Selective Serotonin Reuptake Inhibitors (SSRIs)

What is serotonin and how it is linked to depression

Serotonin acts as a neurotransmitter, a type of chemical that helps relay signals from one area of the brain to another. Although serotonin is manufactured in the brain, where it performs its primary functions, some 90% of our serotonin supply is found in the digestive tract and in blood platelets.

There are many researchers who believe that an imbalance in serotonin levels may influence mood in a way that leads to depression. Possible problems include low brain cell production of serotonin, a lack of receptor sites able to receive the serotonin that is made, inability of serotonin to reach the receptor sites, or a shortage in tryptophan, the chemical from which serotonin is made. If any of these biochemical glitches occur, researchers believe it can lead to depression, as well as obsessive-compulsive disorder, anxiety, panic, and even excess anger.

One theory about how depression develops centers on the regeneration of brain cells -- a process that some believe is mediated by serotonin, and ongoing throughout our lives. According to Princeton neuroscientist Barry Jacobs, PhD, depression may occur when there is a suppression of new brain cells and that stress is the most important precipitator of depression. He believes that common antidepressant medications, such as Celexa, Lexapro, Prozac, and Paxil -- designed to boost serotonin levels -- help kick off the production of new brain cells, which in turn allows the depression to lift.

Although it is widely believed that a serotonin deficiency plays a role in depression, there is no way to measure its levels in the living brain. Therefore, there have not been any studies proving that brain levels of this or any neurotransmitter are in short supply when depression or any mental illness develops. And while blood levels of serotonin are measurable -- and have been shown to be lower in people who suffer from depression -- what doctors still don't know for certain is whether or not the dip in serotonin causes the depression, or the depression causes serotonin levels to drop.

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About SSRI

In healthy brain synapses, one neuron communicates with another via neurotransmitters that traverse across a small gap between them known as a synapse. Neurotransmitter molecules activate receptor molecules on the post-synaptic neuron surface, causing the post-synaptic neuron to become active. Once activation has occurred, the post-synaptic neuron releases the neurotransmitter molecules back into the synapse where they are taken back up by the pre-synaptic neuron for reuse in a future message.

The Selective Serotonin Reuptake Inhibitors, or SSRIs for short, are a popular family of antidepressant drugs frequently prescribed today. Selective serotonin reuptake inhibitors are thought to work by slowing down the reuptake of neurotransmitter molecules (in this case specifically serotonin molecules) by pre-synaptic neurons. Because serotonin reuptake is prevented, serotonin molecules end up staying in the synapse longer than they normally would, and get more of a chance to activate the post-synaptic neuron. There are several types of serotonin receptors, and some medications work on specific receptors better than others.

Therapeutic effects of antidepressants may vary in people, due in part to each person's genetic makeup. It's thought that people's sensitivity to antidepressant effects, especially selective serotonin reuptake inhibitor effects, can vary depending on:

  • How each person's serotonin reuptake receptor function works.
  • His or her alleles — the parts of chromosomes that determine inherited characteristics, such as height and hair color, which combine to make each person unique
Some SSRIs are available in extended-release form or controlled-release form, often designated with the letters XR or CR. These forms provide controlled release of the medication throughout the day or for a week at a time with a single dose.

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Available Medications

Fluoxetine (Prozac) is used for the treatment of major depressive disorder, obsessive compulsive disorder (OCD; a person experiences obsessions, or repetitive uncontrollable thoughts, and compulsions, or repetitive uncontrollable behaviors such as repeatedly washing one's hands), bulimia nervosa (an eating disorder characterized by binges and vomiting), and panic disorder (an anxiety disorder accompanied by feelings of terror that strike suddenly and repeatedly with no warning) with or without agoraphobia (anxiety about being in situations from which escape might be difficult or embarrassing). Prozac used for the treatment of premenstrual dysphoric disorder (mood changes associated with the menstrual cycle), is packaged as Sarafem (fluoxetine hydrochloride).

Side effects of Prozac include: chest pain, chills, hemorrhage (bleeding or abnormal flow of blood), hypertension (high blood pressure, palpitation (irregular and/or forceful beating of the heart), increased appetite, nausea, vomiting, weight gain, agitation, amnesia (impaired memory), confusion, emotional lability (rapidly changing mood), sleep problems, and an increased need to urinate.

Prozac should not be used in combination with monoamine oxidase inhibitors (MAOIs), which are another type of antidepressant medication, or thioridazine (a medication used to treat psychotic disorders, severe depression or anxiety, or severe behavior problems in children). In addition, people should be careful about using Prozac in combination with NSAIDs (pain medication such as ibuprofen), aspirin or other drugs that affect blood coagulation since this increases the risk of bleeding. There is also a risk of developing Serotonin Syndrome, a cluster of uncomfortable and potentially dangerous side effects including agitation, hallucinations, coma, chills, headache, fluctuations in blood pressure, rapid heart beat, raised body temperature, nausea, vomiting, diarrhea, profuse sweating, confusion, and restlessness. As a result, people taking Prozac should avoid taking other medications that affect serotonin such as triptans (used for treating migraines), tryptophan (5-HTP, a dietary supplement used for depression), linezolid (an antibiotic used to treat infections), tramadol (used for pain), St. John's Wort (an herb used for depression), or other SSRIs/SNRIs.

Sertaline (Zoloft) is used for treating major depressive disorder, OCD, panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder, and social anxiety disorder (fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others). Side effects of Zoloft include: impotence (a consistent inability to sustain or achieve an erection), heart palpitations (irregular and/or forceful beating of the heart), chest pain, hypertonia (increased muscle tightness), increased appetite, back pain, myalgia (muscle pain), yawning, male and female sexual dysfunction, rhinitis (irritation of the nose), and tinnitus (ringing in the ears). As with Prozac, Zoloft should not be used with MAOIs or thioridazine. In addition, people taking Zoloft should not take pimozide (Orap), a medication used for the treatment of Tourette's Disorder (characterized by motor and oral tics). Zoloft may also affect a person's lithium levels (used for the treatment of bipolar disorder), so close monitoring may be necessary. There is also a risk of Serontonin Syndrome when taking Zoloft.

Paroxetine (Paxil) is used for the treatment of major depressive disorder, social anxiety disorder, OCD, panic disorder, generalized anxiety disorder (GAD; an exaggerated or unfounded state of worry and anxiety, often about such everyday matters as health, money, family, or work ), and PTSD. Side effects include: asthenia (lack of energy), sweating, nausea, decreased appetite, sleepiness, dizziness, insomnia, tremor, nervousness, impotence, problems with ejaculation and other male genital disorders, dry mouth, and constipation. The same warnings listed above apply, people taking Paxil should avoid MAOIs, thioridazine, and pimozide. In addition, the same potential for Serotonin Syndrome exists when taking Paxil.

Citalopram (Celexa) is used for the treatment of major depressive disorder. Side effects include: tachychardia (rapid heart rate), postural hypotension (a drop in blood pressure due to a change in body position), hypotension (low blood pressure), paresthesia (abnormal skin sensensations such as numbness, tingling, pricking, or burning), migraine, increased flatulence, weight gain, weight loss, impaired concentration, amnesia (impaired memory), increased depressive symptoms, increased appetite, suicide attempts, confusion, amenorrhea (cessation of a woman's period), coughing, blurry vision, rash, itching, and increased need to urinate. As with the above medications, people taking Celexa should avoid MAOIs, thioridazine, pimozide, NSAIDs, aspirin, or other drugs that affect coagulation; and watch for signs of Serotonin Syndrome.

Escitalopram (Lexapro) is used for the treatment of major depressive disorder and GAD. Side effects include: heart palpations, hypertension (high blood pressure), light-headedness, migraine, heartburn, abdominal cramps, gastroenteritis (inflammation or infection of the stomach or intestines), limb/muscle/joint pain, fever, hot flushes, chest pain, weight gain, increased appetite, lethargy, irritability, impaired concentration, bronchitis (inflammation and swelling of the airways of the lung) nasal/sinus congestion, coughing, sinus headache, rash, blurry vision, tinnitus (ringing in the ears), increased need to urinate, and urinary tract infections. As with the above medications, people taking Lexapro should avoid MAOIs, thioridazine, pimozide, NSAIDs, aspirin, or other drugs that affect coagulation; and watch for signs of Serotonin Syndrome.

Practically speaking, SSRIs are easy to use. They are taken only once a day, which increases the likelihood that people will comply with treatment and take their medications. They are available in pill form and sometimes as liquids. The pill form is most often prescribed. As with any medication, the risk of overdose is always a possibility. Overdose can cause vomiting, seizures, and even death, particularly when people mix SSRI's with other drugs or with alcohol. In general, reports of overdose with SSRIs are rare, and SSRIs are considered fairly safe medications. To reduce the risk for overdose, your physician may write you a prescription for a small quantity of medication at a time, which will require that you refill your prescription frequently.

Increasing a depressed person's amount of serotonin in their brain does not always improve their mood. Some depressed people also need help increasing levels of additional neurotransmitters such as norepinephrine. Often, people who don't respond to SSRI's will receive a trial of newer antidepressants that also target other neurotransmitters that impact mood.

Side effects of SSRIs

All SSRIs have the same general mechanism of action and side effects. However, individual SSRIs have some different pharmacological characteristics. That means you may respond differently to certain SSRIs or have different side effects with different SSRIs. For instance, you may have unpleasant side effects with one SSRI but not another. Also, they're less likely to have adverse interactions with other medications and are less dangerous if taken as an overdose.

Side effects of SSRIs include:

  • Nausea.
  • Sexual dysfunction, including reduced desire or orgasm difficulties.
  • Dry mouth.
  • Headache.
  • Diarrhea.
  • Nervousness.
  • Rash.
  • Agitation.
  • Restlessness.
  • Increased sweating.
  • Weight gain.
  • Drowsiness.
  • Insomnia
You may experience less nausea with extended- and controlled-release forms of SSRIs.

Serotonin syndrome and SSRIs

A rare but potentially life-threatening side effect of SSRIs is serotonin syndrome. This condition, characterized by dangerously high levels of serotonin in the brain, can occur when an SSRI interacts with antidepressants called monoamine oxidase inhibitors (MAOIs). Because of this, don't take any SSRIs while you're taking any MAOIs or within two weeks of each other. Serotonin syndrome can also occur when SSRIs are taken with other medications, including:

  • Pain relief medication such as tramadol (Ultram).
  • Migraine medications such as sumatriptan (Imitrex) and rizatriptan (Maxalt).
  • Supplements that affect serotonin levels, such as St. John's wort
Serotonin syndrome requires immediate medical treatment. Signs and symptoms include:

  • Confusion.
  • Restlessness.
  • Hallucinations.
  • Extreme agitation.
  • Fluctuations in blood pressure.
  • Increased heart rate.
  • Nausea and vomiting.
  • Fever.
  • Seizures.
  • Coma.
Drug Interactions

Given together, tryptophan and any of the SSRIs may cause headache, nausea, sweating, and dizziness. Taking an SSRI within two weeks of an MAOI (such as Marplan or Parnate) may cause serious side effects; you should wait at least two weeks between stopping MAOIs and starting an SSRI, or at least five weeks after stopping an SSRI and starting an MAOI.

Combining Paxil and warfarin may cause excess bleeding. If you're taking cimetidine, which can cause an increase in the blood levels of Paxil, your dosage of Paxil should be adjusted.

Research suggests that Zoloft, unlike MAOIs or tricyclics, doesn't necessarily appear to cause problems when mixed with alcohol. However, Zoloft's manufacturers don't recommend the combination.

There are no known dangerous reactions between nonprescription drugs and Zoloft, but because it's theoretically possible, be sure to talk to your doctor about any other drugs you take. Combining Zoloft with either digitoxin (Crystodigin) or warfarin (Coumadin) may cause unwanted side effects.

Safety concerns with SSRIs

Studies show that Paxil increases the risk of birth defects in women taking the drug during their first trimester of pregnancy. Women who take Paxil during their first three months of pregnancy are nearly two times as likely to give birth to a child with a birth defect — in particular a heart defect — as are women taking other antidepressants.

The American College of Obstetricians and Gynecologists recommends avoiding Paxil during pregnancy, if possible. If you're taking Paxil and you're considering getting pregnant, talk to your doctor or mental health provider about switching to another antidepressant or stopping treatment. Don't stop taking Paxil without contacting your doctor first, though.

Also, the FDA warns that infants whose mothers took SSRIs while pregnant may be at an increased risk of persistent pulmonary hypertension. This risk is increased in women who take SSRIs at 20 weeks or later in pregnancy. This rare but serious lung problem occurs when a newborn's circulatory system doesn't adapt to breathing outside the womb.

Use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) or anticoagulants, such as warfarin (Coumadin), while taking SSRIs may increase the risk of gastrointestinal bleeding and should be monitored by your doctor.

Recent studies have shown that Symbyax and other antipsychotics should not be prescribed to older people for treatment of dementia-related psychosis. Symbyax and other antipsychotic drugs raise the risks of heart failure, sudden death and pneumonia in older people with dementia-related psychosis.

Stopping treatment with SSRIs

SSRIs aren't considered addictive. However, stopping treatment abruptly or missing several doses can cause withdrawal-like symptoms, including:

  • Nausea.
  • Headache.
  • Dizziness.
  • Lethargy.
  • Flu-like symptoms
This is sometimes called discontinuation syndrome. Talk to your doctor before stopping so that you can gradually taper off.

Suicidal feelings and SSRIs

Antidepressants may be associated with worsening symptoms of depression or suicidal thoughts or behavior in those ages 18 to 24. These symptoms or thoughts are most likely to occur during the first one to two months of treatment or when you change your dosage, but they can occur at any time during treatment. Be sure to talk to your doctor about any changes in your symptoms. You may need more careful monitoring when starting treatment or changing dosage, or you may need to stop the medication if your symptoms worsen. Adults age 65 and older taking antidepressants have a decreased risk of suicidal thoughts.

How can you tell if an SSRI will work?

The straight answer to this question is that until an antidepressant is tried it is impossible to know whether it is the right one for any individual, and it takes a number of weeks (two to eight) to know whether it is going to work.

The first medicine to try is often decided on the grounds of its other effects rather than its antidepressant properties (since all antidepressants are equally effective). Some of these considerations are listed below.

• Is it sedative?
• Is it more alerting?
• Will it help anxiety as well? (Anxiety often goes hand-in-hand with depression.)
• Will it help another disorder, eg obsessive compulsive disorder, that coexists with the depression?
• Does it mix well with other medicines that a person is taking?
• Is it okay if the person has other illnesses?
• Has the person taken it before to good effect?

To make the best initial choice, the doctor needs to know exactly how a person is affected by depression. Some of these other effects may be very helpful in one person, but a problematic side effect in another: sedation is useful in someone whose sleep is disrupted, but not for someone who is sleeping too much.

Sources and Additional Information:
http://resources.atcmhmr.com/poc/view_doc.php?type=doc&id=13018&cn=5
http://www.mayoclinic.com/health/ssris/MH00066
http://www.healthyplace.com/depression/antidepressants/selective-serotonin-reuptake-inhibitors-ssris/menu-id-68/
http://www.healthline.com/galecontent/selective-serotonin-reuptake-inhibitors
http://www.netdoctor.co.uk/diseases/depression/selectiveserotoninreputakeinhibitors_000147.htm
http://www.webmd.com/depression/recognizing-depression-symptoms/serotonin

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