Antidepressants Flashcards

1
Q

what are the types of depression

A

reactive, major depressive disorder and bipolar affective

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2
Q

what are the physiological features of Depression?

A

decreased sleep appetite changes fatigue and psychomotor dysfunction can also cause menstrual irregularities palpitations constipation headaches and nonspecific body aches

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3
Q

what are the psychological features of depression?

A

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

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4
Q

what are the cognitive features of depression?

A

decreased concentration suicidal ideation

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5
Q

what antihypertensive and cardiovascular drugs cause depression

A

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

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6
Q

what sedative-hypnotic drugs cause depression

A

alcohol, benzodiazepines, barbiturates, meprobamate

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7
Q

what Anti-inflammatory and analgesic drugs cause depression

A

indomethacin, phenylbutazone, opiates, pentazocine

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8
Q

what steroids can cause depression

A

corticosteroids, oral contraceptives, estrogen withdrawal

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9
Q

Other drugs that induce depression

A

anti-parkinson, anti-neoplastic, neuroleptics

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10
Q

what is the BIOGENIC AMINE” HYPOTHESIS OF DEPRESSION

A

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
Alterations in 5HT1A/2C and a2 receptors
NET = Norepinephrine transporter, SERT = Serotonin transporter
DAT = Dopamine transporter (minor)

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11
Q

What is the NEUROENDOCRINE HYPOTHESIS OF DEPRESSION

A

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

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12
Q

What is the NEUROTROPHIC HYPOTHESIS OF
DEPRESSION

A

Brain-derived neurotrophic factor (BDNF) is critical in Neural plasticity, resilience, neurogenesis
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
(however, some animal studies have provided opposing evidence, BDNF knock out animals and increase BDNF following stress)

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13
Q

what is the integration of hypotheses of depression

A

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 down regulation of the HPA axis

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14
Q

What are the main classes of drugs

A

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

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15
Q

What are the targets of Antidepressants

A

MAO, 5HT reuptake, NE reuptake and a2 receptors
some block transporters to increase neurotransmitters

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16
Q

Why does therapy take 4-8 weeks

A

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!

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17
Q

What is the mechanism of action for MAOIs

A

NE and serotonin usually degraded by MAO when inhibited there is an increase amount of NE and 5HT packaged in vesicles so more NE and 5HT end up being released from vesicles into the synapse

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18
Q

What are non-selective MAO inhibitors

A

phenelzine (nardil) and Tranylcypromine (parnate)

19
Q

what are MAO-B selective

A

selegline (eldepryl/ensam) and safinamide (xadago)

20
Q

What are MAO-A selective

A

moclobemide (manerix)

21
Q

What are MAO inhibitor side effects

A

Severe SE: headache drowsiness dry mouth weight gain orthostatic hypotension and sexual dysfunction
HTN crisis: avoid certain foods and drugs
interactions with OTC cold preparation diet pills
avoid foods with tyramine
Herbal products for depression St. John wort

22
Q

what are tricyclic antidepressants

A

used to treat major depression panic disorder chronic pain and enuresis can be extremely dangerous depressed patient more likely to be suicidal (2 weeks into treatment)

23
Q

What are tertiary amines

A

Inhibit both NE and 5HT reuptake via NET and SERT
Also act as receptor antagonists:
Antihistamine (H1)
Antimuscarinic
Antiadrenergic (a1)
Major Side Effects: These agents cause the most sedation, autonomic side effects, and weight gain
Other Side Effects: Conduction disturbances of heart

24
Q

What is Imipramine (tofranil)

A

tertiary amine is metabolized to desipramine used for enuresis and ADHD

25
Q

What is Amitriptyline(Elavil)

A

a tertiary amine that is metabolized to nortriptyline

26
Q

What is Trimipramine (Surmontil) and Clomipramine (Anafranil)

A

a tertiary amine Used for OCD

27
Q

What is Doxepin (Adapin, Sinequan)*

A

a tertiary amine

28
Q

What are secondary amines

A

Drugs: Desipramine (Norpramin)* Nortriptyline (Pamelor)* Protriptyline (Vivactil)
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)

29
Q

What is the MOA for SSRI

A

serotonin transporter pumps are blocked which increases the amount of 5HT in the synapse so 5HT stays in synapse longer and remain active longer

30
Q

What are the SSRI drugs

A

Fluoxetine (Prozac): Little autonomic SE, no sedation
Fluvoxamine (Luvox)

Paroxetine (Paxil)*
sertraline (Zoloft)*
Citalopram (Celexa)*
Escitalopram oxalate (Lexapro)*: Isomer of citalopram

31
Q

what are features of SSRIs

A

Uses Depression, Alcoholism, OCD, Enuresis, PTSD, Eating Disorders, Social
Phobias, Panic Anxiety, PMDD, GAD
Side Effects: N/V, headache, sexual dysfunction, anxiety, insomnia, tremor
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

32
Q

what are SSRI+5HT1A partial agonists

A

Vilazodone (Viibryd)-approved 2011 IC50 for SERT and 5HT1A similar (0.5 nM)
(60-70% intrinsic activity) Reduced sexual side effects vs pure SSRIs
Similar 5HT1A actions to: Aripiprazole (Abilify)-atypical antipsychotic Buspirone (Buspar)-partial 5HT1A for anxiety
Vortioxetine (Brintellex)
-approved 2013 SERT (2 nM), 5HT1A partial agonist (15 nM)
(70-80% intrinsic activity), and 5HT3 (4 nM)

32
Q

What are SNRIs?

A

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORs (SNRIs)
Venlafaxine (Effexor): NET & SERT Inhibitor, Treats GAD & panic disorder -Diabetic neuropathy? Migraine prophylaxis?
Desvenlafaxine (Pristiq): NET & SERT Inhibitor Treatment of vasomotor symptoms associated with menopause?

33
Q

Duloxetine (cymbalta)

A

SNRI, NET & SERT Inhibitor, Treats GAD, Treats peripheral neuropathy

34
Q

Milnacipran (Ixel)

A

SNRI, NET & SERT Inhibitor Approved for fibromyalgia

35
Q

Levomilnacipran (Fetzima)

A

SNRI -Active enantiomer of milnacipran NET & SERT Inhibitor

36
Q

What are NSRI

A

Norepinephrine selective reuptake inhibitors
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

37
Q

What are SNDRIs

A

Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors
Triple Blockers” or “Triple Reuptake Inhibitors (TRIs)”
Tesofensine (NeuroSearch) & Brasofensine
Tesofensine currently being researched as an appetite suppressant
NS2359 (GSK) & dov216303 (Merck)
Next-generation candidates for the treatment of depression
NS2359 was DCd and dov216303 may launch by 2011

38
Q

What are rapidly acting Antidepressants NMDA antagonists

A

Ketamine-subanesthetic doses
Scopolamine (muscarinic and NMDA antagonist)
Lanicemine (a.k.a. AZD6765)
“low trapping”
GLYX-13 partial NMDA antagonist
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)

39
Q

What is PPD

A

Postpartum depression: 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 receptors

40
Q

What is Brexanolone (zulresso)

A

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

41
Q

New Agents in Development

A

Psychedelics: MDMA (ectasy), psilocybin, and LSD (acid)
*5HT2C Receptor Antagonists
*Metabotropic Glutamate Receptor Agonists
*Reversible Inhibitors of Monoamine Oxidase-A (RIMAs):
* Moclobemide (MOC; Manerix)
* Brofaromine (BRO)
* Are as effective as TCAs and better tolerated

42
Q

what are non-pharm considerations

A

Electroconvulsive Therapy
*Psychotherapy
*Hospitalization

43
Q

What are pharmacotherapeutic considerations

A

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