Antidepressants

Question 1

Monoamine theory of depression

Answer 1

Increase in monoamines–> lower depression, Decrease–> depression (not entirely true (takes long time for it to work) but still works from pharmacological perspective)

MAO depression theory results from functionally deficient monoamine (NE and 5HT) transmission in the CNS

known antidepressants drugs (TCAs and MAOi) facilitate monaminergic transmission

drugs such as reserpine that depletes amines to cause depression

Simple MAO hypothesis no longer tenable as an explanation of depression BUt pharmacological manipulation of MOA transmission remains the most successful approach to treating depression

Question 2

Neurotransmitter localization in the brains

Answer 2

neurons containing NE are located in the locus coeruleus and innervate the entire brain

Neurons containing serotonin are located in 2 groups of raphe nuclei and project to the entire brain

Neurons containing Dopamine are located in the substantia nigra (project to the striatum) and the VTA of the midbrain

Neurons containing ACh are located in the basal forebrain (septal nuclei and nucleus basilis –> hippocampus and neocortex)

Question 3

Norepinephrine synapse

Answer 3

Tyrosine is taken up into the axon,
Tyrosine hydroxylase converts tyrosine –> DOPA
DOPA decarboxylase converts DOPA–> dopamine (DA)

DA is taken up into vesicle and converted DA–> NE by Dopamine B hydroxylase

When Ca channels are activated by depolarization, CA allows the vessicles to release the NE into the cleft

NE from synaptic cleft binds a2 and inhibits the vesicles release

NE is taken back up via reuptake (COCAINE BLOCKS)
Metabolized or extra neuronal uptake, diffuse into blood , can be inactivated in the neuron via MAO

Question 4

TCAs

Answer 4

Acutely reuptake is inhibited and NE increases in the synapse

Chronically, the increased NE, downregulates the post synaptic receptors and NE increases greately in the synapse

Question 5

SSRIs

Answer 5

SERT is blocked and 5HT remains in the synapse

Down regulation in post synaptic receptors

Question 6

Mirtazapine

Answer 6

a2 antagonist and increases NE release in the synapse

heteroreceptors on 5HT neurons, and increase 5HT in the synapse

Question 7

MAO i

Answer 7

Phenelzine, will all downregulate the receptors

Question 8

Restated Monoamine hypotheisis

Answer 8

Depression is due to a biogenic amine receptor or transmission imbalance, the various drugs act to change the imbalance and restore a more normal affect

Question 9

The pharmacological treatment of affective disorder in order of usage

Answer 9

1. SSRIs
2. SNRIs
3. Atypical drugs
4. TCAS
5. MAOi

Question 10

SSRIs (5HT uptake inhibitors)

Answer 10

FLUOXETINE, FLUVOXAMINE, PAROXETINE, SERTRALINE, CITALOPRAM

Antidepressant actions are similar in efficacy and time- course to those of TCAs

Acute toxicity is less than that of the tricyclic antidepressants and MAOi, therefore overdose risk is reduced

SEs include nausea, insomnia, and sexual dysfunction

No food reactions, but dangerous serotonin reaction (hyperthermia, muscle rigidity, Cardiovascular collapse) can occur if given with MAOis

FDA also now requires warnings about association of SSRIs and SNRIs with the neuroleptic malignant syndrome

Question 11

ANTIDEPRESSANTS black box warning

Answer 11

in clinical settings, antidepressants increased the risk of suicidal thinking and behavior in children an dadolescents with depression and other psychiatric disorders, anyone considering the use of antidepressants in a child or adolescent must balance the risk with the clinical need, pts who are starting therapy should be observed closely, families and caregivers should discuss any observations of wosening depression, symptoms, suicidal thinking, and behavior, or unusal changes in behavior, can be used with cautio in MDD or obsessive compulsive disorder

Question 12

symptoms of SSRI withdrawal

Answer 12

dizziness, light headedness, vertigo or feeling faint, shock like sensations, paresthesia, anxiety, diarrhea, fatigue, gait instability , headache, insomnia, irritability, nausea or vomiting, tremor, visual disturbance (neuro and GI symptons)

but fluoxetine rarely gets this because it has a very long t.5 so naturally the body tapers off

Question 13

SSRI Approved USes

Answer 13

MDD, OCD, Panic disorder, social anxiety, PTSD, GAD, PMS (PDD), hotflashes associated with menopause

Question 14

commonly perscribed SSRIs

Answer 14

Fluoxetine (prozac)- first SSRI on market, CYP450 2D6 (tamoxifen) and 2C19, long half life active metabolite (7 days), now abailable as a sustained release, PDD use

Sertraline- similar in action to fluoxetine with less effects on metabolism, shorter t.5, OCD, PTSD, Panic, PDD

Paroxetine- hotflashes

Fluvoxamine- OCD

Citalopram and Escitalopram- most specific SSRI, Citalopram can cause prolonged QT interval

Question 15

SNRIs (Serotonin- norepinephrine reuptake inhibitors)

Answer 15

drugs block both 5ht and NE reuptake, Side effect profile is more like SSRIs

Duloxetine- MDD and anxiety, also approved for neuropathic pain syndromes, fibromyalgia, back pain and osteoarthritis pain, discontinuation syndrome, use with caution in patients with LIVER disease PAIN is a big reason of perscription

Venlafaxine- MDD and anxiety, off label for migraine and cataplexy

Milnacipran- approved for fibromyalgia, MDD

Question 16

SNRIs vs TCAS

Answer 16

SNRIs AND TCAs both- inhibit 5HT and NE reuptake, treate neuropathic pain and depressive disorders

TCAs ALSO block muscarinic receptors- (blurred vision, xerostomia, urinary retention, constipation, narrow angle glaucoma), Histamine H1 receptors- sedation, alpha adrenergic receptors (orthostati HTN, dizziness, reflex tachycardia

Question 17

Atypical antidepressants

Answer 17

Bupropion- Weakly blocks NE and dopamine uptake, standard and extended release, nicotine withdrawal and SAD, no weight gain or sex dysfunction

Mirtazapine- blocks presynaptic alpha 2 receptors in brain, increases appetite, AIDS pts

Trazodone- weak SSRI, sedating, also used for insomnia, low incidence of CV side effects, can cause priapism

Vortioxetine (MDD drug, has a SSRI like action in addition to 5HT 1A agonist and 5HT 3 antagonist

Question 18

TCAs

Answer 18

block NE and 5HT reuptake
Now used secondarily to SSRIs and SNRIs and atypicals

Decreases REM and increases stage 4 sleep

Prominant anticholinergic effects

Cardiac side effects- Due to anticholinergic effects and increased NE concentrations, palpitations, tachycardia and arrhythmias, EKG–> QRS intervals and flattened or inverted T waves reflect a slowed conduction time and significant alterations in the electrophysiology of the heart

TCA overdose- hyperpyrexia (hyperthermia), changes in bp, seizures, coma, Cardiac conduction deficits, treatment is symptomatic, observe for at least 3 days because of long half lives

Drug interactions- sympathomimetic drugs- particularly indirect acting agents, effects absorption and metabolism of other drugs

Question 19

Therapeutic uses of TCAs

Answer 19

MDD, enuresis in childhood (imipramine)
Chronic pain- amitriptyline
OCD

Question 20

MAOis

Answer 20

block the oxidative deamination of naturally occurring biogenic amines (NE, DA, and 5HT, and ingested amines)in the mito chondria
Monoamine oxidase is found in neurons, its also found in the liver, lung and other organs)
2 forms MAO A and B- antidepressant action probably due to inhibition of MAOA

Phenelzine are irreversible inhibitor of MAO

Depression ish treatment

Question 21

MAOi uses

Answer 21

antidepressant action takes 2 or more weeks

Produces mood elevation in depressed patients, may progress to hypomania particularly in bipolar disease

corrects sleep disorders in depressed patient, may produce stimulation in people without depression

Lowers blood pressure, often produces orthostatic hypotension, acute toxicity can produce agitation, hallucinations, hyperpyrexia, convulsions, and changes in blood pressure

bulimia off label use

Question 22

tyramine containing foods

Answer 22

potent releases of norepinephrine, with monamine oxidase inhibiting the norepinephrine (in the liver)
but if youre taking maoIs you cant inhibit the NE release

Over ripe veggies, fruits (figs, banans, meats that are fermented, sausages, fish , milks and cheeses, foods with yeas and beer and wine,

Question 23

What if antidepressant drugs alone are not effective

Answer 23

augmentation with antipsychotic agens

MDD (olanzapine, aripiprazole, quetiapine, brexpiprazole)

Physiological treatments- ECT, TMS and DBS

Ketamine

Esketamine- fast acting nasal spray

Question 24

St johns wort

Answer 24

hyperricin, maoI activity, blood interactions (increase 3A4 expression, lowers efectiveness of birth control pills, protease inhibitors in AIDs, cyclosporine