More medications are available to treat depression than ever before. Some antidepressant classes have fallen out of favor, while others have risen in popularity. Currently, the most commonly prescribed antidepressants are drugs that have been developed since the mid-1980s. SSRIs lead the list in popularity. Some medications don’t fall into one class. They include bupropion (Wellbutrin), mirtazapine (Remeron), venlafaxine (Effexor), and duloxetine (Cymbalta). Two older classes of antidepressants, tricyclic antidepressants (TCAs) and MAOIs, are still very useful �?some people take them without being bothered by side effects �?but on average their side effects have made them less appealing as a first-line treatment. (See What You Should Know About Medications.) 
  

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs stepped into the spotlight in the late 1980s. The serotonin system involves many regions of the brain and affects mood, arousal, anxiety, impulses, and aggression. SSRIs slow the reuptake of serotonin �?that is, they keep it from being quickly reabsorbed by the neurons that released it. By blocking reuptake, they permit serotonin to work for a longer time at receptor sites (see How SSRIs Work ). SSRIs also appear to change the number and sensitivity of receptors and to indirectly influence other neurotransmitters, including norepinephrine and dopamine.
 
Prozac, the first SSRI introduced, quickly became a celebrity. Not only did it relieve depressive symptoms in many people, but it also appeared to help with a wide variety of problems, including anxiety, shyness (social phobia), obsessions (obsessive-compulsive disorder), and eating disorders (anorexia or bulimia). Other SSRIs have since been introduced to the market (see Selective Serotonin Reuptake Inhibitors SSRIs ).
 
SSRIs have several advantages over the TCAs and MAOIs that came before them. Unlike TCAs, they rarely cause side effects like dry mouth, constipation, or dizziness. Nor do they disrupt heart rhythms, a potentially fatal side effect of an overdose of TCAs. And with SSRIs, you don’t have to worry about dietary restrictions, as you would if you took MAOIs.
 
On the other hand, SSRIs do have their own problems. The best known of these are sexual side effects. It’s fairly common for men taking these medications to have problems sustaining an erection. Both sexes may find that the drugs dampen desire or make it difficult to reach orgasm (see Sexuality and SSRIs).
 
Other side effects include nausea, insomnia, and a slight increased risk of excessive bleeding, particularly if taken with aspirin or the blood thinner warfarin (Coumadin). Ironically and tragically, SSRIs can also increase the risk of suicidal tendencies in a small percentage of adults and children taking them (see Can Antidepressants Trigger Suicide? and Treating Depression in Teens and Children).
 
In addition, SSRIs can interact with certain antihistamines, anticonvulsants, other antidepressants, and drugs used to quell mood disorders. One such problem, called the serotonin syndrome, can occur when MAOIs overlap with SSRIs. This condition is marked by a racing heart, fever, sweating, high blood pressure, trembling, and confusion. Potentially, at least, it can also occur when an SSRI is combined with lithium or the herb St. John’s wort. Fortunately, this happens rarely.
 
Although these side effects may seem daunting, keep in mind that some of the older antidepressants also can be dangerous. The main advantage of SSRIs and other newer antidepressants isn’t necessarily that they cause fewer side effects or less discomfort, but that the most dangerous side effects tend to occur less frequently.

One drawback to SSRIs is that they frequently dampen sexual response. One study suggested that as many as half of all people taking these medications may experience some sexual problems. In addition to reducing interest in sex, SSRIs can make it difficult to become aroused, sustain arousal, and reach orgasm. Some people taking SSRIs aren’t able to have an orgasm at all. If you experience any sexual problems while taking an SSRI, talk with your doctor or therapist. In some cases, sexual difficulties may stem not from the medication, but rather from the underlying depression. If your medication is the problem, your doctor or therapist may suggest one of the following strategies:  

• Lowering the dose. Sexual side effects may subside at a lower, although still therapeutic, dose.
  
• Taking a drug holiday. Depending on how long the drug usually remains in your body, you might stop taking it for a few days before a weekend, if that’s when you hope to have sex. This is hardly spontaneous, but it can work if you carefully follow your doctor’s directions about how to stop and resume your medication. However, there is always a chance that this might cause a relapse.
  
• Switching to a different drug. Certain antidepressants, such as bupropion (Wellbutrin), mirtazapine (Remeron), TCAs, and MAOIs, are less likely to cause sexual problems. There are some reports that bupropion may actually boost sexual drive and arousal, as well as the intensity or duration of an orgasm.

Adding a drug. In both men and women, sildenafil (Viagra) may counteract the negative sexual effects of SSRIs. Adding bupropion (Wellbutrin) to your treatment may also help.

Since the early 1990s, many newer antidepressants have supplanted MAOIs and TCAs as treatment options. The change reflects a number of factors �?for example, the newer antidepressants have less severe side effects, are easier to prescribe, and have been promoted with intense marketing campaigns. In any case, having more treatment options available increases the likelihood that people who are depressed will find one that works for them. 

These newer medications, which don’t fall neatly into a single class, often work through mechanisms that differ from those of the older classes of antidepressants. For example, bupropion (Wellbutrin) affects the neurotransmitters norepinephrine and dopamine, and mirtazapine (Remeron) affects norepinephrine and serotonin. On the other hand, venlafaxine (Effexor) and duloxetine (Cymbalta) work in part by slowing the reuptake of serotonin, like SSRIs do, but they also slow the reuptake of norepinephrine. Because of their twofold action, they are designated as dual serotonin and norepinephrine reuptake inhibitors.
 
Side effects vary from medication to medication (see Medications Used for Depression). Because these medications are fairly new, much isn’t known yet about long-term side effects, but none are apparent at this time.
 
In general, studies haven’t found that the newer medications are more or less effective than older ones like SSRIs. But, as mentioned previously, individuals respond differently to different antidepressants. So while a newer medication may not work better for all �?or even most �?people, some individuals may find it more helpful or may tolerate it better than another drug.
 
Doctors are still inclined to prescribe an SSRI first because they have more experience with SSRIs (since these drugs have been available longer and more research has been done using them) and people have tolerated them well. However, these newer drugs can be good second choices and may become more common first choices in time.

TCAs, named for their three-ring molecular structure, have been used since the 1960s. Doctors believe TCAs lift depression mainly by increasing the availability of both norepinephrine (which affects mood, anxiety, and drive) and serotonin (which affects mood, arousal, anxiety, impulses, and aggression). TCAs do this by slowing the reabsorption of these neurotransmitters into the neurons that released them.
 
At the same time, though, TCAs influence another neurotransmitter, acetylcholine, which can lead to dizziness, constipation, blurred vision when reading, and trouble urinating. These drugs can also cause weight gain. But their most serious side effect is a dangerously abnormal heart rhythm, so they aren’t the first choice of antidepressants for people with heart disease. While TCAs are generally safe for people with healthy hearts, a two-week supply of pills could fatally disrupt heart rhythms if a person were to attempt suicide by taking them all at once.

The neurotransmitters norepinephrine and serotonin are members of a class of compounds called monoamines. They are normally broken down in the body by the enzyme monoamine oxidase. MAOIs block this enzyme, raising the levels of norepinephrine and serotonin in the brain. That can relieve mood problems, anxiety, and other hallmarks of depression.
 
The two most commonly used MAOIs are tranylcypromine (Parnate) and phenelzine (Nardil). These drugs may be especially helpful if your depression includes features that are considered atypical, such as oversleeping rather than insomnia or weight gain rather than weight loss. They can also relieve the extreme anxiety of panic attacks.
 
As with other antidepressants, MAOIs have a variety of side effects. They can cause sedation, insomnia, and weight gain. MAOIs can also leave you feeling stimulated or restless. Dizziness sometimes occurs, which is particularly troubling to older adults who are more prone to disabling falls. In addition, a relatively small number of people taking MAOIs develop liver damage.
 
But the greatest source of inconvenience �?and occasionally danger �?is that people taking MAOIs must avoid eating a substance called tyramine. Normally, monoamine oxidase breaks down tyramine. If you are taking an MAOI, however, tyramine does not get broken down and can build to unsafe levels. In high concentrations, tyramine can cause a dangerous and rapid increase in blood pressure, and on rare occasions leads to a stroke. Therefore, if you take MAOIs, you must avoid foods that contain tyramine �?such as yogurt, aged cheese, pickles, beer, and red wine.

People who have problems with depression may also experience mood swings �?like the ups and downs seen in various forms of bipolar disorder �?so a mood stabilizer, such as lithium (Eskalith, Lithane, and others) or valproate (Depakote), may be added to treatment. Even if you don’t have a tendency toward mood cycling, these medications can sometimes build on the effects of an antidepressant, improving your response.

No matter what medications you take, always tell your doctor about uncomfortable or worrisome side effects immediately. You and your doctor can often alleviate side effects with a few simple steps. Here are some suggestions for dealing with common side effects of antidepressants:
 
Dry mouth. Drink a lot of water, chew sugarless gum, and brush your teeth frequently.
 
Constipation. Eat whole grains, bran cereal, prunes, and hearty servings of fruits and vegetables. Drink plenty of water.
 
Trouble urinating. If you have difficulty starting urination, your doctor may be able to adjust your medication to relieve this problem.
 
Dizziness. Sudden changes in position can lead to a sharp drop in blood pressure that causes dizziness. To counter this effect, rise slowly from a chair or when getting out of bed. Also, drink plenty of fluids.
 
Daytime drowsiness. This problem usually occurs at the beginning of treatment and may not last long. In some cases, it may help to take medication at bedtime, but ask your doctor about this first. If you feel drowsy, don’t drive or use heavy equipment.
 
Trouble sleeping. Sleep often improves after a few weeks, but sometimes a mild sleep aid or a switch to another medication is necessary.
 
Nausea. Often, nausea disappears within a few weeks. It may help to take the drug shortly after a substantial meal.
 
Agitation. You might feel uncomfortably nervous or restless after you start taking a drug. Jittery feelings may pass within a few weeks. But in relatively rare cases, agitation will persist; sometimes it’s an early symptom of worsening depression or mania.
 
Headache. Headaches may come and go. Some persist, but they usually disappear within a few weeks.
 
Sexual difficulties. Sometimes sexual problems are transient or not related to the drug. Talk with your doctor about sexual problems that don’t pass soon. Also, see Sexuality and SSRIs. 
   
If side effects continue to bother you, your doctor may change your dosage, shift the time of day that you take the medication, or split the dosage into smaller amounts to be taken over the course of the day. Or he or she may recommend combining the drug with another one, switching to a different drug, or replacing drugs with therapy or other forms of treatment.
 
Call your doctor right away if you feel more depressed instead of less or if you feel worse for any reason.

When depression isn’t treated, there’s a high likelihood that it will recur. Roughly half of those who have a single untreated episode of major depression will go on to have another. The second untreated episode boosts the odds of a third. Once that occurs, the chances of having a fourth episode are 90%. Over a lifetime, people with untreated major depression will have an average of five to seven episodes, and episodes often accelerate, becoming more frequent and more severe. 
 
Bipolar disorder, dysthymia, and all other mood disorders are also more likely to persist or recur if they go untreated. As with depression, episodes occur more frequently and become more intense over time. This suggests that it’s best to treat major depression, bipolar disorder, and dysthymia as early as possible.

Aggressive treatment pays off
Recurrences also occur more frequently if treatment has not wholly eradicated depressive symptoms. Therefore, treatment should aim for maximum relief.
 
It’s best to gradually increase the dose of an antidepressant until no further improvement is seen. Preliminary research also supports continuing with the full, therapeutic dose even after you start to feel better, rather than risk taking a lower dose that may be only partially effective. Yet inadequate dosages are a common problem. Primary care doctors who are less experienced with psychopharmacology are often reluctant to increase doses, and people who are uneasy about taking medication may be reluctant to try a higher dose.
 
Here are some other strategies worth considering in search of a lasting, full recovery:

• switching to a different antidepressant if the first one is not adequately effective
• combining two antidepressants that have different mechanisms of action
• adding a second drug (not primarily an antidepressant) that may augment the effect of the antidepressant you’re taking
• combining medications and therapy.

To prevent a relapse, it’s important to continue taking your medication even after you feel better. A study from the Journal of the American Medical Association divided into two groups 150 people with dysthymia or double depression who had responded to treatment with sertraline (Zoloft). Some of these people continued to take the drug, while the rest took a placebo. After 18 months, only 6% of the group taking sertraline had relapsed, compared with 23% of the placebo group.
 
Most psychiatrists will recommend that you stay on your medication for about a year after a first episode of depression. If you have had several episodes, your doctor will probably recommend maintenance treatment indefinitely. 

Is it a relapse or not?
When you stop taking an antidepressant, you may experience uncomfortable symptoms as your body readjusts. These might include stomach upset, loss of appetite, or diarrhea; flulike symptoms such as a runny nose, sweating, muscle aches, or fever; and a variety of other symptoms such as tingling, restlessness, trouble sleeping, vivid dreams, fatigue, dizziness, or lightheadedness.
 
Sometimes people also experience mood changes, such as irritability, sadness, anxiety, agitation, or crying spells. It can be difficult to know whether this is a result of stopping the medication or if the original depression is returning. The best way to tell is to wait a short time. Symptoms linked to coming off an antidepressant almost always disappear within several days or weeks. If symptoms of depression continue, however, see your doctor about restarting the antidepressant.
 
Tapering off your medicine slowly can help you avoid this problem. The medications most likely to cause these symptoms are the ones that leave the body rapidly �?so your doctor may switch you to one that stays in your system longer and then gradually ease you off that one.