Antidepressant Drugs, SSRI
Antidepressant Drugs, SSRI
SSRIs are prescribed primarily to treat mental depression. Because they are as effective as other types of antidepressants and have less serious side effects, SSRIs have become the most commonly pre-scribed antidepressants for all age groups, including children and adolescents.
In addition to treating depression, some SSRIs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other disorders including:
SSRIs often are prescribed for other "off-label" uses including:
- various mental disorders including schizophrenia
- menopause-related symptoms such as hot flashes
- geriatric depression
- loss of mental abilities in the elderly
- nicotine withdrawal
- premature ejaculation
The advantages of SSRIs over other types of antidepressants include:
- Most SSRIs can be taken in one daily dose as compared with three to six daily pills.
- Because they lessen cravings for carbohydrates, SSRIs usually do not cause weight gain.
- Since SSRIs do not appear to affect the cardiovascular system, they can be prescribed for people with high blood pressure or heart conditions.
- Since SSRIs are not particularly dangerous even in high doses and are unlikely to cause permanent damage if misused, they may be prescribed for suicidal adults.
SSRIs are mood enhancers only in depressed individuals. They have little effect on people who are not clinically depressed. However some experts believe that SSRIs are over-prescribed and should be reserved for those with major disabling depression.
Citalopram hydrobromide — Celexa; a SSRI that is highly specific for serotonin reuptake.
Dopamine — A neurotransmitter and the precursor of norepinephrine.
Escitalopram oxalate — Lexapro; a SSRI that is very similar to Celexa but contains only the active chemical form.
Fluoxetine — Prozac; the first SSRI; marketed as Sarafem for treating PMDD.
Fluvoxamine — Luvox; a SSRI that is used to treat obsessive-compulsive disorder as well as other conditions.
Monoamine oxidase inhibitor (MAOI) — An older class of antidepressants.
Neurotransmitter — A substance that helps transmit impulses between two nerve cells or between a nerve cell and a muscle.
Norepinephrine — A hormone released by nerve cells and the adrenal medulla that causes constriction of blood vessels.
Obsessive-compulsive disorder (OCD) — An anxiety disorder characterized by obsessions, such as recurring thoughts or impulses, and compulsions, such as repetitive behaviors.
Off-label use — A drug that is prescribed for uses, periods of time, or at dosages that are not FDA-approved.
Paroxetine hydrochloride — Paxil; a SSRI that is used to treat mental depression, OCD, and various other disorders.
Premenstrual dysphoric disorder (PMDD) — Premenstrual syndrome (PMS); symptoms including back and abdominal pain, nervousness and irritability, headache, and breast tenderness that occur the week before menstruation.
Serotonin — 5-Hydroxytryptamine; a substance that occurs throughout the body with numerous effects including neurotransmission.
Serotonin syndrome — A group of symptoms caused by severely elevated serotonin levels in the body.
Sertraline — Zoloft; a SSRI that is used to treat mental depression and a variety of other disorders.
Types of ssris
As of 2005, six brand-name SSRIs and generic equivalents were available in the United States:
- Celexa (citalopram hydrobromide) for treating depression
- Lexapro (escitalopram oxalate) for treating depression and generalized anxiety disorder
- Luvox (fluvoxamine) for treating OCD
- Paxil (paroxetine hydrochloride) for treating depression, generalized anxiety disorder, OCD, panic disorder, social anxiety disorder, PMDD, and PTSD
- Prozac and Prozac Weekly (fluoxetine) for treating depression, OCD, and bulimia nervosa; marketed as Sarafem for treating PMDD
- Zoloft (sertraline) for treating depression, OCD, panic disorder, social anxiety disorder, PMDD, and PTSD.
When Prozac first became available in 1988, it was hailed as a new wonder drug and quickly became the most popular antidepressant ever prescribed. Many millions of Americans have taken Prozac and more than 70% of them claim to have benefited from it. Within a few years other SSRIs became available and, by 2000, Zoloft prescriptions outnumbered those for Prozac.
Lexapro is the newest SSRI. Celexa and Lexapro are very similar, with chemical structures unrelated to other SSRIs. Celexa is a mixture of two isomers—forms of the same chemical—whereas Lexapro is the active isomer alone. They appear to be highly selective for serotonin, only minimally inhibiting the reuptake of the neurotransmitters norepinephrine and dopamine. Paxil is structurally unrelated to other SSRIs and is more selective for serotonin than Luvox, Prozac, or Zoloft, but less selective than Celexa and Lexapro. Paxil becomes distributed widely throughout body tissues and the CNS, with only 1% remaining in the circulatory system.
Mode of action
Mental depression is believed to be related to the low activity of one or more neurotransmitters in the brain—the chemical messengers that cross the gap or synapse between nerve cells. Although it is not understood exactly how most SSRIs work, they are designed to increase the level of serotonin in the brain. This can reduce the symptoms of depression and other psychological disorders.
Serotonin is released by nerve cells and then—in a process called reuptake—is reabsorbed by the cells to be used again. SSRIs interfere with reuptake by blocking the serotonin reuptake sites on the surfaces of nerve cells, thereby making more serotonin available for brain activity. Paxil inhibits the transporter molecule that moves serotonin back into the cell. SSRIs are said to selectively interfere with the reuptake of serotonin, without affecting the uptake or activities of other neurotransmitters. In contrast, older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) affect numerous neurotransmitters, brain cell receptors, and brain processes, increasing the likelihood of serious side effects.
However it is becoming clear that the serotonin neurotransmitter system is far more complex and widespread throughout the body than was thought initially. Although serotonin receptors are particularly common in areas of the brain that control emotion, it is known now that there are at least six different types of serotonin receptors that send different signals to different parts of the brain. Serotonin also appears to affect other neurotransmitter systems—including dopamine—to at least some extent. Thus increasing the levels of serotonin may not be the only reason why SSRIs relieve depression.
SSRIs are not effective for treating anxiety or depression in 20-40% of patients. However some research suggests that the use of SSRIs in the early stages of depression can prevent major depressive disorders.
Although different SSRIs appear to be equally effective, individuals respond differently to different SSRIs and side effects may vary. Thus finding the best SSRI for an individual may be a matter of trial-and-error. It usually takes two to four weeks after starting an SSRI before symptoms begin to improve. Luvox may take one to two months for noticeable improvement. Paxil may take as long as several months, although sleeping often improves within one or two weeks of beginning the medication. If there is no response after a few weeks or if side effects occur, the patient may be switched to another SSRI. Prozac is the most commonly prescribed SSRI for children, in part because it is available in liquid form that is easier to swallow.
Although Luvox is the only SSRI that is FDA-approved for use in children—and only for obsessive-compulsive behavior—thousands of young people have been treated with SSRIs for:
- attention deficit/hyperactivity disorder (ADHD)
A 2004 study found that among depressed adolescents, 60% improved with Prozac alone, whereas 75% reported improvement with Prozac combined with cognitive behavioral therapy.
SSRIs sometimes are prescribed to relieve depression accompanying alcoholism. A recent study found that, although type A alcoholics responded to Zoloft in conjunction with a 12-step individual therapy program, type B alcoholics—those with the most severe drinking problems—did not benefit from Zoloft and, in some cases, increased their alcohol intake.
Usually SSRIs are started with a low dosage that may be gradually increased. In older adults SSRIs remain in the body longer than in younger adults. The blood levels of Paxil can be 70-80% higher in the elderly as compared with younger patients. Therefore lower doses usually are prescribed for older people. Older patients with other medical conditions or who are taking many different drugs also may need smaller or less frequent doses. The dosage of an SSRI also varies according to the individual and the condition that is being treated. SSRIs may be taken with or without food, on a full or empty stomach. However taking SSRIs with food or drink may lessen side effects such as stomach upset or nausea.
Celexa is supplied as tablets or as an oral solution equivalent to 2 mg per ml (0.03 oz.), taken once per day in the morning or evening:
- adults: 20 mg per day, increasing to 40 mg if necessary, to a maximum of 60 mg per day
- older adults: 20 mg per day to a maximum of 40 mg
Lexapro is supplied as 5-, 10-, or 20-mg tablets or as a 1 mg per ml (0.03 oz.) liquid. The recommended dose is 10 mg per day, with a possible increase to 20 mg per day after at least one week.
Average dosages of Luvox for treating OCD and depression are:
- adults: one 50-mg tablet at bedtime; may be increased up to a maximum of 300 mg daily; dosages of more than 100 mg per day should be divided into two doses, one taken in the evening and one in the morning
- children aged 8-17: initially one 25-mg tablet at bedtime; may be gradually increased by 25 mg per day every four to seven days, up to a maximum of 200 mg per day; daily dosages of more than 50 mg should be divided into two daily doses.
Average doses of Paxil for treating depression are:
- adults: 20 mg (10 ml, 0.3 oz.) of oral suspension, one 20-mg tablet, or one 25-mg extended-release tablet, once a day in the morning, increased by 10 mg per week to a maximum of 50 mg—25 ml (0.75 oz.) of oral suspension—or a 62.5-mg extended-release tablet
- older adults: 10 mg (5 ml, 0.15 oz.) of oral suspension or a 10-mg tablet daily, increased to a maximum of 40 mg (20 ml, 0.6 oz.); one 12.5-mg extended-release tablet daily, increased to a maximum of 50 mg
Because of its sedating effect, Paxil may be taken in the evening rather than in the morning as usually recommended. Oral suspensions need to be shaken well before measuring with a small measuring cup or measuring spoon. Extended-release tablets should be swallowed whole, not broken or chewed. Dosages may be different for treating disorders other than depression.
Typical dosages of Prozac are:
- one 10-20-mg daily capsule or solution taken in the morning; increased up to as much as 40 mg daily if there is no improvement in one month, up to an 80-mg maximum
- one 90-mg capsule per week of Prozac Weekly once the depression is under control
- one 20-mg capsule of Sarafem per day, taken in the morning, every day or for only 14 days of a menstrual cycle; maximum of 80 mg per day; Sarafem is supplied in seven-day blister packs to help keep track of the days
- children: initially one 5-10-mg capsule or solution per day.
Zoloft is available as capsules, oral solutions, or tablets:
- adults: 50 mg daily, taken in the morning or evening, up to a maximum of 200 mg daily for severely depressed individuals
- older adults: 12.5-25 mg per day, taken in the morning or evening; may be increased gradually
- for treating OCD in children aged 6-12: 25 mg per day, taken in the morning or evening; may be increased gradually to a maximum of 200 mg per day
- children aged 13-17: initially 50 mg per day, in the morning or evening, may be increased gradually to a maximum of 200 mg per day.
Zoloft oral concentrate should be mixed with 4 oz (133 ml) of water, ginger ale, lemon-lime soda, lemonade, or orange juice and taken immediately.
Missed doses of SSRIs are handled differently depending on the SSRI and the number of doses per day. An effective SSRI may be prescribed for six months or more. Some experts recommend continuing on the SSRI indefinitely to prevent the recurrence of depression.
Medical conditions that may affect the use or dosage of at least some SSRIs include:
- drug allergies or allergies to other substances in medications
- manic-depressive (bipolar) disorder
- brain disease or mental retardation
- seizures or epilepsy
- Parkinson s disease
- liver or severe kidney disease
- abnormal bleeding problems
- diabetes mellitus
- heart disease
- a recent heart attack
SSRI use during pregnancy may not be safe, particularly during the third trimester. Exposure of fetuses to Celexa and other SSRIs during the late third trimester have led to very serious complications, including serotonin syndrome—a condition in which high serotonin levels cause severe problems. Symptoms in a newborn may be the result of a direct toxic effect of the SSRI or withdrawal from the drug. SSRIs pass into breast milk and may negatively affect a baby.
A possible link between SSRIs and suicide attempts in depressed adults remains controversial. Three studies in early 2005 drew conflicting conclusions concerning an association between suicidal behavior and the use of SSRIs. However a February 2005 study found a close correlation between the dramatic decrease in suicides in the United States and Europe and the introduction of SSRIs.
In October 2004, the FDA concluded that antidepressants, including SSRIs, increased the risk of suicidal thoughts and behaviors in children and adolescents who suffered from depression and other psychiatric disorders. They recommended extreme caution in prescribing SSRIs for children. In the last three months of 2004, SSRI prescriptions for children and adolescents fell by 10%.
Symptoms that may lead to suicidal tendencies can develop very suddenly in children and adolescents taking SSRIs; they may include:
- new or worsening depression
- severe worrying
- extreme restlessness
- frenzied excitement
- panic attacks
- impulsive behavior
- aggressive behavior
- thinking about, planning, or attempting to harm one's self
SSRIs remain in the body for some time after the medication is stopped:
- Celexa for at least three days
- Luvox for at least 32 hours
- Paxil for at least 42 hours
- Prozac for up to five weeks
- Zoloft for at least three to five days
SSRIs can cause what the manufacturers refer to as "discontinuation syndrome" when the medication is stopped. Since this occurs most often when the drug is stopped abruptly, usually the dose is gradually reduced before stopping the drug completely. The occurrence of discontinuation syndrome depends on the SSRI, the dosage, and the length of time that the drug was used. Paxil appears to induce more serious withdrawal symptoms than other SSRIs. Symptoms of Paxil withdrawal appear within 1 to 10 days of stopping the drug. Because of its long half-life in the body, Prozac rarely causes withdrawal symptoms, although symptoms have been known to appear within 5 to 42 days of stopping Prozac.
Withdrawal symptoms may include:
- weakness or fatigue
- nervousness or anxiety
- restlessness or agitation
- trembling or shaking
- fast heart rate
- breathing difficulties
- chest pain
Although withdrawal symptoms usually wear off, in some patients some symptoms appear to continue indefinitely.
Other precautions concerning SSRIs include:
- a 50% chance that an episode of depression will recur at some point after stopping the drug
- a 90% risk of recurrence following two episodes of depression
- reports of patients developing tolerance to an SSRI, requiring increased dosages for effectiveness
- the long-term effects of SSRIs are unknown
- SSRIs are expensive: at least $2-$3 per pill; over $150 for 4 oz. (133 ml) of liquid Prozac
- some insurance plans to not cover mental health medications.
Common side effects
The most common side effects of SSRIs include:
- dry mouth
- sour or acid stomach or gas
- decreased appetite
- stomach upset
- weakness or fatigue
- nervousness or anxiety
- sexual problems
Most common side effects disappear as the body adjusts to the drug. Nausea may be relieved by taking the medication with meals or temporarily dividing the dose in half.
Certain side effects occur more frequently depending on the SSRI:
- Side effects of Celexa usually are mild and disappear as the body adjusts.
- Luvox and Zoloft are more likely to cause gastrointestinal upset, including stomach irritation, nausea, and diarrhea.
- Paxil is more likely to cause dry mouth, constipation, and drowsiness. Paxil is significantly more sedating than other SSRIs, which may benefit patients with insomnia.
- The most common side effect of Prozac is nausea during the first two weeks on the drug; nervousness and anxiety also are common with Prozac.
- Paxil, Prozac, and Zoloft often reduce appetite.
- Up to 30% of those on Zoloft suffer headaches and 20% suffer from insomnia.
Studies with Luvox have found that children may experience different side effects than adults, the most common being:
- dry mouth
- a stuffy or bloody nose
- muscle twitching or tics
- thinning hair
- abnormal thinking
Sexual side effects
Any SSRI can affect sexual interest or performance. Side effects include increased or, more often, decreased sexual interest, difficulty reaching orgasm or ejaculation, and impotence.
Although manufacturers initially reported that sexual problems were very rare side effects of SSRIs, most patients in clinical trials were never asked specifically about sex and were reluctant to raise the issue. After a few years it became apparent that sexual problems were commonplace among SSRI users, affecting as many as 70%. Among men taking Paxil, 23% report problems with ejaculation. Between 40% and 70% of those taking Prozac report negative sexual side effects, especially loss of interest.
Less common or rare side effects
Less common—but potentially serious—side effects of at least some SSRIs may include:
- flu-like symptoms
- nasal congestion or a runny nose
- sore throat
- skin rash
- itching or tingling, burning, or prickling of the skin
- body aches or pain
- muscle or joint pain
- abdominal cramps or pain
- decreased or increased appetite
- weight loss
- weight gain, especially after a year on an SSRI
- mouth watering
- increased frequency or amount of urination
- menstrual changes or pain
- chest congestion or pain
- difficulty breathing
- taste changes, including a metallic taste in the mouth
- blurred vision or other visual changes
- loss of voice
- teeth grinding
- trembling or shaking
- hair loss
- sensitivity to sunlight
- anxiety or agitation
- abnormal dreams
- lack of emotion, apathy
- memory loss
Rare side effects that may occur with some SSRIs include:
- symptoms of low blood sugar or sodium
- bleeding gums or nosebleeds
- unusual bruising
- irregular or slow heartbeat (less than 50 beats per minute)
- painful urination or other difficulties with urination
- purple or red spots on the skin
- skin conditions
- red or irritated eyes
- inability to move the eyes
- swelling of the face, ankles, or hands
- increased or decreased body movements
- tics or other sudden or unusual body or facial movements or postures
- changes in the breasts, including leakage of milk
- increased depression
- mood or mental changes
- abnormal behaviors
- difficulty concentrating
- lethargy or stupor
- suicidal thoughts or tendencies
Various other SSRI side effects have been observed in clinical practice although their incidence is not known.
Symptoms of overdose
Although overdose rarely occurs with SSRIs, symptoms include two or more severe side effects occurring together. More common symptoms of SSRI overdose include:
- flushing of the face
- enlarged pupils
- fast heart rate
- upset stomach
- nausea and vomiting
- trembling or shaking
Rare symptoms of SSRI overdose include:
- deep or fast breathing with dizziness
- muscle pain
- difficulty urinating
- bluish skin or lips
- fast, slow, or irregular heartbeat
- low blood pressure
- memory loss
SSRIs interact with many other drugs, often in similar ways. Alcohol may increase SSRI-induced drowsiness and should not be used when taking some SSRIs. Luvox appears to cause the most serious drug interactions, whereas Celexa has relatively few interactions. A combination of Luvox and Clozaril can cause low blood pressure and seizures.
The interaction of SSRIs with MAOIs can be fatal. In addition to antidepressant MAOIs, the antibiotic linezolid (Zyvox) is an MAOI. There must be at least a two-week interval between stopping one drug and starting the other. There should be at least a three-week interval between an MAOI and either Paxil or Zoloft, if either type of antidepressant was taken for more than three months. Because of its long half-life in the body, it is necessary to wait five to six weeks after stopping Prozac before starting on an MAOI.
Some of the drugs that can interact negatively with SSRIs include:
- other antidepressants
- various medications for anxiety, mental illness, or seizures
- sedatives and tranquilizers
- sleeping pills
- St. John's wort
Drugs that may cause severe heart problems if taken in conjunction with some SSRIs include:
- astemizole (Hismanal)
- cisapride (Propulsid)
- terfenadine (Seldane)
- thioridazine (Mellaril), which should not be taken for at least five weeks after stopping Prozac
Drugs that may affect the blood levels of an SSRI or the length of time that an SSRI remains in the body include:
- antifungal drugs
- cimetidine (Tagamet)
- tricyclic antidepressants
- Dilantin and phenobarbitol, which may decrease the blood levels of Paxil
Some SSRIs may cause higher blood levels of other medications including:
- alprazolam (Xanax and others)
- anticoagulants or blood-thinners such as warfarin (Coumadin)—SSRIs can increase warfarin blood levels dramatically
- aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen and naproxen
- carbamazepine (Tegretol)
- diazepam (Valium)
- digitalis glycosides (heart medicines)
- phenytoin (Dilantin and others)
- propanolol (Ineral and others)
- theophylline or theophylline-containing drugs
- triazolam (Halcion and others)
- tricyclic antidepressants
Rarely, some drugs may interact with an SSRI to cause serotonin syndrome including:
- buspirone (BuSpar)
- bromocriptine (Parlodel)
- dextromethorphan (cough medicine such as Robitussin DM)
- levodopa (Sinemet)
- lithium (Eskalith)
- meperidine (Demerol)
- moclobemide (Manerex)
- nefazodone (Serzone)
- pentazocine (Talwin)
- other SSRIs
- street drugs
- sumatriptan (Imitrex)
- tramadol (Ultram)
- trazodone (Desyrel)
- venlafaxine (Effexor)
Serotonin syndrome may occur shortly after the dose of a drug is increased.
Serotonin syndrome may be suspected when at least three of the following symptoms occur together:
- uncontrollable excitement
- poor coordination
- trembling or shaking
- mental changes
- fluctuating vital signs
Increasingly physicians are combining an SSRI with other medications, either to increase effectiveness or to counteract side effects. Prozac sometimes is prescribed along with:
- an anti-anxiety drug such as Valium (diazepam)
- Desyrel (trazodone), a different type of antidepressant, for patients with insomnia
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