Feeling Good: The New Mood Therapy
Page 46
Finally, blockade of the brain’s muscarinic receptors causes side effects such as dry mouth, constipation, blurred vision, difficulties getting your urine flow started, and a speeding up of the heart, even when you are resting. Because of these effects on the heart, the tricyclic medications in Table 20–2 with the strongest effects on-these muscarinic receptors may not be advisable for patients with cardiac problems. Drugs with strong anticholinergic effects can also create problems with memory. Many patients have told me that they cannot remember a word they want to use, or they forget someone’s name when they take these drugs. The memory effects are dose-related and should disappear when you stop taking the drug.
You can see that two of the tricyclic drugs in Table 20–2 (desipramine and nortriptyline) have relatively weak anticholinergic effects. These two drugs will be the least likely to cause side effects like dry mouth and forgetfulness. These two also tend to have weaker effects on the histamine and alpha-adrenergic receptors. Because they have fewer side effects, they are among the most popular tricyclic antidepressants.
The effects of antidepressant drugs on these three brain receptor systems do not completely explain all their side effects. In the right-hand column, I have listed many of the more common or significant side effects for each drug. For example, you will see that some of them can cause skin rashes. Some tricyclics, most notably clomipramine (Anafranil), can cause seizures, and so this drug would not be a good choice for individuals with epilepsy.
Table 20–2. Side Effects of Tricyclic Antidepressantsa
aThe + to + + + ratings in this table refer to the likelihood that a particular side effect will develop. The actual intensity of the side effect will vary among individuals and will also depend on how large the dose is. Reducing the dose can often reduce side effects without reducing effectiveness.
bMany side effects, if troublesome, can be minimized by a reduction in dosage. Side effects are usually greatest in the first few days and tend to disappear later.
cThe drugs that are the most sedative may also have greater antianxiety effects. In other words, they may calm you and make you less nervous. When given at night, the sedative agents help reduce insomnia.
If you and your doctor are choosing one of the antidepressants listed in Table 20–2, you might want to consider the side-effect profile when making your choice. This is because all these medications are comparably effective, so their side effects may be the most important criteria for you in deciding among them. So if you are having trouble sleeping at night, one of the more sedative antidepressants may be useful. These sedative agents are also somewhat calming and so they might be helpful if you are experiencing anxiety.
Many of the side effects of the tricyclic antidepressants listed in Table 20–2 occur in the first few days. With the exception of dry mouth and weight gain, these side effects frequently diminish as you become accustomed to the drug. If you can simply put up with the side effects, many of them will disappear after a few days. If the effects are strong enough to make you uncomfortable, your doctor may decide to reduce the dose, which usually helps.
Some side effects suggest you are taking an excessive dose. These include difficulty in urination, blurred vision, confusion, severe tremor, substantial dizziness, or increased sweating. A dose reduction for such symptoms is definitely indicated. A stool softener or laxative can help if constipation develops. As noted above, light-headedness is most likely to occur when you stand up suddenly, because the blood flow to your brain is temporarily diminished. The dizzy feeling usually persists for only a few seconds. If you get up more carefully and slowly, or if you exercise your legs before standing (by tightening and then relaxing your leg muscles, as when you run in place), this should not be a problem. The movement of your legs causes your leg muscles to “pump” the blood back up to your brain. Support stockings can also help.
Some patients describe feeling “strange,” “spaced out,” or “unreal” for several days when they first start taking a tricyclic antidepressant. In my experience, one of the tricyclics called doxepin (Sinequan) seems more likely to cause this “spaced out” effect. When patients report feeling strange on the first day or two of taking an antidepressant, I usually advise them to stick with it. In nearly all cases the sensation disappears completely within a few days.
If you give patients sugar pills (placebos) they think are antidepressants, they will also report side effects that are similar to the side effects reported by patients taking antidepressants. For example, in one study, 25 percent of the patients taking clomipramine reported difficulties sleeping, so you might conclude that this drug causes insomnia in a quarter of those who take it. However, 15 percent of the patients in the same study who received only placebo also reported insomnia. So the likelihood of insomnia actually caused by clomipramine would be 25 percent minus 15 percent, or 10 percent. Clearly, this side effect is “real,” but it is somewhat less common than you might at first expect.
Such studies indicate that many “side effects” may not actually be caused by the medication you are taking. Some side effects may result from fears about the medication, or from the depression itself, or from other stressful events in your life such as a conflict with your spouse, rather than from the drug itself.
Side Effects of the Tetracyclic Antidepressants. You can see in Table 20–3 on pages 536–537 that the side effects of the tetracyclic antidepressants are similar to those of the tricyclic antidepressants. However, they have some special side effects of their own that should be considered if you are taking one of these drugs. Maprotiline (Ludiomil) appears to be more likely than the eight tricyclic antidepressant drugs to cause seizures, a particularly troublesome side effect. Although the likelihood of seizures is low, patients with a history of seizures or head trauma should probably avoid this drug. Recent studies suggest that the likelihood of seizures with maprotiline is significantly greater when the dose is increased too rapidly, or when patients are kept on higher-than-recommended doses (225 to 400 mg per day) for more than six weeks.16 Therefore the manufacturer has suggested that maprotiline should be started and increased very slowly, and that the dose should be maintained at no more than 175 mg per day if patients take this drug for more than six weeks.
Amoxapine (Asendin) has a distinct and troublesome type of side effect not shared with most other antidepressants. This is because one of its metabolites blocks dopamine receptors in the brain, much like antipsychotic drugs such as chlorpromazine (Thorazine) and many others which are used in the treatment of schizophrenia. Thus, patients who take amoxapine can in rare instances develop some of the same types of side effects that occur in patients who take antipsychotic drugs. For example, women may experience galactorrhea (the production of milk by the breast.) Any of several so-called “extrapyramidal” reactions can also develop. One of them, called akathisia, is a motor restlessness syndrome. This is an unusual kind of muscular “itchiness”—your arms or legs feel intensely restless and so you cannot sit still. You feel the compulsion to keep moving or pacing about. Akathisia is uncomfortable but not dangerous.
In rare instances amoxapine can also cause symptoms that mimic Parkinson’s disease. Symptoms include passive inactivity, a “pill-rolling” tremor of the thumb and fingers while at rest, decreased swinging of the arms when walking, stiffness, stooped posture, and others. If these symptoms develop, notify your doctor right away. She or he will probably want you to stop the drug and try an alternative medication. Although alarming, these symptoms are not dangerous and should disappear when you stop taking the amoxapine.
However, a more serious side effect of amoxapine (as well as many other antipsychotic drugs) is called “tardive dyskinesia.” Patients with tardive dyskinesia develop involuntary, repetitious movements of the face, especially the lips and tongue. The abnormal movements can also involve the arms and legs. Once it begins, tardive dyskinesia sometimes becomes irreversible or difficult to treat. The risk appears to be the highest among elderly women, but it
can occur with any patient. The risk of tardive dyskinesia also increases the longer you have been on the drug, but it can develop after only a brief period of treatment at a low dose.
Table 20–3. Side Effects of Tetracyclic Antidepressantsa
aThe + to + + + ratings in this table refer to the likelihood that a particular side effect will develop. The actual intensity of the side effect will vary among individuals and will also depend on how large the dose is. Reducing the dose can often reduce side effects without reducing effectiveness.
bEPS = extrapyramidal symptoms (described in text) including akathisia and dystonic reactions and tardive dyskinesia.
CNMS = neuroleptic malignant syndrome. This is a potentially fatal reaction that also occurs in reaction to antipsychotic drugs (also known as neuroleptics). The symptoms include increased fever, rigid muscles, altered mental status, irregular pulse or blood pressure, rapid heart, profuse sweating, and abnormal heart rhythms.
Finally, as if that weren’t enough to frighten you, amoxapine can, in rare cases, cause a dreaded complication known as neuroleptic malignant syndrome, or NMS. NMS consists of high fever, delirium, and muscle rigidity, along with changes in blood pressure, heart rate and rhythm, and sometimes death. All these risks should obviously be carefully balanced against any potential benefits of amoxapine; it may sometimes be difficult to justify using this medication when so many equally effective and safer drugs are readily available.
Tricyclic and Tetracyclic Antidepressant (TCA) Drug Interactions. I described the problem of drug interactions in Chapter 19. Briefly, when you are taking more than one drug, there is a possibility that the drugs may interact in ways that will be detrimental to you. One drug may cause the level of the second drug to increase or decrease in your blood. As a result, the second drug may cause excessive side effects (if its blood level gets too high) or it may become ineffective (if its blood level falls). In addition, sometimes the interaction of two drugs can lead to toxic reactions that are quite dangerous.
A number of drug interactions for the tricyclic and tetracyclic antidepressants are listed in Table 20–4 on pages 540–547. This list is not comprehensive, but it does include many of the more common or important interactions. If you are taking any other medications along with a TCA, it would be wise to review this table. Note that both prescription and nonprescription drugs are listed, including many psychiatric and nonpsychiatric drugs as well. In addition, you should ask your physician and pharmacist if there are any drug interactions among the drugs you are taking.
You can see in Table 20–4 that smoking cigarettes and drinking alcohol can both cause the blood level of a TCA to fall, thus reducing the likelihood that the drug will be effective. Your doctor may need to do a blood test to find out if your blood level is adequate. In addition, alcohol can enhance the sedative effects of the tricyclic antidepressants, a combination that can be quite hazardous if you are driving or operating dangerous machinery.
Certain antidepressants can be particularly hazardous for individuals with specific medical conditions. In particular, the tricyclics can be dangerous to individuals with cardiovascular disease, including those with a previous heart attack, abnormalities in heart rhythm, or high blood pressure. Special precautions should also be taken for individuals with thyroid disease. Make sure you mention any medical problems you have to the doctor who is prescribing your antidepressant so that she or he can take the proper precautions.
As noted above, several of the tricyclic and tetracyclic antidepressants can cause seizures in rare instances. An incidence of seizures as high as 1 percent to 3 percent has been reported with clomipramine, imipramine, and maprotiline.17 These estimates may be overly high. At any rate, the risk can be reduced by making sure the dose is not excessive and by raising the dose gradually. Nevertheless, these drugs should be used with caution, if at all, in individuals with a history of seizure disorders, head trauma, or other neurologic disorders associated with seizures. In addition, caution should be used if these drugs are combined with other drugs that can lower the seizure threshold, such as the major tranquilizers (neuroleptics) and others. Rapid withdrawal from sedative agents, such as alcohol, minor tranquilizers, and barbiturates can also trigger seizures, and so clomipramine, imipramine, and maprotiline should be used with great caution in combination with these agents.
Table 20–4. Drug Interaction Guide for Tricyclic and Tetracyclic Antidepressants (TCAs)a
Note: The drugs in the left-hand column can interact with TCAs. The comments describe the types of interactions. This list is not exhaustive; new information about drug interactions comes out frequently. If you are taking a TCA and any other medication, ask your doctor and pharmacist if there are any drug interactions you should know about.
Antidepresssants
Drug
Comment
tricyclic and tetracyclic antidepressants (TCAs can interact with other TCAs)
desipramine causes an ↑ in other TCAs—abnormal heart rhythms can result
SSRIs
TCA levels can ↑ (as much as 2- to 10-fold); abnormal heart rhythms can result; SSRI levels can also ↑
MAOIs
serotonin syndrome b [especially clomipramine (Anafranil)];
low blood pressure;
hypertensive reactions
serotonin antagonists, including trazodone (Desyrel) and nefazodone (Serzone)
nefazodone may cause low blood pressure
bupropion (Wellbutrin)
↑ in risk of seizures; extreme caution required
venlafaxine (Effexor)
probably okay; in theory TCA could cause ↑ in venlafaxine blood levels
mirtazapine (Remeron)
information not yet available
Antibiotics
Drug
Comment
chloramphenicol (Chloromycetin)
TCA levels and toxicity may ↑
doxycycline (Vibramycin)
TCA levels and effectiveness may ↓
isoniazid (INH, Nydrazid)
TCA levels and toxicity may ↑
Antifungal Agents
Drug
Comment
imidazoles such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral) and miconazole (Monistat vaginal suppositories or cream)
TCA levels may ↑, especially nortriptyline
griseofulvin (Fulvicin)
TCA levels may ↓
Diabetes Medications
Drug
Comment
insulin
greater-than-expected drop in blood sugar
oral hypoglycemic drugs
greater-than-expected drop in blood sugar
Medical Conditions
Condition
Comment
glaucoma
highly anticholinergic TCA can trigger attacks of narrow-angle glaucoma; symptoms include eye pain, blurred vision, and halos around lights
heart disease
use TCA with extreme caution; may trigger abnormal heart rhythms
liver disease
use TCA with caution; the metabolism by the liver may be impaired, with excessively high blood levels and increased side effects and toxic effects
seizure disorder
use TCA with caution; TCA may cause ↑ in seizures (TCA lowers the seizure “threshold”)
thyroid disease
use TCA with caution in patients with thyroid disease or those taking thyroid medication; may trigger abnormal heart rhythms
Medications for Abnormal Heart Rhythms
Drug
Comment
disopyramide (Norpace)
abnormal heart rhythms
epinephrine
TCA may enhance the effects, leading to rapid heart, abnormal heart rhythms, and ↑ in BP
quinidine
blood levels of quinidine and TCA may ↑; abnormal heart rhythms and weakened heart muscle can lead to congestive heart failure
Medications for High B
lood Pressure
Drug
Comment
beta-blockers such as propranolol (Inderal)
beta-blockers may cause increased depression; TCA may cause greater-than-expected drop in BP
clonidine (Catapres)
TCA [e.g., desipramine (Norpramin)] may reduce effectiveness of clonidine because blood levels ↓
calcium channel blockers
BP drop may be greater than expected
guanethidine (Ismelin)
may lose antihypertensive effect when combined with TCA [e.g., desipramine (Norpramin)]
methyldopa (Aldomet)
BP drop may be greater than expected, especially with amitriptyline (Elavil); some TCAs [e.g., desipramine (Norpramin)] may reduce the antihypertensive effect
prazosin (Minipress)
BP may ↑ because levels of prazosin may ↓
reserpine (Serpasil)
may cause greater-than-expected drop in BP; may also cause excessive stimulation
thiazide diuretics such as hydrochlorothiazide (Dyazide)
blood-pressure drop may be greater than expected; effects of TCA may increase
Medications for Low Blood Pressure (for patients in shock)
Drug
Comment
epinephrine
TCA may enhance the effects, leading to rapid heart, abnormal heart rhythms, and ↑ in BP