Psychopharmacological Treatment to Reduce Suicide RiskPublished on Psychiatric Times(http://www.psychiatrictimes.com)

Psychopharmacological Treatment to Reduce Suicide RiskApril 02, 2012 | Suicide [1], Bipolar Disorder [2], Schizoaffective [3], Schizophrenia [4], CulturalPsychiatry [5], Mania [6], Addiction [7]By Maurizio Pompili, MD, PhD [8] and Mark J. Goldblatt, MD [9]

Adequate treatment of the underlying psychiatric illness consistently appears to be the mosteffective use of medication in suicidal patients.

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Suicide may be the culmination of a complex combination ofpsychological, biological, social, and cultural factors, and it is particularly likely to occur duringperiods of individual, family, and socioeconomic crises associated with loss and shame. Psychiatricdisorders, especially depression, bipolar disorder, and substance abuse, are most often associatedwith suicide.1,2In bipolar disorder, mixed manic-depressive states are often associated with increasedsuicide risk.3 Suicide rates are also surprisingly high among persons who have anxiety disorders, andsevere anxiety may accompany suicidal behavior. However, evidence of the efficacy of antianxietymedications in lowering suicide risk is limited.4The effect of treatment on suicide risk has been a topic of growing research interest in recent years.There is limited evidence that psychiatric treatments reduce suicide risk, although a decrease in thelong-term suicide rate for patients with mood disorders treated with lithium, neuroleptics, andantidepressants has been reported in more recent studies.5 Psychiatric treatments as diverse aspsychotherapy, rapid hospitalization, and ECT can be lifesaving in acute emergencies, but there arelimited data to suggest that any of them decrease suicide risk.4In this article, we review psychopharmacological interventions that have been associated withsuicide prevention in patients with major psychiatric illnesses.Clozapine and other novel antipsychoticsThe first FDA-approved medication with an antisuicide indication was clozapine for schizophrenia.The regulatory approval in 2003 was largely based on the International Suicide Prevention Trial(InterSePT), a remarkable randomized trial that compared clozapine with olanzapine in patients withschizophrenia and schizoaffective disorder who were at high risk for suicide.6 In that trial, suicidalbehavior (measured by suicide attempts, hospitalizations, and rescue interventions) was significantlydecreased in patients treated with clozapine.The efficacy of other antipsychotic drugs in reducing suicide risk has not been adequately tested.However, some evidence suggests that olanzapine may reduce suicidal ideation when given incombination with a mood-stabilizing agent in patients with bipolar I disorder mixed-episode.7Quetiapine (300 to 600 mg) may help prevent suicide in patients with bipolar depression.8,9 When

compared with lithium and paroxetine, quetiapine (600 mg) was associated with a statistically significant reduction in suicidal ideation (as measured by

the Montgomery-Asberg Depression Rating Scale [MADRS]).10,11 Quetiapine may reduce suicidal ideation and may be considered for patients with otherPage 1 of 5

Psychopharmacological Treatment to Reduce Suicide RiskPublished on Psychiatric Times(http://www.psychiatrictimes.com)

diagnoses for which clozapine cannot or should not be used.

LithiumIn 1986, Jamison12 prophetically stated:One of the most interesting questions in preventive medicine today is the impact of lithium onsuicide rates. There are no systematic data available at this time [about its efficacy], although it canbe hoped that a well-documented answer will be possible within the next 10 years. Until then, wemust rely upon preliminary speculations and clinical observations.Just a decade later, the first scientific evidence convincingly supported a suicide risk–reducing effectof long-term treatment of bipolar and other manic-depressive disorders with lithium.13,14

A recent meta-analysis of data on long-term lithium treatment in bipolar disorder or a mix of majormood disorders supported a marked reduction (5-fold, or approximately 80%) in risk of suicideattempts and of completed suicides.15 Interestingly, the researchers also found that the proportion ofsuicide attempts relative to completed suicides during treatment with lithium was more than 2-foldhigher, which suggests reduced lethality of suicidal behavior. The evident beneficial effects of lithiumin reducing mortality from suicide are all the more remarkable in light of its potentially lethal toxicityin acute overdoses.

What is already known about pharmacotherapy interventions for reducingsuicidality?

? Robust treatment of the underlying psychiatric illness has been the mosteffective antisuicide approach.

What new information does this article provide?

? Clozapine appears to be useful in decreasing suicide risk in persons withschizophrenia; lithium appears effective for suicidal bipolar patients.

What are the implications for psychiatric practice?

? SSRIs are useful in the treatment of suicidal depressed patients.However, patients should be carefully monitored, especially adolescentswho receive these agents.

AntidepressantsEvidence that antidepressant treatment decreases suicide risk or suicide attempts is mixed. It isoften based on data from correlative or “ecological,” pharmacoepidemiological studies that comparesuicide rates by regions or years with concurrent rates of prescriptions for antidepressant drugs.16

There have been moderate decreases in overall suicide rates, varying by sex and age-groups, insome Nordic countries and in the US since the 1990s; these decreases are possibly associated withthe emergence of the modern, less toxic antidepressants that now dominate current clinicalpractice.17,18 Data from observational studies indicate that SSRIs may be associated with a reducedrisk of suicide in adults with depression, while their use may increase suicidality in adolescents.19

This remains a controversial topic. Findings from a meta-analysis of randomized placebo-controlledstudies suggest a modestly increased risk of suicidality associated with the use of antidepressants inpediatric patients.20 However, a more recent review of suicides in adolescents found that only 1.6%of these young people had recently been exposed to SSRIs.21 Most adolescents who died by suicidewere not taking antidepressants at the time of their death. Following the introduction of the FDA’sregulatory action on restriction of antidepressants in children and adolescents, there has been anincrease in suicides. The decrease in antidepressant prescriptions for children and adolescentsparalleled the increase in suicide rates; before the FDA’s warning, the suicide rates had beendecreasing.22,23 These findings support the use of SSRIs as part of a comprehensive treatment planfor adolescents with significant depression.Medication nonadherence occurs for various reasons and presents risk of relapse of depression withan increase in symptoms. Relational psychopharmacology emphasizes collaboration between patient

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Psychopharmacological Treatment to Reduce Suicide RiskPublished on Psychiatric Times(http://www.psychiatrictimes.com)

and pharmacologist toward a shared goal of symptom relief.24 Bostwick25(p353) suggests thatpharmacologists rely on “informed intuition and close follow-up” as part of an empathic therapeuticrelationship that enables the patient to tolerate some amount of adverse effects and delay inachieving therapeutic response.Patients who independently interrupt or discontinue treatment without consulting their prescribingphysician are at greatly increased risk for recurrence or early relapse. The decision to discontinuemedication may provide relief from unpleasant adverse effects; however, there are associated risksrelated to recurrence of symptoms. These risks appear to be higher if medications with shorterhalf-lives are abruptly discontinued.26 Furthermore, findings from some studies indicate thatantidepressant discontinuation is associated with increased risk of suicide.27

The therapeutic alliance may minimize unilateral actions that lead to premature termination ordiscontinuation of pharmacological treatments. The therapeutic alliance enables the patient totolerate unpleasant adverse effects.Antiepileptic drugsThese agents are receiving increasing attention because of a possible association with suicidalthoughts or behaviors. Recent studies, however, have yielded inconsistent findings regarding suiciderisk conferred by specific antiepileptic drugs (AEDs). In patients with epilepsy, heightened suiciderisk has also been attributed to comorbid psychiatric conditions.28

In 2008, the FDA reported an apparent suicide risk among epileptic patients treated withanticonvulsants. However, questions have been raised about the report; the anticonvulsants groupedtogether were pharmacodynamically highly heterogeneous. The report also included outcomes ofquestionable comparability, including suicidal ideation, suicidal acts, and 4 completed suicides.Moreover, the data were acquired as passive and incidental “adverse event reports” of uncertainreliability and completeness.29 Parenthetically, it is curious that epileptic patients would volunteer forpotential exposure to placebo treatment.

It is unclear whether the action of AEDs in patients with affective disorders is similar to that inpatients with seizure disorders. It is crucial to determine whether suicide risk with anticonvulsantsand high-potency benzodiazepines with anticonvulsant activity carries over to psychiatric patients,because these drugs are widely used to treat serious psychiatric disorders.30Two studies haveexamined this potential association between AEDs and suicide risk, with inconclusive results.31,32

Reported investigations that examined suicide risk and AEDs are strikingly inconsistent in theirrankings of relative risks associated with particular drugs. Nevertheless, levetiracetam, lamotrigine,and topiramate were among the top 3 AEDs with the highest observed suicide risks in at least 2 ofthe 5 reported analyses. Levetiracetam was among the top 3 drugs in all 5 studies that foundincreased suicide risk. Lamotrigine and topiramate appeared in the top 3 in 3 of the 5 studies. Onlytopiramate has been associated with clinical depression. These 3 drugs differ in theirpharmacodynamics. Thus, it is difficult to conclude which biological mechanisms lead to increasedsuicide risk.33

Lamotrigine monotherapy is an effective and well-tolerated treatment for mania and bipolardepression, and it may be used as an augmentation strategy for unipolar depression.34

Other pharmacological issuesSome pharmacological challenges go beyond diagnostic categories. There are many clinicalchallenges in which medications play key roles in reducing generalized symptoms, such as anxietyand insomnia, that worsen during a psychosocial crises and are associated with increased suiciderisk. Adequate treatment of insomnia and agitation is important anecdotally in suicidal patients.Although suicide rates are surprisingly high among persons with anxiety disorders and severeanxiety may accompany suicidal behavior, evidence that antianxiety medications may alter suiciderisk is limited.4 Acute relief of agitation in suicidal depressed patients may play a significant role insuicide prevention.ConclusionAdequate treatment of the underlying psychiatric illness consistently appears to be the mosteffective use of medication in suicidal patients. Although studies are limited, there are indicationsthat some medications will provide specific antisuicidal protection. The use of illness-specificmedication provided through the therapeutic relation-ship is key to decreasing the risk of suicide.Clozapine has shown some efficacy at reducing suicide risk in schizophrenia, and olanzapine andquetiapine appear promising. Similarly, lithium has been shown to be effective for patients who havebipolar disorder. SSRIs are useful in the treatment of suicidal depressed adults. However, patientswho are receiving SSRIs, especially adolescents, should be carefully monitored. Additional research

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Psychopharmacological Treatment to Reduce Suicide RiskPublished on Psychiatric Times(http://www.psychiatrictimes.com)

is urgently needed to determine the safety of antiepileptic drugs.A good therapeutic alliance is key to effective pharmacotherapy. By forging a therapeuticrelationship, the prescribing psychiatrist encourages patient adherence and enables physician andpatient to monitor suicide risk across the spectrum of diagnoses and possible adverse effects. References: References1. Robins E, Murphy GE, Wilkinson RH, et al. Some clinical considerations in the prevention of suicidebased on a study of 134 successful suicides. Am J Pub Health. 1959;49:888-899.2. Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: clinical aspects. Br JPsychiatry. 1974;125:355-373.3. Pompili M, Rihmer Z, Innamorati M, et al. Assessment and treatment of suicide risk in bipolardisorders. Exp Rev Neurother. 2009;9:109-136.4. Baldessarini RJ, Tondo L. Psychopharmacology for suicide prevention. In: Pompili M, ed. Suicide: AGlobal Perspective. London: Bentham Science Publishers Ltd; 2012.5. Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406 mood-disorder patients with andwithout long-term medication: 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9:279-300.6. Meltzer HY, Alphs L, Green AI, et al; International Suicide Prevention Trial Study Group. Clozapinetreatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT)[published correction appears in Arch Gen Psychiatry. 2003;60:735]. Arch Gen Psychiatry.2003;60:82-91.7. Houston JP, Ahl J, Meyers AL, et al. Reduced suicidal ideation in bipolar I disorder mixed-episodepatients in a placebo-controlled trial of olazapine combined with lithium or divalproex. J ClinPsychiatry. 2006;67:1246-1252.8. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trialof quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.9. Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapinemonotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER IIstudy) [published correction appears in J Clin Psychopharmacol. 2007;27:51]. J ClinPsychopharmacol. 2006;26:600-609.10. Young AH, McElroy SL, Bauer M, et al; EMBOLDEN I (Trial 001) Investigators. A double-blind,placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase ofbipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71:150-162.11. McElroy SL, Weisler RH, Chang W, et al; EMBOLDEN II (Trial D1447C00134) Investigators. Adouble-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults withbipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71:163-174.12. Jamison KR. Suicide and bipolar disorders. Ann N Y Acad Sci. 1986;487:301-315.13. Baldessarini RJ, Tondo L, Hennen J. Effects of Lithium treatment and its discontinuation onsuicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84.14. Tondo L, Baldessarini RJ, Hennen J, et al. Lithium treatment and risk of suicidal behavior inbipolar disorder patients. J Clin Psychiatry. 1998;59:405-414.15. Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-termlithium treatment: a meta-analytic review [published correction appears in Bipolar Disord.2007;9:314]. Bipolar Disord. 2006;8(5, pt 2):625-639.16. Baldessarini RJ, Tondo L, Strombom IM, et al. Ecological studies of antidepressant treatment andsuicidal risks. Harv Rev Psychiatry. 2007;15:133-145.17. Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand.2000;102:113-117.18. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States,1985-1999. J Clin Psychiatry. 2004;65:1456-1462.19. Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: asystematic review of observational studies. CMAJ. 2009;180:291-297.20. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressantdrugs. Arch Gen Psychiatry. 2006;63:332-339.21. Dudley M, Goldney R, Hadzi-Pavlovic D. Are adolescents dying by suicide taking SSRIantidepressants? A review of observational studies. Australas Psychiatry. 2010;18:242-245.22. Katz LY, Kozyrskyj AL, Prior HJ, et al. Effect of regulatory warnings on antidepressant prescriptionrates, use of health services and outcomes among children, adolescents and young adults [published

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correction appears in CMAJ. 2008;178:1466]. CMAJ. 2008;178:1005-1011.23. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidalitywarnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry.2007;164:1356-1363.24.Sabo AN, Rand BI. The relational aspects of psychopharmacology. In: Sabo AN, Havens L,eds. The Real World Guide to Psychotherapy Practice. Cambridge, MA: Harvard University Press;2000:34-59.25. Bostwick M. Pharmacotherapy and the therapeutic alliance in the treatment of sociality. In:Michel K, Jobes DA, eds. Building a Therapeutic Alliance With the Suicidal Patient. Washington, DC:American Psychological Association; 2011:353-375.26. Shelton RC. The nature of the discontinuation syndrome associated with antidepressant drugs. JClin Psychiatry. 2006;67(suppl 4):3-7.27. Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation and risk of suicide attempt: aretrospective, nested case-control study. J Clin Psychiatry. 2009;70:1069-1077.28. Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or falsealarm? Epilepsia. 2009;50:978-986.29. Food and Drug Administration. Statistical review and evaluation: antiepileptic drugs andsuicidality. 2008. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA.pdf.Accessed February 27, 2012.30. Pompili M, Tatarelli R, Girardi P, et al. Suicide risk during anticonvulsanttreatment. Pharmacoepidemiol Drug Saf. 2010;19:525-528.31. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. Suicide-related events in patients treatedwith antiepileptic drugs. N Engl J Med. 2010;363:542-551.32. Gibbons RD, Hur K, Brown CH, Mann JJ. Relationship between antiepileptic drugs and suicideattempts in patients with bipolar disorder. Arch Gen Psychiatry. 2009;66:1354-1360.33. Pompili M, Baldessarini RJ. Epilepsy: risk of suicidal behavior with antiepileptic drugs. Nat RevNeurol. 2010;6:651-653.34. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotriginemonotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry.1999;60:79-88. Source URL: http://www.psychiatrictimes.com/psychopharmacological-treatment-reduce-suicide-risk

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