Trip Answers

Question answered:06/03/08

Clinical Evidence has a section on premenstrual disorder (November 2006 search) and lists the use of SSRIs as a trade off between benefits and harms (1). Specifically they note (2)

“Premenstrual symptoms

Compared with placebo SSRIs improve premenstrual symptoms over two to six cycles compared with placebo (moderate quality evidence)

Mood

Compared with placebo SSRIs improve premenstrual mood compared with placebo (moderate-quality evidence).

Physical symptoms

Compared with placebo SSRIs improve physical symptoms compared with placebo (moderate-quality evidence).

Adverse effects

SSRIs cause frequent adverse effects. Current evidence indicates no clear relationship between SSRIs and increased risk for suicide, but there is concern that SSRIs may increase the risks of self-harm and suicidal ideation. Regulatory authorities in Europe, the UK, and the USA have issued warnings about the use of SSRIs in children and adolescents.

Benefits

Selective serotonin reuptake inhibitors versus placebo:

We found one systematic review and five subsequent RCTs . The review (search date not reported, 15 RCTs, 844 women with premenstrual syndrome; 20–30% withdrawal rate, analysis by intention to treat in most trials) assessed any selective serotonin reuptake inhibitor (SSRI; fluoxetine [7 RCTs], sertraline [5 RCTs], citalopram [1 RCT], fluvoxamine [1 RCT], and paroxetine [1 RCT]) compared with placebo.  It found that continuous or luteal phase SSRIs significantly reduced overall premenstrual symptoms over two to six cycles compared with placebo. Four RCTs identified by the review reported physical and behavioural symptoms separately, and found similar significant reductions with SSRIs compared with placebo. Separate analysis of results for fluoxetine and sertraline performed by the review found similar results.  One subsequent RCT of continuous fluoxetine for three cycles found similar improvements in overall symptoms compared with placebo and found limited evidence that fluoxetine 20 mg daily may be more effective than fluoxetine 10 mg daily.  One subsequent RCT of continuous or luteal phase sertraline for three cycles, and two of luteal or continuous paroxetine for three cycles also confirmed the results of the review. One subsequent RCT found that continuous venlafaxine significantly improved overall premenstrual symptoms over 4 months compared with placebo.

Harms

The review found that significantly more women taking SSRIs than placebo withdrew because of adverse effects (OR 2.4, 95% CI 1.6 to 3.7). Common adverse effects associated with SSRIs were nausea, drowsiness and fatigue, insomnia, headache, and decreased libido. Results in the subsequent RCTs were similar, with significant increases in these adverse effects as well as increased asthenia, female genital disorders, tremor, dry mouth, dyspepsia, and diarrhoea associated with SSRIs.

Harms alerts:

There is concern that SSRIs may increase the risk of self harm and suicide. Regulatory authorities for Europe, the UK, and the USA have issued warnings about the use of SSRIs in children and adolescents. The US Food and Drug Administration (FDA) also issued a public health advisory safety alert regarding the use of paroxetine in women during pregnancy, based on a retrospective epidemiologic study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. This study suggested an increase in the risk of overall major congenital malformations with paroxetine compared with other antidepressants (OR 2.20; 95% CI 1.34 to 3.63).

Comment

The review found that SSRIs were very effective compared with placebo despite the significant statistical heterogeneity (P 

An MeRec Bulletin from 2003 entitled Tackling Premenstrual Syndrome (3) notes:

 

“Selective serotonin-reuptake inhibitors (SSRIs) are the drugs of choice for women with PMDD. A systematic review of 15 RCTs of SSRIs in 994 women with severe premenstrual dysphoric symptoms found that SSRIs improved physical and psychological symptoms. The most frequently studied drugs were fluoxetine and sertraline. However, fluoxetine (at a dose of 20mg daily) is the only SSRI currently licensed in the UK for PMDD.

 

The largest trial of fluoxetine in such patients was a six-month, double-blind RCT that compared fluoxetine 60mg daily, fluoxetine 20mg daily and placebo in 313 women with late luteal-phase dysphoric disorder (an older term with similar criteria to PMDD). For the 277 women who completed the first cycle, the luteal-phase score (based on tension, irritability and dysphoria) improved from baseline by 52% with fluoxetine 60mg, 44% with fluoxetine 20mg and 7% with placebo. However, the analysis of this study has been criticised, and more people withdrew because of side effects on the 60mg dose, which is not licensed for PMDD.

 

Symptoms of PMDD recur soon after stopping SSRIs, but RCTs have not evaluated SSRIs’ longterm effects in this condition. Intermittent fluoxetine dosing during the luteal phase only, has been suggested as a safer and cheaper option to continuous treatment. However, fluoxetine is not currently licensed for such use, and more evidence is required.”

 

 

 

 

1. http://clinicalevidence.bmj.com/ceweb/conditions/woh/0806/0806.jsp

2. http://clinicalevidence.bmj.com/ceweb/conditions/woh/0806/0806_I28.jsp

3.  http://www.npc.co.uk/MeReC_Bulletins/2002Volumes/vol13no3.pdf

 

 

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