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One treatment strategy for premenstrual dysphoria is intermittent luteal phase dosing of serotonergic antidepressants. Some studies of this strategy begin the antidepressant 14–16 days before the onset of menses. Others use symptom-onset dosing. These intermittent approaches avoid antidepressant risks associated with long-term continuous dosing, including weight gain, sexual dysfunction, and risk of withdrawal. Fine. But does this dosing strategy actually work? How well does it work compared with continuous dosing?
Hi! Jim Phelps here for the Psychopharmacology Institute. You know, it’s wonderful when we want an answer to an important clinical question and someone has done all the hard work for us. This time, it’s Thomas Reilly and colleagues, whose systematic literature review of 1,000 relevant articles identified 8 randomized trials of intermittent vs continuous dosing. Bingo! A meta-analysis of 8 head-to-head trials. Let’s look at the result and then consider some implications. The result: No difference in outcomes between intermittent and continuous dosing. But if you were a skeptic, you’d have some trouble with this study for several reasons, such as that 2 different dosing strategies are lumped, beginning the SRI in the luteal phase and beginning it at symptom onset. Not all the outcome measures were the same. Several of the studies were quite small. And most concerning, there’s very significant heterogeneity, such as studies with opposite outcomes. For example, in a study on intermittent dosing, 16 of 18 women were responders vs only 6 of 13 with continuous dosing. That’s a 9-fold advantage for intermittent dosing. By contrast, in another study, only 4% on intermittent dosing were responders vs 38% on continuous dosing. Right; the opposite finding. These results disagree so widely that we’d have to look more closely at each study to see what’s going on, not lump response rates in a meta-analytic average.
So, digging further, the authors of this meta-analysis looked at dropout rates and absolute symptom scores instead of percentage of responders. But the overall result was still the same, with no difference in outcomes with intermittent vs continuous SRI dosing. So, lowering our skepticism at least for a moment, we’ll look at the medications used. In the 8 comparison studies, there are really only 2 antidepressants involved—sertraline and citalopram. Well, yes, there were 2 studies using paroxetine, but I hope that’s fallen out of your toolkit by now with its higher incidence of weight gain and withdrawal problems. Dosages? One study used 50 mg of sertraline; 2 studies used 50 mg–100 mg. One study of citalopram used 20 mg; 2 studies used 10 mg–30 mg or 20 mg–40 mg. One other side note here: A 2006 publication looked at 3 dosing strategies using sertraline and found efficacy with as little as 25 mg–50 mg.
Finally, some clinical implications per the authors’ discussion. First, do women experience any withdrawal symptoms with intermittent dosing? Two randomized trials of intermittent dosing looked for this and found none. Presumably, that’s because there’s not enough time for the brain’s serotonin system to adapt to the medication by, for example, decreasing brain serotonin receptor density, which is likely a key component of antidepressant withdrawal. Therefore, unless continuous dosing is warranted for other reasons, intermittent dosing for perimenstrual symptoms should be “considered more commonly” say the authors. That’s a nice gentle way of putting it, don’t you think? Second, with intermittent dosing, symptom response begins within hours, with benefits peaking in 2 days. So, in premenstrual dysphoria, the mechanism of action of SRIs appears to be different than in depression. Different how? Well, it looks like their effect is on the synthesis of allopregnanolone. You’ll remember that allopregnanolone is a metabolite of progesterone, so its levels fall when progesterone falls in the menstrual cycle. Although multiple factors contribute to premenstrual dysphoria, including genetic and psychosocial factors, a relative insensitivity to allopregnanolone is now thought to be a central component as well.
According to a recent review of sex steroid biochemistry, SRIs don’t just increase allopregnanolone. Although this is still under study, it appears that they might increase it in women whose allopregnanolone is low and decrease it in those who have high levels. Obviously, this is of interest to us in psychiatry, though, with the advent of medications for depression that target the sex steroid system.
The third brief clinical implication of the efficacy of intermittent dosing is stigma. The authors of this meta-analysis note that the differences between the action of SRIs in PMS and in depression “may improve the perception of these medications among the PMDD community.” Another gentle way of putting it.
In summary then, if there’s no difference in efficacy between intermittent and continuous dosing in premenstrual dysphoria, one would need additional reason for continuous dosing to take on the attendant risks of weight gain, sexual dysfunction, and risk of withdrawal when stopping. This study did not differentiate luteal-phase dosing vs symptom-onset dosing, so you’re still on your own there.
For more on this, the references include a useful review of allopregnanolone’s role in PMDD, which is linked here at the Psychopharmacology Institute. It’s biochemically detailed, but it shows how far we’ve come in understanding mechanisms.
Abstract
Background: Intermittent (luteal phase) dosing of selective serotonin reuptake inhibitors is one treatment strategy for premenstrual syndromes such as premenstrual dysphoric disorder. This avoids the risk of the antidepressant withdrawal syndrome associated with long-term continuous dosing.
Aims: To compare intermittent dosing to continuous dosing in terms of efficacy and acceptability.
Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, PubMed and CINAHL for randomised trials of intermittent compared with continuous dosing of selective serotonin reuptake inhibitors in premenstrual syndromes. We extracted response rates, dropout rates and changes in symptom scores. We used random effects meta-analyses to pool study-level data and calculated odds ratio for dichotomous data and standardised mean difference for continuous data. Risk of bias was assessed using the Cochrane risk-of-bias tool. The study was registered with PROSPERO (CRD42020224176).
Results: A total of 1841 references were identified, with eight studies being eligible for analysis, consisting of a total of 460 participants. All included studies provided response rates, six provided dropout rates and five provided symptom scores. There was no statistically significant differences between intermittent and continuous dosing in terms of response rate (odds ratio: 1.0, 95% confidence interval (CI): 0.23-4.31, I2 = 71%), dropout rate (odds ratio 1.26, 95% CI: 0.39-4.09, I2 = 33%) or symptom change (standardised mean difference: 0.04, 95% CI: -0.27 to 0.35, I2 = 39%). All studies had a moderate or high risk of bias.
Conclusion: Since intermittent dosing avoids the potential for withdrawal symptoms, it should be considered more commonly in this patient population.
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Reference
Reilly, T. J., Wallman, P., Clark, I., Knox, C. L., Craig, M. C., & Taylor, D. (2022). Intermittent selective serotonin reuptake inhibitors for premenstrual syndromes: A systematic review and meta-analysis of randomised trials. Journal of Psychopharmacology, 02698811221099645.
Related References
Hantsoo, L., & Epperson, C. N. (2020). Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiology of Stress, 12, 100213.
