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Re: TCAs do have their good points Sunnely

Posted by Elizabeth on June 29, 2001, at 18:50:34

In reply to Re: TCAs do have their good points Elizabeth, posted by Sunnely on June 28, 2001, at 0:09:24

> I'm not sure I understand your logic here. I believe I was comparing SSRIs in general with TCAs in general and not subclasses of TCAs.

Right: you were comparing them in general, while I was comparing the more benign TCAs with the SSRIs. (For the most part, it's not clear what the differences in toxicity among the SSRIs are: fluoxetine has a reuptation for being more stimulating, fluvoxamine seems to cause nausea more often, paroxetine may carry greater risk of weight gain, etc.)

What I'm saying is that there are TCAs that have relatively benign side effect profiles, and these TCAs are often more tolerable than SSRIs because they lack the characteristic side effects of the SSRIs (notably the near-universal sexual dysfunction).

I don't believe it's useful to make generalisations about the relative tolerability of TCAs and SSRIs: although some TCAs (notably amitriptyline) are very poorly tolerated, and some of them also have increased risk of cardiac complications (protriptyline) and/or seizures (maprotiline), there are TCAs available that have relatively benign side effect and safety profiles. (Lofepramine is an excellent one, but we don't have it here in the USA.)

> I can't argue with you in the differences in receptor affinities you described above between tertiary amine TCAs and secondary amine TCAs.

That's true, although you can't predict TCA pharmacological properties based on the structure of the side chain alone: although the side chain plays a major role, the core "tricyclic" (dibenzazepine) structure is undoubtedly involved in the pharmacology of these drugs too; for example, consider the differences among the secondary amines nortriptyline, desipramine, protriptyline, and maprotiline.

> Again, can't argue with you on this. But again, as a class, SSRIs are less liable to cause orthostatic hypotension compared to the TCAs, when used in used in any group of age or gender population.

And again, it depends which TCA you are talking about -- practically speaking, lumping them all together (and lumping all patients together too) isn't useful, and to make a generalisation that tricyclics are unsafe and poorly tolerated is misleading.

SSRIs have their own side effects which should not be ignored and which make them less tolerable for many patients than the preferred TCAs (nortriptyline, desipramine). Some patients even prefer tricyclics with more side effects, such as imipramine, doxepin, protriptyline or amitriptyline, to the SSRIs.

Differences among the various SSRIs in their propensity to cause characteristic side effects are less predictable, probably because we don't have as good an understanding of the differences among the SSRIs and the clinical consequences of these differences. (We do know that citalopram and paroxetine are the more selective SSRIs, that fluoxetine and norfluoxetine are less selective, and that sertraline is less potent, but we haven't been able to make much of this information.)

The safety issue is more generalisable, although it should be emphasised that tricyclics *can* be used safely with appropriate monitoring and consideration for individual patient characteristics (such as the risk of suicide attempts, various cardiac risk factors, the possibility of a seizure disorder, use of other drugs, etc.).

> As you said TCA levels should be monitored, and IMHO, at least for a couple of reasons: 1. possible toxic levels, 2. "therapeutic levels," and 3. compliance.

Therapeutic ranges aren't established for all TCAs (therapeutic monitoring is also complicated by the presence of active metabolites). In practise (and this may be the most practical way to go about using TCAs), doctors usually resort to serum level monitoring only if there are specific risk factors such as other drugs or medical conditions (the person should be checked for these *before* trying TCA therapy), or deficiency in the cytochrome enzyme p450 2d6 (a fairly common genetic condition, particularly, as you point out, in people of European descent), which can be tested for relatively easily (and I believe this test should be given before treatment as well).

> Desipramine which is mainly metabolized by CYP2D6 can lead to toxic blood levels when combined with Prozac and Paxil (both potent inhibitors of CYP2D6).

I found this out abount 5 years ago, when I had a problem combining a low dose of DMI (50 mg) with fluoxetine. (I later had a pecular reaction to a normal dose of dextromethorphan (in one of those OTC cough syrups that don't work < g >), and several other bad experiences with TCAs by themselves, so it's possible that I'm one of the unlucky people who can't use these drugs in normal doses; if I do try using them again, I would definitely want to get serum level monitoring.

It should also be noted that, although "Caucasians" (i.e., whites) represent the majority of people with this enzyme deficiency, it does occur in other races. (Recall that many Americans who would be considered "black," for example, have some "white" ancestry. This is one of the many reasons I'm not into classifying people by their race.)

> Nortriptyline, believed to have a "therapeutic window" is one TCA that definitely requires periodic monitoring of blood levels, especially if it seems to be losing its antidepressant effect.

Nortriptyline and amitriptyline (of course: part of the therapeutic activity of AMI results from significant metabolism into NOR) do have a therapeutic window (their dose-response curves are shaped like an inverted U: if the serum level becomes too high, they can start to become less effective).

> Again, I agree with you on this that SSRIs are not for everyone and not everyone who is depressed requires an SSRI (or an antidepressant).

Not just that: not all types of depression respond well to SSRIs. Admittedly, my sample is skewed, but I've encountered a lot of people with moderate to severe endogenous depression (and a few with more severe cases of atypical depression) who simply didn't respond to SSRIs at all (one of these people is myself), as well as many folks with panic disorder (which doesn't respond to all antidepressants) who cannot tolerate the activating side effects of the SSRIs. The other new antidepressants, especially Effexor and Remeron (and, to a lesser extent, Serzone and Wellbutrin), offer hope for non-SSRI-responsive depressed patients, but sometimes the TCAs turn out to be the most effective and are tolerated well (particularly if you choose the right TCA for the individual patient -- NOR and DMI are both relatively benign, but DMI can cause more activation and jitters while NOR has more sedating and anticholinergic effects, although these are mild with both drugs).

> Indeed, depression is not uncommonly co-morbid with other conditions such as panic disorder, OCD, PTSD, schizophrenia, bipolar disorder, substance abuse, Parkinson's disease, dementing processes, etc. I guess I was mainly referring to the uncomplicated type of major depression.

Classic (so-called "endogenous") depression may actually respond better to TCAs than to SSRIs. SSRIs seem to be better suited, however, for milder depressions such as dysthymia; atypical depression; and depression with certain comorbid anxiety disorders such as OCD, PTSD, social phobia, and borderline personality disorder.

> However, with the extra potentially serious baggage that TCAs carry with them, it has been relegated (per prescribers' choice) to second-line therapy when it comes to treating major depression (per se).

*Usually*, an SSRI is the first choice treatment, yes. There are prescribers who feel, based on their clinical experience, that in some cases a TCA is preferable, even if the patient needs to be given very small prescriptions (e.g., only 5 days at a time) or even hospitalised in order to prevent suicide attempts.

TCAs don't have the broad-spectrum efficacy of SSRIs and MAOIs. They're best suited to classic major depression or panic disorder (serotonergic TCAs such as imipramine and clomipramine may be more effective, although some patients with PAD do respond to NOR or DMI; maprotiline has been found to be ineffective in PAD -- which puts it even lower on the list of "best tricyclics" < g >).

> In fact, I believe in some studies, TCAs appear to be more efficacious than SSRIs in severe depression.

Not so much for severe depression in general, but when they specifically look at a subtype called "melancholic features," the results are more compelling. (Although atypical depression and mood-reactive depressions have traditionally been regarded as less severe than melancholia (AKA "endogenous depression" -- this older terminology should not be taken to mean that other types of depression are not endogenous), I've encountered people with nonmelancholic depression whose illness would be considered "severe.")

> Technically speaking, amoxapine (Asendin) is classified as an antidepressant.

That's not what I'd call a "technical" classification. It's mainly a legal and marketing designation: amoxapine is labelled and marketed as an antidepressant. Drugs can be chemically similar but have different pharmacological and clinical effects. (TCAs as a group are chemically similar to phenothiazines, e.g.) For that matter, they can also be pharmacologically similar but be marketed for different purposes: for example, Compazine is marketed for nausea (more so than for psychosis), but other dopamine-antagonist phenothiazines (and possibly atypical antipsychotics as well) have robust antinausea effects. So does promethazine, a phenothiazine which is a weak dopamine antagonist but a strong antihistamine, and is often used as an antiemetic, an antianaphylactic, and a sedative, but not as an antipsychotic: although chemically of the same class as chlorpromazine (Thorazine), fluphenazine (Prolixin), trifluoperazine (Stelazine), thioridazine (Mellaril), etc., promethazine (Phenergan) is not an effective antipsychotic nor should it be referred to as an antipsychotic. Then there's the case of Luvox -- the SSRI (and perfectly good antidepressant) -- that is labelled only for OCD!

Drugs can be classified by their chemical structures (phenothiazine, benzodiazepine), by their clinical uses (antidepressant, antipsychotic, anxiolytic), by their pharmacology (selective serotonin reuptake inhibitor, monoamine oxidase inhibitor, nicotinic-cholinergic agonist, etc.), or by their clinical uses (anxiolytic, antidepressant, antipsychotic), depending upon information what you want to convey. Amoxapine could be called a mixed antidepressant-antipsychotic, a dibenzazepine compound, a mixed norepinephrine reuptake inhibitor/dopamine antagonist with alpha-1 adrenergic, histaminic, and muscarinic cholinergic antagonist activity. All of these descriptions are equally accurate, but the information they convey is different.

The "tricyclics" -- the class of dibenzazepine drugs including imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, protriptyline, trimipramine, doxepin, amoxapine, and maprotiline (as well as others, such as lofepramine and dothiepin, that are not used in the USA) is described according to a common chemical structure, but the name "tricyclic" is imprecise and it is only by convention that it is generally taken to refer to these drugs. There are plenty of "tricyclic" compounds (for example, some of the antipsychotics, and the anticonvulsant carbamazepine) that are not antidepressants (although both antipsychotics and CBZ sometimes can be used as AD augmentors, and CBZ alone is sometimes effective in TRD, these aren't their primary uses and they aren't the most effective drugs for depression) and don't share the pharmacological features of the "tricyclic antidepressants."

Tricyclics are norepinephrine reuptake inhibiting drugs with a range of other effects, and classifying them by their pharmacology would be rather unwieldy. "Norepinephrine reuptake inhibitor" or "mixed serotonin-norepinephrine reuptake inhibitor" would adequately describe the pharmacologic effects of these drugs that are known to contribute to their therapeutic effects in depression, though.

Re amoxapine:

> Similar to other antipsychotics with D2 blocking effect, it carries with it a full range of extrapyramidal side effects - acute dystonic reactions, akathisia, pseudoparkinsonism, and tardive dyskinesia.

It does have a risk of these effects. So do all the antipsychotic drugs used today. The risk is *lower* with amoxapine when compared with the older antipsychotics (it's more comparable, I think, to the atypical antipsychotics such as risperidone).

After I failed to tolerate nortriptyline, a psychiatric researcher with whom my pdoc was consulting suggested adding amoxapine to the MAOI I was already taking (I was trying to augment the MAOIs with TCAs). He said that he's found this combination helpful (and safe and generally well-tolerated) for patients like me who have classic melancholia along with chronic milder depression (dysthymia or residual depression). I would like to give another try to MAOI-TCA combinations, although I would insist on using desipramine and on monitoring serum levels. (Secondary amines are a little simpler to monitor and to use in combination with other drugs because they have less complicated metabolic pathways than their tertiary precursors.)





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