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.
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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