Depression and Diabetes: Clinical Assessment and Pharmacotherapy

1
Depression and Diabetes Clinical Assessment and
Pharmacotherapy

• Sam Ellis, PharmD, CDE
• Ellen Fay-Itzkowitz, LCSW, CDE
• Barbara Davis Center for Childhood Diabetes
• University of Colorado Health Sciences Center
• Keystone 2008

2
Depression in Kids without Diabetes

• 2.5 of children (5-9) are depressed
• 8.3 of teens (12-17) are depressed(1)
• Early Onset Depression ? persist, recurs and may
  predict more severe depression and suicidal bxs
  later in life(2)

• Birmaher, B. et.al. (1996) Journal of Child and
  Adolescent Psychiatry
• Weissman, MM. et.al. (1999) Journal of the
  American Medical Association

3
What Do we Know about Depression in Kids with
Diabetes
4
Indicators of Depressive Symptoms in 12 to 17
year olds with type 1 Diabetes

• 49 participants (12-17yo)
• Beck Depression Inventory (BDI)
• 36.7 with depressive symptoms
• Girls problems with decision making and sleep
• Boys change in appetite

Reviera, A. et.al. (2007) PR Health Science
Journal
5
Role of Socioeconomic Status, Depression, QOL and
Glycemic Control on Teens with Type 1

• 222 Participants (12-17yo)
• Childrens Depression Inventory (CDI)
• Poor glycemic control was associated with lower
  SES and increased depression

Hassan, K. et.al. (2006) Journal of Pediatrics
6
Depressive Symptoms in Children and Adolescents
with Type 1 Diabetes

• 145 Participants (10-18yo)
• Childrens Depression Inventory (CDI)
• 15.2 had depressive symptoms
• - less SMBG
• - increased A1C (8.7)
• - increased family conflict

Hood, K. (2006) Diabetes Care
7
Prevalence and Correlates of Depressed Mood among
Youth with Diabetes SEARCH

• 2672 Participants (10-21yo)
• includes type 1 and type 2
• Center for Epidemiologic Studies Depression Scale
  (CES-D)
• 14 Mild Depressive Symptoms
• 8 Moderate to Severe
• ? A1C and ? ED visits
• Depression among youth with diabetes kids
  without diabetes

Lawrence, J.M. (2006) Pediatrics
8
In Summary

• Depression appears to be 2-3 times more prevalent
  among children and adolescents with diabetes
• Diabetes and Depression DONT MIX
• ? A1c
• ? SMBG
• ? ED Admits
• ? Long Term Complications

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So Now What?
10
Identifying Depression in Youth

• Routine Screening in Kids ? 10
• Who?
• How?
• Questionnaire vs. Clinical Interview

Silverstein, J. et. al. (2005) Care of Children
and Adolescents with Type 1 Diabetes A Statement
of the ADA
11
First- Know the Symptoms

• ? A1C
• Frequent ED admissions
• ? SMBG
• Persistent Sad or Irritable Mood
• Appetite Disturbance ?
• Problems with Concentration
• Indecision ?
• Sleep Disturbance ?
• Poor School Performance

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Symptoms (Cont.)

• Social Withdrawal
• Guilt
• Worthlessness
• Physical Complaints
• Lack of Enthusiasm or Motivation
• Low Energy
• Drug and/or Alcohol Abuse
• Thoughts of Death or Suicide

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Get Your Tools Out
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WHO-5

• Developed by the World Health Organization
• 5 items
• Measures emotional well-being
• Easily scored
• Validated for use with type 1 teens
• ? 29 depression
• WHO recommends ICD-10
• No suicide question

De Wit, M. et.al. (2007) Diabetes Care
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Childrens Depression Inventory (CDI)

• Approved for use in children and adolescents
  (ages 7-17)
• 27 items (CDI-Short- 10 items)
• Parent/Child/Teacher versions
• Suicide question
• Validated in children and adolescents with T1D
• Score ? 13 clinical depression
• Can be purchased for clinical use at
  http//www.pearsonassessments.com/tests/cdi.htm

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The Clinical Interview

• Diagnostic Interview requires behavioral health
  specialist (LCSW, LPC, PhD or MD)
• Anyone can screen for depression
• PHQ-2
• Primarily used in teens and adults
• 2 quick questions
• Little interest or pleasure
• Feeling down, depressed or hopeless

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Suicide Screening

• Third leading Cause of Death in 15-24 year olds
• Be Alert to Risk Factors
• Depression or Other Psychiatric Illness
• Alcohol/drug abuse
• Prior attempts
• Relationship Break-Ups
• Recent Bereavement
• Ask about Plan
• Talk with Parents
• Mental Health Referral/Hospitalization

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Yep, Looks Like Depression!
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The Next Step
1) Sherill, J., Kovacs, M. (2002) Nonsomatic
Treatment of Depression. Child Adolescent
Psychiatry
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Managing Depression in Diabetes

• Sam Ellis, Pharm.D., BCPS, CDE
• Assistant Professor
• University of Colorado School of Pharmacy

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Objectives

• List the pros and cons of various treatment
  strategies utilized in the outpatient management
  of depression.
• Describe the differences among pharmacologic
  agents used in the management of depression
• Describe the FDA advisory on SSRI agents and
  suicidality and the impact on diagnosing,
  treatment and suicide risk.

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Antidepressants and Suicide

• FDA Black Box Warning added for all
  antidepressants in October 2004
• Risk of suicidality in children, adolescents, and
  adults younger than 25 years
• Based on Meta-analysis of industry-sponsored
  trials
• Suicidal behavior increased (RR1.95, 95CI
  1.28-2.98)

• Sample Black Box Warning
• Antidepressants increased the risk compared to
  placebo of suicidal thinking and behavior in
  children, adolescents and young adults in
  short-term studies of MDD and other psychiatric
  disorders..

23
FDA Mandate for Pediatric AD

• black box warning designed to improve monitoring
  of patients started on AD therapy
• Clearly warn the patient and family about risk
• Patient Medication Guide distributed with each
  new prescription and refill
• Risk appears greatest in the first few weeks of
  therapy
• Monitoring
• Weekly visits for first 4 weeks
• Biweekly until 12 weeks
• As clinically indicated beyond 12 weeks

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TADS Fluoxetine CBT

• RTC with blinded fluoxetine and open-label CBT
• Initial treatment of MDD in adolescents (12-17yo)
• 12 weeks of therapy (fluoxetine 10-40mg)

TADS. JAMA292807-202004
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Fluoxetine CBT
Childrens Depression Rating Scale
Suicidal Ideation Questionnaire-JHS
FluCBT plb p0.001 FluCBT Flu OR CBT
p0.02 Flu CBT p0.01
FluCBT plb p0.02 Flu OR CBT vs plb
pNS FluCBT flu or CBT pTADS. JAMA292807-202004
26
Decline in Treatment of Pediatric Depression
after FDA Mandate

• Pediatric Cohort with newly dx depression
  (N65,349)
• Evaluation of rates of diagnosis and treatment
  after FDA changes
• Time-series model using 5 years pre and 2 years
  post mandate

Libby AM, et al., Am J Psy. 2007 164884-91
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Diagnosis and Treatment of Depression after the
FDA Mandate
Prescribing of SSRIs before and after FDA Mandate
Diagnosis of Depression in Pediatrics
Libby AM, et al., Am J Psy. 2007 164884-91
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Early Evidence of FDA Mandate on Suicide in
Children and Adolescents

• Evaluation of large pharmacy claims database
• Determined SSRI use by age
• Compiled suicide data from the CDC

Gibbons, et al. Am J Psy. 20071641356-63
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Suicidality in RTC and in Cohort Studies

• Most often occurs early in treatment (acute
  phase)
• Occurs after dosing changes (both titration up
  and down (within 1 month)
• Occurs in patients who are non-adherent to AD
• Diminishes the longer a person takes AD
• Must monitor closely during acute phase
• and after titrations

30
Jump Forward to 2008

• The FDA advisories may have had the unintended
  effect of discouraging the prescription of
  antidepressants for pediatric patients and
  pediatric utilization of antidepressants without
  compensatory increases in other specific
  treatments.
• A major concern missed in this controversy is
  that less than 50 of children and adolescents
  with depression ever receive treatment at all.

Cynthia Pfeffer, Am J Psy June 2007
Graham Emslie, Am J Psy, Jan 2008
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Antidepressant Treatment

• All agents have similar efficacy when comparably
  dosed
• Choices made empirically based on
• Patient or family hx of response
• Concurrent conditions/medications
• Depression subtype
• Adverse effect profile
• Drug cost

Fluoxetine is the only FDA approved AD for
pediatrics
32
Drug Classes

• SSRI SNRI
• Fluoxetine (Prozac) Venlafaxine (Effexor)
• Sertraline (Zoloft) Duloxetine (Cymbalta)
• Paroxetine (Paxil, CR) Alpha-2 Antagonist
• Fluvoxamine (Luvox) Mirtazapine (Remeron)
• Citalopram (Celexa) Catacholamine
  reuptake inh
• Escitalopram (Lexapro) Bupropion (Wellbutrin)

Commonly used in anxiety disorders only FDA
approved drug for pediatrics
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Pharmacotherapy

• Three (3) phases of therapy
• Acute achieve remission, 6-12 weeks
• Continuation keep symptoms in remission using
  full-dose therapy, 6-12 months
• Maintenance long-term therapy for those at high
  risk for relapse (prior episodes, strong family
  history)
• Adequate trial
• Full therapeutic doses for 6-8 weeks and in some
  cases up to 12 weeks (if no response, failure)

34
SSRIs

• Mechanism
• selective reuptake inhibition of serotonin
• First-line therapy
• Fluoxetine only FDA approved agent for
  children/adolescents
• Similar or superior efficacy to others
• Lower side effects, safer, convenient dosing
• Generally choose cheapest available
• Recognize differences between agents

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Dosing in Children/Adolescents

• SSRI titration Schedule
• Drug Starting Dose Increments
  Effective dose Max Dose (mg) (mg)
  (mg) (mg)
• Citalopram 10 10 20 60
• Fluoxetine 10 10-20 20 60
• Fluvoxamine 50 50 150 300
• Paroxetine 10 10 20 60
• Sertraline 25 12.5-25 50 200
• Escitalopram 5 5 10 20

Cheung, et al. Pediatrics2007e1313-26
36
SNRIs

• Mechanism
• selective serotonin and norepinephrine reuptake
  inhibition
• Common side effects
• Nausea, dizziness, insomnia, constipation,
  sweating
• Venlafaxine can cause hypertension

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SNRI Venlafaxine

• Effexor (immediate release)
• Dose
• 25mg BID, increase by 25-50mg every week to max
  of 150mg
• Effexor XR (extended release)
• Dose
• 37.5-75mg QD initially, increase by 37.5mg every
  week to maximum of 150mg

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SNRI Duloxetine

• Cymbalta (delayed release)
• Dosage forms 20, 30, 60mg capsules
• Dose
• 20mg BID initially, titrate up to 60mg daily
  (once daily or 30mg BID)
• Also has indications for diabetic peripheral
  neuropathy and generalized anxiety disorder

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Bupropion

• Mechanism
• Weak inhibitor of norepinephrine and dopamine
  uptake, no effect on serotonin
• Lowers the seizure threshold, especially in
  bulimic patients
• Contraindicated in bulimic and anorexic patients
• Immediate release higher incidence, may be due to
  peak concentrations
• Has mild stimulating properties
• May be useful for patients presenting with
  difficulty concentrating or fatigue
• Does not cause sexual dysfunction

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Bupropion

• Dosage forms
• Wellbutrin 75, 100mg immediate release tablet
• Wellbutrin SR 100, 150, 200mg sustained-release
  tablets
• Wellbutrin XL 150mg, 300mg extended-release
  tablets
• Dose
• Wellbutrin 100mg BID x 3 days, then 100mg TID
  (max 450mg TID-QID)
• Wellbutrin SR 150mg QD x 3 days, then 150mg BID
  (max 200mg BID)
• Wellbutrin XL 150mg QD x 3 days, then 300mg QD
  (max 450mg QD)

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Mirtazapine

• Mechanism
• Enhances the release of norepinephrine by
  blocking a2-adrenergic autoreceptors and
  5-HT2A/5-HT3 autoreceptors
• Little affinity for a1 and acetylcholine
  receptors
• High affinity for histamine-1 receptors
• Sedation, weight gain (appetite increase), and
  dry mouth are more prominent at lower doses
• 150 pediatrics/adolescents experience suicidality

42
Mirtazapine

• Dosage forms
• 7.5, 15, 30, 45mg tablets
• 15, 30, 45mg disintegrating tablets
• Dose
• 7.5-15mg QHS initially, increase by 7.5mg weekly
  (max 30mg)
• Useful for the thin, depressed geriatric patient
  with insomnia

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Side Effects of Antidepressants
44
Initial Therapy

• Considerations in agent selection
• Cost, dosing convenience
• Co-morbidities (e.g. depression with insomnia)
• Side effect profile
• Previous response to therapy, family members
  response to therapy
• Drug-drug/drug-disease interactions
• Prefer SSRIs as first-line therapy

45
Side Effects and Selection

• Peripheral neuropathy
• Duloxetine, TCAs, venlafaxine
• Insomnia
• Mirtazapine, TCAs, trazodone
• Paroxetine, citalopram, escitalopram
• Concurrent anxiety
• SSRIs that cause more sedation paroxetine,
  citalopram, or escitalopram
• Erectile dysfunction
• Bupropion, mirtazapine, duloxetine

46
Response vs. Remission

• Response
• Usually defined as a 50 reduction in symptoms
• Remission
• A return to normal mood and normal functioning
• Use Ham-D (rating scale to monitor for response and
  remission
• If a drug has given a response, you can possibly
  obtain remission by adjusting the dose or
  augmenting the therapy

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Response

• 1 week decreased anxiety, improved sleep /
  appetite
• 1-3 weeks increased activity, self-care,
  concentration and memory, thinking normalizes,
  increased risk for suicide (monitor closely)
• 2-4 weeks relief of depressed mood

48
Lack of Response

• Optimization
• Maximize dose
• Drug substitution
• Can be difficult (titrations, length of time,
  loss of effect)
• Combination
• Choose from a different class, monitor ADEs

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Treatment Duration

• Acute phase
• Generally 6-12 weeks
• Goal obtain remission
• Start low dose, titrate to max tolerated
• Augment or switch, if necessary
• Continuation phase
• After remission is obtained, 6-12 months
• Goal eliminate residual symptoms, restore level
  of functioning, self-care behaviors, prevent
  relapse
• Continue regimen that induced remission

50
Treatment Duration

• Maintenance phase
• Continue therapy for 12-36 months or indefinitely
  to prevent relapse
• Discontinuation phase
• If no relapse during continuation, gradual
  reduction in those with 6 months therapy
• Taper over several weeks to avoid discontinuation
  syndrome
• Imbalance, GI, sleep, anxiety, agitation,
  irritability, crying spells

51
Zoloft Effects during Maintenance in Adults with
Diabetes
Remission of Depression in maintenance
Effects of Depression control on A1c
Lustman PJ, et.al., Ach Gen Psychiatry. 2006
52
Summary

• Decrease in diagnosing and prescribing for
  depression has occurred since the FDA Mandate
• Fluoxetine is still the only FDA approved AD for
  pediatric use and combination with CBT results in
  decreased suicidality
• Other antidepressants can be used but exact
  dosing is unclear. Tailor AD choice by taking
  advantage of ADEs/symptoms of depression, costs.
• Continue AD use for 6-12 months if achieved
  remission and make sure to maximize dose and
  augment or switch if partial response
• Monitor closely during acute 6-8 weeks and after
  dosing changes or discontinuation

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Assessment and Treatment of Children and
Adolescents with Depression
Screen every visit
Major Depression
Mild Depression
Moderate Depression
Consider consulting Mental Health
Monitor q 1-2 weeks
Not Improved
Initiate Medication and/or CBT
Active Support and close monitoring q1-2 weeks
Not Improved

(reassess dx)
Partially Improved
Improved
1. Add or maximize therapy
2. Continue to assess closely for
ADE/adherence and changes to self-care 3.
Consult mental health
Continue to follow
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Future Needs

• Further data defining suicidality in
  peds/adolescents
• Long term studies assessing differences in acute
  vs maintenance suicidality
• Treatment algorithms designed specifically for
  the depressed patients with diabetes
• Creating multidisciplinary treatment approaches

55
Conclusions

• The prevalence of depression is 2 fold greater in
  patients with diabetes
• Better detection/screening is essential to
  improving diabetes self-care
• Treatment with combined fluoxetine and CBT is the
  preferred option in MDD
• Suicidality is of concern immediately after
  initiating therapy and after dose titration
• Future multidisciplinary management approaches
  are critical in the identification, treatment and
  follow up in our diabetes patients