Answers to your questions about SSRIs
Which SSRI is best? What drug interactions should you be most concerned about? The authors provide evidence-based answers to 7 frequently asked questions.
Risk of bleeding. Combining any SSRI with a nonsteroidal anti-inflammatory drug (NSAID) without the addition of an acid-suppressing agent would cause 1 in 250 patients to experience an upper GI bleed, a recent study found.11 One in 500 patients treated with an SSRI and an antiplatelet agent developed an upper GI bleed. If a patient taking an SSRI requires antiplatelet or anticoagulant therapy, it is crucial to alert him or her to the risk and to carefully review signs and symptoms of bleeding. Hepatitis C, cirrhosis, hepatic failure, and portal hypertension are independent causes of coagulopathy, so patients with any of these conditions face an elevated risk of bleeding and would need to be monitored more closely.11 Avoid prescribing fluoxetine for patients with severe liver disease; an SSRI with a shorter half-life would be a more appropriate choice.
Serotonin syndrome. Combining an SSRI with a drug that affects serotonin (venlafaxine, mirtazapine, and serotonin receptor agonists such as sumatriptan, TCAs, St. John’s wort, meperidine, and tryptophan) or a drug that exhibits monoamine oxidase inhibition properties (isocarboxazid, linezolid, phenelzine, phentermine, selegiline, and tranylcypromine) may lead to serotonin syndrome. This toxidrome is identified by autonomic instability, neuromuscular changes, and altered mental status in a patient who has ingested a substance that could elevate serotonin levels, but typically resolves within 24 hours after the serotonergic agent is discontinued.12
Because of the high risk of serotonin syndrome when a monoamine oxidase inhibitor (MAOI) is combined with an SSRI, do not prescribe a drug in this class until the patient has been off the SSRI for at least 2 weeks. Fluoxetine has a longer half-life, so a patient should be off of it for 5 weeks before taking an MAOI.13
TABLE 2
CYP 450 interactions: Beware of these drug pairings9,10,13-17
| SSRI* | Other medications |
|---|---|
| Fluoxetine | Aripiprazole Clopidogrel Codeine Dextromethorphan Diazepam Duloxetine Haloperidol Metoprolol Phenobarbital Phenytoin PPIs Risperidone Tamoxifen TCAs Tramadol Venlafaxine |
| Fluvoxamine | Amitriptyline Clopidogrel Clozapine Cyclobenzaprine Diazepam Imipramine Naproxen Phenobarbital Phenytoin PPIs Theophylline |
| Paroxetine | Aripiprazole Codeine Dextromethorphan Duloxetine Haloperidol Metoprolol Risperidone TCAs Tramadol Venlafaxine |
| *Sertraline is a modest CYP 2D6 inhibitor. | |
| CYP, cytochrome; PPIs, proton pump inhibitors; SSRI, selective serotonin reuptake inhibitor; TCAs, tricyclic antidepressants. | |
4. What precautions are necessary when starting a patient on an SSRI or modifying therapy?
Dosing is the initial concern, with adjustments made based on specific patient factors. Elderly patients should be started on a low dose and titrated up more slowly than younger patients, for example. Low starting doses are also recommended for patients with hepatic dysfunction.14-17
“Start low and go slow” is a good rule to follow when prescribing an SSRI to anyone whom you suspect may be intolerant to common side effects—a patient with GI symptoms associated with depression, for example.
Patient comorbidities affect choice of agent as well as dose. For a patient with a creatinine clearance <20 mL/min, citalopram and escitalopram should be used with caution.14,15 Paroxetine should be initiated at lower doses for patients with a creatinine clearance <30 mL/min. While citalopram and escitalopram may not be ideal SSRIs for patients with renal impairment because of the potential for accumulation, they lack the substantial drug interactions and marked discontinuation syndrome seen with SSRIs such as paroxetine.
Two key concerns when changing from an SSRI to another class of antidepressant, or vice versa, are the increased risk of adverse events and a reduction in symptom control. A cross-titration strategy is appropriate for most such changes, provided the other drug is not an MAOI.
Discontinuation syndrome, which can be remembered by the mnemonic FInISH (Flu-like symptoms, Insomnia, Imbalance, Sensory disturbances, and Hyperarousal),18 is also a concern when antidepressant therapy is modified. The likelihood that a patient will develop discontinuation syndrome appears to be related to dose and agent, but not to the duration of treatment.19
While discontinuation syndrome is self-limiting, it is prudent to taper SSRI therapy whenever possible to minimize the risk of this adverse event, especially with paroxetine. A sample taper would be to reduce paroxetine by 10 mg per day every 5 to 7 days until the dose is down to 5 to 10 mg daily, then to discontinue the drug completely.20 Cross-titration to a different medication will also prevent withdrawal symptoms and minimize the risk that a patient who was taking the maximum dose of an SSRI will develop serotonin syndrome.21 Because of the long half-life of fluoxetine and its metabolite, norfluoxetine, fluoxetine is less likely than other SSRIs to cause discontinuation syndrome. Basically, it self-tapers.
