1 pharmacotherapy of depression and anxiety vickie corbett ripley, pharmd, bcpp clinical pharmacist...

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Pharmacotherapy of Depression and Anxiety

Vickie Corbett Ripley, PharmD, BCPP

Clinical Pharmacist Practitioner

Coastal Plain Hosptial

Rocky Mount, NC

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Pharmacotherapy for Major Depression

Etiology and Pathophysiology Diagnosis and clinical presentation Antidepressant efficacy

and side effects Treating major depression Special Populations Other treatment options Drug interactions

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Limbic System Dysfunction

4

Spectrum of Psychiatric Disorders

ANXIETY

AFFECTIVE

PSYCHOSES

Panic disorderGADOCDAgoraphobia

Major DepressionBipolar DisorderDysthymia

SchizophreniaSchizoaffective

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Anxiolytics

Norepinephrine

Anti-Psychotics

Dopamine

Anti-Depressants

Serotonin

Neurotransmitters and Psychiatric Pharmacotherapy

GABA, others

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Phases of MDD Treatment

Severity

Time

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Recurrence After Recovery from Major Depression

n = 555 Unipolar Depressives (1985-1994)

The NIMH Collaborative Depression Study, 1977-1992

15

33

4654

60 6167 70 73 74 75

0

25

50

75

100

0.5 1 2 3 4 5 6 7 8 9 10

Cumulative Probability of Recurrence, %

Time to Recurrence, years

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Diagnosis of mental illnessDiagnosis of mental illness

DSM IV (Diagnostic and Statistical Manual of Mental Disorders – 4th edition)– Lists criteria necessary to meet diagnosis

– Useful for standardizing diagnoses

To meet most diagnoses generally must– Interfere with social or occupational functioning

– Must be interpreted in context of culture

DSM IV (Diagnostic and Statistical Manual of Mental Disorders – 4th edition)– Lists criteria necessary to meet diagnosis

– Useful for standardizing diagnoses

To meet most diagnoses generally must– Interfere with social or occupational functioning

– Must be interpreted in context of culture

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Multiaxial AssessmentsMultiaxial Assessments

Axis I – Clinical Disorders Axis II – Personality disorders and

mental retardation Axis III – General medical conditions Axis IV – Psychosocial and

Environmental problems Axis V – Global assessment of

functioning (GAF)

Axis I – Clinical Disorders Axis II – Personality disorders and

mental retardation Axis III – General medical conditions Axis IV – Psychosocial and

Environmental problems Axis V – Global assessment of

functioning (GAF)

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Axis I disordersAxis I disorders

Mood disorders– Major depressive disorder

– Bipolar disorder

Anxiety disorders– Generalized anxiety disorders

– Panic disorder

– Social phobia

– Obsessive Compulsive Disorder

Psychotic disorders - schizophrenia

Mood disorders– Major depressive disorder

– Bipolar disorder

Anxiety disorders– Generalized anxiety disorders

– Panic disorder

– Social phobia

– Obsessive Compulsive Disorder

Psychotic disorders - schizophrenia

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DSM IV Classification of Major Depressive Episode

Depressed mood and/or loss of Interest present during a two week period

Plus at least FOUR of the following symptoms:– Weight change

– Sleep disturbance

– Psychomotor agitation or retardation

– Loss of energy

– Feelings of worthlessness/guilt

– Loss of ability to concentrate

– Suicidal ideations

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Psychiatric Patient Presentation

Chief Complaint History of Present Illness Past Medical History Family and Social Histories Medications Allegies Review of Systems

Physical Examination Mental Status Exam

– Appearance, behavior, and speech

– Mood and Affect

– Sensorium

– Intelligence

– Thought process

Labs

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Symptoms of Depression and Serotonin Function

Depressed or elated Mood Appetite changes Sleep changes Decreased libido Increased pain sensitivity Circadian rhythm disturbances Body temperature changes

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Physical and Social Functioning in Depression and Chronic Illness

None Hyper-tension

Diabetes Arthritis AnginaOnly

CAD Depres-sion

0

10

20

30

40

50

60

70

80

90

100

Perc

ent o

f Per

fect

Fun

ctio

ning

None Hyper-tension

Diabetes Arthritis AnginaOnly

CAD Depres-sion

Physical Function Social Function

Wells, et al. J Amer Med Assoc 1989; 262:914-919

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Symptoms of Depression (Sig: E caps)

S Sleep

I Interest

G: Guilt

E Energy

C Concentration

A Appetite

P Psychomotor retardation

S Suicidality

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Treatment choices

Psychotherapy Light Exercise Diet Medication Medication and Psychotherapy Electroconvulsive therapy (ECT)

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Psychotherapies

Interpersonal therapy Cognitive therapy Behavior therapy Group therapy

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Psychotherapy

Less severe Less chronic Nonpsychotic Previous positive response Medical contraindication to medication

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Algorithm for Treatment of Uncomplicated Major Depression

1st line: Favorite SSRI or TCA – Failed trial: switch to alternative

– Partial response - increase dose, switch or augment

– Fully remits (maintain at least 4 to 6 months or longer)

2nd line: Switch or Augment– Switch to other favorite - TCA or SSRI

– Augment with Li or TCA plus the SSRI (consult with psychiatrist)

3rd line: Failed or Partial response to 2nd line– Consult with psychiatrist

– Switch (nefazodone, mirtazepine, bupropion, venlafaxine)

– Augment with Li or TCA plus the SSRI

Adapted from Kando JC et al: in Pharmacotherapy, 4th ed, Dipiro, eds., 1999, p 1156

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Target Symptoms and Therapeutic Response Rates

Week One:– anxiety

– insomnia

– decreased appetite

Weeks two and three:– increase in energy

– increase suicide risk

– increase in libido

Up to 4 to 8 Weeks:– Improvement in

dysphoria or sadness

– improvement in pessimism

– improvement in anhedonia

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Treatment strategies if no response Confirm compliance Maximize dose Change drug Combine antidepressants Augmentation therapy

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Augmentation medications

Lithium AED’s Stimulants Thyroid Estrogen Sleep aids Pain meds

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Melancholic Depression

Clinical Presentation–Subtype of severe depression–Nearly complete absence of capacity for pleasure–Diurnal mood swings (worse in the morning)–Excessive guilt and weight loss

Unclear if SSRI’s as effective as TCA’s in treatment

Some data indicate that mirtazapine and venlafaxine more effective than SSRI’s

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Atypical Depression

Clinical Presentation–Weight gain or increased appetite–Hypersomnia–Heavy feeling in arms or legs (leaden

paralysis)–Interpersonal rejection sensitivity

MAOI’s greater efficacy than TCA’s

Efficacy of SSRI’s relative to MAOI’s unclear

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MDD with psychotic features

Clinical Presentation:–Delusions or hallucinations present

during depressive episodes

Usually need an antidepressant and an antipsychotic

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Differentiation Between Depression and Dementia

Area Depression Dementia Depression history (self/family) Present Absent Depression symptoms precede

cognitive deficit Present Absent Duration of Symptoms Weeks Months-Years Cognitive Deficit Complains Silent Concern Cognitive Function Test

Performance deficits Inconsistent Consistent Response to MSE questions "I don't Know" Attempts to

answer Effort on Testing Little Tries hard

Baker FM. J National Med Assoc 1991; 83:340-344

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AnxiolyticsBenzodiazepines Anti-

PsychoticsPhenothiazinesButyrophenonesAtypicals

Anti-Depressants TricyclicsMAO InhibitorsSSRIsMood Stabilizers

Psychiatric Pharmacotherapy

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Serotonin receptors

5-HT 2– agitation

– akathisia

– anxiety

– panic attacks

– insomnia

– sexual dysfunction

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Serotonin receptors

5-HT 3– nausea

– gastrointestinal distress

– diarrhea

– headache

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Dopamine receptors

Stimulation can lead to – agitation

– aggravation of psychosis

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Norepinephrine receptors

Stimulation can lead to– activation

– hypertension

– panic

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Alpha 1 adrenergic receptors

Blockade can lead to– dizziness

– orthostatic hyotension

– reflex tachycardia

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Histamine receptors (H1)

Blockade can lead to– sedation

– weight gain

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Muscarinic cholinergic receptors Blockade can lead to

– blurred vision

– dry mouth

– sinus tachycardia

– constipation

– urinary retention

– memory impairment

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Medications

TCA MAOI SSRI SNRI (venlafaxine) NDRI (buproprion) NaSSA (mirtazipine) SARI (nefazadone)

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SSRI and New AntidepressantsMetabolism

Drug T½, h ActiveMetab

MetabT½

Time toSS, days

Non-Linear

Fluoxetine 45-137 Yes 200-250 20-45 Yes

Sertraline 26 Yes 62-104 5-15 DMSert

Paroxetine 21 --- No 4-10 Yes

Fluvoxamine 15 --- No 3-4 Yes

Venlafaxine 4-6 Yes 9-11 3 No

Nefazodone 2-4 Yes 18 3-4 Yes

Mirtazapine 20-40 --- No 5-10 No

Citalopram 35 Yes 49 7-17 No

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Antidepressant Side Effects Drug Sedation Anticholinergic Orthostatic Amitriptyline ++++ +++ ++++ Doxepin ++++ +++ +++ Nortriptyline +++ +++ ++ Desipramine ++ ++ +++ Trazodone +++ - +++ Bupropion - + - Fluoxetine -/+ - - Sertraline -/+ - - Paroxetine ++ + - Venlafaxine +/++ + + Nefazodone ++ + + Mirtazapine ++++ ++ +

Adapted from: MJ Dewan et al J Geriatr Psychiat Neurol 1992; 40-44

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Single mechanism drugs

Mostly noreinephrine– desirpramine

– buproprion

Mostly serotonin– SSRI’s

– nefazadone

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Serotonin reuptake Inhibition Norepinephrine reuptake inhibition Anticholinergic effects Alpha1 blockade Histamine blockade

Tricyclic Antidepressants

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Tricyclic Antidepressants

Useful in the treatment of a number of conditions–Depression

–Migraine prophylaxis

–Neuropathic pain

–Obsessive compulsive disorder (Clomipramine)

–Enuresis

–Panic disorder

–Sleep disorders

–Attention deficit / hyperactivity disorder

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Tricyclic Antidepressants

Clomipramine (Anafranil) 25-250mg Amitriptyline (Elavil) 50-300mg Doxepin (Sinequan) 25-300mg Imipramine (Tofranil) 30-300mg Desipramine (Norpramin) 25-300mg

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Tricyclic Antidepressant

Secondary amine– Desipramine (Norpramine)

– Nortriptyline (Pamelor)

– Protriptyline (Vivactil)

Tertiary amine– Amitriptyline (Elavil)

– Clomipramine (Anafranil)

– Imipramine (Tofranil)

– Doxepine (Sinequan)

– Trimipramine (Surmontil)

Greater NE relative to 5HT activity

Greater anticholinergic effects

Greater NE relative to 5HT activity

Greater anticholinergic effects

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With most TCA’s start with 50 mg and increase by 25 to 50 mg every 3 days (lower for nortriptyline or protriptyline)

Secondary amine– Desipramine -- 100 to 300 mg– Nortriptyline -- 50 to 150 mg– Protriptyline -- 15 to 60 mg

Tertiary amine– Amitriptyline -- 100 to 300 mg– Clomipramine -- 100 to 250 mg– Imipramine -- 100 to 300 mg– Doxepin -- 100 to 300– Trimipramine 100 to 300

Secondary amine– Desipramine -- 100 to 300 mg– Nortriptyline -- 50 to 150 mg– Protriptyline -- 15 to 60 mg

Tertiary amine– Amitriptyline -- 100 to 300 mg– Clomipramine -- 100 to 250 mg– Imipramine -- 100 to 300 mg– Doxepin -- 100 to 300– Trimipramine 100 to 300

Tricyclic Antidepressant

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TCA plasma concentrations

Nortriptyline - Curvilinear conc/response profile– 50 to 150 ng/ml

Desipramine– 125 to 300 ng/ml

Imipramine– 200 – 300 ng/ml

Not routinely performed but can be useful in certain situations

Should be obtained at steady state (at least 1 week after initiating or dose change)

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TCA Adverse Events

Anticholinergic effects Antihistaminic effects Alpha1 adrenergic blockade Sexual dysfunction Cardiac conduction delays

– Can result in arrhythmias in overdose Decreased seizure threshold Toxic in overdose

– Do not use in acutely suicidal patients

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Preferred uses of TCA’s

Depression with– Pain

– Fibromyalgia

– Migraine

– insomnia

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Least preferred uses of TCA’s

Patients in whom anticholinergic effects would be problematic

Overweight patients Suicidal patients Cardiac patients Patients with dementia

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Selective Sertotonin Reuptake Inhibitors (SSRI’s)

Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro)

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Uses of SSRI’s

Depression Social phobia Panic disorder Obsessive compulsive disorder Bulimia Nervosa Post Traumatic Stress Disorder Pre Menstrual Dysphoric Disorder (Sarafem)

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SSRI Dosing

Dosing– Fluoxetine -- 20 to 60 mg– Paroxetine -- 20 to 50 mg – Sertraline -- 50 to 200 mg– Fluvoxamine -- 100 to 300 mg– Citalopram -- 20 to 60 mg– Escitalopram – 10 to 40 mg

Relatively safe in overdose Relatively safe in patients with cardiovascular

disease

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SSRI Adverse Effects

Gastrointestinal– Nausea, vomiting, diarrhea

Sexual dysfunction Headache insomnia Fatigue Agitation Akathesia and dystonic reactions

– 5HT can reduce DA levels

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Differences between SSRI’s

Most likely to cause sedation– Paroxetine, fluvoxamine

Paroxetine– Mild anticholinergic effects

Fluoxetine– Higher rates of anxiety and nervousness

Sertraline– More diarrhea

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When to use SSRI

First line monotherapy Depression Anxiety (start with low doses) OCD Panic

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Least preferred use of SSRI

Patients with sexual dysfunction Patients with secondary refractoriness Patients with nocturnal myoclonus Patients with consistent agitation Patients with consistent insomnia

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SSRI Withdrawal Syndromes

More likely to occur with short t1/2 agents (paroxetine warning)

May affect up to 1/3 of patients and more likely to be reported with short half-life agents

May be due to sudden decrease in available synaptic 5HT in face of down-regulated receptors

Onset in 24 to 72 hours and last up to 7-14 days Symptoms: dizziness, nausea, lethargy, headache,

flu-like symptoms, parasthesia (electrical “shock-like” sensations)

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Discontinuation syndrome

Worse with short acting drugs Taper dose Flu-like symptoms Anxiety GI distress Mood, appetite, sleep changes

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Serotonin Syndrome

Symptoms–Altered mental status – confusion, agitation

–Autonomic dysfunction – diaphoresis, tachycardia, BP changes, fever

–Neuromusucular abnormalities – clonus

Allow 2 weeks between MAOI and other antidepressant administration–5 weeks for fluoxetine

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Serotonin Syndrome

Occurs when several serotonergic drugs combined

Often involves MAOI’s as one of the drugs

Other serotonergic drugs implicated»SSRI’s»TCA’s»Serotonin releasing agents (i.e. MDMA or

“ecstasy”)»Dextromethorphan, meperidine, others

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Potent 5HT2 receptor antagonist Relatively weak 5HT reuptake inhibition Alpha1 receptor blockade Metabolism:

– OH-Nefazodone = 1.5 - 4 hours

– triazole-dione = 18 hours

– mCPP = 4-8 hours

Usual Dosage: 300 - 600 mg/day in 2 divided doses Preserves sleep architecture Potent CYP3A4 inhibitor

Nefazodone (Serzone, Bristol-Myers Squibb)

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Therapeutic uses of nefazadone depression in association with

– anxiety, agitation, sleep disturbances

Prior SSRI induced sexual dysfunction Inability to tolerate SSRI’s Tolerance to SSRI’s

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Lest preferred use of nefazadone Patients with hypersomnia Non-compliance with BID dosing Retarded depression Patients with difficulty with dose titration

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Dual-Action Drugs

Norepinephrine and serotonin

– clomipramine

– venlafaxine

– mirtizapine

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NaSSA

Noradrenergic and specific serotonergic antidepressant

– mirtazipine (Remeron) 15-90mg

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Mirtazapine (Remeron®, Organon) Initial Dosing:

– Start with 15mg qd (hs) (supplied as 15 and 30 mg tablets)– Average effective dose is 20-25mg qd– Maximum dose=45mg qd

Half life – Women have longer half-life than men 37 vs 26 hours– Half-life allows for qd dosing

Dosage adjustments:– Any dosage should be made after one to two weeks– Adjust dose for hepatic disease– Slow titration in the elderly

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Mirtazapine (Remeron, Organon)

Receptors: -5HT2 and 5HT3 antagonist, histamine 1, minimal activity on alpha 1, muscarinic, and dopamine

Common Side Effects: Somnolence, dry mouth, weight gain Cautions: Can precipitate mania, hepatotoxicity (dose adjust in

hepatic disease) Drug Interactions: additive cognitive and motor CNS

depression, Metabolized by CYP2D6, 1A2, 3A4,Wait 14 days after stopping MAOI

Dosing: Start with Start with 15mg qd, usually 20-25 mg qd, maximum dose = 45mg qd

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Therapeutic uses of mirtazapine Depression with anxiety or agitation Depression with insomnia Problems with SSRI’s Weight loss Severe depression Loss of response to SSRI’s

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Least preferred uses of mirtazapine Hypersomnia Motor retardation Cognitive slowing overweight

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SNRI

Serotonin/norepinephrine reuptake inhibitor

– venlafaxine (Effexor) 75-375mg

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Serotonin reuptake inhibition Norepinephrine reuptake inhibition Dopamine reuptake inhibition

Usual dose: 75 to 225 mg

Dose

Venlafaxine (Effexor, Wyeth-Ayerst)

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Therapeutic uses of venlafaxine At low doses, use as an SSRI At high doses has dual action Patients with hypersomnia Patients with GAD Patients with weight gain

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Least preferred use of venlafaxine Agitated patients Patients with sexual dysfunction Patients with insomnia Patients with labile HTN

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Venlafaxine Adverse Effects

Nausea, constipation Headache Dizziness Nervousness Somnolence Dry mouth Sexual dysfunction Increased blood pressure (monitor closely)

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NDRI

Norepinephrine/dopamine reuptake inhibitor

– buproprion (Wellbutrin) 200-450mg

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Therapeutic uses of buproprion Patients with retarded depression patients with hypersomnia Non-responders to SSRI’s Non-tolerators of SSRI’s Patients concerned about sexual dysfunction Patients concerned about weight gain Patient with cognitive slowing

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Least preferred use of buproprion Patients with seizure disorders Patients who are seizure prone Patients with head injury Patients non-compliant with multiple daily doses Patients with agitation Patients with insomnia

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Comparative Safety and Tolerability Summary

Nausea

–Common with all

–Dose related, dissipates with use Diarrhea- higher incidence with Sertraline Dry Mouth- VEN, NEF > PAR, SER > FLU, FVX Anorexia- More likely with Fluoxitine, Venlafaxine Anxiety/nervousness- More common with Fluoxitine Sexual Dysfunction- all SSRIs, Ven > Nefazodone

CL DeVane Human Psychopharmacology 1995; 10:S185-S193,

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Monoamine Oxidase Inhibitors (MAOI’s)

Used in patients with atypical MDD/ anxiety Phenelzine (Nardil) Tranylcypromine (Parnate) Hypertensive crisis can occur when combined with

high tyramine foods or sympathomimetics– Aged cheeses, sour cream, wines, beer, canned or processed meats,

fermented foods, coffee, chocolate

– Amphetamines, ephedrine, other decongestants

Doses: Phenelzine – 15 to 90 mg

Tranylcypromine – 20 to 60 mg

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MAOI adverse effects

All agents– Sexual dysfunction

– Mild anticholinergic effects

More likely with phenelzine– Orthostatic hypotension

– Sedation

More likely with tranylcypromine– Insomnia

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Drugs Metabolized by Human Liver Cytochromes P450s

Superfamily

Families

Subfamilies

Memberswith narrowtherapeuticindex

TheophyllineImipramine

(S)-WarfarinPhenytoinCarbamazepineTolbutamide

ImipramineDesipramineAmitriptylineNortriptylineThioridazine

TerfenadineCyclosporineTriazolamImipramineCarbamazepine

1

A

2

C

1A2 2C9/19

P-450

D

2D6

3

A

3A4

D. Rodrigues Pharmacogenetics Conf, May 1996

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Inhibition of Cytochromes P450 Drug 1A2 2C 2D6 3A4

Fluoxetine (Prozac)

0 ++ ++++/++++ ++/+++

Sertraline (Zoloft)

0 ++/++ +/++ ++/++

Paroxetine (Paxil)

0 0 +++ 0

Fluvoxamine (Luvox)

++++ ++ 0 +++

Venlafaxine (Effexor)

0 0 0/+ ?

Nefazodone (Serzone)

0 0 0 ++++

Mirtazapine (Remeron)

0 0 0 0

Citalopram (Celexa)

0/? 0/? 0/+ 0

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1A2substrates/inhibitors Antispychotics TCA’s Fluoroquinolones theophylline

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Drug interactions

1A2

– Fluvoxamine ++++

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2D6substrates/inhibitors Antiarrhythmics Antipsychotics Beta blockers Opiates TCA’s

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Drug interactions

2D6

– Fluoxetine ++++

– Sertraline +

– Paroxetine ++++

– Venlafaxine +?

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2Csubstrates/inducers/inhibitors Barbiturates NSAIDS Warfarin Antifungals TCSA’a

86

Drug interactions

2C

– Sertraline ++

– Fluoxetine ++

– Fluvoxamine ++

87

3A4 substrates/inducers/inhibitors Antiarrhythmics Antifungal Antihistamines Antipsychotics Barbiturates Benzodizepines Calcium channel blockers Grapefruit juice TCA’s

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Drug interactions

3A4

– Sertraline +

– Fluoxetine ++

– Fluvoxamine +++

– Nefazadone ++++

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Drug Interactions - Herbal Remedies

St. John’s Wort (Hypericum perforatum)– Drugs that interact with MAOIs

Ginko (Ginko biloba)– Anticoagulants (2 cases), or ASA

Kava (Piper methysticum)– Benzodiazepines (1 alprazolam case), alcohol

Ginseng (Siberian ginseng)– potentiates MAOIs, stimulants (caffeine) and haloperidol

Yohimbine (Pausinystalia yohimbine) a2 antagonist – TCA, MAOIs, antimuscarinic agents potentiate yohimbine

Wong AHC et al Archives Gen Psychiatry 1998; 55(11) 1033-1044

Wong AHC et al Archives Gen Psychiatry 1998; 55(11) 1033-1044

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St. John’s Wort Reduces the AUC of the HIV-1 PI Indinavir

Open-label, Eight healthy volunteers (6M/2F) 29-50 yo

Indinavir 800 mg orally(q8h x4) Blood samples 0-8 hours (AUCss) Before and after SJW 300 mg tid x 14 d

(Hypericum Buyers Club) AE’s: taste changes (50%), nausea (25%),

circumoral paresthesias (25%) associated with indinavir. Reduced intensity and duration with SJW.

Increased resistance and Tx failure? 0

25

50

75

100

AUC Cp 8h Cpmax

Per

cent

Dec

reas

ePiscetelli SC Burstein AH, Alfaro RM, The Lancet, 2000; 355(9203) 12 FebPiscetelli SC Burstein AH, Alfaro RM, The Lancet, 2000; 355(9203) 12 FebPiscetelli SC Burstein AH, Alfaro RM, The Lancet, 2000; 355(9203) 12 FebPiscetelli SC Burstein AH, Alfaro RM, The Lancet, 2000; 355(9203) 12 Feb

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Basic algorithm

Monotherapy

– Allow time for drug to work (4-6 weeks)

– Symptoms will resolve gradually

– Maximize dose

92

Selection of Antidepressant

Presenting symptoms Previous response Family history Neurotransmitter profile Co-morbid conditions Human data

Side effect profile Potential drug interactions Patient age Compliance Cost

93

Monitoring Antidepressant Therapy Monitor antidepressant regimen

– Is the dosage appropriate?– Response favorable and adequate?– Side effects present?

Review new chart entries– New orders?– New Diagnoses?– Changes in life events?

Review progress notes– Physician, nursing, social service, psychiatric service

Continue therapy– 9-12 months if first episode. If multiple: chronic maintenance

S.M. Feldman ASCP November 1995

94

Clinical Management of Treatment Emergent Adverse Effects

Continuation of current pharmacotherapy Dose Reduction Trial period of discontinuing medication Antidepressant substitution Adjunctive therapy (cases reported)

95

Combining other medications

Add augmentation therapy Consider drug interactions Monitor other medications - OTC’s and herbals - beta blockers - steroids

96

Combining medications

Use two drugs with different mechanisms SSRI plus

– venlafaxine

– mirtazipine

– buproprion

– nefazadone

– Or combinations of non SSRI’s

97

Depression Co-MorbidityDepression Co-Morbidity

20%Diabetes mellitus20%Myocardial infarction

30% to 50%Parkinson's disease11% to 30%Epilepsy

35% to >50%Chronic pain15%Chronic medical illness

20% to 50%Stroke25% to 38%Terminal solid tumors

Depression Prevalence Medical Illness

98

Concurrent medical disorders

Asthma - avoid MAOI Cardiac disease - avoid TCA Dementia - avoid TCA and other anticholinergic

drugs Seizures - avoid buproprion and TCA Glaucoma - avoid TCA HTN - watch orthostasis

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Antidepressant Selection in the Cardiac Patient

Avoid concomitant Type IA antiarrhythmics (TCA with quinidine or procainamide)

BUP, SSRIs, VFX, SRZ appear to be low risk for arrhythmias and orthostatic hypotension

Venlafaxine is associated with increases in BP MAOIs, Trazodone, maprotiline, amoxapine,

SSRIs, and venlafaxine have not been well studied in CHF

APA Practice Guidelines, Am J Psychiatry

100

Comorbid MDD and Cardiac Disease

Tricyclic antidepressants complicate and/or are contraindicated in specific cardiac conditions– Hx ventricular arrhythmia

– subclinical sinus node dysfunction

– conduction defects (including asymptomatic)

– prolonged QT intervals

– recent history of myocardial infarction

Consider using bupropion, fluoxetine, sertraline, paroxetine, nefazodone, citalopram or ECT

APA Practice Guidelines, Am J Psychiatry

101

Comorbid MDD and Cardiac Disease

MAO inhibitors may induce orthostatic hypotension and lead to drug-drug interactions

Monitor patient for emergence of cardiac symptoms, ECG changes, or orthostatic BP decrements

Major depression is a major risk factor for increased cardiac morbidity and mortality.

APA Practice Guidelines, Am J Psychiatry

102

Depression and Coronary Artery Disease

Januzzi et al. Archives of Internal Med 2000;160(13):1913-21.

103

Case of JC

30 year old, married female, 4 children Feelings of helpless, hopeless, worthless, guilt Started with birth of last child 6 months ago Sleepy and tired all the time, no energy East too much Decreased libido No interest in much FH + depression No other medical problems

104

Case of BH

54 year old married female, 2 children grown 30 year hx MDD Multiple medications have been tried Medical Dx – fibromyalgia, IBS, chronic sinusitis Meds – Remeron. Lortab, Bently, Allegra D,

various OTC and herbals Previous Ads – Prozac, Paxil, AMI, Effexor,

Zoloft, Serzone, Celexa, “everything else” c/o weight gain, still depressed

105

MDD Presentation in Late Life

Often lacks family history of depression Highest Suicide risk of all age groups

– twice the risk in elderly white males– less in elderly black males– same in females

Often associated with medical illness– Stroke (50% develop clinically significant depression)

– Parkinson’s disease (40 to 90% have associated depression)

Typically seen by primary care physicians and may need referrals to mental health specialist for certain aspects of treatment

106

Diagnosis and Treatment of Depression in Late Life

Recognition may be more difficult in late life– “normal aging” and overshadowed by physical illness

Similar social and demographic risk factors: – female sex, single (esp. widowed), stressful life events, lack of

supportive social network

Treatment with sufficient:– doses (plasma concentrations) of antidepressants

– length of treatment (e.g. at least 6 to 12 weeks in the elderly) to maximize likelihood of recovery

– maintenance treatment for 6 to 12 or more months

NIH Consensus Development Conference

107

MDD Symptomatology in Late Life

Symptoms: irritability, agitation, somatic delusions

Somatic complaints: pain syndromes (general, headache, chest, GI), cardiac (palpitations, tightness), abdominal (constipation)

Loss of interest or pleasure may appear as apathy

108

Symptomatology in Late Life (cont’d)

Difficulty in concentration may appear as inattentiveness

Disorientation, memory loss, distractibility as “dementia”

– 10% of “senile or pseudo dementia” is actually depression (now called “dementia syndrome of depression”)

– depression can coexist with dementia

Heterogeneity of geriatric depression (early Vs late onset)

– early onset has more recurrences, more (+) family history

109

Response to Effective Treatment of Depression in Late Life

Majority should expect partial or complete remission of depressive symptoms

Amelioration of pain and suffering associate with physical illness

Enhancement of general mental, physical and social functioning

Minimization of cognitive disability

NIH Consensus Development Conference

110

MDD Presentation in the Elderly

“R.M., a 71-year-old male, is brought for psychiatric evaluation by his daughter, C.M., with whom he has been living for the past 3 years. C.M. reports that R.M. had been in good health until 3 months ago when he was noted to keep to himself and began showing little interest in his usual activities. She reports that he used to be a happy, very outgoing personality He has lost weight over the past 4 months, has been noted to be irritable, anxious, and has trouble falling asleep. He also frequently becomes agitated over insignificant things. He has appeared on occasion to be confused and slow in understanding concepts. ....”

LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18

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MDD Presentation in the ElderlyCont’d

“...His recent physical examination is normal except for benign prostatic hypertrophy (BPH). Laboratory examinations are WLN except for a subnormal serum creatinine. He currently is on no medication except for a daily stool softener and a bulk laxative.

Mental Status Examination reveals a thin, nervous, sad-appearing man. His responses to questions are slow. Affect is sad. He shows no signs of delusions or hallucinations. He shows mild impairments in his ability to think through problems and mathematical exercises. He denies suicidal ideation but feels hopeless at the present time.”

LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18

112

MDD Presentation in the Elderly

“How does a depressive episode in late life, such as that in R.M., differ from a depressive episode earlier in life?”

“What is R.M.’s differential diagnosis?” “Should R.M. be placed on antidepressant therapy?” What factors would influence drug selection?

LK Laird and WH Benefield, Jr. Applied Therapuetics, 1996, pp 76/15-18

113

The Case of R.M., Cont’d

How does the pharmacokinetic profile of the SSRI’s affect your choice?

What are the significant drug interacts that should be considered with R.M.’s pharmacotherapy if treatment for other common disorders were added?

114

For a first episode of depression patients should be on medication for at least 12 months

115

For a second episode of depression, the patient should be on medication for 2 to 3 years

116

For a third episode of depression, most patients stay on medication for life

117

When deciding to take a patient off an antidepressant, the patient’s medical and psychosocial situations must be considered

118

Patient education

Do not perpetuate the stigma of psychiatric illness

Treat the patient with the same empathy, respect and concern you would treat a patient with a medical disorder

Explain depression as a medical disorder Do not be afraid to discuss the signs and

symptoms of depression

119

Patient education

Encourage compliance with medication Help patients understand the medications and

common side effects Help patients understand there is no magic

bullet, but most people are successfully treated

120

Questions

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