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. Zalsmans 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
 ECNPneuroscience applied

Develop young researchers

Four Schools
Week-long programme of intensive
training for 50 young psychiatrists
General (Oxford); Child and Adolescent; Old Age
(Venice), research methods (Madrid)

One Workshop
Annual three-day interactive workshop
for 100 young scientists

All participants supported by ECNP for travel,

registration and accommodation
www.ecnp.eu 4
 ECNPneuroscience applied

Seminars 4 per year

Two days of interactive training for 50 participants
3 ECNP Seminar Awards ( 1,000 each)

New: ECNP Internships

lab experience or clinical
observership
ECNP Certificate- Unique, European-
wide qualification for young researchers
in the science and treatment of
disorders of the brain

www.ecnp.eu 5
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
Child and Adolescent Division
Geha Mental Health Center, Tel Aviv University, Israel
 Safe environment: Anti-suicide shower head

Engel & Zalsman IJAMH, 2005

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, Lithium,
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
The
phenomena
SUICIDE
1,000,000 people a year worldwide
Over 150,000 in Europe

About 65,000 in the EU countries

Males 5 times more

Attempts are common (x10) -

mostly females
 Suicide in the World 2013

Chang et al., BMJ. 2013; 347: f5239.

Suicide in children & adolescents

First / Second leading

cause of death until age
24y
Suicide before puberty is
rare (Pfeffer 1996)
If you dont ask you dont 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, 2005

Asking is not dangerous

Gould et al., JAMA 2006
Definitions
An act of self harm with at
least partial intent to die
(Posner et al., 2010)
CSSRS
Spectrum Theory: ideation- attempt
(aborted/disrupted)-completed
 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. with permission C.E3
 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 19841986 90%

Finland 53 19871988 94%

*Pittsburgh 140 19841994 82%

Apter 1993, Shaffer 1996, Marttunen 1991, Brent 1999; *case-control studies D14
QUALITATIVE AND QUANTITATIVE
PSYCHOLOGICAL AUTOPSY OF 70
HIGH-SCHOOL STUDENTS
TRAGIC VS. REGRESSIVE NARRATIVES

Prof. Gil Zalsman MD, MHA*

Mrs. Yochi Siman-Tov MEd**
Prof. David Tzuriel PhD**
*Child Psychiatry Department, Tel Aviv University, Israel
& Molecular Imaging, Columbia University, US
**Bar Ilan University & Ministry of Education, Israel
IASP conference OSLO 2013 (Wed 17:00-17:30, Olympia
 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 2.5)
Low self disclosure (Horesh Zalsman and Apter 2004)
Length of crisis 0.8 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%)
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
Tragic Narrative Vs. other narratives
Shorter crisis (Humiliation) p=0.006
Less negative life events p= 0.03
Less psychiatric diagnoses p=0.03
More functional gap p=0.039
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
Treatment of the suicidal adolescent
1. Close observation
2. Safe environment
3. Aggressive treatment of depression
4. Lithium, Clozapine, ECT, Ketamine
5. CBT-A
6. IPT-A
7. DBT-A
8. Family TX
 Antidepressant and Suicide
Large-scale ecological studies of antidepressants indicate that initiation
of pharmacotherapy is not associated with an increased risk of suicide,
while continuation of pharmacotherapy for depression is associated with
a reduced risk of suicide. (Sondergard L et al., Acta psychiatrica Scandinavica 2006 ;
Sondergard L et al., International clinical psychopharmacology 2006; Sondergard L et al.,
Archives of suicide research 2007).
There is evidence that SSRIs might increase suicidal thoughts, but not
actual suicidal behaviour, in early-phase pharmacotherapy of depression
in adults. (Cipriani A, Canadian journal of psychiatry 2007)
However, the rate of emergent suicidal ideation is low and the risk-benefit ratio
for pharmacotherapy for depression appears to favor its use. (Mulder RT, Acta
psychiatrica Scandinavica 2008 ; Zisook S et al., The Journal of clinical psychiatry 2010)

In depression, the administration of sertraline is associated with lower suicidal

ideation and behaviour but not with emergent suicidal thinking or behavior.
(Nelson JC et al., , The American Journal of Geriatric 2007)
 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., The Journal of clinical psychiatry 2013)

Ecological studies do not show increased sales of antidepressants to be

associated with an increase in suicide rates. (Grunebaum Curr Psychiatr 2007
; Castelpietra G, Acta psychiatrica Scandinavica 2008; Isacsson G, Acta psychiatrica
Scandinavica 2009; Kapusta Acta psychiatrica Scandinavica 2009)

It remains unclear whether drugs for depression decrease or increase

suicidal risk in bipolar patients. Pacchiarotti I etal., AJP 2013

However, 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. (Gusmao R et al. PLoS One 2013)
 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, although there is evidence to suggest
an increased risk of suicidal ideation in this population.
Adding cognitive behavioral therapy (CBT) to fluoxetine
may lead to less suicidal ideation and behaviour than
treatment with fluoxetine alone.

March JS et al., The Treatment for Adolescents With

Depression Study (TADS): long-term effectiveness and safety
outcomes. Archives of General Psychiatry 2007; 64(10): 1132-
43.
 Lithium and Suicide Tx
As psychiatric disorders are a major risk factor for suicidal
behaviour, their pharmacological treatment contributes
substantially to the prevention of suicide.(Wasserman et al, 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., BMJ 2013; Baldessarini et al., AGP
2006; Kessing et al., AGP 2005)

which was supported by the findings of a large-scale

naturalistic cohort study comparing lithium with valproate.
(Goodwin FK, JAMA 2003)
 Lithium vs Valproate
A specific anti-suicidal effect of lithium was suggested in a population of
suicide attempters treated with lithium (Lauterbach et al., Acta Psychiatrica
Scandinavica 2008 ) although the number of deaths was very small (3 deaths
vs. no deaths on lithium).
A large-scale naturalistic study suggested that anticonvulsant mood
stabilizers might also have protective effects against suicide attempts.
Unadjusted rates of suicide were greater during treatment with divalproex than
during treatment with lithium for emergency department suicide attempt (313
vs 108 per 1000 person-years; P<0001), suicide attempt resulting in
hospitalization (105 vs 42 per 1000 person-years; P<0001), and suicide death
(17 vs 07 per 1000 person-years; P = 004). Gibbons RD, AGP 2009
But After adjustment for age, sex, health plan, year of diagnosis, comorbid
medical and psychiatric conditions, and concomitant use of other psychotropic
drugs, risk of suicide death was 27 times higher (95% confidence interval [CI],
11-63; P = 003) during treatment with divalproex than during treatment with
lithium. Corresponding hazard ratios for nonfatal attempts were 17 (95% CI, 12-
23; P = 0002) for attempts resulting in hospitalization Oquendo et al., AJP 2011
 Antipsychotics and Suicide Tx
Clozapine is the only drug with an official indication in
the US of reducing suicide risk in psychosis. A meta-
analysis of the effects of clozapine in comparison with
other dopamine and serotonin-receptor antagonists
(e.g., olanzapine and risperidone) demonstrated anti-
suicidal effect in schizophrenia. (Asenjo Lobos et al.,
Cochrane Database Syst Rev 2010)
However, in another meta-analysis, quetiapine
showed no specific effect compared with other
dopamine antagonists on the occurrence of suicide
and attempted suicide. (Suttajit et al., Cochrane
Database Syst Rev 2013)
 Ketamine and Suicide Tx
Ketamine shows promising results in systematic
review as a potentially effective and rapid
treatment of suicidal thoughts, independent of
improvement in depression, and with minimal
side effects (Reinstatler et al., 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.
 ECT and Suicide Tx
ECT was shown to rapidly reduce suicide risk
in case series but no controlled trials have
been conducted. (Kellner et al., AJP 2005;
Patel M et al., The journal of ECT 2006)
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
Suicide prevention Strategies:
systematic review
of the evidence 2005-2014
Gil Zalsman, Keith Hawton, Danuta Wasserman, Kees van Heeringen, Ella Arensman, Marco
Sarchiapone, Vladimir Carli, Cyril Hschl, Ran Barzilay, Judit Balazs, Gyrgy Purebl, Jean Pierre
Kahn, , Pilar Alejandra Siz, Cendrine Bursztein, Ulrich Hegerl and Joseph Zohar

Zalsman G. et al., Lancet Psychiatry, in press 2016

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

Experts in suicide research from all
over Europe.
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

Oxford Criteria for Evidence Strength

Oxford Centre for Evidence-based

Medicine Levels of Evidence
(March 2009).
The European Unified Suicide Prevention
53 The European Unified Suicide Prevention Platform (EUSPP) l Leiden 12-14/2/2015
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. et al., Lancet Psychiatry, in press 2016
 IDF suicide rate in 20 years effect of guns restrictions
Fig 1 Number of suicides, suicide rates, and three year moving
average for rates of suicide, IDF Mandatory service, 1992-2012
40 30.00
Implementation of program
Number of suicides

Suicide rate
No of suicide

35
25.00
Three year moving
average of suicide rate
30
Suicide rates
20.00
25

20 15.00

15
10.00

10

5.00
5

0 0.00

Years

Lubin G et al., 2010; Laor L unpublished data; Shelef et al., 2016 in press
 Golden Gate - San Francisco
Suicide Hot Spot

100 suicides a year

 Okland Bridge SF

No suicides
Moher Cliffs, Ireland
Moher Cliffs, Ireland
Moher Cliffs, Ireland
Shepard Pratt Hospital, Baltimore, Maryland
 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., BMJ, 2004

 TV

TVprevention promotion clips

addressing gate keepers
Neurobiology
Suicidal Behavior Runs in Families
(A Roy et al 1990, DA Brent et al., 1996)

Ernest Hemingway
Familial Transmission and Gene-Environment Interaction

Caspi and Moffitt, Nature Reviews Neuroscience, July 2006, with permission
Suicidal Behavior Runs in Families
Direct main effect approach
TPH1
TPH2
SERT
COMT
MAO
5HTs
DR
NET
BDNF
Wolfram (WFS1)
Etc
Equivocal results
MZ>DZ but far from 100%
 GWAS

A pilot genome-wide association

and gene expression array study of
suicide with and without major
depression

Zalsman et al., The World Journal of Biological Psychiatry, 2011

GxE D
Childhood Adversity
 5-HTT-LPR- serotonin transporter linked polymorphism region

promoter

5 44bp

A functional polymorphism consists of two common alleles, a

short (S) and long (L) variants, differing by 44 bp
S<<L

Lesch et al. 1994, Heils et al. 1996

 5HTTLPR
Gene X Environment Interaction
Caspi et al. 2003

Caspi et al. Science, 2003

 Social supports and serotonin transporter gene
moderate depression in maltreated children.
Kaufman J et al. Proc Natl Acad Sci USA
2004; 101:17316-17321

(N=101)

Maltreated children (57 age 10-15; were removed from their parents' care)
with the s/s genotype and no positive supports had the highest depression ratings.

Positive supports reduced risk.

Eley et al., Mol Psychiatry 2004 N=1990, age 10-20
Zalsman et al. Am J Psychiatry 2006, 163:1588-1593
Genetic screening in Pediatric ER for suicide prevention?

Clinically depressed

E.R. DNA sample

GWAS
Inpatient
outpatient
OOPS!!!!
Risch N et al. JAMA, 2009;302:492

Meta-analysis of 14 studies found no

significant association (OR=1.05)
Karg et al. 2011
Timing is Critical
Monograph given at the Nobel Forum Conference,
Stockholm, Sweden June 10, 2009

Zalsman, Eur Psychiatry. 2010;25(5):284-6

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
Normal Brain Development

243 Scans from 145 healthy children

1. Giedd JN, et al., Child psychiatry branch of

the NIMH longitudinal structural MRI study
of human brain development.
Neuropsychopharmacology. 2015

2. Giedd JN. The amazing teen brain. Sci Am.

2015
 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

 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, NIMH with permission

Pruning
The process of removing certain above-ground
elements from a plant; in landscaping this process
usually involves removal of diseased, non-
productive, or otherwise unwanted portions from
a plant
Are brains of adolescents
and adults are different?
**Pick of suicidality during in adolescence
Reading Emotions Differently
12y 22y

When reading emotion, teens (left) rely more on the

amygdala, while adults (right) rely more on the frontal
cortex.
Deborah Yurgelon-Todd, 2000
 Amygdala response to fearful faces as a function
of age.

Casey et al., Dev Psychobiol 52: 225235, 2010.

Hare et al., Biological Psychiatry 63:927-934, 2008.
 later development
of prefrontal regions relative to subcortical
regions involved in emotional processes.

Casey et al., Dev Psychobiol 52: 225235, 2010.

Zalsman et al., Eur Neoropsychopharmacology 2015
WKY
 WKY

The Wistar Kyoto (WKY) rat, is

stress-reactive, and is considered as
a genetic animal model of
depression with anxiety-like
behaviors
(Exposure to stress) at different developmental windows

G X E X Gender X T

T3 (58)
T1 (27) T2 (44)

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

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