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A naturalistic study of paroxetine in premenstrual syndrome

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A naturalistic study of paroxetine in premenstrual syndrome
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  European Neuropsychopharmacology 7 (1997) 201–206 A naturalistic study of paroxetine in premenstrual syndrome:efficacy and side-effects during ten cycles of treatment a, b b a * ¨Charlotta Sundblad , Ida Wikander , Bjorn Andersch , Elias Eriksson a ¨ ¨  Institute of Physiology and Pharmacology ,  University of Goteborg ,  Goteborg ,  Sweden b ¨ ¨  Institute of Obstetrics and Gynaecology ,  University of Goteborg ,  Goteborg ,  Sweden Received 2 April 1996; accepted 21 January 1997 Abstract Eighteen women with severe premenstrual syndrome (PMS) (premenstrual dysphoric disorder, PMDD) were treated openly withparoxetine for 10 consecutive menstrual cycles. Dosage was flexible (5–30 mg/day); also, the patients were free to chose betweencontinuous medication and medication in the luteal phase only. The rating of premenstrual irritability, depressed mood, increase inappetite, and anxiety/tension was markedly lower during treatment with paroxetine than before, and this reduction in symptomatologyappeared unabated for the entire treatment period. Sedation, dry mouth, and nausea were common side-effects but declined during thecourse of the trial; in contrast, reduced libido and anorgasmia, which were reported by almost 50% of the participants, were not improvedwith time. The results indicate that the beneficial effects as well as the sexual side-effects of serotonin reuptake inhibitors persistunchanged for at least 10 consecutive cycles of treatment.  ©  1997 Elsevier Science B.V. Keywords :   Premenstrual syndrome; Premenstrual dysphoric disorder; Paroxetine; Serotonin reuptake inhibitor; Long-term treatment;Tolerability; Sexual side-effects; Libido; Anorgasmia 1. Introduction  exception, these trials have had a duration of six cyclesonly or less. Thus, studies exploring the efficacy andThe premenstrual syndrome (PMS) (premenstrual tolerability of long-term treatment with SRIs in PMS aredysphoric disorder, PMDD) is characterised by a cluster of warranted.psychiatric and somatic symptoms that are present during In a recent controlled trial (Eriksson et al., 1995) wethe luteal phase of the menstrual cycle. The cardinal showed that the selective serotonin reuptake inhibitorsymptoms of PMS are irritability and depressed mood; in paroxetine (Turner et al., 1989; Caley and Weber, 1993) isaddition, tension, increased carbohydrate craving, bloating, superior to placebo as well as to the noradrenaline reuptakeand breast tenderness are common complaints (Frank, inhibitor maprotiline for the treatment of PMS; in that1931; Halbreich et al., 1982; Merikangas et al., 1993; study, medication lasted for three consecutive menstrualAmerican Psychiatric Association, 1994). cycles. In order to elucidate whether the efficacy andSeveral trials have shown that drugs inhibiting the side-effects of paroxetine persist for a longer period, thereuptake inactivation of transmitter in serotonin synapses patients participating in the controlled trial were offered to(serotonin reuptake inhibitors; SRIs) markedly reduce the medicate openly with paroxetine for 10 additional cycles.symptoms of PMS (Eriksson et al., 1990; Rickels et al., This open trial had a naturalistic design; thus, the dosage1990; Stone et al., 1991; Sundblad et al., 1992; Menkes et was flexible and the patients were free to elect whetheral., 1992; Wood et al., 1992; Sundblad et al., 1993; Steiner they should medicate throughout the cycle or during lutealet al., 1995; Eriksson et al., 1995); however, with one phases only (cf. Sundblad et al., 1993). During the courseof the treatment, as well as during two cycles after the *Corresponding author. Tel.:  1 46 31 7733400; fax:  1 46 31 414008.  treatment had been discontinued, the participants per- 0924-977X/97/$17.00  ©  1997 Elsevier Science B.V. All rights reserved PII   S0924-977X(97)00404-5  202  C  .  Sundblad et al .  /   European Neuropsychopharmacology  7 (1997) 201 – 206  formed daily rating of irritability, depressed mood, anxie- analogue scale (0–100 mm; 0 mm 5 no complaints, 100ty/tension, increased appetite/carbohydrate craving, bloat- mm 5 maximal complaints): (1) irritability, (2) depresseding, and breast tenderness. Possible side-effects were mood, (3) tension/anxiety, (4) increased appetite and/orregistered in the end of each treatment cycle. carbohydrate craving, (5) bloating, and (6) breast tender-ness. For analysis of data, the mean of the five dayspreceding the menstrual bleeding was used as a measure of  2. Experimental procedures  premenstrual symptomatology.In order to obtain a global assessment of possible drug 2.1.  Recruitment of participants  effects, after the tenth treatment cycle the patients wereasked to estimate how they had felt with respect to theirAll women had participated in a previous placebo- premenstrual complaints during the treatment period ascontrolled drug trial comparing the efficacy and tolerability compared to how they had felt before (enormously im-of paroxetine, maprotiline, and placebo (Eriksson et al., proved, much improved, somewhat improved, no change,1995). To be included in that trial, they should fulfil the somewhat deteriorated, much deteriorated, or enormouslyDSM-III-R criteria of late luteal phase dysphoric disorder; deteriorated).in addition, they should display at least 100% higherself-rating (using a visual analogue scale) with respect to 2.4.  Analysis of data irritability and/or depressed mood during the luteal phasethan during the follicular phase for two consecutiveFor statistical analysis, the rating during the five daysreference cycles. Women with any other ongoing psychiat-preceding the menstrual bleeding in each treatment cycleric or somatic illness were excluded. For details withwas used as a measure of premenstrual symptomatology.respect to inclusion and exclusion criteria, see our previousSince symptom rating obtained with VAS cannot bereport (Eriksson et al., 1995). All women that had com-expected to be normally distributed, nonparametric statis-pleted the controlled trial were invited to participate in thetics (Wilcoxon signed-rank test) were used for all analyses;open study regardless of whether they had medicated withyet, all values are presented as means 6 SEM.  p -valuesparoxetine, maprotiline, or placebo. , 0.05 were regarded as statistically significant. 2.2.  Medication 2.5.  Registration of side - effects Treatment started at the first day of menstruation; duringBefore the start of the trial, the participants werethe first and second week, the dose was one tablet dailyinformed of the various side-effects that could be expectedcontaining 10 mg of paroxetine. For the third and fourthfrom treatment with paroxetine. For registration of un-weeks of treatment, and for the rest of the trial, thewanted effects of the treatment, the participants completedrecommended dose was two tablets daily, i.e. 20 mg of a questionnaire comprising 19 possible side-effects at theparoxetine. However, patients experiencing marked side-end of each treatment cycle; in addition, they were askedeffects of the treatment were instructed to decrease theto indicate any additional symptom, not appearing in thedose to one tablet (10 mg) – or even half a tablet – daily;list, which they attributed to the treatment.on the other hand, patients experiencing mild or no side-effects, and an unsatisfactory reduction of premenstrualcomplaints during the course of the first premenstrualphase, were allowed to increase the dosage from two to  3. Results three (30 mg) or four (40 mg) tablets daily. Also, duringthe course of the first treatment cycles, the patients were  3.1.  Number of drop - outs and fulfillers allowed to choose whether to medicate continuously (i.e.the same dose throughout the cycle), intermittently (i.e. Twenty-three subjects accepted the protocol and startedmedication during luteal phases only), or semi-intermit- medication with paroxetine. Five patients dropped outtently (i.e. lower dose during follicular phases than during during the course of the first four cycles because of luteal phases). After the onset of the menstruation in the side-effects: migraine ( n 5 1), sedation ( n 5 2), vertigo ( n 5 tenth treatment cycle, the patients were instructed to 1), and sexual dysfunction ( n 5 1). Four of these patientsgradually reduce and stop the medication. completed at least one cycle of treatment; all these fourwomen reported a considerable reduction in premenstrual 2.3.  Registration of symptoms  irritability and depression during medication. 18 patientsfulfilled the trial protocol.During the ten treatment cycles and the two post-treat- Mean age ( 6 SEM) of the patients completing the trialment cycles, the participating women performed daily was 39 ( 6 1.4) years. Mean duration ( 6 SEM) of PMS/ rating of the following six symptoms using a visual PMDD was 8 ( 6 1.1) years. One patient reported that she  C  .  Sundblad et al .  /   European Neuropsychopharmacology  7 (1997) 201 – 206   203 had been treated for depression; no other patient reportedany previous episodes of affective illness. 3.2.  Medication During the first treatment cycles, dosage and drugregimen were individualized on the basis of the symptomreduction achieved and on the side-effects experienced.During the rest of the trial, the mean daily dose takenduring the late luteal phase was 17.3 ( 6 1.3) mg. Sixpatients chose to take the same dose of paroxetine continu-ously throughout the cycle, five patients medicated inter-mittently (i.e. during the luteal phase only), whereas sevenpatients elected a semi-intermittent drug regimen (i.e.continuous medication but with lower doses in the follicu-lar than in the luteal phase) (Fig. 1). Due to worsening of premenstrual complaints, three patients did not manage totaper the medication after 10 cycles of treatment. 3.3.  Effect assessment  The premenstrual symptom ratings (mean of five days)of irritability, depressed mood, and increased food cravingin the two reference cycles used for the confirmation of thediagnosis (see Methods), in the ten treatment cycles, and inthe two cycles following the discontinuation of medication,are shown in Fig. 2.The symptom rating during the ten cycles of treatmentwas stable; thus, neither a further improvement nor arelapse were observed during the course of the trial. Thepremenstrual ratings were significantly lower during thetreatment cycles ( 5 mean of treatment cycles 1–10) thanduring the reference cycles ( 5 mean of reference cycles1–2) for the following symptoms: irritability (see Fig. 2,  p 5 0.0002), depressed mood (see Fig. 2,  p 5 0.0003),increased appetite (see Fig. 2,  p 5 0.0005, anxiety (beforetreatment: 30.8 6 4.7, during treatment: 7.8 6 1.7,  p 5 0.01), Fig. 2. Self-rated depressed mood, irritability, and food craving (VAS0–100 mm) in the luteal phases of two pretreatment reference cycles (RC1–2), ten cycles of paroxetine treatment (TC 1–10), and two cycles afterthe medication had stopped (non-treatment cycles, NTC 1–2) in womenwith severe premenstrual syndrome. The bars represent group means withstandard errors;  n 5 15–18. For a statistical comparison of symptom ratingbefore, during, and after treatment, see Section 3. and bloating (before treatment: 40.2 6 4.8, during treat-ment: 26.6 6 5.4,  p 5 0.002). The reduction in breast tender-ness did not reach statistical significance (before treatment:31.1 6 6.5, during treatment: 22.0 6 5.2,  p 5 0.06).During the posttreatment reference cycles ( 5 mean of posttreatment cycles 1 and 2), a significant relapse wasobserved with respect to the symptoms irritability (  p 5 0.04) and depressed mood (  p 5 0.01) but not for thesymptoms increased appetite, anxiety, bloating, and breast Fig. 1. Doses of paroxetine taken during the late luteal phases and doseregimen (continuous, intermittent or semi-intermittent).  tenderness. Notably, due to a severe worsening of premen-  204  C  .  Sundblad et al .  /   European Neuropsychopharmacology  7 (1997) 201 – 206  Table 1 al., 1993; Steiner et al., 1995) over placebo for the Self-rated global change of premenstrual complaints during treatment treatment of PMS has been confirmed in a large number of  with paroxetine ( n 5 18) controlled trials. The purpose of this open, naturalistic Global assessment Number Percentage of  study was not to establish the efficacy of paroxetine, but to of subjects subjects explore whether the beneficial effect of the drug is Enormously improved 8 44.5 maintained during 10 consecutive cycles, and to what Much improved 9 50.0 extent the unwanted effects of the treatment decline with Somewhat improved 1 5.5 time. No change/deterioration 0 0 All 22 subjects completing at least one cycle of parox-strual complaints, three subjects were unable to taper the etine treatment reported an improvement in premenstrualmedication; these subjects are included neither in the complaints during treatment as compared to how they hadstatistical analysis of the symptomatology during the two felt before.We have previously reported a similar responseposttreatment cycles nor in the mean values from the two rate (20/22 patients) when evaluating the efficacy of posttreatment cycles displayed in Fig. 2. paroxetine in a controlled trial; in the same study, theAs shown in Table 1, all participants rated themselves as responses to placebo and maprotiline (a noradrenalineglobally improved regarding their premenstrual symptoms reuptake inhibitor), respectively, were considerably lessduring the ten cycles of treatment as compared to how they impressive (Eriksson et al., 1995). Thus, although ahad felt before the onset of medication. placebo effect can never be excluded in an open trial, itseems likely that the marked response to paroxetine in this 3.4.  Tolerability data  group of patients is indeed to great extent related to thepharmacodynamic effects of the drug.The possible side-effects of treatment most commonly A flexible dose regimen (5–40 mg/day) was applied.reported by the patients completing the study are shown in The finding that the mean dose of paroxetine taken duringTable 2. Side-effects such as dry mouth, nausea, constipa- luteal phases was 17 mg/day supports the notion thattion, and sedation clearly declined during the course of somewhat lower doses of SRIs are required for thetreatment, while reduced libido, anorgasmia, sweating, and management of PMS (Eriksson et al., 1990; Sundblad etvertigo appeared to persist unabated throughout the trial. al., 1992, 1993; Steiner et al., 1995) than for the treatmentof depression or obsessive compulsive disorder. 3.5.  Continuation  The feasibility of intermittent administration of an SRIfor the treatment of PMS has previously been demon-After the study, nine of the 18 participants chose to strated in placebo-controlled trials using clomipramineresume medication with paroxetine. The reasons for not (Sundblad et al., 1993) or citalopram (Wikander et al.,resuming treatment were full or partial remission of 1996) as active compounds. In the present trial, a majoritypremenstrual complaints ( n 5 4), side-effects ( n 5 4), and of the patients elected to medicate intermittently in thepregnancy ( n 5 1). luteal phase only, or semi-intermittently with lower dosesin the follicular than in the luteal phase.Previous investigations suggest that the beneficial effects 4. Discussion  of SRIs when used for chronic disorders such as obsessivecompulsive disorder (Levine et al., 1989; Greist et al.,The superiority of paroxetine (Eriksson et al., 1995) and 1995), panic disorder (Modigh et al., 1989), and bulimiaother strong SRIs (Stone et al., 1991; Sundblad et al., nervosa (Goldstein et al., 1995) are not characterized by1992; Menkes et al., 1992; Wood et al., 1992; Sundblad et the development of tolerance. One important conclusion of  Table 2The ten most frequently reported unwanted symptoms attributed to treatment with paroxetine during a 10-cycle trial. C1 5 cycle 1, C10 5 cycle 10C1 C2 C3 C4 C5 C6 C7 C8 C9 C10Sedation (%) 56 50 44 44 33 33 39 33 22 22Nausea (%) 56 33 11 22 6 6 6 6 6 6Dry mouth (%) 50 22 28 17 22 22 17 6 17 6Anorgasmia (%) 44 50 50 44 44 44 44 44 33 50Reduced libido (%) 39 44 39 39 39 44 44 50 44 50Constipation (%) 33 28 22 17 17 17 17 17 11 6Yawnings (%) 28 17 11 11 11 11 22 17 6 6Sweatings (%) 28 22 22 39 39 33 28 22 28 22Vertigo (%) 22 17 6 22 22 17 17 17 22 22Headache (%) 11 11 17 6 11 22 22 11 6 6  C  .  Sundblad et al .  /   European Neuropsychopharmacology  7 (1997) 201 – 206   205 the present trial is that the paroxetine induced reduction in why, e.g., the nausea induced by SRIs is the subject of airritability and depressed mood in women with PMS marked tolerance, whereas the beneficial effects of theappears to be stable throughout a treatment period of 10 drugs, as well as the sexual side-effects, are not. Oneconsecutive cycles; thus, the response in treatment cycle possible explanation would be that the receptor subtype/s/ 10 was neither more nor less pronounced than that in mediating the effects of SRIs on nausea are more inclinedtreatment cycle 1. This finding is in line with a previous to be down-regulated when stimulated than are thosereport by Pearlstein and Stone (1994) investigating the mediating the therapeutic effects and the sexual side-effect of long-term treatment with fluoxetine in women effects, respectively. That all the effects of SRIs are notwith premenstrual complaints; their study comprised 60 mediated by the same serotonin receptor subtype does lendpatients and lasted for one and a half years; however, no support from previous research; thus, whereas SRI-induceddaily symptom rating was performed. In contrast, a large, nausea is believed to be mediated at least partly by 5HT3controlled multi-centre trial did lend some support for the receptors, the sexual side-effects may be due to an increaseconcept of a slight time-related reduction in the efficacy of in 5HT2 receptor activation (for refs, see Eriksson andfluoxetine when used for PMS (Steiner et al., 1995). Also, Humble, 1990). Which receptor subtype/s/ that arethe results of a recent trial using the selective SRI mediating the beneficial effect of SRIs in PMS remains tocitalopram in PMS suggest that continuous medication be established; however, the beneficial effect of the partialmay be associated with a tolerance phenomenon that is 5HT1A agonist buspirone in women with premenstrualavoided by intermittent administration of the drug (Wikan- complaints (Rickels et al., 1989) suggests that the post-der et al, to be published). When comparing the lack of synaptic 5HT1A receptor may be involved.tolerance to the beneficial effects of paroxetine reported in A relapse of premenstrual complaints after the dis-this paper with data from previous studies, the fact that 2/3 continuation of short-term treatment with fluoxetineof our subjects elected to medicate intermittently or semi- (Menkes et al., 1992) or clomipramine (Sundblad et al.,intermittently should be taken into consideration. Also, the 1993) has previously been reported; the present studypossibility that there may be differences between the indicates that also after ten cycles of treatment with andifferent SRIs with respect to the possible development of SRI, the relapse rate is considerable.tolerance should not be ruled out. In conclusion, this naturalistic trial indicates that theMost side-effects observed were of a kind that can be beneficial effects of paroxetine in the treatment of PMS doexpected when medicating with paroxetine (Turner et al., not decline during the course of a 10-cycle period. In1989; Caley and Weber, 1993). Whereas side-effects such addition, the data obtained reinforce the notion that theas dry mouth, nausea, and sedation clearly declined during sexual side-effects of SRIs are common and that they dothe course of treatment, other side-effects persisted not decline with time.throughout the trial. Of particular importance in thiscontext are the sexual side-effects; thus, reduced libido andanorgasmia were reported by about 50% of the participants  Acknowledgments and showed no tendency to decline during the course of the study. Several patients reported that the occurrence of This study was supported by grants from the Swedishsexual side-effects was the major reason why they pre- Medical Research Council (8668), The Foundation of the¨ ¨ ¨ferred intermittent to continuous drug administration. Soderstrom-Konigska Nursing Home, Fredrik and IngridWhen interpreting the large number of subjects reporting Thuring’s Foundation, and the Knut and Alice Wallen-sexual side-effects, it should by considered that the side- berg’s Foundation. Excellent technical assistance waseffect rating was conducted in a phase of the menstrual provided by Margareta Lundgren and Norunn Persson.cycle – i.e. premenstrually – which per se may beassociated with a reduction in libido (Dennerstein et al.,1994). However, the assumption that the sexual dysfunc-  References tion reported by the patients is indeed to a large extent dueto the pharmacodynamics of paroxetine is supported by the  American Psychiatric Association (1994) Diagnostic and statisticalmanual of mental disorders, 4th ed. APA Press, Washington DC, pp. fact that sexual side-effects were reported more often by 715–718. patients on paroxetine (30%) than by patients on placebo Balon, R., Yeragani, V.K., Pohl, R. and Ramesh, C. (1993) Sexual (5%) or maprotiline (10%) in our previous controlled trial. dysfunction during antidepressant treatment. J. Clin. Psychiatry 54, Moreover, previous reports have suggested that women  209–212. medicating with SRIs for other indications than PMS also  Caley, C.F. and Weber, S.S. (1993) Paroxetine: a selective serotoninreuptake inhibiting antidepressant. Ann. Pharmacother. 27, 1212– experience sexual side-effects more often than has been 1222. earlier assumed (Balon et al., 1993; Patterson, 1993; Shen Dennerstein, L., Gotts, G., Brown, J.B., Morse, C.A., Farley, T.M. and and Hsu, 1995) and that these side-effects do not decline Pinol, A. (1994) The relationship between the menstrual cycle and with time (Monteiro et al., 1987).  female sexual interest in women with PMS complaints and volunteers. An issue of considerable pharmacological interest is  Psychoneuroendocrinology 19, 293–304.
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