Antidepressant Drugs

Types and differences of antidepressants

Although all antidepressants are about equally effective against depression, the different types of antidepressants vary greatly. In general, they are grouped into classes according to which neurotransmitters they affect and how they affect these neurotransmitters.

Monoamine oxidase inhibitors (MAOIs) were the first antidepressant drugs to be developed. They work by blocking monoamine oxidase enzymes (the chemicals that break down neurotransmitters). Currently, MAOIs are rarely prescribed to a patient initially because when they are taken with certain foods they can cause life threatening problems, and newer antidepressants have fewer side effects. However, MAOIs remain quite effective for certain disorders, especially when other antidepressant medications do not work.

MAOIs include:

Tricyclic antidepressants (TCAs) were the only alternatives to MAOIs available for many decades. TCAs block the reuptake of the neurotransmitters norepinephrine, serotonin and, to lesser degrees, dopamine in the brain. In general, physicians are prescribing TCAs less often as the first course of treatment because the newer antidepressants have fewer side effects.

Tricyclic antidepressants include:

In addition, the drug clomipramine (Anafranil) may be prescribed in an "off-label" manner. This means that it is prescribed for a purpose other than which it was originally intended, and has not been approved for use as an antidepressant by the U.S. Food and Drug Administration.

Selective serotonin reuptake inhibitors (SSRIs) are newer antidepressant medications that have fewer side effects than MAOIs or TCAs. They work by specifically blocking the reuptake of serotonin without affecting levels of norepinephrine or dopamine.

SSRIs include:

In some cases, the drug fluvoxamine (Luvox) may also be prescribed off-label to treat depression.

Norepinephrine and dopamine reuptake inhibitors (NDRIs) work by blocking the reabsorption of dopamine and norepinephrine without affecting serotonin levels. This allows the medications to avoid many serotonin-related side effects (e.g., sexual side effects). The only NDRI available in the United States is bupropion (Wellbutrin).

Serotonin and norepinephrine reuptake inhibitors (SNRIs) block the reuptake of serotonin and norepinephrine without affecting dopamine levels. These include duloxetine (Cymbalta) and venlafaxine (Effexor). TCAs are also primarily SNRIs.

Norepinephrine-serotonin modulators block certain receptors that accept serotonin and norepinephrine. The only medication in this class available in the United States is mirtazapine (Remeron).

Some antidepressants specifically block both the reuptake and receptors of serotonin. These serotonin modulators include nefazodone (Serzone) and trazodone (Desyrel).

In addition, newer antidepressant medications are under development.

Conditions treated with antidepressants

All antidepressants are about equally effective against depression, though different patients may respond better to one medication than another. The choice of which antidepressant to try first is based on a number of factors, including the patient’s symptoms, the side effects of a particular drug and any other disorders the patient may have.

Antidepressants may also be combined with other medications to treat depression-related symptoms. For example, depression with symptoms of psychosis (e.g., hallucinations, delusions) is generally treated with both an antidepressant and an antipsychotic.

In addition to treating depression, antidepressants have many other potential therapeutic uses. Some have been approved by the U.S. Food and Drug Administration (FDA) and others have off-label uses, which means that although they are not specifically approved for a particular condition, they are widely accepted to be effective and often prescribed for that condition.

Other conditions that may be treated with antidepressants include:

• Dysthymia. A chronic form of depression. Selective serotonin reuptake inhibitors (SSRIs) are often prescribed to treat this condition.
• Bipolar disorder. Mood disorder characterized by alternating patterns of mania and depression. Antidepressants may be used after or at the same time as treatment with a mood stabilizer.
• Seasonal affective disorder (SAD). A Mood disorder marked by recurrent episodes of depression that happen during certain seasons of the year, particularly late fall and winter. The norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion (Wellbutrin XL) was recently approved by the FDA to help prevent major depressive episodes in individuals with a history of this condition.
• Anxiety disorders. There are a variety of anxiety disorders that are treated with antidepressant medications, including obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD) and panic disorder. These conditions may be treated with tricyclic antidepressants (TCAs) and SSRIs.
• Bulimia. An eating disorder that is characterized by patterns of binge eating and purging. This condition may be treated with TCAs, SSRIs and monoamine oxidase inhibitors (MAOIs).
• Attention deficit hyperactivity disorder (ADHD). The norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion may be used to treat ADHD, which is characterized by inattentiveness and hyperactivity.
• Autism. This developmental disorder, which is characterized by problems with communication and behavior, may be treated with SSRIs.
• Borderline personality disorder. This personality disorder, characterized by impulsive behavior and unhealthy thought processes, may be treated with SSRIs.
• Enuresis. TCAs may be prescribed for this condition which involves involuntary urination.
• Chronic pain disorders. Many chronic pain disorders (e.g., nerve pain, fibromyalgia, migraine heachaches) may be treated with TCAs and other Serotonin and norepinephrine reuptake inhibitors.

In addition, bupropion may be given to patients who are trying to stop smoking.

Conditions of concern with antidepressant medications

All antidepressants may increase the risk of seizures in certain patients, including those with epilepsy. Selective serotonin reuptake inhibitors (SSRIs) and the non-tricyclic antidepressant serotonin and norepinephrine reuptake inhibitors (SNRIs) are generally the safest to use in patients with a history of seizures.

Patients with prostate conditions (e.g., enlarged prostate), certain forms of glaucoma (an eye disease) or heart conditions are usually not prescribed tricyclic antidepressants (TCAs). An electrocardiogram (records the electrical activity of the heart) is typically required for patients with heart disease or patients over the age of 40 years before they are prescribed TCAs.

The norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion is not recommended in patients with a history of major head trauma, a central nervous system tumor or an active eating disorder. Buproprion can cause seizures even in patients without any history of these.

Monoamine oxidase inhibitors (MAOIs) are usually avoided in patients with congestive heart failure and those with high blood pressure (hypertension). Serotonin modulators are not generally used in patients with heart disease.

Potential side effects

Newer antidepressant medications are generally safer and better tolerated than older antidepressants. Most side effects are temporary and/or dose-related, which means that they improve when the dosage is reduced and worsen when the dosage is increased.

The U.S. Food and Drug Administration (FDA) issued a warning that antidepressants may increase the risk of suicide in certain people. The reason for this side effect is not fully understood. However, it may be because antidepressants often cause improvements in physical side effects of depression, such as fatigue, before providing relief of emotional side effects, such as a sad mood or anxiety. In some cases, this may give individuals who had previously contemplated suicide the energy to act on their impulse. Therefore, it is important for people taking antidepressants to be monitored for unusual behavior.

Side effects occur frequently during the early phases of antidepressant treatment. A physician can usually suggest tips on how to manage most of these, which may include:

• Nausea. May be lessened if the medication is taken with a meal.
• Weight gain. Eating healthy foods and exercising may help reduce this side effect, which appears to occur most commonly with the tricyclic antidepressants (TCAs).
• Fatigue. Taking the medication shortly before bedtime can help reduce this side effect.
• Insomnia. Taking the medication in the morning may help reduce this side effect, which appears to be more likely to occur with selective serotonin reuptake inhibitors (SSRIs).
• Dry mouth. Sipping water, sucking on ice chips and chewing gum may help reduce this side effect, which is most likely to occur with TCAs.
• Constipation. Eating plenty of fiber may help reduce this side effect, which is most likely to occur with TCAs.
• Dizziness. Taking the medication at bedtime can help reduce this side effect.
• Agitation or restlessness. Exercising may help reduce this side effect, which is most likely to occur with SSRIs.
• Sexual dysfunction. Includes a decreased libido and problems achieving orgasm. This is most likely to occur with the SSRIs. Switching to an antidepressant that is not associated with sexual dysfunction, such as bupropion, nefazodone or mirtazapine, or an serotonin and norepinephrine reuptake inhibitor (SNRI), may help reduce this side effect.

Patients may experience withdrawal if an antidepressant is discontinued abruptly. Symptoms of withdrawal usually go away after the drug is out of the patient’s system or the patient’s body has had a chance to adjust to the medication change. The symptoms of withdrawal include the common side effects of the medication as well as headache, irritability, diarrhea and tingling sensations.

Serotonin syndrome is a rare but serious risk of any medication that increases serotonin levels and must be identified as rapidly as possible. It occurs most commonly from drug interactions (e.g., using both monoamine oxidase inhibitors or TCAs and SSRIs). This condition may eventually progress to rhabdomyolysis (destruction of muscle) and potentially fatal liver failure. Initial symptoms may include confusion and flushing (becoming red in the face).

The norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion causes little or no weight gain and minimal sexual side effects. In rare cases, it may cause jitteriness or akathisia (restless arms and legs). Common side effects include gastrointestinal upset and excessive sweating. Bupropion may also cause seizures.

In rare cases, serotonin and norepinephrine reuptake inhibitors (SNRIs) may cause increased blood pressure, rapid heart rate and confusion.

The serotonin modulator nefazodone may cause confusion or vision changes (e.g., blurred vision). Nefazodone should not be used by patients with liver problems. In 2002, the U.S. Food and Drug Administration (FDA) issued a warning regarding the risk of liver failure in patients treated with nefazodone.

The serotonin modulator trazodone causes significant drowsiness and is often given in low doses along with other antidepressants to treat insomnia although it is not approved by the FDA for the treatment of insomnia. Other side effects may include dizziness, lightheadedness when rising, dry mouth and blurred vision. It may also exacerbate cardiac problems. In addition, trazodone is the only antidepressant that may cause priapism (persistent, painful erections). Trazodone-induced priapism may not go away on its own and surgery is typically required in such cases.

Drug or other interactions

Alcohol consumption is generally not recommended while taking any class of antidepressant. Drugs that affect the liver may increase the levels of most antidepressants in the system, which can lead to a potentially dangerous overdose. This is particularly true for tricyclic antidepressants (TCAs).

The heartburn medication cimetidine (Tagamet) can increase the effects of many antidepressants, including desipramine, doxepin, imipramine, paroxetine and sertraline.

Smoking may reduce the effects of some TCAs. Certain TCAs may increase the sensitivity of the skin to sunlight. It is generally recommended that patients taking these medications wear sunscreen when outdoors. Some medications, such as certain antacids, may reduce the effectiveness of some selective serotonin reuptake inhibitors (SSRIs).

SSRIs, especially fluoxetine and paroxetine, can have marked effects on the metabolism of other medications, thereby affecting the blood levels of these medications.

Monoamine oxidase inhibitors (MAOIs) can have potentially life-threatening interactions and require dietary and medication restrictions.

Symptoms of antidepressant overdose

Newer antidepressants are generally safer than older antidepressants when taken in excess (overdose). Many of these newer medications cause unpleasant side effects, but are not usually lethal when taken in doses that exceed the physician’s recommendation. In most cases, the symptoms of overdose are similar to the side effects of the medication, but more severe.

Tricyclic antidepressants (TCAs) can be very dangerous in overdose, and may possibly result in death. Any symptoms of overdose require immediate medical attention. Symptoms include:

• Rapid heartbeat
• Seizures
• Hot, dry skin
• Dry mucous membranes
• Dilated pupils
• Agitation
• Hallucinations
• Hypertension (high blood pressure)
• Cardiac arrhythmias (irregular heartbeat)

Symptoms of overdose of the norepinephrine and dopamine reuptake inhibitor (NDRI) bupropion include:

• Seizures
• Hallucinations
• Loss of consciousness
• Rapid heartbeat

Overdose of the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine may not cause symptoms. When they are present, however, symptoms may include drowsiness, increased heartbeat, impaired memory and generalized convulsions (less severe than full seizures). Symptoms of nefazodone (a serotonin modulator) overdose include hypotension (low blood pressure) and excessive drowsiness.

Pregnancy use issues

Studies do not agree on the safety of antidepressants during pregnancy or breastfeeding. Most antidepressants do not seem to be associated with an increased risk of birth defects or miscarriage. However, it is important to note that the selective serotonin reuptake inhibitor (SSRI) paroxetine appears to be more likely to be associated with birth defects, and that some antidepressants may be associated with reduced birth weight.

Most antidepressants also seem to be safe during breastfeeding. Though the medications are excreted in breast milk, they do not appear to cause any harm to the infant. Regardless, the benefits and potential risks of antidepressants must be weighed for each patient. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may be associated with greater risks than selective serotonin reuptake inhibitors. Any woman taking antidepressants who is nursing, pregnant or plans to become pregnant should discuss the medication with an obstetrician.

Child use issues

Only the selective serotonin reuptake inhibitor (SSRI) fluoxetine has been approved for use in children, although other SSRIs (and only SSRIs) may also be prescribed for children. However, the U.S. Food and Drug Administration (FDA) has advised that antidepressants may increase the potential risk for suicidal thoughts and behavior in children taking them. Close monitoring by a physician of any child on these medications is recommended.

Elderly use issues

Antidepressants generally work as effectively in elderly patients as in younger adults. Older patients, however, may be more sensitive to side effects and often require lower initial doses. Antidepressants may take longer to take effect for these patients, as well. Because of their associated side effects, tricyclic antidepressants should generally be avoided in elderly patients.