Adolescent Suicidality

Clinical Management and Psychopharmacology

Prof. Gil Zalsman MD, MHA
Director, Geha Mental Health Center
And Adolescent Day Care Unit
Sackler Faculty of Medicine
Tel Aviv University, Israel
&
Associate Research Scientist
Molecular Imaging and Neuropathology Division
Psychiatry Department
Columbia University, USA

Chair of the ECNP educational committee

ECNP school for child psychiatry, Venice
April 6th, 2016

Prof. Zalsman’s ethical disclosure

Nothing to disclose

ECNP European college of
neuropsychopharmacology

ECNP
Who we are, what we do?
Gil Zalsman – Chair of Education

www.ecnp.eu 3

Old Age (Venice).ecnp. registration and accommodation www. Child and Adolescent. ECNPneuroscience applied Develop young researchers  Four Schools  Week-long programme of intensive training for 50 young psychiatrists  General (Oxford).eu 4 . research methods (Madrid)  One Workshop  Annual three-day interactive workshop for 100 young scientists • All participants supported by ECNP for travel.

Unique. European- wide qualification for young researchers in the science and treatment of disorders of the brain www.000 each)  New: ECNP Internships  lab experience or clinical “observership”  ECNP Certificate.eu 5 .ecnp. ECNPneuroscience applied  Seminars – 4 per year  Two days of interactive training for 50 participants  3 ECNP Seminar Awards (€ 1.

Venice working group 1996 .

Donald J Cohen 1940-2001 .

Three advices for building a career in child psychiatry research Pick a subject Find a mentor Built a database .

How do I start? Research question disorder method population .

Create your own DATA BASE!!! .

Geha MHC Child and Adolescent Day Center .

Israel . Tel Aviv University.Child and Adolescent Division Geha Mental Health Center.

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2005 . Safe environment: “Anti-suicide” shower head Engel & Zalsman IJAMH.

Lithium. Clozapine.My Message  Suicidal behavior is not rare after puberty  Complete suicide is rare and hard to predict  Risk assessment and recording is essential  Pharmacotherapy include SSRIs. ECT and maybe Ketamine  SSRIs do not cause more completed suicides  Animal model prove GxExT interaction  Prevention in the national level is effective  Connection and Compassion are critical .

The phenomena .

000 in Europe  About 65.000 people a year worldwide  Over 150.SUICIDE  1.000.000 in the EU countries  Males 5 times more  Attempts are common (x10) - mostly females .

2013. 347: f5239.. . BMJ. Suicide in the World 2013 Chang et al.

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Suicide in children & adolescents  First / Second leading cause of death until age 24y  Suicide before puberty is rare (Pfeffer 1996) .

.If you don’t ask you don’t know  90% of suicide victims suffered from a mental disorder  60% of suicide victims met their primary care physician in the month prior to suicide Mann et al. JAMA. JAMA 2006 . 2005  Asking is not dangerous Gould et al..

Definitions  “An act of self harm with at least partial intent to die” (Posner et al.attempt (aborted/disrupted)-completed .. 2010)  CSSRS  Spectrum Theory: ideation.

NSSI Non Suicidal self Injury New @ DSM 5 No Intent to die Typically BLPD .

—U NITED STATES— Leading causes of death in pediatric age CAUSE # OF DEATHS Accidents 6573 Homicide 1861 Suicide 1574 Age 21-> Cancer/Leukemia 759 7%lower sui Heart Disease 372 Congenital Anomalies 213 Lung Disease 151 Stroke 60 1631 Diabetes 40 Blood Poisoning 36 HIV 36 NCHS 2001. from Schaffer D.E3 . with permission C.

*case-control studies D14 . Brent 1999. Shaffer 1996. New York State Columbia University Psychiatric Institute PSYCHIATRIC DISORDER IN ADOLESCENT SUICIDE —PSYCHOLOGICAL-AUTOPSY STUDIES— LOCATION N YEARS % Israel 43 mid-1980s 90% *New York 120 1984–1986 90% Finland 53 1987–1988 94% *Pittsburgh 140 1984–1994 82% Apter 1993. Marttunen 1991.

Gil Zalsman MD. US **Bar Ilan University & Ministry of Education. REGRESSIVE NARRATIVES Prof. Yochi Siman-Tov MEd** Prof. Israel IASP conference OSLO 2013 (Wed 17:00-17:30. Israel & Molecular Imaging. David Tzuriel PhD** *Child Psychiatry Department. Olympia . Columbia University. MHA* Mrs.QUALITATIVE AND QUANTITATIVE PSYCHOLOGICAL AUTOPSY OF 70 HIGH-SCHOOL STUDENTS TRAGIC VS. Tel Aviv University.

“Typical” suicide victim in Israeli schools 2003-2011(n=70) • Male • Low SES • Low graded school • Academic difficulties • School counselor knows him • Suicide risk undetected • Truancy!! • Mean 4 negative life events (SD 2.8 year • Peers knew (46%) • Trigger: interpersonal discord M/P humiliation (60%) • Hanging (72%) near home (67%) late night (95%) during January (23%) or September (17%) .5) • Low self disclosure (Horesh Zalsman and Apter 2004) • Length of crisis 0.

Narrative constructs-findings • Regressive narrative • Stable narrative (low) • Tragic narrative • Romantic narrative .

Narrative constructs-findings • Regressive narrative • Stable narrative (low) • Tragic narrative (20%) • Romantic narrative .

03 • Less psychiatric diagnoses p=0. other narratives • Shorter crisis (Humiliation) p=0.03 • More functional gap p=0.039 .006 • Less negative life events p= 0.Tragic Narrative Vs.

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Risk Assessment .

Risk Assessment  Male!!!  Psychopathology (MDD)  Previous attempt  Impulsive aggression  Loss  Living alone  No support system .

Risk Assessment  Substance abuse  Problem with the law  Genetics  Hopelessness.Despair  Helplessness  Poor decision making  Bulling  Humiliation and Shaming .

Treatment .

CBT-A 6. Close observation 2. IPT-A 7. ECT. DBT-A 8. Aggressive treatment of depression 4. Clozapine. Family TX . Ketamine 5.Treatment of the suicidal adolescent 1. Safe environment 3. Lithium.

Acta psychiatrica Scandinavica 2006 . The American Journal of Geriatric 2007) .. Sondergard L et al. Acta psychiatrica Scandinavica 2008 . . Archives of suicide research 2007). (Cipriani A. (Nelson JC et al. The Journal of clinical psychiatry 2010) • In depression.. (Sondergard L et al. while continuation of pharmacotherapy for depression is associated with a reduced risk of suicide.. • There is evidence that SSRIs might increase suicidal thoughts.. International clinical psychopharmacology 2006. Sondergard L et al. the rate of emergent suicidal ideation is low and the risk-benefit ratio for pharmacotherapy for depression appears to favor its use. Antidepressant and Suicide • Large-scale ecological studies of antidepressants indicate that initiation of pharmacotherapy is not associated with an increased risk of suicide. Zisook S et al. (Mulder RT. Canadian journal of psychiatry 2007) • However. in early-phase pharmacotherapy of depression in adults. the administration of sertraline is associated with lower suicidal ideation and behaviour but not with emergent suicidal thinking or behavior.. but not actual suicidal behaviour.

. Acta psychiatrica Scandinavica 2008. Kapusta Acta psychiatrica Scandinavica 2009) • It remains unclear whether drugs for depression decrease or increase suicidal risk in bipolar patients. (Gusmao R et al. The Journal of clinical psychiatry 2013) • • Ecological studies do not show increased sales of antidepressants to be associated with an increase in suicide rates.. Acta psychiatrica Scandinavica 2009. Castelpietra G. Pacchiarotti I etal. AJP 2013 • However. Antidepressant and Suicide • The results of one RCT suggest that SSRIs might exert a stronger effect compared with norepinephrine-dopamine reuptake inhibitors on reduction of suicidal thoughts during the initial weeks of pharmacotherapy in high-risk depressed patients (Grunebaum MF et al. Isacsson G. (Grunebaum Curr Psychiatr 2007 . a recent evaluation of the relationship between changes in the prescription of antidepressants in 29 European countries and changes in suicide rates found a clear inverse correlation. PLoS One 2013) .

. 64(10): 1132- 43. . Archives of General Psychiatry 2007. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. SSRIs and Suicide in Pediatric Population • In children and adolescents with depression. evidence (RCTs) does not support avoidance of use of antidepressant medication because of increased risk of suicidal behaviour. • Adding cognitive behavioral therapy (CBT) to fluoxetine may lead to less suicidal ideation and behaviour than treatment with fluoxetine alone. although there is evidence to suggest an increased risk of suicidal ideation in this population. March JS et al.

AGP 2005) • which was supported by the findings of a large-scale naturalistic cohort study comparing lithium with valproate.. JAMA 2003) . BMJ 2013. Lithium and Suicide Tx • As psychiatric disorders are a major risk factor for suicidal behaviour. Eur Psychiatry 2012) • There is reasonably strong evidence from RCTs that lithium is effective in reducing the risk of suicidal behaviour in people with mood disorders (Cipriani et al. their pharmacological treatment contributes substantially to the prevention of suicide... AGP 2006. Kessing et al. Baldessarini et al. (Goodwin FK.(Wasserman et al.

risk of suicide death was 2·7 times higher (95% confidence interval [CI]. 1·2- 2·3. 1·1-6·3. P<0·001). and concomitant use of other psychotropic drugs. AGP 2009 • But After adjustment for age. P = 0·03) during treatment with divalproex than during treatment with lithium. year of diagnosis. health plan. Corresponding hazard ratios for nonfatal attempts were 1·7 (95% CI. sex.. P = 0·04). comorbid medical and psychiatric conditions. Gibbons RD. P = 0·002) for attempts resulting in hospitalization Oquendo et al. • A large-scale naturalistic study suggested that anticonvulsant mood stabilizers might also have protective effects against suicide attempts.. suicide attempt resulting in hospitalization (10·5 vs 4·2 per 1000 person-years. AJP 2011 . Lithium vs Valproate • A specific anti-suicidal effect of lithium was suggested in a population of suicide attempters treated with lithium (Lauterbach et al. no deaths on lithium). and suicide death (1·7 vs 0·7 per 1000 person-years. P<0·001). Acta Psychiatrica Scandinavica 2008 ) although the number of deaths was very small (3 deaths vs. Unadjusted rates of suicide were greater during treatment with divalproex than during treatment with lithium for emergency department suicide attempt (31·3 vs 10·8 per 1000 person-years.

quetiapine showed no specific effect compared with other dopamine antagonists on the occurrence of suicide and attempted suicide.g. Cochrane Database Syst Rev 2013) . (Suttajit et al. olanzapine and risperidone) demonstrated anti- suicidal effect in schizophrenia. Cochrane Database Syst Rev 2010) • However. in another meta-analysis.. A meta- analysis of the effects of clozapine in comparison with other dopamine and serotonin-receptor antagonists (e. Antipsychotics and Suicide Tx • Clozapine is the only drug with an official indication in the US of reducing suicide risk in psychosis. (Asenjo Lobos et al...

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and with minimal side effects (Reinstatler et al. independent of improvement in depression. . Ketamine and Suicide Tx • Ketamine shows promising results in systematic review as a potentially effective and rapid treatment of suicidal thoughts. Drugs R D 2015) • but effects on suicide attempts or death by suicide have not yet been shown and effects on suicidal ideation longer than a few days have not been demonstrated..

. Patel M et al. (Kellner et al. The journal of ECT 2006) .. ECT and Suicide Tx • ECT was shown to rapidly reduce suicide risk in case series but no controlled trials have been conducted. AJP 2005.

Prevention .

Mann et al., JAMA 2005, 294:2064-2074

Suicide prevention Strategies

90%

40%

Mann et al., JAMA. 2005;294(16):2064-2074.

)2005) Lowering suicides with prevention plans
Mann et al., JAMA 2005, 294:2064-2074

? Public edu
22-73% Doc edu
33-40% Gatekeepers edu
3.2% More pharmacotherapy

? More therapists

1.5-9.5% Weapon control
19-33% Cooking gas

23% OTC control
? Media contol

Cendrine Bursztein. Danuta Wasserman. Ella Arensman. Pilar Alejandra Sáiz. Ran Barzilay. Kees van Heeringen. et al. György Purebl. Lancet Psychiatry. Marco Sarchiapone. Judit Balazs. Jean Pierre Kahn. Keith Hawton. Cyril Höschl..Suicide prevention Strategies: systematic review of the evidence 2005-2014 Gil Zalsman. Vladimir Carli. in press 2016 50 The European Unified Suicide Prevention Platform (EUSPP) l Leiden 12-14/2/2015 . Ulrich Hegerl and Joseph Zohar Zalsman G. .

• United Kingdom • Sweden • The Netherlands • Ireland • Italy • Czech Republic • Hungary • France • Spain • Germany • Israel 51 The European Unified Suicide Prevention Platform (EUSPP) l Leiden 12-14/2/2015 .Experts in suicide research from all over Europe.

The European Unified Suicide Prevention .Oxford Criteria for Evidence Strength Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009).

53 The European Unified Suicide Prevention Platform (EUSPP) l Leiden 12-14/2/2015 .

. Lancet Psychiatry. et al.Strong evidence Healthcare approaches Treatment of depression Restriction of (Pharmacotherapy and psychotherapy) Access to lethal means Chain of care School-based universal prevention Gatekeeper training Education of primary More research needed care physicians Media training Screening in primary Internet based interventions care Helplines Public Health approaches Zalsman G. in press 2016 .

.00 5 0 0. 2010. Shelef et al.00 25 20 15. 1992-2012 40 30. 2016 in press .00 15 10. Laor L unpublished data.00 Implementation of program Number of suicides Suicide rate No of suicide 35 25.00 Years Lubin G et al. IDF suicide rate in 20 years – effect of guns restrictions Fig 1 Number of suicides.00 10 5. IDF Mandatory service.00 Three year moving average of suicide rate 30 Suicide rates 20. and three year moving average for rates of suicide.. suicide rates.

San Francisco Suicide “Hot Spot” 100 suicides a year . Golden Gate .

Okland Bridge SF No suicides .

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Ireland .Moher Cliffs.

Moher Cliffs. Ireland .

Moher Cliffs. Ireland .

Shepard Pratt Hospital. Maryland . Baltimore.

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. BMJ. Limiting pack size of analgesics (Paracetamol & Salicilates) 16/9/98 • Deaths lower by 22% • Non fatal OD lowered by 29% • Liver transplant reduced by 30% • Some shift to ibuprofen (not fatal) Hawton et al. 2004 .

TV TVprevention promotion clips addressing gate keepers .

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Neurobiology .

. DA Brent et al.Suicidal Behavior Runs in Families (A Roy et al 1990. 1996) Ernest Hemingway .

with permission .Familial Transmission and Gene-Environment Interaction Caspi and Moffitt. July 2006. Nature Reviews Neuroscience.

Suicidal Behavior Runs in Families Direct main effect approach •TPH1 •TPH2 •SERT •COMT •MAO •5HT’s •DR •NET •BDNF •Wolfram (WFS1) •Etc…… Equivocal results MZ>DZ but far from 100% .

The World Journal of Biological Psychiatry. GWAS A pilot genome-wide association and gene expression array study of suicide with and without major depression Zalsman et al.. 2011 .

GxE D Childhood Adversity .

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differing by 44 bp S<<L Lesch et al. a short (S) and long (L) variants.serotonin transporter linked polymorphism region promoter 5’ 44bp A functional polymorphism consists of two common alleles. 1996 . 1994. Heils et al. 5-HTT-LPR.

5HTTLPR Gene X Environment Interaction Caspi et al. 2003 . 2003 Caspi et al. Science.

Proc Natl Acad Sci USA 2004. . Social supports and serotonin transporter gene moderate depression in maltreated children. Kaufman J et al. were removed from their parents' care) with the s/s genotype and no positive supports had the highest depression ratings. 101:17316-17321 (N=101) Maltreated children (57 age 10-15. Positive supports reduced risk.

.Eley et al. Mol Psychiatry 2004 N=1990. age 10-20 .

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Zalsman et al. Am J Psychiatry 2006. 163:1588-1593 .

R. DNA sample GWAS Inpatient outpatient .Genetic screening in Pediatric ER for suicide prevention? Clinically depressed E.

JAMA.OOPS!!!!  Risch N et al. 2009.05) .302:492 Meta-analysis of 14 studies found no significant association (OR=1.

2011 .Karg et al.

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2010. Eur Psychiatry. 2009 Zalsman. Stockholm.25(5):284-6 .Timing is Critical Monograph given at the Nobel Forum Conference. Sweden June 10.

Suggestion: G x E x Gender x Timing White Matter 450 Volum e in cubic cm 400 350 300 250 4 6 8 10 12 14 16 18 20 22 Age in years .

Are brains of children and adolescents different? **Almost no suicides under 10 .

2015 2. Giedd JN.. Giedd JN. Neuropsychopharmacology. Sci Am. 2015 . Child psychiatry branch of the NIMH longitudinal structural MRI study of human brain development. et al. The amazing teen brain.Normal Brain Development 243 Scans from 145 healthy children 1.

White Matter White Matter White Matter 450 Volum e in cubic cm 400 350 300 Male (152 scans from 90 subjects) 250 Female (91 scans from 55 subjects) 4 6 8 10 12 14 16 18 20 22 95% Confidence Intervals Age in Age in years years From Jay Giedd. NIMH with permission .

NIMH with permission . Are brains of children and adolescents different? Gray Matter Brain Development in Healthy Children & Adolescents Longitudinal and Cross-Sectional Data (243 Scans from 145 Subjects) Frontal Gray Matter 240 Volume in 220 200 4 6 8 10 12 14 16 18 20 22 Age in years From Jay Giedd.

or otherwise unwanted portions from a plant . non- productive. in landscaping this process usually involves removal of diseased.Pruning The process of removing certain above-ground elements from a plant.

Are brains of adolescents and adults are different? **Pick of suicidality during in adolescence .

2000 . Deborah Yurgelon-Todd. while adults (right) rely more on the frontal cortex. teens (left) rely more on the amygdala.Reading Emotions Differently 12y 22y When reading emotion.

Amygdala response to fearful faces as a function of age.. Dev Psychobiol 52: 225–235. 2008. Biological Psychiatry 63:927-934. Casey et al. 2010.. . Hare et al.

later development of prefrontal regions relative to subcortical regions involved in emotional processes. Dev Psychobiol 52: 225–235. . Casey et al.. 2010.

Eur Neoropsychopharmacology 2015 .Zalsman et al..

WKY .

and is considered as a “genetic animal model of depression” with anxiety-like behaviors . WKY The Wistar Kyoto (WKY) rat. is stress-reactive.

(Exposure to stress) at different developmental windows G X E X Gender X T T3 (58) T1 (27) T2 (44) WKY .

Wet cage . Elevated maze 2.Stress manipulations 1. Restrains 3.

Elevated maze .

Wet cage .

Restrains .

Control 2: Enrichment
(psychotherapy?)

Behavioral tests for “depression”

1. Forced Swim Test X2
2. Saccharine test
3. Open field with novel
object

Saccharin test for anhedonia

Open field .

Rats MRI and brain perfusion Tel Aviv University MRI .

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good genes bad genes bad genes good genes good life good life bad life bad life early timing late timing good genes bad life bad genes late timing bad life early timing best OUTCOME worse GxExT interaction in depression .

Lithium.My Message  Suicidal behavior is not rare after puberty  Complete suicide is rare and hard to predict  Risk assessment and recording is essential  Pharmacotherapy include SSRIs. Clozapine. ECT and maybe Ketamine  SSRIs do not cause more completed suicides  Animal model prove GxExT interaction  Prevention in the national level is effective  Connection and Compassion are critical .

tau.ac.org .zalsman@post.zalsman.il www.