Abstract
Premenstrual dysphoric disorder, which affects 3–8% of women of reproductive age, is characterized by a combination of symptoms that may include depressed mood, irritability, anxiety and/or physical symptoms. These symptoms occur during the luteal phase of the menstrual cycle, with remission generally occurring within 3 days after the onset of menses. Presently, treatment guidelines for premenstrual dysphoric disorder focus on lifestyle management and psychopharmacologic interventions, with selective serotonin reuptake inhibitors being considered the first line of medication intervention. The US Food and Drug Administration and Health Canada recently approved paroxetine for the treatment of premenstrual dysphoric disorder. This article reviews the properties of this medication and its use in the treatment of premenstrual dysphoric disorder.
Keywords
A substantial number of women suffer from some premenstrual symptomatology, the most common disorders of which are premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). PMDD can be differentiated from PMS in that the latter is characterized by milder physical and mood symptoms [1]. Impairment must exist in order for a diagnosis of PMDD to be given and, as a result, it is significantly less prevalent than PMS [2]. PMDD is characterized by a combination of symptoms that may include depressed mood, mood swings, irritability and/or anxiety, and is often accompanied by physical symptoms such as breast tenderness, headache, and joint and muscle pain (Box 1) [3]. The symptoms occur during the luteal phase of the menstrual cycle, with remission generally occurring within 3 days after the onset of menses [3]. Up to 75% of women of reproductive age experience some symptoms of PMS, whereas PMDD affects 3–8% of these women [4,5]. Symptoms of PMDD usually begin in the patient's early 20s; however, women commonly do not present for treatment until their mid to late 30s [6]. Unfortunately, the etiology of PMDD is largely unknown; however, the current consensus seems to be that it is triggered by normal ovarian function as opposed to hormonal imbalance [7].
There are presently no objective tests available for diagnosing PMDD; however, several scales now exist to facilitate this process [8]. A complete medical and psychiatric history must be obtained from the patient, and a screening that assesses physical symptoms, medical disorders and family history of heritable disorders should be conducted [7]. The key to making a diagnosis of PMDD is the prospective daily ratings of symptoms recorded by the patient, which should be charted for at least two consecutive symptomatic menstrual cycles and corroborated by a physician.
At present, treatment guidelines for PMDD focus on both lifestyle management and psychopharmacologic interventions. Anecdotal support exists suggesting that reducing intake of caffeine, refined sugars and sodium may alleviate some PMDD symptoms [6]; however, no controlled trials exist supporting this notion. Some studies also support the use of calcium carbonate or magnesium in treating PMDD [7,9]. Some evidence for efficacy does exist for nonpharmacologic strategies such as cognitive behavioral relaxation therapy and aerobic exercise [10]. Furthermore, charting a woman's symptoms on a daily basis (which should be carried out for diagnostic purposes anyway) can provide insight into when the symptoms occur and what exacerbates them, allowing for lifestyle adjustments to be made accordingly.
Although the aforementioned treatment strategies can aid in reducing symptomatology, in the majority of cases, further therapeutic intervention is necessary in order to achieve remission [6]. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacologic treatment for PMDD and are effective with both continuous and intermittent (luteal-phase) administration [6,9,11–17]. Antidepressants that increase serotonergic activity (e.g., clomipramine [18,19]) have previously been considered the second-line treatment for PMDD [6], but are now rarely prescribed for this purpose due to their lower tolerability. Hormone therapies, such as oral contraceptives containing drospirenone (an analog of spironolactone – a diuretic and aldosterone antagonist [6,20]), are considered an alternative approach if the patient does not respond to the first- or second-line medications [6]. In the past, progesterone and progestogens have been used in treating premenstrual symptoms; however, empirical evidence does not support the efficacy of these treatments [21,22]. Gonadotropin-releasing hormone (GnRH) agonists have been shown to be effective in treating many symptoms associated with PMDD [23,24]. Due to the limitations associated with these treatments, including difficult administration, high cost and potential side effects, they are often only used after other pharmacologic interventions have failed [6].
Criteria for premenstrual dysphoric disorder.
In most menstrual cycles during the past year, symptoms must occur during the week before menses and remit a few days after onset of menses. Five of the following symptoms, including at least one of 1, 2, 3 or 4, must be present:
Depressed mood or dysphoria
Anxiety or tension
Affective lability
Irritability
Decreased interest in usual activities
Concentration difficulties
Marked lack of energy
Marked change in appetite, overeating, or food cravings
Hypersomnia or insomnia
Feeling overwhelmed
Other physical symptoms, e.g., breast tenderness or bloating
Symptoms must interfere with work, school, usual activities or relationships
Symptoms must not merely be an exacerbation of another disorder
Criteria A, B, and C must be confirmed by prospective daily ratings for at least two consecutive symptomatic menstrual cycles
Chart modified from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [3].
Overview of the market
Preliminary data exist for all SSRIs (e.g., paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram and escitalopram) and one serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine, supporting their efficacy in treating premenstrual symptoms, but the preponderance of efficacy has been reported with fluoxetine, sertraline and paroxetine. Nonetheless, until recently only two of these medications, namely fluoxetine and sertraline, had been approved by the US Food and Drug Administration (FDA) for the indication of PMDD [25]. A controlled release (CR) formulation of paroxetine was recently approved by the FDA [101] as well as Health Canada [102] for continuous (daily) and intermittent (each day for 2 weeks prior to menses) administration for the treatment of PMDD. To date, no empirical studies have been conducted directly comparing the different SSRIs in the treatment of PMDD (see Table 1 for an indirect comparison of paroxetine with other SSRIs).
Paroxetine vesrsus its competitors for PMDD treatment.
CR: Controlled release; IR: Immediate release; PMDD: Premenstrual dysphoric disorder.
Adapted from [42].
Studies demonstrating the efficacy of intermittent dosing of paroxetine for treating PMDD have significantly affected the prescribing practices of clinicians. As it is recommended that paroxetine be taken once daily, patient compliance is typically better for this medication than others that are often administered two or more times/day. Adherence can be a particular concern with PMDD, where patients can become incapacitated for up to 2 weeks/month, making paroxetine a desirable option in treating this disorder. However, the long-term effectiveness of intermittent dosing has yet to be determined and side effects that can be encountered with continuous dosing may be a barrier to compliance. Thus, at the present time, available pharmacologic treatments leave some unmet needs in patients with PMDD.
Introduction to paroxetine
Chemistry
Paroxetine hydrochloride has a chemical structure unrelated to other SSRIs or antidepressants. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as [-]-trans-4R-(4-fluorophenyl)-3S-[(3,4-methylenedioxyphenoxy)methyl] piperidine hydrochloride hemihydrate, with an empirical formula of C19H20FNO3·HCl·<sp>1</sp>/<sb>2</sb>H2O (Figure 1) [103]. Paroxetine is an odorless, off-white powder that has a melting point between 120 and 138 °C, a solubility of 5.4 mg/ml in water, and a molecular weight of 374.8 (or 329.4 as a free base [28]).
Paroxetine hydrochloride.
Pharmacodynamics
The efficacy of paroxetine in the treatment of PMDD seems to be related to the potentiation of serotonergic activity in the CNS, which results from inhibition of neuronal reuptake of serotonin [26,103].
Pharmacokinetics & metabolism
Tablets of paroxetine contain a degradable polymeric matrix, which controls the dissolution rate of the medication for a 4–5-h period [103]. In addition, an enteric coat delays the start of drug release until the medication has left the stomach [103]. Subsequent to oral dosing, paroxetine is completely absorbed [103]. It is distributed throughout the body with only approximately 1% remaining in the plasma [103]. The mean elimination half-life of paroxetine has been shown to be 15–20 h with single doses of paroxetine at 12.5, 25, 37.5 and 50 mg, and the bioavailability of 25 mg is not affected by food consumption [103]. See Table 2 for a list of the main pharmacokinetic properties of paroxetine.
Main pharmacokinetic characteristics of paroxetine controlled release.
AUC: Area under the curve; Cmax: Maximum plasma concentration.
Adapted from [28].
Paroxetine is comprehensively metabolized after oral administration, with the principal metabolites being polar and conjugated products of oxidation and methylation, which are readily cleared [103]. Conjugates are mainly with glucoronic acid and sulfate [103]. Major metabolites have been isolated and identified; however, their relative potencies are approximately 1/50 of the parent compound and are thus essentially inactive [103]. Cytochrome (CYP)450IID6 is primarily responsible for the metabolism of paroxetine [103].
Clinical efficacy
The efficacy of paroxetine in treating PMDD has been established in several clinical trials. See Table 3 for an overview of Phase I and II clinical trial results, and Table 4 for an overview of Phase III clinical trials. Open-trial studies of paroxetine found it to be effective in the acute phase for the treatment of PMDD [27], and found symptom reduction to persist across ten consecutive menstrual cycles [28]. Eriksson and colleagues found that paroxetine was significantly more effective in reducing premenstrual symptoms than both a placebo and maprotiline, a norepinephrine reuptake inhibitor [29]. Phase III clinical trials have generally found paroxetine CR to be well tolerated and effective in treating mood symptoms at both 12.5 and 25 mg doses [30–33].
Overview of Phase I and II clinical trials of paroxetine IR use for PMDD.
Cmax: Maximum plasma concentration; DB: Double-blind; I: International; IR: Immediate release; MC: Multicenter; Med: Medication group; NA: Not available; PBO: Placebo; PC: Placebo-controlled; PG: Parallel group; PMDD: Premenstrual dysphoric disorder; R: Randomized; Tmax: Time to reach Cmax.
Adapted from [106].
Overview of Phase III clinical trials of paroxetine (CR) use for PMDD.
3A: Three-arm; COPE: Calendar of premenstrual experiences; CR: Controlled release; DB: Double-blind; FD: Fixed dose; MC: Multicenter; Med: Medication group; PBO: Placebo; PC: Placebo-controlled; PG: Parallel group; PMDD: Premenstrual dysphoric disorder; R: Randomized; VAS: Visual analog scale.
Postmarketing surveillance
Safety & tolerability
The most common adverse events noted in clinical trials utilizing continuous and luteal-phase dosing of paroxetine included nausea, asthenia, decreased libido, somnolescence, insomnia, female genital disorders, sweating, dizziness, diarrhea and constipation [103]. See Table 5 for the incidence of the most frequently reported adverse events across paroxetine trials for PMDD. Several medications, when administered in conjunction with paroxetine, may cause adverse experiences for the patient. Such medications include: tryptophan, monoamine oxidase inhibitors (MAOIs), pimozide, serotonergic drugs, thioridazine, warfarin, triptans, drugs affecting hepatic metabolism, cimetidine, phenobarbital, phenytoin, drugs metabolized by CYPP450IID6, drugs metabolized by CYPP450IIIA4, trycyclic antidepressants, drugs highly bound to plasma protein, drugs that interfere with hemostasis (e.g. nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin and warfarin), alcohol, lithium, digoxin, diazepam, procyclidine, β-blockers, and theophylline [103].
Most frequent adverse events reported in Phase III paroxetine clinical trials.
Adapted from [106].
Both the FDA [104] and Health Canada [105] asked the manufacturers of SSRIs, as well as some other newer antidepressants, to include a boxed warning in their labeling, as well as expanded warning statements in information packages, to alert both healthcare providers and patients of an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents. As previously mentioned, PMDD symptomatology does not usually appear until women are in their 20s [6]. Nonetheless, it is possible for women to develop this disorder during adolescence. At this point, the use of SSRIs in this population of women is not recommended. However, if all alternative treatments have been unsuccessful and the clinician does choose to utilize SSRIs, very close monitoring of the adolescent is strongly recommended.
Regulatory affairs
Paroxetine has been approved for use in the treatment of PMDD in the USA, Canada and Europe. In addition to being approved for PMDD, paroxetine has been approved for indications of major depression, obsessive–compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder and generalized anxiety disorder [103].
Conclusion
First introduced by Robert Frank in 1931 [34], the concept that mood and menstruation are related is long standing. Throughout the course of the past several decades, it has become clear that experiencing mild premenstrual symptomatology is a normal physiologic occurrence. Nevertheless, it has been only recently that PMDD has been acknowledged as a distinct clinical entity requiring treatment. As a result, in the past, the majority of women with this disorder were left untreated. When it became recognized that PMDD causes functional impairment and negatively affects quality of life, a number of pharmacologic treatments were introduced, with high doses (up to 60 mg/day) of fluoxetine and sertraline being the first of the SSRIs [35]. Subsequently, the efficacy of paroxetine in doses as low as 12.5 mg/day in treating PMDD has been established.
A novel and clearly significant contribution to the field of PMDD has been the introduction of intermittent dosing of SSRIs as a treatment intervention. Although continuous (daily) dosing of the SSRIs is an effective treatment for PMDD, as women are generally only symptomatic for up to 14 days of their menstrual cycle, intermittent dosing is a mode of treatment found to be equally successful [36]. With intermittent dosing, SSRIs are administered cyclically in the luteal phase of the menstrual cycle, followed by 14 days off the medication in the follicular phase [35]. It has been proposed that luteal-phase administration of SSRIs produces fewer side effects in the patient than continuous administration; however, at present, no conclusive evidence exists in support of this hypothesis.
Future perspective
The success of intermittent SSRI administration in treating PMDD has led to further investigation into the mechanisms of action involved in the CNS. Recent theories suggest that in addition to serotonin, other neurotransmitters, including γ-aminobutyric acid (GABA) and progesterone metabolites such as allopregnanolone, may be involved [37–39]. Studies are currently underway using proton magnetic resonance spectroscopy (1H-MRS) to measure cellular activity during different phases of the menstrual cycle, which will hopefully provide us with a better understanding of the neurobiology of PMDD. Epperson and colleagues found that cortical GABA levels declined across the menstrual cycle in healthy women, while these levels increased from the follicular phase to the mid- and late-luteal phases in women with PMDD [40]. Preliminary data from another study suggest a decline in the ratio of N-acetyl-aspartate to creatine in the medial prefrontal cortex and the cingulated gyrus from the follicular to the luteal phases of the menstrual cycle; however, no differences were found between women with PMDD and healthy controls [41]. Further knowledge of this disorder could also be gained by conducting studies in which antidepressant levels are measured in patients' sera during the follicular and luteal phases of the menstrual cycle. This would indicate whether the metabolism of the medication changes with the phase of the cycle and could potentially help to differentiate women with PMDD from those experiencing premenstrual exacerbation of their symptoms. Although both continuous and luteal-phase administration of SSRIs have been shown to be valuable for treating PMDD, their role in long-term maintenance has yet to be determined [35]. However, practitioners must tailor treatment on a case-by-case basis and, as a result, SSRI administration may sometimes continue indefinitely in clinical settings. Therefore, long-term pharmacologic treatment of PMDD with SSRIs requires further investigation. Studies of antidepressant levels in sera throughout the menstrual cycle may also provide clinicians with an insight into the length of time for which intermittent dosing can be effective and ways to extend this period. In addition, in the future it would be useful to conduct head-to-head trials comparing the different SSRIs in order to gain a better understanding of the comparative benefits and drawbacks of each medication. Although historically there have been significant advances in the field of PMDD, further research needs to be conducted to delineate the complex mood–menstruation connections that exist between female steroidal hormones, neurotransmitters and effects on mood and anxiety.
Executive summary
Paroxetine inhibits neuronal reuptake of serotonin, resulting in potentiation of serotonergic activity in the CNS.
A degradable polymeric matrix controls the dissolution rate of paroxetine for a 4–5-h period, and an enteric coat delays the start of drug release until the medication has left the stomach.
Paroxetine is completely absorbed after oral administration and is distributed throughout the body with only approximately 1% remaining in the plasma.
The mean elimination half-life of paroxetine has been shown to be 15–20 h, and bioavailability does not seem to be affected by food consumption.
In clinical trials, paroxetine immediate release (IR) and both 12.5 and 25 mg doses of paroxetine controlled release (CR) have been shown to be effective in treating premenstrual dysphoric disorder.
The most common adverse events are: nausea, asthenia, decreased libido, somnolescence, insomnia, female genital disorders, sweating, dizziness, diarrhea and constipation.
Specific serotonin reuptake inhibitors are not recommended for the treatment of children and adolescents.
Several medications, including tryptophan and monoamine uptake inhibitors, when administered in conjunction with paroxetine, may cause adverse experiences for the patient.
Paroxetine is available in 10, 20, 30 and 40 mg IR tablets, or as paroxetine CR in 12.5, 25 and 37.5 mg tablets. It is also available as a 10 mg/5 ml oral suspension.
The therapeutic dose range is: 10–60 mg (paroxetine IR) and 12.5–50 mg (paroxetine CR).
The usual initial dose for PMDD is: single daily dose of 12.5 mg/day (paroxetine CR).
Dose changes should not be instituted after periods of less than 1 week.
Information resources
Important review articles:
Dimmock PW, Wyatt KM, Jones PW, O'Brien PM: Efficacy of selective serotonin-re-uptake inhibitors in premenstrual syndrome: a systematic review. Lancet 356, 1131–1136 (2000).
Freeman EW: Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder. CNS Drugs 18(7), 453–468 (2004).
Macdougall M, Steiner M: Treatment of premenstrual dysphoria with selective serotonin re-uptake inhibitors: focus on safety. Expert Opin. Drug Saf. 2(2), 161–166 (2003).
Pearlstein T: Selective serotonin re-uptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard? Drugs 62(13), 1869–1885 (2002).
Yonkers KA: Paroxetine treatment of mood disorders in women: premenstrual dysphoric disorder and hot flashes. Psychopharmacol. Bull. 37(Suppl. 1), 135–147 (2003).
Several clinical trials have investigated the efficacy of paroxetine in the treatment of PMDD:
Cohen LS, Soares CN, Yonkers KA et al.: Paroxetine controlled release for premenstrual dysphoric disorder: a double-blind, placebo-controlled trial. Psychosom. Med. 66, 707–713 (2004).
Eriksson E, Hedberg MA, Andersch B, Sunblad C: The serotonin re-uptake inhibitor paroxetine is superior to the norepinephrine re-uptake inhibitor maproptiline in the treatment of premenstrual syndrome. Neuropsychopharmacology 12(2), 167–176 (1995).
Pearlstein TB, Bellew KM, Endicott J, Steiner M: Paroxetine controlled release for premenstrual dysphoric disorder: remission analysis following a randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 7(2), 53–60 (2005).
Steiner M, Hirschberg AL, Bergeron R, Holland F, Gee MD, Van Erp E: Luteal phase dosing with paroxetine controlled release (CR) in the treatment of premenstrual dysphoric disorder. Am. J. Obstet. Gynecol. 193(2), 352–60 (2005).
Other information from GlaxoSmithKline's clinical trial registry can be obtained from the following website [106]: