Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Psychopharmacology of Suicide

Barbara J. Limandri, PhD, PMHNP, BC

Abstract

Despite the psychotherapeutic and pharmacotherapeutic advances in the treatment of depressive, anxiety, and psychotic disorders over the past several decades, the suicide rate in the United States has increased over the past 18 years. Medications are safer and more difficult to use in overdosing, but not necessarily more efficacious in bringing about complete remission of symptoms. The current article focuses on the theories and psychosocial and neurobiological correlates of suicide with the intent of formulating intervention strategies to prevent suicide. Particular attention is on medications that may contribute to suicidal ideation and behaviors and those that show evidence of reducing the risk of suicide. [Journal of Psychosocial Nursing and Mental Health Services, 57(12), 9–14.]

Abstract

Despite the psychotherapeutic and pharmacotherapeutic advances in the treatment of depressive, anxiety, and psychotic disorders over the past several decades, the suicide rate in the United States has increased over the past 18 years. Medications are safer and more difficult to use in overdosing, but not necessarily more efficacious in bringing about complete remission of symptoms. The current article focuses on the theories and psychosocial and neurobiological correlates of suicide with the intent of formulating intervention strategies to prevent suicide. Particular attention is on medications that may contribute to suicidal ideation and behaviors and those that show evidence of reducing the risk of suicide. [Journal of Psychosocial Nursing and Mental Health Services, 57(12), 9–14.]

Exploring psychotherapeutic issues and agents in clinical practice

Many anticipated that the introduction of serotonin reuptake inhibitors (SRIs) in the 1980s would improve the therapeutic outcomes of depressive and anxiety disorders and relieve the burden of these illnesses. However, these new generation medications only provided safer pharmacological treatments with lower cardiotoxicity and less concern that patients would kill themselves with their antidepressant medications.

The suicide rate in the United States has increased by 33% from 1999–2017, and suicide is now the tenth leading cause of death in the United States (Centers for Disease Control and Prevention [CDC], 2019). It is the third leading cause of death for youth ages 10 to 14, the second leading cause of death for individuals ages 15 to 34, and fifth leading cause of death for individuals ages 45 to 54 (National Institute of Mental Health, 2019). Firearms are the most common means for death at 7.3% and account for 50.6% of all suicide deaths, followed by suffocation (including hanging and asphyxiation) at 4%, and poisoning (including drug overdose) at 2% (CDC, 2019).

Terminology

The terminology and language related to suicide have negative connotations and possible underlying stigma; therefore, it is necessary to clarify terms to use in reference to suicidal events. The CDC (2019) designates two types of self-directed violence: suicidal and non-suicidal. The distinguishing feature is intent. In non-suicidal self-injury, such as self-harming behaviors, the intent is to interrupt emotional pain, whereas in suicidal self-injury, the intent is to die. Asking individuals if they want to harm themselves does not assess for suicidal intention. The critical question is “Have you been thinking of killing yourself?” Terms such as completed suicide or successful suicide imply an accomplishment and failed attempt implies ineffectiveness, both connotations that are inappropriate and certainly non-therapeutic. Similarly, suicide gesture, suicide threat, and manipulative act convey a punitive attitude on the part of the professional that is more likely to impede the therapeutic relationship. Therefore, the preferred terms of suicide, death by suicide, or suicide attempt are clearer and nonjudgmental references to suicide events (American Psychiatric Nurses Association [APNA], 2019). Although suicidality is frequently used in the literature, it is an ambiguous term that includes suicidal thinking/ideation and suicidal behaviors, which are different concepts. A person may feel despair and hopelessness to the extent that he/she thinks about dying but does not necessarily plan or act on these thoughts and feelings. Suicidal behaviors include planning to kill oneself and putting into place the necessary conditions to carry out the act. In assessment, it is important to ascertain the person's intent, plans, means, and accessibility of means for a full picture.

Research Challenges

Although the suicide rate is high, it is a rare event, which makes it a challenge to research. Drug trials to determine adverse events and therapeutic efficacy usually exclude participants who have a history of suicide or other risk factors, therefore, limiting before-marketing assessment of drug effects on suicidal thinking or behaviors. Randomized clinical trials may use treatment as usual and wait-list patients for controls; however, specific monitoring for suicidal risk factors over time with this group is rare and only suicides or suicide attempts are included in adverse effects (Poindexter, Nazem, Barnes, Hostetter, & Smith, 2019; Riblet, Shiner, Young-Xu, & Watts, 2017).

There is no complete account of suicide attempts. The CDC collects data from hospitals and medical examiners; thus, data are limited to what is reported as suicide or suicide attempts. However, many of these events go unreported due to stigma. Finally, it is not possible to research antecedents to suicidal thinking and behaviors in those individuals who kill themselves on their first and only attempt. Such limitations interfere with fully understanding the phenomenon of suicide, and therefore intervening meaningfully. What then causes suicide?

Theories of Suicide and Correlates

Much of the current research provides statistical data about risk and protective factors associated with suicidal events and correlations among many aspects of individuals who report suicidal thinking and behavior. One of the most researched psychosocial theories of suicide seems to be the interpersonal theory of suicide proposed by Joiner, Van Orden, Witte, and Rudd (2009), who devised multiple studies to verify this theory.

Interpersonal Theory of Suicide

Derived from a systematic review of the literature, Joiner et al. (2009) arrived at three constructs central to suicidal behavior: (a) the perceived thwarted belongingness or sense of connection to others, (b) perceived burden to others and sense of worthlessness, and (c) the acquired capability to act on their intent driven by a low fear of death and heightened threshold for pain (Van Orden et al., 2010). This theory has been tested with different inpatient and community populations including adolescents, young adults (Czyz, Berona, & King, 2015), older adults (Cukrowicz, Jahn, Graham, Poindexter, & Williams, 2013), military personnel (Bryan, Clemens, & Hernandez, 2012), and gay and lesbian adults (Kim & Yang, 2015). Although the constructs are well established, more research is needed to support the generalizability of the theory.

Neurobiological Correlates

Pharmacological application to suicide prevention requires a neurobiological basis that is more difficult to establish. Some biomarkers to predict suicide include electroencephalogram (EEG) changes (Li, Duan, Cui, Chen, & Liao, 2019) and specific gamma oscillations of quantitative EEG rhythms (Arikan, Gunver, Tarhan, & Metin, 2019), lower brain-derived neurotrophic factor in women who attempted suicide (Kudinova, Deak, Deak, & Gibb, 2019), dysfunction of major neurotransmitters (e.g., serotonin, catecholamines, GABA, glutamate) (Sudol & Mann, 2017), and imbalance between pro- and anti-inflammatory cytokines in people who die by suicide (Pandey, Rizavi, Zhang, Bhaumik, & Ren, 2018). Much of the neurotransmitter research has focused on decreased serotonergic function in individuals with depression but has not established a distinction in those who eventually kill themselves (Mann et al., 2019; Steinberg et al., 2019); however, these studies are based on small samples with inconsistent results.

Additional studies have mapped various brain regions and circuits with altered function and connectivity, including delayed activity between the amygdala and orbitofrontal cortex and dorsolateral prefrontal cortex (Wei et al., 2018). The paracentral cortical thickness, ventral prefrontal cortex volume, and fronto-limbic connections in adolescents and young adults who attempt suicide (Fan et al., 2019; Fradkin et al., 2017) may partially explain the increased suicidal ideation and behavior in adolescents with and without SRI medication. Another study demonstrated preliminary evidence of reduced GABA resulting in cortical inhibition in adolescents that contributed to decreased impulsivity and suicide ideation (Lewis et al., 2019). As GABA is an inhibitory neurotransmitter, decreasing GABA contributes to more erratic neural firing, hence impulsivity.

Comorbidity With Mental Disorders

Persons with bipolar disorder, schizophrenia, major depressive disorders, anxiety disorders, borderline personality disorder, and attention-deficit disorders have a higher lifetime prevalence for suicide and suicide attempts (Bergfeld et al., 2018; Khan, Faucett, Morrison, & Brown, 2013). The annual suicide rate for persons with schizophrenia and schizoaffective disorder is five times higher than the general population (Balhara & Verma, 2012; Vasiliu, 2019), with the greatest period of vulnerability at first episode and up to the first year of diagnosis (Balhara & Verma, 2012). When any mental disorder is complicated by substance use, especially alcohol, suicide rates increase related to disinhibition effects and accidental overdose (Restrepo, Gutierrez-Ochoa, Rodriguez-Echeverri, & Sierra-Hincapie, 2019; Yule et al., 2019).

Additional Risk Factors

Traumatic brain injury (TBI) contributes to approximately 30% of injury-related deaths in the United States (Taylor, Bell, Breiding, & Xu, 2017). Studies indicate the suicide risk within 1 year of a TBI is 41 per 100,000 individuals, whereas the rate of suicide risk in those without TBI is 20 per 100,000 individuals (Madsen et al., 2018). The rate increases with the severity and repetitiveness of the injury, and Veterans who experienced a TBI while on active duty present with clinically worse outcomes and suicide risk (Soberay, Hanson, Dwyer, Plant, & Gutierrez, 2019). Symptomatology of TBI includes insomnia, social isolation, and sense of burden to others (Soberay et al., 2019; Wadhawan et al., 2019), symptoms that also relate to the interpersonal theory of suicide.

Adverse childhood experiences (ACE) and traumatic events in adulthood add another layer of risk for suicide (Thompson, Kingree, & Lamis, 2019). Felitti et al. (2019) found a two- to four-fold increase in the risk of suicide attempts in persons who experienced four or more categories of ACE. When there is convergence of ACE and military experience, the risk for suicide further increases (Blosnich & Bossarte, 2017).

Nursing and Pharmacological Interventions

Connecting the accumulative research on suicide into a model (Figure 1) provides direction for interventions. Suicide is a multifaceted problem, requiring interventions for psychological, social, and biological factors. Some risk factors can be addressed (e.g., barriers to care, substance use, mental disorders). Building on the protective factors can counterbalance the risk factors. Intervening at the biological level is complicated by the unclear association of specific neurophysiological targets for medications.

Contributors to suicide model.

Figure 1.

Contributors to suicide model.

Serotonergic Agents

The serotonergic agents have been the primary class of medications to treat depressive and anxious symptoms that herald suicidal ideation and behavior; however, the U.S. Food and Drug Administration (FDA) added a black box warning to all SRIs in 2004 based on a meta-analysis of 372 randomized clinical trials (Friedman, 2014). There was a substantial decrease in prescriptions of antidepressant agents to children, adolescents, and young adults thereafter; yet deaths from suicide among this population increased from 2000–2017 (CDC, 2019).

How can a medication targeting depressive symptoms contribute to worsening illness and even suicide? Upon further research, the more activating SRIs (e.g., sertraline, fluoxetine) (Marken & Munro, 2000; Nazeer, 2017) may stimulate impulsivity in teens and young adults who are already prone to poor judgment in immediate situations (Scahill, Hamrin, & Pachler, 2005; Søndergård, Kvist, Andersen, & Kessing, 2006). Other contributory factors to consider in suicidal ideation among youths taking SRIs are the timing of occurrence of ideation related to activation and symptom improvement, adherence to regular dosing, and voluntary sudden discontinuation (Asarnow, Fogelson, Fitzpatrick, & Hughes, 2018; Hammerness, Vivas, & Geller, 2006; Inder et al., 2016). In general, however, use of serotonergic agents, including serotonin-norepinephrine reuptake inhibitors, is modestly effective in treating symptoms of depression when used judiciously and suicide risk is monitored closely during titration (Bergfeld et al., 2018; Khan et al., 2013). In addition, mirtazapine (Remeron®), trazodone (Oleptro®), vortioxetine (Trintellix®), and vilazodone (Viibryd®) may be useful in reducing symptoms of depression and anxiety. The prevailing caution, however, is that any antidepressant medication may precipitate manic symptoms and contribute to switching to a bipolar diagnosis requiring careful monitoring and a different treatment plan (Malhi, 2015; Mousavi, Johnson, & Li, 2018)

Anti-Suicide Medications

Given that there is no clear neuro-physiological mechanism for suicide, what medications provide relief of suicidal ideation? The only drug that is FDA-approved for suicide is clozapine (Clozaril®), and the data relate strictly to individuals diagnosed with schizophrenia or schizoaffective disorder (Kane, 2017; Riesselman, Johnson, & Palmer, 2015). Consideration of clozapine early in treatment is especially important given that risk for suicide is highest during the first episode and up to 1 year after initial diagnosis (Balhara & Verma, 2012). However, studies convincingly show lithium as an effective adjunctive medication for those with depressive symptoms and suicidal ideation, even in as low a dosage as 300 mg daily (D'Anci, Uhl, Giradi, & Martin, 2019; Kanehisa et al., 2017). In a naturalistic study, the incidence of suicide in 15 Alabama counties was significantly lower than the rest of the state and nationwide and was correlated with the naturally occurring lithium concentration in the water supply (Palmer, Cates, & Gorman, 2019). The mechanism of action for both clozapine and lithium are still unclear; however, by altering the serotonergic metabolism in the amygdala and prefrontal cortex, there is an improvement in aggressive impulsivity and decision making (Malhi et al., 2018).

Ketamine and esketamine have been found to be effective in treatment-resistant depression, where suicide is a high risk (Albott et al., 2018; Daly et al., 2018). Ketamine infusions for depression are not yet FDA approved, therefore, are more expensive and may not be covered by insurance. Imposing a high cost for treatment in such a vulnerable population may place individuals at greater risk if the ketamine does not provide relief of symptoms. Esketamine (Spravato®) is administered by nasal spray and used in conjunction with oral antidepressant agents. The medication is available through a restricted distribution system and the prescriber needs to be trained in the administration to assure full dosage (U.S. FDA, 2019).

Summary and Pearls for Practice

Suicide is the worst outcome of mental disorders and situational crises and is a highly preventable event. No one treatment strategy is more effective than another; however, universal screening for suicidal ideation and behavior is essential in determining the best treatment plan. Some controversy remains regarding the use of SRIs, especially in youth and young adults; yet, these medications are still the standard of treatment for depressive and anxiety symptoms that drive suicidal behaviors. Use of any medication requires careful monitoring of therapeutic and adverse effects during the initial titration. When initiating medication, the prescriber needs to schedule at least weekly follow up for clients who also screen positively for suicidal ideation and behaviors and assure support networks are available through psychotherapy and family and community resources.

Psychiatric nurses need education in the screening, assessment, and intervention in suicide prevention. The APNA (2019) offers a competency-based certification program to provide such education, as does the American Foundation for Suicide Prevention (2019). Some tips for psychiatric nurses in helping clients with suicidal ideation include:

  • Conduct universal suicide screening using the Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al., 2014) or the Patient Health Questionnaire-9 (Kroenke, Spitzer, & Williams, 2001) for all new patients and every time the clinical situation changes.
  • Follow up a positive suicide screen with more in-depth suicide assessment using the C-SSRS, Triage Version (Posner et al., 2014) in combination with interviewing skills to increase reliability.
  • Newly diagnosed patients with schizophrenia need to be monitored closely for suicide throughout the first year of treatment, and clozapine should be considered a treatment of choice if suicidal ideation presents.
  • Patients with bipolar disorder, especially with mixed features, should be carefully monitored for suicide.
  • Children, youth, and young adults who are treated with SRIs need to be carefully monitored for suicide risk throughout the course of treatment and especially during titration to a therapeutic dosage.

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Authors

Dr. Limandri is Professor Emerita, Linfield College, School of Nursing, McMinnville, Oregon.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Barbara J. Limandri, PhD, PMHNP, BC, Professor Emerita, 9136 SW 36th Avenue, Portland, OR 97219; e-mail: limandribj@gmail.com.

10.3928/02793695-20191112-02

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