Depression and Drugs

Question 1

Depression is classified as major depression (unipolar depression) or bipolar depression (manic depressive illness). Depressive episodes are characterized by what?

Answer 1

Depressed or sad mood 
Pessimistic worry 
Diminished interest in normal activities
Mental Slowing 
Poor Concentration 
Suicidal Ideation 
--occurring most days for a period of at least 2 weeks

Question 2

What is the Monoamine Hypothesis?

Answer 2

Reserpine: found to precipitate depression in some patients
–deplete dopamine, serotonin and NE in rat brain
Iproniazid and Isoniazid: found to lift depression of these chronically ill patients, shown to inhibit monoamine oxidase (MAO)
These data of monoamine depletion leading to depression and monoamine preservation leading to mood elevation generated the monoamine hypothesis

Question 3

The monoamine hypothesis was buttressed by studies on the mechanism of action of various types of antidepressant drugs. What do TCAs and MAOI do?

Answer 3

Tricyclic Antidepressants:
–block the monoamine (NE and 5HT) reuptake pumps of amine neurotransmission.
MAOI:
–block a major pathway for the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released.

Question 4

The pharmacological actions of both TCAs and MAOI classes of antidepressants are immediate but what?

Answer 4

Clinical effects of the drugs take several weeks to become manifest

• -this suggests that there are longer term changes triggered by the drugs
• -2 to 4 weeks to produce any improvement and 6-8 weeks to achieve benefit

Question 5

All currently available antidepressant drugs enhance monoamine neurotransmission by one of several mechanisms, which are?

Answer 5

Common mechanism of the serotonin transporter (SERT)
Norepinephrine transporter (NET) or both

Question 6

Now lets go through drugs according to their Mechanism of Action. First up are the Monoamine Oxidase Inhibitors (MAOIs). These drugs include Isocarboxazid, Phenelzine, Tranylcypromine and Selegiline. What are some features?

Answer 6

MAO is a mitochondrial enzyme found in nerve and other tissues

• -in neuron MAO functions as a safety value to oxidatively deaminate and inactivate any excess neurotransmitter molecules that may leak out of synaptic vesicles when the neuron is at rest
• -there are two isozymes of MAO: MAO-A and MAO-B. MAO-A preferentially deaminates NE and Serotonin
• -the antidepressant effect of MAOIs correlates with inhibition of MAO-A

Question 7

Which MAOI drugs work on MAOA and MAOB?

Answer 7

Phenelzine, Isocarboxazid, Tranylcypromine bind irreversibly and nonselectively to MAO-A and MAO-B
Selegiline: MAO-B inhibitor for tx of Parkinson’s. Can work in high doses by inhibiting MAO-A as well. First transdermal delivery system.

Question 8

What are the actions, uses, PK, and AE for MAOI?

Answer 8

Actions: although MAO is fully inhibited after several days of treatment, the antidepressant action is delayed several weeks
Uses: rarely used in clinical practice due to toxicity and potentially lethal food and drug interactions
PK: well absorbed orally
AE: drowsiness, insomnia, nausea, orthostatic hypotension, weight gain, muscle pain and sexual dysfunction

Question 9

MAO inhibitors are associated with two classes of serious drug interactions, what is the first drug interaction?

Answer 9

MAOI + SSRI, SNRI, TCAs or meperidine

• -life threatening serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, and change in mental status)
• -result of overstimulation of 5-HT1A and 5-HT2 receptors
• -an irreversible MAO inhibitor with a serotonergic agent is the most toxic reported combo.
• MAOI must be discontinued for at least 2 weeks before starting a serotonergic agent and vice versa.

Question 10

What is the second drug interactions with MAOI?

Answer 10

MAOI + tyramine in the diet or with sympathomimetic substrates of MAO
–cheeses, meats, chicken, red wines are all normally inactivated by MAO in the gut
–tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in headaches, stiff neck, tachycardia, hypertension, arrhythmias, seizures
Phentolamine or Prazosin are used in the management of tyramine induced HTN

Question 11

An overdose of a MAOI can produce what? and what is the management of an overdose?

Answer 11

Overdose:
–instability, hyperadrenergic symptoms, psychotic symptoms, confusion, delirium ,fever and seizures
Management:
–cardiac monitoring, vital support and gastric lavage

Question 12

What is discontinuation syndrome?

Answer 12

Occur with all antidepressant drugs

–worsening of depressive symptoms, confusion, disorientation, psychosis and anxiety

Question 13

Moving on to the TCAs. What are these drugs?

Answer 13

Amitriptyline
Clomipramine
Desipramine
Imipramine
Nortriptyline 
--alternative for patients who do not respond to SSRIs

Question 14

What is the mechanism of action of TCAs?

Answer 14

Block the uptake of NE and serotonin by nerve terminals by competition for the binding site of the carrier protein.
–increased monoamine concentration in the cleft
In addition, most TCAs block alpha adrenergic, muscarinic, histamine and 5-HT receptors

Question 15

What are the various affinitys for SERT and NET in regards to the TCA drugs?

Answer 15

Clomipramine: little affinity for NET but potently binds and blocks SERT
Desipramine and Notriptyline: more selective for NET

Question 16

What are the actions and PK for TCAs?

Answer 16

Actions: onset of mood elevation requires 2 weeks or longer
PK: well absorbed orally, can penetrate the CNS, variable half lives due to their lipophilicity, first pass metabolism in the liver, initial treatment period is 4-8 weeks and dose can at that point be lowered, excreted via the kidneys

Question 17

What are the AE of TCAs?

Answer 17

1. Block of Muscarinic Receptors: urinary retention, constipation, aggravation of narrow angle glaucoma
2. Increased Catecholamine Activity: cardiac overstimulation
3. Inhibit cardiac fast sodium channels: results in arrhythmias (most common cause of death)
4. Block alpha 1 adrenoceptors: orthostatic hypotension and reflex tachy (serious in elderly)
5. H1 Blockade: sedation and weight gain
6. Sexual Effects: high serotonergic agents (clomipramine)

Question 18

What are the drug interactions and precautions with TCAs?

Answer 18

Drug Interactions:
–increased TCA levels with CYP2D6 inhibitors
—CYP2D6 polymorphism associated with slow metabolism of TCAs
–Anti-HTN meds exacerbate the orthostatic hypotension
Precautions:
–narrow therapeutic index
–depressed patients who are suicidal should only be given limited quantities

Question 19

What is common in overdose with TCAs and what is discontinuation syndrome?

Answer 19

Overdose:
–lethal arrhythmias including ventricular tachycardia and fibrillation
–tx includes sodium bicarb to reverse the conduction block
Discontinuation Syndrome:
–flu-like symptoms, myalgia, excessive sweating, headache, nausea, insomnia

Question 20

Moving on to the next class of Anti-depressants are the SSRIs (selective serotonin reuptake inhibitors). What are these drugs?

Answer 20

Citalopram
Escitalopram
Fluoxetine
Fluvoxamine 
Paroxetine
Sertraline

Question 21

SSRIs inhibit serotonin reuptake. What are some features of SSRIs?

Answer 21

Little blocking activity at muscarinic, alpha adrenergic and histamine receptors
–so common side effects arent seen
Safe even when in overdose
Most common antidepressants in clinical use

Question 22

What are the actions and uses of SSRIs?

Answer 22

Actions: block reuptake of serotonin
–increased concentrations of the neurotransmitter in the cleft
–take at least 2 weeks to produce improvement in mood
Uses: depression
–OCD, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder and bulimia
-first line for premature ejaculation

Question 23

What are the PK and AE for SSRIs?

Answer 23

PK:
–Fluoxetine has a much longer half life (50 hours)
–Paroxetine and Sertraline undergo fecal excretion all other SSRIs have kidney excretion
AE:
–decreased libido, delayed orgasm, or diminished arousal.
–increased serotonergic activity in the gut (nausea, GI upset, diarrhea)

Question 24

What are the drug interactions for SSRIs?

Answer 24

1. Fluoxetine and Paroxetine: potent inhibitors of CYP2D6
   - -CYP2D6 is responsible for elimination of TCAs, neuroleptic drugs, and some anti-arrhythmic and beta blockers
2. Fluvoxamine: inhibitor of CYP1A2, CYP2C19, and CYP3A4
3. Citalopram, Escitalopram and Sertraline: low potential for interactions
4. Cause serotonin syndrome when used in the presence of a MAOI or other serotonergic drug

Question 25

What are the overdoses and discontinuation syndrome for SSRIs?

Answer 25

Overdose: seizures and fatalities are very low
Discontinuation syndrome:
–sudden withdrawal of SSRIs
–nervousness, anxiety, irritability, tearfulness, electric shock sensations, dizziness, insomnia, confusion
–most likely to occur with short half life drug such as paroxetine
–less likely to occur with fluoxetine due to the long half life

Question 26

Next class of drugs are the SNRIs (serotonin and NE reuptake inhibitors). These drugs are Venlafaxine and Duloxetine. What are some features?

Answer 26

Block reuptake of 5-HT and NE

–differ from TCAs by their lack of receptor blocking activity at H1, muscarinic and alpha 1 receptors

Question 27

What are features of the SNRI – Venlafaxine?

Answer 27

Potent inhibitor of 5HT uptake and at higher doses NE uptake.
–inhibits reuptake of dopamine very weakly
Free from alpha 1 ,cholinergic, and H1 receptor blocking properties
AE: nausea, dizziness, sexual disturbances

Question 28

What are features of the SNRI — Duloxetine?

Answer 28

Inhibits 5-HT and NE reuptake at all doses
–metabolized in the liver to numerous metabolites
–do not give to hepatic insufficiency patients
AE: nausea, dry mouth, constipation, decreased appetite, fatigue, sexual dysfunction

Question 29

What are drug interactions and discontinuation syndrome with SNRIs?

Answer 29

Drug Interactions: relatively fewer CYP450 interactions than the SSRIs
Discontinuation Syndrome: when venlafaxine is abruptly stopped, due to its short half life

Question 30

The next anti depressant drug is an NDRIs (NE and Dopamine reuptake inhibitor). The only drug in this class is Bupropion. What are some features?

Answer 30

Bupropion
–metabolite hydroxybupropion moderate inhibitors of NE and dopamine uptake
–increases NE and dopamine release
–assists in decreasing the craving and attenuating the withdrawal symptoms for nicotine in tobacco users
–not associated with sexual dysfunction due to the lack of serotonergic component
Overdose = seizures