2012 AACP Suicidal Behavior in Bipolar Disorder

1. 2012 AACP Suicidal Behavior in Bipolar Disorder Frederick K. Goodwin MD

2. Suicide Pool Overlap SuicidalIdeation Suicide SuicideAttempts Gutheil T. 2000.

3. Factors to Consider in Assessing Suicide Risk • Lifetime history, nature, seriousness, & number of previous attempts and aborted attempts • Presence, history, and lethality of suicidal ideation, intent, or plans • Access to means for suicide and the lethality of those means, such as access to a firearm • Presence of hopelessness, psychic pain, decreased self-esteem, narcissistic vulnerability • Presence of severe anxiety, panic attacks, agitation, impulsivity • Presence and history of aggression and violence • Nature of cognition, such as loss of executive function, thought constriction (tunnel vision), polarized thinking, closed-mindedness, poor coping and problem-solving skills • Presence of psychotic symptoms, such as command hallucinations or poor reality testing • Presence of alcohol or other substance use APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition, adapted from Adapted from APA’sPractice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors cont’d

4. Factors to Consider in Assessing Suicide Risk (cont) • Presence of major psychiatric disorders, such as MDD, BP, schizophrenia, anorexia nervosa, alcohol use disorder, other substance use disorders, cluster B personality disorders • Recent psychiatric hospitalization • Presence of disabling medical illness, especially with poor prognosis • Demographic features, such as age, race, marital status, sexual orientation • Presence of acute or chronic psychosocial stressors, which may include actual or perceived interpersonal losses, financial difficulties or changes in socioeconomic status, family discord, domestic partner violence, & past or current sexual or physical abuse or neglect • Absence of psychosocial support, such as poor relationships with family, unemployment, living alone, unstable or poor therapeutic relationship, recent loss of a relationship APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition, adapted from Adapted from APA’sPractice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors cont’d

5. Factors to Consider in Assessing Suicide Risk (cont) • History of childhood traumas, particularly sexual and physical abuse • Family history of or recent exposure to suicide • Absence of protective factors, such as children in the home, sense of responsibility to family, pregnancy, life satisfaction, cultural beliefs, or religiosity APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition, adapted from Adapted from APA’sPractice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors

7. Lifetime Suicide Rates in Major Affective Disorder • 31 studies • 9389 patients (primarily inpatients) • Bipolar and recurrent unipolar groups not reported separately • Suicide prevalence: • 18.9% (weighted mean) Goodwin & Jamison, 2007 7347

8. Lifetime Suicide Rates in Major Affective Disorder • More recent studies have included more representative samples (broad range of severity, primarily outpatients) • These new estimates are in the 8 –10 % range, both for Unipolar and Bipolar groups

11. Suicidal ideation is not a useful predictor of suicide • NIMH Colab Study: the largest prospective study of suicide in major affective disorder (UP and BP) ever done (n=964) • Follow-up at 1,5 and 10 years • Those who committed suicide in the first year (the most important period for management decisions) (n=13) communicatedless severe ideation than depressed comparison patients. Fawcett et al 1990

12. Prior Suicide Attempts predict Suicide in Depressed Adults, but not robustly In the large prospective NIMH study, the majorityof suicides (51%) had no prior attempt There were fewer prior attempts among those who did commit suicide at 1 year than among those who did not At 10 year follow-up there was a trend for suicide attempts to predict suicide (p < 0.1) (attempts were a chronic risk factor) Fawcett et al 1990

13. Prior Suicide Attempts predict Suicide, but not robustly • Only 8% - 12% of patients who make suicide attempts commit suicide within 10 years (Ettlinger 1986, Tejedor 1999) • Of suicides with prior attempts 10% did so within 1 year of attempt (retrospective) (Robins 1960) • Study of 1397 suicides in Finland: 38% of female and 19% of male suicides had attempt within 1 year (Isometsa 1997) (retrospective) • But among near fatal attempters, only 7% committed suicide during 5 yrs of follow-up (Beautris 04) 7767

14. Is Suicide Risk a Separate Heritable Behavior? • Suicide runs in Families-Independent of Disorders-Tsuang 83, Egeland 85, Brent 96, Roy 91,95 • Impulsivity and aggression run in families- Brent 96, McGirr 2010 • Hopelessness-base line and reactive are trait Like- Young 96, Mann 99 • Anxiety and Depression run in families-Stein 99,Leckman 83,Beidel 97,Kendler 95

15. Twin Studies of Concordance for Suicide No. of Twins Fisher’s Concordant for Exact Test Suicide (Two-tailed) Study MZ DZ P Haberlandt ‘67 9/51 0/98 <.001 Juel-Nielsen and Videbech ‘70 0/15 0/58 . . . Zair ‘81 1/1 0/0 . . . Roy et al ‘91 7/62 2/114 <.01 TOTALS 17/129 2/270 <.001 6583

16. Risk Factors for Suicide in Bipolar Adults (Current) • Severe depression with anxiety, agitation, global insomnia and hopelessness • Mixed—dysphoric mania • Mood cycling in episode • Substance abuse • Transition periods/early recovery stage • Impulsive and/or violent behavior Goodwin FK. 2009. Goodwin and Jamison 2007

17. Risk Factors in Bipolar Disorder(by History) • Family hxof suicide/impulsivity/violence • Prior suicide attempts, especially if high on the lethality scale • Hxof impulsive and/or violent behavior • Hxof severe depressions with anxiety/agitation/global insomnia • Relatively early in course of illness (?) Goodwin FK, Jamison KR. Manic-Depressive Illness. 2007.

18. Factors in Inpatient Suicide • Retrospective; 76 inpatients who suicided in the hospital or within one week of discharge • Only 49% had ever made a prior attempt; 78% denied suicidal ideation just before the suicide • 42 % of suicides occurred on q 15 min checks or constant observation, and 28 % had a no suicide contract in effect • 42 % were on anxiolytics, almost all at LOW DOSES. Less than 10% were on atypicals Busch and Fawcett 2003

19. Suicidal Behavior: Specific Preventive Treatment? • Acute severe anxiety/agitation1 • Short-term treatment with benzodiazepines, anticonvulsants, or atypical antipsychotics • Impulsivity/violence2 • Short- and long-term treatment with lithium and/or anticonvulsants and/or atypical antipsychotics 1. Apter, et al. 1990; Fawcett, et al. 1990; Ohring, et al. 1996; Stein, et al. 1998; Hall et al. 1999; Schnyder. 1999. 2. Apter, et al. 1990; Fawcett, et al. 1990; Goodwin FK, Jamison KR. 1990. Adapted from Fawcett. 2000.

20. Suicidal Behavior: Specific Preventative Treatments? • Mixed states AC’s + lithium + atypicals? Avoid antidepressants • Cycling within Anticonvulsants episode and lithium (rapid cycling) Avoid antidepressants • Comorbid substance AA or NA; naltrexone abuse Anticonvulsants (?) Atypical antipsychotics (?) Goodwin FK. 2008; Fawcett J. 2000.

21. So, what is the evidence that mood stabilizers can reduce the long term risk of suicide in bipolar patients?

22. Prien et al. 1974* Kay & Petterson 1977 Poole et al. 1978 Ahlfors et al. 1981 Venkoba-Rao et al. 1982 Hanus & Zapletalek 1984 Lepkifker et al. 1985 Nilsson & Axelsson 1990 Modestin & Schwarzenbach 1992 Müller-Oerlinghausen et al. 1992 Rihmer et al. 1993 Felber & Kyber 1994 Lenz et al. 1994 Sharma & Markar 1994 Koukopoulos et al. 1995 Nilsson 1995 Greil et al. 1996, 1997a,b* Bocchetta et al. 1998 Coppen & Farmer 1998 Tondo et al. 1998 Bauer et al. 2000* Brodersen et al. 2000 Kallner et al. 2000 Coryell et al. 2001 Rucci et al. 2002 Bowden et al. 2003* Calabrese et al. 2003* Goodwin et al. 2003 Yerevanian et al. 2003 Angst et al. 2005 Gonzalez-Pinto et al. 2005 [( * ) RCTs] Pooled RR (4.91) 0.01 0.1 1 10 100 1000 Risk Ratio (RR; 95%CI) Lithium vs.Suicide andAttempts(n=31 studies) Baldessarini et al. Bipolar Disord 2006; in press. Baldessarini et al. 2006.

23. 7806

24. Suicide and Suicide Attempts Among Bipolar Patients Randomly Assigned to Lithium or Carbamazepine (n=380) A 2.5-year Randomized Prospective Study Suicide Total suicidal Suicide attempts behavior Lithium 0 0 0 Carbamazepine5 4 9* *p<0.01. Thies-Flechtner K, et al. 1994.

25. Large (> 10,000 patients) population based studies of maintenance lithium vsdivalproexin bipolar disorder

26. Suicide risk in bipolar disorder during treatment with lithium and divalproex • A retrospective cohort study conducted at two large HMOs with a population-based sample of 20,638 plan members with DSM IV bipolar I or II disorder ( age 14 or older) • Exclusions: DSM IV diagnosis of schizophrenia or dementia/cognitive disorder • DSM IV Schizoaffective diagnoses subsequent to bipolar diagnoses censored at that point • Treatment exposure measured using computerized pharmacy records of all initial and refill prescriptions • Main outcomes: suicide attempt requiring hospitalization; suicide attempt requiring ER intervention; suicide Goodwin et al JAMA 2003

27. Suicide risk in bipolar disorder during Rx with lithium and divalproex (con’t) • Treatment guidelines in the two HMOs call for combined mood stabilizers only after monotherapy has failed • Patients followed from time of first prescription to death, disenrollment from the plan, or study termination • A total of 60,060 person years of observation; mean follow-up per indivdual: 2.9 years • Ratio of suicide attempts to suicide: 6.4 :1 • Potential confounding factors were identified for each patient: (1) comorbid medical or axis1 psychiatric diagnoses and (2) concomitant exposure to antidepressants, typical antipsychotics, and atypical antipsychotics (quantified from the pharmacy records) Goodwin et al JAMA 2003

28. Suicide Risk in Bipolar Disorder during Treatment with Lithium and Divalproex events/1,000 pt-years *Sig. Diff from lithium alone (p<.04) ** p<.001 The lithium +VPA pts had failed monotherapy Goodwin,Simon et al. JAMA 2003

29. Suicide Risk in Bipolar Disorder during Treatment with Lithium and Divalproex (cont...) Risk ratios of events relative to patients on lithium (controlling for age, sex, coexisting meds, & comorbid dx) The lithium + VPA patients had failed monotherapy **P <.01 **P <.03 Goodwin FK, et al. JAMA. 2003;290:1467-1473.

30. Distribution of Initial Mood Stabilizer Prescriptions According to Year of Initial Bipolar Disorder Diagnosis Goodwin et al JAMA 2003 The year a patient entered the clinic was a major determinant of medication choice. ( naturalistic randomization)

31. Suicide risk in bipolar disorder during Rx with lithium and divalproex (con’t) • Pharmacy records overestimate drug use because patients are not always adherent. The literature indicates that adherence rates for lithium and divalproex are similar, so the overestimation would not bias in favor of either drug. If anything, this error would tend to blur differences between drugs. • Stability of the differential risk: suicide attempts were consistently lower among lithium patients than divalproex patients throughout the eight-year period. • The risk of suicide attempt was significantly higher among patients who switched mood stabilizers during the course of the study, regardless of the direction of the switch. Goodwin et al JAMA 2003

32. Risks of suicide and suicide attempts in a Medicaid population (BP I & II, n=12,662): anticonvulsants vs lithium • Importance of public sector data to complement data from private health plans • Methodology similar to Goodwin et al except only the initial episode of medication use was tracked • 12,662 patients and 7017 person years of exposure vs 20,638 patients and 60,060 person years in the Goodwin et al study • Gabapentin included as a “mood stabilizer” in this study Collins and McFarland, J Aff Dis 2008

33. Risks of suicide and suicide attempt in a Medicaid population (BP I & II, n=12,662): anticonvulsants vs lithium Based on Cox proportional hazards models adjusted for age, gender, year of diagnosis, co-occurring medical and psychiatric conditions, and concomitant use of other psychotropic medication with lithium users as the reference group Collins and McFarland, 2008 J. of Affect. Disord.107, 23-28

34. Risks of suicide and suicide attempt in a Medicaid population: anticonvulsants vs lithium (con’t) • There were a total of 4 suicides in in the lithium and the divalproex groups combined, vs 23 in the Goodwin et al study • Suicides/1000 patient years on lithium were 0.78 vs 0.70 in the Goodwin et al study • The risk ratio (divalproex vs Lithium) was 1.5 for suicide (p=0.1) and 2.7 for attempts (p<.001)

35. Lithium vs ACs [Baldessarini R, Tondo L: Pharmacopsychiatry 2009, in press]

36. Population based studies of antidepressants in the prevention of suicide

37. ATTEMPTS AND COMPLETIONS Barbui et al 2009

38. Summary • Most studies focus on suicide attempts to get an adequate sample size, but SA is not a surrogate for suicide; suicide ideation is even less so. • Bipolar patients are at high risk for suicide when in a depression or mixed state • Anxiety/panic symptomsin depressed patients clearly increase the risk of suicide in the near term • Focus treatment on symptom clusters that increase acute risk; (anxiety/panic; insomnia; impulsivity; mixed states; rapid cycling; substance abuse) • Lithium is the only mood stabilizer shown to reduce suicide and should be so recognized by FDA