AffLifecycle

Gender and Mood: 

Gender and Mood David Printz, MD Bipolar Disorder Research Clinic New York State Psychiatric Institute Columbia University

Mood Disorders with Sexual Dimorphism: 

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: 

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: 

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: 

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: 

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: 

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: 

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): 

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

Unipolar Illness in Women: Incidence and Prevalence Data: 

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

Gender Effects in BPD: 

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: 

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: 

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: 

Episodes During 12 Months Follow Up Bauer, et al, 1994

Gender and Episode Frequency: 

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

Slide18: 

Tondo and Baldessarini, Am J Psychiatry,1998

Slide19: 

Tondo and Baldessarini, Am J Psychiatry,1998

Rapid Cycling in Women: Theories: 

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: 

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?: 

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: 

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?: 

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

Slide25: 

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: 

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.

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

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: 

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

Slide30: 

EF LF EL LL

Method: 

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

Menstrual Phase Effects: 

Menstrual Phase Effects

Slide34: 

F=2.90, df=3, p=0.05

Slide35: 

F=3.21, df=3, p=0.036

Preliminary Observations: 

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.

Slide37: 

EF LF EL LL

Perimenstrual Mood ChangesPossible Pathophysiology: 

Perimenstrual Mood Changes Possible Pathophysiology

Slide39: 

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

Is Estrogen an Antidepressant?: 

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.

Estrogen in Peri-Menopause: 

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

Estrogen Effects on 5HT: 

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

Evidence for a 5HT/Estrogen Connection: 

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: 

3α 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 GABAA Direct agonism: At μM concentrations, produce Chloride influx without GABA

Slide46: 

Your use of this service is governed by Terms and Conditions. Please review our Privacy Policy for details on how we protect information that you supply. Chloride influx produced by GABA in presence of allopregnanlone and TH-deoxycorticosterone

Slide47: 

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

Slide48: 

Gibbs, et al, 1999 NMDA Receptor

Neurosteroid Effects: 

Neurosteroid Effects *NMDA(-) AMPA/Kainate (+)

Effects of Neurosteroids: 

Effects of Neurosteroids Antidepressant Anxiolytic Anticonvulsant Neuroprotective / neurotrophic

Mood Stabilizer Effects on GABA and Glutamate : 

Mood Stabilizer Effects on GABA and Glutamate

Slide52: 

Progesterone Allopregnanolone Stress Menstrual Cycle (L > F) Diurnal Variation (+) (~) (~) Pregnancy (+)

Treatment: 

                                                                "I don't mind at all. I take St. John's wort." Treatment

Slide54: 

"I considered hormone replacement therapy. But for me, husband replacement therapy worked much better."

Conclusions: 

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.