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ADM8283 - SECTION 4: THE TRI-CYCLIC ANTIDEPRESSANTS

 

Like the MAO inhibitors, the TCAs have broad effects on neurotransmitters. They are potent in increasing the availability of norepinephrine and serotonin, and have an antagonistic effect on the alpha I subgroup of norepinephrine receptors.

In plain English, this means that they help a person to have both more active serotonin and norepinephrine mechanisms operating in the areas of the brain where mood is controlled through the actions of these two chemicals. This helps to keep mood elevated.

I have personally utilized the TCAs throughout the history of my practice due to their effectiveness. I have often been considered anachronistic for my continued use of these medications by colleagues, especially in the face of new medications available.

However, as with so many psychotropic medications, they are being rediscovered and are in favor once again. The TCAs had fallen out of favor due to their inconvenient side-effect profile, and more importantly due to their cardiovascular side effects.

These medications have an antihistamine and anticholinergic effect. The combinations of all these chemical effects are responsible for the TCAs' tendency to cause sedation, weight gain, constipation, urinary retention, blurred vision and dry mouth.

Orthostatic hypertension is another side-effect of this medication, one with cardiovascular implications. This means that people who have been lying down for a long period of time and suddenly jump up will find that their blood pressure will not keep up with their posture. The result of this is a fainting spell if the person doesn’t get up gradually.

More importantly, though, the other cardiovascular side-effect of this medication is to cause cardiac arrhythmias, which makes overdosage with the TCAs a real possibility.

In very real terms, this means these medications must be carefully monitored by the physician when the client is taking them, and the mental health clinician must be advocating for this careful monitoring when he/she has a client who is taking these medications. There must also be good communication when there is any suicidal ideation on the part of the client, so the physician can ensure that an overdose does not occur.

I must point out, however, that the potential use in suicide, while significant, has been somewhat overblown. Patients should be warned that taking more than two weeks worth of medication (2,000 to 3,000 mg.) can be lethal. And clearly a clinician's conscience would be greatly damaged should these medications be used in a suicide attempt.

However, a plethora of over-the-counter medications, such as Aspirin and Tylenol, are far more dangerous and far more likely to be utilized in a suicide attempt. The patient who utilizes a therapeutic agent in a suicide attempt should be considered as having made a transferential statement about his/her relationship with the therapist or the doctor.

There are also a number of other side-effects common to this group of medications that warrant watching, as well as many contraindications that must be watched and supervised when these medications are being used.

There is another problematic disadvantage of tricyclics. Because the dosage must be built up gradually due to the side-effects, the therapeutic effect of these medications could take as long as one month to build up effectively.

With all of these disadvantages, the question that gets raised, then, is why do I still recommend using them? Simply said, they work. In certain cases, they work more effectively than the more recent additions to the medication arsenal, the SSRIs that we will study in a later chapter.

I may go somewhat out on a limb in saying this, but the SSRIs are not as effective as the TCAs in treating classically presenting depression. The SSRIs have their effect by blocking the reuptake of the neurotransmitter serotonin as it carries messages within the nervous system, but have almost no effect on norepinephrine.

Because norepinephrine elevation helps with depression, it is only logical that medications that elevate both serotonin and norepinephrine would be more helpful in addressing depression. (When we get to the section on the SSRI medications, we will discuss how the SSRIs work and the reasons they are useful in more detail.)

The major tricycle antidepressants that have been in regular use are as follows: Elavil (Amitriptyline), Pamelor (Nortriptyline), Tofranil (Imipramine), and Norpramin (Desipramine). Tofranil is also distributed under the trade name, Janimine, and Pamelor under the trade name, Aventyl, although these names are not as widely known.

There are a great number of other TCAs in the medication arsenal, some of which the reader is not likely to run across. For simplicity's sake, we will look more closely at the four major TCAs previously mentioned. We will, however, provide summary pages and very brief comment at the end of this chapter for the other medications - on the off chance that they may show up in usage.

While not getting into the chemistry of the TCAs in too great detail, these medications are usually broken down into some smaller groupings. There are the "Secondary Amines" and the "Tertiary Amines". The secondary amines are the desmethylatid form of the tertiary amines.

Norpramin is the desmethylatid form of Tofranil and Pamelor is the desmethylatid form of Elavil. This just means that the chemistry is related, but different enough to have different effects and different side effects. It also means that different patients will respond to some of these medications better than others.

Generally speaking, the desmethylatid forms of the TCAs tend to produce less troublesome side effects. Of the four medications mentioned, Elavil has the worst anticholinergic effects of the medications in this group, therefore, I rarely use it.

Elavil, however, has been used in the treatment of headaches for decades. The TCAs, in general, have also been used for other kinds of pain management. In fact, this history of usage has informed current research about the use of antidepressants that potentiate both norepinephrine and serotonin in terms of treating pain.

We will look at some of the subtleties of the use of these medications in this section. First, however, let's begin by showing the summary pages for these four TCAs. Once again, we have made the pages easily printable, so the reader can have copies for reference.

 

                                             Elavil Summary Page


Trade Name: Elavil (1965)........................Chemical Name: Amitriptyline
Antidepressant type: TCA......... Usual Dosage: 150-300 mg/qd
Pill sizes and types: All tablets come in biconvex, disc shaped pill; 10 mg. in blue, 25 mg. in yellow, 50 mg. in beige, 75 mg. in orange. Also, 5 mg. light red oral suspension.
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Clients with psychotic or endogenous depression, particularly when anxiety is also present.
When Elavil is used as opposed to other medications: When other, more commonly used medications have failed to produce a therapeutic response.
Side-effects: With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Drowsiness and impairment of mental/physical abilities. Dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and GI distress are also symptoms.
Contraindications and cautions in use: Not to be taken by clients with known hypersensitivy to TCAs. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Not to be taken during the acute recovery phase for myocardial infarction. Must not be taken by clients with glaucoma, or liver or kidney damage. Should not be taken by clients taking thyroid medication. Should be administered carefully with clients with hyperthyroid. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy. Use during lactation is contraindicated. Withdrawal symptoms are noted. Contraindicated for children under 12.
Comments: Due to the availability of medications with fewer dangers and side-effects, there are very limited circumstances under which this medication will currently be used. However, it is still used for clients who do not respond to more common medications for depression. It is also used in the treatment of headaches.

                                     Norpramin Summary Page


Trade Name: Norpramin (1982)........................Chemical Name: Desipramine
Antidepressant type: TCA......... Usual Dosage: 100-200 mg/qd
Pill sizes and types: All pills come in round, biconvex glossy tablet, 10 mg. in blue, 25 mg. in yellow, 50 mg. in green, 75 mg. in orange, 100 mg. in peach.
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Clients with psychotic and endogenous depression, including depressed phase of bi-polar disorder, and involutional melancholia. Occasionally used with dysthymic depression.
When Norpramin is used as opposed to other medications: When other, more commonly used medications have failed to produce a therapeutic response.
Side-effects: With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Drowsiness and impairment of mental/physical abilities. Dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and GI distress are also possible side effects.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Not to be taken during the acute recovery phase for myocardial infarction. Should be used cautiously in clients with liver damage. Should not be taken by clients taking thyroid medication. Should be administered carefully with clients with history or urinary retention or elderly patients. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy or lactation. Some withdrawal effects noted.
Comments: With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Drowsiness, dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and GI distress are also possible side effects.

                             Tofranil/Janimine Summary Page


Trade Name: Tofranil or Janimine (1960).................Chemical Name: Imipramine
Antidepressant type: TCA......... Usual Dosage: 150-200 mg/qd
Pill sizes and types: 10 mg - Reddish-brown triangular tablet; 25 mg., 50 mg. and 75 mg. - Reddish-brown round tablet
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Clients with depression, children with enuresis.
When Tofranil is used as opposed to other medications: When other, more commonly used medications have failed to produce a therapeutic response. For childhood enuresis.
Side-effects: Tremors, weight gain. With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Increased seizure risk. Extrapyramidal symptoms. Hypertension or hypotension. May aggravate or precipitate psychotic episodes in schizophrenic clients. Hypotension, dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and anorexia are also possible side effects.
Contraindications and cautions in use: Not to be taken by clients with known hypersensitivy to TCAs. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Extreme caution must be used for patients with cardiovascular disease or history of myocardial infarction, or clients taking thyroid medication. Contraindicated with clients with liver or kidney damage. Should be administered carefully with clients with history or urinary retention or elderly patients. Caution should be exercised in clients with low convulsive threshold. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy. Use during lactation is contraindicated. Withdrawal symptoms possible with sudden discontinuation of this medicine.
Comments: Due to the availability of medications with fewer dangers and side-effects, there are very limited circumstances under which this medication will currently be used.

                                 Pamelor/Aventyl Summary Page


Trade Name: Pamelor or Aventyl (1977) ................Chemical Name: Nortriptyline
Antidepressant type: TCA......... Usual Dosage: 75-100 mg/qd
Pill sizes and types: 10 mg. or 25 mg. - White and yellow opaque capsule.
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Clients with endogenous depression.
When Pamelor is used as opposed to other medications: When other, more commonly used medications have failed to produce a therapeutic response.
Side-effects: Hypotension and hypertension. Confused states. With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Increased seizure risk. Extrapyramidal symptoms. Jaundice. Weight gain or loss. In schizophrenic patients, may exacerbate psychosis. Increased risk of seizures. May cause increased hostility. In clients with bi-polar disorder, may precipitate manic phase. May exaggerate response to alcohol. Dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and anorexia are also possible side effects.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Should be administered carefully to clients with cardiovascular disease or taking thyroid medication. Should be administered carefully with clients with history or urinary retention or elderly patients. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy or during lactation. Withdrawal should be administered gradually.
Comments: Pamelor has a stimulating effect useful with low energy patients, as well as a better side effects profile than many of the other TCAs.

Now that we have presented our summary pages on the four TCAs commonly used, it is time to look at the patients for whom these medications are helpful.

Patients who present with the classical signs of depression, such as hopelessness, motor retardation, coupled with poor sleep and poor appetite (with the appetite loss often leading to weight loss of more than 10 pounds) are usually the people who are most effectively treated with these medications.

An important clue is examining the sleep pattern with which the patient presents. Insomnia in classic depression usually includes initial sleep disturbance (difficulty falling asleep that may last as long as two hours) coupled with terminal insomnia (for example, waking up at 3 o’clock in the morning without being able to return to sleep).

Part of the TCA effectiveness is in reducing REM sleep, thereby limiting dreaming. (This is ironic given that the SSRIs that we will study later tend to cause an increase in vivid dreaming.)

If you look at the summary pages for these medications, you may note that these medications are generally recommended for endogenous depression. For some of these, this includes depression that is found in the depressive phase of bipolar disorder. Patients who have psychosis with their depressions also fall in this arena.

These depressions, for reasons that will be examined later, just don't seem to be treated as well by the SSRI medications like Prozac and Zoloft.

So, if one has determined that a TCA antidepressant may be more effective for the particular manifestation of depression that you are seeing, how do you begin to select one medication as opposed to another?

In the year 2002 we tend to struggle in determining which SSRI to use and consider side effect profiles that would lead us to use Prozac or Paxil or Zoloft. During the heyday of TCAs, similar ideas were used in attempting to identify Elavil/Pamelor responders as opposed to Tofranil/Desipramine responders.

The theory here is that different kinds of patients will respond better to one group of TCAs as opposed to the other. It is my sense that this differentiation is largely insignificant. The truth of the matter for me is that Tofranil and its desmethylatid form, Desipramine, are the mainstay of medications I use in treating classically presenting severe depressions. I begin with them. Given that I am a clinically oriented psychiatrist, I then will look to change my medication approaches based upon what is observed to work.

When using Tofranil, I usually start at 50 mg. for the first week of treatment, moving up in 50 mg. increments usually up to 150 mg. at bedtime. One week into the full dosage you then look for the therapeutic effect of the medication.

This step-wise increase in dosaging is a way of minimizing the anticholinergic side effects of the medication. If the side effects prove intolerable, gradually switching the patient from Tofranil to Desipramine will reduce the dry mouth or urinary retention that often accompanies the use of these medications.

Dosing with Desipramine is largely identical. Much had been made back in the 70's regarding the “therapeutic window” of Desipramine. It was not uncommon practice to get blood levels of this medication to prove therapeutic effectiveness. From my perspective in working with real people, it is much more efficient to judge the responses of the medication clinically than with blood levels.

The use of Pamelor should then be considered if one month on Tofranil and a subsequent two weeks on Desipramine fails to produce the desired antidepressant effect. Pamelor is more potent than the other medications and the dose range would be exactly half of the other two, with 75 to 100 being the full therapeutic dosage.

As I mentioned, I rarely use Elavil to treat patients, as the side effects are very difficult on the person taking it. There are other newer medications in this group that you may occasionally come across. They are all generally in the TCA family and work on the norepinephrine systems. This group includes Asendin, Sinequan (also called Adapin), Vivactil (also called Triptil), and Ludiomil.

It is my sense that these newer TCA medications have not necessarily offered advantages over their earlier TCA counterparts in terms of effectiveness of side-effect profiles. However, Vivactil happens to be a medication that I personally will tend to use for certain patients, and other physicians may find good uses for one or more of these. While not covering them in detail, we will provide some information, beginning with summary pages.

 

                                    Asendin Summary Page


Trade Name: Asendin(1989) ........................Chemical Name: amoxapine
Antidepressant type: TCA......... Usual Dosage: 200-300 mg/qd
Pill sizes and types: 25 mg. - White, heptagonal, scored tablet 50 mg. - Orange, heptagonal, scored tablet. 100 mg. - Blue, heptagonal, scored tablet.
How it Works: Inhibits re-uptake of norepinephrine, and, to lesser degree, serotonin, and blocks response of dopamine receptors to dopamine.
Most Common Uses: Clients with symptoms of depression who have not responded to other medications.
When Asendin is used as opposed to other medications: For patients with depression concurrent with psychotic or schizoaffective symptomatology.
Side-effects: The most serious side effects involve tardive dyskinesia and extrapyramidal symptoms, similar to patients taking anti-psychotic medications, and with high medication doses, sinus tachycardia, myocardia infarction, and stroke. Reduces the seizure threshold. Dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and GI distress are also symptoms.
Contraindications and cautions in use: Not to be taken by clients with known hypersensitivy to TCAs. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Not to be taken during the acute recovery phase for myocardial infarction, or in presence of congestive heart failure. Must not be taken by clients with glaucoma, or liver or kidney damage. Clients should be monitored for tardive dyskinesia and signs of seizures. May precipitate or aggravate psychosis in schizophrenics. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy or lactation. Withdrawal should be administered gradually.
Comments: Because of anti-psychotic effects, this medication may still have some uses. However, serious side effects such as tardive dyskinesia and extrapyramidal symptoms may occur, so this medication must be carefully administered.

                               Adapin/Sinequan Summary Page


Trade Name: Adapin or Sinequan (1982).....................Chemical Name: Doxepin
Antidepressant type: TCA......... Usual Dosage: 75-150 mg/qd
Pill sizes and types: Capsules of 10, 25, 50, 75, 100, and 150 mg.
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Clients with psychotic depression, including bi-polar disorder (depressed type), dysthymic clients with somatic complaints, and alcoholic clients with anxiety or depression.
When Adapin is used as opposed to other medications: For patients who require a sedative effect in combination with antidepressant effects.
Side-effects: With high medication doses, sinus tachycardia, myocardia infarction, and stroke. Increase seizure risk. Extrapyramidal symptoms. Hypertension or hypotension. May aggravate or precipitate psychotic episodes in schizophrenic clients. Drowsiness, dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and GI distress are also possible side effects.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Not to be taken during the acute recovery phase for myocardial infarction. Must not be taken by clients with glaucoma, or liver or kidney damage. Should be administered carefully to clients taking thyroid medication. Should be administered carefully with clients with history of urinary retention or elderly patients. Will exaggerate effects of alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy or lactation. Withdrawal should be administered gradually.
Comments: Due to the availability of medications with fewer dangers and side-effects, there are very limited circumstances under which this medication will currently be used. However, this medication has a better sedative effect than other TCAs and may be used when this sedative effect is needed in combination with antidepressant effects.

 

                                   Vivactil/Triptil Summary Page


Trade Name: Vivactil or Triptil ........................Chemical Name: Protriptyline
Antidepressant type: TCA......... Usual Dosage: 15-40 mg/qd
Pill sizes and types: White, round tablet of 10 mg.
How it Works: Inhibits norepinephrine and serotonin uptake. This allows more of these neurotransmitters to act in neurons of the limbic system.
Most Common Uses: Depressed clients who are apathetic and withdrawn.
When Vivactil is used as opposed to other medications: For patients who oversleep and overeat and who are unable to utilize Wellbutrin, which has similar ameliorative effects, but is safer to use.
Side-effects: May exaggerate response to alcohol. Dry mouth, blurred vision, decreased libido, skin rash and photosensitivity, nausea and anorexia are also possible side effects. In schizophrenic patients, may exacerbate psychosis. Increased risk of seizures. May cause increased hostility. In clients with bi-polar disorder, may precipitate manic phase.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Must not be taken by clients with glaucoma, or tendency towards urinary retention. Should not be taken by clients. Should be administered carefully with clients with cardiovascular problems or taking thyroid medication. Will exaggerate effects of alcohol and other CNS depressants. Will cause physical/mental impairments sufficient to contraindicate use while performing hazardous tasks. It has not been established whether it is safe to take this medication during pregnancy or during lactation. Withdrawal should be administered gradually.
Comments: This medication has been largely replaced by Wellbutrin, which is utilized effectively for patients with depression who oversleep and overeat. It can still be useful for patients who show these symptoms, but do not respond well to Wellbutrin.

                                      Ludiomil Summary Page


Trade Name: Ludiomil (1982)...........................Chemical Name: Maprotiline
Antidepressant type: TCA......... Usual Dosage: 75-150 mg/qd
Pill sizes and types: Round, film-coated, convex tablets: 10 mg. - Cream colored; 25 mg. - Orange; 50 mg. - Dark orange; 75 mg. - Red-orange.
How it Works: Inhibits reuptake of norepinephrine and inhibits presynaptic uptake of catecholamines.
Most Common Uses: Clients with endogenous depression, including depressed phase of bi-polar disorder and involutional melancholia.
When Ludiomil is used as opposed to other medications: This medication is seldom used.
Side-effects: May exaggerate response to alcohol and other CNS depressants. Dry mouth, blurred vision, decreased libido, increased perspiration, headaches, nausea and fatigue are common side effects. May cause photosensitivity and rash. In schizophrenic patients, may exacerbate psychosis. Increased risk of seizures. In clients with bi-polar disorder, may precipitate manic phase.
Contraindications and cautions in use: Not to be taken by clients with known hypersensitivy to TCAs. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Contraindicated for patients with seizure disorder, or patients in acuter recovery phase of myocardial infarction. Must not be taken by clients with glaucoma, or liver or kidney damage. Should not be taken by clients taking thyroid medication. Should be administered carefully with clients with history of urinary retention or elderly patients. May exaggerate responses to alcohol and other CNS depressants. It has not been established whether it is safe to take this medication during pregnancy or during lactation. Not recommended for use in children.
Comments: This medication is seldom used in the treatment of depression. If a doctor is prescribing it, given the range of other treatment options, it would be helpful to request clarification about why it is the choice for treatment.

Asendin is a medication that appears to have both antidepressant and anti-psychotic effects. The anti-psychotic properties are due to its effects on the brain's dopamine systems. Later in this training, we will look at another, more widely used medication with similar properties - Wellbutrin. Asendin may be seen as a less successful precursor to this preferable medication.

Because it can cause the same kind of extrapyramidal side effects as some of the older anti-psychotic medications, Asendin's usage as an antidepressant has been very limited.

Sinequan has properties very similar to Elavil, and its value as an antidepressant may lie in its sedative effects. Ludiomil was touted as a "quadracyclic antidepressant", as opposed to a "tricyclic antidepressant". At the risk of sounding silly, four chemical rings did not seem to offer any benefits over three chemical rings in terms of antidepressant properties. This medication is rarely used.

On the other hand, I will still use Vivactil on occasion. This TCA has an invigorating effect that is useful for major depressions, but with a "cleaner" side-effects profile.



Review Questions for Section V

At this point in the training, you should be able to answer the following questions:

1. Why must patients with suicidal ideation be monitored carefully when they are taking TCA medications?
2. What kinds of clients seem to be treated more effectively with TCA medications than with SSRI medications?
3. Under what conditions would the TCA medications likely be considered by a physician?


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