SSRI Antidepressants

(Serotonin-Specific Reuptake Inhibitors)

Individual Medications in This Class

• fluoxetine (Prozac)
• sertraline (Zoloft)
• paroxetine (Paxil)
• fluvoxamine (Luvox)

Pharmacology

The medications most frequently prescribed for uncomplicated major depressive illness are the so-called serotonin-specific reuptake inhibitors, or SSRI's for short. These medications increase levels of serotonin in synapses in the brain by reducing the ability of the presynaptic nerve cell to reabsorb the neurotransmitter after it is released. As far as the postsynaptic nerve cell can tell, the presynaptic cell is releasing more serotonin. Thus these agents are said to facilitate serotonergic neurotransmission. If this is unclear, see more-than-basic neurophysiology.

Prozac, which was released in the United States in 1987, was the first medication of this type released in the US. We now have several drugs available which appear to work in this manner (see below). Although all of these agents have the same efficacy, risks, and side effects in clinical studies, individuals often react very differently to different medications in this class. The reason for this is unclear, but probably involves genetic variation in receptors and in brain physiology.

Indications and Benefits

There are good reasons why the SSRI's are so commonly prescribed. First they are as effective (but no more effective) than the older, tricyclic antidepressants in treating new-onset depression, but have fewer side effects (but they do have side effects! see below). In addition, they are helpful in treating several other conditions, including panic disorder, obsessive-compulsive disorder (OCD), eating disorders, social phobia, and possibly post-traumatic stress disorder (PTSD). Thus they are seen as sort of "broad-spectrum" psychiatric medications by many clinicians. A good response is probably seen in 70% or so of individuals with uncomplicated major depression, as compared with a 30% placebo rate. This means that if you have a never been treated and have a depressive illness there is about a 2/3 chance you will get better on medication, but have a 1/3 chance you would get better if he gave you salt tablets. These medicines a similar efficacy in treating panic attacks, but they may be less effective than the minor tranquilizers in reducing generalized anxiety. In OCD, it is common to see a moderate reduction (perhaps 50%) in symptoms. In my experience, the SSRI's are sometimes helpful but less dependable in the treatment of eating disorders and PTSD.

Usually, these medications do not work immediately, but require two to four weeks for the full therapeutic effect to develop. This may be frustrating, as the side effects are generally worst during the first week or two of treatment. Some symptoms, such as crying spells, may improve faster than others, such as insomnia and low energy.

When starting an antidepressant, it is useful to identify target symptoms of major depression, such as crying spells, suicidal ideation, or early morning awakening which are easy to monitor, to help follow medication response. Ideally, one likes to see complete improvement in all of the original depressive symptoms. However, it is possible to have a partial response to the medication, which can often be improved by adjustment of dosage or, if necessary, augmentation with a second medication.

Risks and Side Effects

Although many popular books may suggest otherwise, many individuals do experience significant and problematic side effects with these medications. SSRI's often have a stimulating (amphetamine-like) effect which is most prominent in the first few days of treatment. This is often marked by insomnia, feeling "hyper" or "wired", and an increase in anxiety or restlessness. Usually, this effect is mild and easily tolerated, but some people may become extremely uncomfortable. This problem may be minimized by starting the medication at low dosages (5-10 mg per day of Prozac) and working up slowly over several weeks. Early overstimulation must be distinguished from antidepressant-induced mania or rapid cycling. (See below)

There are a number of other common side effects which are more uncomfortable and annoying than they are serious. These include mild headache, nausea, insomnia, and an increase in vivid dreams, and sedation. Most of these symptoms improve after the first week or two of treatment. For instance, sleep may worsen for a week or two due to the stimulating effect of the medication, but then improve markedly as depression with its associated sleep disturbance resolves.

Sexual disfunction is one of the most common and problematic side effects seen with SSRI's. This problem most commonly involves a decrease in sexual interest or drive, and may occur in over 50% of individuals on these medications. A smaller group of patients experience true impotence including inability to orgasm, erectile dysfunction, or ejaculatory failure. These effects are reversible with discontinuation of medication, and can sometimes be managed with the addition of other medications, a change to a different class of antidepressant, and occasionally by switching to a different SSRI.

Antidepressant-Induced Mood Instability

Like all other antidepressants, the SSRI's can cause mood to become less stable. Briefly, some patients may respond well, perhaps too well, to SSRI's or other antidepressant medications, and then develop either excessively elevated mood or increased instability of mood. Individuals with bipolar types of mood disorders are most vulnerable to this effect. A good psychiatric evaluation by a qualified professional, combined with responsible followup which includes ongoing mood monitoring, is the best protection against this potentially serious treatment complication.

The Serotonin Syndrome

The SSRI's are not the only medications which increase levels of serotonin. Other drugs which can have this effect include the tricyclic antidepressants, many of the newer "third generation" antidepressants, the monoamine oxidase inhibitor antidepressants, lithium, stimulants, the anti-anxiety agent Buspar, the "fen-phen" weight loss medications, some herbal remedies such as St. John's Wort, and some street drugs such as speed, cocaine, and ecstasy. These substances are called "serotonergic agents."

If serotonin levels in the brain become too high, a number of mental and physical side effects can result. Collectively, these symptoms are called the "serotonin syndrome." This syndrome can be mild, but occationally becomes severe, and has resulted in fatalities. It is most likely to occur when two or more serotonergic agents are taken simultaneously. Combinations which include MAOI's are particularly risky in this regard, and are often strictly contraindicated. Although serious forms of this syndrome are rare, particularly on a single theraputic agent, symptoms of this nature should clearly be reported to a physician familiar with this syndrome.

Symptoms of the serotonin syndrome commonly include restlessness, tremor, diarrhea, nausea, confusion, agitation, anxiety, muscle jerks or rigidity, fever, dilated pupils, shortness of breath, sweating, rapid heart rate, and altered blood pressure.

SSRI Discontinuation Syndrome

For a number of years, psychiatrists happily explained to patients that there was no problem with discontinuing the SSRI antidepressants abruptly. However, as more patients have complained that this is not the case, it has become recognized that abrupt discontinuation of SSRI antidepressants can cause several annoying, although not serious, side effects. These may include light-headedness or dizziness, nausea, diarrhea, jitteriness, muscle jerks, and tremor. This syndrome is usually mild, begins 2-4 days after stopping a SSRI, and resolves in a week or so. It can be avoided by gradually tapering the medication rather than stopping it abruptly.

LINKS ON THE SEROTONIN SYNDROME:

• Serotonin Syndrome Diagnostic Criteria
• Serotonin Syndrome, Abstract: Martin, TG

Other Drug Interactions

Since the SSRI's are mildly sedating, reasonable caution should be exercised driving, operating equipment, etc., especially if combined with other drugs such as antihistamines or tranquilizers which can also cause sedation. Some individuals report that they become more easily intoxicated on drinking alcohol when taking an SSRI. Since alcohol is a depressant, it is best to avoid it when being treated for depression, in any case.

SSRI's can inhibit normal enzymes in the liver which break down and help remove other drugs from the system. This can effect the elimination of other drugs which use these enzymes. For example, Prozac will interfere with the metabolism a tricyclic antidepressant, nortriptyline. This interaction can cause nortriptyline toxicity, but can also be used to advantage, such as to increase blood levels of nortriptyline in people who have difficulty tolerating adequate dosages. These interactions are complex, and are not listed here, but is always a good idea to check with your prescribing doctor if on an antidepressant and starting a new medication. A few drugs must be specifically avoided because increases in their blood levels can occur which can be dangerous: cisapride (Propulsid), a heartburn medication, terfenadine (Seldane), an allergy medication, and astemizole (Hismanal), a stomach ulcer medication.

Alcohol and SSRI's

Drinking alcohol when taking an SSRI is not a good idea for several reasons. Alcohol is a central nervous system depressant, and since the SSRI's can cause sedation, the combination can be dangerous if driving or operating heavy equipment. Many people report that when taking an SSRI, even if they do not feel sedated, alcohol effects them more strongly than usual, and one drink may feel like two to four. In addition, alcohol can depress mood. I would argue that it makes little sense to be taking both a depressant and an antidepressant, particularly if you are having problems being depressed.

Given all this, alcohol is not absolutely contraindicated when taking an SSRI, and some people are able to continue social use of alcohol cautiously and responsibly without ill effect. Moderation, meaning no more than one or two drinks once or twice a week, is certainly recommended.

Useful Links

• DrugInfoNet Serotonin FAQ
• Dr. Bob's Psychopharmacology Link