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Depression and Diabetes: Clinical Assessment and Pharmacotherapy

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.

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Depression and Diabetes: Clinical Assessment and Pharmacotherapy

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  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) • Children’s 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) • Children’s 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 DON’T MIX •  A1c •  SMBG •  ED Admits •  Long Term Complications

  9. 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

  12. 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

  13. Get Your Tools Out

  14. 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

  15. 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

  16. 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

  17. 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

  18. Yep, Looks Like Depression!

  19. The Next Step 1) Sherill, J., Kovacs, M. (2002) Nonsomatic Treatment of Depression. Child Adolescent Psychiatry

  20. Managing Depression in Diabetes Sam Ellis, Pharm.D., BCPS, CDE Assistant Professor University of Colorado School of Pharmacy

  21. 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.

  22. 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……..”

  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

  24. 439 Randomized 112 Assigned Placebo 109 Received Fluoxetine Alone 111 Assigned CBT Alone 107 Received Fluoxetine + CBT 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. JAMA292;807-20:2004

  25. Fluoxetine ± CBT Children’s Depression Rating Scale Suicidal Ideation Questionnaire-JHS Flu+CBT > plb; p=0.001 Flu+CBT > Flu OR CBT; p=0.02 Flu >CBT; p=0.01 Flu+CBT > plb; p=0.02 Flu OR CBT vs plb p=NS Flu+CBT > flu or CBT; p<0.05 TADS. JAMA292;807-20:2004

  26. 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

  27. 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; 164:884-91

  28. SSRI Prescription Rates by Age Suicide Rates in Children and Adolescents 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. 2007;164:1356-63

  29. 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

  31. 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

  33. 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. 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

  35. 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. Pediatrics;2007:e1313-26

  36. SNRI’s • Mechanism • selective serotonin and norepinephrine reuptake inhibition • Common side effects: • Nausea, dizziness, insomnia, constipation, sweating • Venlafaxine can cause hypertension

  37. 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

  38. 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

  39. 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

  40. 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)

  41. Mirtazapine • Mechanism: • Enhances the release of norepinephrine by blocking α2-adrenergic 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

  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

  43. 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 SSRI’s as first-line therapy

  45. Side Effects and Selection • Peripheral neuropathy • Duloxetine, TCA’s, venlafaxine • Insomnia • Mirtazapine, TCA’s, trazodone • Paroxetine, citalopram, escitalopram • Concurrent anxiety • SSRI’s 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 (< 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

  47. 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

  49. 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

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