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Gender and Mood:

Gender and Mood

PowerPoint Presentation:

Women and Bipolar Disorder

Mood Disorders with Sexual Dimorphism:

Women and Bipolar Disorder Mood Disorders with Sexual Dimorphism Unipolar depression (MDD): females > males Bipolar disorder: females more prone to rapid cycling Mood syndromes related to hormonal shifts: Premenstrual dysphoric disorder (PMDD) Postpartum depression Perimenopausal and postmenopausal depression

Unipolar Illness in Women: Incidence and Prevalence Data:

Women and Bipolar Disorder Unipolar Illness in Women: Incidence and Prevalence Data National Comorbidity Survey (NCS): MDD: 21% ♀ / 12.7% ♂ PMDD 5% Post-partum affective illness: “Blues” 26-85%; up to 10 days postpartum Depression 10%; onset within first 4 wks postpartum Psychosis 0.5%; highly recurrent Perimenopausal age range: 10% incidence of MDE symptoms  ratio of MDE ( ♀ : ♂ ) 4:1

Unipolar Illness in Women: Incidence and Prevalence Data:

Women and Bipolar Disorder Unipolar Illness in Women: Incidence and Prevalence Data National Comorbidity Survey (NCS): MDD: 21% ♀ / 12.7% ♂ PMDD 5% Post-partum affective illness: “Blues” 26-85%; up to 10 days postpartum Depression 10%; onset within first 4 wks postpartum Psychosis 0.5%; highly recurrent Perimenopausal age range: 10% incidence of MDE symptoms  ratio of MDE ( ♀ : ♂ ) 4:1

Premenstrual Dysphoric Disorder:

Women and Bipolar Disorder A. In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3), or (4): (1) markedly depressed mood , hopelessness or self-deprecating thoughts (2) marked anxiety , tension, feelings of being "keyed up," or "on edge" (3) marked affective lability (4) persistent and marked anger or irritability or increased interpersonal conflicts (5) decreased interest in usual activities (e.g., work, school, friends, hobbies) (6) subjective sense of difficulty in concentrating (7) lethargy , easy fatigability, or marked lack of energy (8) marked change in appetite , overeating, or specific food cravings (9) hypersomnia or insomnia (10) a subjective sense of being overwhelmed or out of control (11) physical symptoms : e.g., breast tenderness, headaches, joint pain and "bloating." Premenstrual Dysphoric Disorder

Premenstrual Dysphoric Disorder:

Women and Bipolar Disorder B . The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school). C. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as Major Depressive Disorder, Panic Disorder, Dysthymic Disorder, or a Personality Disorder (although it may be superimposed on any of these disorders). D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) Premenstrual Dysphoric Disorder DSM-IV Criteria Sets for Further Study, 1994

Treatment of PMDD:

Women and Bipolar Disorder Treatment of PMDD Serotonin Specific Reuptake Inhibitors (SSRIs) Luteal phase treatment with SSRIs Gonadal steroids GnRH agonists (e.g., Lupron )

Unipolar Illness in Women: Incidence and Prevalence Data:

Women and Bipolar Disorder Unipolar Illness in Women: Incidence and Prevalence Data National Comorbidity Survey (NCS): MDD: 21% ♀ / 12.7% ♂ PMDD 5% Post-partum affective illness: “Blues” 26-85%; up to 10 days postpartum Depression 10%; onset within first 4 wks postpartum Psychosis 0.5%; highly recurrent Perimenopausal age range: 10% incidence of MDE symptoms  ratio of MDE ( ♀ : ♂ ) 4:1

Post-partum Depression (PPD):

Women and Bipolar Disorder Post-partum Depression (PPD) Kumar and Robson, 1984

Unipolar Illness in Women: Incidence and Prevalence Data:

Women and Bipolar Disorder Unipolar Illness in Women: Incidence and Prevalence Data National Comorbidity Survey (NCS): MDD: 21% ♀ / 12.7% ♂ PMDD 5% Post-partum affective illness: “Blues” 26-85%; up to 10 days postpartum Depression 10%; onset within first 4 wks postpartum Psychosis 0.5%; highly recurrent Perimenopausal age range: 10% incidence of MDE symptoms  ratio of MDE ( ♀ : ♂ ) 4:1

PowerPoint Presentation:

Women and Bipolar Disorder

Gender Effects in BPD:

Women and Bipolar Disorder Gender Effects in BPD Men and women with BPD have: Equal prevalence rates. Similar age of onset. Men and women with BPD differ in terms of longitudinal course: Rapid Cycling Bipolar Disorder (RCBD). Hormonal transitions.

Rapid Cycling Bipolar Disorder:

Women and Bipolar Disorder Rapid Cycling Bipolar Disorder Derived from studies of lithium failure Definition: 4 or more episodes, last 12 months Prevalence = 15% of BPD patients Not a stable phenotype Predictors: female gender antidepressant use thyroid disease Dunner and Fieve, 1974. Dunner 1979; Winokur 1969

Validation of Rapid Cycling for DSM-IV:

Women and Bipolar Disorder Validation of Rapid Cycling for DSM-IV Pooled data from four academic sites. All sites actively studying RC (to improve reliability/accuracy of assessment of episode number). Comparison of subjects with and without lifetime history of RC (n=120). Episodes distinct if polarity switch occurred or remission > duration of proximate episode. Bauer et al, 1994

Episodes During 12 Months Follow Up:

Women and Bipolar Disorder Episodes During 12 Months Follow Up Bauer, et al, 1994

Gender and Episode Frequency:

Women and Bipolar Disorder Gender and Episode Frequency % Female Episodes/12 Months Bauer, et al, 1994

PowerPoint Presentation:

Women and Bipolar Disorder Tondo and Baldessarini, Am J Psychiatry ,1998

PowerPoint Presentation:

Women and Bipolar Disorder Tondo and Baldessarini, Am J Psychiatry ,1998

Rapid Cycling in Women: Theories:

Women and Bipolar Disorder Rapid Cycling in Women: Theories Increased depressive episodes in women with BPD leading to increased anti-depressant use. Hormonal fluctuations acting to drive episode frequency.

Episode Type by Gender:

Women and Bipolar Disorder Episode Type by Gender 2 retrospective studies suggest more hospitalizations for mania in men and depression in women. Angst, 1978. Roy-Byrne, 1985. 2 studies found no gender difference. Winokur et al, 1994. 10 year prospective study, n=131. Hendrick et al, 2000. Retrospective study, n=131.

Are Women More Vulnerable to AD?:

Women and Bipolar Disorder Are Women More Vulnerable to AD? Retrospective review of 129 patients (55% female) Rate of rapid cycling: 56% of pts with prior AD exposure vs. 42% without Females: 77 vs. 41% Males: 36 vs. 42% Yildiz and Sachs, 2003

Evidence for Hormonal Effects on Mood in Affective Illness:

Women and Bipolar Disorder Evidence for Hormonal Effects on Mood in Affective Illness Unipolar syndromes occur during drops in estrogen/progesterone: Premenstrual Postpartum Perimenopausal Iatrogenic affective symptoms: HRT lowers depression scores. Affective symptoms have been associated with OCP and GnRH agonists.

What do we know about bipolar disorder during times of hormonal flux?:

Women and Bipolar Disorder What do we know about bipolar disorder during times of hormonal flux?

PowerPoint Presentation:

Women and Bipolar Disorder Estimated 7% of women in asylums had symptoms originating in post-partum period. Focus on psychosis, catatonia and delerium. “Where mania really appears in the puerperal state, it is… only a link in the chain of attacks of maniacal-depressive insanity. The puerperium cannot therefore be regarded as the cause, but only as the last impulse to the outbreak of the disease” E. Kraepelin, 1913

Postpartum Vulnerability:

Women and Bipolar Disorder Postpartum Vulnerability NIMH Genetics Initiative (1998): ½ bipolar women report “severe emotional disturbance” related to childbirth. 1/3 of these began during pregnancy. Viguera, et al (2000): Retrospective study of women with bipolar I/II discontinued from lithium.

PowerPoint Presentation:

Women and Bipolar Disorder

Working hypothesis: Rapid cycling is more common in women due to triggering by hormonal cycles. :

Women and Bipolar Disorder Working hypothesis: Rapid cycling is more common in women due to triggering by hormonal cycles. Mood should fluctuate in relation to the menstrual cycle in women with RCBD. Episodes may preferentially originate in particular phases of menstrual cycle.

Perimenstrual Mood Changes:

Women and Bipolar Disorder Perimenstrual Mood Changes 25 female RCBD subjects Daily self-ratings of mood for mean of 12 menstrual cycles Found no systematic relationship between mood and cycle but 11/25 had consistent changes. Limitation in mood instrument. Leibenluft et al 1999

PowerPoint Presentation:

Women and Bipolar Disorder EF LF EL LL

Method:

Women and Bipolar Disorder Method All rated days were allocated to one of the four phases: EF, LF, EL or LL based upon timing of menses. Mean and SD of each phase obtained for each subject and converted to z scores. Comparisons made within subject across the cycle and within the entire group.

Subjects:

Subjects ID Type Cycles Studied Mood Stabilizers 001 NRC 22 VPA 002 NRC 13 LTG 003 RC 9 VPA, LTG 004 RC 19 Lithium, VPA, LTG 005 RC 9 LTG 006 RC 11 LTG, quetiapine, TPM 007 RC 7 Lithium 008 RC 10 Lithium 009 RC 5 Lithium, VPA, LTG, ziprasidone Mean 11.7

Menstrual Phase Effects:

Women and Bipolar Disorder Menstrual Phase Effects Subject 001 002 003 004 005 006 007 008 009 Dx NRC NRC RC RC RC RC RC RC RC Sleep EM EL DM ANX IRR FXN = ANOVA significant by phase

PowerPoint Presentation:

Women and Bipolar Disorder F=2.90, df=3, p=0.05

PowerPoint Presentation:

Women and Bipolar Disorder F=3.21, df=3, p=0.036

Preliminary Observations:

Women and Bipolar Disorder Preliminary Observations All subjects had at least one dimension of mood which varied significantly with menstrual phase. There were differences between individuals in phase relationships (Subgroups?). As a group, elevated mood peaked in the late follicular phase and depressed mood in early follicular phase.

PowerPoint Presentation:

Women and Bipolar Disorder EF LF EL LL

Perimenstrual Mood Changes Possible Pathophysiology:

Women and Bipolar Disorder Perimenstrual Mood Changes Possible Pathophysiology Estrogen Progesterone Mood Early Follicular ↔ ↔ Depressed Late Follicular  ↔ Elevated Early Luteal    Stable Late Luteal  

PowerPoint Presentation:

Women and Bipolar Disorder Is estrogen an antidepressant? Clinical trials Neurotransmitter effects: 5HT Is progesterone a mood stabilizer? Neurosteroids Neurotransmitter effects: glutamate, GABA

Is Estrogen an Antidepressant?:

Women and Bipolar Disorder Is Estrogen an Antidepressant? Potential mechanism: 5HT modulation Clinical data: Werner et al 1934: estrogen injection > placebo for depression. Improvement in depressive symptoms in postmenopausal women without MDD. Variable results across several studies of estrogen in perimenopausal/postmenopausal women with MDD.

PowerPoint Presentation:

Women and Bipolar Disorder

Estrogen in Peri-Menopause:

Women and Bipolar Disorder Estrogen in Peri-Menopause N=50 in perimenopause MDD, dysthymia or minor depression Not receiving psychotropics Double blind, placebo controlled treatment with 100 μ g transdermal 17 β -estradiol. Soares et al 2001

Estrogen Effects on 5HT:

Women and Bipolar Disorder Estrogen Effects on 5HT Estrogen ↑ Tryptophan Hydroxylase ↓ Serotonin Transporter ↓ 5HT1A Autoreceptor ↓ MAO Enzyme Levels ↑ 5HT Tone

Evidence for a 5HT/Estrogen Connection:

Women and Bipolar Disorder Evidence for a 5HT/Estrogen Connection PMDD responding to luteal SSRI use SSRI>TCA in postpartum depression: PPD less response to TCA than non post-partum depression. Open label response rates: 67% TCA, 79% SSRI. 8 week open label sertraline: 95% response rate, 66% remission. Women may be more sensitive to tryptophan depletion

3α Reduced Neurosteroids:

Women and Bipolar Disorder 3 α Reduced Neurosteroids Progesterone metabolites : Allopregnanolone (3  , 5  TH Progesterone) 3  , 5  TH deoxycorticosterone Pregnanolone (3  , 5  TH Progesterone) Allosteric regulation: At nM concentrations, increase frequency and duration of GABA-induced channel opening. Most potent known endogenous positive allosteric regulator of GABA A Direct agonism: At μ M concentrations, produce Chloride influx without GABA

PowerPoint Presentation:

Women and Bipolar Disorder Chloride influx produced by GABA in presence of allopregnanlone and TH-deoxycorticosterone

PowerPoint Presentation:

PREGNENOLONE PROGESTERONE ALLOPREGNANOLONE CHOLESTEROL ACETATE HMG CoA reductase P450scc 3 β-HSD 5 α-reductase GABA receptor ( - ) (+)

PowerPoint Presentation:

Women and Bipolar Disorder Gibbs, et al, 1999 NMDA Receptor

Neurosteroid Effects:

Women and Bipolar Disorder Neurosteroid Effects GABA Glutamate Estradiol - -/+ * Pregnenolone-S - + Progesterone + 0 Pregnanolone –S 0 - Allopregnanolone + 0 Allopregnanolone-S 0 - * NMDA(-) AMPA/Kainate (+)

Effects of Neurosteroids:

Women and Bipolar Disorder Effects of Neurosteroids Antidepressant Anxiolytic Anticonvulsant Neuroprotective / neurotrophic

Mood Stabilizer Effects on GABA and Glutamate :

Women and Bipolar Disorder Mood Stabilizer Effects on GABA and Glutamate Glutamate GABA Lithium ↓ Valproate ↓ ↑ Carbamzepine ↓ Lamotrigine ↓ Topiramate ↓ ↑

PowerPoint Presentation:

Women and Bipolar Disorder Progesterone Allopregnanolone Stress Menstrual Cycle (L > F) Diurnal Variation (+) (~) (~) Pregnancy (+)

Treatment:

Women and Bipolar Disorder                                                                  "I don't mind at all. I take St. John's wort." Treatment

PowerPoint Presentation:

Women and Bipolar Disorder "I considered hormone replacement therapy. But for me, husband replacement therapy worked much better."

Conclusions:

Women and Bipolar Disorder Conclusions Mood disorders are influenced by gender, likely via hormonal state and transitions. This allows for some degree of anticipation. Mood disorders are greatly under-treated; presenting an opportunity for internists, gynecologists and others to improve identification and reduce morbidity and mortality. The marriage of improved basic science knowledge of hormonal influences on brain and mood, as well as greater understanding of mood disorder phenomenology, provides hope for more specific and effective treatments.

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