23/05/18. Mood changes in postmenopausal women treated with progesterone

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1 //8 Is Premenstrual syndrome (PMS) / Premenstrual dysphoric disorder (PMDD) due to paradoxical effects of progesterone metabolites and possible to treat? Torbjörn Bäckström MD., PhD., Professor Umeå Neurosteroid Research Center, Department of Clinical Sciences, Obstetrics and Gynecology, Norrlands University Hospital, Umeå, Sweden. Support: EU structural fund, Swedish research council Medicine, Västerbottens county, Umeå Municipal, Northen Sweden health region Disclosure: Owns shares in: Umecrine AB, Asarina Pharma AB, Umecrine Cognition AB Symptom and hormone variations in patients with PMDD/PMS n=8 cycles in 9 patients Bäckström et al 98 Mood changes in postmenopausal women treated with progesterone Cyclicity disappears in anovulatory cycles Progesterone but not placebo is give negative mood symptoms in postmenopausal women receiving estrogen / progesterone or placebo N=8, two cycles in the same persons with one spontaneous anovulatory cycle Hammarbäck et al, Acta Endocrinol 99; : - Negative mood score 8 Estradiol, mg/day Progesterone mg/day or placebo Day of cycle Andreén et al, Psyconeuroendocrinol Synthesis of GABA-A receptor modulating steroids Mitochondrial transport of cholesterol is rate limiting for allopregnanolone synthesis in brain. Scientific background The GABAA receptor TSPO GAMS -OH Progesterone -deoxycortisol Cortisol osterone Anatomical distribution of GABAA receptor subclasses. α is very sensitive to allopregnanolone aa-cortisol α-dht Androstanediol Bäckström et al, Springer NY 8 Wisden et al. J. Neurosci. ;99: The GABA system CNS s general moderating system The GABAA receptor is a chloride channel The GABA-A receptor is target for - GABA - GABA-A receptor modulating steroids (GAMS) - barbiturates - benzodiazepines - ethanol emotional center Sensitive to GAMS memory center α amygdala Thalamus, globus pallidus

2 Allopregnanolone, nmol/l Irritabillity, score Depression, score //8 Symptom and allopregnanolone relation during menstrual cycle in women with PMDD Negative mood curve correlates with allopregnanolone serum concentration r=.;p<.. n=8 cycles in 9 patients Wang et al. J. Clin. Endocrinol. Metab. 99;8:-8 Bäckström et al. CNS Drugs. ;():-. Ovulation Menstration 8 Days in idealizised menstrual cycle GABA steroid Paradox Why is that? In the menstrual cycle an increase in allopregnanolone is related to development of negative mood but In animal studies allopregnanolone is anxiolytic, antiepileptic, and sedative Benzodiazepins, barbiturates, alcohol and allopregnanolone have a bimodal action. High concentrations are anxiolytic, anti-aggressive, sedative/anaesthetic, and antiepileptic. Wang MD, et al. Int Rev Neurobiol ;:-9. Paul SM, Purdy RH. Neuroactive steriods. FASEB J 99;:-. Bäckström T, et al. Steroids in relation to epilepsy and anaesthesia. Ciba Found Symp 99;:-. Low concentrations induce strong negative mood, irritability and aggression in % of individuals. Moderate changes in % of individuals. Beauchamp MH, et al. Allopregnanolone, place aversion in rats. Pharmacol Biochem Behav ;:9-. Fish EW, et al. Alcohol, allopregnanolone and aggression in mice. Psychopharmacology ;:-8. Lee GP, et al. Severe behavioral complications following amobarbital injection. Neurology 988;8:-. Kurthen M, et al. Severe negative emotional reactions in amytal procedures. Cortex 99;:-. Masia SL, et al. Emotional outbursts during intracarotid amobarbital procedure. Neurology ;:9-9. Yoshimura H, et al. Psychotropic drugs and maternal aggression in mice.psychopharm.989;9:9 Miczek K, et al. Alcohol, benzodiazepine GABAa receptor and aggression. Rec. Dev Alcohol 99;:9- Wenzel et al. Negative reaction on midazolam. J Am Soc Echocardiogr ; : 9-. GABA receptor sensitivity is different in PMDD - the paradoxical response Dysphoria Anxiety Irritability Baseline Anxiolysis Sedation Drug response Expected effect Example: -% of patients given a low dose benzodiazepine respond with severe anxiety and aggression and -% with a moderate paradoxical response rather than an expected sedation. This is overcome by administration of a higher dose. Among women -8% have PMDD, -% severe PMS. Paradoxical effect Physiological concentration range Drug concentration / Dose Fig from Löfgren 9 Effects of allopregnanolone and alcohol on the frequency of attack bites in mice with alcohol-heightened aggressive behavior Negative mood relates to increasing plasma allopregnanolone in postmenopausal women taking oral progesterone Progesterone / allopregnanolone (Low concentration) increases amygdala reactivity in women on aversive pictures fmri. Indicates paradoxical effect. Mice Miczek Human ** Andréen et al Negative mood * * * Allopregnanolone and alphaxalone has similar biphasic effect as alcohol on aggressive behavior in mice Physiological range during luteal phase > Allopregnanolone (nmol/l) Allopregnanolone in physiological range has a biphasic relation to negative mood symptoms in humans Progesterone / Allopregnanolone Effect of oral progesterone administration on responses in amygdala assessed with fmri van Wingen GA, van Broekhoven, Verkes RJ, Petersson KM, Bäckström T, Buitelaar JK, Fernandez G. Progesterone selectively increases amygdala reactivity in women. Molecular Psychiatry. 8 ;:- Plasma concentrations after oral Progesterone

3 //8 High progesterone / allopregnanolone reduce activity in amygdala at aversive pictures. The expected effect and opposite to low concentration Inhibition of allopregnanolone effect van Wingen G, van Broekhoven F, Verkes RJ, Petersson KM, Bäckström T, Buitelaar J, Fernandes G. How progesterone impairs memory for biologically salient stimuli in healthy young women. J Neurosci ;:- with Reduced fmri is obtained with Benzodiazepines in a dose that cause anxiolytic effects. Paulus, et al. Arch. Gen. Psychiatry., Plasma concentrations after oral progesterone Right amygdala at high Progesterone Phase IIa clinical study Exploratory Phase IIa clinical study (UM) completed Ø Double-blind, randomised, placebo-controlled study. Ø Population: of women Ø Criteria: PMDD verified according to DSM-IV by prospective ratings during at least two menstrual cycles using the validated DRSP scale Ø showing ovulation during cycle Ø having usable ratings and Ø given doses of Ø Sub group population: The patients that were given as intended during the symptomatic premenstrual period. Ø Primary endpoint: change in symptoms and impact of symptoms assessed by daily ratings using the validated DRSP tool for PMDD* Ø Grading of psychological parameters and physical symptoms Ø Severity of everyday social functioning and work performance graded Ø graded rating scale ranging from not at all to extreme Overwhelming response from patients wanting to enrol in the trial Outcome conclusions Sepranolone is safe and well tolerated, alleviates symptoms and improves symptom-induced impairment in daily life GABA-A receptor modulating steroids (GAMS), metabolites of stress and sex- hormones, induce symptoms and disorders. Treatment by blocking GAMS Using an unique new principle * EMA and FDA guidelines GABA-A modulating steroid antagonist (GAMSA) Patients treated with Sepranolone. Total population (n=) including patients not treated during the symptomatic premenstrual period. All treated patients, (intention to treat analysis) including patients not treated according to the study protocol during the symptomatic period. Total premenstrual symptom score (p=.) n= n= Sub-group treated as intended (n=). Sub-group of patients that started according to the study protocol showed highly significant beneficial effects of Sepranolone on: Total premenstrual symptom score (p=.) a)bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, Timby E, Wulff M, Ehrenborg A, Bäckström T. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC)-A randomized controlled trial. Psychoneuroendocrinology. Jun;8:- n= n= Sepranolone Sepranolone twice as effective as YAZ Sepranolone has an effect size of.a in total symptom reduction compared to placebo, vs. YAZ standardized effect size of.b b)yonkers, et.al.efficacy of a New Low-Dose Oral Contraceptive With Drospirenone in Premenstrual Dysphoric Disorder. Ob&Gyn..();9. Summarized impairment scores during the pre and menstrual cycles in the placebo and UC treated groups Thank You

4 //8 PMS and oral contraceptives Bäckström et al 99 Treatment of women with PMDD using GnRH-agonist for induction of anovulation in a doubleblind cross-over study, n= Pre Buserelin Hammarbäck,Bäckström 988 Breast tenderness Irritability score Cherful score Pre GnRH agonist - - Sepranolone modulates the allopregnanolone-induced decrease in Saccadic Eye Velocity (SEV) in healthy women. - clinical trial protocol UNC Sepranolone modulates the allopregnanolone-induced decrease in SEV in healthy women - data from clinical trial report Exploratory single-center, pharmacodynamic study in healthy women during follicular phase Single-blind, cross-over design Intravenous bolus administration of ALLO alone or ALLO + Sepranolone (two doses). mg/kg allopregnanolone +. mg/kg Sepranolone IV +. mg/kg Sepranolone IV Assessment of GABA A receptor activity (SEV and sedation) before and following drugs Bengtsson SKS, Nyberg S, Hedström H, Zingmark E, Jonsson B, Bäckström T, Bixo M. Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. Psychoneuroendocrinology. Feb;:- AUC -8 change in saccadic velocity (min Deg/sec) following single i.v. injections of allo alone or allo in combination with Sepranolone Allo Allo + low dose Sepranolone Allo + high dose Sepranolone P=. P=. Result of primary analysis: SEV AUC allo vs. allo+sepranolone (both Sepranolone doses combined) p=. Bengtsson SKS, Nyberg S, Hedström H, Zingmark E, Jonsson B, Bäckström T, Bixo M. Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. Psychoneuroendocrinology. Feb;:-) Patients treated as intended in protocol Sub group analysis Analysis of the sub-group of patients that started according to the study protocol showed highly significant beneficial effects of UC on: Sepranolone meets FDA s primary endpoint* in phase IIa study. Double-blind, placebo controlled trial in of patients Patients received five doses over days from ovulation Two doses, mg and mg tested; pooled data below *Total symptom score of symptoms Total premenstrual symptom score (p=.) Cardinal negative mood score (p=.) Impairment score (p=.), which measures the impact of symptoms on daily life in the week prior to menstruation Overall effect showed an 8 % correction of premenstrual symptoms Statistically significant reduction in total premenstrual symptom score (p=.) compared to placebo Sepranolone twice as effective as YAZ by indirect comparison Sepranolone has a standardized effect size of. in total symptom reduction as compared to placebo, vs. YAZ standardized effect size of. (*KA Yonkers, et.al.efficacy of a New Low-Dose Oral Contraceptive With Drospirenone in Premenstrual Dysphoric Disorder. Ob&Gyn..();9). n= n= N= n= Sepranolone Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, Timby E, Wulff M, Ehrenborg A, Bäckström T. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC)-A randomized controlled trial. Psychoneuroendocrinology. Jun;8:-

5 //8 Highly significant effect in Treated as Intended population Highly statistically significant reduction in pre-menstrual symptom score in treated as intended population (p =.) Some patients initiated too early and may thus have been drug-free during the days with peak ALLO concentration just prior to next menstruation Self rated Irritability Scores in women with PMDD in different situations placebo citalopram: continuous citalopram: semiintermittent citalopram: intermittent n= n= Sepranolone Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, Timby E, Wulff M, Ehrenborg A, Bäckström T. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC)-A randomized controlled trial. Psychoneuroendocrinology. Jun;8:- Wikander et al 998 Mean (SE) symptom changes in women with PMDD and Controls using daily prospective symptom ratings with the Cyclicity Diagnoser Depression Irritability PMDD Epidemiology of Premenstrual Symptoms and Complaints All women with menstrual cycles As many as -8% have premenstrual symptoms -% PMS -8% PMDD Sundström-Promaa et al 999 Anxiety Days of menstrual cycle ). de la Gandara Martin and de Diego Herrero, 99; Hylan et al., 999; Ramcharan et al., 99; Wittchen et al., ; Woods et al., 98 ). Angst et al., ; Wittchen et al., ). American Psychiatric Association, 99; Andersch et al., 98; Angst et al., ; Campbell et al., 99; Chawla et al., ; Cohen et al., ; Deuster et al., 999; Gehlert and Hartlage, 99; Johnson et al., 988; Ramcharan et al., 99; Rivera-Tovar and Frank, 99; Sveindottir and Backstrom, ; Wittchen et al., ; Woods et al., 98 Diagnosis Criteria Symptoms Required Duration of symptoms PMS VS PMDD PMS PMS PMDD ICD- ACOG DSM-IV of mood of mood - days days Synptom free - - days postmens Functional Impairment Prospective Charting days postmens Not required Required Required Not required cycles Required ( cycles) PMDD in DSM-IV A. Five symptoms, one from symptoms below, in most menstrual cycles the past year, present the premenstrual week absent post menstrual week Depression, Irritability, Anxiety/tension, Affect lability Decreased interest, Difficulty in concentrating, Fatigue, Out of control, Insomnia Change in appetite, Breast tenderness, Swelling B. Markedly Interfere with work, social-and family-life C. Should not be an exacerbation D. Criteria A-C must be confirmed by daily prospective symptom ratings in two consecutive menstrual cycles

6 //8 PMS ACOG A. Two symptoms, one from symptoms below, in most menstrual cycles the past year, present days during the premenstrual week absent post menstrual week Depression, Irritability, Anger burst Anxiety/tension, Confusion, Social withdrawal Change in appetite, Breast tenderness, Abdominal bloating B. Interfere with work, social-and family-life C. Should not be an exacerbation D. Criteria A-C must be confirmed by daily prospective symptom ratings in two consecutive menstrual cycles PMS: ICD - - CM CRITERIA Only ONE of the following symptoms required: Psychological discomfort Feeling of bloating / weight gain Breast tenderness Swelling of hands and feet Various aches and pains Poor concentration Sleep disturbance Change in appetite Pure PMS PM aggravation Hammarbäck et al 989 Hammarbäck et al 989 No PMS Comparison between severe PMS / PMDD patients and controls with regard to symptoms during menstrual cycle Cyclicity Diagnoser (CD) scale daily rating = absence of symptoms, Hammarbäck et al = maximal severity of symptoms M. Bixo et al. / Psychoneuroendocrinology (Sundström et al., 999). ()