Pharmacologic Treatment of Depression · Objectives 3 1. Describe the common pharmacologic agents used to manage depression in the elderly population. 2. Discuss the efficacy, safety

Linda Sobeski Farho, PharmD, BCPSAssistant Professor, Pharmacy Practice

UNMC College of Pharmacy

Critical Issues in GeriatricsJune 24, 2010

Pharmacologic Treatment of Depression

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Disclosure

I have no conflicts or commercial interests related to this presentation

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Objectives

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1. Describe the common pharmacologic agents used to manage depression in the elderly population.

2. Discuss the efficacy, safety and tolerability of common pharmacologic agents used to manage depression in the elderly.

3. Examine the appropriate selection of antidepressant therapy for an elderly patient with specific symptoms and/or co-morbidities.

Goals of AD Therapy in the Elderly

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Symptom improvement Therapeutic response (50% decrease in symptoms) Therapeutic remission (asymptomatic) Reduction in disability Improved functional status Improved quality of life

Complications: Relapse: ↑ in symptoms within 6 months of remission Recurrence: new episode >6 months after remission Resistance: no to partial response to trial of 2 or more

antidepressants

Rajji TK, Mulsant BH, Lotrich FE, et al. Use of antidepressants in late life depression. Drugs Aging 2008: 25(10):841-853.

Pharmacology

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Biochemical theory Antidepressant drugs work by: Increasing serotonin Increasing norepinephrine Increasing both

Influence of Age on AD Therapy

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Altered drug pharmacokinetics: Decreased rates of drug absorption and onset of action Increased elimination half-life of drugs Alterations in plasma protein binding Variable decrease in hepatic clearance Decreased renal clearance of active metabolites


Presenter

Presentation Notes

Decreased gastric acid, decreased GI motility, decreased intestinal blood flow, decreased intestinal villous surface area Increased body fat, decreased lean body mass, decreased extracellular water volume Decreased liver blood flow and mass Decreased renal blood flow, decreased GFR, decreased tubular secretion

Influence of Age on AD Therapy

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Altered receptor sensitivity or neurotransmission: Decreased baroreceptor reflex Increased serotonergic extrapyramidal effects Increased incidence of SIADH ↑ Noradrenergic effects of medication ↑Anti-adrenergic effects of medication ↑Anticholinergic effects of medication


Presenter

Presentation Notes

Noradrenergic: Dry mouth, urinary retention, tachycardia, hypertension Antiadrenergic: Bradycardia, CHF exacerbation, hypotension Anticholinergic: Constipation, urinary retention, delerium

Principles of Drug Selection

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Changes in pharmacokinetics and pharmacodynamics Comorbid medical and psychiatric conditions Concomitant drug therapy Expected side-effect profile Previous response to therapy (if known) Cost of therapy or formulary restrictions

Special Considerations in the Elderly

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All antidepressants are equally efficacious SSRIs are first line due to improved tolerability Start low and go slow Dose adjustment in renal impairment: mirtazapine Fewer drug interactions with: Citalopram, escitalopram, sertraline, venlafaxine,

mirtazapine Compliance may be difficult to achieve Response time may be longer in elderly: >6-12 weeks Higher risk of relapse in elderly: continue >2 years

after remission

Pre-Pharmacotherapy Evaluation

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History and physical Blood pressure (include orthostatic measurements) Liver and renal studies Electrocardiographic findings Left bundle branch block, bifasicular block, second-

degree AV block, QT prolongation, atrial fibrillation

Medications Associated with Depression

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Class Drugs

CNS Agents Benzodiazepines, alcohol, levodopa, amantandine, major tranquilizers, stimulants (rebound)

Cardiovascular agents β-blockers, clonidine, methyldopa, prazosin, digitalis, procainamide, thiazides, hydralazine

Chemotherapeutics Vincristine, vinblastine, L-asparaginase, azathioprine, bleomycin, cisplatin, cyclophosphamide interferon, tamoxifen

Steroids Prednisone, estrogen agents

Anticonvulsants Primidone, phenytoin, phenobarbital, carbamazepine, ethosuximide

Others Cimetidine, non-steroidal anti-inflammatory agents (NSAIDs), disulfiram, phenylephrine

Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Physician 2004;69:237-2382.

Drug Classes for Depression

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Class Drugs

SSRIs fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine

SNRIs venlafaxine, desvenlafaxine, duloxetine

TCAs Tertiary amines: amitriptyline, doxepin, imipramine, Secondary amines: desipramine, nortriptyline

MAOIs phenelzine, tranylcypromine, selegiline

Others mirtazapine, bupropion

Selective Serotonin Reuptake Inhibitors

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First-line therapy due to safety and tolerability Low potential for fatal overdose Low incidence of anticholinergic and sedative effects Little to no influence on cognition Few adverse cardiovascular side effects

Once daily dosing Effective for mood and anxiety Common adverse effects:

Nausea (slow titration, take with food) Diarrhea Anxiety Sleep disturbance Headache Sexual dysfunction (15-30%)

Other ADEs of SSRIs in Elderly

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Platelet dysfunction and gastrointestinal bleeding Apathy Anorexia Extrapyramidal symptoms Hyponatremia and SIADH (12-25%) Serotonin syndrome TCAs, MAOIs, tramadol, dextromethorphan, meperidine

Draper B, Berman K. Tolerability of selective serotonin reuptake inhibitors: issues relevant to the elderly. Drugs Aging 2008;25(6):501-519.

Presenter

Presentation Notes

Hyponatremia: usually develops within the first few weeks of therapy, but may take months to develop; usually resolves within 2 weeks of drug discontinuation. Factors associated with the development of SSRI-induced hyponatremia include older age, female gender, concomitant use of diuretics, low body weight, co-morbid medical illnesses and lower baseline serum sodium level.

SSRIs

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Drug Dose (mg/d) Comment

Fluoxetine 10-60 Long half-life, once weekly dose available;many drug interactions; insomnia, wt loss, agitation, EPS; available in liquid; Beers list

Sertraline 50-200 Insomnia, EPS

Fluvoxamine 100-300 Many drug interactions; anticholinergic effects, wt loss; less sexual dysfunction

Citalopram 20-60 Available in liquid; less EPS/bleeding risk

Escitalopram 10-20 Limited dosing range

ParoxetineParoxetine CR

20-50 Many drug interactions; anticholinergic effects (dose dependent), EPS, sedation; available in liquid; withdrawal symptoms common

Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Phys 2004;69:2374-2382.


Selective Serotonin/NE Reuptake Inhibitors

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First or second-line therapy Dual mechanism Effective for mood and anxiety May be useful in treatment resistant depression Risk of serotonin syndrome combined with certain drugs Common adverse effects: Nausea Irritability Insomnia Sexual dysfunction Tremor

SNRIs

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venlafaxine 75-225 Dose dependent hypertension; available in XR

duloxetine 20-60 Many drug interactions; FDA: peripheralneuropathy



Tricyclic Antidepressants (TCAs)

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Effective and inexpensive Beneficial in neuropathic pain Poorly tolerated in elderly due to extensive ADEs NOT first line therapy High fatality risk with overdose (cardiotoxicity) Common adverse effects: Sedation Cardiac conduction abnormalities Decreased seizure threshold Anticholinergic effects Orthostasis Confusion Weight gain

TCAs

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Desipramine 100-200 Less anticholinergic effect, less sedation

Nortriptyline 75-125 Less anticholinergic effect, less orthostasis



Unutzer J. Late-life depression. NEJM 2007;357;2269-2276.

Monoamine Oxidase Inhibitors

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Tranylcypromine, phenelzine, selegiline Side effect profile limits use in older adults Numerous drug-drug and drug food interactions Must comply with tyramine-free diet No diet restriction with selegiline at lower doses

Meperidine, narcotics, decongestants

Reserved for treatment resistant depression (3rd line) Prescriber should be experienced with MAO-I use Adverse effects: Orthostasis

Bupropion

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↑ Activity of dopamine and NE Generally safe and well-tolerated Dosage range: 200-300mg/d Available in SR and XL forms Useful in patients with lethargy, sedation, fatigue May be helpful in smoking cessation Lacks sexual side effects and weight gain Low risk of overdose Adverse effects:

Seizures Irritability, anxiety, agitation Insomnia GI symptoms

Mirtazapine

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Serotonergic at low doses; noradrenergic at higher doses

Dosage range: 15-45mg/HS Available in sublingual form Lacks sexual side effects Lacks significant drug interactions Low doses (<30mg): sedation & appetite stimulation Clearance reduced in renal impairment

Trazodone

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Not recommended as a primary antidepressant Adverse effects: Sedation Orthostasis Priapism (rare)

Low doses (25-50mg/HS) may be useful for insomnia

Stimulants

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Methylphenidate, dexamphetamine, modafinil Data suggest usefulness in specific patient groups Terminally ill patients Medically ill elderly patients Apathy

Potential advantages: Accelerated response Energizing effect

Adverse effects: insomnia, anxiety, tachycardia, hypertension, tremor, HA, anorexia, wt loss, GI disturbances

Hardy SE. Methylphenidate for treatment of depressive symptoms, apathy, and fatigue In medically ill older adults and terminaly ill adults. Am J Geriatr Pharmacother 2009;7(1):34-59.

Target Sx and Comorbidity Considerations

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Symptom/Comorbidity Drug Selection

Anxiety SSRI or SNRI

Insomnia Mirtazapine

Psychomotor retardation Bupropion or stimulants (methylphenidate)

Weight loss Mirtazapine

BPH Avoid TCAs

Dementia SSRIs or venlafaxine; avoid TCAs and paroxetine

Parkinson’s disease Venlafaxine, bupropion; avoid TCAs, MAOIs, possibly SSRIs (if with MAOB-I)

Seizure disorder Avoid bupropion, TCAs

Neuropathic pain Duloxetine

Cardiac disease SSRIs, bupropion; avoid TCAs, SSRIs + Icantiarrhythmics, venlafaxine in HTN

Cost Considerations

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Drug Generic $4 Geriatric Considerations

Fluoxetine Yes Y Long half-life, drug interactions

Sertraline Yes N

Paroxetine Yes Y Drug interactions, ADEs

Citalopram Yes Y Well tolerated

Escitalopram No N

Venlafaxine Yes N

Duloxetine No N Indication for neuropathic pain

Desvenlafaxine No N

Mirtazapine Yes N Sedation, weight gain

Bupropion Yes N Seizure risk

Medication Adherence

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Non-adherence rate is as high as 40-75% Factors associated with non-adherence Attitudes, perceptions, preferences Beliefs about etiology of depression/treatment Patient/provider communication Cognitive impairment Substance abuse Polypharmacy Cost of treatment Social support Gender/race

Zivin K, Kales HC. Adherence to depression treatment in older adults: a narrative review. Drugs Aging 2008;25(7):559-571.

Patient Aversion to AD Therapy

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Fear of dependence Resistance to viewing depressive symptoms as a

medical illness Concern that antidepressants will prevent natural

sadness Prior negative experiences with medications for

depressions

Givens, JL, Datto CJ, Ruckdeschel K, et al. Older patients’ aversion to antidepressants: a qualitative study. J Gen Intern Med 2006;21:146-151.

Presenter

Presentation Notes

Many patients express a fear of becoming dependent upon antidepressant medications. In addition to a global concern of dependence, there were two worries that seemed particularly relevant to antidepressants. One of these was the concern of needing prolonged treatment. The attribution of depression to social causes, such as stress, bereavement, medical concerns, etc., may led to a resistance to pharmacologic treatment. In other words, the medication is not seen as addressing the root cause of the depression, an thus was not valued. Patients were concerned that medication would take away their reality and make them unnaturally happy. For these depressed elders, the themes of loss were common, and the experience of geniune sadness was valued and seen as an appropriate normal occurrence. Furthermore, some patients did not want to be too happy, as this might connote betrayal or create distance from others. Some patients described taking medication in the past, with troublesome side effects, particularly related to sedation. This resulted in a refusal to accept treatment.

Neutraceuticals for Depression

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St. John’s Wort American ginseng Siberian ginseng Gotu kola Lavendar Schisandra Ginkgo biloba

St. John’s Wort

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Hypericin inhibits monoamine oxidase Hypericin and hyperforin inhibit serotonin reuptake Effective in mild to moderate depression Numerous drug interactions ↓Drug levels of: statins, TCAs, warfarin, nifedipine,

cyclosporine, oral contraceptives, protease inhibitors, theophylline, digoxin

↑ Drug effect of: beta-2 agonists, benzodiazepines, SSRIs

Phototoxicity

Summary

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Pharmacotherapy is effective in treating depression in older adults

Goals of therapy are to achieve remission, improve functional status, and improve quality of life

Drug selection in the older population is largely based on pharmacokinetics/pharmacodynamics, co-morbid conditions, concomitant drug therapy, drug side effect profiles, previous response to therapy, and cost

Trade Name Conversion

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Drug (Trade) Drug (Trade)

Fluoxetine (Prozac) Amitriptyline (Elavil)

Sertraline (Zoloft) Nortriptyline (Pamelor)

Citalopram (Celexa) Desipramine (Norpramin)

Escitalopram (Lexapro) Doxepin (Sinequan, Adapin)

Fluvoxamine (Luvox) Imipramine (Tofranil)

Paroxetine (Paxil) Clomipramine (Anafranil)

Venlafaxine (Effexor) Phenelzine (Nardil)

Desvenlafaxine (Pristiq) Tranylcypromine (Parnate)

Duloxetine (Cymbalta) Selegilene (Emsam)

Bupropion (Wellbutrin) Methylphenidate (Ritalin and others)

Trazodone (Desyrel)

Nefazodone (Serzone)

Questions

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Pharmacologic Treatment of Depression · Objectives 3 1. Describe the common pharmacologic agents used to manage depression in the elderly population. 2. Discuss the efficacy, safety