Antidepressants

Antidepressants

My Generation: Depression in the Older Adult Jody F Agins MSN, RNP, FNP/GNP-BC Collaborative Medical Provider Group PLLC [email protected] Objectives Describe prevalence, etiology & presentation of depression in the elderly Recognize assessment tools recommended in elderly depression Discuss antidepressant therapy with

elderly considerations I have no conflicts CDC & Elder Depression ~7 million over age 65 experience yearly By 2020, World Health Organization prediction of developed countries Depression second leading cause of disability and untimely death, only after heart disease Living in the community Less than 1% to about 5%

Hospitalization & Home healthcare 11.5% - 30% Long Term Care Residents 50% Reminders. Major Depressive Disorder (MDD) Severely depressed mood Loss of interest in daily activities that interferes with daily life for at least two weeks Persistent depressive disorder

Depressed mood lasting for at least two years Bipolar disorder Cycling mood changes from extreme highs to extreme lows Major vs Minor Depression Older adults have lower rates of major depression than younger, but experience minor depression or significant depressive symptoms > younger groups Baby Boomers are trending significantly higher rates of depressive disorders than

previous groups I hope I die before I get old My Generation Almost 50 years ago Pete Townshend & The Who Anthem for baby boomer generation, who started turning 65 in 2011 Depressive Symptoms Are Different Sadness is not a major symptom Feeling empty

Hopeless, cranky, nervous, or guilty for no reason Sudden lack of enjoyment in favorite pastimes Sleep problems

Fatigue or Insomnia Loss of concentration Loss of memory Eating too much/ little Headaches Increased aches & pains GI / digestive issues Elderly Depression A Different Presentation

Psychosis Delusions: Paranoia Hallucinations: Primarily auditory Psychomotor disturbance Agitation Slowing Depression Risk Factors Genetics Past depressive episodes / BPD Stress

Death of family / friends; lack of support Financial issues Co-Morbidities 80% of older adults have at least 1 chronic disease state, 50% > 2 Heart disease, CVA, cancer, COPD, ETOH or drug use PAIN & disability; dementia Depression By Co-Morbidity

Post CVA: 25% to 50% Alzheimers Disease: 20% to 25% Cancer: 18% 39% Parkinsons disease: 10% 37% Rheumatoid arthritis: 13% Diabetes: 5% 11% Myocardial infarction: 15% 19%

Cardiology Recommendations: Depression Screening American College of Cardiology & American Heart Association ST-segment elevation MI Screen - while hospitalized, 1 month after hospital discharge, then yearly Depression in hospital after MI Significant predictor of 1-year cardiac mortality for both men & women Significantly more likely to die of cardiac causes & have arrhythmic episodes than patients without

depression CDC Statistics & Elder Suicide Highest rates of suicide of any age group Particularly among men Highest: Over age 85 70% see PCP within a few months of suicide > 1/3 within the week Elderly Suicide Attempts 1 in 5 elderly suicide attempts are successful Firearms

Hanging Drowning Not being included - "silent suicides Overdoses, self-starvation or dehydration, "accidents" Double suicides involving spouses or partners occur most frequently Assessment Tool For Suicide Risk S Male Sex A Age (young/elderly) D Depression P

E R S O N S Previous attempts ETOH Reality testing (Impaired) Social support (lack of) Organized plan No spouse

Sickness Why Higher Risk Depression? Vascular depression hypothesis Cerebrovascular disease can predispose, precipitate, or perpetuate depression Hypertension, diabetes, coronary artery disease, CVA Silent stroke Lesions / scar tissue impairing linkage basal ganglia and prefrontal cortex Delirium & Hospitalization

85 % of ALL hospitalized adults Regardless of cause, can persist months after discharge 2013 Study: 80% (ages 18 to 99) scored lower on cognitive testing than age & education would have predicted Nearly two-thirds had scores similar to patients with traumatic brain injury or mild Alzheimers disease Only 6% cognitively impaired before hospitalization 1 in 4 discharged ICU patients displayed PTSD symptoms, a rate similar to that of combat veterans or rape victims ICU night sound reduction by using earplugs: decreased

risk of delirium by 53% Vascular Depression Hypothesis MRI Atrophy of hippocampus PTSD, depression, dementia Atrophy of prefrontal cortex & amygdala regions Controls cognition, mood, anxiety Ischemic changes Directly related to length of illness Brain-Derived Neurotrophic Factor (BDNF)

Supports survival of existing neurons, encourages growth & differentiation of new neurons & synapses Highly active in hippocampus, cerebral cortex, basal forebrain Areas vital to learning, memory, higher thinking Important for long-term memory Also secreted by contracting skeletal muscle plays role in muscle repair, regeneration, differentiation Vascular Depression Hypothesis Glucocorticoids (Stress) Cause neuronal atrophy and retraction of dendritic processes in hippocampus (very high

levels of GC receptors) Down regulate BDNF Influences neuronal survival, differentiation &synaptic strength Continuous electrical activity required to maintain synaptic connections with other neurons (use-it-or-lose-it), downshift is part of the shrinking of connections The Chemical Imbalance and Possible Symptoms

Medications Linked to Depression Antipsychotics Digoxin Hydralazine

- Beta blockers - Stimulants - PPI & H2 blockers Efavirenz (HIV AV) - Corticosteroids Antineoplastic agents - Benzodiazepines Anti-Parkinsons agents Statins Hormone-altering drugs - Anticonvulsants Triptans - Anticholinergic drugs Diagnostics

Scales Geriatric Depression Scale Cornell Depression Scale for Dementia TSH, B12, etc Medication Review Ask about suicide thoughts & plans Treatment Options Factors to Consider in Choosing an Antidepressant Medication Safety, tolerability, cost

Ease of administration Daily number of doses Titration schedule Patient preference Nature of prior response to medication Co-occurring psychiatric or general medical conditions Anticipated Adverse Effects Potential drug interactions Half-life

Where To Start Doses Start Low Go Slow BUT GO SOMEWHERE Selective Serotonin Reuptake Inhibitors (SSRIs) Generally first line of treatment Efficacy essentially equal across class Major differences in tolerability / pharmacokinetics Each SSRI has slightly different pharmacological / pharmacokinetic profile

Different half lives, durations, potencies, etc Different effects on other neurotransmitters Possible distinct clinical activity, side effects, interactions SSRIs Examples of subtle differences Prozac: Fluoxetine Least selective, affects norepinepherine & dopamine, activating @ higher doses, long half life Useful in tapering off SSRIs

More likely to induce mania Zoloft: Sertraline Slight affect on dopamine, may improve energy, motivation, concentration, hypersomnia Only slight CYP2D6 More GI side effects max absorption with food SSRIs Examples of subtle differences Paxil: Paroxetine Mild central anticholinergic action Increased somnolence, calming

Cognitive dulling Inhibits Nitric Oxide Synthetase Inc erectile dysfunction Shortest half-life More weight gain issues Celexa: Citalopram Nausea; QT risk over 20 - 30mg daily Well tolerated without relevant CYP 450 SSRIs Examples of subtle differences Lexapro: Escitalopram

Active (S) isomer of citalopram Most serotonin selective = more rapidly effective More effective than citalopram in acute response & remission QT prolongation with higher doses SSRIs - Side Effects Cardiovascular Orthostatic hypotension, mild bradycardia, conduction abnormalities - QT interval prolongation Gastrointestinal

Nausea, vomiting, dyspepsia, anorexia, diarrhea CNS Nervousness, akathisia, bruxism, insomnia, headache, tremor, somnolence, fatigue, cognitive dulling Sexual Decreased libido, delayed orgasm, anorgasmia SSRIs - Side Effects Weight gain or weight loss Increase risk of bleeding!! May affect platelet activity Uterus & GI tract most likely Caution with surgery, other meds

SIADH (hyponatremia) Very common in older adult & those receiving diuretics Reverses after SSRI discontinuation Fractures & Daily SSRI Use Multiple studies double risk of fractures Spine Hip 2017 study Talwin: 11 yrs 10,000 subjects 2-fold increase in risk of clinical fragility fracture in patients older than 65 yrs

An increased risk of falling and lower bone mineral density at the hip Potential Drug Interactions: Pharmacokinetic - Inhibitor fluoxetine & paroxetine: CYP2D6 inhibitors risperidone, aripiprazole, brexpiprazole, iloperidone, nebivolol, metoprolol, linezolid, dextromethorphan, atomoxetine, bupropion Prodrugs: tamoxifen, codeine, tramadol, hydrocodone

fluoxetine CYP 2C9/19 & 3A4 Phenytoin, warfarin sertaline mild inhibitor of CYP 2D6 Potential Drug Interactions: Pharmacodynamic Serotonin Syndrome Additive with other serotonin enhancers: Other antidepressants, meperidine, methadone, tramadol, tapentadol,1st gen antihistamines, lithium, buspirone, triptans, dextromethorphan, St Johns wort, etc

Bleeding Combination with anticoagulant medications may increase risk- also NSAIDs or other GI irritants Atypical Antidepressants Dopamine / Norepinephrine Reuptake Inhibitor bupropion - Wellbutrin Serotonin / Norepinephrine Reuptake Inhibitor

Venlafaxine - Effexor duloxetine - Cymbalta desvenlafaxine Pristiq levomilnacipran Fetzima (more NSRI) 2 + Histamine antagonist mirtazapine Remeron bupropion (Wellbutrin) Affects DA > NE reuptake (activating) Also partial agonist nicotinic Ach receptors Little to no effect on serotonin

No benefit in anxiety Slow onset Best benefit Lethargy, fatigue, or daytime Can be added to SSRI due to different neurotransmitter actions Non-additive side effects bupropion Less nausea, diarrhea, somnolence, and sexual dysfunction than SSRIs

Insomnia, agitation, tremors, sweating Weight loss Lowers seizure threshold Dopamine activity may exacerbate psychosis in schizophrenia / agitated states Inhibitor of CYP2D6 caution with adding to fluoxetine or paroxetine SNRIs

venlafaxine (Effexor) desvenlafaxine (Pristiq) duloxetine (Cymbalta) levomilnacipran (Fetzima) AE similar to SSRIs & include Sweating, tachycardia, urinary retention Should be avoided in uncontrolled hypertension as may cause dose-dependent increases in diastolic blood pressure venlafaxine (Effexor)

Low dose (< 75 mg/day) Serotonin effects predominate Comparable to SSRIs in efficacy and AE Higher doses (150 - 375 mg/d) Norpinepherine effects dominate Comparable to adding 2o TCA to an SSRI Hypertension (BP needs to be monitored) Weight loss . Agitation Short half life even in XR forms CYP2D6 substrate: caution with inhibitors, impaired hepatic function & poor metabolizers 2D6

desvenlafaxine (Pristiq) Active metabolite of venlafaxine 70% of benefit from venlafaxine due to metabolized into desvenlafaxine Developed for depression & vasomotor symptoms of menopause Unlike venlafaxine, no involvement of CYP450 2D6 for clearance Reduction of few potential interactions No genetic variability in clearance duloxetine (Cymbalta)

Increases serotonin and norepinephrine Similar to venlafaxine, more balanced Inhibition of reuptake of both serotonin & NE is balanced throughout dosing range Approved for Diabetic Neuropathy, Fibromyalgia, musculoskeletal pain, GAD Off label: stress incontinence Less likelihood of hypertension Compared to venlafaxine duloxetine

Adverse Effects Most Common Nausea (20%), somnolence (20%), insomnia, and dizziness Others Muscle spasm / jerking (legs), decreased appetite, weight loss, fatigue, paresthesias Erectile dysfunction Mostly Men: Decreased libido, anorgasmia, urinary dysfunction duloxetine Contraindicated with ESRD

No dose adjustments for mild renal impairment. Moderate liver impairment:Child-Pugh Class B Doses of only 20mg Plasma clearance reduced (up to 85%) AUC increased up to 5-fold Half-life tripled Cymbalta contraindicated any evidence of hepatic insufficiency duloxetine Pharmacokinetic

CYP1A2 Inhibitors Cipro fluvoxamine CYP1A2 Inducers: Cigarette or cannabis smoke Cabamazepine Omeprazole Increase risk of adverse effects from duloxetine Increased

clearance Decr efficacy Bioavailability dec 33% in smokers Levomilnacipran: Fetzima Almost selective for NE Like adding tricyclic antidepressant onto SSRI May be advantageous Prominent fatigue Anergia

More pronounced functional impairments Treatment emergent sexual dysfunction From serotonin medications Patients not responding to or intolerant of SSRIs Levomilnacipran Common SE Irritability, constipation, tachycardia, palpitations, vomiting Dose-related: urinary hesitation, erectile dysfunction Interactions

Strong CYP3A4 inhibitor: Do not exceed 80 mg/day Serotonin Syndrome with other serotonin meds Caution Renal impairment dose adjustment mirtazapine (Remeron) Weak antidepressant at lower doses Better with anxiety, weight loss, sleep Blocks histamine (H1 receptors) 7.5mg & 15mg Blocks serotonin

30mg & 45mg mirtazapine (Remeron) Side effects, cautions, interactions Weight gain, sedation at lower doses Increased risk of falls Elimination half-life ranges 20 - 40 hours Dosage increases every 714 days Additive with other serotonin drugs serotonin syndrome Cleared by CYP 1A2, 2D6, 3A4 Potential pharmacokinetic interactions

Inc risk QTc prolongation with other Qt meds Antidepressant Augmentation Antipsychotics May reduce anxiety, agitation, psychotic symptoms May mood FDA Approved as adjunct Aripiprazole (Abilify) 2 5 mg/d Brexpiprazole (Rexulti) 0.5 3 mg/d Increases Dopamine activity Also partial agonist at 5 HT1A receptors Quetiapine (Seroquel) 150-300 mg/day

Folate and Depression 30% achieve remission with antidepressants alone Augmentation with other drug classes is accepted and effective strategy Costdrug interactionsAE Folate needed in pathway for production of serotonin, norepinephrine & dopamine Must be converted to methylfolate 50% of population have efficient conversion 40% convert only a limited amount of folate

10% of population lack enzyme activity Folate Options OTC folic acid supplements (up to 400 mcg/ day) might be worth a trial before going to augmenting Methylfolate products may be an option if folic acid is not effective No definitive evidence it works better just hypothetically Much more expensive than simple folic acid Depression:

Treatment Response in Older Adult Time to full response longer May require up to 8 to 12 weeks For a first-time depressive episode Treatment for up to 2 years may be required For 3 or more episodes Lifelong maintenance treatment may be needed Dosage reduction may lead to relapse; thus dosages to which patients respond should be maintained

Increased Suicide Risk With Treatment One study found suicide risk in men over age 66 in first month of antidepressant therapy to be 5-fold higher with SSRIs than with other antidepressants No difference in risk was observed in the second month or subsequent months of treatment Increased Suicide Risk With Treatment Temporal disparity

increases motivation, energy, side effects (ie., akathisia) prior to benefit on mood Effects on synaptic neurotransmitters (hours days) Experience of side effects (hours days) Therapeutic Benefit (8-12 weeks) 0 1 2

3 Weeks 4 5 6 7

Electroconvulsive Therapy Response rates from 70-90% Most efficacious antidepressant Contraindication: ICP, intracranial tumors 3x/wk with avg number of treatments 8-12 may need maintenance Side effects: Short term memory loss

If two trials of antidepressants have failed, ECT becomes a first-line option Especially effective for depression exhibiting psychotic features, not responded to antipsychotics and antidepressants Psychotherapy A MUST May include Cognitive-behavioral therapy Supportive psychotherapy Problem-solving therapy Interpersonal therapy Mindfulness

Increased exercise & exposure to bright light have also shown benefit in the depressed elderly population In Conclusion Remember to screen Make sure youre treating the right thing! Depression, bipolar, schizophrenia Start low, go slow. BUT GO Dont be afraid to push doses or add adjunct medications while watching for AE Follow up & encourage support

Thanks for listening!! Take some time to enjoy today!! Jody

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