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Leslie Walker MD Case Western Reserve University Dept. of Psychiatry April 2017 Objectives Review prevalence of TRD and suicide 2. List appropriate stepwise strategies to treat TRD 3. Identify differential diagnoses of TRD 1. Suicide in the US >41,000 completed (3:1 M:F) = 12.6/100,000 population >490,000 hospital visits (3:1 F:M) Age & Suicide (afsp.org) Ethnicity & Suicide (afsp.org) Methods & Suicide (afsp.org) Risk Factors for Suicide Historical Factors FH of suicide FH of psychiatric illness Personal history of suicide attempts Experienced child abuse Environmental Factors Health Factors Risk Factors for Suicide Historical Factors Environmental Factors Access to lethal means “Contagion” after exposure to suicide or media reports Prolonged stress Recent stress/loss Health Factors Health Risk Factors for Suicide Psychiatric Illness Major Depression (80-90% of suicides) Bipolar Disorder Schizophrenia, other Psychotic Disorders, or psychotic symptoms in any disorder Borderline or Antisocial Personality Disorder Conduct Disorder (age <18) Anxiety Disorders Substance Abuse Serious and/or Chronic Health Conditions & Pain Treatment-Resistant Depression Failure to achieve remission after two well-established antidepressant treatment trials known to have been of evidence-based acceptable dose and duration Develops in about 30% of patients with MDD (Greden et al, 2011) Most common mimics of TRD: Noncompliance Inadequate treatment Medical illness including dementia Substance abuse Demoralization Bereavement Facilitating Factors: sleep deprivation, caregiver strain, abusive relationship, burnout or severe work stress Key Concepts in TRD Treat as early as possible (typical onset age 15-24). No medication has been shown to be superior. First, optimize the current regimen. If partial response, augment. Treat to remission. Openly address stigma to encourage med adherence. Prescribe exercise and nutrition for all. (Greden et al, 2011) Roadmap for TRD Greden et al, 2011 Initial Complementary Options Psychotherapy Cognitive Behavioral Therapy Interpersonal Therapy Vitamin D at least >30 Folate 800+ mcg daily B12 1 mg daily Omega-3 Fatty Acids EPA & DHA ie fish oil caps 1000 mg qd-BID Bright light therapy 10,000 lux, 20-30’ q am Effective AD Titration (1) Target the minimum therapeutic dose. (2) Increase at 2-week intervals if no significant response, until either: significant response maximum dose tolerated by patient maximum usual therapeutic dose https://www.cms.gov/Medicare-Medicaid-Coordination/FraudPrevention/Medicaid-Integrity-Education/Pharmacy-EducationMaterials/Downloads/ad-adult-dosingchart.pdf (2013) Therapeutic Doses of AD SSRIs FDA-approved max Fluoxetine 20-80mg (to 120mg in OCD) 80mg Paroxetine 20-80mg qhs 60mg Paroxetine CR 25-75mg qhs 75mg Sertraline 100-200mg (300mg in OCD) 200mg Citalopram 20-80mg 40mg FDA warning on QT prolongation Escitalopram 10-30mg Fluvoxamine 100-300mg qhs Low dose venlafaxine ER 75-150mg 20mg 300mg 375mg Therapeutic Doses of AD SSRI+ 5HT receptor FDA-approved max Viibryd 10-40mg 40mg Trintellix 5-30mg 20mg SNRIs Venlafaxine ER 150-450mg 375mg Pristiq (desvenlafaxine) 50-150mg 100mg Duloxetine 60-180mg 120mg Fetzima 40-120mg 120mg Therapeutic Doses of AD Other mechanism FDA-approved max Trazodone 150-600mg qhs 400/600mg Nefazodone 300-600mg 600mg Mirtazapine 30-60mg qhs 45mg Buproprion SR/XL 300-450mg 450mg Therapeutic Doses of AD TCAs FDA-approved max Nortriptyline 75-200mg qhs 150mg Dose that gives 12-hour serum level 75-150 ng/mL Amitriptyline 100-300mg qhs Vivactil (protriptyline) 15-60mg Doxepin 100-300mg qhs MAOIs EMSAM patch (selegiline) 6-12mg Nardil (phenelzine) 15-30mg TID Parnate (tranylcypromine) 30-60mg 150/300mg 60mg 300mg 12mg 90mg 60mg Effective AD Titration (1) Target starting dose to minimum therapeutic dose as a planned titration based on patient factors. i.e. sertraline in an anxious patient with major depression: Target therapeutic dose: 100mg Start 25mg each morning. Increase by 25mg every 5-7 days til you reach 100mg daily. Call me if you have bothersome side effects, or if any of your symptoms get worse (like insomnia or anxiety), or if you have thoughts of death or suicide. Effective AD Titration (2) Increase at 2-week intervals if no significant response, until significant response, maximum dose tolerated by patient, or maximum usual therapeutic dose is reached. i.e. After 2 weeks at sertraline 100mg, patient feels a little better, more energy, more hopeful, but not dramatically better. Increase to 125 or 150mg daily depending on whether patient tolerated the initial titration easily. After 2 weeks at 150mg, patient feels much better, able to enjoy hobbies, more productive at work. Stay at 150mg. Effective AD Titration (1) Target a minimum therapeutic dose. (2) Then increase at 2-week intervals if no significant response, until significant response, maximum dose tolerated by patient, or maximum usual therapeutic dose is reached. (3) If patient has no clinical response at max dose, taper off the medication and try a new medication. (4) If there is a significant improvement, hold at that dose and watch over next 4-12 weeks. Partial Response (“Plateau”) When patients have clearly improved on an antidepressant at maximum dose tolerated, but are not in remission (<5 DSM-5 criteria met over past 2 weeks, or HAM-D <9) Keep the baseline antidepressant and begin an augmentation strategy. Roadmap for TRD Greden et al, 2011 Augmentation Strategies for SSRIs Buproprion SR or XL 150-450mg daily L-methyl-folate (Deplin) 15mg daily Very low energy? TSH >2.5? OSA on CPAP? Liothyronine (T3) 25-50 mcg daily Modafinil 100-400mg daily Still can’t sleep? Mirtazapine 7.5-60mg qhs Nortriptyline to a 12-hour serum level of 75-150 Augmentation Strategies for SSRIs lithium carbonate ER qhs or BID target 12-hr serum level of 0.6-1.0 follow lithium level, thyroid and renal functions Atypical antipsychotics (aripiprazole, quetiapine, olanzapine, brexiprazole) warn re EPS (extrapyramidal symptoms), TD (tardive dyskinesia, weight gain and increased lipids follow AIMS, weight, waist circumference, labs Less evidence for augmentation 5-HT 1A Agonists Buspirone (BuSpar) 15-60mg daily in BID-TID dosing Pindolol SAM-e (s-adenosylmethionine) rd 3 Line Options MAOIs – must washout from 5HT medicines first Tranylcypromine (Parnate) 30-60mg daily Phenelzine (Nardil) 45-90mg daily Selegiline (Emsam patch) 6-12mg/24 hrs ECT (electroconvulsive therapy) rTMS (repetitive transcranial magnetic stimulation) ? IV ketamine – available at CCF if criteria met VNS (vagal nerve stimulation) ? DBS (deep brain stimulation) Permanent Antidepressant Rx 3+ previous episodes of MDD. 2 episodes plus FH or >120 days spent depressed in lifetime. 1 episode plus FH or >12o days spent depressed in lifetime or Early age of onset TRD Psychosis Prompt relapse following previous discontinuation Previous SA or prominent SI during current episode Current severity (i.e. PHQ >9, HAM-D >18) Comorbid medical condition or occupation that makes relapse hazardous Abnormal labs: elev cortisol, abnl HPA axis measures MRI evidence of hippocampal or amygdala atrophy (Greden et al, 2011) Recurrent episode? (1) Re-evaluate to confirm major depressive episode. (2) If current medication is not at max dose, increase current medication dose every 2 weeks until response, intolerant, or max dose. (3) If 3+ episodes or FH of bipolar disorder, consider including a mood stabilizer (i.e. lithium, lamotrigine, atypicals) in your maintenance therapy. Differential Diagnosis of TRD Bipolar (Type I or II) Depression PTSD or other anxiety disorder ADHD or ADD-I MCI or dementia Comorbid alcohol, MJ, or other drug abuse Depression as part of or presenting symptom of a new medical diagnosis Chronic pain Personality disorder Depression in Medical Illness Endocrine Hypothyroidism (and watch for hyperthyroidism) Diabetes mellitus Low testosterone PMDD, pregnancy, postpartum, perimenopause Neurology Sleep apnea and other sleep disorders Parkinson disease and other dementias Multiple sclerosis Epilepsy Oncology Pancreatic CA Depression as a Side Effect Interferon-alpha Accutane Chantix FDA warning on all antidepressants (2004) and anticonvulsants (2009) regarding possible risk of suicidal thoughts/behaviors in ages 15-24 after initiation of treatment (first 1-2 months) has been associated with decreased diagnosis and treatment and increased suicide rates History, physical exam, then … MOCA if over 60 CBC – r/o anemia TSH, fT4 – r/o hypothyroidism or hyperthyroidism B12, folate, D CMP – r/o hepatic or renal dysfunction Consider HCG, testosterone Consider gene testing if multiple antidepressants have failed or not been tolerated (ie Genomind, Genesight) Genetic testing Some genes coding for 5HT or DA transport proteins, receptors, etc. Some genes coding for some of the hepatic enzymes involved in the metabolism of psychoactive drugs, which can guide your dosing strategy if patient is a fast or slow metabolizer at a particular enzyme. Genetic testing can tell you if your patient MAY be more likely to have side effects or non-response to a particular drug or class of drugs. Genetic testing cannot tell you EFFICACY – whether your patient will respond to a particular medication. Print Resources Greden JF, Riba MB, McInnis MG. Treatment-Resistant Depression: A Roadmap for Effective Care. APPI, 2011. Jamison, KR. Night Falls Fast: Understanding Suicide. Random House, 1999. MacKinnon DF. Still Down: What to Do When Antidepressants Fail. JHU Press, 2016. Solomon, A. The Noonday Demon: An Atlas of Depression. Scribner, 2001; new edition 2015. Organizations AFSP (American Foundation for Suicide Prevention) afsp.org/chapter/afspnorthern-ohio/ NAMI (National Alliance on Mental Illness namigreatercleveland.org