Introduction

Suicide is currently on the rise with rates increasing alarmingly during the past decade. There are many risk factors for suicidal behavior, and mental illness is at the top of the list.

Methods

Although a variety of medications have been evaluated in the literature, lithium and clozapine continue to have the most evidence supporting their use in decreasing suicidality.

Results

It is clear that medications are indispensable regarding the reduction of suicidality; however, a holistic approach must be taken when caring for this patient population.

Discussion

This review focuses on the specific role that lithium and clozapine have in the reduction of suicidal behavior.

Suicide has been on the rise in the United States during the past decade and has found its way within the top 10 leading causes of death for the first time in 2008.1,2  In 2012, there were 40 600 deaths attributed to completed suicide, which is more than double the amount attributed to homicide.3  It has been estimated4  that, every 24 seconds, a suicide is attempted, which results in 1.3 million attempts per year. Every 13 minutes, an average of 1 person completes a suicide attempt, and there are 25 attempts for every completed suicide.3 

A further look at suicidality reveals that there are certain groups of individuals who are at a greater risk for suicide attempt and completion. Risk factors for suicide attempt include female sex, older persons, and individuals suffering from substance-use disorders or other mental illness.4  Although females tend to have a higher rate of suicide attempt, males have a higher rate of suicide completion.3  In 2013, the highest rate for suicide completion was in people who were 45 to 64 years old.3  The second-highest rate occurred in those that were age 85 years and older.3  Although adolescents have fewer total suicides than the older population does, suicide is the second leading cause of death in adolescents and young adults. Self-harm attempts versus completion of suicide in youths is estimated at a rate of 25:1, compared with about 4:1 in the elderly population.3  People with mental illnesses, such as depression, bipolar disorder, schizophrenia, schizoaffective disorder, anxiety disorders, and some personality disorders, are also at a greater risk for suicidal behaviors and completing suicide.5  Depression and bipolar disorder have been associated with a 10 to 15 times higher rate of suicide completion compared with the general population,5  and 50% of those diagnosed with schizophrenia or schizoaffective disorder attempt a suicide in their lifetime with a 10% completion rate.6 

Because suicide has become such a public crisis, it is important to try to evaluate interventions that may benefit the population. Guidelines suggest favorable evidence in support of the efficacy of interventions, including pharmacologic therapy and cognitive behavioral therapy.7,8  This particular review aims to describe the evidence supporting the role that lithium and clozapine therapy may have in the reduction of suicidal behaviors, including attempts, ideations, and completions.

Evaluated articles were identified through a literature search of the Cochrane Library, EBSCO databases, MEDLINE, and PubMed through February 2015 (see Appendix Table). A search for ongoing trials was additionally conducted through review of http://clinicaltrials.gov. Key terms used included suicide, suicidality, clozapine, and lithium. Results reviewed were limited to those published in the English language and involving humans. Clinical trials, pertinent review articles, and meta-analyses were scrutinized when conducting this review.

APPENDIX:

Summary of lithium and clozapine literature

Summary of lithium and clozapine literature
Summary of lithium and clozapine literature

Lithium

Lithium is a mood stabilizer that displays a comparatively robust level of evidence in recent years regarding antisuicidal effects. The protective effects appear to be seen in patients with both major depression as well as bipolar disorders, particularly when treatment is long-term, defined as an average of 18 months.9  Although lithium's mechanism of protecting against suicide is unknown, various theories have been proposed. Lithium is postulated to facilitate serotonin neurotransmission and it might lead to an increase of serotonin in critical brain regions. Lithium has also been speculated to have antisuicidal effects by influencing aggressive and impulsive traits that are thought to be involved in the mediation of suicidal behavior.10,11  Another explanation is the role of lithium in reducing relapse of mood disorder.12  A number of studies specifically examining the potential for suicide protection are described in detail below.

One of the largest population samples examining suicide outcomes was conducted by Goodwin and colleagues13  in 2003. This retrospective-cohort study compared the risk of suicide attempts and completed suicides in lithium versus divalproex.13  This was a sample of 20 638 health plan members from California and Washington who were at least 14 years old with a diagnosis of bipolar disorder. The study found that divalproex was associated with greater rates of suicide attempt (31.3 versus 10.8 per 1000 person-years; P < 0.001) and suicide death (1.7 versus 0.7 per 1000 person-years; P = 0.04) compared with lithium. This study concluded that the risk of suicide attempt and death is lower for patients treated with lithium compared with divalproex in bipolar disorder. In contrast with this data, a 2.5-year study done by Oquendo and colleagues,14  completed in 2011, suggested that were was no difference in time to suicide attempt or suicide event in lithium versus valproate in patients with bipolar disorder. Out of 98 participants with a history of previous suicide attempt, 35 patients (16 from the lithium group and 19 from the valproate group) had 45 suicide events (attempt, hospitalization, or rescue). However, this study was considerably smaller and did not meet power requirement. Therefore, clinically significant differences between the drugs could not be ruled out explicitly.

To more-clearly explain some of the mixed data available, a meta-analysis was conducted by Baldessarini and colleagues15  in 2006. Studies were evaluated to compare suicide rates and attempts in patients that had major affective disorders treated with, versus without, long-term lithium therapy (average of 18 months).15  This review included findings from 31 open-labeled and randomized, controlled trials (see Appendix). The primary outcome measure evaluated the effects of lithium in attempted, versus completed, suicide. There were 33 340 participants and 85 229 person-years of exposure included in the studies analyzed. For the primary outcome studied, there was a greater risk of completed (risk ratio [RR] = 4.86; 95% confidence interval [CI], 3.36-7.02)] and attempted suicides (RR = 4.98; 95% CI, 3.56-6.96) in the “without lithium” treatment arm. The pooled estimate was RR = 4.91 for all suicidal acts. Therefore, the authors reported the overall incidence of suicides and attempts was almost 5-fold lower when patients were treated with lithium, which indicates an 80% reduction of risk. Limitations to this report include imprecise definitions of actual exposure times, number of participants remaining at risk for prolonged periods of time, few studies analyzed had suicidal events as primary outcomes, and reporting on treatments other than lithium was limited and not able to be analyzed.

A randomized trial conducted by Lauterbach et al11  studied patients with depressive disorders who had attempted suicide within the past 3 months. Patients (n = 167) were randomized to receive lithium or placebo for 12 months in addition to usual care. There were no significant differences in the primary composite outcomes of suicide attempts or completed suicides (adjusted HR, 0.517; 95% CI, 0.18–1.43). However, a post hoc analysis did show a significant difference in completed suicides because there were zero in the lithium group and 3 in the placebo group (P = 0.049). Limitations to that study include a sample size that did not meet power requirements and a high drop-out rate in both groups.

More recently, Cipriani and colleagues12  conducted a meta-analysis that evaluated lithium compared with various interventions, including placebo and active treatment for at least 12 wk in patients with mood disorders. The active compounds that were compared with lithium included amitriptyline, carbamazepine, valproate, fluoxetine, fluvoxamine, imipramine, lamotrigine, mianserin, maprotiline, nortriptyline, olanzapine, phenelzine, quetiapine, and thyroid hormone. The main outcome measures were the number of people who completed suicides, participated in deliberate self-harm, and death from any cause. Participants that met criteria for the analysis included 6674 men and women with mood disorders (unipolar depression, bipolar disorder, schizoaffective disorder, dysthymia, and rapid cycling) from 48 randomized controlled trials. Lithium was shown to be more effective than placebo in reducing suicides with an odds ratio (OR) of 0.13 (95% CI, 0.03–0.66) and, in all-cause mortality (OR, 0.38; 95% CI, 0.15–0.95). Lithium did not have statistical significance versus placebo in preventing self-harm. There were no statistically significant differences in risk of suicide or all-cause mortality between lithium and any active comparator. However, lithium did prove to be more effective than carbamazepine in reducing self-harm events (OR, 0.14; 95% CI, 0.02–0.83). A main limitation of that review was the low amount of primary evidence. Most studies (60%) had a sample size of fewer than 100 people, and there were low overall suicide and self-harm events.

Clozapine

Clozapine is an atypical antipsychotic that is primarily prescribed for treatment resistant schizophrenia. Evidence has shown that long-term treatment with clozapine can greatly reduce suicidality among patients with schizophrenia or schizoaffective disorder.16  Clozapine has antagonistic effects at serotonin receptors and enhances serotonin release, which, in theory, decreases impulsive-aggressive and suicidal behaviors.16  Several studies that investigated the role of clozapine in decreasing suicidality are discussed below.

A retrospective analysis was conducted by Spivak et al17  to evaluate clozapine's effect on suicidality and aggressive behavior in patients with schizophrenia. In this study, 30 treatment-resistant patients with chronic schizophrenia were placed on clozapine and 30 nontreatment resistant patients with chronic schizophrenia were placed on a typical antipsychotic for 1 year. Positive and negative symptoms were measured using the Positive and Negative Syndrome Scale. Depression and anxiety were measured with the Hamilton Rating Scale for Depression (HRSD) and the Hamilton Anxiety Rating Scale. Aggression and impulsivity were measured using the Overt Aggression Scale (OAS) and the Impulsivity Scale (IS). There were no significant changes in Positive and Negative Syndrome Scale when treated with clozapine, but clozapine did significantly reduce rates in the OAS (P < 0.05), IS (P < 0.05), HRSD (P < 0.05), and Hamilton Anxiety Rating Scale (P < 0.01). Although not statistically significant, more patients on other antipsychotics attempted suicide (n = 5) than did patients on clozapine (n = 0). The study concluded that reduction of anxiety and depression might be the cause for reduced aggression and suicidality. The main limitation to that study was its retrospective design.

An open-label, nonrandomized 6-month study by Spivak and colleagues,16  published in 2003, compared clozapine versus haloperidol in the reduction of suicidality in patients with chronic schizophrenia. That study included 44 participants who were divided into 2 groups, based on whether or not they fit the criteria to be considered “treatment resistant.” The treatment-resistant participants (n = 18) were given clozapine, whereas the other participants (n = 26) received haloperidol decanoate. The patients were evaluated at baseline and 6 months after starting the study medication. The results showed that, at 6 months, the clozapine-treated group had a significantly greater reduction in the OAS (P < 0.001), the OAS “physical aggression against self” item (P < 0.001), the HRSD (P < 0.05), the HRSD suicide item (P < 0.01), and the IS (P < 0.005). The clozapine-treated group also had a significantly greater reduction in the Positive and Negative Syndrome Scale score (P < 0.05). The reduction in the HRSD suicide item and the OAS “physical aggression against self” were correlated significantly with reduction in the IS scale (r = 0.75, P < 0.03; r = 0.8, P < 0.03, respectively) and OAS scores (r = 0.88, P < 0.03; r = 0.9, P < 0.03, respectively). This study supports the previous study because there was a strong correlation between the reduction of suicidality and the reduction of impulsive-aggressive behavior in the patients treated with clozapine. Limitations of this study are that the study design was open-label and that the participants were not chosen based on their history of aggressive, impulsive, or suicidal behaviors.

Meltzer and colleagues,6  in 2003, conducted the InterSePT (International Suicide Prevention trial), which compared the effects of clozapine and olanzapine on suicidality in a randomized, open-label study with masked ratings. The participant pool included men and women, aged 18 to 65 years, who had a diagnosis of schizophrenia or schizoaffective disorder and were at a high risk for suicide. The patients were recruited from 67 medical centers in 11 countries, and the duration of the study was 2 years. A total of 956 patients were randomized to receive clozapine (n = 479) or olanzapine (n = 477). The primary outcomes included suicide attempts, hospitalization because of suicide risks, and a rating of “much worse” or “very much worse” suicidality compared with baseline. The main findings of this study showed a significant decrease in suicidal behavior in patients treated with clozapine versus olanzapine (HR, 0.76; 95% CI, 0.58–0.97; P = 0.03). Participants in the clozapine group also had fewer suicide attempts than did participants in the olanzapine group (34 versus 55; P = 0.03). Likewise, the clozapine participants had fewer hospitalizations (82 versus 107, P = 0.05) and fewer rescue interventions (118 versus 155, P = 0.01) than the olanzapine group. In all categories, the authors concluded clozapine was superior to olanzapine.

A retrospective chart review conducted by Modestin and colleagues,18  in 2005, evaluated the antisuicidal effects of clozapine. That study included 94 participants who were in psychiatric treatment for 6 weeks, but they were not treated with clozapine. The same 94 patients were then started on clozapine for 6 weeks to compare the clozapine-free period to the clozapine-treatment period. The frequency of suicidal behavior and serious suicidal behavior significantly decreased during the clozapine period versus the clozapine-free period (P < 0.0001; OR, 11.6; 95% CI, 3.4–39.9; and P = 0.027; OR, 12.3, 95% CI, 1.6–97.5, respectively). Although clozapine did show a reduction in suicidality, the study's population may have been too limited. Researchers in that study did not take into account that some patients had continued antidepressants, which may also reduce suicidality and confound results.

In the only meta-analysis published on this topic to date, 6 comparable studies were found that examined rates of suicide or suicide attempted during long-term clozapine versus other treatments.19  The 6 studies had a total of 240 564 patients with schizophrenia or schizoaffective disorder according to DSM-IIIR or DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders). All studies showed a decrease in suicidal risks with clozapine versus other treatments (RR = 3.29; 95% CI, 1.72–6.32; P < 0.0001). Rates of completed suicide were lower in the clozapine group than they were in the other treatments (RR = 2.9; 95% CI, 1.47–5.72; P = 0.002).19  The meta-analysis concluded that patients with chronic schizophrenia or schizoaffective disorder were 3 times less likely to attempt or complete suicide when treated with clozapine compared with other agents. The results of that analysis were limited by the included studies. One study used was a randomized trial; all other studies incorporated other, weaker study designs.

Challenges in determining the true value of clozapine exist, particularly considering ethical concerns in conducting a randomized, placebo-controlled trials with at-risk patients. The relatively low suicide-completion rate in trials makes determining significance difficult. A recent nested case–control study of Swedish participants with schizophrenia or schizoaffective disorder used matched cases to determine a 70% reduction (OR, 0.29; 95% CI, 0.09–0.97) of completed suicides in patients exposed to second generation antipsychotics including clozapine.20  In light of evidence available, clozapine treatment may be beneficial in patients who are deemed to be at risk for completing suicide, particularly those with schizophrenia or schizoaffective disorder.

A review article on suicide in bipolar disorder published in 2014 concludes that lithium has been the most important breakthrough regarding suicide prevention.21  Based on available publications with somewhat limited data, it can be deduced that lithium is associated with a decreased risk of suicide when compared with placebo in depressive and bipolar disorders, suggesting an important clinical role. In patients who present with a high risk of attempting suicide and have no contraindications, initiation of lithium therapy should be a treatment consideration.

Clozapine also demonstrates clinical significance in reducing suicidality in patients with schizophrenia and schizoaffective disorder. Although large, randomized, controlled trials are lacking, clozapine performs better than other antipsychotics did for suicidality in several studies. Additional randomized, prospective studies are needed to clarify the role of psychotropics in reducing suicide risk. Guidelines published in 2003 by the American Psychiatric Association,7  on assessing and treating suicidal behavior, specifically highlight the benefits of using pharmacologic agents, including lithium and clozapine, to decrease suicidality but also stress the importance of using a multifactorial approach.

When making the decision to initiate lithium or clozapine, one must consider the risk versus benefit profile for the individual patient. Lithium has well-documented efficacy in mood disorders; however, tolerability can limit its use in some patients.8  In addition, the narrow therapeutic range can cause a significant overdose risk in the actively suicidal patient. For patients with psychotic disorders such as schizophrenia, guidelines recommend using clozapine after 2 failed trials of other antipsychotics because of the proven increased efficacy with clozapine.22  However, use of this agent in suicidal patients can be challenging, as shown by the Risk Evaluation and Mitigation Strategy, with the risk of agranulocytosis.23  Additional significant adverse effects, such as the elevated risk for metabolic syndrome, may also limit the use of clozapine.

Overall, a number of factors should be considered when addressing the problem of suicidality. Building a therapeutic alliance, promoting adherence to treatment, providing education to patients and families, and psychotherapy all have central roles in the management of suicidal behavior. Medications, particularly lithium and clozapine, should be considered as a treatment option in patients as a part of a multifactorial treatment approach. The true role of medications is currently not fully understood but likely has an integral part in successful management of this challenging patient population.

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Competing Interests

Disclosures: None of the authors have any interests to disclose.