12,13
3. Reduces suicide rates 60–80% in studies comparing lithium to placebo as well as lithium to other medications.14
4. Suicide attempt rates are also significantly reduced.
5. These suicide preventive effects are likely present for both unipolar and bipolar mood disorders.15
6. Lithium’s suicide protective mechanism of action is not certain, but is possibly related to its effects in reducing aggression and impulsivity.
In addition to stabilizing mood, lithium has a large evidence base for providing a protective effect against suicide among bipolar and unipolar depressed patients.
While the majority of the studies are not RCTs and therefore have limitations, the risk-reducing effects are consistent and robust enough for expert opinion to support lithium as an effective intervention for suicide risk.
Studies found reductions in both attempts and suicide deaths compared with placebo as well as compared with other older mood stabilizers.
Clinical Considerations
Patients with mood disorders have as high as a 30 times greater risk of suicide15 compared with the general population. Lithium is considered a first-line treatment option in several international guidelines,16 and is a well-known augmentation strategy for unipolar depression. For any patient with a mood disorder and a history of past or current suicide risk, these significant potentially lifesaving benefits of lithium should be weighed against its side effect and medication risk profile.
Adverse effects especially with long-term use of lithium include possible renal and cardiac effects, and hyponatremia. Common side effects include nausea, tremor, thirst, weight gain, diarrhea, and dermatologic side effects. Additionally its relatively narrow therapeutic index along with these potential long-term effects require regular blood test monitoring of lithium levels and checks on renal and thyroid laboratory studies. Lithium toxicity can be dangerous and requires medical evaluation and treatment; early symptoms include diarrhea, nausea/vomiting, muscle weakness, drowsiness, incoordination, and muscle twitching. (See Stahl Prescriber’s Guide for detailed guidance about prescribing lithium since there are potential long-term adverse effects that must be regularly monitored.)4
Its adverse effects, requirements for blood monitoring, narrow therapeutic index, relative lack of industry profit potential, and perhaps stigma related to lithium, have most likely been the reasons that lithium remains highly underutilized, especially given the strength of evidence for its robust suicide risk-reducing potential. Perhaps the fact that suicide prevention has not been a primary independent clinical target until recent years has also contributed to its underutilization.
Consider lithium for targeting suicide risk reduction for patients with any mood disorder.
Closely consider, assess, and monitor risk of suicide in any patient with a mood disorder, given the fact that half to two-thirds of all suicides occur in patients with mood disorders.
Also consider lithium if full remission has not been achieved for a mood disorder patient, especially when suicide risk is present.
Would generally consider the use of lithium for longer term improvements, not necessarily as a short-term antisuicidal agent. It is not clear how rapidly lithium works on suicide risk, given the methodological limitations of the data.
Follow usual baseline laboratory and regular lithium monitoring including renal, thyroid, and other metabolic side effects.
D Clozapine
Clozapine was the first medication to receive a suicide preventive indication and from 2003 until 2020 it was the only medication in the USA with a suicide preventive indication, related to its risk-reducing potential in patients with schizophrenia. Clozapine is also known for its use in improving symptoms in treatment refractory patients with schizophrenia and schizoaffective disorder, as well as for its efficacy for negative symptoms. Schizophrenia and schizoaffective disorders are certainly among the more potent health condition risk factors for suicide with as many as 50% of people living with schizophrenia attempting suicide and approximately 10–13% dying by suicide.17 Traditional (or first generation) antipsychotics such as haloperidol have not been shown to reduce suicide risk. When the atypical antipsychotic medications were noted to improve cognition in a way the older antipsychotic class had not, other effects were speculated and then observed. Early excitement about clozapine’s potential to reduce suicide risk by as much as 80% in patients with schizophrenia was described by several groups including Meltzer et al.18
In a landmark study by Meltzer et al., 980 patients with schizophrenia or schizoaffective disorder were randomized to clozapine versus olanzapine. Of the nearly 1000 patients, 27% had been refractory to previous medications and were considered high risk for suicide based on prior attempts or current ideation. They were studied over a two-year period under matched study conditions. Results showed significantly fewer patients treated with clozapine attempted suicide (38% fewer, 34 versus 55 on olanzapine), and fewer required hospitalization or rescue interventions, antidepressants, or anxiolytics. Although five clozapine and three olanzapine subjects died by suicide during the two-year period, clozapine is still considered to have reduced risk overall, since those numbers were much smaller and lethality of method, possibly as, or more, important than intent, is known to have a large bearing on attempts being lethal versus surviving the attempt.18
Despite the strong evidence base leading to FDA regulatory approval for schizophrenia patients with a history of recurrent suicidal behavior clozapine has been an underutilized medication.19 One impediment to the evidence-based use of clozapine for suicide risk and treatment-resistant schizophrenia has been clinician fear of serious adverse effects (e.g., severe neutropenia), and lack of knowledge about how to manage more common adverse effects such as sialorrhea, constipation, and tachycardia.20There has been a resurgence of interest in supporting clozapine prescribing, with initiatives in New York state and the Netherlands that provide call centers and education materials.21–23
Clinical Takeaways: Clozapine and Suicide Prevention
Clozapine should be considered for any patient with schizophrenia or schizoaffective disorder, especially those patients who have known suicide risk.
Keep in mind that schizophrenia and schizoaffective disorders are health conditions known to elevate suicide risk significantly, and therefore all patients with these chronic psychotic conditions should have their suicide risk assessed on an ongoing basis.
Please see The Clozapine Handbook (Meyer & Stahl) released in May 2019 that covers all aspects of clozapine prescribing in detail.24 A new online resource has also emerged (https://smiadviser.org) supported by grants from the US Substance Abuse and Mental Health Services Administration (SAMHSA) and the American Psychiatric Association (APA). This online resource not only provides educational modules about clozapine, but also allows clinicians to register for free in order to obtain consultations about patients.
E Ketamine
Ketamine induces rapid-onset and short-duration improvement in depressive and suicidal symptoms in Treatment-Resistant Depression and likely other mood disorders as well, and reduces chronic pain after short intravenous infusions.25 In 2016, ketamine received a fast track designation by the FDA and in 2019 nasal esketamine (Spravato) was FDA-approved in the USA for Treatment-Resistant Depression in conjunction with other antidepressant medications. And in 2020 esketamine also received FDA approval with an indication for treating depressive symptoms in adults with MDD with suicidal thoughts or behaviors. Ketamine is now available in intravenous (ketamine) and intranasal (esketamine) forms.
History of Ketamine
Ketamine has a colorful history originally launched as an anesthetic in 1970, with not only analgesic and sedation effects, but bronchodilation, anti-inflammatory, and later found to have neuroprotective effects. Used on soldiers in Vietnam, and adult and pediatric surgical and burn cases, general, spinal, and regional anesthetic indications, then in veterinary medicine use in animals, it soon became a recreational club drug related to its hallucinogenic properties. A “dissociative” anesthetic, people may disconnect from their environment leading to usually transient dissociative symptoms. In recent years, ketamine has shown significant therapeutic effects in major depression, bipolar disorder, anxiety, and PTSD.
Ketamine has clear therapeutic benefits for depression with response rates from 50–70% within hours to single dose even in patients who have not responded to more than one prior antidepressant.26–28 However, antidepressant effects last only a few days.
There is both excitement in the clinical field and the public related to its potential to improve Treatment-Resistant Depression and depression with suicidal ideation, and concern related to side effects especially over the long term, the short-term nature of the response, and practical accessibility given the mode of delivery is limited to intravenous and intranasal only available under physician supervision at approved health centers.29, 30 Additionally, concern arose related to the rise in clinical providers starting around 2010, some of whom are not trained in mental health.31 A 2017 consensus statement examined the data and limitations related to ketamine’s use in mood disorders and expresses a cautious approach due to concerns about small sample sizes, shortage of long-term data and substance abuse potential.32
Mechanism of Action
NMDA receptor antagonist and glutamate modulator. NMDA receptors are present at high densities in the PFC, pyramidal cells, and hippocampus, and blocking NMDA in these areas could theoretically lead to increases in GLU output. Theoretically it may have antidepressant effects at low (subanesthetic) doses related to glutamate activity. However not all NMDA receptors have demonstrated a clear antidepressant effect. Potential other mechanisms include binding at many different receptor sites: mu opioid, 5HT, NE, alpha-7, nicotinic, muscarinic receptors – a typical “dirty drug” in the MOA sense.
At different doses it potentially has different effects from nocioceptive, to anesthetic, to hallucinogenic.
Intravenous Ketamine Dosing for Treatment Refractory Depression
Krystal et al. initially settled on what became the recommended dosing strategy of 0.5 mg/kg ketamine infused intravenously over 40 minutes, derived from earlier psychosis studies, aiming for therapeutic benefits without producing delirium or an anesthetized state.33 Frequency of dosing for early phase initiation of treatment ranges from one–three times/week and maintenance dosing frequency ranges from weekly to once every six weeks.32
Side Effects of Ketamine and Esketamine
– increased blood pressure, increased cardiac output
– increased intracranial pressure
– tachycardia or bradycardia
– N/V (no p.o. intake 30 min pre- and 2 hrs post-)
– cognitive problems, perceptual effects, hallucinations
– sedation
– vivid dreams
– i.v. ketamine only: respiratory depression or apnea with large doses or rapid infusion
Long-term safety is not well known. Also relatively unknown is ketamine’s impact on suicidal behavior, as it is mainly known to improve suicidal ideation.
Figure 9.2 Rapid antidepressant effect for unmedicated treatment resistant patients with MDD
Zarate et al. found a rapid change in depressive symptoms following intravenous ketamine infusion.26
Figure 9.3 Effect of a single dose of intravenous ketamine on suicidal ideation
Wilkinson reviewed multiple studies and found these rapid, positive effects on suicidal ideation.31
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