Antidepressants for Major Depression - Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI)

In one of our previous articles we discussed on why and how serotonin impacts our mood and mental stability. The three main neurotransmitters involved in depression are dopamine, norepinephrine, and serotonin (also known as 5-HT). When brain levels of one or more neurotransmitter are low or unbalanced, depression and other conditions can result. Generally, antidepressant drugs work by increasing the production or decreasing the breakdown of one or more neurotransmitter.

The new type of antidepressants (known as selective serotonin and norepinephrine reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors, or SNRIs for short) affect serotonin, as well as as norepinephrine and other neurotransmitter systems such as dopamine. SNRIs work like SSRIs in that they inhibit the reuptake of neurotransmitters at the synaptic junction. While low levels of both neurotransmitters are associated with depression, norepinephrine is thought to be involved more with alertness and energy, while serotonin influences mood. By increasing levels of both, SNRIs work on different aspects of depression.

Antidepressants, in general, may also work by playing a neuroprotective role in how they relieve anxiety and depression. It's thought that antidepressants may increase the effects of brain receptors that help nerve cells keep sensitivity to glutamate — an organic compound of a nonessential amino acid — in check. This increased support of nerve cells lowers glutamate sensitivity, providing protection against the glutamate overwhelming and exciting key brain areas related to anxiety and depression.

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

Are there differences among the SSRIs and SNRIs in achieving remission in patients with major depression?

Remission of depression in the patient is the doctor's main goal. According to Dr. Jeffrey Kelsey, Medical Director, Georgia Institute of Mood and Anxiety Disorders, all of the antidepressants that are available in the U.S. market today are equally effective when it comes to response rates. "However, when it comes to remission, the data shows that SNRIs, dual-acting antidepressants, will, in some patients, confer an advantage. And the tricky part is going into it, we don't know which patients will benefit from one approach to the other."

Kelsey says "SSRIs are very effective treatments but some patients are going to get more benefit from a dual-acting antidepressant."

SNRIs Anti-depressants

Trazodone (Desyrel) inhibits serotonin reuptake in addition to blocking certain types of serotonin, norepinephrine, and histamine receptors. Histamine is a both a biological chemical involved in immune responses as well as a neurotransmitter. In low doses, Trazodone can be used as a sleep aid, especially for people who experience insomnia as part of their depression. Side effects of Trazodone include: allergic reactions, irregular heartbeat, prolonged and painful erection, drowsiness, fatigue, lethargy (exhaustion), psychomotor retardation (slow movements), lightheadedness, dizziness, difficulty concentrating, confusion, impaired memory, disorientation, excitement, agitation, anxiety, tension, nervousness, restlessness, insomnia, nightmares, anger, hostility and, rarely, hypomania, visual distortions, hallucinations (sensing things that aren't really there), delusions (false, fixed beliefs), and paranoia (suspicious fear).

Buproprion (Wellbutrin) is often a first choice treatment for Major Depressive Disorder. This medication is just as effective as SSRIs in treating depressive symptoms, with less risk of weight gain and sexual side effects. In addition to serotonin and norepinephrine, buproprion also inhibits dopamine reuptake. The most common side effects of buproprion are dry mouth, constipation, headaches, and insomnia. Care must be taken when using buproprion at higher doses, as it has been known to cause seizures.

Venlafaxine (Effexor) is often used for the treatment of depressive illnesses, but large numbers of studies demonstrating treatment success are lacking. In addition to inhibiting serotonin reuptake, venlafaxine inhibits norepinephrine and dopamine reuptake. Venlafaxine does not interfere with other brain chemicals, which makes it less "messy" and more powerful than other antidepressants. Some evidence suggests that venlafaxine relieves depressive symptoms more quickly than other medications with fewer side effects, and that it can be combined safely with other medications. However, more research is necessary to substantiate these claims.

Nefazodone (Serzone) inhibits serotonin reuptake by blocking a particular type of serotonin receptor. Serzone is sedating, and is useful for relieving anxiety and severe insomnia. Furthermore, sexual side effects are mild, if any. Unfortunately however, nefazodone is a strong inhibitor of liver enzymes and should be used cautiously. Many medications are metabolized in the liver, and functional liver enzymes are essential to proper liver functioning and overall health.

Mirtazapine (Remeron) blocks serotonin and norepinephrine reuptake. Mirtazapine is sedating, and has the disagreeable side effect (for most) of weight gain in comparison with other SSRIs. Although few studies clearly demonstrate Mirtazapine's usefulness in treating unipolar depression, this medication may be a good option for people who have experienced significant weight loss during their depressive episodes.

Which SNRI Antidepressant is Best?

Two recent studies found Cymbalta (duloxetine) and Effexor XR (extended-release venlafaxine) comparable in effectiveness. In both studies, patients took either 60 mg per day of Cymbalta or 150 mg per day of Effexor XR for 6 weeks. For 6 more weeks, patients continued on whichever drug they had started, with doses adjusted to as high as 120 mg per day for Cymbalta and 225 mg per day for Effexor XR. Nearly 75% of patients taking Effexor XR finished 12 weeks of treatment as compared to about 65% of patients taking Cymbalta. Cymbalta was associated with more nausea, but a few patients taking Effexor XR experienced increases in blood pressure.

In other studies, Cymbalta produced general responses that were better than placebo (inactive sugar pills) and similar to those seen with drugs from another class of antidepressants known as selected serotonin reuptake inhibitors (SSRIs)—most commonly Prozac (fluoxetine) or Paxil (paroxetine). An analysis of separate studies done with Cymbalta and Prozac found little difference in effectiveness between the two drugs.

As for Effexor XR, an analysis of over 40 studies that involved about 4,000 patients found that taking this medication was associated with a higher success rate than other types of antidepressants. Success was defined as an improvement of 50% or more in the rating scales used to measure depression. In the analysis, 73.7% of patients taking Effexor XR were considered to be successful, as compared with 61.1% of those taking a selected serotonin reuptake inhibitor (SSRI) and 57.9% taking a tricyclic antidepressant (TCA). In addition, fewer patients taking Effexor XR stopped taking medication before their studies were scheduled to end.

Another study of 348 adults compared the effects and side effects of Effexor XR and the miscellaneous antidepressant, extended-release bupropion (Wellbutrin XL) for 12 weeks. While both antidepressants worked about equally, Effexor XR may have produced more sexual side effects, which caused more patients in the Effexor XR group to stop treatment.

Drugmaker, Wyeth says Pristiq also may be a treatment option for patients who are on multiple medications. The compound has a low risk of drug-drug interactions. This is important when considering that depression often is a co-morbid condition in medically ill patients and that these patients frequently are taking multiple medications.

Side effects of SNRIs

All SNRIs have the same general mechanism of action and side effects. However, individual SNRIs have some different pharmacological characteristics. That means you may respond differently to a certain SNRI or have different side effects with a different SNRI. For instance, you may have unpleasant side effects with one SNRI but not another.

Side effects of SNRIs include:

- Nausea
- Vomiting
- Dizziness
- Insomnia
- Sleepiness
- Trouble sleeping
- Abnormal dreams
- Constipation
- Sweating
- Dry mouth
- Yawning
- Tremor
- Gas
- Anxiety
- Agitation
- Abnormal vision, such as blurred vision or double vision
- Headache
- Sexual dysfunction

Nausea is less common with the extended-release form of SNRIs.

Before Taking These Drugs

Just as with other antidepressants, you've got to be sure to tell your doctor if you've ever had allergies to any antidepressants, foods, preservatives, or dyes, and if you have suffered from manic depression, convulsions, or seizures. Be sure to report liver disease, since this condition may raise blood levels of any antidepressant, which can increase the risk of side effects. And if you've had a recent heart attack, you may not be able to take antidepressant medication.

In the last few years, some study results and case reports suggested that taking antidepressants was linked with an increase in suicides, attempted suicides, and thinking about suicide—especially for children, teens, and young adults. Generally, the risk is higher in first month or so and then appears to decrease as the body adjusts to the medication. Depressed individuals may be more likely to attempt or commit suicide whether or not they are taking antidepressants. Nevertheless, in 2004, the FDA required the manufacturers of all antidepressants to include on their labels the following safety warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

Possible Important Adverse Interactions with SNRI Antidepressants

As with all antidepressants, you should talk to your doctor before taking any other drugs (even nonprescription medications).

Both Effexor XR and Cymbalta may raise blood pressure in some patients. Your blood pressure should be controlled before starting treatment and should be monitored regularly.

Effexor also tends to increase the heart rate, especially at higher doses. Use Effexor with caution if you've recently had a heart attack, suffer from heart failure, or have an overactive thyroid gland.

Effexor may also cause cholesterol levels to rise in some patients who take it for 3 months or longer. This effect is more common among patients taking higher doses of Effexor.

Mydriasis (prolonged dilation of the pupil of the eye) has been reported with EFFEXOR XR. You should notify your physician if you have a history of glaucoma or increased eye pressure.

You will not be able to use Cymbalta if it causes an allergic reaction. In addition, you should not take Cymbalta if you have uncontrolled narrow-angle glaucoma, a disease that causes increased pressure in the eyes.


An overdose of Effexor, combined with other drugs or alcohol, can be fatal. If you suspect an overdose, seek medical attention immediately.

Published retrospective studies report that Effexor overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that Effexor-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of Effexor in overdosage as opposed to some characteristic(s) of Effexor-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Symptoms of Effexor overdose include: Sleepiness, vertigo, rapid or slow heartbeat, low blood pressure, seizures, coma.

There is limited clinical experience with Cymbalta overdose in humans. In premarketing clinical trials, cases of acute ingestions up to 1400 mg, alone or in combination with other drugs, were reported with none being fatal. Postmarketing experience includes reports of overdoses, alone or in combination with other drugs, with duloxetine doses of almost 2000 mg. Fatalities have been very rarely reported, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg.

Signs and symptoms of overdose (mostly with mixed drugs) included:

- serotonin syndrome,
- somnolence,
- vomiting, and
- seizures.

Serotonin syndrome and SNRIs

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

- Pain relief medication such as tramadol (Ultram)
- Migraine medications such as sumatriptan (Imitrex) and rizatriptan
- Supplements that affect serotonin levels, such as St. John's worth

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

SNRIs and Pregnancy and Breast-Feeding

If you want to get pregnant while you're on an antidepressant, you're going to have to weigh the risks to your baby against the risks to you if you don't take the drug. As with most antidepressants, what we know about their activity in pregnant women is mostly obtained from animal studies, not from large-scale studies in humans.

The effects of Effexor XR and Cymbalta during pregnancy have not been adequately studied. If you are pregnant or are planning to become pregnant, tell your doctor immediately.

If Effexor or Cymbalta is taken shortly before delivery, the baby may suffer withdrawal symptoms. It's also known that Effexor and Cymbalta appears in breast milk and could cause serious side effects in a nursing infant. You'll need to choose between nursing your baby or continuing your treatment with these SNRIs.

If a woman needs to take an antidepressant during pregnancy, most of the time the doctor will recommend an SSRI like Zoloft or Lexapro.

You and your doctor should weigh the potential risks to the fetus and to you before you decide whether or not to take antidepressants during pregnancy.

There's always a potential for adverse reactions in nursing infants. If you're a new mom, you need to weigh the risks to you of not taking medication against the potential harm to your baby.

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