Thus, most patients who are prescribed sertraline will probably require upward dose adjustments. This is an important consideration, since administering insufficient doses of an antidepressant can result in treatment failure and unnecessary drug substitutions. Kinetics Fluoxetine and paroxetine and possibly fluvoxamine inhibit their own metabolism, which can lead to disproportionate increases in plasma levels nonlinear kinetics at higher doses.
However, as a precaution, physicians should prescribe reduced doses of fluoxetine, fluvoxamine, and paroxetine to patients whose ability to eliminate drugs is already substantially impaired e.
The human aging process is accompanied by reductions in liver and kidney function that can extend the half-life and increase the blood levels of many drugs, including some of the SSRIs. As shown in Table 1 , dose adjustments are recommended when prescribing citalopram, paroxetine, and fluvoxamine to elderly patients. Their benign cardiovascular profile and broad therapeutic range make them relatively safe in overdose.
Common side effects associated with SSRI therapy include nausea and sexual dysfunction. Although the SSRIs are well tolerated as a class, their distinct secondary effects on the body i. For example, significant weight loss may benefit obese patients but may be hazardous to patients who are frail.
Likewise, activating effects can be helpful for patients with extreme psychomotor retardation but can lead to added distress and polypharmacy e. Although it is impossible to anticipate exactly how a given person will respond to a particular SSRI, consideration of possible differences in secondary effects may help the clinician to make the most favorable match between patient and drug. Thus, it is quite likely that many patients will take at least 1 other drug—be it an over-the-counter cough syrup, a nasal decongestant, or an antibiotic—with their SSRI at some time during treatment.
For some patients e. SSRIs are relatively safe when administered alone, but the risk of combining them with other medications varies significantly from agent to agent. Underlying this variability is the cytochrome P CYP system, a group of enzymes that metabolizes most marketed drugs.
All of the SSRIs are extensively biotransformed by the P system, but fluoxetine, fluvoxamine, and paroxetine also significantly inhibit 1 or more of the major P enzymes. In contrast, citalopram and sertraline do not substantially inhibit P enzymes. Open in a separate window When initiating therapy with an SSRI, the single most important means of avoiding adverse drug interactions is to make a list of every medication the patient is taking.
On the basis of this inventory and what is known about the P system, physicians can predict which antidepressants are least likely to conflict with an existing regimen.
If a patient has already been prescribed an SSRI with a high potential for Pmediated drug interactions, several steps can be taken to avoid problematic situations when other forms of therapy are initiated. The first step is to become familiar with the drugs that are most likely to interact with the particular SSRI in a clinically meaningful way. These include agents that become toxic with relatively minor elevations above the therapeutic dose Table 3 or are inactive in their unmetabolized form e.
In either case, the best course is to select an alternative medication, if one is available. For example, ibuprofen or another nonopiate analgesic could be substituted for codeine to treat minor pain. Likewise, an antiarrhythmic drug not in class IC could be prescribed instead of propafenone. If a safer alternative does not exist, agents with a narrow therapeutic range that are quite likely to be affected by an SSRI should be started at a lower-than-usual dose, and the patient should be closely monitored for adverse reactions.
Open in a separate window Self-Medication Self-medication with over-the-counter preparations, leftover or borrowed prescription drugs, and alternative medicines e. Therefore, educating the patient about the risks of combining SSRIs either individually or as a class with other drugs is a critical component of safe and effective therapy. For example, patients taking fluvoxamine for either depression or obsessive-compulsive disorder should be cautioned against the use of benzodiazepines outside of a doctor's care, since interactions between fluvoxamine and benzodiazepines can cause oversedation.
Two commonly self-administered drugs that have the potential to interact with all SSRIs are dextromethorphan, an ingredient in many cough syrups, and St.
John's wort Hypericum perforatum , an increasingly popular herbal antidepressant. Both agents affect serotonin in fact, a constituent of St. John's wort appears to be a naturally occurring serotonin uptake inhibitor and therefore may have additive effects when combined with SSRIs. Coprescribing SSRIs with monoamine oxidase inhibitors is contraindicated because of the possibility of such reactions.
To avoid potentially serious clinical situations, physicians should inform patients about both the risks and the warning signs of adverse interactions between SSRIs and other commonly used and abused serotonergic drugs, including meperidine and amphetamines.
Augmentation Strategies Lithium and buspirone are commonly coprescribed with antidepressants to boost efficacy. Although lithium is not susceptible to Pmediated drug interactions, it appears to have nonspecific serotonergic effects and therefore may interact with SSRIs in the manner described above.
Buspirone is metabolized by the CYP3A4 enzyme, which is substantially inhibited by fluvoxamine. Elderly Patients The elderly, as a group, tend to take many medications on a daily basis.
Because the aging body eliminates drugs less efficiently and is more sensitive to pharmacotherapeutic side effects, adverse reactions resulting from drug-drug interactions are not only more common but also potentially more severe and longer lasting in older patients. Choosing an agent with a low propensity for drug interactions is therefore especially important for the management of late-life depression.
All drug combinations should be carefully monitored among elderly patients who are frail or medically ill. For patients taking SSRIs, abrupt withdrawal can cause malaise, light-headedness, restlessness, sleep and sensory disturbances, and headache. Although not life-threatening, such symptoms can be distressing to the patient, since they may easily be mistaken for symptoms of returning depression. The severity of SSRI withdrawal syndrome appears to vary according to the half-life of the drug.
Fluoxetine, which has the longest half-life of the SSRIs see Table 1 , appears to produce the fewest withdrawal symptoms, while paroxetine, which has the shortest half-life, produces the most pronounced discontinuation effects.
If abrupt discontinuation of any SSRI is medically necessary, patients should be monitored carefully and informed about withdrawal symptoms. Occasionally, SSRIs may need to be discontinued because of adverse events.
In these cases, a long half-life can be problematic. Patients who develop intolerable adverse symptoms while taking fluoxetine, for example, may suffer from these symptoms for several days or weeks while the drug and its metabolites are cleared from the body. In contrast, drug-induced adverse events produced by the other SSRIs most likely will resolve more quickly, since these agents are more rapidly cleared from the body see Table 1.
Switching from one SSRI to another appears to be effective in most cases, 55 probably because of the significant chemical and pharmacologic differences between these agents. Intraclass switching appears to be a safe strategy as well even when abrupt substitutions are medically necessary , since the SSRIs have a broad therapeutic range. The risk of switching from an SSRI to an antidepressant from another class depends on the characteristics of both medications.
Citalopram and sertraline, which have relatively little effect on the P system and wash out of the body relatively quickly, are the least likely of the SSRIs to interact with a replacement drug. Fluvoxamine and paroxetine carry a moderate risk of interaction because they inhibit major P enzymes but linger in the body for only a week or so after discontinuation. Fluoxetine, which along with its active metabolite potently inhibits relevant P enzymes and remains in the system far longer than the other SSRIs, is the agent most likely to interfere with the metabolism of a substitute antidepressant.
Drugs to watch when switching from fluoxetine include TCAs, venlafaxine, and bupropion, each of which is metabolized to some extent by CYP2D6 and each of which is associated with potentially serious adverse events cardiovascular toxicity, hypertension, and seizures, respectively at elevated blood concentrations of drug. An agent with linear kinetics may be more appropriate for patients with kidney or liver dysfunction, while an agent with a low potential for short-term weight loss may be more appropriate for frail patients.
Among patients who take multiple medications, it is preferable to use agents with a low potential for drug interactions. Special attention should be paid to the individual characteristics of SSRIs when discontinuing therapy or when switching to another agent, since the length of the half-life can affect the severity of withdrawal symptoms and the likelihood that a potential inhibitor will affect the metabolism of the replacement drug.
It is important to remember that each patient may respond to a given SSRI or combination of an SSRI and another drug differently and that it is not always possible to predict which agent will be the most effective for a given patient. However, understanding the individual characteristics of the SSRIs and keeping a watchful eye on a patient's response can help primary care physicians avoid or minimize potentially problematic clinical situations.
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