There are three main classes of antidepressant medications, plus some other new ones that do not fit clearly into any category. They are (1) the tricyclic or heterocyclic medications such as amitriptyline or desipramine, (2) the monoamine oxidase inhibitors such as phenelzine, and (3) selective serotonin reputake inhibitors such as fluoxetine (prozac) or sertraline. Medications within any one class are more similar to each other than they are different, and differences within one class are primarily differences in side effects. Again, like the antipsychotic medications, some consumers will respond much better to one of these drugs than to a very similar drug from the same class.

When to use Antidepressants

1. Depression: It is often difficult to predict which depressed consumer will respond to antidepressants, and which will not respond. Indicators that a consumer is more likely to respond to medication include endogenous signs (weight loss, early morning awakening, feeling worse in the morning and feeling better as the day goes on), depressions that do not seem to have a major reactive component (that is, where there is no obvious reason why the consumer is depressed). A pervasive sense of anhedonia, where even things the person used to enjoy are no longer fun and a sense of hopelessness are other important characteristics of depressed people who respond to antidepressant drugs. Many of these consumers with endogenous depressions have a family member who is also depressed, or has made suicide attempts, or who is alcoholic. It may be worth giving the consumer a trial of antidepressant medication, even without a clear endogenous pattern, especially if the depression is long standing and has not responded to psychosocial treatments.
Most consumers with an endogenous type of depression do very well just with an antidepressant and do not need a combination of different meds. Consumers who are agitated or have a major sleep problem may respond faster if given a minor tranquilizer for a few days at the beginning of treatment, along with an antidepressant. Some consumers with a very agitated depression, especially if they have psychotic symptoms, respond better initially to a combination of an antipsychotic medication in addition to an antidepressant. Consumers with a delusional depression initially respond much better to antipsychotic and antidepressant medications than to antidepressants alone. Antidepressants seem ineffective in consumers going through a typical grief reaction or with a typical neurotic or reactive depression.
These medications can be used along with antipsychotics, with common sleeping pills, or with ECT(electroconvulsive therapy, also known as 'shock' treatment, an often very effective treatment for some depressions. For more information, call AMI/FAMI for a free copy of "All about ECT"-ed). Antidepressants are useful in combination with lithium in consumers who are in the depressed phase of a manic depressive illness.
The best indicator of which antidepressant to start is which one worked in the past for either that consumer or someone in his immediate family.

2. Panic Attacks: These drugs are called "antidepressants" because that is the condition where they were first used. They are effective in a number of other conditions, and could be called "anti-panic" medications. These meds are not particularly useful in generalized anxiety, but many of the antidepressants (with the clear exception of bupropion (Wellbutrin) are more effective in decreasing the frequency of true panic attacks than anti-anxiety medications such as Valium or Librium. Many people with agoraphobia (fear of going out) have a combination of panic along with anticipatory anxiety. Antidepressants will often block the panic, without effecting the anticipatory anxiety which is most effectively treated with behavioral therapy.

3. Obsessive Compulsive Disorder (OCD): OCD has until recently been considered unresponsive to medication. An increasing number of research studies have demonstrated that several antidepressants are extremely helpful with many consumers who have this often disabling disorder. Fluoxetine (Prozac) seems ineffective in the 20 mg./day dose normally used with depressed consumers, but helps many OCD consumers when used in higher doses of 60-80 mg./day. Clomipramine (Anafranil) has recently been approved specifically for use with OCD. Typically one starts clomipramine at 25 mg/day and then increases the dose to 150 mg/day. A typical dose range is 150-250 mg/day. Other antidepressants that effect the serotonin system also seem to be effective in OCD.

4. Bulimia: There are reasonable data that antidepressants are useful for at least some consumers with bulimia, whether they are depressed or not. They can decrease the frequency and severity of the binging, and help consumers to establish more control over their own eating.

5. Cocaine craving: There are increasingly good data that antidepressants can be useful in many people addicted to cocaine and trying to withdraw. Desipramine has been more frequently studied, but other antidepressants are probably also effective. These medications can help decrease the craving for the drug, and prevent the post-withdrawal depression that is common in habitual users. Just as when treating depression, there is often a several week delay between starting the medication and seeing a positive response.

6. Miscellaneous: Antidepressants are also useful in a variety of other conditions. They can empower pain medications and are often very useful as part of a combination of drugs in treating severe and chronic pain. They seem to have a specific effect on some migraine type headaches, even apart from their potential for pain relief. They can treat a variety of what are called "stage four sleep disorders", which can include night terrors and enuresis in kids. Finally, they are effective for some kinds of school avoidance when other therapy has not worked.

B. Tricyclic or heterocyclic antidepressants: eg. amitriptyline (Elavil), nortriptyline (Pamelor) and doxepine (Sinequan). Most of the commonly used antidepressants are "tricyclics" (referring to their three-ring molecular structure). New antidepressants similar to the tricyclics are now being developed. The entire class of antidepressants is now referred to as heterocyclic antidepressants in the newer literature.

1. Side Effects:
a. These drugs are all extremely dangerous when taken as an overdose, and a severely depressed, potentially suicidal consumer should not be given more than a one week supply. Trazodone, fluoxetine (Prozac) and sertraline (Zoloff) are newer antidepressants which are supposed to be much safer if taken as an overdose, while amoxapine (Asendin) and amitriptyline (Elavil) are probably somewhat more dangerous in an overdose.

b. With the possible exception of bupropion, all antidepressants magnify the effect of alcohol, and a few drinks will make a consumer on these medications more intoxicated than he or she would normally get. In addition, alcohol increases the lethality of antidepressants, and a normally non-lethal overdose may become lethal if combined with alcohol.

c. Anticholinergic side effects are common. Almost all of the antidepressants except fluoxetine (Prozac), trazodone (Desyrel) and bupropion (Wellbutrin) produce the kind of autonomic side effects (side effects related to the involuntary part of the nervous system responsible for basic system regulation) typical of other anticholinergic drugs. These include dry mouth, blurred vision, constipation, and, in rare cases, urinary retention, heart palpitations or tachycardia (speeding pulse) and increased sweating. (Trazodone does cause a dry mouth, but does it through a different mechanism than blocking acetylcholine.) These meds can, on rare occasions, aggravate certain kinds of glaucoma (increased pressure in the eyeball) and eye pain or the need for special eye drops should be asked about.

d. Cardiovascular (heart) side effects include orthostatic hypotension, increased pulse and EKG changes. The most serious of these side effects are sudden irregularities of the heart beat or heart block where the electrical impulses cannot spread through the heart normally. While sudden death has been reported in rare cases the effects on the heart are very complicated and not all bad. The tricyclic antidepressants (eg. amitriptyline, desipramine) act on the heart very much like quinidine, a medication used to stabilize certain kinds of heart beat irregularities. In fact, a consumer with heart problems who normally required quinidine can often reduce or eliminate their dose of this drug while taking an antidepressant.

e. Neurological complications are fairly rare. Grand mal seizures can be caused by these medications. Bupropion (Wellbutrin) and maprotiline (Ludiomil) seem to have a higher incidence of seizures than the other antidepressants. Other side effects include drowsiness, slurred speech and hand tremor. Like any other anticholinergic medication, these drugs can also cause a reversible organic brain syndrome that can start with some confusion, and progress to a full delirium that may be difficult to distinguish from a psychotic episode.

f. Weight gain is a common problem caused by all of the heterocyclic and MAOI antidepressants. The newer antidepressants, including trazodone (Desyrel), bupropion (Wellbutrin), fluoxetine (Prozac) and sertraline do not normally cause weight gain and may cause some weight loss.

g. The antidepressants can cause decreased libido and impotence. They can also block menstrual periods, although this seems less common. Decreasing the dose of medication or switching to a different antidepressant is sometimes useful in dealing with these problems.

h. Antidepressants can trigger a manic episode in some susceptible people. In addition, some schizophrenic consumers are reported to get more disorganized or more paranoid when taking antidepressants. Finally, these medications can cause some consumers to start "rapid cycling", having rapid depressed to manic mood swings more often than once a month.

i. Various allergies can also occur, and any consumer on any drug who reports a new rash should have it investigated. Also as with the antipsychotic meds, agranulocytosis (drop in white blood cell count) has been reported, and any consumer with a sore throat, sudden chills or fever should have an emergency complete blood count (CBC).

j. Abrupt withdrawal of these drugs sometimes produces nausea, vomiting, abdominal cramps, diarrhea, chills, insomnia and anxiety lasting 3-5 days. This withdrawal is not medically dangerous but can be uncomfortable. When quitting, these meds should usually be gradually withdrawn over several weeks or even longer, especially if the person has been taking the medication for some time.

k. Finally, while these medications usually help sleep, occasionally they will produce nightmares. These can be controlled by lowering the dose, giving it earlier in the day or in divided doses. Agitation and nervousness are uncommon but reported side effects of these meds.

2. Dosage and Use of Heterocyclic Antidepressants

Before starting antidepressants, especially in an older consumer, or if there is a history of heart problems, an EKG should be obtained and if there is any question of heart disease, a medical clearance obtained as well. The usual dose for both imipramine (Tofranil) and amitriptyline (Elavil) is to start at 50-75 mg a day for 2-3 days, and if there are no serious side effects to gradually increase the dose to 150-300 mg/day. It takes from 5 days to 3 weeks for these drugs to be effective, and a reasonable trial is at least 3 weeks of medicine in doses above 150 mg/day. After the dose is stabilized, most or all of the drug can be given right before bedtime to minimize the sedative and other side effects, and to help insure a good night's sleep.

Your doctor should take blood samples to get serum levels. It is now possible to get a blood sample and determine how much of the medication is actually present. One consumer may have 10 times the serum level of another, while taking the same daily dose. For some of the medications such as nortriptyline, there appears to be a "therapeutic window". Serum levels within a certain range (50-150 ng./ml) are more effective than levels either below or above this range. For other antidepressants, lower levels seem ineffective but higher levels seem ok, except for their higher side effects. For most of the antidepressants, we can measure a serum level but there is not yet enough research to know what the serum levels mean, and how much is too much.

C. Monoamine oxidase inhibitors (MAOIs ) eg. phenelzine (Nardil) and tranylcypromine (Parnate). These medications have always been widely used in England, and have been increasingly used in the U.S. over the past few years. Some consumers will respond to MAOIs who have not had any response to the other medications. MAOIs seem to be particularly useful in consumers with "atypical depression". These consumers often have problems with anxiety and agoraphobic symptoms, may have weight gain instead of the more common weight loss, may sleep too much instead of too little. Some researchers suggest that consumers with "hysteroid dysphoria", a vague constellation of symptoms and marked sensitivity to rejection, may respond specifically to MAOIs. Other authors feel that consumers with bulimia and agoraphobia may respond better to these drugs than to the more traditional antidepressants.

Antidepressants (continued)

1. Side Effects of MAOIs

a. Hypertensive Crisis: The most common serious side effect is a hypertensive crisis (very rapid very high elevations of blood pressure to dangerous levels). This reaction is caused by an interaction between the MAOI and foods containing tyramine, or between MAOI and drugs that have effect on the sympathetic nervous system. The MAOIs work by interfering with the enzyme that breaks apart certain neurotransmitters. This same enzyme also breaks apart tyramine, an amino acid that naturally occurs in certain food. Since the MAOI keeps this tyramine from being deactivated, it can rapidly accumulate to high levels and cause the increase in blood pressure.
The symptoms of a hypertensive crisis may include a severe headache, palpitations, nausea and vomiting, unexplained nose bleed or chest pain. A blood pressure check can quickly determine whether there is a problem or not. Such crises are rare, especially if consumers are compliant with the food restrictions, but can lead to strokes and other catastrophes.

Foods that must be avoided when on
MAOI antidepressants include:
Aged Cheeses (essentially
everything except
blandAmerican cheese)
Pickled Herring
Chicken Liver
Broad Beans (fava beans)
Chianti and other Red Wines
Sausage (aged salami, etc.)
Dried, salted fish
Foods containing chocolate
Yogurt and sour cream
Aged Foods (over-ripe bananas)
Monosodium glutimate (MSG)
Soy Sauce
Meat tenderizer

b. MAOIs interact with a large number of other medications, often in dangerous ways. For example, there have been some deaths because consumers taking an MAOI were given Demerol (a potent pain medication). If you are taking an MAOI let all treating physicians, dentists, etc know. Some form of emergency notification, either by a card in your wallet or something else, is also a useful precaution.
Many non-prescription cold and allergy medications can cause a hypertensive reaction, as can stimulants such as amphetamines and cocaine. Consumers taking MAOIs are strongly advised to check with either their doctor or with a pharmacist about drug interactions before taking any other medication.

c. MAOIs can also cause orthostatic hypotension (drop in blood pressure when the consumer stands up quickly). This can cause temporary dizziness or even fainting, and is often severe enough to limit the dose of medication that can be used.

d. MAOIs are activating rather than sedating drugs for most people. This is often an advantage since they usually do not cause the sedation that is common with other antidepressants, but this same activating effect can interfere with sleep. Most people prefer to take these medications early in the day rather than at night as the tricyclics are usually taken. At times it is useful to give low dose trazedone at night if sleep disturbance is a significant problem. Some people do get sedated from the MAOIs, and feelings of lethargy a few hours after taking the medication is not uncommon.

e. Other side effects are possible, but usually less of a problem or less common. Constipation or diarrhea is sometimes reported, as is dry mouth, transient impotence, skin rash and occasional complaints of blurred vision. Serious liver toxicity is rare, but has been reported with phenelzine (Nardil).

MAOIs Dosage

You must be off all other antidepressants for at least 10 days before starting a MAOI and off fluoxetine [Prozac] for 6 weeks. Similarly, if you switch between different MAOIs there must be at least a 10 day drug free period. The dose of the medication is gradually increased over a week or two, and as with the other antidepressants it usually takes 3 weeks or longer for the medications to be effective.

D. Serotonergic Medictions: ex. fluoxetine (Prozac) and sertraline (Zoloff)
A number of new antidepressants have recently been developed that affect the serotonergic part of the nervous system. These medications are very well tolerated with relatively few side effects, but some consumers complain of increased anxiety, nausea and headaches. They tend to cause weight loss rather than the weight gain, they are activating rather than sedating. They are less lethal after an overdose than the other antidepressants (along with trazodone which also seems relatively less lethal), and have fewer cardiac side effects. Suicide is always a risk in a depressed consumer who is beginning to come out of their depression and become activated, but there is no evidence that Prozac increase this suicide risk.
This new class of medication has some advantages over older antidepressants, but the differences are evolutionary rather than revolutionary. While these medications do not appear any more effective overall than other medications, they may well work on certain consumers who do not respond to traditional antidepressants. It has been reported anecdotally that these serotonergic antidepressants may be particularly useful to some consumers with a character disorder along with a depression. Such serotonergic antidepressants may also be particularly useful in some consumers with headaches, and some consumers with obsessive compulsive disorder.
A typical dose of fluoxetine (Prozac) is a single 20 mg tablet a day although older consumers may not tolerate this high a dose, and most consumers with obsessive compulsive disorder will require much more. Fluoxetine has an extremely long half life, which means it will remain in the body for weeks after someone stops taking it. There are dangerous interactions between serotonergic antidepressants such as fluoxetine and a number of other commonly used medications, incuding the other antidepressants. Fluoxetine and the other SSRIs can cause dangerous interactions with MAO inhibitors, and can dramatically raise the serum level of heterocyclic antidepressants. As a result, THERE SHOULD BE AT LEAST A FIVE WEEK BREAK BETWEEN STOPPING FLUOXETINE (Prozac) AND STARTING AN MAOI, AND SEVERAL WEEKS BEFORE STARTING ANY OTHER ANTIDEPRESSANT. The other SSRIs, since they have a shorter half-life, do not need as long a wash-out before starting another medication.

E. Miscellaneous New Antidepressants

1. Trazodone (Desyrel) has almost no anticholinergic effect. In addition, trazodone is less likely than the tricyclic antidepressants to potentiate heart block (block of electrical impulses between different parts of the heart) in consumers with preexisting heart disease. Trazodone is much safer in overdoses than the older medications and causes less orthostatic hypotension (drop in blood pressure when you stand).
On the other hand, trazodone is very sedating. Originally it was thought that trazodone needed to be taken more than once a day to be effective, but recent studies have suggested that taking the entire dose before bed is both safe and effective. Trazodone may increase the irritability of the heart muscle in certain consumers with preexisting heart disease. Finally, it has been reported to cause priapism (very painful, long lasting erections of the penis) that has required surgery and led to permanent impotence in a few consumers. A typical dose of trazodone is 150-600 mg/day.

2. Bupropion (Wellbutrin) was introduced as having fewer side effects than the older antidepressants. It has less anticholinergic side effects (dry mouth, blurred vision, constipation) than the tricyclic antidepressants. It causes less blood pressure problems, and has less effect on the electrical activity of the heart. It is also an activating rather than a sedating medication, and does not seem to cause the weight gain associated with tricyclics. Finally, it is safer if taken in overdose.
The initial introduction of bupropion was delayed because of a high incidence of seizures in several consumers, all of whom had anorexia. Bupropion does seem to have a higher incidence of seizures than the other antidepressants. This is dose related, and the seizure incidence increases ten fold when the dose in increased to the 450-600 mg/day range. Another relatively new antidepressant, maprotiline (Ludiomil) also seems to have a relatively high seizure frequency, especially in the higher dose ranges.
A normal dose of bupropion is around 300 mg/day, usually divided into 100 mg three times a day. No single dose should exceed 150 mg to decrease the risk of seizure. Bupropion is typically started at 100 mg twice a day, and increased no sooner than every 3 days to decrease the risk of seizure.

Pharmacologic profiles of tricyclic and
tetracyclic antidepressants
Antidepressant Anticholinergic Sedative Inhibition of Re- uptake
Effect Effect Norepinephrine Serotonin
Tricyclic tertiary amines
amitriptyline +++++ +++++ +++ +++
imipramine +++ +++ +++ +++
(Surmontil) +++ ++++ ++ +
(Adapin, Sinequan) +++ ++++ +++ ++
Tricyclic secondary amines
(Norpramin, Pertofrane) ++ + +++++ ++
(Vivactil) ++++ 0 +++++ ++
(Aventyl, Pamelor) ++ ++ ++++ ++
(Asendin) + ++ ++++ ++
New Antidepressants
(Ludiomil) + ++++ ++++ +
(Desyrel) 0 ++++ + ++
(does cause dry mouth)
(Prozac) 0 0 0 +++++
(Wellbutrin) 0 0 + 0

F. Which Antidepressant to Use:

All of the currently available antidepressants seem equally effective, although for unclear reasons a particular medication might be dramatically more effective in a particular individual. Unfortunately, there is no way to rationally decide which medication will work for which consumer. Physician's often select an antidepressant based on their familiarity with a specific medication. The different antidepressants do have somewhat different potential side effects, however, and it is reasonable to select a medication whose side effect profile will be least troublesome to the particular consumer. The main side effects to consider in choosing a medication are degree of sedation, degree of anticholinergic activity (dry mouth, blurred vision, etc.), and cardiovascular side effects. For example, desipramine is only mildly sedating and has relatively little anticholinergic side effects (dry mouth, blurred vision, etc.). Where either sedation or blurred vision has been a problem, this might be a good drug to choose. Fluoxetine (Prozac) might be the drug of choice if no sedation can be tolerated. Fluoxetine usually does not cause weight gain, but increases anxiety in some susceptible consumers. Doxepin, on the other hand, is very sedating, and where insomnia has been part of the problem, the sedative side effect of this medication might be a useful "side effect".
Another consideration comes into play if the first antidepressant does not work and a second medication is being considered. Some of the antidepressants seem to work relatively more on the norepinephrine system, while others seem to affect serotonin. Although there are little hard data to support the practice, it probably makes sense to choose a second medication as different as possible from the first, ineffective drug.

This material was created by Ronald J Diamond, M.D.
University of Wisconsin Department of Psychiatry

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