Are Antidepressants and Antipsychotics Safe in Children and Adolescents? William A. Kehoe, Pharm.D., MA, FCCP, BCPS Professor of Clinical Pharmacy and Psychology Chairman, Department of Pharmacy Practice TJ Long School of Pharmacy and Health Sciences University of the Pacific Stockton, CA 95209 Learning objectives After attending this session, participants will be able to: 1. describe the clinical uses and efficacy of antidepressants in children and adolescents; 2. describe the clinical uses and efficacy of antipsychotics in children and adolescents; 3. discuss what is known about the safety of antidepressants and antipsychotics in children and adolescents; and 4. outline an appropriate plan for monitoring antidepressant or antipsychotic therapy for efficacy and safety in children and adolescents. I. Introductory Comments A. How common is depression in kids 1. Surgeon General’s Report a. 10%-15% of children/adolescents have symptoms of depression b. 5% of children/adolescents 9-17 y.o. have MDD c. 500,000 youngsters attempt suicide each year and 2,000 are successful 2. Age is a factor in prevalence a. 1% of preschoolers b. 2% of school-aged children c. 5%-8% of adolescents B. What types of diagnoses do we see in children (Lekhwani et. al., J Child Adolesc Psychopharmacol 2004;14:95-103)? Here are some numbers at discharge. 1. Behavior disorders 84.7% 2. Mood disorders 11.3% 3. Anxiety disorders 8.3% 4. Psychotic disorders 1.3% 5. “Other” 11.6% C. What types of medications are used in children? (Lekhwani et. al., J Child Adolesc Psychopharmacol 2004;14:95-103). Here are some numbers at discharge. 1. Stimulants 60.5% 2. Antidepressants 12% 3. Atypical antipsychotics 12% 4. Alpha-2 agonists (clonidine, guanfacine) 9% 5. Mood stabilizers 2.3% 6. Typical antipsychotics 3% D. Antidepressant use has been increasing 1. AD use increased by 1.7 fold 2. TCA use decreased by 30% 3. SSRI use increased by 10 times (0.5 to 4.6/1,000 patients receiving ADs) 4. TCAs more likely to be discontinued E. Do antidepressants work in children and adolescents? 1. Problems with trying to determine if antidepressants work in kids a. Few well-designed studies b. Most were of short duration c. Many unpublished studies had negative results d. SSRIs associated with positive benefits in published trials, but these were reduced when unpublished data included e. Clearly, larger, well-designed studies are needed f. Many clinicians feel that these medications are effective F. What are antidepressants used for in children and adolescents? 1. Major depressive disorder (MDD): only fluoxetine is FDA approved for this indication. Other antidepressants have been used including TCAs, all other SSRIs, bupropion, venlafaxine, and mirtazapine. 2. Obsessive-compulsive disorder: fluvoxamine, sertraline, fluoxetine, and clomipramine are FDA approved. Other SSRIs also used. 3. Other anxiety disorders: While not FDA approved, SSRIs are commonly used for generalized anxiety, social anxiety disorder, and separation anxiety disorder based on efficacy in adults. 4. Attention deficit disorder: TCAs have shown efficacy as has bupropion. SSRIs have had minimal efficacy. Venlafaxine has shown some efficacy for adults, fewer data for kids. None are FDA-approved for this. Atomoxetine (Strattera) is not an antidepressant, but is a norepinephrine reuptake blocker like other antidepressants. It is effective. G. Are antidepressants effective in children and adolescents? 1. Summary of clinical trial information: Report 10 of the AMA Council on Scientific Affairs (A-05) (available at the website for the American Academy of Child and Adolescent Psychiatry www.aacap.org) Drug No. of Trials Duration Drug vs. Placebo Paroxetine 3 8-12 weeks All 3 negative Fluoxetine 2 8-9 weeks Both positive Sertraline 2 10 weeks One trend and one negative. Combined data positive for some outcomes Venlafaxine 2 8 weeks Both negative Citalopram 2 8-12 weeks One positive and one negative Nefazodone 2 8 weeks One trend and one negative Mirtazapine 2 8 weeks Both negative Escitalopram (Am 1 8 weeks Negative. Post- hoc Acad Child Adolesc showed some Psychiatry efficacy in 2006;45:280-88) adolescents H. Treatment for Adolescents with depression study (TADS) 1. 12-week, multicenter, randomized, controlled trial with four treatment groups a. fluoxetine alone b. cognitive-behavioral therapy (CBT) c. fluoxetine with CBT d. placebo 2. Primary outcome variable = Children’s Depression Rating Scale- Revised 3. 439 patients aged 12-17 years enrolled 4. Results of TADS: Efficacy a. fluoxetine + CBT > placebo (p=0.001) b. fluoxetine + CBT > fluoxetine alone (p=0.02) or CBT alone (p=0.01) c. fluoxetine alone > CBT alone (p=0.01) d. Response rates i. fluoxetine + CBT = 71% ii. fluoxetine alone = 60.6% iii. CBT alone = 43.2% iv. placebo = 34.8% 5. Results of TADS: Suicidal outcomes a. 29% of enrollees with significant suicidal ideation requiring intervention b. All treatments reduced suicidality c. Fluoxetine + CBT reduced suicidality significantly more than other treatments d. 7/439 patients attempted suicide – none successful I. Suicidality and antidepressants 1. Chronology of events leading to latest episode a. 1990: Series of 6 cases published for fluoxetine b. 1991: Series of pediatric cases published c. 1991: Re-examination (meta-analysis) of data seemed to support safety d. 2003: MHRA in UK suggested that all SSRIs except fluoxetine be avoided in children e. 2003: Later that year FDA discouraged use of paroxetine in children f. 2004 (Feb): FDA holds first hearing i. Recommended further study of data g. 2004 (Mar): FDA surprises many by asking mfgrs for 10 ADs to include warning in PI h. 2004 (summer): analysis of data by FDA using Columbia University’s classification system confirms risk i. 2004 (Oct): FDA recommends black box warning on all ADs for use in pts < 18 y.o. and creates Medication Guide 2. What do we know about the risk?6,7,8 a. FDA analyzed data for fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, and mirtazapine b. Used suicidal outcomes based on scheme from Columbia University c. “Outcome 3” = definitive suicidal behavior or ideation used as primary outcome d. 25 studies identified, 23 evaluable e. included over 4,000 patients Condition RR(95%CI) Condition RR(95%CI) Fluoxetine 0.92(0.39,2.19) All Ads in 1.71(1.05,2.77) All trials MDD trials Paroxetine 2.65(1.00,7.02) SSRIs in 1.41(0.84,2.37) All trials MDD trials Sertraline 1.48(0.42,5.24) Non-MDD 2.17(0.72,6.48) All trials trials Citalopram 1.37(0.53,3.50) All trials 1.78(1.14,2.77) All trials All drugs Venlafaxine 4.97(1.09,22.72) All trials Mirtazapine 1.58(0.06,38.37) All trials Summary of data after using Columbia criteria and including TADS data: Report 10 of the AMA Council on Scientific Affairs (A-05) (available at the website for the American Academy of Child and Adolescent Psychiatry www.aacap.org) Analysis Relative Risk for suicidal behavior or ideation All trials of antidepressants for any 1.95 (1.28-2.98) indication SSRIs for clinical trials for major 1.66 (1.02-2.68) depressive disorder 3. Suicidality in children and adolescents a. Community samples – past 6 months i. 7.5% with suicidal ideation ii. 1.6% with suicidal attempts iii. Those with MDD iv. 23% with suicidal ideation in past 6 months v. 37.5% had ‘done something about’ suicide in their lifetimes 4. Caveats to interpreting data on suicidality a. Most studies were small and short duration b. Unclear when event occurred (during withdrawal?) c. Studies were not powered to look at this outcome variable statistically d. Definition of suicidal behavior or ideation not clear e. Outcome often based on answer to one question on rating scale f. High risk patients often excluded from trials g. Don’t know what impact dose of AD may have h. No comp leted suicides attributed to drugs i. Risk is higher for untreated depression j. Epidemiological studies show that increased prescribing of antidepressants associated with lower suicide rates 5. Risk factors for suicidal behavior or ideation to consider a. Prior history of suicidality b. Use of multiple ADs c. Chronic depression d. Comorbid substance abuse e. History of physical abuse f. Access to means of suicide 6. What should we do with antidepressants right now? a. Close observation for all new antidepressants b. Look for lack of improve ment or worsening, or development of suicidal thoughts or self- injurious behaviors c. Look for anxiety, panic, agitation, irritability, insomnia, hostility, impulsivity, mania or hypomania, and akathisia d. This is especially true when starting medication or whe n increasing the dose 7. Other issues to consider when using antidepressants in kids a. Gastrointestinal complaints common b. Central nervous systems side effects include insomnia (sedation possible), agitation, jitteriness, tremor, EPS, disinhibition c. Activating effects i. Prepubertal children may be more prone to activation effects early in therapy. ii. Agitation, increased motor activity, disinhibition iii. Induction of mania (switching) 8. One final thought...has the recent attention and controversy over antidepressants in kids affected treatment of depression? Psychiatric News September 2, 2005. a. Significant drop in antidepressant prescribing temporally related to initiation of Black Box Warning in PI. b. Nearly 20% reduction in antidepressant prescriptions in kids i. More rational use? ii. Fear of liability leading to fewer kids being treated for depression? II. Antipsychotics in children and adolescents A. Nomenclature 1. First generation antipsychotics (FGA) = “typical” or “conventional” agents 2. Second generation antipsychotics (SGA) = “atypical” or “new” agents B. Pharmacological comparisons Comparison FGA SGA Primary mechanism of Blocks dopamine-2 Blocks dopamine-2 action receptors receptors to lesser degree plus serotonin-2A receptors Ancillary Properties Acetylcholine antagonist Acetylcholine antagonist Histamine antagonist Histamine antagonist Alpha-adrenergic antagonist Alpha-adrenergic antagonist Related to potency at D-2 Variable degrees among blockade agents Extrapyramidal side effects Yes – higher with higher Yes – variable with D2 antagonism risperidone most likely Tardive dyskinesia Yes – about 5% per year Possibly – but risk much lower than with FGA Metabolic side effects Yes – but less common than Yes – most likely with with SGA clozapine and olanzapine - Metabolic syndrome - Weight gain - Hyperglycemia/new onset Diabetes - Lipid abnormalities Cardiac conduction Yes – most likely with low Yes – most likely with abnormalities potency agents, e.g., ziprasidone thioridazine C. How are atypical antipsychotics used in children (J Clin Psychiatry 2005;66(Suppl7):29-40 + Medline search) Condition Evidence for Efficacy Aggression/Conduct Disorder 6 controlled trials, several open trials Bipolar disorder 1 controlled trial, several open label trails, case reports, chart reviews Schizophrenia 1 controlled trial + several open trials Autism/PDD 2 controlled trials, several open trials Tourette’s disorder Several controlled and open trials Other uses AHDH, augmentation of antidepressants, anxiety disorders, eating disorders. Open trials, case reports, anecdotal evidence D. Thoughts about using SGAs in children 1. Children are developing and are different in many ways a. Neurodevelopment and plasticity b. Reproductive development c. Pharmacokinetic differences with adults i. Hepatic function ii. Renal function and GFR iii. Fat tissue mass iv. Protein binding 2. Use is well established, but based on limited evidence a. Most often used off- label 3. Use is increasing (Patel et al. J Am Acad Child Adolesc Psychiatry 2005;44(6):548-56) E. Specific issues related to the use of SGAs 1. Sedation a. Most common side effect b. Can occur with all agents and is dose-related c. Children and adolescents appear at higher risk d. Tolerance can develop e. Aripiprazole may be different in that it is frequently “activating” at first. This is more likely with high starting doses, rapid escalation of the dose, and withdrawal of concurrent sedating drugs. 2. Weight gain a. Possibly related to histamine antagonism, serotoninergic mechanisms possibly involved b. Clozapine ~ olanzapine > risperidone ~ quetiapine > ziprasidone ~ aripiprazole i. Interindividual variability so watch patients closely ii. Not really prevented by cotreatment with stimulants c. Children and adolescents seem more prone tha n adults d. BMI = (wt lbs x 703)/height2 inches e. When to become concerned i. Impact on health (A) Increase in BMI >5% of baseline within 3 months of initiation (B) Increase in BMI z-score > 0.5 standard deviation for age/gender (C) Entry into at-risk = BMI > 85th-95th percentile plus obesity-related condition or risk ii. Impact on psychosocial condition f. Encourage diet and exercise and monitor weight 3. Hyperglycemia, new onset diabetes and metabolic syndrome a. May be related to weight gain and other mechanisms i. Risk may be increased with cotreatment with divalproex b. Can be seen within the first few months of treatment c. Clozapine ~ olanzapine > quetiapine > risperidone > aripiprazole ~ ziprasidone (both low risk) d. For discussion see results of Consensus Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care 2004;27(2):596-601. e. Metabolic syndrome in children and adolescents i. Waist > 95th percentile or BMI > 95th percentile ii. Fasting triglycerides > 110 mg/dL iii. Fasting HDL < 40 mg/dL iv. BP > 90th percentile for age/gender v. Fasting BG > 110 mg/dL f. Monitoring parameters i. Fasting blood glucose and lipids at 3 months then q 6 months ii. Height/weight/BMI monthly x 3 then q 3 months 4. Lipid abnormalities a. Seen in total, LDL, HDL cholesterol, and triglycerides i. TG correlated with weight changes b. Clozapine ~ olanzapine > risperidone ~ quetiapine > aripiprazole ~ ziprasidone (both low risk) c. Monitor as above d. Diet and exercise 5. Extrapyramidal side effects a. Related to potency as D-2 antagonist i. Risperidone > aripiprazole ~ ziprasidone ~ olanzapine > quetiapine (low risk) b. More likely in children and adolescents than adults for FGAs possibly also for SGAs c. Akathisia occurs, may be concern for aripiprazole d. Management strategies i. Use low initial doses ii. Select drug based on risk iii. Consider anticholinergic drug 6. Hyperprolactinemia a. Related to potency of D-2 antagonism b. Risperidone > olanzapine ~ ziprasidone > aripiprazole ~ quetiapine (very low risk) i. dose-related ii. increased risk with cotreatment with OCs iii. may normalize with time and resolves on DC iv. more likely in children and adolescents c. Results i. sexual dysfunction ii. anemorrhea/oligome norrhea iii. hirsutism iv. breast symptoms d. Monitoring i. morning prolactin annually 7. Tardive dyskinesia a. Children at higher risk with FGAs b. Fewer data for SGAs, but there appears to be risk c. Generally reversible upon discontinuation of the drug 8. QTc Prolongation a. Seen with both FGAs and SGAs b. Predisposes to torsades de pointes c. Ziprasidone is the only SGA for which monitoring QTc is indicated. Avoid if > 450 msec F. Baseline assessments and follow- up (See Correll et al. Child Adolesc Psychiatric Clin NA 2006;15:177-206) 1. Things to consider when choosing an agent a. Patient’s and family medical histories b. Dietary and exercise habits c. Baseline symptoms that may mimic side effects d. Pubertal stage and maturity e. EKG if indicated (ziprasidone) f. Others: good medical exam with appropriate labs 2. Baseline and follow-up assessments a. Height, weight, BMI b. Vital signs c. Neuromotor signs d. Diet and exercise habits e. Sedation and appetite f. Blood tests: CBC with differential, electrolytes, LFTs, TFTs, kidney function, glucose and lipids at baseline, then at 3 and 6 months then q 6 months. Only need to repeat TFTs annually unless taking lithium or presents symptoms. Any of these tests should be repeated earlier if signs and symptoms suggest. g. Prolactin: baseline only if symptoms suggest a problem, only repeat if abnormal at baseline References 1. Sung S, Kirchner J. Depression in children and adolescents. Am Fam Physician 2000;62:2297-08, 2311-12. 2. Gould M, King R, Greenwald S, et al. Psychopathology associated with suicidal ideation and attempts among children and adolescents. J Am Acad Child Adolesc Psychiatry 1998;37:915-23. 3. American Academy of Child and Adolescent Psychiatry and the American Psychiatric Association. Joint Statement for the Record, Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, U.S. House of Representatives, September 9, 2004. 4. Murray M, de Vries C, Wong I. A drug utilization study of antidepressants in children and adolescents using the General Practice Research Database. Arch Dis Child 2004;89:1098-102. 5. Treatment for Adolescents with Depression Study Team. Fluoxetine, cognitive- behavioral therapy, and their combination for adolescents with depression. Treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA 2004;292:807-20. 6. FDA Center for Drug Evaluation and Research. Background on suicidality caused by antidepressant drug treatment. Memorandum by Dr. Gregory Dubitsky. www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-08-TAB06- Dubitsky-Review.pdf. 7. FDA Center for Drug Evaluation and Research. Background on suicidality caused by antidepressant drug treatment. Review and evaluation of clinical data by Dr. Tarek Hammad. www.fda.gov/ohrms/dockets/ac/04/briefing/2004- 4065b1-10-TAB08-Hammads-Review.pdf. 8. FDA Center for Drug Evaluation and Research. Background on suicidality caused by antidepressant drug treatment. Review and evaluation of clinical data by Dr. Andrew Mosholder. www.fda.gov/ohrms/dockets/ac/04/briefing/2004- 4065b1-11-TAB09a-Mosholder-review.pdf . 9. Gibbons R, Hur K, Bhaumik D, Mann J. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005;62:165-72. Other useful references l Jureidini J, et al. Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328:879-83. l Finley P. Antidepressants, suicide, and the FDA: a loose association. Ann Pharmacother 2004;38:1739-42. l Cohen J. Antidepressants: an avoidable and solvable controversy. Ann Pharmacother 2004;38:1743-46. l Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338-43. l Whittington C, et al. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-45. l Correll C, Penzner J, Parikh U, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatric Clin NA 2006;15:177-206. l Patel N, Crismon M, Hoagwood K, et al. Trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry 2005;44(6):548-56. l Findling R, Steiner H, Weller E. Use of antipsychotics in children and adolescents. J Clin Psychiatry 2005;66(Suppl 7):29-40.
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