Antidepressants

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Antidepressants

• Chris Pelic M.D.
• Associate Dean for Students
• Medical University of South Carolina

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Objectives

• Learn the monamine theory of depression
• Understand how the various antidepressants work
  (MAOIs, TCAs, SSRIs, SNRIs, etc)
• Learn common side effects for antidepressant
  medications
• Understand basic pharmacodynamic and
  pharmacokinetic properties of some of the more
  common antidepressants

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History of Antidepressants

• Discovered by serendipity in 1950s
• Iproniazid - antitubercular drug
• First antidepressant observed to elevate mood and
  stimulate activity in many patients
• Monoamine oxidase inhibitor
• Multiple side effects off market
• Reserpine depletion of NE/SE

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History of Antidepressantscontinued

• 1957-58 - Imipramine TCA was tried to treat
  schizophrenia (NOT EFFECTIVE)
• Tried as antidepressant and effective
• Monoamine theory of depression
• (Serotonin/norepinephrine)

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History of Antidepressantscontinued

• Multiple TCAs and MAOIs marketed
• Search for meds with less SE began
• First SSRI, fluoxetine was released in 1987
• Multiple SSRIs developed
• Other norepinephrine/dopamine reuptake inhibitors
  have been developed

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Who gets an antidepressant?

• People who are depressed
• People who are anxious (all anxiety d/o)
• People with chronic pain/sleep difficulty
• Prophylaxis for depression (post-partum)
• Other Bedwetting

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Types of antidepressants

• Selective Serotonin-Reuptake Inhibitors
• fluoxetine, sertraline, paroxetine, citalopram,
  escitalopramfluvoxamine
• Tricyclic Antidepressants
• amitriptyline, amoxapine, desimpramine, doxepin,
  imipramine, maprotiline, nortriptyline,
  protryptiline, trimipramine
• Monoamine Oxidase Inhibitors
• phenelzine, tranylcypromine, seligiline

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Types of antidepressantscontinued

• Norepinephrine/dopamine reuptake inhibitor
• Bupropion
• Serotonin/norepinephrine (central antagonist)
• Mirtazapine
• Serotonin antagonist and reuptake inhibitor
• Trazodone, nefazodone
• Serotonin/norepinephrine/?dopamine reuptake
  inhibitor
• Venlafaxine, duloxetine

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• THE MEDS.

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Monoamine Oxidase Inhibitors

• Inhibits monoamine oxidase
• Increases synaptic concentatration of monoamines
  Serotonin and Norepinephrine
• Stop 2 weeks before starting another
  antidepressant
• Risk of serotonin syndrome when used with other
  drugs
• Tyramine Hypertensive crisis
• Most common SE hypotension.
• Most serious SE hypertensive crisis
• May be better for atypical depression

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Monoamine Oxidase Inhibitorscontinued

• Tranylcypromine (Parnate) Irreversible MAO A
• Phenelzine (Nardil) - Irreversible MAO A
• Selegeline (EMSAM) comes in patch. Mainly MAOI
  B but cross over to A. No diet restrictions at
  low dose.

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Tricyclic AntidepressantsGeneral

• Serotonin/Norepinephrine reuptake inhibitors
• Effective but anticholinergic, antihistamine,
  cardiac effects prominent
• Lethal in overdose
• Used for sleep/pain/migraines/anxiety too
• 2 drugs have a TCA structure that are not
  antidepressants
• 1. cyclobenzaprine
• 2. carbamazepine

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Tricyclic AntidepressantsGeneral

• Can check level
• Paxil, Prozac can increase levels (2D6)
• Not generally first line tx now
• Tertiary amines have greater analgesic properties
  than secondary amines
• For anxiety start very low

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Tricyclic AntidepressantsTertiary Amines

• Amitriptyline (Elavil, Amitril, Endep)
• Clomipramine (Anafranil)
• Imipramine (Tofranil, Antipres)
• Trimipramine (Surmontil)
• Doxepin (Sinequan, Adapin)

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Tricyclic AntidepressantsSecondary amines

• Nortriptyline (Pamelor, Aventyl)
• Desipramine (Norpramin)
• Protriptyline (Vivactil)
• Less adverse effects (anticholinergic) than
  tertiary amines
• Some are metabolites are tertiary amines

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Amitriptyline

• Dosed qhs
• Serum Half Life 21 hours
• Frequently used for insomnia/pain/fibromyalgia

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Imipramine

• Dosed qhs
• Used for MDD, and enuresis (3rd line)
• Obtain serum levels in pediatric population
• Cases of sudden cardiac death in kids
• Not used much as full dose antidepressant

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Desipramine

• Primarily norepinephrine drug
• Used in past for ADHD (not first line)
• CLOMIPRAMINE
• Primarily serotonergic drug
• Used for mostly for OCD (not first line)

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• THE SSRIs

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SSRIs as a class

• 30-40 incidence of sexual dysfunction
• Can be sedating or activating
• Used for anxiety and depression
• Take a few weeks to work
• Thought to increase BDNF
• High doses needed for OCD
• First line for depression/anxiety
• Slower titration for anxiety

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Fluoxetine (SSRI) - PROZAC

• Usually prescribed in am
• Long half life days (has act. metabolite)
• Activating, minimal weight change
• Useful in pregnancy (CAT C), eating d/o
• Useful in anxiety d/o start low
• Comes in generic, liquid, weekly
• Potent P450 2D6 inhibitor (Inc TCA level)
• Indications MDD, OCD, Panic D/O Bulimia, PMDD

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Paroxetine (SSRI) - PAXIL

• Short half life (potential for flu-like
  withdrawal)
• Mild-modest weight gain
• May have more sexual dysfunction (Inhibits Nitric
  O. Synthetase)
• More potential for teratogenic effects
• Inhibits Cytochrome P450-2D6 (Inc. TCA levels)
• Indications MDD, social phobia, panic d/o, PTSD,
  OCD, GAD

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Sertraline (SSRI) - ZOLOFT

• Often used in anxiety d/o (eg PTSD) and pregnancy
  (cat C)
• Minimal weight change, can have GI side effects
• Indications MDD, OCD, Panic d/o, Social Phobia,
  PTSD, PMDD

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Fluvoxamine (SSRI) - LUVOX

• Not used clinically often but can be useful
  alternative
• Increases caffeine half life
• Indications OCD, GAD (CR)

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Citalopram (SSRI) - CELEXA

• Dosed in am often but can cause sedation
• Minimal weight change
• Used in medically sick or polypharmacy due to low
  med-med interactions

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Escitalopram (SSRI) LEXAPRO

• Dosed in the am usually
• Also used for complex medical patients
• Newest SSRI, few med-med interactions
• S-Enantiomer of celexa (active med)
• In theory less SE than celexa (sedation
  particularly if it was a problem)
• Celexa 20mg10mg lexapro
• Indications MDD, GAD

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NRIs

• Not indicated for depression
• Maprotiline
• Reboxetine

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Bupropion (NDRI) - WELLBUTRIN

• Norepinephrine/dopamine reuptake inhibitor
• Dosed in am and mid afternoon
• May worsen anxiety
• No sexual dysfunction
• May suppress appetite or cause insomnia
• Dose dependent risk of seizures low at approved
  doses
• Contraindications seizure disorder, eating d/o
• Indications MDD, smoking cessation
• OFF LABEL ADHD

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Nefazodone (SARI)- SERZONE

• Serotonin antagonist and reuptake inhibitor
• Blocks Serotonin-1 Receptor (5-HT-1)
• 1. Anti-depressant effect
• Blocks 5-HT-2a Activity
• 1. Blocks 5-HT-2a inhibition of 5-HT-1
• 2. Blocks sexual dysfunction
• 3. Blocks Insomnia and anxiety effects

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Serzone nefazodone (SARI)

• Black box warning on death from acute liver
  failure (one per 250,000)
• May take off market. Name brand is off market.

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Trazodone (SARI) - DESYREL

• Serotonin antagonist and reuptake inhibitor
  (SARI)
• No associated liver failure
• Used mostly for sleep and adjunct for depression
• Risk of priapism (1/6000)

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Venlafaxine (SNRI) - EFFEXOR

• Similar activity TCAs- SNRI
• Can cause serotonin withdrawal/short half life
• Serotonin/Norepinephrine reuptake Inhibitor
• Selective Serotonin Reuptake Inhibitor (lt150
  mg/day)
• Norepinephrine Reuptake Inhibitor (gt150 mg/day)
• Minimally inhibits dopamine uptake
• ? It can elevate diastolic BP)
• XR Indicated for MDD, GAD, Social Phobia, panic
  d/o

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Duloxetine CYMBALTA

• SNRI
• Similar to venlafaxine with main difference that
  has SNRI effects even at low dose
• Associated with liver failure (rare)
• Has short half-life/potential for withdrawal
• Indicated for depression, fibromyalgia, and
  diabetic neuropathy (higher dose often needed)

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Mirtazapine - REMERON

• Norepinephrine/serotonin antagonist
• Blocks Pre-synaptic alpha 2 adrenergic Receptors
• Enhances central noradrenergic activity
• Blocks post-synaptic 5-HT2, 5-HT3 Serotonin
  Receptors
• Enhances central Serotoninergic activity at
  5-HT-1

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Remeron Mirtazapinecontinued

• Significant antihistamine activity
• Dose dependent effect
• Dose 15 mg antihistamine effects predominate
• Dose 45 mg Noradrenergic effects predominate
• Antihistamine Symptoms
• Weight gain
• Sedation

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Antidepressant Withdrawal

• Occurs with sudden antidepressant withdrawal
• Symptom onset occurs within 24 hours to 2-3 weeks
  
• Likely results from cholinergic overdrive
• Symptoms similar to Organophosphate Poisoning or
  THE FLU
• Most common with Paxil, effexor, cymbalta
• Not seen with Prozac (naturally tapers)

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Clinical Pearls

• Start with an SSRI, SNRI, or NDRI for depression
• Chose on basis of patient history, family
  history, side effect profile, cost
• Bupropion, trazodone, nefazodone, mirtazapine
  no sexual dysfunction

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What you need to know Mood Stabilizers

• Chris Pelic M.D.
• Associate Dean for Students
• Medical University of South Carolina

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Objectives

• Learn definition of a mood stabilizer
• Understand the proposed mechanisms for the most
  commonly used mood stabilizers (valproic acid,
  lithium, carbamazepine)
• Know the most common side effects of lithium,
  valproic acid, and carbamazepine
• Learn the medications used to treat dementia
  (mechanism, side effects)
• Learn the medications used for ADHD

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Mood Stabilizer????

• A mood stabilizer is a medication used in the
  treatment of Bipolar Disorder to suppress swings
  between mania and depression.
• Some meds seem just antimanic drugs
• Can also treat cyclothymia, personality d/o mood
  lability, aggression/impulsivity
• Term developed with loose meaning

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History

• 1817 Lithium discovered by Johan Arvedson
• In 1890, Doctors Robert B. Cloud, Christopher
  Columbus Garrett, and W. H. Whitehead established
  the first hospital in America, the Lithia Springs
  Sanitarium
• Natural lithium water in treating alcoholism,
  opium addiction, and compulsive behavior
• Mania had not yet been identified as such

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History continued

• Dr Cloud Lithium Santiarium

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History continued

• Lithium Carbonate was discovered as treatment for
  mania in 1948 by Australian Psychiatrist John F.
  Cade working with rats
• 1970, FDA approved Li
• 1970 first report Carbamazepine useful in mania
• Valproic acid soon folllowed
• Typical antipsychotic agents used in the hospital
  setting
• Newer anticonvulsants then began to be looked at
• Atypical agents used for acute mania, mixed
  episodes, and maintenance

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Who Gets a Mood Stabilizer?

• People with BPAD I, II, and cyclothymia
• People with personality disorders
• People with unipolar depression (e.g lithium,
  lamictal)
• People with behavioral/anger/impulsive outbursts
  (intermittent expl. d/o, MR, ODD, etc)
• People with anxiety or in alcohol withdrawal

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• The Meds

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Types of Mood Stabilizers

• Lithium indicated for acute mania and long term
  control of BPAD
• Depakote indicated for treatment of mania
• Tegretol XL indicated for BPAD
• Lamictal indicated for maintenance treatment of
  BPAD
• Topamax, Neurontin, Keppra, Trileptal also used
  with little to no evidence
• All atypical antipsychotics are indicated for
  acute mania. Some have mixed episode indication
  and others have maintenance indication.

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Types of Mood Stabilizerscontinued

• Benzodiazepines used but not indicated (effective
  anti-manic agents usually in adjunct)
• Typical antipsychotic agents used when atypical
  agents and regular mood stabilizers cannot be
  used

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Lithium

• Gold standard for treatment of Bipolar disorder
• Effective as antimanic and antidepressant
• Side effects often limit compliance tremor,
  polydipsia, hypothyroidism hyperthyroidism,
  weight gain, nausea/vomiting, cognitive
  blunting, worsen psoriasis, hair loss, diarrhea,
  renal problems

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Lithium

• Steady state reached in 5 days
• Therepeutic trough levels
• Maintenance Bipolar Disorder 0.6 to 1.2
  meq/liter

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Lithium proposed mechanism

• i) Modulation of neurotransmitters by lithium
  likely readjusts balances between excitatory and
  inhibitory activities, and decreased
  glutamatergic activity may contribute to
  neuroprotection.
• (ii) Lithium modulates glycogen synthase,
  kinase-3beta, cyclic AMP-dependent kinase, and
  protein kinase C, which may be critical for the
  neural plasticity involved in mood recovery and
  stabilization.
• (iii) Lithium adjusts signaling activities
  regulating second messengers, transcription
  factors, and gene expression.

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Lithium Before starting

• Check BMP, TFTS, EPT, /- EKG
• Tell pt to maintain current salt intake
• See if pt is on meds that can impair renal
  excretion diuretics, ACE inhibitors, NSAIDS

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Lithium Maintenance

• Once pt is on therapeutic dose.
• Check BMP, Li trough level, TFTs 2x/year if no
  problems
• Reassess pts other meds (NSAIDS)
• Most patients develop polydipsia with chronic use
• Can cause Epsteins Heart Anomaly

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Renal Toxicity of Lithium

• 10-20 pts on li for gt10 years have morphological
  kidney changes
• Chronic lithium ingestion has been associated
  with several different forms of renal injury
• Nephrogenic DI is the most common
• Renal tubular acidosis
• Nephrotic syndrome
• Chronic interstitial nephritis

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Lithium - Overdose

• Symptoms slurred speech, incoordination,
  tremor, weakness, increased thirst, increased
  urine output, rash, diarrhea, vomiting, low blood
  pressure, rare abnormal rhythms, drowsiness,
  coma, seizures, stupor

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Hemodialysis

• Lithium is the most dialyzable toxin known, due
  to its low molecular weight, negligible protein
  binding, and volume of distribution similar to
  that of water

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Depakote - (Divalproex Na and Valproic Acid)

• Anticonvulsant
• Effective anti-manic medication
• Considered a first line treatment
• Comes in generic (valproic acid), liquid, IV
  form, regular release, DR, and ER
• Side effects weight gain, headaches, somnolence,
  GI upset hair loss, rash, dizziness, rare
  hepatotoxicity, rare pancreatitis, rare
  thrombocytopenia

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Depakote (Divalproex Na)

• Steady state reached in 3 days

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Depakote (Divalproex Na) proposed mechanism

• Increases or potentiates GABA in the brain
  (inhibitory NT)
• Puts brakes on the brain
• Seems effective as antimanic and anticonvulsant

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Depakote (Divalproex Na) Before Starting

• Check LFTs, CBC prior to starting
• Do not use in liver disease
• Good choice if patient also has migraines or
  seizures

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Depakote - Maintainance

• At stable level clinically, check LFTs, CBC,
  trough level 1-2/year (unless otherwise
  indicated)
• Can use higher doses in acute phase
• Watch for drug interactions
• Can cause neural tube defects - 5
• ? Polycystic ovary disease

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Tegretol - Carbamazepine

• Carbamazepine is used to treat certain types of
  seizures in the treatment of epilepsy
• Relieves facial nerve pain
• Used for alcohol withdrawal, mood stabilizer
• Like other tricyclic compounds, carbamazepine has
  a moderate anticholinergic action which is
  responsible for some of its adverse effects

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Tegretol - Carbamazepine

• Reaches steady state in 4-5 days
• Will increase metabolism of itself over time so
  you may need increased doses later in tx.

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Tegretol - Carbamazepine

• Common side effects dizziness or
  lightheadedness, dry, walking, drowsiness or
  fatigue, double vision, nausea or vomiting,
  clumsiness, delay in urinating
• Less Common Side Effects of carmbamezpine
  aplastic anemia, hepatitis, rash

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Tegretol - Carbamazepine proposed mechanism

• Mechanism unknown
• Believed to be serotonergic and block voltage
  sensitive Na channels
• Modulates high voltage Ca channels
• Reduces polysynaptic responses

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Neurontin - gabapentin

• Adjunctive anticonvulsant
• Mechanism of Action Structurally related to
  GABA, but does not bind to GABA sight
• Side Effects Mild sedation
• Uses ?Good anti-anxiety effects, alcohol
  withdrawal, neuropathic pain
• Evidence does not seem to support use as mood
  stabilizer
• Expensive placebo??

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Trileptal - Oxcarbazepine

• Carbamazepine (anticonvulsant) with an oxygen
  stuck on it
• Mechanism of Action Blocks voltage sensitive Na
  channels, Modulates high voltage Ca channels
• Most common side effects (occurring in at least
  5 of patients in clinical studies) were
  dizziness, somnolence, double vision, fatigue,
  nausea, vomiting, incoordination, abnormal
  vision, abdominal pain, tremor, indigestion, and
  abnormal gait.
• Watch for hyponatremia,

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Lamictal - Lamotrigine

• Phenyltriazine class (an anticonvulsant)
• Mechanism inhibit voltage sensitive Na channels
  stabilizing membranes modulating release of
  excitatory amino acids
• Good particularly for BPAD-depression/maintenance
• Potential for serious rash (Stevens-Johnson
  Syndrome 0.3-0.8)

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Topamax- Topiramate

• Anticonvulsant
• Mechanism of Action State dependent Na channel
  action, Enhances GABA, Antagonizes the glutamate
  reception
• Side Effects 10 memory cognitive problems,
  weight loss 1/3
• Not indicated yet as mood stabilizer

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Benzodiazepines

• Not indicated but useful to slow down the manic
  patient
• Most frequently used are ativan, klonopin

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Stimulants

• Christopher Pelic M.D.
• Associate Dean for Students
• Medical University of South Carolina

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Stimulants ADHD/Narcolepsy

• ADHD- inattention or hyperactivity with onset
  before age 7 that is seen in 2 or more settings
• Narcolepsy REM sleep attacks, Cataplexy,
  hypnogogic/hypnopompic hallucinations
• Obstructive sleep apnea

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ADHD Treatments (medication options)

• Established Treatments
• Psychostimulants (1st line)
• Atomoxetine (1st line)
• Bupropion (2nd line)
• TCAs (2nd- 3rd line)
• Probable Efficacy
• Modafinil
• Alpha-2 agonists

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Stimulants

• Increase dopamine and norepinephrine release
• Stimulate certain areas of the brain to focus
  better
• FDA classifies a substance as psychostimulant
  if nucleus accumbens is activated
• In use for behavioral disorders in children
  since 1930s
• Many studies to document safety and efficacy
• 70-85 response rate
• do not use this to confirm diagnosis!

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Stimulants

• Special consideration
• Motor tics
• Problems with growth/insomnia
• Anxiety d/o (children w/ co-morbid anxiety may
  improve on MPH, according to MTA study)
• Seizure d/o
• Children under 6 years old may be safely treated,
  starting with methylphenidate, once all
  psychosocial treatments have been implemented

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Methylphenidate Formulations
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Amphetamine Formulations
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Match the formulation with the needs of the
patient and family

• Have to know when youth needs the
  psychostimulant (e.g., early in AM for school
  only, or including homework, peer activities,
  week-ends)
• Parent and teen sometimes have definite
  preferences for one or another, and so do HMOs
• Train parents to observe efficacy and side
  effects through the day and into the evening

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Serious side effects of psychostimulants

• Sudden cardiac death
• Anecdotal, but not irrelevant
• Cases thus far have been primarily in patients
  with pre-existing cardiac conduction defects
• Ask about history of sudden tachycardia,
  fainting, and family history of sudden cardiac
  death prior to initiating
• 30 cases of psychosis or formal hallucinations
  discontinue the medication
• Growth Suppression (MTA 2004) effects are likely
  to be made up in late teens or by drug holidays
  especially at risk, those with nausea and vomiting

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Modafinil - PROVIGIL

• Used mostly for narcolepsy/sleep apnea
• Main mechanism unknown
• Modafinil, like other stimulants, increases the
  release of monoamines but also elevates
  hypothalamichistamine levels
• Activates glutamatergic circuits while inhibiting
  GABAergic neurotransmission

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ADHD Treatments (other medication options)

• Atomoxetine
• Potent norepinephrine (NE) reuptake inhibitor
• highly selective
• inhibits presynaptic NE transporter

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ADHD

• Clonidine is used as an adjunct
• Bupropion is used off label for ADHD

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Dementia Medications

• Christopher Pelic M.D.
• Associate Dean for Students
• Medical University of South Carolina

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Memory loss Alzheimers

• Loss of cholinergic, serotonergic, and glutamate
  neurons
• Plaques, tangles, tau, amyloid
• Progressive memory loss
• Medications are used to try and slow the
  progression (they do not prevent, cure, or stop
  the disease)

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Donepezil (Aricept)

• Acetylcholine esterase inhibitor
• Inhibits the break down of acetylcholine
• Used in mild to moderate dementia
• Side effects nausea, headache, vomiting,
  appetite suppression
• OTHER inhibitors tacrine (liver toxicity),
  rivastigmine, galantamine

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Memantine (Namenda)

• NMDA antagonist
• Side effects dizziness, headache, constipation