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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 Drug class 2003* 2007* Any 46 48.7 Antidepressant 28.3 23.4 Stimulant or atomoxetine 21.7 28.4 Antipsychotic 8.7 10.6 Anxiolytic 1.7 1.8 Hypnotic/sedative 0.8 2.6 Total pop 78157 79469 *rates per 1000 children Adverse drug reactions in hospitalized children (n = 173) by drug class % Speranza et al Drug Safety 2008; 31:885960 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 Biases • Selective reporting • 5% threshold for reporting in clinical trials • Contagion Perspectives Half empty Toxicologist Half full Clinician Antidepressant prescribing in Australian general practice 2001-2004: Rate per 100 encounters variable < 12 12-17 20+ Any AD 0.11 1.48 4.18 SSRI 0.03 1.08 2.38 fluoxetine 0.003 0.08 0.28 paroxetine 0.003 0.13 0.48 other SSRI 0.02 0.87 1.62 tricyclic 0.14 0.92 0.17 0.47 0.07 venlafaxine Harrison CM, Britt HC MJA 2005;182:92 Antidepressants and suicide • 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 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 only thought attributable to treatment, yielding estimated rate of 50/100,000 patient years • Influence of chronic treatment on mortality is unknown Antispychotics- other adverse effects • Weight gain, dental caries, somnolence, dystonia all > 1% • Diabetes, estimated 400/100,000 patient years • Depression, estimated 800/100,000 patient years (NZ prospective surveillance study of treatment for patients < 15 years) 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 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 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 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 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 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 ... • Small population shifts nevertheless push more people into an at risk category (Eunethydis review) Psychostimulants and sleep • Parental reports of sleep problems are high but not supported... bipolar, monotherapy if feasible and use of topiramate in combined therapy Guiding principles for effective prescribing of psychotropic medication to children and adolescents Development • Children... 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,
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