Watts Antidepressants Flashcards
Types of depression
-Reactive (60%)
-Major depressive disorder (25%)
-Bipolar affective (15%)
Physiological symptoms of depression
-Decreased sleep
-Appetite changes
-Fatigue
-Psychomotor dysfunctions
-Menstrual irregularities
-Palpitations
-Constipation
-Headaches
-Nonspecific body aches
Psychological symptoms of depression
-Dysphoric mood
-Worthlessness
-Excessive guilt
-Loss of interest/pleasure in all or most activities
Cognitive symptoms of depression
-Decreased concentration
-suicidal ideation
What must be ruled out when diagnosing depression?
It is not caused by drugs, medical conditions, or bereavement
What drugs can cause drug-induced depression?
-Antihypertensive and Cardiovascular
-Sedative-hypnotics
-Anti-inflammatory and analgesics
-Steroids
-Anti-Parkinson
-Anti-neoplastic
-Neuroleptics
What is the biogenic amine hypothesis of depression?
-Reserpine causes depression by deleting NE and 5HT from vesicles
-Agents that increase 5HT and NE are effective for treating depression
-Genetic polymorphisms in SERT promoter
-Alteration in 5HT1A/2C and alpha2 receptors
What is the neuroendocrine hypothesis of depression?
-Changes in hypothalamic-pituitary-adrenal 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 and elevated CRF found in almost all depressed patients
-Overactivity of HPA may desensitize feedback response in hypothalamus an pituitary
-Elevated CRF causes insomnia, anxiety, and decreased appetite and libido
-Antidepressants and ECT reduce CRF levels
What is the neurotrophic hypothesis of depression?
-Brain-derived neurotrophic factor is critical in neural plasticity, resilience, neurogenesis
-Stress and pain decrease BDNF levels in animals
-Decrease in volume of hippocampus
-BDNF has antidepressant activity in animals
-Depressed patients have reduced BDNF levels
-Antidepressants increase BDNF levels and may increase hippocampal volume
Which hypothesis of depression is correct?
All hypotheses can explain depression
What are the main classes of antidepressants?
-MAOIs
-TCAs
-SSRIs
-SNRIs
-5-HT2 antagonists
-Tetracyclic and unicyclic antidepressants
Why does antidepressant therapy take 2-3 weeks?
-Neuroadaptive responses?
-Activation of presynaptic receptors?
-Presynaptic adaptation?
-Postsynaptic adaptation?
-No one really knows
Mechanism of action of MAOIs
-Norepinephrine and serotonin are normally degraded by monoamine oxidase
-Blocking this degradation causes the vesicles to increase the amount of NE and 5HT that are packaged
-These vesicles then release more NE and 5HT into the synapse
What are the non-selective MAO inhibitors?
-Phenelzine
-Tranylcypromine
What are the MAO-B selective inhibitors?
-Selegiline
What are the MAO-A selective inhibitors?
-Moclobemide
What class of MAO inhibitors is irreversible?
Non-selective MAO inhibitors
What are common side effects associated with MAO inhibitors?
-Headache
-Drowsiness
-Dry mouth
-Weight gain
-Orthostatic hypotension
-Sexual dysfunction
-Hypertensive crisis
What are common interactions with MAOIs?
-Cold preparations and diet pills
-TCAs, SSRIs, L-DOPA
-Foods with tyramine
-St. Johns Wort
Indications for TCAs
-Depression
-Panic disorder
-Chronic pain
-Enuresis (bed wetting)
Overdose/toxic effects of TCAs
-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 amine mechanism of action
-Inhibits both NE and 5HT reuptake via NET and SERT
-Also acts as antagonists on H1 histamine receptors, muscarinic receptors, and alpha1 receptors
Major side effects associated with tertiary amines
-Sedation
-Autonomic side effects
-Weight gain
-Conduction disturbances of the heart (not major)
What are the tertiary amines used?
-Imipramine
-Amitriptyline
-Clomipramine (used for OCD)
-Doxepin
What is imipramine metabolized to?
Desipramine
What is amitriptyline metabolized to?
Nortriptyline
What are the secondary amines used?
-Desipramine
-Nortriptyline
-Maprotiline (NET inhibitor)
Side effects of secondary amines
Less sedation, anticholinergic effects, autonomic effects, weight gain, and cardiovascular effects compared to tertiary amines
What are the SSRIs used?
-Fluoxetine (little autonomic SE, no sedation)
-Fluvoxamine
-Paroxetine
-Sertraline
-Citalopram
-Escitalopram
What are SSRIs used for?
-Depression
-Alcoholism
-OCD
-Enuresis
-PTSD
-Eating disorders
-Social phobias
-Panic anxiety
-PMDD
-GAD
Side effects of SSRIs
-Nausea/vomiting
-Sexual dysfunction
-Anxiety
-Insomnia
-Tremors
Side effects of abruptly discontinue SSRIs
-Brain zaps
-Dizziness
-Sweating
-Nausea
-Insomnia
-Tremor
-Confusion
-Vertigo
What drugs can cause serotonin syndrome?
-MAOIs
-TCAs
-Metoclopramide
-Tramadol
-Triptans
-St. Johns Wort
Symptoms of serotonin syndrome
-Hyperthermia
-Muscle rigidity
-Restlessness
-Myoclonus
-Hyperreflexia
-Sweating
-Shivering
-Seizures
-Coma
How to treat serotonin syndrome
-Discontinuation of medication and management of symptoms
-Administration of serotonin antagonists (cyproheptadine or methysergide)
-Benzodiazepines to control myoclonus
What are the SSRI+5HT1A partial agonists?
-Vilazodone
-Vortioxetine
Differences between SSRI+5HT1A partial agonists and pure SSRIs
SSRI+5HT1A partial agonists have less sexual side effects vs pure SSRIs
What are the tetracyclic and unicyclic antidepressants used?
-Maprotiline
-Mirtazipine
-Bupropion
Maprotiline mechanism of action
NET inhibitor
Mirtazapine mechanism of action
-Alpha2 antagonist
-5HT2 and 5HT3 antagonist
-H1 antagonist
Bupropion mechanism of action
-DAT inhibitor
-NET and SERT inhibitor
-Also treats GAD
-Zyban for smoking cessation
What are the 5-HT2 antagonists/SERT inhibitor?
Trazodone (Off-label hypnotic)
What are the SNRIs?
-Venlafaxine
-Desvenlafaxine
-Duloxetine
-Milnacipran
-Levomilnacipran
Venlafaxine clinical pearls
-NET and SERT inhibitor
-Treats GAD and panic disorder
-Diabetic neuropathy
-Migraine prophylaxis
Desvenlafaxine clinical pearls
-NET and SERT inhibitor
-Approved by FDA February 2008
-Treatment of vasomotor symptoms associated with menopause?
Duloxetine clinical pearls
-NET and SERT inhibitor
-Treats GAD
-Treats peripheral neuropathy
Milnacipran clinical pearls
-NET and SERT inhibitor
-Approved for fibromyalgia
Levomilnacipran clinical pearls
-Active enantiomer of milnacipran
-NET and SERT inhibitor
-Approved in 2013
What are the norepinephrine selective reuptake inhibitors?
-Reboxetine
-Atomoxetine
Reboxetine clinical pearls
-Possibly less side effects than Prozac
-Licensed in over 50 countries by 2007
-The FDA declined the license for use in the USA for unknown reasons
Atomoxetine clinical pearls
-Originally intended to be an antidepressant drug (not approved!)
-Used for ADHD
What are the serotonin-norepinephrine-dopamine reuptake inhibitors?
-Tesofensine
-Brasofensine
What are triple blockers used for?
-Early research as Parkinson’s therapies
-Tesofensine is currently being researched as an appetite suppressants
What are the NMDA antagonists?
-Ketamine - subanesthetic doses
-Scopolamine (muscarinic and NMDA antagonist)
-Lanicemine
Esketamine side effects
-Depression
-Drug interactions
How to treat postpartum depression
-SSRIs (fluoxetine and paroxetine)
-Venlafaxine
-CBT and counseling
-Brexanolone
Brexanolone mechanism of action
-Allopregnanolone levels increase during pregnancy
-GABAa receptors desensitize
-Allopregnanolone levels return to normal postpartum
-Brexanolone resensitizes GABAa receptors
New antidepressants in development
-Psychedelics: MDMA (ecstasy), psilocybin, and LSD (acid)
-5HT2C receptor antagonists
-Metabotropic glutamate receptor agonists
-Reversible inhibitors of monoamine oxidase-A (RIMAS)
Non-pharmacologic considerations for treatment of depression
-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
Pharmacology of Filbanserin
-Hypoactive sexual desire disorder
-Developed as antidepressant
-Polypharmacology - agonist at 5HT1A, antagonist at 5HT2A/C
-Regional selectivity - prefontal cortex
-Controversial approval
Types of bipolar
-Bipolar 1 disorder
-Bipolar 2 disorder
-Cyclothymia disorder
-Unspecified bipolar and related disorder
-Substance-induced mood disorder
Bipolar symptoms
-Mania
-Hypomania
-Depression
-Mixed mania and depression
Symptoms of mania
-Euphoria/elation
-Irritability/anger
-Impulsive high risk behavior
-Aggressive
-Grandiose ideas
-Decrease sleep and appetite
-Difficulty concentrating
-Delusions
-Flight of ideas
-Hallucinations
What is hypomania?
Less severe mania
Treatments of bipolar disorder
-Hospitalization
-Psychotherapy
-Pharmacotherapy
What drugs are used to treat bipolar disorder?
-Lithium
-Anticonvulsants
-Atypical antipsychotics
-Calcium-channel blockers (verapamil, nimopidine)
-Combo therapy (+BZD)
Lithium clinical pearls
-Mechanism not clearly understood
-Deletion of PIP2 and associated signaling
-Modulate GSK3
-Small therapeutic index
-Acute vs chronic
-Lag time for effectiveness
-Loading dose
Anticonvulsants used for depression
-Sodium valproate
-Carbamazepine
-Lamotrigine
-Topiramate
Anticonvulsant mechanism of action
-Increase GABAergic tone (increase GAD activity, inhibit GABA transaminase)
-Block Na+ channels
-Block T-type Ca2+ channels
-Inhibits histone deacetylase (HADAC5)
Atypical antipsychotics used for depression
-Olanzapine
-Olanzapine + fluoxetine
-Quetiapine
-Risperidone
-Ziprasidone
-Lurasidone
-Aripiprazole
