Overall, paroxetine has more anticholinergic side effects than other SSRIs, the likely result of its higher affinity for muscarinic receptors ( TABLE 1 ). Its potential sedating effect,7 which can be extremely disturbing to some patients, may be a desired feature for others. A patient with insomnia, for example, might benefit from taking paroxetine at bedtime or switching to a less activating SSRI, such as citalopram or escitalopram. Excessive activation, such as significant insomnia, may also be a warning sign of undiagnosed bipolar disorder. Thus, careful screening is needed prior to switching medications or adding a hypnotic agent. (See the box below “Treating depression in primary care: Tips from a psychiatrist”.)
A switch to another SSRI is not the only way to alleviate a troublesome side effect, of course. Insomnia can also be managed by adding a short course of trazodone to the drug regimen or by switching the patient to mirtazapine or a tricyclic antidepressant (TCA).8
Augmentation with either bupropion or mirtazapine may alleviate sexual side effects and should be tried prior to switching the patient to a different antidepressant; however, the positive effects of augmentation should be balanced with any additional adverse events either agent may cause. For male sexual dysfunction, a trial of a phosphodiesterase inhibitor such as sildenafil is another alternative.
TABLE 1
SSRIs: Neurotransmitter affinity and side effects9
| Neurotransmitter/enzyme | SSRIs with most potent affinity* | Likely side effects |
|---|---|---|
| Serotonin | Paroxetine Sertraline Fluoxetine Citalopram Fluvoxamine | Sexual dysfunction, including anorgasmy; GI disturbance; activation |
| Dopamine | Sertraline Paroxetine Fluoxetine Fluvoxamine Citalopram | Extrapyramidal |
| Norepinephrine | Paroxetine Fluoxetine Sertraline Fluvoxamine Citalopram | Tremor; tachycardia; elevated BP |
| Muscarinic receptors | Paroxetine Sertraline Fluoxetine Citalopram Fluvoxamine | Anticholinergic (blurred vision, constipation, dry mouth) |
| *SSRIs listed in order of potency; escitalopram would be expected to have effects comparable to citalopram. | ||
| BP, blood pressure; GI, gastrointestinal; SSRI, selective serotonin reuptake inhibitors. | ||
Treating depression in primary care: Tips from a psychiatrist
- Use a validated instrument for depression screening and monitoring treatment success—preferably the PHQ-9 (http://www.lphi.org/LPHIadmin/uploads/.PHQ-9-Review-Kroenke-63754.PDF), which is validated for primary care practice. Use it at subsequent visits to track treatment response. The goal is not just response to treatment but remission of depressive symptoms, both of which are correlated with a decrease in the PHQ-9 total score.
- Take a careful history of bipolar symptoms and family history before starting a new patient on an SSRI. The DIGFAST mnemonic (http://www.usmle-forums.com/usmle-step-1-mnemonics/793-dig-fast-mnemonic-mania-symptoms.html) can help. Failure to respond to an SSRI or exacerbation of symptoms such as restlessness or insomnia once treatment has started should prompt you to consider a missed diagnosis.
- Consider augmentation strategies for patients who show partial improvement on an SSRI, rather than throwing out the gain with a wholesale switch to another drug. If a patient is only 30% better on the first agent you prescribe, try adding a second agent, which may significantly boost the response rate. Suggestions for SSRI augmentation include lithium, thyroid hormone, bupropion, and aripiprazole.
- Make sure the patient has been on a therapeutic dose for a sufficient period of time—at least 4 weeks—before chalking up a lack of response to an SSRI failure. Very often a patient is started on, say, 50 mg of sertraline and never titrated up. Many patients will not respond to the starting dose; those who don’t should be tried on higher doses of a single agent until tolerability factors predominate, maximum approved dose is reached, or remission of symptoms is obtained.—Christopher White, MD, JD
3. What drug interactions with SSRIs should I be most concerned about?
Like other psychotropic medications, SSRIs interact with drugs in a number of ways. There are interactions that occur at the cytochrome (CYP) 450 level and can result in toxicity or loss of effect, interactions that increase the likelihood of bleeding, and interactions that can lead to serotonin syndrome.
CYP 450 interactions. Depending on the CYP substrates that the SSRI and the other medication act upon, the result could be an increased concentration of the other agent and increased or decreased concentrations of the SSRI. The additive toxicity that could result has the potential to result in rare SSRI-associated adverse events, such as seizures and syndrome of inappropriate antidiuretic hormone (SIADH). Three exceptions to the increased concentration interaction are codeine, tamoxifen, and clopidogrel. Codeine, which relies on CYP metabolism to morphine, may have less analgesic effect if given with a CYP inhibitor. Tamoxifen may not be converted to endoxifen if given with a CYP inhibitor, resulting in a potentially lower therapeutic effect. Theoretically, a similar interaction could occur with clopidogrel when a CYP inhibitor is administered concurrently.
Fluoxetine, fluvoxamine, and paroxetine are the SSRIs with the greatest likelihood of having a significant CYP 450 interaction by inhibiting the metabolism of medications mediated by CYP 2D6, CYP 1A2, and CYP 2C19.9,10 (A partial list of medications and drug classes mediated by these substrates appears in TABLE 2 .)