4/24/15 InstantGraﬁcaon:&Pharmacologic& … · 2018. 4. 4. · 4/24/15 1...

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Instant Gra.fica.on: Pharmacologic Treatment of Depression, Anxiety,

and Apathy

Financial Disclosure

•  Nothing to report

FDA Disclosure

•  Any off-‐label uses of medica.ons will be explicitly stated as such

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DEPRESSION

Depression •  DSM V Criteria

•  Low mood or anhedonia x 2 weeks •  4/8 neurovegeta.ve symptoms

•  SIGECAPS (Sleep, interest, guilt, energy, concentra.on, appe.te, psychomotor, suicidality)

•  Difficult to differen.ate from symptoms of chronic illness •  Rely on psychological symptoms more

•  “Atypical Depression” •  Increased irritability, anger,

hypersomnolence, hyperphagia, leaden paralysis

•  Mood reac.vity •  Rejec.on sensi.vity

•  Anxiety a common comorbidity •  Screening instruments

•  PHQ-‐9, BDI, HAM-‐D, HADS, CES-‐D •  Point prevalence of 24%

Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Pava JA, Rosenbaum JF. Major depressive subtypes and treatment response. Biol Psychiatry. 1997 Oct 1;42(7):568-‐76.

Depression Circuitry

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Board Ques.on •  Which of the following symptoms is more specific for a mood disorder, as opposed

to a physical symptom of a comorbid medical illness?

–  A. Insomnia –  B. Decreased appe.te –  C. Poor concentra.on –  D. Hopelessness –  E. Psychomotor slowing

Depression-‐-‐Treatment •  1st Line: Psychotherapy (CBT, suppor.ve, dynamic) •  2nd Line: SSRIs •  3rd Line:

–  Bupropion •  fewer sexual side effects, •  ac.va.ng •  seizure risk

–  Mirtazapine •  good for insomnia •  Good for loss of appe.te •  Good for nausea

–  Venlafaxine •  good for anxiety •  Ac.va.ng •  HTN •  ? Helpful for chronic pain

–  Duloxe.ne •  Good for chronic pain

–  Buspirone •  Few side effects

FDA-‐Approved 1st Line An.depressants

•  Fluoxe.ne –  MDD, OCD, panic

•  Sertraline –  MDD, OCD, panic, PTSD, social

•  Paroxe.ne –  MDD, GAD, panic, social, PTSD, OCD

•  Citalopram –  MDD

•  Escitalopram –  MDD

•  Venlafaxine –  MDD, GAD, panic, social

•  Desvenlafaxine –  MDD

•  Vor.oxe.ne –  MDD

•  Bupropion –  MDD, Smoking cessa.on

•  Mirtazapine –  MDD

•  Vilazadone –  MDD

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Serotonin

Schatzberg, A.F., & Nemeroff, C. B. (Eds.). (2009). The American Psychiatric Publishing Textbook of Psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Publishing, Inc.


STAR*D •  Rush et al, 2006

–  >3000 pa.ents , primary care and specialty clinic selngs

•  Step 1: Citalopram ini.al monotherapy –  36% remission

•  Step 2: Nonremimers switched medica.ons (Bup, Sert, or Ven), augmented (Bup or Busp) or added psychotherapy/CBT –  all op.ons led to 30% remission

•  Step 3: Nonremimers switched (Mirt or Nort), augmented (Lith or T3) –  Either op.on led to 13% remission

•  Step 4: Nonremimers switched to (Mirt or Tran) + Ven –  Either op.on led to 13% remission

•  Total % remission aoer 4 steps: 67%

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STAR*D

STAR*D •  Lessons learned: –  Switching = Augmen.ng –  Switch within class = Switch between classes –  Treatment resistance is common, and difficult to achieve remission aoer first two steps

•  Further STAR*D analysis: –  Pa.ents who do not achieve remission relapse quickly within 6 mo

–  66% of those achieving remission had significant exacerba.on of symptoms within 6 mo

– More likely to have exacerba.on if at Step 3 or 4

Treatment of Depression

•  SSRIs –  Fluoxe.ne 10-‐60 mg/day –  Paroxe.ne 10-‐50 mg/day

–  Sertraline 25-‐150 mg/day

–  Citalopram 10-‐40 mg/day

–  Escitalopram 5-‐30 mg/day

•  Start low, go slow •  Effect seen in 2-‐6 weeks •  Side effects come first –  H1: seda.on, appe.te –  A: orthostasis, sexual SEs –  ACh: vision, cons.pa.on, urinary reten.on, dry mouth

–  5-‐HT: nausea, diarrhea –  D: EPS, akathisia, dysphoria

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5-‐HT

Norepinephrine

5-‐HT Selec.vity

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Dopamine

Histamine

Adrenergic

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Acetylcholine

Side effects

•  Most common reason people do not con.nue their an.depressants –  so have to educate

•  Really related to the mechanism of ac.on

Molecular Targets of ADs

www.preskorn.com

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Side Effects of An.depressants •  SSRIs

–  Pro-‐5-‐HT •  Nausea •  Diarrhea •  Headaches •  Insomnia

–  An.-‐ACh •  Dry mouth •  Cons.pa.on •  Urinary reten.on •  Blurry vision

–  An.-‐DA •  Akathisia •  Dysphoria/suicidality

–  An.-‐NE •  Orthostasis

–  An.-‐platelet •  GI bleeding (esp on

coumadin) –  An.-‐K channel

•  QTc prolongaFon (esp citalopram)

–  Discon.nua.on syndrome •  Flu-‐like, dysesthesias,

dizziness, agita.on, delirium –  SIADH

•  Hyponatremia

•  SNRIs –  All of the SSRI side effects –  Pro-‐NE

•  Hypertension

Side effects Khawam etal, Cleve Clinic J or med 2006 Class Common side effects

SSRI-‐serotonin Nausea, jimeriness/anxiety, sexual dysfxn, sleep disturbance, bradycardia, citalopram and arr at high doses (incr Qtc), bleeding (plt fxn inhib), paradoxical rxn, extrapyr

SNRI-‐serotonin, ne Nausea, Sexual dysfxn, sleep disturbance, htn

TCA-‐serotonin, ne, antagonize muscarinic, histamine, alpha

QT prolonga.on, an.cholinergic (gastroparesis, weight gain), slowed cogni.on, orthostasis

Dopamine-‐ne reuptake inhib

Insomnia, headache, irritability, seizures

Alpha-‐2 antagonist-‐serotonin and ne antagonist, histamine

Weight gain, sleepiness, dizziness (orthostasis), cons.pa.on, an.cholinergic?

MAOI-‐monoamines Tyramine related htn crisis, orthostasis

Which an.depressant for which pa.ent Schultz etal, cleve clinic j of med 2013

PaFent anFdepressant

Major depression SSRI

Chronic pain SNRI or TCA

Anxiety SSRI, SNRI

Chronic Fa.gue or Fibromyalgia SNRI

Insomnia Mirtazipine or TCA

Geriatric Mirtazipine

Diabetes SSRI, Buproprion

Cardiac SSRI

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Go to an.depressants -‐-‐no significant drug interac.ons

•  SSRI—Sertraline, Citalopram •  Venlafaxine •  Mirtazapine

Board Ques.on •  The an.depressant mirtazapine has proper.es that may render it par.cularly

helpful in cancer pa.ents with anorexia-‐cachexia or insomnia. Which of the following statements regarding mirtazapine is true?

–  A. It has low affinity for H1 receptors –  B. It agonizes 5-‐HT2 receptors –  C. It agonizes 5-‐HT3 receptors –  D. Its side effects include cons.pa.on and drowsiness –  E. It is commonly associated with neutropenia

An.depressants with alterna.ve methods of administra.on

•  Liquid concentrates –  Fluoxi.ne –  Sertraline –  Citalopram –  Escitalopram –  Paroxi.ne

•  Oral dissolving tabs – Mirtazipine

•  Topical patch –  Selegiline (MAO-‐B inhibitor)

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An.depressants

•  Before star.ng check – Cbc – Cmp – Tsh, free t4 – ECG

An.depressants

•  If you are going to start, start at low doses (1/2 normal dose) and .trate upward as tolerated once every 14 days

An.depressants

•  Have a few an.depressants you feel comfortable with

•  Know side effects and warn your pa.ents •  Start low and go slow •  Make sure they have follow up esp if have risk of suicidality

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Aggressivity of An.depressant Treatment

•  Mild-‐Moderate: PHQ 0-‐9 •  Reevaluate/monitor •  Refer for counseling/nonpharm treatment

•  Moderate-‐Severe: PHQ 10-‐19 OR interfering with health maintenance

•  Reevaluate/monitor •  Refer for counseling •  Start AD, benefit in 4 weeks •  Seek out psychosocial solu.ons/aoercare

•  Severe: PHQ 20-‐27 OR any SI OR any psychosis OR interfering with cri.cal treatment

•  Reevaluate/monitor •  Start s.mulant/seda.ve/an.psycho.c •  Hospitalize •  May need surrogate decision maker

www.psych.org

ADs in Organ Failure

•  Renal Failure – Dose reduce 50% – Cau.on: •  Paroxe.ne •  Venlafaxine •  Desvenlafaxine

•  Liver failure – Dose reduce 50% – Avoid: •  Duloxe.ne •  Nefazodone •  Bupropion

Other risks of ADs

•  SSRIs associated with peri-‐opera.ve bleeding/transfusion (Mahdanian 2014)

•  ADs are chemical cousins to: –  An.psycho.cs (chlorpromazine) –  An.eme.cs (prochlorperazine) –  An.arrhythmics (quinidine) –  An.bio.cs (iproniazid) –  Muscle relaxants

(cyclobenzaprine) –  An.hypertensives (reserpine)

•  I hesitate if: –  Sig. GI (N/V/D) –  Sig. bleeding –  Sig. cardiac/pulm –  Sig. infec.on –  Gelng cri.cal care –  Autonomic instability –  Metabolic disarray –  Delirium/agita.on –  Exo.c med regimen –  Pregnant/Breasteeding

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A Word About Ketamine •  14 RCTs since 2000 •  Small Ns (10-‐50) •  0.5-‐1.5 mg/kg dosing as

infusion or ECT anesthe.c •  20-‐90% of pts had 15-‐75%

reduc.on in depression scores (MADRS, HAMD) seen in 1-‐2 days

•  UNM experience: No benefit yet in 3 pa.ents

•  NMDA antagonist (glutamate)

•  Emergence symptoms include psychosis, derealiza.on, depersonaliza.on

•  Pretreatment with benzos = nega.ng effect?

SSRI Discon.nua.on syndrome •  use for over 6-‐8 weeks –  down regula.on of postsynap.c serotonin receptors

•  With abrupt stopping (within hours-‐3days), rela.ve decline in serotonin

•  SX –  Flu –  Nausea –  Imbalance –  Insomnia –  Sensory disturbance –  Dysphoria, anxiety

SSRI discon.nua.on syndrome

•  Occurs with ssri’s with short half life: – Paroxe.ne (21) – Sertraline (26) – Citalopram (35) – Escitalopram (30) – Fluoxe.ne (90) —only one which self tapers

•  Tx with tapering or reintroduc.on of an.depressant

•  Resolves in 1-‐2 weeks

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Other discon.nua.on syndromes

•  Serotonin discon.nua.on syndromes –  Can also occur with SNRI, TCA, MAOI

•  TCA upregulate cholinergic receptors –  Discon.nua.on can lead to Parkinsonism, mania

•  Discon.nua.on of any an.depressant can lead to mania or hypomania

Serotonin syndrome •  Occurs when giving

synergis.c serotonergic meds together

•  Sx –  Mental status changes –  Autonomic instability –  Neuromuscular hyperac.vity

•  Tx –  Suppor.ve—fluids,

monitoring, benzos –  Stop offending agent –  +/-‐ cyproheptadine (5-‐HT

antagonist) Boyer, E.S., & Shannon, M. (2005). The Serotonin Syndrome. New England Journal of Medicine, 352, 1112-‐1120.

Serotonin syndrome •  Other an.depressants (SSRIs/SNRIs/TCAs/MAOIs) •  Triptans •  Muscle relaxers (cyclobenzaprine) •  Opiates

–  Fentanyl –  Tramadol –  Dextromethorphan –  Methadone

•  Mo.lity agents –  Metoclopramide –  Ondansetron

•  An.bio.cs (linezolid)

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Board Ques.on •  Which of the following signs or symptoms is more indica.ve of serotonin

syndrome than of neurolep.c malignant syndrome?

–  A. Spontaneous or inducible clonus –  B. Tachycardia –  C. Elevated body temperature –  D. Elevated crea.ne phosphokinase –  E. Diaphoresis

ANXIETY

Anxiety Disorders

•  Generalized Anxiety Disorder •  Obsessive-‐Compulsive Disorder •  Social Phobia •  PTSD •  Panic Disorder

•  Caveat: Anxiety disorders are easily confused for each other, but treatments are generally the same

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Anxiety Disorders •  Generalized anxiety

–  Free-‐floa.ng excessive worry –  Restless, fa.gue, irritability, tension,

insomnia, poor amen.on (3)

•  PTSD –  Incr arousal (2) –  Re-‐experiencing (1) –  Avoidance (3)

•  OCD –  Recurrent persistent intrusive thoughts or

behaviors

•  Panic disorder –  Palpita.ons, SOB, dizziness, impending

doom, +/-‐ agoraphobia

Anxiety Disorders-‐-‐Treatment •  1st Line: Cogni.ve Behavioral Therapy •  2nd Line: SSRIs

–  Higher doses in OCD ie. Fluoxe.ne 80 mg daily, sertraline 200 mg daily •  3rd Line: Tricyclic an.depressants* (limited by side effects)

–  Nortriptyline 25-‐150 mg daily •  4th Line: Benzodiazepines

–  Lorazepam 0.5-‐3 mg daily –  Clonazepam 0.25-‐3 mg daily –  Alprazolam 0.25-‐3 mg daily

•  5th Line: An.convulsants –  Pregabalin 300-‐600 mg daily –  Gabapen.n 100-‐900 mg daily

•  6th Line: Atypical an.psycho.cs –  aripiprazole 1-‐10 mg daily –  que.apine 12.5-‐100 mg daily –  risperidone 0.5-‐3 mg daily –  olanzapine 2.5-‐10 mg daily


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Treatment of Anxiety •  Benzodiazepines for acute treatment

–  Alprazolam 0.5-‐3 mg/day –  Lorazepam 0.5-‐6 mg/day –  Clonazepam 0.5-‐6 mg/day –  Diazepam 2-‐20 mg/day

•  Biological effect ooen less than published half-‐life

•  Oxazepam/Temazepam/Lorazepam (OTL) bemer in liver failure (avoid hepa.c metabolism)

•  An.depressants for longer-‐term prophylaxis

•  An.psycho.cs in severe cases

Non-‐enteral Anxiety Treatment •  Benzodiazepines •  An.psycho.cs •  Opiates •  An.-‐adrenergics •  An.convulsants

•  IV Lorazepam 0.5-‐2mg q4-‐6h •  IV Diazepam 2.5-‐10mg q4-‐6h •  IV Midazolam 1-‐5mg q2-‐4h •  IV Haloperidol 1-‐10mg q4-‐6h •  IV Chlorpromazine 25-‐200mg

q6h •  IV Dexmedetomidine

0.2-‐1mcg/kg/hr •  PO Clonidine 0.1-‐0.2mg q8h

(TP Qweek) •  IV Valproic Acid 250-‐500mg

q6h •  IV/IM Pentobarbital 50-‐200mg

q8h

hmps://drjorgebernal.files.wordpress.com/2014/09/wpid-‐wp-‐1410354719956.jpeg

Board Ques.on •  Which benzodiazepine is metabolized predominantly by Phase II conjuga.on and

avoids hepa.c CYP metabolism?

–  A. Diazepam –  B. Clonazepam –  C. Alprazolam –  D. Lorazepam –  E. Chlordiazepoxide

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APATHY

Apathy •  Disorder of mo.va.on

(Marin 1991) •  Apathy < Abulia <

Akine.c mu.sm •  Dis.nct from

depression, although a symptom of depression

•  When not accompanied by low mood, apathy should be suspected

•  Most common neuropsychiatric symptom in Alzheimer’s demen.a

•  Diagnos.c criteria (Starkstein et al 2008) –  A. Lack of mo.va.on –  B. 4 weeks of 1 sx from each

domain •  1. diminished goal directed behavior

–  Lack of effort –  Dependency on others

•  2. diminished goal directed cogni.ons –  Lack of interest in novel things –  Lack of concern about problems

•  3. diminished consequences of goal directed behavior –  Unchanging affect –  Lack of emo.onal response to

events

Apathy

Stern, T. A., Rosenbaum, J. F., Fava, M., Biederman, J., & Rauch, S. L. (2008). MassachuseGs General Hospital Comprehensive Clinical Psychiatry. Philadelphia, PA: Mosby Elsevier.

Cummings, J.L. (1993). Frontal-‐subcor.cal circuits and human behavior. Archives of Neurology, 50(8), 873-‐880.

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Apathy •  1. Are you interested in learning new things? •  2. Does anything interest you? •  3. Are you concerned about your condi.on? •  4. Do you put much effort into things? •  5. Are you always looking for something to do? •  6. Do you have plans and goals for the future? •  7. Do you have mo.va.on? •  8. Do you have the energy for daily ac.vi.es? •  9. Does someone have to tell you what to do each day? •  10. Are you indifferent to things? •  11. Are you unconcerned with many things? •  12. Do you need a push to get started on things? •  13. Are you neither happy nor sad, just in between? •  14. Would you consider yourself apathe.c? •  Starkstein et al., Stroke 1993;24:1625-‐30

S.mulants

•  Belong to the phenethylamine class • 

hmp://proteopedia.org/wiki/index.php/Image:Cocaine-‐dopamine.gif


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Methylphenidate (Ritalin) •  DA/NE reuptake inhibitor •  Time to effect 30 min, peak

effect 2 hours, ½ life 3 hours •  90% renally cleared •  Effect may be higher in pts

with more dopamine release

•  Indicated for narcolepsy, ADHD, POST

•  Off-‐label use includes depression, apathy, fa.gue, opiate-‐induced seda.on, cogni.ve enhancement

•  Start 2.5-‐5mg qam, q2pm •  Can double dose at every

dose if ineffec.ve •  Up to 60 mg/day tolerated •  Benefit usually observed by

staff first

Methylphenidate (Ritalin) •  At lower doses:

–  Improves mood –  Improves focus –  Improves energy –  Improves appe.te

•  At higher doses: –  Anxiety –  Insomnia –  Anorexia –  Tremors –  Psychosis, mania –  HR/BP increase –  Seizures –  Dysrhythmias

•  Precau.ons –  VS pre and post dose changes –  Black box warning for cardiac

problems –  Minimal drug interac.ons –  Addic.on poten.al –  Seizure risk

–  Long ac.ng less efficacious –  Withdrawal of drug usually

uneventul, but can precipitate adverse events with other medica.ons (NMS, parkinsonism)

Safety/efficacy •  ADMET trial, 2013

–  20 mg/day –  Weight loss –  Anxiety –  21% apathy improved

•  CRF meta-‐analysis, 2014 –  Avg 20 mg/day –  Anxiety –  Nausea –  Anorexia –  Ver.go

•  Woods series, 1986 –  66 medically ill depressed –  75% improved –  1 pt had CV complica.on (HR) –  Others: rare ectopy, dysrhythmia

•  Satel review, 1989 –  10 RCTs, open series –  Safer than tricyclics –  Bemer efficacy in geriatric,

medically ill •  Hardy review, 2009

–  19 RCTs –  Fa.gue, apathy, depression –  Geriatric, pallia.ve pts –  Appears well tolerated –  Not clearly effec.ve,

heterogeneous data

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Amphetamine/Dextroamphetamine

•  Adderall (A + D) •  Dexedrine (D alone) •  DA/NE reuptake inhibitors and

increase vesicular DA/NE release

•  Indirect effects of decreasing GABA

•  Time to effect 1 hour, peak effect 3 hours, ½ life 4-‐6 hours

•  Indicated for narcolepsy and ADHD

•  Off label use for depression, fa.gue, cogni.on, apathy

•  Dextroamphetamine more dopaminergic than L-‐amphetamine

•  Adderall 10 mg qam, q2pm • 

Increase to 1 mg/kg/day

•  Dexedrine 2.5-‐5 mg qam, q2pm

•  Increase to 40 mg/day

Amphetamine/Dextroamphetamine

•  At lower doses: –  Improves mood –  Improves focus –  Improves energy –  Improves appe.te

•  At higher doses: –  Anxiety –  Insomnia –  Anorexia –  Tics/Tremors/stereotypy –  Psychosis, mania –  HR/BP increase –  Seizures –  Dysrhythmias

•  Check VS pre and 1 hour post

•  Cau.on if cardiac condi.on, addic.on history, seizure history

Dopamine Agonists •  Non-‐ergots •  Ropinirole •  Pramipexole

•  Ergots •  Bromocrip.ne •  Lisuride •  Pergolide •  Cabergoline

•  NMDA antagonists •  Amantadine (IV) •  Meman.ne

•  Benefits: mood, apathy, parkinsonism

•  •  Non-‐ergots more selec.ve for

D2 type, less D1 and 5-‐HT binding (fewer side effects)

•  Side effects: dyskinesias, DDS, psychosis, punding, pathologic gambling, pulmonary fibrosis, valvular fibrosis, nausea, dizziness, hypotension, narcolepsy, edema

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Dopamine Agonists •  Pramipexole in BPAD

depression •  4 RCTs, 20-‐50 pts, 1-‐3mg

daily •  2 studies of acute phase

with posi.ve response

•  4 open studies of long-‐term response, 11-‐40 pts, 6-‐12 months

•  Mixed efficacy/tolerability

•  May work well in pts who fail tradi.onal therapies, including ECT

Board Ques.on •  Which of the following medica.ons has been associated with seizures at usual

doses and therefore must be used with cau.on in seizure-‐prone pa.ents?

–  A. Methyphenidate –  B. Dextroamphetamine –  C. Bromocrip.ne –  D. Amantadine –  E. Modafinil

Ques.ons

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