Prof p hazell side effects and safety issues hanoi

Antidepressants and suicide• 3 suicide deaths in first year after treatment initiation out of 20,906 initiations British Columbia prescribing database • Individual case reports however

Child and adolescent psychopharmacology: Side effects and safety issues

Prof Philip Hazell Rivendell Child Adolescent and Family Mental Health

Service

Disclosure Statement: Philip Hazell

Prevalence of psychotropic drug use among children 0-17 yrs in Iceland

Zoega et al J Child Adolesc Psychopharm 2009 19:757-64

Adverse drug reactions in hospitalized

children (n = 173) by drug class

Speranza et al Drug Safety 2008;

31:885-960

%

Sources of data

• Systematic reporting from acute clinical trials and subsequent safety monitoring

• Surveillance systems

• Reports within data sets such as GP

databases, managed care

• Selective reporting

• 5% threshold for reporting in clinical trials

• Contagion

Half full

Clinician

Half empty Toxicologist

Antidepressant prescribing in Australian general

Antidepressants and suicide

• 3 suicide deaths in first year after treatment

initiation out of 20,906 initiations (British

Columbia prescribing database)

• Individual case reports however appear in media drawing association between SSRI prescribing and death

• Few adolescent suicide deaths have detectable SSRI post mortem (Dudley et al review), even amongst those prescribed SSRI (Utah youth

suicide study) This does not preclude

discontinuation syndrome as a causal factor

AD prescribing and suicide

12-19 yrs in UK

Wheeler et al BMJ 2008; 336: 542

Antidepressants and suicide related

events

• Of 20,906 children who initiated antidepressant therapy, there were 266 attempted and 3 completed suicides,

which yielded an event rate of 27.04 suicidal acts per

1000 person-years (95% confidence interval [CI]:

23.9-30.5 suicidal acts per 1000 person-years) There were

no meaningful differences in the rate ratios comparing

fluoxetine with citalopram, fluvoxamine paroxetine and

sertraline Tricyclic agents showed risks similar to those

of selective serotonin reuptake inhibitors (RR: 0.92 [95% CI: 0.43-2.00]) (British Columbia prescribing database)

Antidepressants- other adverse

effects

• Decrease in growth velocity

• Activation, especially in younger patients

• Precipitate hypomania in vulnerable

patients

• Sedation

• Sexual dysfunction

Psychostimulants and sudden

• 2/25 deaths occurred soon after treatment

initiation Pre-existing cardiac anomalies

implicated (Eunethydis review)

Psychostimulants and suicide

Psychostimulants and cardiovascular risk

Psychostimulants and sleep

• Parental reports of sleep problems are

high but not supported by objective data

Sleep hygiene, melatonin, clonidine,

medication switch are other options

Atomoxetine and death

• Death rate on treatment estimated to be 0.6/100,000 patient years (BMJ Best

Practice review)

Atomoxetine and suicide related

events

• Suicide related events reported in 0.4%

trial participants receiving active treatment versus none receiving placebo

Atomoxetine and liver failure

• Three reported cases

• Rare but serious idiosyncratic event

Antispychotics and death

• GP data base study identified 30 deaths in patients < 18 prescribed antispychotics 24 had prexisting serious physical illnesses

Of remaining 6 only 1 thought attributable

to treatment, yielding estimated rate of

50/100,000 patient years

• Influence of chronic treatment on mortality

is unknown

Antispychotics- other adverse

Relative weight gain in acute trials

for paediatric mania

Singh et al Drugs 2010;70:433-442

Relative weight change in short term trials for paediatric mania

MS = mood stabilizer TOP = topiramate AA = atypical antipsychotic

Correll C J Am Acad Child Adolesc Psychiatry 2007;46(6):687-700

Countering metabolic effects

• Lowest dose that is helpful

• Exercise and dietary counselling

• Concurrent metformin (one positive and

one equivocal trial in youth)

• Use of aripiprazole or ziprasidone

• Augmentation with aripiprazole

• In bipolar, monotherapy if feasible and use

of topiramate in combined therapy

Guiding principles for effective prescribing of psychotropic medication to children and

adolescents

1 Development

• Children are not just undersized adults

• Metabolize and eliminate drugs more quickly

than adults leading to shorter drug half-lives

Require higher weight-adjusted doses and more frequent dosing

• More vulnerable to certain AEs such as growth effects, activation with antidepressants, weight gain with antipsychotics, polycystic ovarian

disease with valproate, rash with lamotrigine

2 Limits of diagnostic classification

• Comorbidity is (even more so than in

adults) the norm

• Drugs target symptoms rather than

disorders

• Apparently different disorders may

represent developmentally specific

manifestations of the same underlying

vulnerability

3 Integration of data from multiple

sources

• Not only should assessment information come from multiple sources, but so should information to help evaluate treatment

effectiveness and tolerability

• Symptom or behaviour checklists can be

of help in this regard

4 Active gathering of adverse

event data

• Growth parameters, pulse rate and BP

should be measured regularly in all

children receiving psychotropic drugs

• A screen for common side effects should

be undertaken at each review

• Clinician must be available to accept calls about possible adverse effects between clinic visits

5 More is not always better

• While polypharmacy is not inherently evil, with

monotherapy it is easier to control treatment variables

• Beware the ‘slippery slope’ ‘Parents who pressure you

to prescribe may also be the parents who will take you to court if things go wrong’ (Nunn, Dossetor and Dey)

• Efficacy often related more to time on treatment than to dose

• Predetermined treatment algorithms can help avoid

chaotic prescribing