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Are Antidepressants and Antipsychotics Safe in Children and Adolescents William by thegza


									      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
     2. describe the clinical uses and efficacy of antipsychotics in children and
     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
   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
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
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
       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
          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

Analysis                                         Relative Risk for suicidal behavior or
All trials of antidepressants for any            1.95 (1.28-2.98)
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
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
                                                             - Lipid abnormalities
Cardiac conduction             Yes – most likely with low    Yes – most likely with
abnormalities                  potency agents, e.g.,         ziprasidone
   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
   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 ~
      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

   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
   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.
   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.
      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
   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
   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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