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For PMDD, Does Symptom-Onset Dosing of an SSRI Work?

For PMDD, Does Symptom-Onset Dosing of an SSRI Work?

For the treatment of premenstrual dysphoric disorder (PMDD), serotonin reuptake inhibitors (SRIs) are considered to be the first-line treatment of choice. A significant body of evidence, including numerous double-blind, randomized controlled trials, supports the effectiveness of SRIs in reducing the emotional, as well as physical, symptoms of PMDD. In general, women respond to low doses of serotonin antidepressants, often at doses lower than typically used to treat major depressive disorder and anxiety disorders. In addition, treatment response to SRIs usually occurs rapidly, often within several days.

While serotonin reuptake inhibitors represent an effective treatment for PMDD, a fair number of women report side effects that interfere with long-term use. Sexual side effects, including decreased libido and anorgasmia, are a common reason for discontinuing treatment. Other problematic side effects include fatigue.

Different dosing strategies may help to minimize the risk of troublesome side effects. For example, some women may elect to only take an SRI during the luteal phase–the last two weeks of their cycle–and to stop the SRI with the onset of menses.

Some women may benefit from symptom-onset dosing, where the SRI is started with the onset of premenstrual symptoms and stopped when menses start. A recent article from Kimberly Yonkers and colleagues takes a closer look at the effectiveness of this approach.  

In this double blind, randomized, clinical trial, 184 women with PMDD were randomized to receive either sertraline (25-100 mg) or placebo. PMDD symptoms were measured using the Daily Ratings of the Severity of Problems. Domains of functional impairment included (1) reduced productivity or efficiency at work, school, home, or daily routine; (2) interference with hobbies or social activities; and (3) interference with relationships. 

Relationship Functioning Shows Greatest Improvement with Sertraline

In this study, women receiving sertraline experienced a greater reduction in the “interference” or overall impact of PMDD symptoms than those receiving placebo. On average, the anger/irritability subscale showed a greater decrease between baseline and end of second cycle in the sertraline group compared to placebo. Sertraline and placebo did not differ in terms of impact on depressive symptoms or physical symptoms. Looking specifically at domains of functional impairment, only relationship functioning improved significantly with sertraline treatment between baseline and the end of the second cycle. (There were no significant improvements in productivity/efficiency or participation in hobbies and social activities). An analysis of potential mediating factors suggested that most or all of the reduction in relationship interference with treatment can be explained by the reduction in anger/irritability symptoms.

While previous studies have shown that continuous treatment and luteal phase dosing with a serotonin reuptake inhibitor is associated with improvements across multiple domains (i.e., physical symptoms, depressive symptoms, and anger/irritability), this study suggests that symptom-onset dosing may be more effective for reducing anger/irritability than other symptoms seen with PMDD. Furthermore, other studies have shown that improvements in functioning may also be impacted by dose and timing of administration. 

Putting the Findings Into a Clinical Context

Individuals with PMDD experience heterogenous symptoms that can be grouped into different symptom clusters. While PMDD with prominent somatic symptoms is common, it is PMDD with prominent anger and irritability that seems to cause the greatest functional impairment and, not surprisingly, has the greatest impact on interpersonal relationships. This study and several others suggest that, while most individuals with PMDD benefit from treatment with serotonin reuptake inhibitors, dosage and timing of medication may be important considerations.

When initiating treatment with an SRI, we generally start with a relatively low dose (for example, fluoxetine at 10-20 mg or sertraline at 50 mg) and monitor symptoms for several consecutive cycles. Daily charting of symptoms is very helpful in terms of tailoring treatment. The dosage and timing of medication can then be adjusted based on effectiveness and tolerability. If side effects are not tolerable, one may consider decreasing the dosage or changing to intermittent dosing (either starting at day 14 of the cycle or at the time of symptom onset). This is a collaborative process, and, because symptoms are compared month to month, it can take some time to settle upon the best regimen.

Ruta Nonacs, MD PhD


Yonkers KA, Altemus M, Gilstad-Hayden K, Kornstein SG, Gueorguieva R. Does Symptom-Onset Treatment With Sertraline Improve Functional Impairment for Individuals With Premenstrual Dysphoric Disorder?: A Randomized Controlled Trial. J Clin Psychopharmacol. 2023 Jul-Aug 01;43(4):320-325. 

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