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
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)
1)
2)
Birmaher, B. et.al. (1996) Journal of Child and Adolescent Psychiatry
Weissman, MM. et.al. (1999) Journal of the American Medical Association
What Do we Know about
Depression in Kids with Diabetes
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
Role of Socioeconomic Status,
Depression, QOL and Glycemic
Control on Teens with Type 1
• 222 Participants (12-17yo)
• Children’s Depression Inventory (CDI)
• Poor glycemic control was associated
with lower SES and increased
depression
Hassan, K. et.al. (2006) Journal of Pediatrics
Depressive Symptoms in
Children and Adolescents with
Type 1 Diabetes
• 145 Participants (10-18yo)
• Children’s Depression Inventory (CDI)
• 15.2% had depressive symptoms
- less SMBG
- increased A1C (>8.7%)
- increased family conflict
Hood, K. (2006) Diabetes Care
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
In Summary…
• Depression appears to be 2-3 times more
prevalent among children and adolescents
with diabetes
• Diabetes and Depression DON’T MIX
–  A1c
–  SMBG
–  ED Admits
–  Long Term Complications
So Now What?
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
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
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
Get Your Tools Out
WHO-5
•
•
•
•
•
•
•
Developed by the World Health Organization
5 items
Measures emotional well-being
Easily scored
Validated for use with type 1 teens
< 50 =  emotional well-being/further testing
 29 = depression
– WHO recommends ICD-10
• No suicide question
De Wit, M. et.al. (2007) Diabetes Care
Children’s 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
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
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
Yep, Looks Like Depression!
The Next Step
Facilitate
Collaboration
Refer for Therapy1
Consider
Medication
1) Sherill, J., Kovacs, M. (2002) Nonsomatic Treatment of Depression. Child Adolescent Psychiatry
Managing Depression
in Diabetes
Sam Ellis, Pharm.D., BCPS, CDE
Assistant Professor
University of Colorado School of Pharmacy
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.
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 (RR=1.95, 95%CI 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……..”
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

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)
439 Randomized
107 Received
109 Received
111 Assigned
112 Assigned
Fluoxetine + CBT
Fluoxetine Alone
CBT Alone
Placebo
TADS. JAMA292;807-20:2004
Fluoxetine ± CBT
Children’s Depression Rating Scale
Suicidal Ideation Questionnaire-JHS
Flu+CBT > plb; p=0.001
Flu+CBT > plb; p=0.02
Flu+CBT > Flu OR CBT; p=0.02
Flu OR CBT vs plb p=NS
Flu >CBT; p=0.01
Flu+CBT > flu or CBT; p<0.05
TADS. JAMA292;807-20:2004
Decline in Treatment of Pediatric
Depression after FDA Mandate



Pediatric Cohort with newly dx depression
(N=65,349)
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; 164:884-91
Diagnosis and Treatment of
Depression after the FDA Mandate
Diagnosis of Depression in Pediatrics
Prescribing of SSRIs before and after FDA Mandate
Libby AM, et al., Am J Psy. 2007; 164:884-91
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
SSRI Prescription Rates by Age
Suicide Rates in Children and Adolescents
Gibbons, et al. Am J Psy. 2007;164:1356-63
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
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.”
Cynthia Pfeffer, Am J Psy: June 2007

“A major concern missed in this controversy is that less
than 50% of children and adolescents with depression
ever receive treatment at all.”
Graham Emslie, Am J Psy, Jan 2008
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
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
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)
SSRI’s

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
Dosing in Children/Adolescents
SSRI titration Schedule
Drug
Starting Dose Increments Effective dose Max Dose
(mg)
Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Escitalopram
10
10
50
10
25
5
(mg)
(mg)
(mg)
10
10-20
50
10
12.5-25
5
20
20
150
20
50
10
60
60
300
60
200
20
Cheung, et al. Pediatrics;2007:e1313-26
SNRI’s

Mechanism
selective serotonin and norepinephrine reuptake
inhibition
 Common side effects:

Nausea, dizziness, insomnia, constipation, sweating
 Venlafaxine can cause hypertension

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
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
Bupropion

Mechanism


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


Weak inhibitor of norepinephrine and dopamine uptake, no
effect on serotonin
May be useful for patients presenting with difficulty
concentrating or fatigue
Does not cause sexual dysfunction
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)
Mirtazapine

Mechanism:

Enhances the release of norepinephrine by blocking α2adrenergic autoreceptors and 5-HT2A/5-HT3 autoreceptors




Little affinity for α1 and acetylcholine receptors
High affinity for histamine-1 receptors
Sedation, weight gain (appetite increase), and dry
mouth are more prominent at lower doses
1:50 pediatrics/adolescents experience suicidality
Mirtazapine

Dosage forms:



Dose:


7.5, 15, 30, 45mg tablets
15, 30, 45mg disintegrating tablets
7.5-15mg QHS initially, increase by 7.5mg weekly (max =
30mg)
Useful for the thin, depressed geriatric patient with
insomnia
Side Effects of Antidepressants
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 SSRI’s as first-line therapy
Side Effects and Selection

Peripheral neuropathy


Insomnia



Mirtazapine, TCA’s, trazodone
Paroxetine, citalopram, escitalopram
Concurrent anxiety


Duloxetine, TCA’s, venlafaxine
SSRI’s that cause more sedation: paroxetine, citalopram, or
escitalopram
Erectile dysfunction

Bupropion, mirtazapine, duloxetine
Response vs. Remission

Response



Usually defined as a 50% reduction in symptoms
Remission

A return to normal mood and normal functioning

Use Ham-D (< 6 is remission) or other clinical 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
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
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
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
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
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
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
Assessment and Treatment of Children
and Adolescents with Depression
Screen every visit
Mild Depression
Moderate Depression
Major Depression
Consider
consulting Mental
Health
Active Support and
close monitoring
q1-2 weeks
Improved
Continue to
follow
Not Improved
Initiate Medication
and/or CBT
Partially Improved
Monitor q 1-2
weeks
Not Improved
(reassess dx)
1. Add or maximize therapy
2. Continue to assess closely for
ADE/adherence and changes to self-care
3. Consult mental health
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
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