Selective Serotonin-Reuptake Inhibitors (SSRIs)
Selective serotonin-reuptake inhibitors (SSRIs) are the first-line treatment for major depression. They work by increasing levels of serotonin in the brain. Because they act specifically on serotonin, SSRIs have fewer side effects than older antidepressants, which have more widespread effects in the body.
SSRIs include fluoxetine (Prozac, generic), sertraline (Zoloft, generic), paroxetine (Paxil, generic), fluvoxamine (Luvox, generic), citalopram (Celexa, generic), and escitalopram (Lexapro, generic). There do not appear to be significant differences among SSRI brands in effectiveness, although individual drugs may have different side effects or benefits for specific people.
At this time, fluoxetine and escitalopram are the only SSRI antidepressants approved for treatment of major depressive disorder in adolescents (ages 12 to 17). Fluoxetine is also approved for children age 8 and older.
In recent years, the FDA has approved vortioxetine (Trintellix) that represents a new type of SSRI. This drug acts like an SSRI but has additional effects, not completely understood, on other serotonin 5-HT receptors in the brain. These new types of SSRIs are approved for treatment of major depression in adults.
Candidates for SSRIs
SSRIs appear to best help people with the following conditions:
- Moderate or severe major depression.
- Persistent depression (dysthymia).
- Premenstrual dysphoric disorder (PMDD). A repackaged form of fluoxetine (Sarafem) is specifically approved for PMDD. Other SSRIs and newer antidepressants may also be helpful.
- Seasonal affective disorder.
- Anxiety disorders.
- Bulimia nervosa.
Duration of Effectiveness and Use
SSRIs take, on average, 2 to 4 weeks to be effective. They may take even longer, up to 12 weeks, in older people and in those with dysthymia. By 14 weeks, depression should be in remission in those who respond to the drugs. Unfortunately, recurrence is common once the drugs are stopped. Studies indicate that the standard SSRIs are generally safe to be taken for the long-term, although it is still unclear which people most benefit from on-going medication. Some doctors recommend withdrawing from medication after a year. If depression recurs, then people should go back on the antidepressant.
Side Effects of SSRIs
Side effects may include:
- Nausea and gastrointestinal (GI) symptoms, which usually wear off over time.
- Insomnia or drowsiness, depending on the drug.
- Agitation and nervousness.
- Dry mouth.
- Heart palpitations (see below for citalopram heart warnings).
- Weight gain varies depending on the SSRI.
- Sexual side effects may include delayed or loss of orgasm and low sexual drive.
- Paroxetine may cause heart-related birth defects if taken during the first 3 months of pregnancy. The most common heart abnormalities are ventricular septal defects, which are holes in the muscular wall that separate the main pumping chambers of the heart. Pregnant women who are being treated for major depression should not stop taking antidepressants without first talking to their doctors. [For more information on antidepressant treatment guidelines during pregnancy, see "Treating Depression During and After Pregnancy" in Treatment section.]
- Citalopram can cause serious heart rhythm problems if taken in doses higher than 40mg/day (or 20 mg/day for people age 60 years and older). People with certain underlying heart conditions, including heart failure and recent heart attack, should not take citalopram in any dose. Let your doctor know if you experience irregular heartbeat, dizziness, or shortness of breath while taking this drug.
- SSRIs can worsen manic symptoms in people with bipolar disorder.
SSRIs can interact with other antidepressants such as tricyclics and, in particular, monoamine oxidase inhibitors (MAOIs). Due to a potentially fatal condition called serotonin syndrome, SSRIs should never be taken in combination with an MAOI or within 2 weeks after discontinuing MAOI treatment. (For more on serotonin syndrome, see the MAOI section below.) Other serious interactions can occur with meperidine (Demerol, generic) and illegal substances (such as LSD, cocaine, or ecstasy). SSRIs also interact with the antibiotic linezolid (Zyvox), opioid painkillers such as tramadol (Ultram, generic), mood stabilizers containing lithium, and cough medicines containing dextromethorphan. People who take SSRIs may drink alcohol in moderation, although the combination may compound any drowsiness experienced with SSRIs, and some SSRIs increase the effects of alcohol.
Cognitive problems, sleep disturbances, increase in depressive symptoms, and electric shock-like symptoms can occur with sudden discontinuation of SSRIs. The symptoms are more likely to occur with antidepressants with shorter half-lives as compared with fluoxetine, which has a long half-life. The dose of the antidepressant should be slowly reduced before stopping.
Other Neurotransmitter Inhibitors
These antidepressants target other neurotransmitters, such as norepinephrine or dopamine, alone or in addition to serotonin.
Dual Action Inhibitors
Dual action inhibitors act directly on serotonin and another neurotransmitter.
Venlafaxine (Effexor, generic), desvenlafaxine (Pristiq), duloxetine (Cymbalta, generic), mirtazapine (Remeron), and levomilnacipran (Fetzima) are serotonin norepinephrine reuptake inhibitors (SNRIs). They target serotonin and the neurotransmitter norepinephrine and are approved for treatment of major depression in adults.
These drugs share many of the side effects of SSRIs, including dry mouth, nausea, and drowsiness. Additional side effects include:
- Venlafaxine (Effexor, generic) and desvenlafaxine (Pristiq) can increase blood pressure and heart rate and should be used with caution in people with high blood pressure or heart disease. They can also cause uterine and vaginal bleeding unrelated to menstruation. Venlafaxine and desvenlafaxine should not be taken during the last trimester of pregnancy as they can cause complications in newborn infants. Some people report severe withdrawal symptoms, including dizziness and nausea.
- Duloxetine (Cymbalta, generic) can worsen narrow-angle glaucoma and liver or kidney problems. Because duloxetine can cause liver damage, people who drink large quantities of alcoholic beverages should not take it. Signs of liver damage include itching, dark urine, yellowing of skin and eyes (jaundice), and fatigue. People should immediately contact their doctor if they experience these symptoms.
- Mirtazapine (Remeron) can cause impulsivity, panic attacks, and restlessness.
Multiple Neurotransmitter Inhibitors (Bupropion)
Bupropion (Wellbutrin, generic) affects the reuptake of serotonin, norepinephrine, and dopamine -- a third important neurotransmitter. In addition to depression, bupropion is also approved for treating seasonal affective disorder (SAD) and, under the trade name Zyban, for smoking cessation. Bupropion causes less sexual dysfunction than SSRIs. About 25% of people experience initial weight loss. Side effects include restlessness, agitation, sleeplessness, headache, and stomach problems. Bupropion has a risk for seizures, which increases with higher doses. High doses may also cause dangerous heart arrhythmias.
Before the introduction of SSRIs, tricyclics were the standard treatment for depression.
Tricyclics are sometimes grouped into two categories:
- Tertiary amines include amitriptyline (Elavil, Endep, generic) and imipramine (Tofranil, generic).
- Secondary amines include desipramine (Norpramin, generic) and nortriptyline (Pamelor, Aventyl, generic). Secondary amines may have fewer side effects, including drowsiness, than tertiary amines, but they are as toxic in high amounts.
Less commonly used tricyclics include doxepin (Sinequan), amoxapine (Asendin), maprotiline (Ludiomill), protriptyline (Vivactil), and trimipramine (Surmontil). These are all available as generics.
Tricyclics are as effective for treating depression but they have many side effects. They may offer benefits for many people with dysthymia, who generally do not respond to SSRIs. They may also be prescribed in lower dosages to be taken at night to help with insomnia.
Side Effects of Tricyclics
Side effects are common with these medications. In an analysis of studies, more tricyclic users discontinued their drugs due to side effects than did SSRI or MAOI users. Side effects most often reported include:
- Dry mouth
- Blurred vision
- Sexual dysfunction
- Weight gain
- Difficulty urinating
Tricyclics can have serious, although rare, side effects:
- They tend to cause disturbances in heart rhythm, which can pose a danger for some people with certain heart diseases. Care should be taken when these medications are prescribed to older people and to those at risk of overdose. In particular, desipramine (Norpramin, generic) has been associated with dangerous heart rhythm abnormalities in people who have a family history of these problems.
- Tricyclics, particularly imipramine, may increase the risk for a lung disease called idiopathic pulmonary fibrosis (IPF), which can cause lung inflammation and scarring. Initial symptoms are breathlessness and dry cough.
- Tricyclics can cause dizziness associated with orthostatic hypotension, a sudden drop in blood pressure when sitting up or suddenly standing.
- Tricyclics can be fatal with an overdose.
Serotonin modulators work to increase the effect of serotonin in the brain. These drugs include trazodone (Desyrel), serzone (Nefazodone), and vilazodone (Viibryd). They may be used to treat major depression and premenstrual syndrome.
Side Effects of Tricyclics
Side effects may occur with these medications. Side effects most often reported include:
- Dry mouth
- Blurred vision
- Difficulty urinating
Serotonin modulators may interact with other antidepressant medicines:
- Serotonin modulators may not be used along with MAO inhibitors.
- They may also interact adversely with SSRIs and Lithium.
Monoamine Oxidase Inhibitors (MAOIs)
Monoamine oxidase inhibitors (MAOIs) block monoamine oxidase, an enzyme which has negative effects on many of the neurotransmitters that are important for well-being. MAOIs include phenelzine (Nardil, generic), isocarboxazid (Marplan, generic), and tranylcypromine (Parnate, generic).
Newer MAOIs, such as selegiline (Eldepryl, Movergan, generic), target only one form of the MAOI enzyme. They may cause fewer side effects than older MAOIs. A skin patch form of selegiline (Emsam) is also available for treatment of major depressive disorder in adults.
Because these drugs can have very severe side effects, they are usually prescribed only for severe depression or when other types of antidepressants do not help (treatment-resistant depression). MAOIs may also be effective for the following conditions:
- Eating disorders
- Post-traumatic stress disorder
- Borderline personality
MAOIs commonly cause the following side effects:
- Orthostatic hypotension (a sudden drop in blood pressure upon standing).
- Drowsiness or insomnia.
- Sexual dysfunction.
- The most serious side effect is severe hypertension (high blood pressure), which can be brought on by eating certain foods having high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products.
- MAOIs can cause birth defects and should not be taken by pregnant women.
Serotonin syndrome is a potentially fatal condition that can occur from interactions of MAOIs with other antidepressants, including SSRIs. Symptoms include confusion, agitation, sweating and shivering, and muscle spasms. There should be at least a 2-week break between taking MAOIs and other antidepressants. MAOIs can have serious interactions with other drugs as well, including some common over-the-counter cough medications. In such cases, severe high blood pressure or dangerous reactions can occur. It is important that people discuss with their doctors any other medications they are taking.
If people fail to respond to antidepressants, doctors may try adding on a different type of drug. (This combination strategy is called "augmentation" or "adjunctive treatment".) Atypical antipsychotics are drugs that are usually prescribed for schizophrenia or bipolar disorder, but may in certain circumstances also play a role in the treatment of severe depression.
Two atypical antipsychotics, aripiprazole (Abilify) and quetiapine (Seroquel, generic), are currently approved in combination with antidepressant therapy for treatment of adults with major depressive disorder. A third approved medication called Symbyax (generic), combines in one pill the atypical antipsychotic olanzapine (Zyprexa, generic) with the SSRI fluoxetine (Prozac, generic).
Atypical antipsychotics can have a number of serious side effects. They include:
- Weight gain, metabolic problems, and increased risk for type 2 diabetes
- Unhealthy cholesterol levels and heart problems
- Extrapyramidal symptoms such as tardive dyskinesia, which are severe and uncontrollable movement disorders
If you are prescribed an atypical antipsychotic, your doctor should carefully monitor your weight, blood sugar (glucose) levels, cholesterol levels, and any signs that may indicate the emergence of extrapyramidal symptoms.
Ketamine, an anesthetic drug, may be helpful for people with severe treatment-resistant or bipolar depression, although it is not approved by the FDA for this use. In preliminary studies, a single intravenous dose of ketamine helped people quickly recover from depression within several hours, and some people sustained benefits for up to a week. (Standard antidepressant drugs usually take about 8 weeks to have an effect.) Evidence of benefit after one or more weeks is less clear. Ketamine blocks the NMDA brain protein receptor, which is involved in glutamate regulation. Glutamate is a brain chemical that is thought to be involved in depression. Ketamine may have serious side effects including hallucinations, irrational behavior, and increased blood pressure. Ketamine can also induce dependence and is sometimes used as a drug of abuse.