B7-9: Antidepressants (Cyclic, MAOI, SSRI/SNRI, NE/5-HT Antagonists) + Manic phase bipolar treatment Flashcards
Background:
What was the early pathophysiological theory for the etiology of depression / mania?
(What drug affecting molecules in this pathway helped support this theory?)
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)
What are the 3 main categories of antidepressant drugs in use?
- Reuptake Inhibitors - TCAs and SSRIs
- Atypical Antidepressants - have adrenergic/5-HT receptor-antagonizing and/or unique reuptake inhibition mechanisms
- Monoamine Oxidase Inhibitors (MAOIs) - selective vs. non- and reversible vs. irreversible
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.)
- Tryptophan Hydroxylase - Trp > 5-hydroxytryptophan (5-HTP) (RATE-LIMITING)
- Aromatic AA Decarboxylase - 5-HTP > 5-hydroxytryptamine (serotonin / 5-HT)
- 5-HT N-acetylase - 5-HT > N-acetyl 5-HT
- 5-hydroxyindole O-methyltransferase - N-acetyl 5 -HT > melatonin
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)?
- 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
- COMT - both intra-/extracellular; requires Mg2+ and S-adenosyl-Met
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.)
- NE - MAO/COMT make MHPG (3-methoxy-4-OH-phenylglycol)
- DA - MAO/COMT make HVA (homovanillic acid)
- 5-HT - MAO and aldehyde dehydrogenase make 5HIAA (5-OH indole acetic acid)
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?)
- Norepinephrine - locus coeruleus (rhomboid fossa!) and lateral tegmental area (ventral midbrain) to widespread cortical/subcortical sites; regulates arousal, mood and BP
- Serotonin - midline raphe nuclei (throughout brainstem) to widespread cortical/subcortical sites; regulates sleep, mood, sexual function and appetite
Basics:
What is the aim of antidepressant treatment over the initial weeks of therapy?
Over months / years?
- 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.)
Basics:
What is the efficacy of antidepressants within the first 6-12 weeks of treatment?
And how effective are they overall at achieving remission?
- Many (~38%) patients have no response in the first 6-12 weeks
- In more than half of patients, remission can not be achieved
Basics:
How long is antidepressant treatment generally?
And in patients with repeated episodes?
- Usually 4-9 months in patients with a single depressive episode
- Treatment should continue for years in patients with ≥ 2 episodes
Background:
What change in serotonergic / noradrenergic systems is strongly correlated with clinical improvements from antidepressant use?
Receptor Downregulation
- antidepressants increase monoamine levels by reuptake / MAO inhibition etc. > MAs continously stimulate inhibitory α-2 and 5-HT1A receptors > receptors are down-regulated > monoaminergic neurons become disinhibited, releasing even more MAs
Name the 4 important tricyclic antidepressants (TCAs).
What is their mechanism of action?
(One of the 4 is slightly different. Which one and how?)
- imipramine, amitriptyline, clomipramine - 5-HT + NE reuptake inhibition
- maprotiline - primarily NE reuptake inhibition (tetracyclic structure)
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)
- H1 histamine receptors - sedation, dizziness, confusion, weight gain
- α1 receptors - orthostatic hypotension, reflex tachycardia, dizziness
- M receptors - anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion, cognitive impairment)
- Cardiac HERG-type K+ Channels - can result in life-threatening ventricular arrhythmias
What are the indications for TCAs?
(5)
(Extra: name the specific TCAs used for 3 of these indications)
- Depression
- Panic Disorders - imipramine, clomipramine
- Noctural Enuresis (bed wetting)
- Neuropathic Pain - amitriptyline, clomipramine
- Migraine Prophylaxis - amitriptyline
How are TCAs administered?
How often do they need to be taken (half-life) ?
What are their important interactions?
- 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
Name 5 important SSRIs.
(+ 1 extra only mentioned in Kato’s practical with its special indication)
(What is their mechanism of action?)
- Fluoxetine - trade name Prozac
- Fluvoxamine
- Paroxetine
- Sertraline
- Citalopram + Escitalopram
- 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.)
What are the 5 main indications for SSRIs?
- Depression - as 1st choice treatment
- Anxiety Disorders
- OCD
- Bulimia Nervosa - but not anorexia
- Premenstrual Dysphoric Disorder - special depressive form of PMS
- (Premature Ejaculation treated w/ dapoxetine)
What are the adverse effects of SSRIs?
(Via which receptors? How can some of these be avoided?)
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)
What is the most dangerous possible complication of SSRI treatment?
With which SSRI is this most likely and how can it be avoided?
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
Which SSRIs have shorter durations of action? Which have longer?
(Approximate half-lives?)
- Paroxetine / Sertraline - shorter; t1/2 ~25-35 hrs
- Fluoxetine - longer; its active metabolite norfluoxetine has t1/2 ~7-9 days
How long does it take for SSRIs to become effective?
What can be done to help with this?
- 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
What are the 6 categories of atypical antidepressants?
(Actually 4 categories + 2 single unique drugs)
- SSNRIs - selective 5-HT + NE reuptake inhibitors
- NRIs - selective NE reuptake inhibitors
- Bupropion - DA/NE reuptake inhibitor
- Tianeptine - 5-HT reuptake enhancer
- SERT/5-HT2A antagonists - also inhibit α1
- α2 / 5-HT antagonists - mirtazapine / mianserine
What are the 2 important SNRIs?
Which one has dose-dependent effects and how?
What is their advantage over TCAs / SSRIs?
- 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
Aside from the usual SERT inhibition-related indications / side effects…
what are 4 unique indications of SNRIs?
And side effects?
- 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
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.)
Reboxetine
- weak anticholinergic effects + can cause sleep disturbances
- (indications: major depressive disorder, panic disorder, ADHD)
Which drug inhibits DAT / NET specifically?
Indications / contraindications?
Special administration?
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
Which atypical antidepressant actually enhances neurotransmitter reuptake?
Indications?
Tianeptine
- enhances 5-HT reuptake > strong anxiolytic
- indicated for depression + anxiety related to alcohol withdrawal syndrome
Which drugs are 5HT2A inhibitors + weak 5-HT reuptake inhibitors?
Extra actions + indications?
(Side effects?)
Trazodone + Nefazodone
- 5HT2A inhib + weak α1 / H1 inhibition > sedation
- Indication: depression with insomnia
- (Side effects: orthostatic hypotension, dizziness, priapism [trazoBONEr] and hepatotoxicity [nefazodone])
Which SERT-inhibiting drug has a special serotonergic mechanism that attenuates one of the common SSRI side effects?
(Not in lecture, but Kato + Lippincott mention it.)
Vilazodone
- inhibits SERT + is also a 5HT1A partial agonist which attenuates the possible side effect of anxiety common to SSRIs
What are the two α2 inhibitor antidepressants?
What other receptors do they effect?
Indications + side effects?
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…)
Which atypical antidepressant can help to re-establish circadian rhythm in depressed patients with sleep disturbances?
Mechanism? Side effects?
Agomelatine
- acts as a melatonin receptor and 5HT2C agonist
- side effect: hepatotoxicity … must monitor liver enzymes
Which MAOI is non-selective?
Other kinetic characterstics?
Indication?
Phenelzine
- non-selective + irreversible MAOI
- used in severe depression
What are the 2 MAO-A selective MAOIs?
Other pharmacodynamics?
Indications? Dosing frequency?
- Moclobemide - reversible MAO-A inhib; indicated for depression + social phobias; given 2-3x/day + dose slowly titrated upward
- Clorgylline - irreversible; indicated for severe resistant depression; higher risk for cheese effect
What is the selective MAO-B inhibitor?
Other important pharmacodynamics? Indications?
Selegiline
- is an irreversible MAO-B inhibitor
- indicated for Parkinson’s disease
What are 4 important potential interactions when administering MAOIs?
And general side effects?
MAOIs can cause insomnia, agitation and sexual disturbances and can interact with…
- Sympathomimetics - increasing their effect
- TCAs / SSRIs - causing serotonin syndrome
- Pethidine - synthetic opioid; AKA meperidine / Demerol; MAOIs increase resp. depression / seizures
- Tyramine - cheese effect; esp. with irreversible MAOI
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?)
- Lithium - as lithium carbonate; chronic tx only
- Anti-epileptics - valproate, carbamazepine, lamotrigine; acute and chronic tx
- Anti-Psychotics - quetiapine, olanzapine, risperidone; ziprasidone or aripiprazole (children / adolescents); for acute tx only
- Benzodiazepines - didn’t see definite info on BZDs but probably acute tx only
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)
Indicated for bipolar disorder (treats mania + inhibits re-entry into mania from depression) and unipolar depression (can enhance AD med effects)
- IP3-DAG Pathway Inhibition - Li inhibits inositol monophosphatase, decreasing IP3 levels
- Na permeability - Li influences cellular Na permeability
- Adenylate Cyclase inhibition - lowers cAMP
- Receptor Uncoupling - Li alters subunits of dopamine + other receptor-associated G proteins
What are the important aspects of lithium carbonate’s pharmacokinetics?
(Administration, absorption, distribution, accumulation, reabsorption etc.)
- 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
What are lithium carbonate’s side effects?
(4 general + 4 more specific + how can one specific side effect be treated?)
- General: tremor, sedation, nausea, vomiting
- Hypothyroidism - G-protein uncoupling → ↓ TSH effect
- Interstitial Nephritis - renal accumulation → HS rxn
- Nephrogenic DI - ↓ ADH effect; can be treated with thiazide diuretics
- Teratogenicity - contraind. in pregnancy
What are the symptoms of lithium toxicity?
Why is this so important specifically for lithium?
- 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
Which 3 of the antiepileptic drugs are given to treat manic phases of bipolar disorder?
- Valproate
- Carbamazepine
- Lamotrigine
Can be used for both acute + chronic mania treatment
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?
Administered acutely in addition to lithium in manic phases, then discontinued as mania subsides, with lithium continued prophylactically even in depressive phases.
- Olanzapine
- Quetiapine
- Risperidone
- Ziprasidone - children/adolescents
- Aripiprazole - children/adolescents
Give an example of a benzodiazepine used for treatment of manic episodes in bipolar disorder.
(Probably unimportant, just the 1 BDZ Kato mentioned here)
Clonazepam
What drugs are used to treat depressive phases of bipolar disorder?
What are the risks of this + how are they dealt with?
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
