Pharmacology of antidepressants

This chapter tries to address Section K2(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to develop an " understand the pharmacology (including toxicology) of anti-depressant and anti-psychotic drugs". Like with antiepileptics, this is a complex topic, and most people trying to answer an exam question on this topic would usually end up tripping over the pharmacodynamics, even if they oversimplified things down to some truly puerile monamine level. That sort of defensive reaction is probably natural, as in the last century of research we really have not come very far along the road to understanding human mood, or how it gets so broken. 

Two questions from the First Part exam have looked at this:

• Question 9(p.2) from the first paper of 2009 (compare and contrast classes)
• Question 3 from the second paper of 2007 (TCA overdose)

Toxicology has subsequently moved into the Fellowship curriculum, which means that probably TCA overdose will never appear again, and it has been over ten years since the last antidepressant class question, which suggests that this whole subject area has been depreciated in the examiners' mind. With that in mind, the reader may wish to limit themselves to the contents of the summary box below:

Chemical classes of antidepressants

"The present antidepressants’ classification does not have a logical and epistemic nomenclature oriented to allow a quick recognition of main adverse drug reactions... and pharmacodynamic interactions", complained Alvano & Zieher (2020)  in one of the best articles on this subject, from which most of what follows has been derived. Without recapitulating the contents of Alvano and Zieher's work, it will suffice to say that the authors, frustrated by the inconsistency and uselessness of the existing systems, proposed their own and then designed a study which demonstrated its superiority on several very logical grounds. The author is also grateful to this paper for introducing him to the term "heuristic fertility", which is supposed to describe something that "serves to achieve or generate knowledge" but instead sounds like a process leading to the proliferation of mental shortcuts (which would also be excellent). Without further ado, here is the Alvano-Zieher system:

Class A I: Monoamine oxidase inhibitors:

• AIa: Irreversible and nonselective: Tranylcypromine, phenelzine, isocarboxazid
• AIb: Irreversible and selective: Selegiline (selects for MAO-B)
• AIc: Reversible selective: Moclobemide

Class A II: Reuptake inhibitors:

• AIIa1: SSRIs: Fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine
• AIIb: SSRI/SNRIs: venlafaxine, duloxetine
• AIIc: Noradrenaline/dopamine reuptake inhibitors: Bupropion

Class A III: α₂-receptor antagonists:

• Mirtazapine

Class A IV: Multimodal drugs

• AIVa: Serotonergic drugs: Trazodone, vilazodone, vortioxetine
• AIVb: Noradrenergic drugs: Mianserine
• AIVc: Noradrenerig/serotonergic/anticholinergic: Amitriptyline, nortriptyline, etc

Class B: Non-monoaminergic drugs:

• Melatonin receptor agonists: Agomelatine

Class C: Weird unclassifiables:

• Steroids, eg. dexamethasone
• Ketamine
• Amphetamines

To discuss the properties of this many classes with this many drugs in them would certainly be outside the scope of what is necessary to discuss an answer for Question 9(p.2) from the first paper of 2009. However, for some incomprehensible reason, one or two examples from each Alvano-Zieher class has been selected here for a slightly more detailed discussion. 

Pharmacokinetics of antidepressants

Absorption and bioavailability

The route of administration for all antidepressants is essentially just oral. None of these drugs have a parenteral formulation, apart from weird substances with vaguely mood-elevating side effects such as amphetamines and ketamine. In fact many studies complain that they are unable to give a straight answer to the question of bioavailability because the drugs were not available in a parenteral formulation. 

	Oral absorption	Bioavailability
Tranylcypromine	Rapidly and completely absorbed	50%
Selegiline	Well absorbed (even better with food)	10%
Moclobemide	Rapidly and completely absorbed	50%
Fluoxetine	Rapidly and completely absorbed	90%
Sertraline	Complete but slow absorption (6-8 hrs)	100%
Citalopram	Complete and rapid absorption	100%
Venlafaxine	Well absorbed (92%)	45%
Duloxetine	Acid-labile; degraded by stomach acid (thus, requires enteric-coated tablets).	50%
Bupropion	Oral absorption is close to 100%	20%
Mirtazapine	Rapidly and completely absorbed	50%
Trazodone	Rapidly and completely absorbed	63-91%
Mianserine	Rapidly and completely absorbed	30%
Amitriptyline	Rapidly and completely absorbed	33-62%
Nortriptyline	Rapidly and completely absorbed	52%
Agomelatine	Well absorbed 78%	less than 5%

In general, most of them are absorbed very well after enteral administration, and though some of them undergo considerable first-pass metabolism, it does not play much of a role in their pharmacokinetics (for example, in the case of bupropion, the main metabolite has essentially the same activity as the parent drug). The only outliers are duloxetine (which is degraded extensively by stomach acid and which needs to be enteric-coated) and agomelatine, which has massive first-pass metabolism and a bioavailability of less than 5%.

Distribution

Most of these drugs are widely distributed and highly protein-bound, as these are the sort of properties one might expect from a lipophilic molecule that penetrates the blood-brain barrier. 

	Volume of distribution (L/kg)	Protein binding
Tranylcypromine	1.75	? high
Selegiline	25	96%
Moclobemide	2	50%
Fluoxetine	14-100	94%
Sertraline	20	99%
Citalopram	12	80%
Venlafaxine	6-7	27%
Duloxetine	25%	90%
Bupropion	19	84%
Mirtazapine	4.8	95%
Trazodone	0.8	95%
Mianserine	15.7	90%
Amitriptyline	19	84%
Nortriptyline	21	93%
Agomelatine	30	95%

The notable exceptions are venlafaxine, which has minimal interest in binding to proteins, and trazodone which seems to be confined to the body water compartment. The rest have volumes of distribution in the 5-20L/kg range, suggesting that they are bound to proteins around the tissues.

Metabolism and clearance of antidepressants

All of these drugs are cleared by the liver in one way or another. Their only real difference is whether or not the metabolites have some sort of activity, and how rapidly they are metabolised (because this has implications for half-life.

Tranylcypromine	Extensively metabolised, probably in the liver, into N-acetylated and ring-hydroxylated metabolites, which retain some limited MAO-inhibitory activity	Minimum renal excretion (4% as unchanged drug)	Half-life is only about 2 hours, but this does not have any relationship to the duration of its effect
Selegiline	Hepatic metabolism; rapidly metabolized by the microsomal enzymes to amphetamine, methamphetamine, and desmethyl-deprenyl	Renal clearance is important: 86% of the active metabolites are recovered in the urine	Elimination half-life of the parent drug is only aout 1.5 hours, but it leaves behind active metabolites with longer periods of activity, and its MAO-I effect is long lasting
Moclobemide	Hepatic metabolism; oxidation of the morpholine ring moiety, aromatic hydroxylation and deamination; multiple inactive metabolites	Renal clearance accounts for very little total clearance, and appears to be unimportant	Half-life is only about 2 hours, but the duration of MAO-I effect is much greater
Fluoxetine	Hepatic metabolism into active metabolite norfluoxetine and multiple other (inactive) metabolites	All the metabolites are renally excreted	Half life is variable and long, 1-4 days
Sertraline	Hepatic metabolism, mainly by N-demethylation to from an extremely long-lived metabolite (with about 10% of the potency of the parent drug, and a half-life of about 100 hours)	50% of the metabolites are renally excreted, and 50% of them are eliminated in the faeces, suggesting that there is some biliary excretion.	Half life is about 26 hours
Citalopram	Hetaptic metabolism by N-demethylation into several active metabolites	50% of the metabolites are renally excreted, and 50% of them are eliminated in the faeces, suggesting that there is some biliary excretion.	Half life is about 36 hours
Venlafaxine	Extensive hepatic metabolism to the major O-demethyl metabolite and 2 minor metabolites.	Elimination of the parent drug is hepatic and of its metabolites is mainly renal (only 4.7% is recovered in the urine as unchanged drug)	Half-life is about 4 hours, which called for an extended release formulation
Duloxetine	Hepatic metabolism into numerous metabolites, mainly by oxidation in the naphthyl ring followed by further oxidation, methylation and conjugation	Elimination of inactive metabolites is mainly renal	Half life is about 12 hours
Bupropion	Hepatic metabolism by CYP2B6, into an active metabolite (hydroxybupropion)	The majority of parent drug and metabolites are eliminated in the urine as glycine conjugates	Elimination half-life is about 18 hours
Mirtazapine	Hepatic metabolism into largely inactive metabolites, mainly by CYP1A2, CYP2D6, and CYP3A4	All metabolites are renally eliminated	Elimination half-life is about 20-40 hours
Trazodone	Hepatic metabolism into tow main metabolites, oxotriazolepyridinpropionic acid (TPA) and mCPP, of which mCPP is more active as an inhibitor of SERT than trazodone itself.	All metabolites are renally eliminated	Elimination half-life is about 7 hours
Mianserine	Hepatic metabolism by aromatic hydroxylation, N-oxidation and N-demethylation.	70% of the metabolites are renally excreted; the rest in the bile	Elimination half-life 10-17 hrs
Amitriptyline	Hepatic metabolism mainly by CYP2D6 into breakdown products which all have some degree of antidepressant activity	All metabolites are renally eliminated	Elimination half-life of around 20 hours
Nortriptyline	Hepatic metabolism mainly by CYP2D6 into breakdown products which all have some degree of antidepressant activity	All metabolites are renally eliminated	Elimination half-life of around 26 hours
Agomelatine	Hepatic metabolism by 7-O-demethylation and hydroxylation; all metabolites are inactive at MT receptors	About 80% of the metabolites are eliminated in the urine, and the rest in the bile	Elimination half-life is about 2.3 hours; duration of activity is much longer

Pharmacodynamics of antidepressants

A single-sentence summary of course cannot capture the messy confusion of neurochemistry which describes mood regulation, and so what follows is by necessity an oversimplification:

Tranylcypromine	By binding to both kinds of monoamine oxidase enzymes, MAOIs increase the availability of catecholamine neurotransmitters (i.e. mainly noradrenaline and dopamine, but also to some extent serotonin)
Selegiline
Moclobemide
Fluoxetine	By inhibiting the reuptake of serotonin from the synaptic cleft, SSRIs increase serotonergic neurotransmission, which is thought to be involved in mood regulation.
Sertraline
Citalopram
Venlafaxine	By inhibiting the reuptake of serotonin and noradrenaline from the synaptic cleft, SSRI/SNRI drugs increase monoamine neurotransmission, which is thought to be involved in mood regulation.
Duloxetine
Bupropion	By inhibiting the reuptake of serotonin and dopamine from the synaptic cleft, SSRI/SDRI drugs increase monoamine neurotransmission, which is thought to be involved in mood regulation.
Mirtazapine	The mechanism of the antidepressant effect of mirtazapine is thought to be the inhibition of presynaptic control of noradrenaline release (i.e. it does the opposite of what clonidine does).
Trazodone	The direct antagonist effect of trazodone at the 5-HT2 receptor results in increased presynaptic noradrenaline release. That receptor is a presynaptic autoregulatory receptor that normally downregulates noradrenaline release as part of a negative feedback loop.
Mianserine	The mechanism of antidepressant effect is thought to be the inhibition of presynaptic control of noradrenaline release. Also, it inhibits reuptake of noradrenaline.
Amitriptyline	Multiple mechanisms of effect, mostly related to the inhibition of reuptake of noradrenaline and serotonin by interference with the function of SERT and NET transport proteins. Additionally, tricyclic antidepressants act as antagonists at muscarinic receptors, histamine receptors and α-adrenergic receptors
Nortriptyline	Multiple mechanisms of effect, mostly related to the inhibition of reuptake of noradrenaline and serotonin by interference with the function of SERT and NET transport proteins
Agomelatine	Mechanism of action is thought to be related to the regulation of dopamine release by melatonin receptor activation (i.e. the effect of agomelatine, as an MT1 and MT2 agonist, is to increase the concentration of dopamine).

Side effects and toxicities

Fortunately, these can be grouped according to class, as all agents from each group tend to have similar side effect profiles. The exception to this rule are the MAOIs, which all have slightly different toxic effects. For example, nothing is quite as good at killing you with hypertensive catastrophes as eating a small amount of blue cheese while on tranylcypromine, but the other two do not seem to have as much of this problem. On the other hand, selegiline is metabolised into amphetamine, which is thought to be responsible for a lot of its positive effects, and that's a unique feature. In contrast, all SSRIs and tricyclics and basically be grouped together, as they all tend to have a fairly stereotypical side effect profile.

Tranylcypromine	Hypertensive crises, hepatotoxicity, seizures, hypoglycaemia, mania, serotonin syndrome. Dangerous pharmacodynamic interactions with other antidepressants and monoaminergic drugs, as well as foods that act as catecholamine precursors
Selegiline	Euphoria, insomnia, hypertension (i.e. the effects of amphetamine intoxication,it being one of the major metabolites)
Moclobemide	Hypertension, restlessness, agitation, nausea, insomnia (i.e. features of sympathomimetic effect)
Fluoxetine	These effects are common to all SSRIs: agitation, diarrhoea, loss or gain of weight, vertigo, and sexual dysfunction; risk of serotonin syndrome with overdose
Sertraline
Citalopram
Venlafaxine
Duloxetine	Agitation, diarrhoea, loss or gain of weight, vertigo; risk of serotonin syndrome with overdose (i.e. similar side effect profile to SSRIs). Additionally, duloxetine can sometimes have anticholinergic side effects, such as xerostomia and urinary retention
Bupropion	Dry mouth, constipation, headache, nausea, insomnia and weight loss. The most common reason for discontinuation is apparently "an unpleasant state variously described as a crazy feeling".
Mirtazapine	Anticholinergic side effects, sedation (antihistamine effect), increased appetite, weight gain
Trazodone	Sedation, diarrhoea, loss or gain of weight, vertigo; risk of serotonin syndrome with overdose
Mianserine
Amitriptyline	Sedation, postural hypotension, anticholinergic side effects, sodium channel blockade in overdose (giving rise to QRS prolongation and ventricular arrhythmias)
Nortriptyline
Agomelatine	Both sedation and insomnia have been reported as side effects, but generally the incidence of side effects seems to be no greater than placebo