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The group of tricyclic antidepressants fall into two major subcategories. There is a group that chemically have terminal amino groups with three carbons attached Ė that is, a tertiary amine group.  This includes drugs like desipramine, nortriptyline and then there are still others that are developed primarily as secondary amine antidepressant drugs in their own right that are not necessarily derived from their precursors by body metabolism. This would include drugs like 

Amoxapine is a curious drug to put in this category. Itís actually the end of demethylated derivative of loxapine, the classic neuroleptic. It shouldnít surprise you if I tell you that I have seen cases of tardive dyskinesia in persons maintained for long periods on amoxapine and I think thatís something to be quite concerned about. Amoxapine has some mixed and central antidopamine neuroleptic-like activity as well as blocking norepinephrine uptake and

The reason for splitting the two categories this way is that the tertiary amine group tend to be much dirtier, more complicated drugs pharmacologically. They interact not only with norepinephrine systems but also variably with serotonin reuptake. So they are in a sense mixed norepinephrine serotonin reuptake. Recently thereís the trendy term is now SNRIs or what have you and there are drugs under development and in clinical trials that are deliberately mixing norepinephrine serotonin properties without some of the disadvantages that come from other properties of these drugs that include antihistaminic sedative properties, anticholinergic autonomic side effect producing properties and most ominously, direct cardiac inhibitory effects that slow down the repolarization and conduction parameters in the EKG and on acute overdose can lead to fatal ventricular arrhythmia cardiac arrest. These older drugs and their secondaries have that property as well, have been very popular drugs for self destructive purposes in

The secondary amine group are considerably less anticholinergic, much less antihistaminic and are relatively selective for the noradrenergic system in the brain and have much less serotonin activity. In fact, desimformate, for example, was one of the most norepinephrine selective of uptake inhibitors that 

More recently, the whole field of depression antidepressant therapeutics has been revolutionized by the introduction of the serotonin reuptake inhibitor group Ė the SRI or the SSRI group of drugs. The first really successful one clinically and commercially was Prozac or fluoxetine. Youíll notice that fluoxetine is the uricemic mixture of the plus and minus and antimeres.

Other older drugs that have been around a surprisingly long time include the recently introduced citalopram which was one of the very first of two or three serotonin reuptake inhibitor antidepressants that was used in Europe from the late 1970s. Fluvoxamine and LuVox has been around a long time even though it came to this country rather recently is paroxetine and sertraline and so on.

Then among some of the older variable drugs clomipramine or Anafranil is a largely serotonin reuptake inhibitor but again a classic tertiary amine tricyclic that interacts with norepinephrine uptake, is very anticholinergic. Very anticholinergic, produces a lot of sedation, confusional effects, autonomic problems. Itís a tough drug for people to take in the real world in adequate doses and 

Venlafaxine is the first, I suppose, along with clomipramine of this new concept of mixing deliberately serotonin and norepinephrine reuptake properties although as I understand it, the in vivo pharmacology of venlafaxine effects are it is mainly a serotonin reuptake inhibitor with a little bit of norepinephrine effect at higher doses. But I wouldnít make an enormous amount of that and I tend to look on

There is yet another group of antidepressants we can consider sort of atypical or otherwise unusual compounds. They include the drug bupropion, Wellbutrin which is a mild stimulant. It looks a bit like methamphetamine structurally and shares with the amphetamines a

Then down at the bottom is mirtazapine, another newer, again unusual drug with a subtle complex pharmacology that involves interactions with, again, both the serotonin and noradrenergic systems. Mirtazapine is a pretty good alpha-2 antagonist and that facilitates the release of norepinephrine and it also has properties of blocking some serotonin receptors, particularly type 2. Some of the type 2 sit

Nevertheless, the MAO inhibitors are very useful drugs. They have powerful antidepressant and other properties and they are drugs that are worth keeping in mind when other standard agents are not working. There are numerous studies now returning to MAOIs. Particularly well studied is phenelzine or Nardil, but much less with the others to date showing that these drugs will rescue 50,60% of

Selegiline is a drug thatís been used mainly in neurology as a mild early antiparkinson medicine and it has some subtle psychotropic properties. Probably mildly anxiolytic and may be mood elevating especially in bigger doses or recently introduced is a skin patch

There are several other experimental selective MAOA inhibitors. MAOA system is the one thatís particularly relevant to serotonin/norepinephrine nerve terminals and MAOA inhibitors of this kind which are short acting and reversible unlike all the other antidepressants which are long acting irreversible. Drugs like maglobamide seem to be a bit safer in terms of interacting. You get much less risk of hypertensive crises and that sort of thing.

Among these drugs one of the great no-nos in contemporary pharmacology is thou shalt never, ever mix any of these drugs, and I mean any of them, including selegiline and maglobamide with a serotonin reuptake inhibitor. The reason for that is that you can get catastrophic central neurotoxic reactions that include confusion, delirium, fever, collapse, coma and some fatalities have 

But if you hold on for a week, two weeks, three weeks, the presynaptic alpha-2 autoreceptors become locked out, desensitized and the presynaptic machinery revs up and actually can go above baseline. So that by the time the drug is working out here at three or four weeks you still block the uptake, youíve restored the presynaptic machinery to normal or more and you have retained sensitivity in the alpha-1 system postsynaptically to mediate the effects of the

With a few drugs, notably nortriptyline, they are pretty good and pretty good data for amitriptyline and imipramine. We have pretty good correlations of blood levels running up usually in the 100-200 nanograms are probably optimal for most patients in terms of the balance between efficacy and safety and tolerability. Tricyclic, the SSRIs, blood levels are virtually meaningless. It really doesnít help much other than to say yes the patient has taken some drug.

The 2C system substrates include the drugs ketoconazole, Nizoral. The 2D6 system is very important to psychotropic drugs because many tricyclics go through that system and other drugs that are of psychiatric interest.

The 3A system is a place where serotonin reuptake inhibitors, tricyclic antidepressants and other drugs tend to go and when you block this enzyme, for example, with fluvoxamine. Antihistamines like terfenadine can build up and kill cardiac induction and kill patients. Cisapride is another one that has the same potential to build up low levels and inhibit cardiac induction and there have been some deaths from these kinds of interactions. Again, this is an enormously complicated topic and would take an entire hour just to even begin to

Nefazodone is another important antidepressant drug that can inhibit 3A and can produce some potentially dangerous drug/drug interactions, again, you need to match this list to the proceeding list and go back and forth and you can make your own guesses about which one is doing what to