pharmacotherapy for major depressive disorder...

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Pharmacotherapy for Major Depressive Disorder Webinar

April 3, 2013

2.00 CONTACT HOURS (60 minute contact hour)

Speaker: Susie Adams, PhD, PMHNP-BC, PMHCNS-BC, FAANP

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AMERICAN NURSES ASSOCIATION CENTER FOR CONTINUING EDUCATION AND PROFESSIONAL DEVELOPMENT

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• Be registered for this activity and pay required fees; • Be present no later than five (5) minutes after starting time; • Remain until the scheduled ending time, and complete the online CNE survey each week; • The survey will be emailed to you and remain open for two weeks following each week of the webinar. You must

complete the online survey and verification before it closes in order to earn contact hours for this activity; • If you attend the entire CNE activity, you will be able to download your Certificate after completing the last evaluation

by right clicking on the certificate image and saving it (“save as”) to your computer; • If you do not attend all the sessions, an adjusted Certificate for contact hours earned will be emailed to you

approximately two weeks after the evaluation survey closes.

ANCC will send an optional follow up email survey four months post webinar to obtain feedback on the effectiveness of the webinar for exam preparation. The ANCC point of contact is Funmi Yusuf at [email protected] 2 contact hours (60 minute contact hour) will be awarded for successful completion of this CNE activity. Partial credit may be awarded as follows: for each session attended Accreditation Statement The American Nurses Association is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. ANCC Provider Number 0023. ANA is approved by the California Board of Registered Nursing, Provider Number CEP6178 for 2.4 contact hours (50 minute contact hour). Conflicts of Interest A conflict of interest occurs when an individual has an opportunity to affect educational content about health-care products or services of a commercial company with which she/he has a financial relationship. The planners and presenter(s)/author(s) of this CNE activity have disclosed no relevant financial, professional, or personal relationship with any commercial companies pertaining to this activity. Commercial Company Support There is no commercial support for this CNE activity. Noncommercial Sponsor Support There is no noncommercial support for this CNE activity. Non-Endorsement of Products The American Nurses Association Center for Continuing Education and Professional Development’s accredited provider status refers only to continuing nursing education activities and does not imply that there is real or implied endorsement of any product, service, or company referred to in this activity nor of any company subsidizing costs related to the activity.

Dear Participants, You are registered to participate in the ANCC Pharmacotherapy for Major Depressive Disorder Webinar. This webinar will take place April 3, 2013, 8-9:30, PM, Eastern Time.

The Content Expert Speaker for the Pharmacology for Major Depressive Disorder is: Susie Adams, PhD, PMHNP-BC, PMHCNS-BC, FAANP.

Below are specific instructions for the course. The course includes contact hours each night for 30 minutes of course material prep. PLEASE pre-read the course materials before each session - this allows you to familiarize yourself with the material before the webinar and can aid in your study and in formulating questions for your speakers. A survey will be emailed to you and will remain open two weeks after each night’s session. You must complete the online survey and verification before it closes in two weeks following each session and the completion of the full webinar in order to earn contact hours for this activity. If you attend the entire CNE activity, you will be able to download your certificate after completing the last evaluation by right clicking on the certificate image and saving it (“save as”) to your computer. If you do not attend all sessions, an adjusted certificate for contact hours will be emailed to your approximately two weeks after the evaluation survey closes.

The webinar starts at 8:00 pm ET. Please log on at 7:50 pm ET.

You will receive the webinar instructions via email from WebEx approximately 1 week before the webinar occurs.

ANCC recommends the following: 1. Have a quiet place at a table or desk, free from distractions 2. Have your program content handbook that was shipped or e-mailed to you 3. Have a pen or pencil for use during the webinar 4. Have your list of questions on the material being covered 5. Please do not record session content

At the end of each webinar session, please complete the online session evaluation. Please contact me with any questions or concerns.

Thank you,

Funmi Yusuf Products & Services Coordinator (CKC) American Nurses Credentialing Center 8515 Georgia Avenue, Suite 400 Silver Spring, MD 20910-3492 301.628.5076 direct tel 301.628.5342 fax [email protected] www.nursescredentialing.org

Pharmacology for Advanced Practice Nurses:

Pharmacotherapy for Major Depressive Disorder Agenda

Speaker: Susie Adams, PhD, PMHNP/BC, PMHCNS/BC, FAANP Learning Strategies – Lecture, Slides, Discussion, Q/A

Gap In Knowledge: The need to provide resources and updated content to advanced practice nurses to support certification and state board requirements for continuing education programs in Pharmacology.

Purpose: To provide advanced practice nurses with basic review of current information in pharmacology topics.

Date/Time Session Code and Learning Objectives April 3, 2013 8:00-9:30pm ET Plus 30 minutes Independent study Preparation

001: Pharmacotherapy for Major Depressive Disorder

Learning Objectives:

1. Recognize symptoms of major depressive disorder 2. Identify steps to combat treatment resistant

depression 3. Identify treatment with a focus on drug therapy 4. Describe major side effects of antidepressant

medication

© 2013 American Nurses Credentialing Center. All Rights Reserved.1

Pharmacotherapy for Major Depressive Disorder (MDD)

© 2012 American Nurses Credentialing Center

American Nurses Credentialing Center

Copyright Disclosure

Any recording or reproduction of materials associated with this review seminar is not permitted, as this material is copyright protected

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material is copyright protected.

Thank you,

ANCC Staff

Material Covered in Presentation

• What is Major Depressive Disorder (MDD)?» Diagnosing MDD using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR)

• Ruling out other causes• Components of good treatment• Antidepressant classes

• Recommended doses

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• Adverse effects• Drug interactions

• Sequenced treatment alternatives to relieve depression (STAR*D)• Augmentation therapies• Treating comorbid illnesses• Other treatment modalities• Treatment resistant depression


DSM‐IV‐TR Definition of MDD

• One or more depressive episodes with one of the following symptoms:

• Depressed mood• Loss of interest or pleasure in nearly all activities for at least 2 weeks

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Observe for ahedonia, dysphoria, apathy, irritability, anger, and social isolation

And four or more of the following…….

5Four or More of the Following to Constitute MDD as Per DSM‐IV‐TR

• At least 5% body weight gain or loss in a month• Insomnia or hypersomnia • Psychomotor retardation or agitation • Fatigue or loss of energy• Diminished ability to think concentrate or make decisions


Diminished ability to think, concentrate, or make decisions• Recurrent thoughts of death or suicide ideation with or without a plan or with attempts• Impaired level of function in work, school, home, or social realm

Severity of MDD According to DSM‐IV‐TR (2000)

• Mild: Patient meets requirements for diagnosis with few or no extra symptoms and functional level is mildly impaired

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• Moderate: Level of functional impairment and symptoms between mild and severe

• Severe: Greater number of symptoms to make diagnosis and significant impairment in work, school, or social realm


Rule Out Other Mental Illness Based on Symptom Presentation

• Bipolar disorder• Dementia• Post traumatic stress disorder• Adjustment disorder

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• Substance-induced mood disorder• Dysthymia• Schizoaffective disorder• Schizophrenia

Who Is Most Likely to Develop MDD?

• 3rd most burdensome disease worldwide• 6.7% of U.S. adults experience depressive disorder in a 12 month period• Prevalence of MDD among U.S. adults (2006–2008)

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• 4.1%, and 9% for all depressions •Women 4.8% vs. men 3.3% for MDD• Did not finish high school 8.1% vs. high school 4.9% and college 3.0%• Married 2.7% vs. never married 5.0% or previously married 7.7%• Unemployed 11.4% vs. employed 2.4%, disabled from working 26%• Have health insurance 3.6% vs. without 7%

Psychiatric Interview

• Questions should focus on criteria for MDD and ruling out other illnesses:

• Duration of symptoms• Times of the day they occur• Sleep pattern• Food intake

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• Energy level• Activity level: What are they doing during the day? Are they going to work or school?• Productivity level: Are they able to concentrate and complete tasks?• Feelings about self• Morbid or suicidal thoughts or plans/past attempts• Determine risk factors or comorbid disorder that could limit drug choices


Rating Scales Can Help Monitor Baseline and Progress

• PHQ-9 (in public domain) http://www.phqscreeners.com/

• Beck Depression Inventory (1961) (BDI-II,1996)

• Hamilton Depression Scale (1960)

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• Hamilton Depression Scale (1960)

• Montgomery Asberg Depression Rating Scale (1979)

• Geriatric Depression Scale

• Likert Scale (Example: rate mood on a scale from 1 to 10)

Rule Out Medical Illnesses That Mimic Depression

Thyroid dysfunction

Chronic pain

Traumatic brain injury

Vitamin deficiency

Anemia

Parkinson's disease

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Lupus

Cushing’s disease

Sleep apnea

Epstein-Barr virus

Cancer

Lab Work

CBC

Thyroid function test

Hepatic panel

BMP

Calcium

Lyme (western blot)

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Vitamin B12

Folate

Vitamin D, 25-OH

Magnesium

Epstein Barr

HIV

RPR


Medications That Mimic Depression

Beta-blockers

Anticonvulsants

Sedatives/hypnotics

Antineoplastic drugs

Benzodiazepines

Calcium channel blockers


yp

Pain killers

Steroids

(Dodd, et al., 2011)

Interferon

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14Pharmacotherapy Is One Treatment Option

Medications together with

Psychotherapy


Development of healthy personal habits(exercise nutrition, and sleep)

Comprise treatment that is more likely to be effective.

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According to the DSM-IV-TR:

• Partial Remission: Some residual symptoms are still present but do not meet MDD criteria or a remission less than 2 months

• Remission: “A period of at least 2 months in which there are not significant symptoms of depression”

Goals of Psychopharmacologic Treatment


significant symptoms of depression

• Symptom reductions that indicate positive response:• Elevated mood• Increased productivity • Decreased negative feelings about self and situation• Improved cognitive function• Better sleep and eating patterns


How to Choose a First‐Line Drug for MDD

• Combine evidence from clinical trails, along with patients symptom profile/and side effects particular for a drug

• Examples• For pain and depression: duloxetine may be a good choice because it is approved for pain caused by fibromyalgia and diabetic

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because it is approved for pain caused by fibromyalgia and diabetic neuropathy, but its SNRI properties also treat MDD• For poor appetite, weight loss, and sleep problems: Consider mirtazapine• For low energy level: Consider bupropion • For anxiety: Consider an SSRI as first line antidepressant choice because as many as 90% of patients with MDD have some anxiety.

Selective Serotonin Reuptake Inhibitors (SSRI)

All inhibit serotonin reuptake into the presynaptic neuron by inhibiting the serotonin transporter and successive changes leading to downregulation of pre and post synaptic receptor

(DAILY DOSE RANGE)

Citalopram 20–40 mg/day Fluoxetine 20–80 mg/day

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Escitalopram 10–20 mg/day Fluvoxamine FOR SOCIAL ANXIETY AND OBESSIVE COMPULSIVE DISORDER 100–300 MG/DAY

Sertraline 50–200 mg/day Paroxetine 20–50 mg/day

SSRI and 5HT1A Partial Agonist

• Vilazadone: (Viibryd®) mechanism of actions are serotonin reuptake inhibitor and 5HT1A partial agonist

• May be a good choice for those patients with anxiety because it has similar receptor activity to buspirone on 5HT1A.

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• Low incidence of adverse sexual effects in preliminary clinical studies

• Start with 10 MG/day for a week, then increase to 20 MG for a week and then titrate to 40MG.


SSRI Adverse Reactions

• Less serious side effects: nausea, diarrhea, dry mouth, somnolence, insomnia, sweating, decreased libido, ejaculatory dysfunction, headache, anxiety, tremor• Serious side effects: hyponatremia, SIADH, bruising/bleeding via interference with platelet production, serotonin syndrome, mania, seizures, QT-prolongation (citalopram)• Suicide ideation in persons under 24: Diagnosis and treatment of

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Suicide ideation in persons under 24: Diagnosis and treatment of depression rates declined 32% after black box warning in primary care settings (Libby, et al., 2007)• Give in AM to decrease possible insomnia.• Discontinuation syndrome: Taper slowly to prevent symptoms such as dizziness, lethargy, vomiting, diarrhea, fever, sweating, malaise, myalgia, electric–shock sensations, agitation, hypomania, incoordination

Serotonin Syndrome

• Most common symptoms in diagnosed cases of serotonin syndrome• Over 50%: Confusion and disorientation, myoclonus,

hyperreflexia• 40%–50%: Muscle rigidity, tremor, hyperthermia,

diaphoresis, sinus tachycardia• 30%–40%: Agitation and irritability, ataxia and

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g y,incoordination, hypertension

• 20%–30%: Coma or unresponsiveness, shivering or chills, dilate pupils, tachypnea

• 10%–20%: Diarrhea, hypotension, flushed skin, non-reactive pupils, Babinski’s reflex, nystagmus, hypomania, seizures, anxiety, diarrhea

• Less than 10%: Salivation, abdominal cramps, diarrhea, dizziness, hallucination

Drug‐Drug Interactions and Serotonin Syndrome

MAOIs (high risk)

SSRI, SNRI, SARI, NaSSA, TCA

Buspirone

Tramadol

Triptan type anti-migraine medications

Lithium

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Excessive serotonin level due to combining serotonergic drugs


Buspirone

Antipsychotics with serotonergic properties like aripiprazole

Some antibiotics –linezolid

St. John’s Wort

Lithium

Methadone

Dextromethorphan

Sibutramine


Norepinephrine‐Dopamine Reuptake Inhibitor (NDRI)

Binds to the dopamine transporter to prevent reuptake of dopamine, blocks norepinephrine reuptake • Brand names are Wellbutrin® or Zyban®

• Bupropion: 100mg TID (start with 100 mg q day or BID)

B i SR 150 t i d il ( t t t 150 d il )

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• Bupropion SR: 150mg twice daily (start at 150 mg once daily)

• Bupropion XL: 150-300 mg once daily (start at 150 mg; can increase to 300 mg after 4 days)

• Bupropion Hydrobromide (Aplenzin®) formulated for use in patients who need a dose higher than 450MG; can be dosed up to 522MG. Dosed once daily.

Important Facts About NDRIs

• Bupropion tends to be activating, so dose in the morning unless immediate release formulation.

• Contraindicated for patients with eating disorders or history of seizure as bupropion lowers threshold for seizures

• Thought to be less likely to eliciting a manic episode in bipolar

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depressed patients

• Use cautiously with patients with renal impairment and hepatic impairment-lower the dose.

• Bupropion is used for smoking cessation (nicotine receptor antagonist) and ADHD.

Important Facts About NDRIs

• Check creatinine prior to starting and from time to time in elderly patients.

• Serious side effects: Psychosis, mania, seizure

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• Other side effects: Dry mouth anxiety, agitation, GI disturbances, weight loss, tremor, insomnia, headache

• Drug-drug interactions: MAOI, TCA, tramadol, Parkinson's disease medications that increase dopamine


Serotonin‐Norepinephrine Reuptake Inhibitor (SNRI)

SNRIs - Blocks the serotonin and norepinephrine transporter which inhibits reuptake. Duloxetine - at higher doses also inhibit dopamine reuptake

•Venlafaxine (Effexor XR®) start at 37.5 mg–75 mg for 7days and then can increase by 75 mg every 4 days.

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y g y y•Max dose is 225 mg; reduce dose by half for liver disease and 25%-50% for renal impairment

• Desvenlafaxine (Pristiq®) 50 mg/day (active metabolite of venlafaxine)100 mg max. renal impairment 50mg q/day to qod

•Duloxetine (Cymbalta®) start at 30mg/day can increase to maximum of 120mg (60 mg BID); avoid with renal and hepatic insufficiency

Important Facts About SNRIs

• SNRIs: Blocks the serotonin and norepinephrine transporter which inhibits reuptake

• Duloxetine: At higher doses also inhibit dopamine reuptake• Metabolized in liver primarily by CYP 2D6• Drug-drug interactions MAOI, anticoagulants, (don’t forget ASA and

NSAIDs), TCAs, CPY2D6 inhibition by duloxetine can reduce conversion of the pro-drug codeine to the active form, phenothiazines-may increase QT i t l

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interval• Monitoring: Check blood creatinine at baseline; monitor BP• Avoid Duloxetine in patient with narrow angle glaucoma and severe renal

impairment and hepatic disease or alcoholism• Side effects: Nausea, headache, insomnia, dizziness, somnolence, GI

disturbances, sexual side effects, increase BP, urinary retention• Serious side effects: Hepatic enzyme elevation and a few cases of liver

damage, seizures, mania, increase SI for those 24 and under

Important Facts About SNRIs

• Venlafaxine: Metabolized by CPY2D6 in liver

• Contraindications: Narrow angle glaucoma or on MAOI

• Monitoring: Cr and BP prior to starting, BP during treatment

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• Drug-drug interactions: Avoid MAOIs, phenothiazines caution with tramadol, anticoagulants

• Side effects: Headache, insomnia, somnolence, GI disturbances, sexual side effects, increased BP, weakness

• Serious SE: Rare seizures, SIADH, mania, suicide ideation 24 and under


Noradrenergic/Specific Serotonergic Agent (NaSSA)

Blocks α2 adrenergic receptors which increase the release of serotonin and norepinephrine and blocks the 5HT2A and 2C, and 5HT3 receptors.

•Mirtazapine: 7.5 mg to 15mg for appetite stimulating effects•For antidepressant: Start at 15mg and can increase after 1–2 weeks; max dose is 45 mg.

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• Blocks α2 adrenergic auto and heteroreceptors which control the release of serotonin and norepinephrine and blocks the 5HT2A and 2C, and 5HT3 receptors.

• Drug-drug interactions avoid MAOI, tramadol, mirtazapine can increase sedating effects of drugs such as hypnotics or alcohol, caution with SNRIs and SSRIs

Important Facts About NaSSAs

• Metabolism: Liver CYP450 substrate of 1A2, 2D6, 3A4• 75% excretion in urine, half-life 20–40 hours• Side effects: Blocks H1 receptor, causes increased appetite, weight

gain and sedation, dry mouth, constipation, hypotension• Serious side effects: Neutropenia, agranulocytosis, rarely seizure,

mania

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• Mirtazapine can be helpful for those patients with significant weight loss, insomnia, and anxiety

• Sedating and appetite stimulating effects tend to diminish in doses over 15MG

• Use cautiously in patients with renal and liver impairment, cancer patients (may decrease WBCs)

• Monitor weight, CBC, and LFTs when clinically indicated

Serotonin‐2A Antagonists/Serotonin Reuptake Inhibitors (SARI)

• Nefazodone: Brand Serzone® was taken off the market because of rare but fatal liver toxicity. Generic is available; not commonly used. 50 to100 MG BID to start, can increase 100 to 200 MG/week, max dose is 600 MG BID

• Trazodone (Desyrel®) 150–600 mg antidepressant, can start with 25–

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50 for insomnia

• Trazodone ER (Oleptro®): Starting dose is 150 mg once daily. May be increased by 75 mg per day every three days. Maximum dose is 375 mg per day.


Important Facts About SARIs

Nefazodone - Inhibits NE and Serotonin reuptake and antagonizes serotonin 5-HT2 receptors.

• Nefazodone: Takes 2–4 weeks to take effect (less likely than SSRIs to cause sexual side effects)

• Dizziness, hypotension, sedation, nausea, insomnia, weakness, visual di t b (bl d i i d h i i l fi ld) ti ti

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disturbances (blurred vision and changes in visual field), constipation, confusion

• Nefazodone inhibits CYP 3A4: Since many drugs require this enzyme, nefazodone will have more drug-drug interactions.

• Drug–drug interactions: Avoid triazolam and alprazolam, MAOIs, certain statins and digoxin metabolized by 3A4 may have increased blood levels if given with nefazodone. Avoid grapefruit juice.

More Important Facts About SARIs

Trazodone antagonizes alpha-1 adrenergic and serotonin 5HT2A receptors and blocks the serotonin transporter (reuptake inhibitor)

• Metabolized by CYP 3A4

• Trazodone side effects (serious): Rarely priapism, seizure, mania, di h th i

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cardiac arrhythmia

• More common adverse effects: Somnolence, GI disturbance, hypotension

• Not known to cause sexual dysfunction

• Block serotonin and norepinephrine reuptake, down regulation of β-adrenergic receptor, anticholinergic effects, Na+ channel blocking

•• Tricyclic Dose range • Imipramine (Tofranil®) 75–300 mg• Desipramine (Norpramin®) 75–300 mg AM of imipramine • Amitriptyline (Evavil®) 75–300 mg • Nortriptyline (Pamelor) 40–200 mg AM of amitriptyline

Cl i i (A f il ®) 75 300

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Tricyclic and Tetracyclic Antidepressants (TCA)


• Clomipramine (Anafranil ®) 75–300 mg• Doxepin (Sinequan®) 75–300 mg• Protriptyline (Vivactil®) 20–60 mg• Trimipramine (Surmontil®) 75–300 mg

• Tetracyclic• Maprotiline (Ludiomil®) 100–225 mg• Amoxapine (Asendin®) 100–600 mg


TCA Side Effects

• Antihistamine: Weight gain, sedation

• Anticholinergic: Blurry vision, tachycardia, urinary retention, dry mouth, constipation, confusion, problems with memory

• β-Adrenergic: Orthostatic hypotension, dizziness

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• Sodium channel blocking effects: Seizures, increased Q-Tc interval, heart block, increased lethality in overdoses

• Other side effects: TCAs can also cause sexual side effects, headache, anxiety

• Paralytic ileus, arrhythmia, increased intraocular pressure, hepatic failure, psychosis

Important Facts About TCAs

• Monitoring: None required for healthy patients; weight, glucose, lipids, EKG in clinically indicated patients

• Contraindication: MI patients, heart block patient, narrow angle glaucoma, dementia, patients with urinary retention, those at risk for suicide due to high risk of overdose nature of TCAs, poor 2D6 metabolizers

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• Keltner and Folks (2005) advises that many providers prescribe only 1 week supply to prevent lethal overdose unless patient is very reliable.

• Drug-drug interactions: MAOIs, SSRI’s, bupropion, and duloxetine, any 2D6 inhibitor, anticholinergic drugs, tramadol, cimetidine, haloperidol, phenothiazine, methylphenidate, antiarrhythmic drugs, digoxin, beta-blocker, calcium channel blockers, antiparkinson’s medications

Irreversible MAO‐A‐B Inhibitors (MAOI)

Irreversibly blocks action of monoamine oxidase A and B by binding permanently to this enzyme thereby preventing breakdown of dopamine, norepinephrine and serotonin•Isocarboxazid (Marplan®) 40 mg/day start 10 MG BID

•Phenelzine (Nardil®) 45-75mg/day; start 15 mg TID

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•Tranylcypromine (Parnate®) 30 mg TID

•Usually used as a second choice treatment because of dietary restrictions and drug–drug interactions and not because of lack of efficacy

•Patients must be reliable to take on restricting diet and OTC drugs that may elicit hypertensive crisis or serotonin syndrome.


Monoamine Oxidase Inhibitors: MAOI‐B

Monoamine oxidase B inhibitor is more selective for preventing breakdown of dopamine, also inhibits reuptake of dopamine, at higher doses it prevents breakdown of serotonin and norepinephrine• Selegiline, Emsam® patch-6mg/24hours, 9mg/24hours, and 12 mg/24 hours

• With 6mg, not necessary to make dietary changes. At higher doses, low tyramine diet is needed.

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• Side effect: Skin irritation at patch site, insomnia, diarrhea, headache, hypotension, dry mouth, elevated BP with doses over 6MG

• Liver metabolism through CYP2B6, CYP2C9, CYP 3A4/5 and CYP 2A6Half-life 18-25 hours

• Washout period of 14 days if discontinuing patch and starting a new antidepressant

MAOI and Diet: The Tyranny of Tyramine

• Tyramine increases peripheral catecholamine release and can create a hypertensive crisis when MAO is blocked. • Foods with Tyramine

•Aged, smoked, dried meats • Fermented foods, like sauerkraut• Spoiled or overly ripe foods• Aged cheese (your favorites, including cheddar, brie, blue)

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• Unpasteurized or draft beer; alcohol-free beer • Fava or broad beans• Soy, tofu, miso soup• Marmite (concentrated yeast extract)• Avocados• Bananas• Caffeinated beverages• Chocolate• Licorice• Chianti/Sherry

MAOIs: Drugs That Augment Catecholamine Action Can Yield Hypertensive Crisis

• Cold medicines: Pseudoephedrine, phenylephrine, nasal sprays, phenylpropanolamine• Catecholamine: releasing or promoting stimulants such as methylphenidate, amphetamine, cocaine, dopamine, epinephrine, norepinephrine, methyldopa

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•Tryptophan and tyrosine• Phentermine: Containing appetite suppressants• Antidepressants that increase NE (TCAs, SNRIs, NDRIs); possibly atomoxetine


Preventing MAOI‐Related Serotonin Syndrome

• If switching to an MAOI, must wait at least 5 half-lives.

• Wait if switching from MAOI from another antidepressant.

• 10 days for most types and at least 2 weeks for SNRI

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• Do not combine with other antidepressants or opioids (dextromethorphan, meperidine, tramadol, methadone).

• Gilman (2005) says morphine, codeine, and oxycodone are OK. These drugs do not have serotonergic activity.

• Avoid MAOIs with other TCA-like drugs: cyclobenzapine and carbamazepine

Sequenced Treatment Alternatives to Relieve Depression (STAR*D)

• Level 1 Citalopram: After 8–12 weeks about 1/3 remitted and 10%–15% responded positively but not enough to be called remission

• Level 2 Switch: 3 switch drugs: bupropion SR, venlafaxine ER or sertraline

•25% remission rate for all

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• Augmentation: Citalopram plus bupropion SR or buspirone

• About 1/3 remission with slightly better response and tolerability for those who took bupropion addition to citalopram

• Cognitive psychotherapy was offered as a switch or augmentation choice in level 2.

Star* D (continued)

• Level 3 • Switch (to mirtazapine or nortriptyline); 12%–20% remission• Augmentation (lithium or T3, liothyronine) 20% remission with less side effects with T3

• Level 4 • Taken off medications (wash out)

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• Started on the MAOI tranylcypromine monotherapy • Combination of venlafaxine ER with mirtazapine • 10% remission rate with less side effects and less medicationdiscontinuation in the venlafaxine/mirtazapine patients

• After 4 levels of treatment, 33% of patients did not obtain remission.


Antidepressant Switching and Augmentation Therapies

• Switch to another antidepressant: 25% of Star*D level 2 patients achieved remission when switched to Bupropion SR, Venlafaxine ER or Sertraline

• Augment with another antidepressant: Bupropion added to SSRI: In Star*D level 2, 29.7% remitted to citalopram with bupropion after non-remission to citalopram alone

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p p p• SSRIs combined with a TCA with noradrenergic effects such as

desipramine or nortriptyline. Positive response rate up to 50%. Must lower the TCA dose due to CYP450 enzyme metabolic inhibition by SSRI.

• Mirtazapine and SSRI: 64% of patients had some improvement after inadequate response to SSRI alone.

• SNRI such as venlafaxine added with a TCA: 64% remission

Augmentation Therapies (T3)

• Thyroid Hormone: 25C50 mcg of T3, liothyronine was found to be better tolerated and equally as effective as adding lithium in the STAR*D study.

• 25 mcg/day was the STAR*D starting dose for 7 days then 50 mcg/day for depression adjunctive therapy.

• Kaplan, Saddock and Sussman (2011) serious side effects of T3 at the

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lower doses used for adjunctive treatment in depression are infrequent.

• Potential drug–drug interactions: May increase action of anticoagulants, patient may need more insulin

•Drugs to avoid include digoxin, amiodarone, sympathomimetics, maprotiline, and ketamine

Buspirone Augmentation

• Dose for augmentation 15–60 mg/day (in divided doses)

• Start 15 mg BID and can add 5 mg every 2 or 3 days

• Buspirone has a short half-life (2–3 hours) so TID dosing is best, but BID is OK.

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• 30% remission rate when used in STAR*D augmentation level 2 along with citalopram (average dose was ≈ 40 mg/day at end of level 2)

• Can be helpful for sexual side effects from SSRIs

• Would be a reasonable augmentation choice for patients who have co-morbid anxiety


Lithium Augmentation

• Recommend dose 600 to 900mg/day (Virani, et al. 2009) in divided doses to reach a therapeutic plasma level of 0.4 to 0.8 mEq/l (Keltner and Folks, 2005)

• STAR*D Level 3: About 20% of patients entered remission when on antidepressant medication plus lithium.

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• Lithium: In STAR*D, patients were started at 450 mg/day and increased to 900 mg/day. Patients with tolerability issues were started at 225 mg/day (this dose would be possible with oral solution) and increased to 450 MG.

•When patients exited the study, lithium median levels were 0.6 mEq/L

Augmentation With L‐methylfolate

• L-methylfolate: Form that is active in the brain

• l-methylfolate: Active form of folic acid which can enter the brain through the blood brain barrier, importance co-factor in the production of monoamines in the conversion of tryptophan to Serotonin and tyrosine to Norepinephrine and Dopomine

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• Helps in the conversion of homocysteine to methionine which may be associated with lower rates of depression

• Suggested dose from available studies 7.5 mg/day

• Well-controlled clinical trials are needed to support the initial findings.

Drugs and Conditions That Lower Folic Acid

ExamplesAntacids-H2 blockers and proton pump inhibitors

Seizure drugs-phenytoin, Carbamazepine and lamotrigine

NSAIDs

Alcoholism

4+ cups/day of coffee

Tobacco smoking

Fluoxetine

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Triamterene

Oral contraceptives

Methotrexate

Cholesterol: Lowering drugs that sequester bile

Fluoxetine

Poor nutrition

Methylenetetrahydrofolate Reductase mutations gene variant C677T


Treat Comorbid Mental Illness and Residual Symptoms

• Patients with residual symptoms or untreated comorbid mental illness are more likely to relapse• Substance abuse: Must be addressed prior to treating mood disorder• Anxiety • ADHD• Insomnia or other sleep disturbance

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• Fatigue • Chronic pain• Sexual dysfunction• Paranoia, feelings of persecution• Make sure these problems are being address by the psychiatric provider or referred to the primary care provider.

Other Treatments: Neuromodulation

• Electroconvulsive therapy (ECT): 70 years of effective treatment, safer with recent refinements. Increases BDNF and other CNS proteins which explain its mechanism of action.

• Repetitive transcranial magnetic stimulation (rTMS): Magnetic coil placed on the scalp directs a strong oscillating magnetic field to depolarize left dorsal lateral prefrontal cortex neurons and increase metabolism

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increase metabolism.

• Vagal nerve stimulation (VNS): First developed as a treatment for seizure patients. Batteries in chest wall activate electrode in the left vagas nerve FDA-approved for MDD (2005) after > 4 other treatments fail. VNS may increase monoamines; VNS takes several weeks for effects to start.

PHCg

HCA

Green represents brain areas where metabolism is decreased in MDD andincreased by rTMS, ECT, and antidepressants, as determined by fMRI, particularly in Brodmann areas 9, 46, DLPFCx).

Red shows where brain metabolism is increased in MDD and decreased by


A HC

C.A. Altar, 2011

ythese interventions, namely, amygdala, parahippocampal gyrus and hippocampus.

Salerian and Altar, in press, Psychiatry Research: Neuroimaging.

Reprinted with permissionfrom C.A. Altar, 2012


Improving Outcomes in Treatment Resistant Depression (TRD)

•Recommendations from University of Michigan Comprehensive Depression Center

• Screen patients with self-rating scales on regular basis (weekly to monthly)• Monitor for early signs of TRD• Thoroughly assess patient by physical exam, obtaining history, and l b t t t

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laboratory tests• Educate patient and family regarding ways to assist recovery by avoiding alcohol and drugs, developing healthy habits, learning what to expect from the antidepressant, and what side effects may be experienced, to stick with medication for mild side effects that often subside • Psychotherapy and adequate trial of antidepressant (time and dose)

(Greden, Riba, & McInnis, 2011)

Improving Outcomes in TRD »Start a previously effective medication if patient stopped the medication or reduced the dose on their own.» Consider SNRI, TCA, and MAOI if SSRI was ineffective.» Combine quetiapine or aripiprazole with an antidepressant (I save this choice for those with psychotic features). » Combine two antidepressants with mechanisms of actions not previously tried.» Augment with lithium, T3, or combined.

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Augment with lithium, T3, or combined.» Supplement with omega-3, vitamin D, and methylfolate.» Encourage patients to start an exercise routine daily if possible.» Start eating a healthy diet (low fat, nutrient dense).» Educate patients to avoid herbal supplements, internet information without checking with provider, to avoid starting other medication such as tramadol without checking.

Greden, Riba, & McInnis, 2011)

Improving Outcomes in TRD

» Educate patients about the importance of adherence to treatment.» Refer for a second opinion if not able to reach remission.» Consider pharmacogenetic testing.» Consider ECT, rTMS, or VNS.» If desperate, consider clinical trials such as DBS or ketamine.» When remission is achieved, maintenance therapy should

ti d i d fi it l

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continued indefinitely.

Resources for your patients and families at http://www.depressiontoolkit.org/

(Greden, Riba, & McInnis, 2011)


Genotype Profile and Antidepressant Choice

• Genes for cytochrome P450 (CYP) enzymes that degrade antidepressants, specifically CYP 2D6, 2C19, 2C9, and 1A2, have between-patient variants in their gene sequence (polymorphisms) that can greatly affect antidepressant metabolism (Mrazek, 2010) and response (Altar, et al., SOBP, 2012).

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• Genes for serotonin function (5HT2A, SERT) that affect response to antidepressants

• Integration of genetic polymorphisms can predict drugs to take with varying levels of caution.

Summary

• MDD is a prevalent and complex illness with biological and environmental contributors.

• MDD requires vigilance by a partnership between the nurse practitioner, patient, and other care providers.

• Physical Illness and other psychiatric illnesses should be ruled out.• First choice for antidepressant treatment should be made with

consideration to presenting symptoms, comorbid illness, side effect profile, and medical contraindications.

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• Treatment resistant depression will likely involve multiple medications and augmentation strategies.

• Successful treatment of residual symptoms will promote remission.

Do antidepressants work? In my clinical opinion yes, I see many patients respond with improved mood and quality of life. On balance, clinical studies concur with this subjective view.

References

Altar, C.A. (1999) Neurotrophins and depression. Trends in Pharmacological Sciences,20, 59-61.

Altar, C.A., Winner, J.G., Allen, J.D., Lorenz, J., Tuchfarber, B., Hall-Flavin, D.K., & Mrazek, D.A. (2012). Improved antidepressant efficacy with a pharmacogenomic treatment support product. Society for Biological Psychiatry, 71 (8S), #902, 291S.

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., rev.). Washington, DC: American Psychiatric Association.

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Brody, B., Leon, A.C., & Kocsis, J. H. (2011). Antidepressant clinical trials and subject recruitment: Just who are symptomatic volunteers? American Journal of Psychiatry, 168, 1245-1247.

Carta, M. G., Hardoy, M. C., Pilu, A., Sorba, M., Floris, A. L., Mannu, F. A.,,Baum, A., Cappai, A., Velluti, C., & Salvi, M. (2008). Improving physical quality of life with group physical activity in the adjunctive treatment of major depressive disorder. Clinical Practice and Epidemiology in Mental Health, 4 (1). Retrieved from http://www.cpementalhealth.com/content/pdf/1745-0179-4-1.pdf


References

Centers for Disease Control and Prevention. (2011). Burden of mental illness. Retrieved from http://www.cdc.gov/mentalhealth/basics/burden.htm

Centers for Disease Control and Prevention. (2012). QuickStats: Prevalence of current depression* among persons aged ≥12 years, by age group and sex — United States, National Health and Nutrition Examination Survey, 2007–2010. Retrieved from http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6051a7.htm

Centers for Disease Control and Prevention. (2012). An estimated 1 in 10 U.S. adults report depression . Retrieved from http://www.cdc.gov/features/dsdepression/

Centers for Disease Control and Prevention (2010) Current Depression Among adult

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Centers for Disease Control and Prevention. (2010). Current Depression Among adult 2006-2008. Morbitity and Mortality Weekly Report, 59 (38) Retrieved from http://www.cdc.gov/mmwr/pdf/wk/mm5938.pdf

Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., Tansella, & M., Barbui, C. (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysis. Lancet, 373(9665), 746-758.

References

Dodd, S., Malhi, G.S., Tiller, J., Schweitzer, I., Hickie, I., Khoo, J.P., Bassett, D. L. Lyndon, B., Mitchell, P. B., Parker, G., Fitzgerald, P. B., Udina, M., Singh, A., Moylan, S., Giorlando, F., Doughty, C., Davey, C. G. Theodoros, M., & Berk, M. (2011). A consensus statement for safety monitoring guidelines of treatments for major depressive disorder. Australian and New Zealand Journal of Psychiatry, 45, 712-725.

Farah, A. (2009). The role of l-methylfolate in depressive disorders. CNS Spectrums, 14,1, supp. 2.

Fournier J.C., DeRubeis R.J., Hollon, S.D., Dimidjian, S., Amsterdam, J.D., Shelton, R.C., & Fawcett., J. (2010). Antidepressant drug effects and depression severity: A

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patient-level meta-analysis. The Journal of the American Medical Association, 303, 47-53.

Gaynes, B.N., Rush, J. A., Trivedi, M. H., Wisniewski, A. R., Spencer, D., & Fava, M. (2008). The STAR*D study: Treating depression in the real world. Cleveland Clinic Journal of Medicine, 75 (1), 57-66.

Gibbons R. D., Brown, C. H., Hur, K., Davis, J. M., & Mann, J. J. (2012). Suicidal thoughts and behavior with antidepressant treatment: Reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Archives of General Psychiatry. 69 (6): 572-9.

References

• Gibbons R, D., Hur, K., Brown, C. H., Davis, J. M., & Mann, J. J. (2012) Benefits from antidepressants: Synthesis of 6-week patient-level outccomes from double blind placebo controlled randomized trials of fluoxetine and venlafaxine. Retrieved from www.archgenpsychiatry.com

• Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and• serotonin toxicity. British Journal of Anaesthesia, 95 (4), 434–441.• Greden, J. F., Riba, M. B., & McInnis, M. G. (Eds.) (2011). Treatment resistant

depression: A roadmap for effective care. Washington DC: American Psychiatric Publishing, Inc.

• Holloway C. Keltner, N. L., & Folks, D. G. (2005) Psychotropic drugs (4th ed.). St. Louis, Missouri: Elsevier Mosby.

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y• J., Cochlin, L. E., Emmanuel, Y., Murray, A., Codreanu, I., Edwards L. M.,

Szmigielski, C., Tyler, D. J., Knight N. S., Saxby, B. K., Lambert, B., Thompson C., Neubauer, S., & Clarke, K. (2011). A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. American Journal of Clinical Nutrition. 93(4), 748-55. Epub 2011 Jan 26

• Holtzheimer, P. E., Kelley, M. E., Gross, R. E., Filkowski, M. M., Garlow, S. J., Barrocas, A.Wint, D., Craighead, M. C., Kozarsky, J., Chismar, R., Moreines, J. L., Mewes, K., Posse, P.R., Gutman, D.A., Mayberg, H.S. (2012). Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Archives of General Psychiatry, 69(2), 150-158.

© 2012 American Nurses Credentialing Center. All Rights Reserved


References

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Libby, A. M., Brent, D. A., Morrato, E. H., Orton, H. D., Allen, R., & Valuck, R. J. (2007). Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. American Journal of Psychiatry, 164(6), 884-891.

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References

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