B7-9: Antidepressants (Cyclic, MAOI, SSRI/SNRI, NE/5-HT Antagonists) + Manic phase bipolar treatment

Question 1

Background:

What was the early pathophysiological theory for the etiology of depression / mania?

(What drug affecting molecules in this pathway helped support this theory?)

Answer 1

Monoamine Theory

a deficiency / excess of monoamine transmission contributed to depression / mania, respectively

(Reserpine, a VMAT blocker, caused depression in 50% of patients)

(other support for theory includes studies showing functional genetic polymorphism of SERT and reduction of 5-HT metabolites in CNS resulting in adverse behavioral changes)

Question 2

What are the 3 main categories of antidepressant drugs in use?

Answer 2

1. Reuptake Inhibitors - TCAs and SSRIs
2. Atypical Antidepressants - have adrenergic/5-HT receptor-antagonizing and/or unique reuptake inhibition mechanisms
3. Monoamine Oxidase Inhibitors (MAOIs) - selective vs. non- and reversible vs. irreversible

Question 3

Background:

What are the steps of serotonin + melatonin synthesis? (4)

(Which step is rate-limiting?)

(Since the antidepressants in use don’t really work on these steps, I don’t think much will be asked about this in MCQs, but it’s good background to have for oral exams.)

Answer 3

1. Tryptophan Hydroxylase - Trp > 5-hydroxytryptophan (5-HTP) (RATE-LIMITING)
2. Aromatic AA Decarboxylase - 5-HTP > 5-hydroxytryptamine (serotonin / 5-HT)
3. 5-HT N-acetylase - 5-HT > N-acetyl 5-HT
4. 5-hydroxyindole O-methyltransferase - N-acetyl 5 -HT > melatonin

Question 4

Background:

What are the two enzymes responsible for the breakdown of monoamine NTs in the body?

Their location (which cell types + where in the cell)?

Answer 4

1. MAO - on outer mitochondrial membrane with flavin cofactor; MAO-A degrades 5-HT and NE in GI tract + nerve endings, MAO-B degrades phenylethylamines in platelets + glia, both degrade DA and tyramine
2. COMT - both intra-/extracellular; requires Mg²⁺ and S-adenosyl-Met

Question 5

Background:

What are the important inactivated metabolites made in the CNS from NE, DA and 5-HT?

(They can be detected in blood / urine samples to indicate levels of monoamine NTs in the body.)

Answer 5

1. NE - MAO/COMT make MHPG (3-methoxy-4-OH-phenylglycol)
2. DA - MAO/COMT make HVA (homovanillic acid)
3. 5-HT - MAO and aldehyde dehydrogenase make 5HIAA (5-OH indole acetic acid)

Question 6

Background:

What nuclei / loci in the brain are the main sites of NE and 5-HT output to other CNS sites?

(What are the general CNS functions regulated by NE + 5-HT?)

Answer 6

1. Norepinephrine - locus coeruleus (rhomboid fossa!) and lateral tegmental area (ventral midbrain) to widespread cortical/subcortical sites; regulates arousal, mood and BP
2. Serotonin - midline raphe nuclei (throughout brainstem) to widespread cortical/subcortical sites; regulates sleep, mood, sexual function and appetite

Question 7

Basics:

What is the aim of antidepressant treatment over the initial weeks of therapy?

Over months / years?

Answer 7

• Weeks: relief of acute symptoms BUT anti-depressants generally take 4-6 weeks to take effect
• Months: prevention of relapse (“maintenance therapy”)
• Years: prevention of repeat episodes (“prophylactic therapy”)

(Note that suicide risk is highest in the first two months of treatment. Risk is highest in young adults 18-25. Antidepressants generally carry black-box warnings about this. This may be due to early effects of increased motivation + energy levels interacting with remaining depressive symptoms as the patient slowly improves.)

Question 8

Basics:

What is the efficacy of antidepressants within the first 6-12 weeks of treatment?

And how effective are they overall at achieving remission?

Answer 8

• Many (~38%) patients have no response in the first 6-12 weeks
• In more than half of patients, remission can not be achieved

Question 9

Basics:

How long is antidepressant treatment generally?

And in patients with repeated episodes?

Answer 9

• Usually 4-9 months in patients with a single depressive episode
• Treatment should continue for years in patients with ≥ 2 episodes

Question 10

Background:

What change in serotonergic / noradrenergic systems is strongly correlated with clinical improvements from antidepressant use?

Answer 10

Receptor Downregulation

• antidepressants increase monoamine levels by reuptake / MAO inhibition etc. > MAs continously stimulate inhibitory α-2 and 5-HT_1A receptors > receptors are down-regulated > monoaminergic neurons become disinhibited, releasing even more MAs

Question 11

Name the 4 important tricyclic antidepressants (TCAs).

What is their mechanism of action?

(One of the 4 is slightly different. Which one and how?)

Answer 11

• imipramine, amitriptyline, clomipramine - 5-HT + NE reuptake inhibition
• maprotiline - primarily NE reuptake inhibition (tetracyclic structure)

Question 12

Besides 5-HT and NE reuptake inhibition…

what 4 physiological mechanisms do TCAs inhibit and what are the resulting side effects?

(3 of these are more common/benign mechanisms to interfere with… but one is much more severe and very important)

Answer 12

1. H1 histamine receptors - sedation, dizziness, confusion, weight gain
2. α1 receptors - orthostatic hypotension, reflex tachycardia, dizziness
3. M receptors - anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion, cognitive impairment)
4. Cardiac HERG-type K+ Channels - can result in life-threatening ventricular arrhythmias

Question 13

What are the indications for TCAs?

(5)

(Extra: name the specific TCAs used for 3 of these indications)

Answer 13

1. Depression
2. Panic Disorders - imipramine, clomipramine
3. Noctural Enuresis (bed wetting)
4. Neuropathic Pain - amitriptyline, clomipramine
5. Migraine Prophylaxis - amitriptyline

Question 14

How are TCAs administered?

How often do they need to be taken (half-life) ?

What are their important interactions?

Answer 14

• Administered orally only once daily due to their 25-30 hr half-life
• Interactions: potentiate alcohol’s respiratory depressive effect; may cause serotonin syndrome (fever, seizure, coma) if co-administered with MAOIs

Question 15

Name 5 important SSRIs.

(+ 1 extra only mentioned in Kato’s practical with its special indication)

(What is their mechanism of action?)

Answer 15

1. Fluoxetine - trade name Prozac
2. Fluvoxamine
3. Paroxetine
4. Sertraline
5. Citalopram + Escitalopram
6. Dapoxetine - for premature ejaculation (remember dapoxetine is for the D!)

(Unlike TCAs they only inhibit 5-HT reuptake via SERT, not NE via NET, and do not inhibit H/alpha/M receptors.)

Question 16

What are the 5 main indications for SSRIs?

Answer 16

1. Depression - as 1st choice treatment
2. Anxiety Disorders
3. OCD
4. Bulimia Nervosa - but not anorexia
5. Premenstrual Dysphoric Disorder - special depressive form of PMS
6. (Premature Ejaculation treated w/ dapoxetine)

Question 17

What are the adverse effects of SSRIs?

(Via which receptors? How can some of these be avoided?)

Answer 17

Preferred over TCAs due to lack of H/alpha/M receptor effects…

• 5-HT2 stimulation - anxiety (usually fades w/ time), insomnia, decreased libido, and delayed ejaculation
• 5-HT3 stimulation - nausea, vomit, GI upset, diarrhea, and headache (can help GI sx to take SSRI with food)

Question 18

What is the most dangerous possible complication of SSRI treatment?

With which SSRI is this most likely and how can it be avoided?

Answer 18

Serotonin Syndrome

• concomittant admin with MAOIs or admin of MAOI too soon after SSRI discontinuation > pathological 5-HT level increase > muscle rigidity, cramps, hyperthermia + hypertension
• fluoxetine takes 4-6 weeks to be adequately eliminated before MAOI admin. also difficult to establish steady state dosage due to complicated distribution

Question 19

Which SSRIs have shorter durations of action? Which have longer?

(Approximate half-lives?)

Answer 19

1. Paroxetine / Sertraline - shorter; t_1/2 ~25-35 hrs
2. Fluoxetine - longer; its active metabolite norfluoxetine has t_1/2 ~7-9 days

Question 20

How long does it take for SSRIs to become effective?

What can be done to help with this?

Answer 20

• onset takes 2-3 weeks and max benefit may not be seen until 12 weeks or more
• sometimes a benzodiazepene is given for immediate anxiolysis and slowly discontinued as the SSRI takes effect

Question 21

What are the 6 categories of atypical antidepressants?

(Actually 4 categories + 2 single unique drugs)

Answer 21

1. SSNRIs - selective 5-HT + NE reuptake inhibitors
2. NRIs - selective NE reuptake inhibitors
3. Bupropion - DA/NE reuptake inhibitor
4. Tianeptine - 5-HT reuptake enhancer
5. SERT/5-HT2A antagonists - also inhibit α1
6. α2 / 5-HT antagonists - mirtazapine / mianserine

Question 22

What are the 2 important SNRIs?

Which one has dose-dependent effects and how?

What is their advantage over TCAs / SSRIs?

Answer 22

• Venlafaxine + active metabolite desvenlafaxine - must be given 2x daily; inhibit SERT at all doses + NET at higher doses (thus can start with small dose + increase if ineffective without having to wait for elimination)
• Duloxetine - inhib SERT/NET equally at all doses
• Advantage: no H/alpha/M-related TCA-like effects; NET inhibition can be useful in neuropathic pain

Question 23

Aside from the usual SERT inhibition-related indications / side effects…

what are 4 unique indications of SNRIs?

And side effects?

Answer 23

• Neuropathic pain disorders: 1) diabetic neuropathy, 2) postherpetic neuralgia, 3) fibromyalgia, and 4) Lower Back Pain
• Side effects: hypertension and tachycardia due to increased NE

Question 24

What is the 1 important NRI drug?

Important side effect other than tachycardia/hypertension?

(Extra: indications?)

(Drug mentioned in Lippincott, seems less important, but on slides / notes.)

Answer 24

Reboxetine

• weak anticholinergic effects + can cause sleep disturbances
• (indications: major depressive disorder, panic disorder, ADHD)

Question 25

Which drug inhibits DAT / NET specifically? Indications / contraindications? Special administration?

Answer 25

**Bupropion** * _Indications_: **stuporous depression** - DA incr. can help with immobility; **smoking cessation** * _Contraindications_: **epilepsy** - may provoke seizure * Must be administered at _2x / day_ due to short half-life

Question 26

Which atypical antidepressant actually _enhances_ neurotransmitter reuptake? Indications?

Answer 26

**Tianeptine** * enhances 5-HT reuptake \> strong _anxiolytic_ * indicated for depression + anxiety related to **alcohol withdrawal syndrome**

Question 27

Which drugs are **5HT2A inhibitors** + **weak 5-HT reuptake inhibitors**? Extra actions + indications? (Side effects?)

Answer 27

**Trazodone + Nefazodone** * 5HT2A inhib + weak α1 / H1 inhibition \> sedation * _Indication_: **depression with insomnia** * (Side effects: orthostatic hypotension, dizziness, priapism [trazoBONEr] and hepatotoxicity [nefazodone])

Question 28

Which SERT-inhibiting drug has a special serotonergic mechanism that attenuates one of the common SSRI side effects? ## Footnote (Not in lecture, but Kato + Lippincott mention it.)

Answer 28

**Vilazodone** * inhibits SERT + is also a **5HT1A partial agonist** which attenuates the possible side effect of anxiety common to SSRIs

Question 29

What are the two **α2 inhibitor** antidepressants? What other receptors do they effect? Indications + side effects?

Answer 29

**Mirtazapine** (more used) + **Mianserine** (older) * also antagonize **5HT2** receptors (anxiolytic, sedative), **5HT3** (anti-emetic) and **H1** (highly sedative) * useful in _depression w/ insomnia_ * side effects: **increased appetite +** **weight gain** (but _no impotence_! just think of a calm, tired, hungry fat man with a raging boner who definitely _will not_ vomit and you'll never forget these...)

Question 30

Which atypical antidepressant can help to _re-establish circadian rhythm_ in depressed patients with sleep disturbances? Mechanism? Side effects?

Answer 30

**Agomelatine** * acts as a **melatonin receptor** and **5HT_2C** **agonist** * side effect: _hepatotoxicity_ ... must monitor liver enzymes

Question 31

Which MAOI is _non-selective_? Other kinetic characterstics? Indication?

Answer 31

**Phenelzine** * non-selective + _irreversible_ MAOI * used in _severe depression_

Question 32

What are the 2 **MAO-A selective** MAOIs? Other pharmacodynamics? Indications? Dosing frequency?

Answer 32

1. **Moclobemide** - _reversible_ MAO-A inhib; indicated for _depression_ + _social phobias_; given _2-3x/day_ + dose slowly titrated upward 2. **Clorgylline** - _irreversible_; indicated for _severe resistant depression_; higher risk for cheese effect

Question 33

What is the **selective MAO-B inhibitor**? Other important pharmacodynamics? Indications?

Answer 33

**Selegiline** * is an _irreversible_ MAO-B inhibitor * indicated for _Parkinson's disease_

Question 34

What are 4 important potential _interactions_ when administering MAOIs? And general side effects?

Answer 34

MAOIs can cause _insomnia_, _agitation_ and _sexual disturbances_ and can interact with... 1. **Sympathomimetics** - increasing their effect 2. **TCAs / SSRIs** - causing serotonin syndrome 3. **Pethidine** - synthetic opioid; AKA meperidine / Demerol; MAOIs increase _resp. depression / seizures_ 4. **Tyramine** - cheese effect; esp. with irreversible MAOI

Question 35

What 4 categories of drugs are used to treat the manic phase of bipolar disorder? (actually 1 single drug + 3 categories) (which categories are used for chronic vs. acute treatment?)

Answer 35

1. **Lithium** - as lithium carbonate; _chronic tx only_ 2. **Anti-epileptics** - valproate, carbamazepine, lamotrigine; _acute and chronic tx_ 3. **Anti-Psychotics** - quetiapine, olanzapine, risperidone; ziprasidone or aripiprazole (children / adolescents); for _acute tx only_ 4. **Benzodiazepines** - didn't see definite info on BZDs but probably acute tx only

Question 36

What are the 2 indications for **lithium carbonate**? What are its 4 _mechanisms of action_? Which one is most likely responsible for its anti-manic effects? (answer will be the first of the 4 listed, other 3 mostly responsible for side effects)

Answer 36

Indicated for **bipolar disorder** (treats mania + inhibits re-entry into mania from depression) and **unipolar depression** (can enhance AD med effects) 1. **IP3-DAG Pathway Inhibition** - Li inhibits inositol monophosphatase, decreasing IP3 levels 2. **Na permeability** - Li influences cellular Na permeability 3. **Adenylate Cyclase inhibition** - lowers cAMP 4. **Receptor Uncoupling** - Li alters subunits of dopamine + other receptor-associated G proteins

Question 37

What are the important aspects of **lithium carbonate**'s pharmacokinetics? (Administration, absorption, distribution, accumulation, reabsorption etc.)

Answer 37

* Administered + absorbed well **orally** * Is _excreted unchanged in urine_ + _doesn't bind serum proteins_ * Slowly accumulates in **neuronal tissues** developing effects after _1-3 weeks_ (so for *chronic treatment only*) * Is partly **actively reabsorbed** in the kidney, _competing with Na⁺_. Any condition with _lower sodium levels will increase lithium reabsorption_ (exercise, diarrhea, diuretics) + thus _increase toxicity risk_

Question 38

What are **lithium carbonate**'s side effects? (4 general + 4 more specific + how can one specific side effect be treated?)

Answer 38

1. _General_: tremor, sedation, nausea, vomiting 2. **Hypothyroidism** - G-protein uncoupling → ↓ TSH effect 3. **Interstitial Nephritis** - renal accumulation → HS rxn 4. **Nephrogenic DI** - ↓ ADH effect; can be treated with _thiazide diuretics_ 5. **Teratogenicity** - contraind. in pregnancy

Question 39

What are the symptoms of **lithium toxicity**? Why is this so important specifically for lithium?

Answer 39

* Hyperactivity, seizure and coma * Lithium has a very _narrow therapeutic window_; serum concentrations of 1.0-1.2 mmol/l are therapeutic and just 1.5-1.7 mmol/l is toxic

Question 40

Which 3 of the antiepileptic drugs are given to treat manic phases of bipolar disorder?

Answer 40

1. **Valproate** 2. **Carbamazepine** 3. **Lamotrigine** Can be used for both acute + chronic mania treatment

Question 41

Which 5 of the _antipsychotic_ drugs can be used to treat mania in bipolar disorder? How are they given? Which two are specifically indicated in _childhood / adolescent_ manic episodes?

Answer 41

Administered acutely in addition to lithium in manic phases, then discontinued as mania subsides, with lithium continued prophylactically even in depressive phases. 1. **Olanzapine** 2. **Quetiapine** 3. **Risperidone** 4. **Ziprasidone** - children/adolescents 5. **Aripiprazole** - children/adolescents

Question 42

Give an example of a _benzodiazepine_ used for treatment of manic episodes in bipolar disorder. (Probably unimportant, just the 1 BDZ Kato mentioned here)

Answer 42

**Clonazepam**

Question 43

What drugs are used to treat depressive phases of bipolar disorder? What are the risks of this + how are they dealt with?

Answer 43

**TCAs** (less so) or **SSRIs** (more so) * Increase the risk of onset of mania (10-60% increase with TCA; 4% with SSRI) * Co-administered with a _mood stabilizer_ (lithium) to decrease mania risk