Ne me parlez pas de la

« Ne me parlez pas de la mort, cela me fait mourir » Sacha Guitry (please, don’t talk to me about death, it kills me)

Suicide: The Place of Mental Disorders in its Etiology and Prevention Alain Lesage md, MPhil Centre de recherche Fernand-Seguin Hôpital L-H Lafontaine affiliated to University of Montreal Montréal, Qc, Canada • Harvard Injury Control Research Center, alesage@ssss. gouv. qc. ca Seminar Series, 12 February 2004

Introduction • Recent controversy over the interpretation of evidence from Scandinavian and other countries of a significant decrease in suicide rates associated with an increase in prescription of antidepressants • raising the issue of whether treatment of depression would be a key suicide prevention strategy

Introduction • little evidence, so far, that any suicide prevention strategy available can have a large effect on its own • many countries adopting a multi-strategies public health suicide prevention approach

Aims • through a public health demonstration in 6 steps, that the treatment of depression would be a potentially effective suicide prevention strategy, – to discuss the role of mental disorders in the etiology and prevention of suicide

First pieces of evidence

Isaacson, G. , 2000, Suicide prevention- a medical breakthrough? Acta Psychiatrica Scandinavica, 102, 113 -117.

Iceland’s report on antidepressants and depression – Sales of antidepressants increased from 8. 4 daily defined doses per 1000 inhabitants per day in 1975 to 72. 7 in 2000, which is a user prevalence of 8. 7% for the adult population. – Suicide rates fluctuated during 1950 -2000 but did not show any definite trend. Rates for out-patient visits increased slightly over the period 1989 -2000 and admission rates increased even more. – Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland: Time series analysis of national data. Br J Psychiatry. 2004 Feb; 184: 157 -62 .

Association between antidepressant prescribing and suicide in Australia, 1991 -2000: trend analysis (Hall et al. , BMJ 2003; 326: 1008 • overall national rates of suicide did not fall significantly, incidence decreased in older men and women and increased in younger adults. • In both men (rs=− 0. 91; P<0. 01) and women (rs=− 0. 76; P<0. 05) the higher the exposure to antidepressants the larger the decline in rate of suicide.

Relationship between antidepressant medication treatment and suicide in adolescents. (Olfson et al. , Arch Gen Psychiatry. 2003 Oct; 60(10): 978 -82. ) • MAIN OUTCOME MEASURES: The relationship between regional change in antidepressant medication treatment and suicide rate stratified by sex, age group, regional median income, and regional racial composition. • RESULTS: There was a significant adjusted negative relationship between regional change in antidepressant medication treatment and suicide during the study period. – A 1% increase in adolescent use of antidepressants was associated with a decrease of 0. 23 suicide per 100 000 adolescents per year (beta = -. 023, t = -5. 14, P<. 001).

Evidence of the effectiveness of suicide prevention strategies • Gunnel, D. , Frankel, S. , 1994, Prevention of suicide : aspirations and evidence, British Medical Journal, 308, 1227 -1233.

Effects of and exposure to possible suicide prevention strategies (Gunnell et Frankel, 1994, BMJ, 308: 1227 -1233) 1 of 3

Secular trends in unemployment and suicide rates (all methods) 15 -44 years old male; England & Wales; Gunnell et al. , 1999; Br J Psychiatry 175: 263 -270)

Effects of and exposure to possible suicide prevention strategies (Gunnell et Frankel, 1994, BMJ, 308: 1227 -1233) 2 of 3

Cochrane reviews evidence: psychosocial and pharmacological treatments of self-harm – Reviewers' conclusions: There still remains considerable uncertainty about which forms of psychosocial and physical treatments of self-harm patients are most effective, inclusion of insufficient numbers of patients in trials being the main limiting factor. There is a need for larger trials of treatments associated with trends towards reduced rates of repetition of deliberate self-harm. The results of small single trials which have been associated with statistically significant reductions in repetition must be interpreted with caution and it is desirable that such trials are also replicated. • Citation: Hawton K, Townsend E, Arensman E, Gunnell D, Hazell P, House A, van Heeringen K. . Psychosocial and pharmacological treatments for deliberate self harm (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Effects of and exposure to possible suicide prevention strategies (Gunnell et Frankel, 1994, BMJ, 308: 1227 -1233) 3 of 3

Contact with services and suicide • In the UK, 80% of the population saw their GP in the past year • In a Montreal ’s psychological autopsy study of young male adults aged 18 -35 – 50% saw their GP in the past year – 25% saw a psychiatrist

Contact with services and suicidal behaviours (Bancroft et al. , 1977 reported by Gunnel & Frankel, 1994) • among self-harmed seen by services – 75% had heard of Samaritans • 4% contacted Samaritans – 10% contacted social worker – 13% contacted clergy

Contact with services and suicide (Gunnel & Frankel, 1994) • average GP will – experience the suicide of a patient every 4 -5 years – meet such patient shortly before suicide every 8 -10 years

Perspective on suicide behaviours: 1 -yr prevalence of suicide, suicide attempts and suicide ideation (based on Quebec’s vital statistics and population surveys in the ‘ 90 s) • Suicide: 20 per 100 000 inhabitants • Attempts : 600 per 100 000 inhabitants • Ideation: 4000 per 100 000 inhabitants

Estimated sample sizes required for the evaluation of interventions targeted at particular population groups (Gunnell et Frankel, 1994, BMJ, 308: 1227 -1233)

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (1 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (2 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (1 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

• Partly reported in Lesage AD, et al. Suicide and Mental Disorders: A Case-Control Study of Young Adult Males. The American Journal of Psychiatry, 151(7), 1063 -1068, 1994.

Psychological autopsies- systematic review • 154 reports identified; 76 met the criteria for inclusion; 54 case series and 22 case-control studies. • median proportion of cases with mental disorder was 91% (95 % CI 81 -98%) in the case series. – In the case-control studies 90% (88 -95%) in the cases and 27% (14 -48%) in the controls. • Co-morbid mental disorder and substance abuse in more suicide cases (38%, 19 -57%) than controls (6%, 0 -13%). • The population attributable fraction for mental disorder ranged from 47 -74% (7 studies) Cavanagh JT, Carson AJ, Sharpe M, Lawrie SM. Psychological autopsy studies of suicide: a systematic review. Psychol Med. 2003 Apr; 33(3): 395 -405.

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (1 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

Suicide as an outcome for mental disorders (Clare & Barraclough, Br J Psychiatry, 1997, 170, 205 -228)

Risk of suicide is lower in depression (Blair-West et al. , 1997, 1999) • previously accepted risk of 10 -15% lifetime • based on hospitalised or outpatient cohorts – the majority of people with depression are not treated • revised conservative lifetime risk of 3. 4% – estimated 7% for males; 1% for females • Blair-West GW, et al. Down-rating lifetime suicide risk in major depression. Acta Psychiatr Scand. 1997 Mar; 95(3): 259 -63.

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (1 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

RCT antidepressants and cognitive-behavioural psychotherapy in chronic depression • • • randomly assigned 681 adults 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. all patients had scores of at least 20 on the 24 -item Hamilton Rating Scale for Depression Remission was defined as a score of 8 or less at weeks 10 and 12. a satisfactory response was defined as a reduction in the score by at least 50 percent from base line blind assessments • A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. Keller MB et al. , N Engl J Med. 2000 May 18; 342(20): 1462 -70.

Cochrane reviews evidence: antidepressants and chronic depression • Reviewers' conclusions: Drugs are effective in the treatment of dysthymia with no differences between and within class of drugs. Tricyclic antidepressants are more likely to cause adverse events and dropouts. As dysthymia is a chronic condition, there remains little information on quality of life and medium or long-term outcome. • Citation: Lima MS, Moncrieff J. Drugs versus placebo for dysthymia (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd

Cochrane reviews evidence: active placebos and antidepressants • Main results: Nine studies involving 751 participants were included. Combining all studies produced a pooled estimate of effect of 0. 39 standard deviations (confidence interval, 0. 24 to 0. 54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0. 17 (0. 00 to 0. 34). – Citation: Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (2 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

Treatment received by individuals with major depression in the last year in early ‘ 90 s Ontario (n=333/8116, 4. 1%) • Depression in Ontario: undertreatment and factors related to antidepressants use (Parikh, Lesage, Kennedy, Goering, 1999, J Aff Dis, 52, 67 -76)

Undertreatment of major depression • The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). (Kessler et al. , JAMA, 2003; 289; 3095 -3105) • 12 -month was 6. 6% (95% CI, 5. 9 -7. 3) (13. 1 -14. 2 million US adults). • 51. 6% (95% CI, 46. 1 -57. 2) of 12 -month cases received health care treatment for MDD, – treatment was adequate in only 41. 9% (95% CI, 35. 947. 9) of these cases, resulting – in 21. 7% (95% CI, 18. 1 -25. 2) of 12 -month MDD being adequately treated.

Demonstrating the potential effect of a suicide prevention strategy based on the treatment of depression in the population: 6 necessary steps (2 of 2) • * I. At least one RCT; II. Case-control or cohort studies; III. Opinions of respected authorities, descriptive studies; IV. Evidence inadequate owing to methodological problems

Lower suicide risk with long-term lithium treatment • Among 5647 patients (33 473 patient-years of risk) in 22 studies, • suicide was 82% less frequent during lithiumtreatment (0. 159 vs. 0. 875 deaths/100 patientyears). • the computed risk-ratio in studies with rates on/off lithium was 8. 85 (95% CI, 4. 12 -19. 1; P<0. 0001). • Tondo L, Hennen J, Baldessarini RJ Lower suicide risk with long-term lithium treatment in major affective illness: a metaanalysis. Acta Psychiatr Scand. 2001 Sep; 104(3): 163 -72.

Suicide Rates in Clinical Trials of SSRIs, other Antidepressants and Placebo: Analysis of FDA Reports (Khan et al. , Am J Psychiatry 2003; 160: 790 -792) • Suicide rates did not differ among the 3 groups

Suicide risk in placebo-controlled studies of major depression (Storosum JG et al. , Am J Psychiatry. 2001; 158(8): 1271 -5) • In 77 short-term studies with 12, 246 patients in dossiers from the Medicines Evaluation Board, the incidence of suicide was 0. 1% in both placebo groups and active compound groups. • In eight long-term studies with 1, 949 patients, the incidence of suicide in the placebo groups was 0. 0% and 0. 2% in the active compound groups.

Reasoning about suicide prevention

Suicide rates in Canada 1950 -1998/9, per 100 000 inhabitants

Four strategies to improve the health of populations (UK, Donaldson) • change health determinants (‘ causes of causes ’) • prevention • protection • improve quality of services

UK National policy of reducing depression and suicide • The Government set targets for reducing psychiatric morbidity and suicide. • A public information strategy was launched to increase understanding and reduce stigma, including a five year 'Defeat Depression' Campaign. • updating General Practitioners in the recognition, detection and management of depression. • Government departments worked with employers and trade union organisations to attempt to reduce work-induced stress. Paton J, Jenkins R, Scott J. Collective approaches for the control of depression in England Soc Psychiatry Psychiatr Epidemiol. 2001 Sep; 36(9): 423 -8.

UK National policy of reducing depression and suicide (continued) • Universal and selective prevention measures aimed to reduce factors associated with depression, such as unemployment. • Measures to reduce suicide include education of health and social care professionals, supporting high-risk groups and restricting access to means of suicide. • The overall suicide rate fell by 11. 7% in five years. Paton J, Jenkins R, Scott J. Collective approaches for the control of depression in England Soc Psychiatry Psychiatr Epidemiol. 2001 Sep; 36(9): 423 -8.

Interpretation of association of increased antidepressants utilisation and decreasing suicide rates (Hall et al. , 2003) • We think that antidepressant prescribing is a proxy measure for exposure to psychosocial and pharmacological interventions delivered by a general practitioner for depression, anxiety, and other comorbid psychological disorders. • Data from Australian general practice surveys indicate that general practitioners identify a wide range of psychological disorders, provide more non-pharmacological than pharmacological interventions, and, when they use pharmacological treatments, rarely provide them without psychosocial assessment and support.

Interpretation of association of increased antidepressants utilisation and decreasing suicide rates (Hall et al. , 2003) (continued) • Recognition of psychological disorders in general practice and general practitioners' use of psychosocial and pharmacological treatments for depression may have improved. • Given these trends in general practice, the association we observed between antidepressant prescribing and suicide may reflect increased recognition, diagnosis, and treatment of depression by general practitioners as much as any pharmacological effects of antidepressant medication. • If this proves to be the most plausible explanation of our data, it supports the public policy of encouraging general practitioners to improve community mental health

Your opinion counts ! • Strength of the evidence that treatment of depression is an effective suicide prevention strategy? – Missing links (step VI) – Secular trends (step V) – confounders (treatment of depression) • Risks with a total population approach – G Rose ’s prevention paradox

Rose’s prevention paradox • arises because many interventions that aim to improve health have relatively small influences on the health of most people. – Thus, for one person to benefit, many people will have to change their behaviour and receive no benefit from these changes.

Argument to Rose’s prevention paradox for treatment of depression • Burden of diseases’ studies showed that depression is the 2 nd and will become first cause of incapacity in industrialised countries • depression is largely undertreated and if treated, often not adequately • increasing treatment of depression may yield important population health gains by reduction of incapacity