1. “Improving Care and Collaboration for Children with Neurologic and Behavioral Conditions” Webinar #1 Depression
January 25th, 2016
1:00pm -2:00pm

2. Kristi Kleinschmit, MD
Dr. Kleinschmit is an Assistant Professor, in the Department of Psychiatry, Division of Child Psychiatry, and is the medical director of the Teenscope and Kidstar day treatment programs at the University of Utah Neuropsychiatric Institute. She is also the program director for the Triple Board and Child Psychiatry Residencies.
Dr. Kleinschmit graduated from Tulane University School of Medicine in New Orleans, Louisiana. She completed a Triple Board residency at the University of Utah School of Medicine. She holds American Board certifications in Pediatrics, Adult Psychiatry, and Child and Adolescent Psychiatry.

3. Shawn Kohler, MD
Dr. Kohler is a child and adolescent psychiatry second year fellow at the University of Utah. He is planning on continuing as an outpatient Child psychiatrist with the University in fall this year. He completed medical school at University of Illinois at Champaign Urbana.

4. Disclosures Funding from: nothing to disclose
Institutional support from: nothing to disclose
I will be discussing off-label use of medications
Any disclosures here

5. CME Credit
Accreditation: This activity has been planned and implemented in accordance with the essential areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Primary Children’s Hospital, the Department of Pediatrics at the University of Utah School of Medicine, and UPIQ. Primary Children’s Hospital is accredited by the ACCME to provide continuing medical education for physicians.
AMA Credit: Primary Children’s Hospital Designates this live activity for a maximum of 8 AMA PRA Category
1 Credit(s)™. Physicians should only claim the credit that commensurate with the extent of their participation in the activity.
Please no changes to this page.

6. Disclaimer
Most of the information today is based on clinical practice of myself and my colleagues, based on evidence when available, but also gleaning from the “art” of psychiatry.
I am using brand names at times for clarification, not to promote any specific one.

7. Objectives
Update on antidepressant options in children/adolescents, including strategies and evidence for switching therapies
Treatment-resistant depression
Referrals to therapists
Please add up to three objectives for this learning session

8. Antidepressant Classes
SSRI’s – Fluoxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine SNRI’s – duloxetine, venlafaxine, desvenlafaxine Other – buproprion, mirtazapine, trazodone, serzone MAOIs – tranylcypromine, phenelzine, isocarboxzid, selegiline transdermal TCAs – amitriptyline, desipramine, clomipramine, nortriptyline

9. Theory about Effect
From Stahl’s Essential Psychopharmacology

10. Selective Serotonin Reuptake Inhibitors (SSRI’s)
Fluoxetine (Prozac)
Escitalopram (Lexapro)
Sertraline (Zoloft)
Citalopram (Celexa)
Fluvoxamine (Luvox)
Paroxetine (Paxil)

11. Depression Placebo-controlled RCTs
Medication
Positive Trials
Negative Trials
Fluoxetine 3
Sertraline 1
Citalopram
Escitalopram
?1-2
?0-1
Paroxetine
?2-3
Mirtazapine
Nefazodone
Venlafaxine 2
Fluoxtine 8-18 MDD
Lexapro MDD

12. SSRI Dosing Chart Medication Starting Dose (mg/d) Increments (mg)
Effective
Maximum
Citalopram 10 20 40
Escitalopram 5
Fluoxetine
10-20 60
Paroxetine
Sertraline 25 50
200

13. SSRI – side effects EPS (either by self or in combo with neuroleptics)
Suicidality
Serotonin syndrome
Activation - akathisia
Mania – 5-6% in some studies.
Apathy / frontal lobe syndrome – mistaken for residual depression or under recognized
Sleep – fluoxetine = Increase REM latency, awakenings, decreased sleep efficiency & REM sleep. ? Medicine or depression effect?
Bleeding -? sertraline
Discontinuation – dizziness, movement disorder, paresthesias, nausea, headache, visual changes

14. Antidepressant Adverse Responses
Symptoms
Incidence
When occurs
Suicidality
Self-harm acts/ thoughts 2%
1-4 weeks
Activation
Inner restlessness, irritability, agitation
3-10%
2-6 weeks
Mania
euphoria, decreased need for sleep
1-5%
2-4 weeks
Discontin-uation
Nausea, insomnia, irritability, parasthesias
4-18%
1-7 days of stopping
Serotonin syndrome
Confusion, restlessness, fever, hyperthermia, hypertonia
<1%
Adding serotonergic medication

15. SSRI – side effects Serotonin Syndrome Mental status changes Agitation
Myoclonus Hyper-reflexia
Diaphoresis Shivering
Tremor Diarrhea
Incoordination Fever

16. Serotonin Syndrome

17. SSRI Comparison Chart Medication Half-life Drug interaction potential
More common side effects
Citalopram
35 hrs
low
sexual SE, long QT
Escitalopram
30 hrs
agitation, $
Fluoxetine
2-4 days
high
agitation, nausea
Paroxetine
20 hrs
Sexual SE, weight gain, sedation, anticholinergic
Sertraline
26 hrs
moderate
diarrhea, nausea

18. Drug-Drug interactions-Inhibition potential

19. Antidepressants and Suicidality
Black Box Warning (2004)
Warning of increased risk of suicidality in pediatric pts taking antidepressants.
FDA Analysis of short-term RCTs
Average risk of spontaneous suicidal thinking / behavior on drug was 4% vs. 2% on placebo
Toxicology studies
0-6% of suicides had antidepressants in blood
25% had active prescriptions for antidepressants
Epidemiological Studies
Regional increases in SSRI use associated with decreases in youth suicide rates
Oct 2004; extended to young adults Dec 2006
Pooled meta-analysis of 24 short-term placebo-controlled RCT
4400 kids (2000 with MDD) on 9 antidepressant drugs
No suicides occurred in these trials
TADS: Increased SI in medication only arm

20. SSRI Prescription Rates in the US, 2002-2005, stratified by age group
Ref: Gibbons, Am J Psych (2007) 20

21. Suicide Rate in Children and Adolescents (Ages 5-19 Years) in the US, 1998-2004
Ref: Gibbons, Am J Psych (2007) 21

22. Fluoxetine (Prozac)
FDA approved for depression in ages 8-18 and OCD ages 7-17
Liquid form is available, can use very low doses. Typical doses are from mg/day.
long half life = 1 to three days; has an active metabolite = norfluoxetine which extends its pharmacologic half life up to 3 weeks. Very little withdrawal effects.
Side effects: Initial restlessness (may be dose related), headaches may be more common. Increasing sedation with increasing doses.
Drug interactions: May inhibit metabolism and increase effects of TCAs, trazadone and diazepam. May antagonize buspirone effects. May displace highly protein bound drugs. May have EKG changes when taken with TCAs. Very little interaction with CNS depressants.
Sleep - decreased REM and increased NREM in rats.

23. Sertraline (Zoloft) FDA approved for OCD in ages 6-17.
Dosing range is mg/day, Best absorbed when taken with food, extremes of doses have been associated with decreased efficacy.
half life is 20 to 28 hours
Metabolism mechanism is different than the others = hydroxylation. Less drug interactions.
Dry mouth and gastric upset (nausea and diarrhea) may occur with initiation and with each dose increase, usually mild and subsides after days, with high doses can be sedating
Most dopaminergic SSRI
Discontinuation syndrome = uncharacteristic irritability/ argumentativeness (unique to children/adolescents)
** liquid form

24. Escitalopram (Lexapro)
FDA approved for depression in ages 12-17
Isomer form of citalopram.
Touted as having less side effects and better tolerated than citalopram
Effectively concentrated citalopram = twice as strong.
Dose: Start 5 mg Qday, increase by 5 mg q 2 weeks, max dose 20 mg `

25. Citalopram (Celexa) Not FDA approved in kids
dosing is the same as fluoxetine, but maximum of 40 mg/day
quite activating but maybe less insomnia vs. fluoxetine, also with decreased REM sleep
Long QT with high doses
very few drug interactions

26. Vilazadone (Viibryd)
Selectively inhibits serotonin reuptake and partially agonizes serotonin 5-HT1A receptors
No studies in kids, not FDA approved
$ per 30 tabs

27. Serotonin Norepinephrine Reuptake Inhibitors (SNRI’s)
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Approved for GAD in teens
Desvenlafaxine (Pristiq)

28. Venlafaxine (Effexor)
serotonin and norepinephrine (and at high doses, dopamine) reuptake blockade
Current uses: Depression, Anxiety disorders
At low doses, think of it as an SSRI. At medium to high doses get involvement of NE and the DA receptors.
Possibly more rapid in onset than other antidepressants.
XR dosing well tolerated, mg/kg/day
Nasty withdrawal syndrome - GI, sweating, dizziness
More adverse reactions in kids

29. Desvenlafaxine (Pristiq)
New isomer form of venlafaxine
No data in kids
$130 per month
Would not recommend using

30. Duloxetine (Cymbalta)
Most like a TCA of the SNRIs
TCAs have been shown not to be effective in children and adolescents secondary to the immaturity of the noradrenergic system.
Limited data in youth
Just became generic

31. Bupropion (Wellbutrin)
norepinephrine and dopamine reuptake inhibitor
No approved uses < 18 y/o
Current uses : Depression, ADHD, smoking cessation
Contraindications - seizure disorder, current or prior diagnosis of bulimia or anorexia, history of closed head injury
Side effects: stimulating (last dose should be before PM), insomnia, agitation, rare GI symptoms
no sexual dysfunction - can add to SSRI and reverse SSRI sexual side effects or to boost efficacy
consider for treatment of depression in people who have history of dopamine seeking behaviors - thrill seekers, stimulant/cocaine abusers, cigarette users
seizure incidence= 1-4/1000 at normal doses

32. Treatment Resistant Depression

33. Switching Antidepressants
Limited data in kids or adults
Kudlow 2014, reviewed evidence of early improvement to predict final response (28 studies) and did lit review of RCT’s for switching (only 3). ONLY ADULT STUDIES.
Contradictory data, but felt comfortable recommending change in management if no response at 4 weeks (increase dose, new medication, augmentation)

34. Treatment: TORDIA Study
12 week RCT conducted at 6 clinical sites
334 patients with MDD, ages 12-18
Had not responded to 2-month initial treatment with an SSRI.
Randomized to 4 treatment strategies
Switch to different SSRI (paraxotine / citalopram or fluoxetine)
Switch to different SSRI + CBT
Switch to venlafaxine
Switch to venlafaxine + CBT
Mean duration of depression around 22 mo’s
Brent, JAMA (2008); Asarnow, J Am Acad Child (2009) 34

35. TORDIA Study Results
CBT + switch to either medication regimen showed a higher response rate
No difference in response rate between venlafaxine and a second SSRI
Treatment with venlafaxine resulted in more side effects and less robust response with severe depression and SI
Poorer response predicted by severity, SI, substance abuse, sleeping medication, and family conflict

36. TORDIA at Week 24
At week 12, responders continued, non-responders were given CBT + med x 12 more weeks
38.9% achieved remission
Likelihood of remission higher and faster if responded by week 12.
At week 6, participants who eventually remitted showed 48% reduction in scales
Augmentation of non-responders within 12 weeks with therapy or mood stabilizer predicted remission
Should give hope, as augmentation of therapy within 3 months, after initial failed trial predicted remission

37. How to treat resistant depression?
Monitor response, and increase dose or switch if none by 6 weeks (or even 4?)
Ensure adherance to meds
Switch to venlafaxine in kids no better than switch to a different SSRI (unlike adult data)
Augment with therapy (if not already doing)
Relook at diagnoses and comorbidities
Refer to psychiatry
ECT, TMS, adjunctive medications

38. SSRI Comparison Chart for guidance in switching:
Medication
Half-life
Citalopram
35 hrs
Fluoxetine**
2-4 days
Paroxetine
20 hrs
Sertraline
26 hrs
Escitalopram
30 hrs
Discuss using half-lives to help with switching strategies.
**Norfluoxetine half life up to 3 weeks

39. Final words on the magic of choosing an antidepressant:
Gather family history. Use what works for other family members
If no family history of SSRI use, go with the FDA approvals or side effect profile.
If still in doubt:

40. Just pick one
If that doesn’t work, pick another one
If that still doesn’t work, and they are at good doses for good amounts of time, feel free to refer or get a second opinion. Or add therapy!

41. Therapists
Don’t only give a name or two, because those folks are usually booked out
Use insurance panel as guide
Have family call the therapist-should take time to talk over the phone a little. Things to ask:
Population works with? (CBT with children/teens)
Family involvement
Availability
While waiting, refer to various on-line help sites that were discussed in initial session.

42. References
Brent D et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression. JAMA. 2008; 299 (8):
Emslie GJ et al. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. Am J Psychiatry ; 167(7):
Kudlow PA, McIntyre RS, Lam RW. Early switching strategies in antidepressant non-responsders: current evidence and future research directions. CNS Drugs

43. Comments/Questions
Reminder: 2nd Team Lead Call, Tuesday, February 21rd @ 1:00pm