SSRI (serotonin selective reuptake inhibitors) have been used to treat depression for two and a half decades worldwide. They were developed in the quest to find medications that were effective in treating depression, but without the side effects of earlier antidepressants.
The human nervous system is made up of the brain, spinal cord and nerves, all of which are made of nerve cells. The nervous system controls all life functions-thinking, feeling, moving, breathing, heart beating, digestion-every bodily or mental activity is controlled by the nervous system.
The nerve cells manage all of this activity through the actions of neurochemicals within the cells and in the space between cells. We probably haven't identified all of the neurochemicals yet, but several that are important in mood and anxiety are serotonin, norepinephrine, dopamine, histamine and acetylcholine. Serotonin seems to have the most effect on mood, although norepinephrine and dopamine also have a role.
In the body, serotonin regulates the gastrointestinal tract and blood vessel tone. In the brain and spinal cord it controls movement, pain perception and appetite and controls body functions.
Serotonin is released into the "synaptic cleft" (space) between two nerve cells. It binds to specific receptors on the receiving (post-synaptic) cell much like a key fits into a lock. About 10% of the serotonin that is released reaches the post-synaptic receptor sites; the other 90% is reabsorbed by the sending (pre-synaptic) cell using monamine transporters (substances that carry the serotonin back into the cell).
SSRI medications prevent serotonin from being carried back into the originating cell; this allows the serotonin to accumulate in the synaptic cleft so that more of it reaches the postsynaptic cell. (This is a simplified explanation, and other processes are involved.)
Depression and anxiety are thought to be caused by an inadequate amount of serotonin in the synaptic cleft; SSRI's help by increasing it.
SSRI's are selective for serotonin; that is, they work on serotonin and have little effect on other neurotransmitters. Most of the side effects of SSRI's are, however, related to their effect on acetylcholine and histamine.
Uses for SSRI's
SSRI antidepressants are effective in treating depression and anxiety. They are also useful in treating other problems:
- Panic disorders
- Obsessive compulsive disorder
- Chronic pain
- Eating disorders
- Premature ejaculation
- Irritable bowel syndrome
- Some personality disorders
Common side effects
Almost everyone who takes an SSRI has some side effects. These most frequently occur in the first few weeks you take the medication, and they often go away within a few weeks. Most side effects are mild to moderate in severity. Severe and serious side effects can occur, however, and you should let your doctor know about any problems you have. The side effects that most often occur with SSRI's are:
- Dry mouth, constipation
- Nausea, vomiting, upset stomach, abdominal cramps, diarrhea
- Grinding your teeth, especially at night
- Dizziness or fainting when you first stand up
- Changes in appetite and weight
- Injuries and bone fractures
- Decrease in sexual desire
- Difficulty in achieving an orgasm, delayed ejaculation, impotence
- Nervousness, restlessness, anxiety
- Tremors, twitches or seizures
- Suicidal thoughts
SSRI antidepressants can interact with many different drugs, and the list may be slightly different for different drugs. In general, medications that may interact with SSRIs include:
- Any and all other antidepressants
- Certain pain medications
- Seizure medications
- Antipsychotic medications
- Some heart medications
- Pain medications
- Some illicit drugs, specifically amphetamines, methamphetamines, MDMA (ecstasy), LSD, cocaine and some designer drugs
Problems with SSRI antidepressants
Serotonin discontinuation syndrome: SSRI antidepressants are not technically addictive because they don't cause "drug seeking behaviors" or cravings. If you stop taking them suddenly, however, you will probably experience withdrawal symptoms. These symptoms are usually mild to moderate, but can be very severe. They can start anywhere from several hours after your first missed dose to several weeks later and can last a few weeks or a few months.
Tapering the medication down prior to discontinuing it reduces withdrawal symptoms, but may not eliminate them. If you are sensitive to the medication, you may have to withdraw very slowly and it can take quite some time to get completely off of the drug.
Common withdrawal symptoms are:
- Twitches, tremors, seizures
- Flu-like symptoms
- Moodiness, anxiety, crying
- Difficulty sleeping, vivid nightmares
- Unusual sensations "brain shivers," "brain zaps," electric shock sensations
Suicide and aggression
As of 2006, the FDA requires drug manufacturers to carry a "black box warning" on all antidepressants warning that there may be an increased risk of suicide in children and adolescents who take them. This is the result of media exposure of studies in Europe and the United States investigating suicide attempts among children who were taking antidepressants.
There have also been anecdotes and stories of aggression and violence in people who are taking antidepressants, including incidents such as the Columbine High School massacre and several murder-suicides. Some people believe these episodes are caused by the antidepressants.
In truth, it is not known whether antidepressants cause suicide and aggression or not. Suicides, suicide attempts, suicidal thoughts and aggression/hostility have occurred with three SSRI antidepressants: fluoxetine (Prozac), sertraline (Zoloft) and paroxetine (Paxil). These episodes occurred in adults as well as children.
In any case, it makes sense to monitor people who are depressed and who are starting treatment with these medications. They should probably have weekly visits face-to-face with a physician or therapist to determine their progress. In addition, it's a good idea to enlist friends and family to help with daily monitoring. Any unusual behavior or thinking should be reported immediately to the physician.
Mania: Mania can appear in people who have bipolar disease and who are not taking a mood stabilizer. Antidepressants can trigger manic or hypomanic episodes (hypomania is mania that is not as severe). Mania can be severe and can include paranoia, psychosis, aggression and violence. Antidepressants can also trigger rapid cycling in bipolar, where the mood shifts from deep depression to wild mania in a matter of hours, then cycles rapidly back to depression.
Use in pregnancy and lactation: There have been recent reports of birth defects and neonatal difficulties when SSRI antidepressants have been taken during pregnancy. A meta-analysis of data by Boston University was released July 2, 2007 that showed that the risk of birth defects is not as high as originally believed.
At this time, it appears that sertraline (Zoloft) and paroxetine (Paxil) may increase the incidence of birth defects when they are taken in the first trimester of pregnancy. The birth defects that occur are oomphalocele and heart defects.
SSRIs should not be taken after the 20th week of pregnancy if at all possible. There is an increased risk of pulmonary hypertension in the baby if they are taken during this period. In addition, the baby may experience withdrawal symptoms after birth.
Most SSRIs are found in breast milk.
Overdose and serotonin syndrome
One of the advantages of SSRI antidepressants is that they have a very wide therapeutic range, making them much safer than earlier antidepressants in the event of overdose. People have recovered from huge overdoses of SSRIs. If an intentional or accidental overdose does occur, the treatment is to support body functions and relieve symptoms.
Serotonin toxicity can occur, however, either from an overdose or-more likely-from concurrent administration of other medications that affect serotonin levels. This toxic reaction is called serotonin syndrome, and it can be serious and deadly.
Symptoms of serotonin syndrome include:
- Agitation, restlessness, anxiety
- Confusion, hallucinations
- Rapid heart rate
- Rapid changes in blood pressure
- Sweating and fever
- Nausea, vomiting, diarrhea
- Tremors, shivers, twitches
- Uncoordinated movements
- Muscle spasms
Serotonin syndrome is rare, but it is a potential problem because many, many medications affect serotonin. When you are taking an SSRI and then add one of these serotonergic medications, you can develop toxicity. Some of the medications that affect serotonin are:
- Narcotic pain medications
- Medications for nausea
- Triptans, medications for migraine headaches
- Dextromethorphan, an ingredient in cough and cold medications
- St John's wort
It's very important to make sure your doctor, and especially your pharmacist, know about all medications that you take, including things you only take occasionally, things you buy over the counter, herbals and alternative treatments.
Controversies and legal problems
There are some controversies over the use of SSRIs and there have been a number of successful lawsuits regarding their use.
Advertising: SSRIs are heavily advertised and marketed, both to physicians and to the public. Some people feel that the drug companies have used marketing to create a perceived need where none exists. They point to the fact that SSRIs are the most prescribed medications ever-and the most financially successful ones. There is also concern that some ads are misleading and that companies have been marketing medications for non-approved uses.
Withholding information: There have been several instances where drug manufacturers appear to have suppressed or withheld information from the FDA and/or the public in order to minimize safety concerns. In one case, the drug manufacturer was accused of attempting to interfere with a trial. This has severely eroded public confidence in the drug manufactures, the FDA and in the medications themselves.
Selective serotonin reuptake inhibitors are the most prescribed class of medications of all time. They are used to treat depression, but not only to treat depression. They are useful in treating a wide range of emotional and physical problems. Side effects do occur, but SSRIs are safer and better tolerated than the older antidepressants they were derived from. They will continue to be used for some years-until the next generation of antidepressants replaces them.