Lecture 67 + 68 - Antidepressants

Question 1

HISTORY AND BACKGROUND

Answer 1

 1950s: Imipramine (1st TCA) as the 1st antidepressant
 Isoniazid (MAOI) an antituberculosis drug
 Additional TCAs
 Present: SSRIs, atypicals, and dual acting
Goals of Therapy: Alleviate signs and symptoms

Question 2

DEPRESSION

Answer 2

 Types of depression
– Reactive (60%)
– Major Depressive Disorder (25%)
– Bipolar Affective (15%)
 Common mental illness of general population
– 10%, underdiagnosed, undertreated, suicidal

Question 3

CLINICAL FEATURES OF DEPRESSION - physiological

Answer 3

decreased sleep, appetite changes, fatigue, psychomotor dysfunctions
– Other: menstrual irregularities, palpitations, constipation, headaches and nonspecific body aches

Question 4

CLINICAL FEATURES OF DEPRESSION - psychological

Answer 4

dysphoric mood, worthlessness, excessive guilt, loss of interest/pleasure in all or most activities

Question 5

CLINICAL FEATURES OF DEPRESSION - cognitive

Answer 5

decreased concentration, suicidal ideation

Question 6

CLINICAL FEATURES OF DEPRESSION - diagnosis

Answer 6

Not due to drugs, medical condition, or bereavement

Question 7

DRUG-INDUCED DEPRESSION - antihypertensive and cardiovascular

Answer 7

reserpine, methyldopa, propranolol, metoprolol, prazosin, clonidine, digitalis

Question 8

DRUG-INDUCED DEPRESSION - sedative hypnotics

Answer 8

alcohol, benzodiazepines, barbiturates, meprobamate

Question 9

DRUG-INDUCED DEPRESSION - anti-inflammatory and analgesics

Answer 9

indomethacin, phenylbutazone, opiates, pentazocine

Question 10

DRUG-INDUCED DEPRESSION - steroids

Answer 10

corticosteroids, oral contraceptives, estrogen withdrawal

Question 11

DRUG-INDUCED DEPRESSION - misc.

Answer 11

anti-parkinson, anti-neoplastic, neuroleptics

Question 12

“BIOGENIC AMINE” HYPOTHESIS OF DEPRESSION

Answer 12

 Reserpine causes depression by depleting NE and 5HT from vesicles
 Agents that increase 5HT and NE are effective for treating depression
 Genetic polymorphisms in SERT promoter (s = short vs l = long allele)
 Alterations in 5HT1A/2C and alpha2 receptors

Question 13

NEUROENDOCRINE HYPOTHESIS OF DEPRESSION

Answer 13

 Changes in Hypothalamic-Pituitary-Adrenal (HPA) Axis
– Stress causes hypothalamus to release CRF,
– CRF promotes release of ACTH from pituitary,
– ACTH promotes release of cortisol from adrenal
 Overactivity of HPA and elevated CRF found in almost all depressed patients
 Overactivity of HPA may desensitize feedback response in hypothalamus and pituitary
 Elevated CRF causes insomnia, anxiety, and decreased appetite and libido
 Antidepressants and ECT reduce CRF levels

Question 14

CRF1 + CRF2 sx

Answer 14

CRF1: arousal, anxiety-like behavior, disruption of sexual behaviors, disruption of sleep
CRF2: slow adaptive recovery, appetite suppression

Question 15

NEUROTROPHIC HYPOTHESIS OF DEPRESSION - BDNF

Answer 15

 Brain-derived neurotrophic factor (BDNF) is critical in
– Neural plasticity, resilience, neurogenesis (neuronal connections)
 Stress and pain decrease BDNF levels in animals
 Decrease in volume (5-10%) of hippocampus (memory and regulates HPA)
 BDNF has “antidepressant” activity in animals
 Depressed patients have reduced BDNF levels
 Antidepressants increase BDNF levels and may increase hippocampal volume

Question 16

INTEGRATION OF HYPOTHESES OF DEPRESSION

Answer 16

 HPA and steroid abnormalities regulate BDNF levels
 Hippocampal glucocorticoid receptors are activated by cortisol during stress (decreasing BDNF)
 Chronic activation of monoamine receptors increases BDNF signaling (> 2 weeks)
 Chronic activation of monoamine receptors leads to a downregulation of the HPA axis

Question 17

MAIN CLASSES OF DRUGS

Answer 17

MAOIs = Monoamine Oxidase Inhibitors
TCAs = Tricyclic Antidepressants; tertiary and secondary amines (a.k.a. SNRIs, see below)
SSRIs = Selective-Serotonin Reuptake Inhibitors SNRIs = Serotonin-Norepinephrine Reuptake Inhibitors
5-HT2 Antagonists
Tetracyclic and Unicyclic Antidepressants

Question 18

Review of Synaptic Neurotransmission

Answer 18

block transporter proteins –> more neurotransmitters in synapse
antidepressants do the same thing - transporter inhibition

Question 19

Why does therapy take 2-3 weeks?

Answer 19

Neuroadaptive responses?
Antidepressants cause the amount of neurotransmitter in the intrasynaptic space to increase.
Is the delay in clinical effect due to…
 Activation of presynaptic receptors?
 Presynaptic adaptation?
 Postsynaptic adaptation?
→ No one really knows!

Question 20

Mechanism of MAOIs

Answer 20

Norepinephrine, Dopamine and Serotonin are normally degraded by Monoamine Oxidase (MAO)
Increased amount of NE and 5HT packaged in vesicles, more NE and 5HT is released from vesicles into the synapse

Question 21

MAO Inhibitors

Answer 21

 Non-selective MAO Inhibitors (irreversible):
– Phenelzine (Nardil)*
– Tranylcypromine (Parnate)*
 MAO-B Selective (irreversible):
– Selegiline (Eldepryl/Ensam)*
 MAO-A Selective (reversible):
– Moclobemide (Manerix)*

Question 22

MAO Inhibitors SEs

Answer 22

 Severe Side Effects: Headache, drowsiness, dry mouth, weight gain, orthostatic hypotension, sexual dysfunction – (Limited use)
 Hypertensive Crisis: Avoid certain foods and drugs!!!!!
 Interactions with OTCs: Cold preparations, diet pills
 Interactions with Rx: TCAs, SSRIs, L-DOPA
 Avoid Foods with Tyramine (partial list): Cheeses, sour cream, liver, sausage, bologna, pepperoni, salami, game meats, salted or pickled herring, shrimp paste, beer, ale, red wine, sherry, vermouth, distilled spirits, avocados, bananas, figs, sauerkraut, soy sauce, miso soup, tofu, fava beans, and ginseng
 Herbal Products for Depression: St. John’s Wort –> MAOI activity

Question 23

Targets of reuptake blockers

Answer 23

monoamine transporters: DAT, NET, SERT
VMAT1 and VMAT2

Question 24

Site of action of reuptake blockers

Answer 24

antidepressants bind the allosteric site, not transported through transporter, block NE and 5HT, have more in the synapse

Question 25

Tricyclic Antidepressants

Answer 25

 Indications for TCAs: Depression, panic disorder, chronic pain, and enuresis
 Overdose/Toxicity: Extremely dangerous, depressed patients are more likely to be suicidal
– Patients are more likely to commit self-harm or suicide 2 weeks into treatment

Question 26

TERTIARY AMINES

Answer 26

 Inhibit both NE and 5HT reuptake via NET and SERT
more potent in blocking reuptake of 5HT
 Also act as receptor antagonists:
– Antihistamine (H1)
– Antimuscarinic
– Antiadrenergic (alpha1)
 Major Side Effects: These agents cause the most sedation, autonomic side effects, and weight gain
 Other Side Effects: Conduction disturbances of heart

Question 27

Examples of Tertiary Amines

Answer 27

Imipramine (Tofranil): Metabolized to desipramine; enuresis and ADHS
Amitriptyline (Elavil): Metabolized to nortriptyline
Clomipramine (Anafranil)* Used for OCD
Doxepin (Adapin, Sinequan)*

Question 28

SECONDARY AMINES

Answer 28

most are better NET than SERT inhibitors
 Drugs:
– Desipramine (Norpramin)*
– Nortriptyline (Pamelor)*
– Maprotiline (Ludiomil)* - NET inhibitor (Tetracyclic reduced side effects)
 Side Effects: less sedation, less anticholinergic, less autonomic, less weight gain, less cardiovascular than tertiary amines
 In general, side effects of ALL TCAs are…
– Anticholinergic, CV (elderly), Neurological, Weight Gain
– Remember patients may be suicidal (depression)

Question 29

Mechanism of SSRIs

Answer 29

Serotonin transporters pumps are blocked, increased amount of 5HT in synapse; 5HT stays in synapse longer and remains active longer

Question 30

Examples of Selective Serotonin Reuptake Inhibitors

Answer 30

– Fluoxetine (Prozac): Little autonomic SE, no sedation
– Fluvoxamine (Luvox)
– Paroxetine (Paxil)*
– Sertraline (Zoloft)*
– Citalopram (Celexa)*
– Escitalopram oxalate (Lexapro)*: Isomer of citalopram

Question 31

Uses of Selective Serotonin Reuptake Inhibitors

Answer 31

Depression, Alcoholism, OCD, Enuresis, PTSD, Eating Disorders, Social Phobias, Panic Anxiety, PMDD, GAD

Question 32

Side effects of Selective Serotonin Reuptake Inhibitors

Answer 32

N/V, headache, sexual dysfunction, anxiety, insomnia, tremor

Question 33

Syndromes of Selective Serotonin Reuptake Inhibitors

Answer 33

 SSRI Discontinuation Syndrome: “brain zaps,” dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo
 Serotonin Syndrome: When given with MAOIs, TCAs; also metoclopramide, tramadol, triptans (i.e. sumitriptan or rizatriptan), St. John’s wort
– Symptoms: hyperthermia, muscle rigidity, restlessness, myoclonus, hyperreflexia, sweating, shivering, seizures, and coma
– Treatment: discontinuation of medication and management of symptoms, administration of serotonin antagonists (cyproheptadine or methysergide); benzodiazepines to control myoclonus

Question 34

SSRI+5HT1A partial agonists

Answer 34

Vilazodone (Viibryd)-approved 2011; Reduced sexual side effects vs pure SSRIs; Similar 5HT1A actions to: Aripiprazole (Abilify)-atypical antipsychotic and Buspirone (Buspar)-partial 5HT1A for anxiety
Vortioxetine (Brintellex)-approved 2013

Question 35

Tetracyclic and Unicyclic Antidepressants

Answer 35

Maprotiline (Ludiomil): NET inhibitor
Mirtazapine (Remeron):
-α2 Antagonist
-5HT2 & 5HT3 Antagonist
-H1 Antagonist
Bupropion (Wellbutrin)*
-DAT Inhibitor
-NET & SERT Inhibitor
-Also treats GAD
-Zyban for smoking cessation

Question 36

5-HT2 Antagonists/SERT Inhibitor

Answer 36

Trazodone (Dyserel)* -5HT2A Antagonist -Weak SERT Inhibitor; Off-label-hypnotic (alpha1 and H1 with 5HT2)

Question 37

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORs (SNRIs)

Answer 37

Venlafaxine (Effexor)*
Desvenlafaxine (Pristiq)*
Duloxetine (Cymbalta)*
Milnacipran (Ixel)*
Levomilnacipran (Fetzima)*

Question 38

Venlafaxine

Answer 38

-NET & SERT Inhibitor
-Treats GAD & panic disorder
-Diabetic neuropathy?
-Migraine prophylaxis?

Question 39

Desvenlafaxine

Answer 39

-NET & SERT Inhibitor
-Approved by FDA on February 2008
-Treatment of vasomotor symptoms associated with menopause?

Question 40

Duloxetine

Answer 40

-NET & SERT Inhibitor
-Treats GAD
-Treats peripheral neuropathy

Question 41

Milnacipran

Answer 41

-NET & SERT Inhibitor
-Approved for fibromyalgia

Question 42

Levomilnacipran

Answer 42

-Active enantiomer of milnacipran
-NET & SERT Inhibitor

Question 43

NOREPINEPHRINE SELECTIVE REUPTAKE INHIBITORS (NSRIs)

Answer 43

 Reboxetine (Vestra, Edronax)*
– Possibly less side effects than Prozac
– The FDA declined the license for use in the USA for unknown reasons
 Atomoxetine (Straterra)*
– Originally intended to be an antidepressant drug (not approved!)
- used for ADHD

Question 44

Selectivity Profiles

Answer 44

Clomipramine, SSRI, SNRI, amitriptyline bind SERT better
Maprotiline, nortriptyline bind NET better
smaller number in ratio has greater affinity

Question 45

Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs)

Answer 45

 “Triple Blockers” or “Triple Reuptake Inhibitors (TRIs)”
NET, SERT, DAT
 Tesofensine & Brasofensine
 NS2359 (GSK) & dov216303

Question 46

Rapidly Acting Antidepressants: NMDA Antagonists

Answer 46

excitatory amino acid ionotropic receptor
 Ketamine- subanesthetic doses
 Scopolamine (muscarinic and NMDA antagonist)
 Lanicemine (a.k.a. AZD6765) “low trapping”
 GLYX-13 partial NMDA antagonist

Question 47

Clinically used NMDA antagonists

Answer 47

 Ketamine-subanesthetic doses
 Esketamine (Spravato) FDA approved Feb 2019 (in conjunction with oral antidepressant)
CNS effects: depression, drug interactions
Intranasal, phased dosing: (twice weekly, weekly, and every two weeks), $600-900/dose
*available only through restricted program (REMS

Question 48

Postpartum Depression (PPD)

Answer 48

 PPD occurs 10-15% (within 4 weeks and can last > 1yr)
 SSRIs (fluoxetine and paroxetine) and venlafaxine
 Others: CBT and counseling
 **Brexanolone (Zulresso) *March 19, 2019
New M.O.A. involving GABA-A receptor

Question 49

Brexanolone (Zulresso)*

Answer 49

 Allopregnanolone levels ↑ during pregnancy
 GABA-A receptors desensitize?
 Allopregnanolone levels return to normal postpartum
 Brexanolone resensitizes GABA-A receptors. (allosteric site)
 REMS Drug
 60 hr infusion
 $20,000-30,000 + hospital costs

Question 50

NON-PHARMACOLOGICAL CONSIDERATIONS

Answer 50

Electroconvulsive Therapy
 Psychotherapy
 Hospitalization

Question 51

PHARMACOTHERAPEUTIC CONSIDERATIONS

Answer 51

 Severity of depression
 Onset of drug action
 Endogenous vs. exogenous depression
 Unipolar vs. bipolar
 Drug Selection
 Dosing
 Duration of therapy
 Compliance
 Other factors

Question 52

Antidepressants and pain

Answer 52

shut down descending pathways in pain signal

Question 53

Pharmacology of Filbanserin (Addyi)*

Answer 53

 Hypoactive sexual desire disorder
 Developed as antidepressant
 Polypharmacology Agonist at 5HT1A, Antag at 5HT2A/C
 Regional selectivity Prefrontal cortex
 Controversial approval

Question 54

BIPOLAR DISORDER

Answer 54

 Introduction:
– Approximately 1.5-3% of Americans have bipolar disorder
– Onset < 30 years old
 Etiology:
– Genetic predisposition
– Biological-5HT and DA
– Environmental

Question 55

BIPOLAR DISORDER - types and symptoms

Answer 55

 Types:
– Bipolar I Disorder
– Bipolar II Disorder
– Cyclothymia Disorder
– Unspecified Bipolar and Related Disorder
– Substance-Induced Mood Disorder
 Symptoms:
– Mania, Hypomania, Depression, Mixed mania and depression

Question 56

FEATURES OF MANIA

Answer 56

 Mania: Euphoria/elation, irritability/anger, impulsive high risk behavior, aggressive, grandiose ideas, decrease sleep and appetite, difficulty concentrating, delusions, flight of ideas, hallucinations
 Hypomania: Less severe mania
 Depression

Question 57

TREATMENT OF BIPOLAR

Answer 57

 Hospitalization
 Psychotherapy
 Pharmacotherapy
Mood Stabilizers: Lithium, anticonvulsants Atypical Antipsychotics
*Calcium-channel blockers (verapamil, nimodipine)
Combination therapy (+benzodiazepine)

Question 58

LITHIUM (light) PHARMACOTHERAPY

Answer 58

 Mechanism not clearly understood -depletion of PIP2 and associated signaling (IP3 and PKC) -modulate GSK3 (Phosphorylation and binding partners)
depletion of substrate (PIP2) for PLC signaling
 Small therapeutic index
 Acute vs. Chronic
 Lag time for effectiveness
 Loading dose

Question 59

ANTICONVULANTS - valproic acid and sodium valproate

Answer 59

 Valproic Acid and Sodium Valproate* Multiple mechanisms of action: Increase GABAergic tone (increase GAD activity, inhibit GABA transaminase); Block Na+ channels (see next page); Block T-type Ca2+ channels
Inhibits histone deacetylase (HDAC5)

Question 60

ANTICONVULANTS

Answer 60

 Carbamazepine (Tegretol)/Oxcarbazepine (Trileptal): Na+ channels
 Lamotrigine (Lamictal): Na+ and Ca2+ (N-, P/Q)
 Topiramate (Topamax)*: Na+ channel (may enhance; GABA at receptor and blocks excitatory AA receptors)

Question 61

ATYPICAL ANTIPSYCHOTICS*

Answer 61

 Olanzapine (Zyprexa)
 Olanzapine + Fluoxetine (Symbyax)
 Quetiapine (Seroquel)
 Risperidone (Risperidol)
 Ziprasidone (Geodone/Zeldox)
 Lurasidone (Lutada)
 Aripiprazole (Abilify)