Lecture 67 + 68 - Antidepressants Flashcards
HISTORY AND BACKGROUND
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
DEPRESSION
Types of depression
– Reactive (60%)
– Major Depressive Disorder (25%)
– Bipolar Affective (15%)
Common mental illness of general population
– 10%, underdiagnosed, undertreated, suicidal
CLINICAL FEATURES OF DEPRESSION - physiological
decreased sleep, appetite changes, fatigue, psychomotor dysfunctions
– Other: menstrual irregularities, palpitations, constipation, headaches and nonspecific body aches
CLINICAL FEATURES OF DEPRESSION - psychological
dysphoric mood, worthlessness, excessive guilt, loss of interest/pleasure in all or most activities
CLINICAL FEATURES OF DEPRESSION - cognitive
decreased concentration, suicidal ideation
CLINICAL FEATURES OF DEPRESSION - diagnosis
Not due to drugs, medical condition, or bereavement
DRUG-INDUCED DEPRESSION - antihypertensive and cardiovascular
reserpine, methyldopa, propranolol, metoprolol, prazosin, clonidine, digitalis
DRUG-INDUCED DEPRESSION - sedative hypnotics
alcohol, benzodiazepines, barbiturates, meprobamate
DRUG-INDUCED DEPRESSION - anti-inflammatory and analgesics
indomethacin, phenylbutazone, opiates, pentazocine
DRUG-INDUCED DEPRESSION - steroids
corticosteroids, oral contraceptives, estrogen withdrawal
DRUG-INDUCED DEPRESSION - misc.
anti-parkinson, anti-neoplastic, neuroleptics
“BIOGENIC AMINE” HYPOTHESIS OF DEPRESSION
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
NEUROENDOCRINE HYPOTHESIS OF DEPRESSION
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
CRF1 + CRF2 sx
CRF1: arousal, anxiety-like behavior, disruption of sexual behaviors, disruption of sleep
CRF2: slow adaptive recovery, appetite suppression
NEUROTROPHIC HYPOTHESIS OF DEPRESSION - BDNF
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
INTEGRATION OF HYPOTHESES OF DEPRESSION
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
MAIN CLASSES OF DRUGS
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
Review of Synaptic Neurotransmission
block transporter proteins –> more neurotransmitters in synapse
antidepressants do the same thing - transporter inhibition
Why does therapy take 2-3 weeks?
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!
Mechanism of MAOIs
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
MAO Inhibitors
Non-selective MAO Inhibitors (irreversible):
– Phenelzine (Nardil)*
– Tranylcypromine (Parnate)*
MAO-B Selective (irreversible):
– Selegiline (Eldepryl/Ensam)*
MAO-A Selective (reversible):
– Moclobemide (Manerix)*
MAO Inhibitors SEs
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
Targets of reuptake blockers
monoamine transporters: DAT, NET, SERT
VMAT1 and VMAT2
Site of action of reuptake blockers
antidepressants bind the allosteric site, not transported through transporter, block NE and 5HT, have more in the synapse
Tricyclic Antidepressants
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
TERTIARY AMINES
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
Examples of Tertiary Amines
Imipramine (Tofranil): Metabolized to desipramine; enuresis and ADHS
Amitriptyline (Elavil): Metabolized to nortriptyline
Clomipramine (Anafranil)* Used for OCD
Doxepin (Adapin, Sinequan)*
SECONDARY AMINES
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)
Mechanism of SSRIs
Serotonin transporters pumps are blocked, increased amount of 5HT in synapse; 5HT stays in synapse longer and remains active longer
Examples of Selective Serotonin Reuptake Inhibitors
– Fluoxetine (Prozac): Little autonomic SE, no sedation
– Fluvoxamine (Luvox)
– Paroxetine (Paxil)*
– Sertraline (Zoloft)*
– Citalopram (Celexa)*
– Escitalopram oxalate (Lexapro)*: Isomer of citalopram
Uses of Selective Serotonin Reuptake Inhibitors
Depression, Alcoholism, OCD, Enuresis, PTSD, Eating Disorders, Social Phobias, Panic Anxiety, PMDD, GAD
Side effects of Selective Serotonin Reuptake Inhibitors
N/V, headache, sexual dysfunction, anxiety, insomnia, tremor
Syndromes of Selective Serotonin Reuptake Inhibitors
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
SSRI+5HT1A partial agonists
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
Tetracyclic and Unicyclic Antidepressants
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
5-HT2 Antagonists/SERT Inhibitor
Trazodone (Dyserel)* -5HT2A Antagonist -Weak SERT Inhibitor; Off-label-hypnotic (alpha1 and H1 with 5HT2)
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORs (SNRIs)
Venlafaxine (Effexor)*
Desvenlafaxine (Pristiq)*
Duloxetine (Cymbalta)*
Milnacipran (Ixel)*
Levomilnacipran (Fetzima)*
Venlafaxine
-NET & SERT Inhibitor
-Treats GAD & panic disorder
-Diabetic neuropathy?
-Migraine prophylaxis?
Desvenlafaxine
-NET & SERT Inhibitor
-Approved by FDA on February 2008
-Treatment of vasomotor symptoms associated with menopause?
Duloxetine
-NET & SERT Inhibitor
-Treats GAD
-Treats peripheral neuropathy
Milnacipran
-NET & SERT Inhibitor
-Approved for fibromyalgia
Levomilnacipran
-Active enantiomer of milnacipran
-NET & SERT Inhibitor
NOREPINEPHRINE SELECTIVE REUPTAKE INHIBITORS (NSRIs)
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
Selectivity Profiles
Clomipramine, SSRI, SNRI, amitriptyline bind SERT better
Maprotiline, nortriptyline bind NET better
smaller number in ratio has greater affinity
Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs)
“Triple Blockers” or “Triple Reuptake Inhibitors (TRIs)”
NET, SERT, DAT
Tesofensine & Brasofensine
NS2359 (GSK) & dov216303
Rapidly Acting Antidepressants: NMDA Antagonists
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
Clinically used NMDA antagonists
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
Postpartum Depression (PPD)
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
Brexanolone (Zulresso)*
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
NON-PHARMACOLOGICAL CONSIDERATIONS
Electroconvulsive Therapy
Psychotherapy
Hospitalization
PHARMACOTHERAPEUTIC CONSIDERATIONS
Severity of depression
Onset of drug action
Endogenous vs. exogenous depression
Unipolar vs. bipolar
Drug Selection
Dosing
Duration of therapy
Compliance
Other factors
Antidepressants and pain
shut down descending pathways in pain signal
Pharmacology of Filbanserin (Addyi)*
Hypoactive sexual desire disorder
Developed as antidepressant
Polypharmacology Agonist at 5HT1A, Antag at 5HT2A/C
Regional selectivity Prefrontal cortex
Controversial approval
BIPOLAR DISORDER
Introduction:
– Approximately 1.5-3% of Americans have bipolar disorder
– Onset < 30 years old
Etiology:
– Genetic predisposition
– Biological-5HT and DA
– Environmental
BIPOLAR DISORDER - types and symptoms
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
FEATURES OF MANIA
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
TREATMENT OF BIPOLAR
Hospitalization
Psychotherapy
Pharmacotherapy
Mood Stabilizers: Lithium, anticonvulsants Atypical Antipsychotics
*Calcium-channel blockers (verapamil, nimodipine)
Combination therapy (+benzodiazepine)
LITHIUM (light) PHARMACOTHERAPY
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
ANTICONVULANTS - valproic acid and sodium valproate
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)
ANTICONVULANTS
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)
ATYPICAL ANTIPSYCHOTICS*
Olanzapine (Zyprexa)
Olanzapine + Fluoxetine (Symbyax)
Quetiapine (Seroquel)
Risperidone (Risperidol)
Ziprasidone (Geodone/Zeldox)
Lurasidone (Lutada)
Aripiprazole (Abilify)
