The monoamine theory suggests that a functional deficit in NE and/or 5-HT is responsible for depression. 

Amphetamines, which cause release of monoamines raise people's mood and cause a rebound low on withdrawal.

TCADs inhibit the reuptake of NE and 5-HT.

TCADs are relatively non-specific in their reuptake inhibition.  Their clinical effects occur after 2-4 weeks.

They are lipid soluble and often undergo first-pass metabolism into active intermediates.

Mitarzapine is an antidepressant of the "other" category.  It blocks alpha-2 receptors, blocking their inhibition of NT release.  This causes more NT to be released by the presynaptic nerve terminal. 

Mitarzapine also blocks 5-HT2 and 5-HT3 receptors...

TCADs are used to treat depression, nocturnal enuresis in children, and neuropathic pain.

TCADs are cardiotoxic due to their three ring structure!  Do not give to patients with heart disease/heart block!

TCADs block alpha-1 receptors causing orthostatic hypotension.

TCADs have antimuscarinic activity (dry mouth, tachydardia, constipation etc.)

Though the degree is much less than with SSRIs, TCADs also inhibit the CYP450 system, increasing the potency of other drugs.

Imiprimine is a TCAD, it exhibits unequal reuptake blockade, blocking the reuptake of NE much more than 5-HT.

This means imipramine is an excitatory antidepressant.  remember that depressed patients that can barely get out of the bed in the morning and are already sedated by their depression should be given a TCAD like imipramine! (not one like amitriptyline, which is sedatory)

Imiprimine is converted into an active metabolite, Desipramine.

Fluoxetine (prozac) is the ONLY approved treatment for depression in children.

Fluoxetine is an SSRI.  Its clinical effects are seen 2-4 weeks after beginning treatment.

Fluoxetine is an SSRI.  It selectively inhibits the reuptake of 5-HT, leading to increased levels in the synapse.  Its brand name is prozac. 

As an SSRI, it is a first choice treatment for depression.  It is also the only drug approved for the treatment of depression in children. 

Fluoxetine is also used as an antibulemic and in OCD (but remember: in OCD, the other SSRI fluvoxamine is a DOC)

Fluoxetine is metabolized by the CYP450 system (specifically CYP2D6).  It has an active metabolite called norfluoxetine.  This metabolite has a half-life of 10 days!  Because of this, it may take 1-2 months for the metabolites to be cleared from the body after discontinuation of treatment. (recall: 4 half-lives!)

Fluoxetine is metabolized by the CYP450 system, but also inhibits the CYP450 system!  This means increased levels of other drugs such as TCADs, neuroleptics, phenytoin, warfarin etc...

SSRIs reduce the seizure threshold! remember the story about bulemics with upset electrolyte balances and SSRI administration. The upset electrolyte balance already favors seizures, and now the SSRI makes this even more likely!

SSRIs also cause a delay in orgasm/ejaculation in a significant portion of patients.  This may be a cause of non-compliance.

Also be weary of Serotonin Syndrome

SSRIs are the preferred treatment for depression nowadays because they have less side effects.  Cardiotoxicity, sedation, and overdose related death are more common with TCADs.

SSRIs selectively inhibit 5-HT reuptake, while TCADs have variable 5-HT and NE reuptake inhibitions.

co-administration of an MAOI with an SSRI could cause serotonin syndrome, a potentially lethal condition.  The MAOI inhibits metabolism of the monoamines (including 5-HT), raising their levels.  SSRIs also raise the levels of 5-HT.  This causes a huge excess of 5-HT, which results in fever, rigidity, myoclonus, hyperreflexia, and coma.  It can lead to death.

MAOIs and TCADs should also be avoided!  (TCADs also block 5-HT reuptake, especially amitriptyline)

This patient has serotonin syndrome.  Remember that fluoxetine is converted to an active intermediate with an long half-life (10days).  It's an SSRI, so it should not be co-administered with an MAOI like phenylzine.  At least 5 weeks should be allowed after the discontinuation of fluoxetine before administering an MAOI.

The drug to treat serotonin syndrome with is IV Dantrolene.  It is a muscle relaxant that antagonizes ryanodine receptors, causing a decrease of Ca++ release from the ER. 

Cyproheptadine, an anti-serotonin agent, may also be administered.

Control the fever with ice-packs.  Control acidosis with sodium bicarb. 

Trazodone is used to treat depression that does not respond to the other antidepressants.  It is very sedating, and is therefore useful to treat depressed patients with agitation and insomnia.

Recall, the active metabolite of trazodone is what is really responsible for the clinical effects.  Its metabolite agonizes 5-HT receptors.

Bupropion is an atypical antidepressant.  It is useful in the treatment of nicotine withdrawal and for patients that don't respond to TCADs.  It has minimal cardiotoxicity, so it may be useful in patients with cardiovascular problems.  (remember TCADs are cardiotoxic)

It works by blocking DA reuptake! 

Do not give to depressed patients with eating disorders because there is an association with convulsions in these patients!

Also be weary of psychotic patients (ex: positive symptomology schizophrenia) in which their DA levels are already too high

Mirtazepine is an atypical antidepressant.  It is sedating.

Mirtazepine acts by blocking the alpha-2 adrenoceptor on the presynaptic nerve terminal of serotonergic and noradrenergic neurons.  This results in increased release of 5-HT and NE.

It also blocks 5-HT2 and 5-HT3 receptors...

Try giving mirtazepine to this patient.  Mirtazepine works by a completely different mechanism and may be effective. 

(mirtazepine = alpha-2 receptor blocker)

Phenelzine and trancypromine are the MAOIs

MAOIs are non-selective, long-acting drugs.  They are second choice drugs for depression, used after SSRIs have been tried.  Remember serotonin syndrome, though!

Patients on an MAOI should are susceptible to serotonin syndrome and NE excess.  Foods like cheese, wines, beer contain tyramine.  This is converted to octopamine, which displaces the NE & 5-HT from vesicles, increasing its release into the synaptic cleft.

High levels of NE cause cardiovascular crises.  5-HT can precipitate serotonin syndrome.

Pseudoephedrine is a sympathomimetic and a component of some OTC decongestants (ex: Sudafed).  It is contraindicated in patients taking MAOIs. 

Don't use pseudoephedrine-containing decongestants when taking MAOIs!

Dextromethorphan is a cough suppressant ("antitussin") found in Robutussin.  Excess of this drug causes dissociative psychadelic symptoms... (Sam you remember this from when you were sick and took too much robitussin at olive garden that one time...yea...)

Dextromethorphan has agonist activity at 5-HT receptors and may inhbibit DA reuptake.  Because this drug stimulates 5-HT receptors, it can precipitate a potentially lethal serotonin syndrome when taken with an SSRI or MAOI.  It is degraded by the CYP450 system and SSRIs inhibit this degredation pathway, therefore it's psychadelic effects can also be exaggerated when the two drugs are coadministered.

What might result from MAOI or SSRI administration if that patient takes ecstacy(MDMA)?

Oral cyproheptadine (5-HT2 antagonist)

IV Dantrolene (muscle relaxant)

Sodium bicarbonate to restore acid/base balance

Ice packs to control fever