THERAPY

Fluoxetine performs in premenstrual syndrome

-Catherine Andrews-

It is posslDle that the antidepressant fluoxetine ['Prozac') will be approved in another indication, meaning that more patients could benefit from treatment with the drug. Canadian researchers have reported that fluoxetine is effective in women with premenstrual syndrome (PMS), particularly the most severe form of PMS, premenstrual dysphoric disorder (pMDD). It is estimated that 40% of European women regularly suffer moderate-to-severe PMS with symptoms ranging from breast tenderness and weight gain to depression, anxiety and even suicidality. Many treatment options have been suggested for women with PMS and PMDD, but currently there is no consistently effective solution. Therapies of the future should look towards the 5-HT (serotonin) neurotransmitter system, indicate results from 2 studies presented at the 21st Congress of the Collegium Internationale Neuropsychopbannacologicum (CINP) [Glasgow, Scotland; July 1998].

About 75% of women with regular menstrual cycles experience some form of PMS; however, only 3-6% of women have PMDD. Current treatment choices for women with PMS include lifestyle interventions, stress management, hormonal or psychotropic therapies and even surgical castration.

A recognised illness The inclusion of criteria for PMDD in the DSM-IV

research diagnostic classification acknowledges that some women in their reproductive years experience extremely distressing emotional and behavioural symptoms before their menstrual period. Using these criteria, PMDD can be differentiated from the milder forms of PMS and, if left untreated, PMDD can seriously impair daily life-functioning, said Professor Meir Steiner from McMaster University, Ontario, Canada.

According to the DSM-IV criteria, symptoms of PMDD must be documented over a I-year period and, in the absence of a biological marker, patients must meet 5 of 11 specified symptoms with at least one of the following:

• marked depressed mood or hopelessness • marked anxiety/tension • marked affective liability • marked anger and irritability.

Looking at serotonin receptolS PMS is broadly classified as a cluster of symptoms

occurring regularly during the week before the onset of menstrual bleeding. Among the most prominent symptoms are mood changes, tension and irritability that typically occur a few days prior to the onset of menses and disappear a few days after menstruation.

The cause of PMDD remains controversial. Currently, it is believed that women with this disorder have normal ovarian function rather than a hormonal imbalance. Consequently, it is thought that a hormonally driven cyclical trigger initiates the PMDD-related biochemical changes that occur in the CNS and other target organs.

Because PMS includes anxiety, irritability and depressive symptoms, there is now evidence that the syndrome may be associated with an imbalance of serotonin in the brain. Consequently, pharmacological therapy with selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, may be beneficial.

Table L Effects of fluoxetine on total mood score" aftel' 1 menstrual cycle

Placebo Fluoxetlne Fluoxetlne recipients 20 mgldlly 6Omg/dIIy

(n = 98) recipients recipients In .. 116) (n = 86)

Baseline total mood score:

56.0 57.2 56.3

Total mood $OO(e alter 1 menstrual cycle:

51 .1 32.4~ 26.6~

Percentage reduction In total mood score:

6.7 43.9·· 52.4-

• as assessed by 1 OOmm visual analogue scale

- P < 0.001 vs placebo

The magic of fluoxetine

Fluoxetine is possibly the most studied antidepressant of modem time. It was one of the first SSRIs to be shown to increase brain levels of serotonin leading to improved mood in patients with depression. Fluoxetine therapy is also associated with improvements in anxiety, suicidal behaviour, and aggression. Results from 2 placebo-controlled studies investigating the efficacy and tolerability of fluoxetine in women with PMDD showed that fluoxetine was significantly superior to placebo in the treatment of mood symptoms, said Professor Steiner. These studies showed that 'the intervention withfluoxetine both 60 and 20mg is overwhelmingly stronger than intervention with placebo' he said.

Fluoxetine lifts mood

The first study was a multicentre, placebo-controlled trial which examined the effects of continuous fluoxetine therapy given over 6 menstrual cycles. * In this double-blind study, 313 women aged between 20 and 45 years were randomly assigned to receive fluoxetine 20 or 60 mg/day, or placebo. The primary outcome measures were the patients' daily assessments of mood symptoms such as irritability, depression and anxiety on a visual analogue scale.

Importantly, fluoxetine recipients had significant improvements in mood after 1 menstrual cycle compared with placebo recipients [see table 1). These improvements persisted over time, and were similar for patients receiving fluoxetine 20 or 60 mg/day.

• See Inpharma 991: 15, 17 JUII 1995; fDJ314489

Inpharma- 10 Oct 1l1li8 No. 11111

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14 THERAPY

Intemtittent may be enough In the second study, the effects of 2 different

fluoxetine treatment regimens were investigated in 2 different patient groups, explained Dr Steiner. 24 women with PMDD and a history of affective disorders or alcoholism received continuous therapy with fluoxetine 20 mglday. Another group of 24 women with PMDD but without any psychiatric history received intermittent therapy with fluoxetine 20 mglday for 14 days premenstrually. For both patient groups, treatment was continued for 3 menstrual cycles. In this study, the primary outcome measure was the standardised Clinical Global Impression (eGI) Efficacy Index, which combines a rating of therapeutic effect and adverse events.

Overall, 66.7 and 75% of women who received continuous and intermittent fluoxetine, respectively, had a positive response to treatment, said Dr Steiner [see table 2). These results suggest that intermittent fluoxetine administration may be as effective as continuous therapy in improving mood symptoms in women with PMS.

Different from depression? Dr Steiner noted that the typical onset of antidepressant

action for SSRIs and other antidepressants is usually 3-6 weeks. The relatively rapid response to fluoxetine treatment seen in both of these studies in women with PMDD lends weight to the hypothesis that this disorder has a different pathology to depression.

Dr Steiner cautioned against extrapolating the positive effects of fluoxetine against PMDD to other SSRIs because fluoxetine has a longer half-life than other agents.

A robust response Additional data presented at the conference on the

potential role of fluoxetine in the treatment of women with PMDD also demonstrated an early and robust response to fluoxetine 20 mglday. Long-term therapy (6-18 months) was most beneficial, with women who discontinued treatment after 3,6, or 9 months reporting a return of symptoms.

Table 2. Effects of continuous or intermittent fluoxetine therapy

Continuous fluoxetine IntennJttent fluoxetlne 20 maldav (n = 24) 20 maldav in = 24)

Number 01 patients with positive response to IheI'apy; 16 18

Number of nonresponders to therapy:

0 1

Number of responders who also experienced adverse events:

6 1

Number of patients withdrawn because 01 adverse effects:

2 3 Number of patients lost to follow-up:

0 1

Adverse effects of fluoxetine therapy were consistent with its known tolerability profile and were usually transient and rarely resulted in patients withdrawing from treatment.

The race is on The race to find a useful pharmacological therapy

Inphann.-10 Oct '111 No. 11M

for women with PMS is hotting up with the results from several other small studies showing that clomipramine, paroxetine, sertraline and citalopram have all compared favourably with placebo for the treatment of irritability, depression and anxiety symptoms in PMS, said Dr Steiner. The prize for a successful agent is significant, not only in terms of pharmaceutical company profits, but also because such an agent would give many women and their families the chance to reduce the monthly disruption to their lives that occurs with PMSIPMDD.

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