SSRIs

TCA's: Mechanism of Action

TCAs work by blocking the reuptake pumps of various NTs; most TCAs affect primarily the reuptake of serotonin and norepinephrine. By reducing the reuptake of these NTs, TCAs increase the levels of NTs in the synapse. Thus, TCAs are thought to increase the levels of 5-HT/NE/DA in the brain. The main difference in action between TCAs and SSRIs is that that only SSRIs selectively act on serotonin reuptake.

It is possible to become physically dependent on TCAs; thus if you stop taking TCAs suddenly, you might suffer withdrawal symptoms.

Common Side Effects

Sedation/fatigue, tremor, insomnia, blurred vision, constipation, urinary hesitancy, confusion, orthostatic hypotension, conduction defects, arrhythmias, aggravation of psychosis, seizures, weight gain, sexual dysfunction (inability to orgasm and decreased libido).

Metabolism

TCAs are rapidly absorbed and metabolized. CYP2C19 is the most important enzyme involved in the metabolism of TCAs, but the enzymes CYP 1A2, 3A4, 2C9 and CYP 2D6 are also involved.

SSRIs

Mechanism of Action SSRIs (Selective Serotonin Reuptake Inhibitors) work by selectively inhibiting the reuptake of serotonin. Thus, more serotonin remains for a longer period of time in the synapses. Although the different SSRIs vary in how effective they are at inhibiting 5-HT reuptake, they all do so selectively, and thus they do NOT have a direct (significant) effect on other NTs.

Common Side Effects Insomnia, sedation (thought not nearly as severe as with the TCAs), tremor, gastronintestinal problems, rashes, sexual dysfunction (decreased libido and difficulty orgasming), acute anxiety.

Metabolism SSRIs inhibit, to varying degrees, the enzymes CYP1A2, CYP2C19, CYP3A4 and CYP2D6. SSRIs and their metabolites can take a long time to completely leave the body. The issue with SSRIs is that in addition to the immediate effect they have on the brain, they also alter the brain in such a way that it takes some time after going off the SSRI for the brain to return to its normal configuration. How much a person's brain has been altered (and thus how long it will take for their brain to become normal again, and thus able to feel the full effects of MDMA), depends on the dose of the SSRI the person was taking, as well as the length of time the person was taking it for. So you can see, the time the person needs to be off an SSRI in order to, say, roll effectively will vary greatly from person to person. And that's not even taking into account a person's unique brain chemistry and metabolism.

Mechanism of Action MonoAmine Oxidase Inhibitors are drugs with inhibit the enzyme Monoamine Oxidase. Monoamine Oxidase is the enzyme responsible for breaking down amines in the human body, and since NTs like serotonin, dopamine, and norepinephrine all have an amine group, they are all broken down by the MAO enzyme. Since MAOIs reduce or prevent MAO from breaking down the NTs, the NTs remain in the synapse longer (also, NT levels build in the presynaptic vesicles, so that MORE NTs are release). The end effect thus, of a MAOI, is higher levels of various NTs. There are two MAOs: i.e., two enzymes responsible for the breakdown of NTs. There is MAO-A, an enzyme which breaks down various amines, including serotonin and norepinephrine, as well a tyramine, a byproduct of the conversion of tryptophan to 5-HT. Then there is MAO-B, an enzyme which breaks down dopamine. Some MAOIs work by inhibiting only one kind of MAO, and some MAOIs have inhibitory affects on both kinds of MAO. MAOIs can also be either REVERSIBLE or IRREVERSIBLE. Irreversible MAOIs bind permanently to the MAO enzyme and prevent MA breakdown for up to two weeks after taking one dose of the MAOI. Reversible MAOIs do not bind to the MAO enzyme and their effects last only for a couple of days.

Common Side Effects Sleep disturbances (either insomnia or fatigue/sedation), weight gain, postural hypertension (high blood pressure), sexual dysfunction.

Metabolism Though MAOIs are metabolized and eliminated fairly rapidly, the inhibition of MAO can persist long after the MAOI can no longer be detected in the body. Thus, metabolism here is not nearly as important as the actual, more long-term effects of taking a MAOI.

Mechanism of Action Amoxapine is a weak 5HT inhibitor and significantly inhibits reuptake NE. It is also a DA receptor antagonist. This drug increases the levels of serotonin and norepinephrine in the brain (much like tricyclics) and decreases dopamine levels, thus amoxapine can act as an antipsychotic (through its effects on dopamine) as well as an antidepressant.

Common Side Effects Similar to the TCAs/tricyclics, see above.

Metabolism Amoxapine is metabolized in the liver by the CYP2D6 enzyme.

Mechanism of Action Bupropion's mechanism of action is not fully understood, but current information indicates that it is a NE and DA reuptake inhibitor, and also acts as a weak 5HT reuptake inhibitor.

Mechanism of Action Both drugs are selective noradrenaline (NA/NE) reuptake inhibitors, sometimes called NARIs.

Common Side Effects Skin rash, redness, swelling, itching,nausea or vomiting, shakiness or trembling; seizures,unusual excitement, weight loss, blurred vision, dizziness or lightheadedness, drowsiness, dry mouth, headache, increased or decreased sexual drive, constipation,heartburn; increased appetite and weight gain, increased sensitivity of skin to sunlight; increased sweating, insomnia, weight loss.

Metabolism Primarily metabolized by the enzyme CYP2D6.

Common Side Effects Dizziness, insomnia, dry mouth, sweating, tremor, aggravation of psychosis, potential for seizures at high doses. May increase libido, especially in women.

Metabolism Several different CYP enzymes (i.e., CYP2B6, 3A4, 2A6, 2E1, and 1A2) can mediate the biotransformation of bupropion. Primarily metabolized by CYP2B6. Inihibits the enzyme CYP2D6.

Mechanism of Action Mianserin is an antagonist of both norepinephrine and serotonin receptors. Specifically, it is a 5HT1c, 5HT2a, and 5HT2c antagonist, as well as an antagonist of the NE alpha-2 receptor and the H1 (histamine) receptor. It does not inhibit the reuptake of any neurotransmitter at therapeutic dosages. There is evidence that 5-HT2C receptors are involved in the control of the activity of the central dopaminergic system, and thus it is thought that mianserin increases DA release in the nucleus accumbens by blocking 5-HT2C receptors.

Common Side Effects Sedation/drowsiness, dizziness, constipation, dry mouth, blurred vision, weight gain. Negligible anticholinergic effects compared to most other ADs.

Metabolism The most important enzymes involved in the metabolism of mianserin are CYP2D6, CYP1A2, and CYP3A.

Mechanism of Action Mirtazapine is an antagonist of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin presynaptic axons. It is also is a potent antagonist of 5HT2 and 5HT3 receptors. As a result, there is increased NE and 5HT activity, especially increased 5HT activitity at the 5HT1A receptors.

Common Side Effects Sedation, increased appetite, dizziness, and weight gain.

Metabolism CYP2D6, CYP1A2, and CYP3A4 are the primary enzymes involved in the metabolism of mirtazapine.

Mechanism of Action Nefazodone is a 5HT2 receptor antagonist and also antagonizes alpha1-adrenergic receptors. It appears to a be a weak serotonin reuptake inhibitor as well. Thus, nefazodone's AD properties probably share some similarilities with the TCAs/SSRIs and with drugs like mianserin and mirtazapine.

Common Side Effects Sedation, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, insomnia, agitation and abnormal vision.

Metabolism Nefazodone inhibits the enzyme CYP3A4, and is metabolized by CYP2D6.

Mechanism of Action Tianeptine increases serotonin uptake thereby increases serotonin levels in the brain. How exactly this occurs is not known.

Common Side Effects Gastralgia, abdominal pain, dryness of the mouth, anorexia, nausea, vomiting, flatulence, insomnia, drowsiness, nightmares, asthenia, tachycardia, extrasystole, precordialgia, dizziness, headaches, faintness, trembling, respiratory discomfort, tightness of the throat, myalgia, lumbago, changes in dreaming.

Metabolism Tianeptine is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. It differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system.

Mechanism of Action Trazodone has agonist activity at 5-HT2C receptors and potent antagonist activity at 5-HT2A receptors, and acts as a weak serotonin reuptake inhibitor. The effects of trazodone are dose-dependent: at low doses it acts as a 5-HT antagonist, whereas at higher doses it acts as a 5-HT agonist (related to the main metabolite CPP). It also antagonizes the alpha 1 and alpha 2 adrenergic receptors.

Common Side Effects Drowsiness, dizziness, insomnia, nausea, agitation.

Metabolism Trazodone is extensively metabolized by CYP34A to its active metabolite, m-chlorophenylpiperazine (mCPP). The enzyme CYP2D6 is also involved in the metabolism of trazodone.

Mechanism of Action Venlafaxine selectively inhibits the reuptake of both serotonin and norepinephrine, thus it is known as an SNRI.

Common Side Effects Nausea, somnolence, sweating, dizziness, sexual dysfunction, insomnia, hypertension, anxiety.

Metabolism Venlafaxine is extensively metabolized by CYP2D6 and somewhat metabolized by CYP3A4. It is also a weak inhibitor of the enzyme CYP2D6.