Review of fluoxetine and its clinical applications in premenstrual dysphoric disorder

Drug Evaluation

2002 © Ashley Publications Ltd ISSN 1465-6566 979

Ashley Publicationswww.ashley-pub.com

1. Overview of current

pharmacotherapy

2. Introduction to the compound

3. Chemistry

4. Pharmacology

5. Clinical efficacy

6. Safety and tolerability

7. Pharmacoeconomics

8. Expert opinion

9. Conclusion

Review of fluoxetine and its clinical applications in premenstrual dysphoric disorderTeri Pearlstein† & Kimberly A Yonkers†Women and Infants Hospital, Providence, Rhode Island, USA

The largest number of antidepressant treatment trials in premenstrual syn-drome and premenstrual dysphoric disorder (PMDD) have been conductedwith fluoxetine. Fluoxetine and other selective serotonin re-uptake inhibitors(SSRIs) clearly reduce premenstrual emotional and physical symptoms andimprove premenstrual psychosocial functioning. Fluoxetine was the first SSRIto be approved by the FDA as a treatment for the emotional and physicalsymptoms of PMDD. Fluoxetine 20 mg has been reported to be effective foremotional and physical premenstrual symptoms with continuous daily dosing(every day of the menstrual cycle) and with luteal phase daily dosing (fromovulation to menses). In addition, premenstrual emotional symptoms havebeen reported to improve with fluoxetine 10 mg in luteal phase daily dosingand with 90 mg 2 and 1 weeks prior to menses. Fluoxetine is generally a well-tolerated treatment for PMDD and discontinuation effects have not beenreported with intermittent dosing regimens.

Keywords: fluoxetine, premenstrual dysphoric disorder, premenstrual syndrome, treatment

Expert Opin. Pharmacother. (2002) 3(7):979-991

1. Overview of current pharmacotherapy

Moderate-to-severe premenstrual symptoms occur in 20 – 50% of menstruatingwomen and ~ 5% of women have severe premenstrual symptoms with impairmentin functioning, called premenstrual dysphoric disorder (PMDD) [1]. To meet thePMDD criteria, at least 5 of 11 possible symptoms should be present in the premen-strual phase, with resolution during the first few days of menses, and at least one ofthe five symptoms must be depressed mood, anxiety, mood lability or irritability. Tomeet the PMDD criteria, it is required that a woman prospectively rate her symp-toms daily over two menstrual cycles and impaired premenstrual functioning shouldbe confirmed. The prospective daily symptom charting is necessary to document thetiming and nature of the premenstrual symptoms and to rule out the presence ofchronic medical or psychiatric disorders, such as depression or anxiety disorders,during the follicular phase.

Several treatment studies summarised below have utilised Likert rating scales fordaily symptom charting on which a woman rates her symptoms daily ranging fromno symptoms to severe or extreme symptoms. Examples of six-point Likert scales(0 = none, 6 = extreme) include the Daily Record of Severity of Problems (DRSP) [2],the Daily Rating Form (DRF) [3], the Daily Assessment Form (DAF) [4] and the Pre-menstrual Assessment Form (PAF) [5]. Other Likert scales used in treatment studiesinclude the Penn Daily Symptom Report (DSR) [6], the Prospective Record of theImpact and Severity of Menstrual Symptoms (PRISM) [7] and the Calendar of Pre-menstrual Experiences (COPE) [8]. Other treatment studies have used a visual ana-logue scale (VAS), a 100 mm line on which a subject rates her symptoms each daybetween anchor points ranging from no symptoms (0 mm) to severe or extremesymptoms (100 mm) [9]. Various scoring methods of the daily symptom recordingscompare the average of symptom scores of the symptomatic premenstrual luteal days

Fluoxetine

980 Expert Opin. Pharmacother. (2002) 3(7)

to the average of symptom scores of the postmenstrual follicu-lar days. In order to confirm the PMDD diagnosis, significantfollicular symptoms need to be absent and a minimum pre-menstrual severity level is usually required.

Abnormalities of the hypothalamic–pituitary–gonadal hor-mones have not been identified in women with PMDD [10].Schmidt and colleagues have proposed that women withsevere PMS and PMDD have a differential sensitivity to nor-mal gonadal steroid fluctuations in each cycle [11]. The specif-ics of this differential sensitivity are unknown but it is likely toinvolve neurotransmitters, particularly serotonin and neuros-teroids. Involvement of the γ-aminobutyric acid (GABA) sys-tem is suggested by decreased premenstrual GABAA receptorsensitivity and altered premenstrual allopregnanolone (ananxiolytic metabolite of progesterone that acts at the GABAAreceptor) levels in some studies of women with PMDD com-pared to controls [12,13]. Abnormal calcium [14], noradrenal[15], melatonin and circadian [16] system functioning have alsobeen seen in women with PMDD.

Abnormalities of the serotonin system are consistently dem-onstrated in women with PMDD compared to women with-out PMDD [12,17-20]. These abnormalities include abnormallevels of whole blood serotonin, serotonin platelet uptake andtritiated imipramine binding, exacerbation of premenstrualsymptoms after tryptophan depletion and abnormal responsesto serotonergic probes, such as buspirone, meta-chlorophenyl-piperazine, L-tryptophan and fenfluramine. Selective serotoninre-uptake inhibitor (SSRI) efficacy in treatment trials has usu-ally been evident by the completion of the first treatmentcycle, indicating a more rapid onset of action compared to the3 – 6 weeks noted in major depressive disorder (MDD). It hasbeen postulated that this rapid action may be due in part toSSRIs increasing allopregnanolone levels, thus increasingGABA as well as serotonin transmission [21,22].

Serotonin dysfunction in PMDD is further suggested bythe consistent efficacy of SSRIs. With the exception of oneolder treatment study with fluvoxamine that did not confirmthe diagnosis of PMDD with daily symptom ratings [23], allcontrolled and open trials of SSRIs have reported efficacy inthe treatment of severe PMS and PMDD. Overall, SSRI tri-als report a 60 – 70% efficacy rate compared to an ~ 30%efficacy rate with placebo. A recent meta-analysis of 15 ran-domised, double-blind, placebo-controlled trials of SSRIs insevere PMS and PMDD reported a 6.91 odds ratio in favourof SSRIs over placebo [24]. This meta-analysis included stud-

ies with continuous daily dosing of SSRIs and studies withluteal phase (ovulation to menses) dosing of SSRIs and theefficacy of daily and luteal phase SSRI dosing was equivalent.Most SSRI studies have been conducted with fluoxetine andthese studies are reviewed below. In addition, positive effi-cacy has been reported in randomised, controlled trials(RCTs) with continuous sertraline [25,26], luteal phase sertra-line [27-30], continuous paroxetine [31] and continuous andluteal phase citalopram [32].

SSRIs have been reported to have a differential superiorityover non-serotonergic antidepressants and placebo in threeRCTs [26,31,33]. Other medications that enhance serotoninhave been reported to decrease premenstrual symptoms, suchas continuous [34] and luteal phase [35] clomipramine, venla-faxine [36], L-tryptophan [37], D-fenfluramine [38] and bus-pirone [39]. Serotonergic agents appear to have a unique andrapid action in reducing premenstrual irritability and dyspho-ria [40]. SSRIs are now considered to be the first-line treatmentfor severe PMS and PMDD [41,42]. There is also an alternativeor adjunctive role for other treatments, such as hormonalmedications, anxiolytics, calcium, nutritional strategies andcognitive therapy in the treatment of PMS and PMDD butthe evidence-based literature for these treatments is muchsmaller than for SSRIs [43,44].

2. Introduction to the compound

Fluoxetine hydrochloride (Sarafem™, Eli Lilly) is a SSRIapproved for the treatment of PMDD by the FDA, as well asfor the treatment of depression, obsessive-compulsive disorderand bulimia nervosa.

3. Chemistry

The chemical name of fluoxetine is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-r-tolyl)oxy]propylamine hydrochloride, itsmolecular formula is C17H18F3NO·HCl and its chemicalstructure is shown in Figure 1. Fluoxetine is a racemic mixtureof the R- and S-fluoxetine enantiomers. The S-enantiomer ismore potent than the R-form as a SSRI.

4. Pharmacology

4.1 PharmacodynamicsAs with other SSRIs, the mechanism of action of fluoxetineinvolves the inhibition of the presynaptic serotonin trans-porter, initially decreasing the firing rate of serotonin neuronsbut ultimately making more serotonin available [45,46]. Of thefive SSRIs available in the US, fluoxetine has the lowest affin-ity to serotonin uptake sites [47]. The mechanism of action offluoxetine in PMDD and depression may also involve increas-ing levels of the progesterone metabolite allopregnanolonewhich has anxiolytic effects through the GABAA receptor. Arecent preclinical study indicated that fluoxetine increasedallopregnanolone levels acutely but reduced allopregnanolone

CH2CH2NHCH3.HClOF

F

F

Figure 1. The chemical structure of fluoxetine.

Pearlstein & Yonkers

Expert Opin. Pharmacother. (2002) 3(7) 981

with chronic administration [48]. Fluoxetine has little affinityfor muscarinic, histaminergic or α1-adrenergic receptors.

4.2 Pharmacokinetics and metabolismPeak plasma conentrations of fluoxetine (15 – 55 ng/ml) areseen 6 – 8 h after a single oral 40 mg dose. Administrationwith or without food does not appear to affect bioavailability.Fluoxetine is ~ 94.5% bound to serum proteins in vitro. Eventhough fluoxetine has a wide volume of distribution, its brainto plasma ratio is 2.6:1, lower than for other SSRIs [47]. Fluox-etine exhibits non-linear kinetics and a relationship betweenclinical outcome or adverse events and blood concentrationsof racemic fluoxetine and norfluoxetine has not been identi-fied to date. There is no known correlation between fluoxet-ine and norfluoxetine enantiomers and clinical outcome oradverse effects [47].

Fluoxetine is extensively metabolised in the liver bydemethylation to its active metabolite norfluoxetine and mul-tiple other metabolites. The metabolism of fluoxetine involvesthe hepatic enzymes cytochrome P450 (CYP) 2D6, 3A4 and2C9. The primary route of elimination is hepatic metabolismto inactive metabolites excreted by the kidney. The elimina-tion half-life of fluoxetine is 1 – 3 days after acute administra-tion and 4 – 6 days after chronic administration. Theelimination half-life of norfluoxetine is 4 – 16 days after acuteor chronic administration. Steady-state levels are usuallyreached in 4 – 5 weeks but may take longer [47].

5. Clinical efficacy

5.1 Intermittent fluoxetine treatment studiesA large multi-centre study comparing luteal phase fluoxetine10 and 20 mg/day and placebo is in press (Table 1) [49]. Thediagnosis of PMDD was determined by DRSP ratings overtwo screening cycles. After a single-blind placebo cycle,260 women who continued to meet criteria for PMDD wererandomly assigned to fluoxetine 10 or 20 mg/day (both n =86) or placebo (n = 88), administered from ovulation to men-ses for three cycles, followed by a one-cycle, single-blind pla-cebo cycle. Fluoxetine 20 mg/day was superior to placebo inreducing the mean luteal DRSP total score (p = 0.005), moodsymptoms (p = 0.001), physical symptoms (p = 0.002) andsocial functioning items (p = 0.021) compared to baseline.Fluoxetine 10 mg/day was superior to placebo in reducing themean luteal DRSP mood (p = 0.004) and social functioningitems (p = 0.033) but not the physical symptom items or thetotal DRSP score, compared to baseline. Significant improve-ments from baseline to treatment end point were noted on thePremenstrual Tension Scale – Clinician Rated (PMTS-C) [50]

with fluoxetine 10 and 20 mg compared to placebo (p = 0.003and 0.043, respectively) [Data on file, Eli Lilly]. Althoughspontaneous reports of decreased libido were significantlymore common with fluoxetine than with placebo (p < 0.007),analysis of the change from follicular phase baseline to endpoint of the Arizona Sexual Experience Scale (ASEX) [51] total

scale score and individual item scores did not show statisticallysignificant differences between the two fluoxetine doses or pla-cebo [Data on file, Eli Lilly]. Significantly more placebo-treated patients reported accidental injury than fluoxetine-treated subjects. Otherwise there were no statistically signifi-cant differences between the treatment groups for any adverseevents reported by ≥ 5% of subjects or adverse events leadingto discontinuation [Data on file, Eli Lilly]. Thus, the results ofthis study suggested that luteal phase fluoxetine 20 mg/daywas superior to placebo in reducing premenstrual emotionaland physical symptoms and improving functioning. Lutealphase fluoxetine 10 mg/day was helpful for decreasing emo-tional symptoms and improving functioning but not forreducing premenstrual physical symptoms.

The only other published study of luteal phase daily dosingof fluoxetine was an earlier open study that compared lutealphase with continuous fluoxetine (both at 20 mg/day) in48 women with PMDD diagnosed by daily ratings with thePRISM [52]. Women were assigned to continuous or lutealphase (both n = 24) fluoxetine dosing. Women with a priorhistory of affective disorder or substance abuse were assignedto continuous dosing and women with no prior psychiatrichistory were assigned to luteal phase dosing. A total of 75% ofthe women on luteal phase dosing and 67% of the women oncontinuous dosing were rated as responders, defined as > 75%improvement in luteal mood symptoms on the PRISM com-pared to baseline. The most frequently reported side effectswere nausea, insomnia, muscle pain/stiffness and headache,occurring in 21% of the women in the luteal phase dosinggroup and 38% of the women in the continuous dosinggroup. The results of this comparative, non-randomised studysuggested that continuous and luteal phase dosing of fluoxet-ine were equally effective.

Another large, multi-centre trial has recently been pub-lished examining the efficacy of the 90 mg formulation offluoxetine in 247 women with PMDD [53] (Table 1). Subjectswith PMDD diagnosed by DRSP ratings who did notrespond to one cycle of single-blind placebo were randomisedto fluoxetine 90 mg administered 14 and 7 days before menses(n = 84), placebo 14 days before menses and fluoxetine 90 mg7 days before menses (n = 83) or placebo 14 and 7 days beforemenses (n = 80) for three menstrual cycles. Analysis of thechange in the mean luteal DRSP total score over the threetreatment cycles from baseline, indicated that the dosing 14and 7 days prior to menses was superior to both 7 days beforemenses (p = 0.022) and to placebo (p = 0.043), whereas dos-ing 7 days before menses was not superior to placebo. Fluoxet-ine 90 mg dosed twice in the luteal phase was also significantlysuperior to placebo on PMTS-C score (p = 0.003), ClinicalGlobal Impression-Severity scale (CGI-S) (p = 0.006) [54],DRSP mood symptom cluster (p = 0.009), DRSP functioningitems (p = 0.035) and the work, family life and social lifescores of the Sheehan Disability Scale [55] (all p < 0.05). Therewere no statistically significant differences between fluoxetine90 mg dosed 7 days before menses and placebo on any of these

Fluoxetine


measures. Neither dosing regimen of fluoxetine was superiorto placebo at improving the DRSP physical symptoms items.Adverse events reported by > 10% of subjects on either regi-men of fluoxetine included nausea, headache and insomnia.Nausea and diarrhoea were significantly more associated withfluoxetine than placebo, while breast pain and infection weresignificantly more associated with placebo than fluoxetine.Thus, the results of this study suggested that fluoxetine 90 mg

14 and 7 days prior to expected menses improved premen-strual emotional symptoms and functioning but not physicalsymptoms. Fluoxetine 90 mg administered 7 days prior tomenses was no more effective than placebo.

5.2 Continuous treatment fluoxetine studiesThree early open studies with women with prospectively-con-firmed PMS, each with 10 subjects, suggested that fluoxetine

Table 1. Randomised, controlled fluoxetine trials in PMS and PMDD.

Study Study design Measures Key findings Ref.

Cohen et al. (In Press)

DBPC, parallelLuteal dosing1 cycle SB placebo, 2 cycles fluoxetine 10 or 20 mg/day (both n = 86) or placebo (n = 88)1 cycle SB placebo

DRSP, PMTS

Luteal phase fluoxetine 20 mg/day superior to placebo on mean total DRSP (p = 0.005), DRSP mood items (p < 0.001), DRSP physical symptoms (p < 0.002), DRSP functioning items (p < 0.05) and PMTS (p < 0.05)

[49]

Miner et al. (2002)

DBPC, parallelDosing 2 and 1 weeks prior to menses1 cycle SB placebo3 cycles fluoxetine 90 mg 2 and 1 weeks prior to menses (n = 84), fluoxetine 90 mg 1 week prior to menses (n = 83) or placebo (n = 80)1 cycle SB placebo

DRSP, PMTS, CGI

Fluoxetine 90 mg 2 and 1 weeks prior to menses superior to placebo on mean total DRSP (p < 0.05), DRSP functioning items (p < 0.05), PMTS (p < 0.05), CGI-S (p < 0.05) but not physical symptomsFluoxetine 90 mg 1 week prior to menses not superior to placebo

[53]

Steiner et al. (1995)

DBPC, parallel2 cycles SB placebo6 cycles fluoxetine 20 or 60 mg/day (n = 96 and 86, respectively) or placebo (n = 95)

VAS Both doses of fluoxetine superior to placebo cycles 1 – 6 in reducing mean VAS of irritability, dysphoria, tension (p < 0.001)≥ 50% reduction in mean VAS of irritability, dysphoria, tension by first cycle in 52% fluoxetine (both doses) vs. 25% placebo (p < 0.001)

[61]

Wood et al. (1992)

DBPC, crossover3 cycles each of fluoxetine 20 mg/day and placebo (n = 8)

COPE Fluoxetine superior to placebo on reducing luteal total (p < 0.005), behavioural (p < 0.005) and physical (p < 0.05) COPE scores compared to baseline

[64]

Menkes et al. (1993)

DBPC, crossover12 day washout between 3.5 cycles each of fluoxetine 20 mg/day and placebo (n = 16)

DRF, PAF Fluoxetine superior to placebo on reducing 8 of 10 DRF symptoms (p < 0.03)Fluoxetine decreased 16 of 18 PAF subscales (p < 0.001) compared to baseline

[66]

Su et al. (1997)

DBPC, crossover1 cycle washout after 3 cycles each of fluoxetine 20 – 60 mg/day and placebo (n = 17)

DRF, VAS Fluoxetine superior to placebo on 10 of 13 DRF symptoms (p < 0.01) compared to baselineFluoxetine superior to placebo and baseline on VAS mood and social impairment (p < 0.01)

[67]

Ozeren et al. (1997)

DBPC, parallel3 cycles fluoxetine 20 mg/day (n = 15) or placebo (n = 15)

COPE 12 of 15 fluoxetine patients vs. 4 of 15 placebo patients had end-point luteal COPE < 40 (p < 0.009)End-point luteal COPE decreased 58% with fluoxetine vs. 23% with placebo compared to baseline (p < 0.0001)

[68]

Stone et al. (1991)

DBPC, parallel1 cycle SB placebo2 cycles fluoxetine 20 mg/day or placebo (both n = 10)

DRF, GAS 9 of 10 fluoxetine patients vs. 2 of 10 placebo patients had ≥ 50% decrease in mean luteal DAF compared to baseline (p < 0.0003)Higher luteal GAS in fluoxetine group vs. placebo (p < 0.009)

[69]

Pearlstein et al. (1997)

DBPC, parallel1 cycle SB placebo2 cycles fluoxetine 20 mg/day (n = 10), bupropion 300 mg/day (n = 12) or placebo (n = 10)

CGI, GAS Fluoxetine superior to bupropion (p < 0.005) and placebo (p < 0.001) in number of responders (CGI = 1 or 2)Higher luteal GAS in fluoxetine group vs. placebo (p < 0.05)

[33]

CGI: Clinical global impression; COPE: Calendar of premenstrual experiences; DBPC: Double-blind, placebo-controlled; DRF: Daily rating form; DRSP: Daily record severity of problems; GAS: Global assessment scale; PAF: Premenstrual assessment form; PMTS: Premenstrual tension syndrome; SB: Single-blind; VAS: Visual-analogue scale.



20 mg/day was helpful for reducing premenstrual symptoms[56-58]. A RCT with fluoxetine 10 mg/day reported efficacybut the method of diagnosis of PMS was not specified anddaily ratings were not obtained [59]. There have been sevenpublished randomised, double-blind, placebo-controlled,continuous-dosing fluoxetine trials [18,60]. Six of these trialseach involved < 35 subjects and one study was a large multi-centre trial (Table 1).

In the large multi-centre trial, Steiner and colleagues uti-lised VAS ratings to confirm the diagnosis of PMDD [61].Subjects who did not respond to two single-blind placebocycles were randomised to fluoxetine 20 or 60 mg/day or pla-cebo in a parallel design for six menstrual cycles. At least onetreatment cycle was completed by 277 women and180 women completed the 6-month trial. The primary treat-ment outcome measure was the percentage of change frombaseline in the mean of the luteal VAS scores of dysphoria,irritability and tension. Analysis of this outcome measuredemonstrated that both doses of fluoxetine were significantlysuperior to placebo by the first cycle (p < 0.001) and througheach of the six treatment cycles (p < 0.001). By the end of thefirst cycle, 52% of women receiving either dose of fluoxetinecompared to 22% of subjects receiving placebo were moder-ately improved (p < 0.001), defined as at least 50% reductionin the mean of the three luteal VAS scores from baseline. ThePMTS self- and clinician-rated total scores showed the superi-ority of both doses of fluoxetine over placebo at the end of thefirst cycle compared to baseline (each p < 0.001) and thePMTS scales correlated well with VAS ratings [62]. Both dosesof fluoxetine improved premenstrual bloating and breast ten-derness but not headaches, although the mechanism underly-ing SSRI efficacy on physical symptoms is not clear [61,63].Increased side effects were noted with fluoxetine 60 versus20 mg/day or placebo (both p < 0.001), including insomnia,nausea, tremor, fatigue, dizziness, anorexia and somnolence.The results of this multisite study largely contributed to theFDA approval of fluoxetine 20 mg/day for the treatment ofemotional and physical symptoms of PMDD. This multi-centre study is the longest acute phase treatment study con-ducted in PMDD to date.

Three of the smaller continuous-phase fluoxetine trials uti-lised a crossover design. Wood and colleagues conducted asmall study using the COPE as the assessment and treatmentoutcome measure [64]. Eight women who met criteria for lateluteal phase dysphoric disorder (LLPDD), the Diagnostic andStatistical Manual III (Revised) [65] diagnosis for PMDD,were randomised to fluoxetine 20 mg/day or placebo for threecycles and then crossed-over to the other treatment for threecycles. Seven of the eight subjects improved on fluoxetine,with a 62% decrease in the mean luteal total COPE score.The mean luteal total (p < 0.005), behavioural (p < 0.005)and physical (p < 0.05) COPE scores were significantly moreimproved with fluoxetine than with placebo compared toluteal baseline scores. The frequency of follicular phase COPEsymptoms (dizziness, headache, insomnia and nausea) that

were similar to potential side effects were not significantly dif-ferent between fluoxetine and placebo groups.

Menkes and colleagues conducted a crossover trial utilisingthe PAF and the DRF to diagnose LLPDD and monitor treat-ment outcome [66]. Sixteen women with LLPDD were ran-domly assigned to receive fluoxetine 20 mg/day or placebo for3.5 cycles, followed by a 12-day washout, followed by crosso-ver to the other treatment condition for an additional3.5 cycles. Fluoxetine significantly improved 17 of 18 PAFsubscale scores (16 subscales p < 0.005, one subscale p < 0.03)while placebo improved 5 of 18 subscale scores (two subscalesp < 0.005, three subscales p < 0.03) compared to baseline.Fluoxetine was also significantly more effective than placeboon 8 of 10 DRF symptom scores (p < 0.03). The side effects ofnausea, insomnia, sweating and menstrual disturbances weresignificantly more associated with fluoxetine than placebo.

Su and colleagues compared flexible-dose fluoxetine to pla-cebo in a crossover study [67]. The diagnosis of PMDD wasdetermined in 17 subjects by DRF ratings and VAS ratings ofdepression, irritability and anxiety for three baseline cycles. Eli-gible subjects were then randomised to flexible-dose fluoxetine(20 – 60 mg/day) or placebo for three cycles, followed by a onecycle washout, followed by three cycles of the other treatment.The mean dose of fluoxetine was 30 ± 11 mg/day. Based onDRF ratings, fluoxetine significantly improved most PMDDsymptoms (depression, anxiety, irritability, mood lability, workinefficiency, social isolation, impulsiveness, food cravings,breast pain and bloating) compared to placebo and baseline(both p < 0.01). Fluoxetine was also superior to placebo andbaseline based on composite VAS mood ratings and socialimpairment ratings (both p < 0.01). Sexual dysfunction wassignificantly more associated with fluoxetine than placebo.

Three of the smaller continuous-phase fluoxetine trials uti-lised a parallel design. Ozeren and colleagues used daily rat-ings on the COPE to diagnose PMDD and monitor response,with response defined as a COPE score of < 40 [68]. Eligiblesubjects were randomised to fluoxetine 20 mg/day or placeboin a parallel design for three cycles. Twelve of 15 subjects whoreceived fluoxetine were responders compared to 4 of 15 sub-jects who received placebo (p < 0.009). Compared to baselineluteal total COPE scores, the end-point luteal total COPEscores decreased by 58% in subjects receiving fluoxetine com-pared to 23% in subjects receiving placebo (p < 0.0001). Twosubjects discontinued the study due to nausea and rash withfluoxetine. Five of the remaining subjects had mild, transientside effects with fluoxetine consisting of gastrointestinal irrita-bility, insomnia and sexual dysfunction.

Stone and colleagues compared fluoxetine and placebo in20 women with LLPDD confirmed with two cycles of DAFratings [69]. Women who continued to meet criteria forLLPDD after an initial single-blind placebo cycle were ran-domised to fluoxetine 20 mg/day or placebo in a paralleldesign for two treatment cycles. Treatment response wasdefined as a ≥ 50% decrease in the mean luteal symptomDAF score compared to baseline. Nine of 10 subjects who

Fluoxetine


received fluoxetine were responders, compared to 2 of 10subjects who received placebo (p < 0.0003). Significant supe-riority of fluoxetine over placebo was noted on luteal GlobalAssessment Scale scores (GAS) [70] compared to baseline(p < 0.009) and on each daily rating LLPDD item(p < 0.02). Approximately half of the subjects in each grouphad mild, transient side effects that did not lead to treatmentdiscontinuation. Women on fluoxetine reported fatigue,decreased appetite, insomnia and difficulty achieving orgasm;women on placebo reported headache, sleep disturbance,decreased energy, anxiety, breast tenderness, nausea andincreased appetite.

Pearlstein et al. expanded this research design in a subse-quent study comparing fluoxetine with bupropion, a non-sero-tonergic antidepressant and placebo [33]. Thirty-four womenwho continued to meet LLPDD criteria based on DAF ratingsafter an initial single-blind placebo cycle were randomised tofluoxetine 20 mg/day, bupropion 100 mg t.i.d or placebo in aparallel design for two treatment cycles. Treatment responsewas monitored with the CGI-Improvement scale and theHamilton Rating Scale for Depression (HRSD) [71]. Definingresponders as having a CGI-Improvement scale score of 1 or 2(much or very much improved), fluoxetine was significantlysuperior to placebo (p < 0.001) and bupropion (p < 0.005) andbupropion was not superior to placebo. Fluoxetine was also sig-nificantly superior to placebo based on end-point luteal GAS(p < 0.05) and on end-point luteal modified HRSD ratings(p < 0.05) compared to luteal baseline ratings. Transient, mildside effects included decreased libido, rash, fatigue, insomniaand palpitations with fluoxetine; headache, insomnia, dizzi-ness, dry mouth, constipation and agitation with bupropion;and headache, dry mouth and delayed orgasm with placebo.This study corroborated the results from a previous study [31]

that SSRIs were selectively effective for PMS and PMDD com-pared to non-serotonergic antidepressants.

5.3 Long-term fluoxetine treatmentThe optimal length of treatment with SSRIs and recurrencerates of PMDD with discontinuation of SSRIs needs system-atic study. After 3 months of luteal phase fluoxetine 10 and20 mg/day, mean total DRSP ratings increased during thepost-treatment single-blind placebo cycle, leading to loss ofsignificant differences between fluoxetine and placebo [49]. Itis unclear if long-term maintenance treatment offers protec-tion from recurrence for some women. Two open trials havesuggested that the efficacy of fluoxetine is maintained over thelong-term. Pearlstein and colleagues followed 60 women withLLPDD over a mean of 18.6 months and all women main-tained their response as determined by the CGI [72]. All21 subjects who discontinued fluoxetine after ≥ 1 year oftreatment had a recurrence of premenstrual symptoms withinthree cycles, most notably irritability and anxiety. Anotherstudy conducted a 1-year follow-up of women who hadreceived 6 months of fluoxetine and compared those womenwho had continued on fluoxetine 20 mg/day and women who

had discontinued fluoxetine [73]. Based on CGI ratings,women who had continued fluoxetine had maintained greatersymptom relief than those who had discontinued fluoxetine.

6. Safety and tolerability

6.1 General tolerability of fluoxetineMeta-analyses and reviews of studies have reported thatSSRIs are significantly associated with fewer side effects andless discontinuation due to side effects than tricyclic antide-pressants (TCAs) [74-76]. A recent meta-analysis of 1258 sub-jects who received fluoxetine 20 mg/day for depressionindicated that the most common events (in at least 2% ofsubjects) leading to discontinuation were asthenia, dizziness,insomnia, nausea, nervousness, somnolence and tremor [75].In general, reviews of studies of side effects in SSRIs havesuggested that small differences exist between the SSRIs andthe side effects with fluoxetine and other SSRIs decrease overtime [77]. One review reported that fluoxetine may have thelowest number of spontaneously reported side effects [76],while another review suggested that fluoxetine may be moreassociated with agitation, anxiety, nervousness, akathisia,sleep disturbances and rash and less associated with GI sideeffects than other SSRIs [78].

6.2 Adverse events with fluoxetineAdverse effects in each of the reviewed fluoxetine PMDDtreatment trials have been listed above. Treatment-emergentadverse events reported by at least 5% of women with PMDDtaking fluoxetine 20 mg/day included anxiety, nervousness,dizziness, insomnia, concentration difficulties, nausea, head-ache, asthenia, pain, accidental injury, infection, rhinitis,pharyngitis and > 7% weight gain or loss [Sarafem™ (fluoxe-tine hydrochloride) package insert 7-11-00. Eli Lilly].

Since women with severe PMS and PMDD may take SSRIsfor a number of years, the long-term side effects of sexual dys-function and weight gain can be troublesome and lead tonon-compliance [79]. Unlike the treatment of MDD, whereswitching to an antidepressant less associated with sexual dys-function or weight gain can be helpful, women with severePMS and PMDD obtain maximal symptomatic relief from aserotonergic antidepressant and alternative serotonergic anti-depressants may similarly be associated with sexual dysfunc-tion and weight gain. The lack of effective treatment optionsfor sexual dysfunction and weight gain make the long-termSSRI treatment of PMDD problematic for women who havethese side effects.

6.3 Sexual dysfunctionRecent reviews of studies of sexual dysfunction with antide-pressants identify several methodological complications, suchas the under-reporting of sexual problems unless directly elic-ited, the failure to ascertain premorbid level of sexual func-tioning, the contribution of depression to sexual dysfunctionand the failure of systematic assessment of sexual functioning



before and after treatment [80,81]. It has been hypothesised thatSSRIs can affect the libido, arousal and orgasm aspects of sex-ual functioning by decreasing dopamine and noradrenalinethrough stimulation of serotonin 5-HT2 receptors, by increas-ing prolactin levels or by decreasing nitric oxide activity butthese possible mechanisms need further study [82-84]. Rates ofsexual dysfunction with fluoxetine has ranged widely in openand controlled trials from 4 – 75% [80].

In a large prospective, open-label trial of antidepressantsconducted on 1022 out-patients with various axis I disorders,sexual dysfunction was reported in 57.7% of 279 subjects onfluoxetine, 62.9% of 159 subjects on sertraline, 62.3% of77 subjects on fluvoxamine, 70.7% of 208 subjects on paroxe-tine, 72.7% of 66 subjects on citalopram and 67.3% of55 subjects on venlafaxine [85]. A previous smaller, open-labelstudy in 42 out-patients with depression, some with comorbidobsessive-compulsive disorder, reported that fluoxetine wasnon-significantly associated with less sexual dysfunction thanparoxetine or sertraline and some aspects of sexual functionimproved with each of the SSRIs [86]. Entry criteria in both ofthese open trials included the absence of sexual dysfunctionprior to starting the antidepressant. A recent controlled studyrandomised 456 out-patients with recurrent MDD to flexible-dose fluoxetine, flexible-dose bupropion SR or placebo in aparallel design for 8 weeks [87]. Fluoxetine and bupropion wereequally effective and tolerated but fluoxetine was significantlymore associated with orgasm dysfunction (p < 0.001),decreased libido (p < 0.05) and decreased arousal (p < 0.05)than bupropion. Thus, most studies suggest that sexual dys-function is a common and problematic side effect with each ofthe SSRIs and a few studies suggest that fluoxetine may beassociated with somewhat less sexual dysfunction than theother available SSRIs. No specific antidote or augmentationstrategy for sexual dysfunction has clear efficacy [84].

The incidence of sexual dysfunction in women withPMDD is unknown and both increased and decreased libidohas been described as premenstrual changes in women. In theluteal phase fluoxetine PMDD study, spontaneous reports ofdecreased libido were significantly more common with fluox-etine than placebo (p < 0.007) [49]. Yet, analysis of the changefrom follicular phase baseline to end point of the total scalescore and individual item scores of the ASEX did not showstatistically significant differences among fluoxetine 10 or20 mg/day and placebo. The assessment of changes in sexualfunction with SSRI treatment in PMDD needs systematicstudy. For women who do report sexual dysfunction withSSRIs, luteal phase dosing may be advantageous compared tocontinuous dosing but this also needs systematic study.

6.4 Weight gainWeight gain is a potential long-term side effect of SSRIs thatcan decrease a patient’s quality of life and compliance, can bedifficult to treat and can potentially cause or exacerbate medi-cal illness. The aetiology of weight gain with SSRIs isunknown but it may involve changes in the autonomic nerv-

ous system control of energy metabolism, changes in serot-onin 5-HT2C receptor activity, increased appetite andcarbohydrate craving or changes in neuropeptide Y or leptinsystems [83,88-90]. As reviewed, studies of weight gain withSSRIs are confounded by the measurement of body weightrather than body mass index, failure to assess baseline weightor premorbid weight, failure to monitor the effect of illness onweight and failure to monitor concomitant medications orsubstance use [90].

In the short-term, SSRIs are generally associated withweight loss [88]. Two recent long-term trials indicate thatfluoxetine is not significantly associated with weight gain. Inone study, 395 patients who had recovered from majordepression with fluoxetine 20 mg/day were randomly assignedto receive fluoxetine or placebo for up to 50 weeks [91]. After26 total weeks of treatment, 4.8% of 293 patients on fluoxet-ine had at least a 7% increase in body weight compared to6.3% of 95 patients on placebo. At 50 weeks of treatment,13.2% of 197 subjects on fluoxetine had gained at least 7% ofbody weight, compared to 7.4% of 95 subjects on placebo,which was non-significant. In another study 284 subjects withMDD were randomised to a flexible-dose titration of fluoxet-ine, sertraline or paroxetine and subjects treated with fluoxet-ine demonstrated a non-significant mean decrease in weightof -0.2% compared to a mean increase of weight of 1% withsertraline and 3.6% with paroxetine after 26 – 32 weeks oftreatment [92]. It was also noted that a ≥ 7% increase in bodyweight occurred significantly more with paroxetine (25.5%)than with fluoxetine (6.8%) or with sertraline (4.2%) after26 – 32 weeks of treatment.

Fluoxetine appears to induce weight loss acutely and doesnot lead to problematic weight gain in the long-term for mostpatients. However, for a minority of patients, > 7% of weightmay be gained, which is difficult to lose after fluoxetine is dis-continued. Nutritional approaches, regular exercise andbehavioural techniques can be helpful and possible augmenta-tion strategies deserve further study [88,90]. The PMDD treat-ment trials to date have been 3 – 6 months in length and thereare no published reports of the long-term effect of SSRIs onweight in women with PMDD. For women with PMDDwho do gain weight on SSRIs over the long-term, luteal phasedosing may offer an advantage compared to continuous dos-ing but this potential advantage requires systematic study.

6.5 Discontinuation effectsCommon SSRI discontinuation effects include dizziness, par-esthesias, tremor, anxiety, nausea and palpitations and thesesymptoms may be secondary to downregulated serotoninreceptors or involvement of other neurotransmitter systems[76,93]. Many antidepressant studies have not systematicallymonitored symptoms following discontinuation of medica-tion and potential discontinuation effects are important sincethey may contribute to non-compliance or be mistaken forrecurrence of depressive symptoms [94]. Reviews indicate thatfluoxetine is associated with fewer discontinuation effects

Fluoxetine


than other SSRIs, presumably due to the long half-lifes offluoxetine and norfluoxetine [76,94].

The issue of SSRI discontinuation is particularly importantin women with PMDD. No SSRI treatment studies inPMDD have systematically monitored discontinuation effectsfollowing medication use. Women with PMDD who takeSSRIs during the luteal phase only are discontinuing the SSRIabruptly each month at the onset of menses. To date, the pub-lished luteal phase trials have studied luteal phase dosages upto fluoxetine 20 mg/day, sertraline 100 mg/day and citalo-pram 30 mg/day. There have been no reports of adverseeffects following discontinuation of these dosages at menses.It is possible that abrupt discontinuation of higher SSRI lutealphase dosages would lead to discontinuation symptoms neces-sitating tapering over the first few days of menses. Futurestudies should address discontinuation effects and considerthe potential confusion between discontinuation symptomsand recurrence of premenstrual symptoms.

6.6 Drug-drug interactionsThe metabolism of both fluoxetine enantiomers and of S-nor-fluoxetine depend on CYP2D6. Poor metabolisers or patientswith CYP2D6 deficiency can have adverse drug interactionsdue to high serum levels of fluoxetine and S-norfluoxetine[47,78]. Fluoxetine can potentially cause increased levels ofother medications metabolised by CYP2D6, such as TCAs,neuroleptics, paroxetine, β-blockers and some antiarrhythmicagents. Increased levels of thioridizine can potentially lead toserious ventricular arrhythmias and these two medicationsshould not be coadministered. Fluoxetine may also potentiallycontribute to increased levels of alprazolam, carbamazepine orcalcium channel blockers through its inhibitory effect onCYP3A4 and to increased levels of phenytoin through itsinhibition of CYP2C9. The inhibition of the metabolism ofother medications by fluoxetine is often not of clinical signifi-cance but the potential interaction exists and should be keptin mind by the clinician [95,96]. MAOIs should not be useduntil 5 weeks after fluoxetine has been stopped and fluoxetineshould not be used until two weeks after MAOIs have beenstopped due to potential serious reactions from their combi-nation [Sarafem™ (fluoxetine hydrochloride) package insert7-11-00. Eli Lilly].

6.7 Pregnancy and breastfeedingSince PMDD occurs during the reproductive years and > 50%of pregnancies are unplanned, many women with PMDDconceive while on SSRIs. Several reviews of studies suggest thatfirst trimester exposure to fluoxetine does not increase the riskof spontaneous abortion, congenital major malformations,premature birth or serious postnatal complications [76,97-99].The database of published reports of exposure during preg-nancy is larger for fluoxetine than all of the other SSRIs com-bined. There have been some reports of increased transientneonatal complications [100,101] and neonatal toxicity (irritabil-ity, increased muscle tone, crying) [102-105] with exposure to

third trimester fluoxetine and some researchers suggest consid-eration of decreasing fluoxetine prior to delivery [99]. Onelong-term controlled study reported an absence of neurobe-havioural developmental problems up to 86 months of age inthe offspring of mothers who took fluoxetine during preg-nancy [106]. Postpartum women with prior PMDD oftenchoose to restart SSRI treatment when menses resume andsome of these women may still be breastfeeding. There havebeen a few cases reported of somnolence, hypotonia [107], colic,poor sleep [108], irritability and poor feeding [109] in infants ofmothers who are breastfeeding and are taking fluoxetine butbreastfeeding infants of mothers taking fluoxetine generally donot have negative effects [110,111].

6.8 Safety in overdoseThere are no published reports of fluoxetine overdose inPMDD. In general, fluoxetine appears to be relatively safe inoverdose, particularly compared to TCAs [95,112,113]. The mostcommon signs and symptoms associated with fluoxetine over-dose are seizures, somnolence, nausea, tachycardia and vomit-ing. Other adverse events that have been reported withoverdose include coma, delirium, QT interval prolongationand ventricular tachycardia, hypotension, mania, neurolepticmalignant syndrome-like events, pyrexia, stupor and syncope.

7. Pharmacoeconomics

Several recent reviews of analyses of retrospective databasesand decision analysis models have established that SSRIs aremore cost-effective treatments than TCAs in the treatment ofMDD. The initial higher drug acquisition costs with SSRIsare offset by decreased healthcare costs, such as physician fees,in-patient and out-patient treatment, laboratory services,other medications and medical costs associated with overdose[114,115]. Reviews have concluded that TCAs and SSRIs areequivalent in efficacy but the decreased healthcare costs andimproved health-related quality of life with SSRIs may alsoresult from improved adherence due to better tolerability, lessswitching to other antidepressants, decreased work absentee-ism and increased long-term maintenance of remission[114,115]. A recent study reported that adherence to recom-mended treatment for depression with fluoxetine was greaterthan adherence to sertraline or paroxetine [116].

There are no reports to date about specific healthcare costsassociated with PMS or PMDD or about adherence to SSRIcontinuous or luteal phase dosing options. Three recent, ran-domly selected community studies using retrospective reportsof PMS have specifically assessed the impact of premenstrualsymptoms on functioning. One study of 1045 women in theUS, UK and France reported that more severe premenstrualsymptoms were associated with increased functional impair-ment [117]. Between 8 – 16% of women missed days of workdue to their PMS and > 50% of women who worked outsideof the home felt that their PMS affected their occupationalfunctioning. Another study of 1022 women in the US deter-



mined that even though relationships with husband and chil-dren were the life domains most burdened by PMS, 20% of allwomen reported missing at least one workday in the prior yearbecause of PMS [118]. The results of this study also suggestedthat the more severe a woman’s premenstrual symptoms are,the more domains of her social and role functioning wereimpaired. A recent study of 1488 women in Germany reportedthat women with PMDD were five times more likely to havepremenstrual impairment of professional and daily activitiesthan women without PMDD [119]. Both decreased premen-strual work productivity, which has not been objectively quan-tified in studies, and premenstrual work absenteeism couldclearly contribute to a pharmacoeconomic impact of PMDD.

A few studies have examined social and role functioning inwomen with prospectively-confirmed PMDD. A study com-paring the luteal phase mean Social Adjustment Scale (SAS)[120] scores of 243 women with PMDD to the SAS scores ofwomen with MDD and dysthymia suggested that womenwith PMDD have a similar degree of functional impairmentduring the premenstrual phase [121]. However, compared tothese other cohorts, PMDD was unique in the greater inter-ference with the marital relationship and parenting role thanwith school or work functioning. As reviewed above, fluoxet-ine has recently been reported to improve premenstrual func-tioning with 10 or 20 mg/day luteal phase dosing on dailyDRSP ratings [49] and with weekly 90 mg dosing administered1 and 2 weeks before menses based on daily DRSP ratings andthe Sheehan Disability Scale [53]. The improvement in pre-menstrual functioning with SSRIs could be of pharmacoeco-nomic benefit but this remains to be studied.

8. Expert opinion

The evidence for the efficacy of continuous, luteal phase andweekly dosing of fluoxetine for PMDD is substantial. Thelong half-life of fluoxetine is advantageous in decreasing thepotential for discontinuation effects with each dosing strategy.Luteal phase dosing is preferred by many women who do notwant to take medication during the asymptomatic follicularphase and it has the potential advantages of financial savings,decreased side effects and decreased fetal exposure if preg-nancy occurs. On the other hand, some women find the

monthly monitoring of the menstrual cycle to identify ovula-tion and the starting of the medication burdensome and theyprefer daily dosing. The administration of the weekly 90 mgfluoxetine dose was helpful when administered 2 and 1 weeksprior to menses but not when administered only 1 week priorto menses. A study of a SSRI administered on symptomaticdays of the luteal phase only (symptom-onset dosing) inwomen with PMDD remains to be conducted. However, thelack of efficacy of fluoxetine 90 mg administered 7 daysbefore menses suggests that symptom-onset dosing may notbe as effective as the administration of SSRIs during ovula-tion, when an unidentified interaction between gonadal hor-monal fluctuations and serotonin may occur.

Psychiatric and medical experts recommend fluoxetine andother SSRIs as first-line treatment for severe PMS andPMDD [41,42]. Despite the clear efficacy of fluoxetine andother SSRIs for PMDD, the potential long-term side effectsof weight gain and reduced sexual interest and enjoyment canlead to decreased quality of life and non-compliance inwomen with PMS and PMDD. Luteal phase dosing may offersome relief from side effects in half of each cycle but weightgain and sexual dysfunction may remain problematic for somewomen with luteal phase dosing as well. The large andincreasing database suggesting safety of fluoxetine duringpregnancy is comforting to women with PMDD who con-ceive while on fluoxetine either with planning or inadvert-ently. Long-term studies of fluoxetine and other SSRIs areneeded in PMDD to confirm that efficacy is maintained long-term and to determine if some women remain asymptomaticfollowing discontinuation of the SSRI.

9. Conclusion

Fluoxetine in continuous and luteal phase 20 mg/day dosing isclearly effective for the emotional and physical symptoms ofPMDD. Recent studies have reported that fluoxetine is alsoeffective for premenstrual emotional symptoms when adminis-tered as 10 mg/day during the luteal phase only or as 90 mg 2and 1 weeks prior to menses. Fluoxetine treatment studies havealso demonstrated improvement of premenstrual social androle functioning in addition to improvement of premenstrualemotional and physical symptoms.

Bibliography

1. AMERICAN PSYCHIATRIC ASSOCIATION: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, American Psychiatric Press, Inc. (1994).

2. ENDICOTT J, HARRISON W: Daily Rating of Severity of Problems Form. Department of Research Assessment and Training, New York State Psychiatric

Institute, New York, NY, USA (1990).

3. ENDICOTT J, NEE J, COHEN J, HALBREICH U: Premenstrual changes: patterns and correlates of daily ratings. J. Affect. Disord. (1986) 10(2):127-135.

4. RIVERA-TOVAR AD, PILKONIS P, FRANK E: Symptom patterns in late luteal-phase dysphoric disorder. J. Psychopathol. Behav. Assess. (1992) 14(2):189-199.

5. HALBREICH U, ENDICOTT J, SCHACHT S, NEE J: The diversity of

premenstrual changes as reflected in the Premenstrual Assessment Form. Acta Psychiatr. Scand. (1982) 65(1):46-65.

6. FREEMAN EW, DERUBEIS RJ, RICKELS K: Reliability and validity of a daily diary for premenstrual syndrome. Psych Res. (1996) 65(2):97-106.

7. REID RL: Premenstrual syndrome. Curr. Probl. Obstet. Gynecol. Fertil. (1985) 8:1-57.

8. MORTOLA JF, GIRTON L, BECK L, YEN SS: Diagnosis of premenstrual

Fluoxetine


syndrome by a simple, prospective, and reliable instrument: the calendar of premenstrual experiences. Obstet. Gynecol. (1990) 76(2):302-307.

9. RUBINOW DR, ROY-BYRNE P, HOBAN MC, GOLD PW, POST RM: Prospective assessment of menstrually related mood disorders. Am. J. Psych. (1984) 141(5):684-686.

10. ROCA CA, SCHMIDT PJ, BLOCH M, RUBINOW DR: Implications of endocrine studies of premenstrual syndrome. Psych. Ann. (1996) 26(9):576-580.

11. SCHMIDT PJ, NIEMAN LK, DANACEAU MA, ADAMS LF, RUBINOW DR: Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N. Engl. J. Med. (1998) 338(4):209-216.

12. SUNDSTROM I, BACKSTROM T, WANG M, OLSSON T, SEIPPEL L, BIXO M: Premenstrual syndrome, neuroactive steroids and the brain. Gynecol. Endocrinol. (1999) 13(3):206-220.

13. GIRDLER SS, STRANEVA PA, LIGHT KC, PEDERSON CA, MORROW AL: Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol. Psych. (2001) 49(9):788-797.

14. THYS-JACOBS S: Micronutrients and the premenstrual syndrome: the case for calcium. J. Am. Coll. Nutr. (2000) 19(2):220-227.

15. PARRY BL: Psychobiology of premenstrual dysphoric disorder. Semin. Reprod. Endocrinol. (1997) 15(1):55-68.

16. PARRY BL, NEWTON RP: Chronobiological basis of female-specific mood disorders. Neuropsychopharmacology (2001) 25(5, Suppl. 1):S102-S108.

17. HALBREICH U, TWOREK H: Altered serotonergic activity in women with dysphoric premenstrual syndromes. Int. J. Psych. Med. (1993) 23(1):1-27.

18. MARCH D, PEARLSTEIN TB, YONKERS KA: Treatment of premenstrual dysphoric disorder. Psychiatr. Clin. North Am. Ann. Drug Ther. (2001) 8:89-108.

19. PARRY BL: The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: therapeutic implications. CNS Drugs (2001) 15(4):277-285.

20. STEINER M, PEARLSTEIN T: Premenstrual dysphoria and the serotonin system: pathophysiology and treatment. J.

Clin. Psych. (2000) 61(Suppl. 12):17-21.

21. GRIFFIN LD, MELLON SH: Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc. Natl. Acad. Sci. USA (1999) 96(23):13512-13517.

22. GUIDOTTI A, COSTA E: Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3 alpha, 5 alpha-tetrahydroprogesterone (allopregnanolone) availability? Biol. Psych. (1998) 44(9):865-873.

23. VEENINGA AT, WESTENBERG HG, WEUSTEN JT: Fluvoxamine in the treatment of menstrually related mood disorders. Psychopharmacology (Berl.) (1990) 102(3):414-416.

24. DIMMOCK PW, WYATT KM, JONES PW, O’BRIEN PM: Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet (2000) 356(9236):1131-1136.

25. YONKERS KA, HALBREICH U, FREEMAN E et al.: Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA (1997) 278(12):983-988.

26. FREEMAN EW, RICKELS K, SONDHEIMER SJ, POLANSKY M: Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch. Gen. Psych. (1999) 56(10):932-939.

27. HALBREICH U, SMOLLER JW: Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. J. Clin. Psych. (1997) 58(9):399-402.

28. FREEMAN EW, RICKELS K, ARREDONDO F, KAO L-C, POLLACK SE, SONDHEIMER SJ: Full- or half-cycle treatment of severe premenstrual syndrome with a serotonergic antidepressant. J. Clin. Psychopharmacol. (1999) 19(1):3-8.

29. JERMAIN DM, PREECE CK, SYKES RL, KUEHL TJ, SULAK PJ: Luteal phase sertraline treatment for premenstrual dysphoric disorder. Arch. Fam. Med. (1999) 8(4):328-332.

30. YOUNG SA, HURT PH, BENEDEK DM, HOWARD RS: Treatment of premenstrual dysphoric disorder with

sertraline during the luteal phase: a randomized, double-blind, placebo-controlled crossover trial. J. Clin. Psych. (1998) 59(2):76-80.

31. ERIKSSON E, HEDBERG MA, ANDERSCH B, SUNDBLAD C: The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome. Neuropsycho-pharmacology (1995) 12(2):167-176.

32. WIKANDER I, SUNDBLAD C, ANDERSCH B et al.: Citalopram in premenstrual dysphoria: is intermittent treatment during luteal phases more effective than continuous medication throughout the menstrual cycle? J. Clin. Psychopharmacol. (1998) 18(5):390-398.

33. PEARLSTEIN TB, STONE AB, LUND SA, SCHEFT H, ZLOTNICK C, BROWN WA: Comparison of fluoxetine, bupropion, and placebo in the treatment of premenstrual dysphoric disorder. J. Clin. Psychopharmacol. (1997) 17(4):261-266.

34. SUNDBLAD C, MODIGH K, ANDERSCH B, ERIKSSON E: Clomipramine effectively reduces premenstrual irritability and dysphoria: a placebo-controlled trial. Acta Psychiatr. Scand. (1992) 85(1):39-47.

35. SUNDBLAD C, HEDBERG MA, ERIKSSON E: Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: a placebo-controlled trial. Neuropsycho-pharmacology. (1993) 9(2):133-145.

36. FREEMAN EW, RICKELS K, YONKERS KA, KUNZ NR, MCPHERSON MK, UPTON GV: Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet. Gyncecol. (2001) 98(5, Part 1):737-744.

37. STEINBERG S, ANNABLE L, YOUNG SN, LIYANAGE N: A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria. Biol. Psych. (1999) 45(3):313-320.

38. BRZEZINSKI AA, WURTMAN JJ, WURTMAN RJ, GLEASON R, GREENFIELD J, NADER T: d-fen-fluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression. Obstet. Gynecol. (1990) 76(2):296-301.

39. LANDEN M, ERIKSSON O, SUNDBLAD C, ANDERSCH B, NAESSEN T, ERIKSSON E: Compounds with affinity for serotonergic receptors in



the treatment of premenstrual dysphoria: a comparison of buspirone, nefazodone and placebo. Psychopharmacology (Berl.) (2001) 155(3):292-298.

40. ERIKSSON E: Serotonin reuptake inhibitors for the treatment of premenstrual dysphoria. Int. Clin. Psychopharmacol. (1999) 14(Suppl. 2):S27-S33.

41. ALTSHULER LL, COHEN LS, MOLINE ML, KAHN DA, CARPENTER D, DOCHERTY JP: The Expert Consensus Guideline Series. Treatment of depression in women. Postgrad. Med. (2001) Spec. No.:1-107.

42. AMERICAN COLLEGE OF OBSTETRICS AND GYNECOLOGY: Premenstrual Syndrome. ACOG Practice Bulletin. American College of Obstetrics and Gynecology, Washington, DC, USA (2000).

43. PEARLSTEIN T, STEINER M: Non-antidepressant treatment of premenstrual syndrome. J. Clin. Psych. (2000) 61(Suppl. 12):22-27.

44. STEVINSON C, ERNST E: Complementary/alternative therapies for premenstrual syndrome: a systematic review of randomized controlled trials. Am. J. Obstet. Gynecol. (2001) 185(1):227-235.

45. BLIER P: Possible neurobiological mechanisms underlying faster onset of antidepressant action. J. Clin. Psych. (2001) 62(Suppl. 4):7-11.

46. STAHL SM: Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J. Clin. Psych. (1998) 59(Suppl. 4):5-14.

47. HIEMKE C, HARTTER S: Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol. Ther. (2000) 85(1):11-28.

48. SERRA M, PISU MG, MUGGIRONI M et al.: Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain. Psychopharmacology. (2001) 158(1):48-54.

49. COHEN LS, MINER C, BROWN E et al.: Premenstrual daily fluoxetine for PMDD: A placebo-controlled, clinical trial using computerized diaries. Obstet. Gynecol. (2002). In Press.

50. STEINER M, HASKETT RF, CARROLL BJ: Premenstrual tension syndrome: the development of research diagnostic criteria and new rating scales. Acta Psychiatr. Scand. (1980) 62(2):177-190.

51. MCGAHUEY CA, GELENBERG AJ, LAUKES CA et al.: The Arizona Sexual Experience Scale (ASEX): reliability and validity. J. Sex Marital Ther. (2000) 26(1):25-40.

52. STEINER M, KORZEKWA M, LAMONT J, WILKINS A: Intermittent fluoxetine dosing in the treatment of women with premenstrual dysphoria. Psychopharmacol. Bull. (1997) 33(4):771-774.

53. MINER C, BROWN E, MCCRAY S, GONZALES J, WOHLREICH M: Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: a randomized, double-blind, placebo-controlled clinical trial. Clin. Ther. (2002) 24(3):417-433.

54. GUY W: ECDEU assessment manual for psychopharmacology. National Institute of Mental Health, US Department of Health, Education and Welfare, Rockville, MD, USA (1976).

55. LEON AC, OLFSON M, PORTERA L, FARBER L, SHEEHAN DV: Assessing psychiatric impairment in primary care with the Sheehan Disability Scale. Int. J. Psych Med. (1997) 27(2):93-105.

56. BRANDENBURG S, TUYNMAN-QUA H, VERHEIJ R, PEPPLINKHUIZEN L: Treatment of premenstrual syndrome with fluoxetine: an open study. Int. Clin. Psychopharmacol. (1993) 8(4):315-317.

57. ELKS ML: Open trial of fluoxetine therapy for premenstrual syndrome. South. Med. J. (1993) 86(5):503-507.

58. RICKELS K, FREEMAN EW, SONDHEIMER S, ALBERT J: Fluoxetine in the treatment of premenstrual syndrome. Curr. Therapeutic Res. (1990) 48(1):161-166.

59. DIEGOLI MS, DA FONSECA AM, DIEGOLI CA, PINOTTI JA: A double-blind trial of four medications to treat severe premenstrual syndrome. Int. J. Gynaecol. Obstet. (1998) 62(1):63-67.

60. ROMANO S, JUDGE R, DILLON J, SHULER C, SUNDELL K: The role of fluoxetine in the treatment of premenstrual dysphoric disorder. Clin. Ther. (1999) 21(4):615-633.

61. STEINER M, STEINBERG S, STEWART D et al.: Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N. Engl. J. Med. (1995) 332(23):1529-1534.

62. STEINER M, STREINER DL, STEINBERG S et al.: The measurement of premenstrual mood symptoms. J. Affect. Disord. (1999) 53(3):269-273.

63. STEINER M, ROMANO SJ, BABCOCK S et al.: The efficacy of fluoxetine in improving physical symptoms associated with premenstrual dysphoric disorder. BJOG (2001) 108(5):462-468.

64. WOOD SH, MORTOLA JF, CHAN YF, MOOSSAZADEH F, YEN SS: Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study. Obstet. Gynecol. (1992) 80(3, Part 1):339-344.

65. AMERICAN PSYCHIATRIC ASSOCIATION: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (Revised). American Psychiatric Press, Inc. Washington, DC, USA (1987).

66. MENKES DB, TAGHAVI E, MASON PA, HOWARD RC: Fluoxetine’s spectrum of action in premenstrual syndrome. Int. Clin. Psychopharmacol. (1993) 8(2):95-102.

67. SU TP, SCHMIDT PJ, DANACEAU MA et al.: Fluoxetine in the treatment of premenstrual dysphoria. Neuropsycho-pharmacology (1997) 16(5):346-356.

68. OZEREN S, CORAKCI A, YUCESOY I, MERCAN R, ERHAN G: Fluoxetine in the treatment of premenstrual syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. (1997) 73(2):167-170.

69. STONE AB, PEARLSTEIN TB, BROWN WA: Fluoxetine in the treatment of late luteal phase dysphoric disorder. J. Clin. Psych. (1991) 52(7):290-293.

70. ENDICOTT J, SPITZER RL, FLEISS JL, COHEN J: The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch. Gen. Psych. (1976) 33(6):766-771.

71. HAMILTON M: A rating scale for depression. J. Neurol. Neurosurg. Psych. (1960) 23:56-62.

72. PEARLSTEIN TB, STONE AB: Long-term fluoxetine treatment of late luteal phase dysphoric disorder. J. Clin. Psych. (1994) 55(8):332-335.

73. DE LA GANDARA MARTIN JJ: Premenstrual dysphoric disorder: long-term treatment with fluoxetine and discont-inuation. Actas Luso Esp. Neurol. Psiquiatr. Cienc. Afines. (1997) 25(4):235-242.

74. ANDERSON IM: Meta-analytical studies on new antidepressants. Br. Med. Bull. (2001) 57:161-178.

Fluoxetine


75. BEASLEY CM JR., KOKE SC, NILSSON ME, GONZALES JS: Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis. Clin. Ther. (2000) 22(11):1319-1330.

76. CALIL HM: Fluoxetine: a suitable long-term treatment. J. Clin. Psych. (2001) 62(Suppl. 22):24-29.

77. ZAJECKA J, AMSTERDAM JD, QUITKIN FM et al.: Changes in adverse events reported by patients during 6 months of fluoxetine therapy. J. Clin. Psych. (1999) 60(6):389-394.

78. GOLDSTEIN BJ, GOODNICK PJ: Selective serotonin reuptake inhibitors in the treatment of affective disorders – III. Tolerability, safety and pharmacoeconomics. J. Psychopharmacol. (1998) 12(3, Suppl. B):S55-S87.

79. SUNDSTROM-POROMAA I, BIXO M, BJORN I, NORDH O: Compliance to antidepressant drug therapy for treatment of premenstrual syndrome. J. Psychosom. Obstet. Gynaecol. (2000) 21(4):205-211.

80. BALDWIN DS: Depression and sexual dysfunction. Br. Med. Bull. (2001) 57:81-99.

81. FERGUSON JM: The effects of antidepressants on sexual functioning in depressed patients: a review. J. Clin. Psych. (2001) 62(Suppl. 3):22-34.

82. ROSEN RC, LANE RM, MENZA M: Effects of SSRIs on sexual function: a critical review. J. Clin. Psychopharmacol. (1999) 19(1):67-85.

83. SUSSMAN N, GINSBERG D: Rethinking side effects of the selective serotonin reuptake inhibitors: sexual dysfunction and weight gain. Psych. Ann. (1998) 28(2):89-97.

84. ZAJECKA J: Strategies for the treatment of antidepressant-related sexual dysfunction. J. Clin. Psych. (2001) 62(Suppl. 3):35-43.

85. MONTEJO AL, LLORCA G, IZQUIERDO JA, RICO-VILLA-DEMOROS F: Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J. Clin. Psych. (2001) 62(Suppl. 3):10-21.

86. ZAJECKA J, MITCHELL S, FAWCETT J: Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual

Inventory. Psychopharmacol. Bull. (1997) 33(4):755-760.

87. COLEMAN CC, KING BR, BOLDEN-WATSON C et al.: A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine. Clin. Ther. (2001) 23(7):1040-1058.

88. FAVA M: Weight gain and antidepressants. J. Clin. Psych. (2000) 61(Suppl. 11):37-41.

89. HARVEY BH, BOUWER CD: Neuropharmacology of paradoxic weight gain with selective serotonin reuptake inhibitors. Clin. Neuropharmacol. (2000) 23(2):90-97.

90. MASAND PS: Weight gain associated with psychotropic drugs. Expert Opin. Pharmacother. (2000) 1(3):377-389.

91. MICHELSON D, AMSTERDAM JD, QUITKIN FM et al.: Changes in weight during a 1-year trial of fluoxetine. Am. J. Psych. (1999) 156(8):1170-1176.

92. FAVA M, JUDGE R, HOOG SL, NILSSON ME, KOKE SC: Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J. Clin. Psych. (2000) 61(11):863-867.

93. ZAJECKA J, TRACY KA, MITCHELL S: Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. J. Clin. Psych. (1997) 58(7):291-297.

94. HADDAD PM: Antidepressant discontinuation syndromes. Drug Saf. (2001) 24(3):183-197.

95. MOURILHE P, STOKES PE: Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Saf. (1998) 18(1):57-82.

96. NEMEROFF CB, DEVANE CL, POLLOCK BG: Newer antidepressants and the cytochrome P450 system. Am. J. Psych. (1996) 153(3):311-320.

97. ADDIS A, KOREN G: Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies. Psychol. Med. (2000) 30(1):89-94.

98. GOLDSTEIN DJ, SUNDELL K: A review of the safety of selective serotonin reuptake inhibitors during pregnancy. Human Psychopharmacol. (1999) 14:319-324.

99. WISNER KL, GELENBERG AJ, LEONARD H, ZARIN D, FRANK E: Pharmacologic treatment of depression during pregnancy. JAMA (1999) 282(13):1264-1269.

100. CHAMBERS CD, JOHNSON KA, DICK LM, FELIX RJ, JONES KL: Birth outcomes in pregnant women taking fluoxetine. N. Engl. J. Med. (1996) 335(14):1010-1015.

101. COHEN LS, HELLER VL, BAILEY JW, GRUSH L, ABLON JS, BOUFFARD SM: Birth outcomes following prenatal exposure to fluoxetine. Biol. Psych. (2000) 48(10):996-1000.

102. MHANNA MJ, BENNET JB, IZATT SD: Potential fluoxetine chloride (Prozac) toxicity in a newborn. Pediatrics (1997) 100(1):158-159.

103. MOHAN CG, MOORE JJ: Fluoxetine toxicity in a preterm infant. J. Perinatol. (2000) 20(7):445-446.

104. NORDENG H, LINDEMANN R, PERMINOV KV, REIKVAM A: Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr. (2001) 90(3):288-291.

105. SPENCER MJ: Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics (1993) 92(5):721-722.

106. NULMAN I, ROVET J, STEWART DE et al.: Neurodevelopment of children exposed in utero to antidepressant drugs. N. Engl. J. Med. (1997) 336(4):258-262.

107. HALE TW, SHUM S, GROSSBERG M: Fluoxetine toxicity in a breastfed infant. Clin. Pediatr. (2001) 40(12):681-684.

108. LESTER BM, CUCCA J, ANDREOZZI L, FLANAGAN P, OH W: Possible association between fluoxetine hydrochloride and colic in an infant. J. Am. Acad. Child Adolesc. Psych. (1993) 32(6):1253-1255.

109. KRISTENSEN JH, ILETT KF, HACKETT LP, YAPP P, PAECH M, BEGG EJ: Distribution and excretion of fluoxetine and norfluoxetine in human milk. Br. J. Clin. Pharmacol. (1999) 48(4):521-527.

110. HENDRICK V, STOWE ZN, ALTSHULER LL et al.: Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk. Biol. Psych. (2001) 50(10):775-782.

111. BURT VK, SURI R, ALTSHULER L, STOWE Z, HENDRICK VC, MUNTEAN E: The use of psychotropic medications during breast-feeding. Am. J. Psych. (2001) 158(7):1001-1009.

112. BORYS DJ, SETZER SC, LING LJ, REISDORF JJ, DAY LC, KRENZELOK



EP: Acute fluoxetine overdose: a report of 234 cases. Am. J. Emerg. Med. (1992) 10(2):115-120.

113. PHILLIPS S, BRENT J, KULIG K, HEILIGENSTEIN J, BIRKETT M: Fluoxetine versus tricyclic antidepressants: a prospective multicenter study of antidepressant drug overdoses. The Antidepressant Study Group. J. Emerg. Med. (1997) 15(4):439-445.

114. FRANK L, REVICKI DA, SORENSEN SV, SHIH YC: The economics of selective serotonin reuptake inhibitors in depression: a critical review. CNS Drugs (2001) 15(1):59-83.

115. WILDE MI, BENFIELD P: Fluoxetine. A pharmacoeconomic review of its use in depression. Pharmacoeconomics (1998) 13(5):543-561.

116. CROWN WH, TREGLIA M, MENEADES L, WHITE A: Long-term

costs of treatment for depression: impact of drug selection and guideline adherence. Value Health (2001) 4(4):295-307.

117. HYLAN TR, SUNDELL K, JUDGE R: The impact of premenstrual symptomatology on functioning and treatment-seeking behavior: experience from the United States, United Kingdom, and France. J. Womens Health Gend. Based Med. (1999) 8(8):1043-1052.

118. ROBINSON RL, SWINDLE RW: Premenstrual symptom severity: impact on social functioning and treatment-seeking behaviors. J. Womens Health Gend. Based Med. (2000) 9(7):757-768.

119. WITTCHEN HU, BECKER E, LIEB R, KRAUSE P: Prevalence, incidence and stability of premenstrual dysphoric disorder in the community. Psychol. Med. (2002) 32(1):119-132.

120. WEISSMAN MM, BOTHWELL S:

Assessment of social adjustment by patient self-report. Arch. Gen. Psych. (1976) 33(9):1111-1115.

121. PEARLSTEIN TB, HALBREICH U, BATZAR ED et al.: Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with sertraline or placebo. J. Clin. Psych. (2000) 61(2):101-109.

AffiliationTeri Pearlstein MD1† & Kimberly A Yonkers MD2

† Author for correspondence1Director, Women’s Behavioural Health Program, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905-2499, USATel: +1 401 453 7955; Fax: +1 401 453 7720;E-mail: [email protected] University School of Medicine, 142 Temple Street, Suite 301, New Haven, CT 06510-2600, USA

Review of fluoxetine and its clinical applications in premenstrual dysphoric disorder

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