Guideline On The Treatment of Premenstrual Dysphoric Disorder (PMDD)
Guideline On The Treatment of Premenstrual Dysphoric Disorder (PMDD)
Guideline On The Treatment of Premenstrual Dysphoric Disorder (PMDD)
Draft Agreed by Efficacy Working Party Adoption by CHMP for release for consultation End of consultation (deadline for comments) Agreed by CNS Working Party Adoption by CHMP Date for coming into effect
April 2010 20 May 2010 30 November 2010 April 2011 21 July 2011 1 February 2012
Keywords
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European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
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Executive summary
There are substantial research data available to support premenstrual dysphoric disorder (PMDD) as a diagnostic entity of a severe form of premenstrual disorder, which causes clinically relevant functional impairment and requires treatment. It is considered a disorder with substantial clinical and public health impact in a [small] subpopulation of menstruating women. The aim of this guideline is to provide guidance for the evaluation of medicinal products in the treatment of PMDD. The present document should be conceived as general guidance, and should be read in conjunction with other applicable EU and ICH guidelines (see Section 3).
1. Introduction (background)
1.1. Epidemiology and classification of PMDD
Up to 70-90 % of women of reproductive age have one or more signs of physical discomfort or emotional symptoms in the premenstrual, i.e. luteal phase of their menstrual cycle. About 20-40 % of menstruating women have premenstrual syndrome (PMS) and experience luteal phase symptoms that are bothersome. A smaller number, up to 8 %, experience more severe symptoms, which lead to substantial distress or functional impairment and are referred to as premenstrual dysphoric disorder (PMDD) (10, 11, 13, 14, 23, 38, 39, 42). Although PMDD, like PMS includes physical symptoms, it always involves a worsening of mood that interferes significantly with the womans quality of life. The burden of illness of PMDD results from the severity of luteal phase symptoms, the chronicity of the disorder and the impairment in work, relationships and activities. In the last decades a very broad diagnostic concept of the premenstrual disorders PMS and PMDD has been used in clinical research, which produced different diagnostic criteria and highly heterogeneous study populations. Recent advances and research data improved the knowledge on diagnosis, frequency, pathophysiologic mechanisms, and treatment options in PMDD. This led to treatment recommendations by learned societies for PMDD.
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In conclusion, for the time being, the most homogeneous study population that can be recruited is with the DSM-IV diagnostic criteria and this population should therefore be used for clinical trials in PMDD (12, 20). As research criteria these DSM-IV criteria are in the process of being updated and further validated, particularly with regard to better quantification of the different domains affected. These changes may influence the position presented in this guideline.
1.4. Treatment
Based on theories regarding the underlying causes of PMDD, two main treatment options have been developed: (1) targeting the hypothalamus-pituitary-ovary axis by abolishing fluctuations in gonadal hormone levels (e.g. GnRH analogues, oestradiol, combined oral contraceptives (COCs)) and (2) targeting brain serotonergic synapses by increasing central serotonergic transmission (e.g. SSRI, NSRI) (4, 22, 31, 32). Since PMDD is an intermittent, cyclic illness periodic and continuous treatment interventions should be considered which may have different impacts on treatment compliance (see 4.3.3) and on long-term safety (see 4.5.3) (6, 15, 21, 43). Other therapeutic approaches include pharmacological treatment of physical symptoms as well as nonpharmacological methods including psycho-behavioural approaches, lifestyle changes and dietary modifications, which are not specifically addressed in this guideline (17).
the key symptoms are not part of the typical PMDD set of symptoms and emotional symptoms are not prominent (23). It is therefore important that the diagnosis of PMDD is accurately documented and other conditions excluded (see 4.1).
2. Scope
The scope of the present document is to provide guidance in the identification of the target population including special populations (adolescents), study duration, efficacy and safety endpoints to establish efficacy and safety in PMDD. Due to the chronic nature of the disorder special attention should be paid to maintenance of effect and long-term safety, and the presence and acceptance of comorbidity (see sections 1.5 and 4.1). With the most recent developments in the diagnosis and understanding of PMDD, it is considered an appropriate target for the development of pharmacological treatment. However, careful considerations on the adequate trial design of clinical studies are required. Up till now no medicinal products are approved in the EU for treatment of PMDD but data referring to the efficacy in the treatment of patients meeting PMDD diagnostic criteria according to DSM-IV are rather described in section 5.1 of the SmPC of some medicinal products, namely fluoxetine-containing medicinal products.
3. Legal basis
This guideline should be read in conjunction with Directive 2001/83 (as amended) and the following CHMP and ICH guidelines: Note for Guidance on Good Clinical Practice - CPMP/ICH/135/95 (ICH E6); Note for Guidance on General Considerations for Clinical Trials - CPMP/ICH/291/95 (ICH E8); Dose-Response information to Support Drug Registration CPMP/ICH/378/95 (ICH E4); Statistical Principles for Clinical Trials CPMP/ICH/363/96 (ICH E9); Choice of Control Group in Clinical Trials CPMP/ICH/364/96 (ICH E10); Clinical investigation of medicinal products in the paediatric population CPMP/ICH/2711/99 (ICH E11); Point to consider on adjustment for baseline covariates CHMP/EWP/2863/99; Guideline on missing data in confirmatory clinical trials CPMP/EWP/1776/99 ; Points to consider on Multiplicity issues in clinical trials - CPMP/EWP/908/99; Points to consider on application with 1. Meta-analysis; 2. one pivotal study CPMP/EWP/2330/99; Extent of Population Exposure to Assess Clinical Safety CPMP/ICH/375/95 (ICH E1); Pharmacokinetic studies in man - EudraLex vol. 3C C3A; Note for guidance on the investigation of drug interactions CPMP/EWP/560/95; Note for guidance on clinical investigation of medicinal products in the treatment of depression CPMP/EWP/518/97; Guideline on clinical investigation of steroid contraceptives in women EMEA/CPMP/EWP/519/98.
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irrespective of cultural background or socioeconomic status, although specific symptoms may vary in frequency by culture background. Diagnosis of PMDD should be based on reliable screening methods. The diagnostic criteria for PMDD require the presence of five out of the 11 Daily Record of Severity of Problems items, at least one being one of four essential mood symptoms (criterion A), as well as interference with work/school/social activity (criterion B). Criterion A symptoms must be present for most of the time during the last week of the luteal phase and must be absent in the week post menses, while the criterion B symptom must markedly interfere with work or school or with usual social activities and relationships with others (see Tables 1 and 3). The method of standardizing and operationalizing DSM-IV criteria should be described in studies of PMDD (33). A minimum duration of 4 days for symptom presence in the last week of the luteal phase is required. Prospective daily monitoring of symptoms for two consecutive menstrual cycles is an absolute requirement to meet DSM-IV criteria and until now considered to be the gold standard in PMDD clinical studies (see Table 1, DSM-IV criterion D, 7). As none of the symptoms are unique to the syndrome, patients need to keep a daily diary of symptoms for at least 2 menstrual cycles to establish the temporal relationship between the onset of symptoms and the premenstrual period and the absence of symptoms or a chronic underlying disorder during the follicular phase (12). Several assessment instruments to establish diagnosis of PMDD are available: e.g. the DRSP (Daily Record of Severity of Problems) (30), the DSR (Penn Daily Symptom Rating), and the MDQ (Menstrual Distress Questionnaire) (10). The method of standardizing and operationalizing DSM-IV criteria should be described in studies of PMDD (33). The choice of the instrument should be justified and validated in the target population (8). Retrospective reporting is not acceptable as retrospective recall of symptoms is unreliable (27). In any method of assessment of PMDD symptoms severity, it is important to determine baseline levels from which to quantify the actual change and cyclicity in symptom severity levels, especially symptom severity pre- and postmenstrually. Various scoring methods compare the average of symptom scores during the premenstrual days with the average of symptom scores postmenses. Although the core element of making a diagnosis of PMDD is the daily, prospective self-report of symptoms, this diary-based information should be supplemented by a structured interview conducted by the study raters (e.g. physicians), who should be properly trained for assessment of patients with the applied rating scales. Methods should be foreseen in the study protocol to assess inter-rater reliability (see 4.2.2). Presence and acceptance of comorbidities PMDD may be a comorbid condition with other axis I disorders of the DSM-IV classification, particularly depression and anxiety disorders (see section 1.5). The most difficult differential diagnosis for clinicians to make is distinguishing between PMDD and MDD. Although the lifetime comorbidity between the two disorders is significant, ranging from 30 to 70%, there is consistent evidence to support the distinct nature of each diagnosis. A key feature of depressive disorders is that symptoms are almost always present every day of the cycle. However, diagnosis of PMDD in the context of another axis I disorder raises a difficult diagnostic issue and to assure the integrity of the diagnosis of PMDD concurrent axis I disorders are not recommended in the study population (19, 42). 4.1.1. Inclusion criteria The following inclusion criteria should be met for phase 3 trials: PMDD should be diagnosed using the DSM-IV criteria. A careful diagnosis based on clearly defined, replicable severity criteria via prospective ratings for two run-in cycles is essential (see sections 4.1 and 4.2 (14)). A regular menstrual cycle: the length varies among individuals and varies slightly within an individual. Therefore cycles within the lower limit of 24 days and an upper limit of 35 days are considered to be within a normal range.
The determination of ovulatory cycles is required for pharmacodynamic trials where ovulation-related underlying mechanisms are studied (14). 4.1.2. Exclusion criteria Not menstruating, including pregnant
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Any axis I disorder (e.g. Dysthymia, MDD, PD, GAD, anxiety disorders), alcoholism or substance abuse during the last 2 years prior to the trial. Any medication for PMS or PMDD including, but not limited to hormones, bromocriptine, GnRH agonists, vitamin B6 (>100mg), calcium supplements (>1500 mg/day), sterols and plantderived products, anxiolytics, and antidepressants during the 3-month period prior to screening and during the study. In case hormonal contraceptives are used before the start of the trial as baseline therapy for contraception (depending on the medication studied), stratified analysis for add-on medication should be pre-specified. Contraindication to study medication depending on the medication studied (see section 1.4).
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and global assessment of symptom severity, improvement and adverse events. Physicians must be trained for using the different rating scales (see 4.1).
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LIST OF ABBREVIATIONS
Abbreviations and Terms
ACOG C-CASA C-SSRS COC COPE DRSP DSR DSM-III/IV GAD GnRH ICD-10 LLPDD MDD MDQ NSRI PD PMDD PMS PMSD SSRI
Definition
American College of Obstetricians and Gynaecologists Columbia Classification Algorithm of Suicide Assessment Columbia Suicide Severity Rating Scale Combined oral contraceptive Calendar of Premenstrual Experience Daily Record of Severity of Problems Penn Daily Symptom Rating Diagnostic and Statistical Manual of Mental Disorders Version III/IV Generalised Anxiety Disorder Gonadotropin-releasing hormone International Classification of Diseases, version 10 Late Luteal Phase Dysphoric Disorder (LLPDD) Major Depressive Disorder Menstrual Distress Questionnaire Norepinephrine and Serotonin Reuptake Inhibitor Panic Disorder Premenstrual dysphoric disorder Premenstrual syndrome Premenstrual Symptom Diary SelectiveSerotonin Reuptake Inhibitor
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Definitions
Table 1: DSM-IV criteria for PMDD
Table 2: ACOG diagnostic criteria for PMS Premenstrual syndrome can be diagnosed if the patient reports at least one of the following affective and somatic symptoms during the 5 days before menses in each of the three prior menstrual cycles*: Affective Depression Angry outbursts Irritability Anxiety Confusion Social withdrawal Somatic Breast tenderness Abdominal bloating Headache Swelling of extremities * These symptoms are relieved within 4 days of the onset of menses, without recurrence until at least cycle day 13. The symptoms are present in the absence of any pharmacologic therapy, hormone ingestion, or drug or alcohol use. The symptoms occur reproducibly during two cycles of prospective recording. The patients suffer from identifiable dysfunction in social or economic performance. (1)
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Table 3: Daily Record of Severity of Problems: psychological/physical and functional impairment items
Each of the items is rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum sum score of 126 is possible on the first 21 items (8).
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