Gender and Mood

David Printz, MD

Bipolar Disorder Research Clinic

New York State Psychiatric Institute

Columbia University

Slide 2

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

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

Treatment of PMDD

Serotonin Specific Reuptake Inhibitors (SSRIs)

Luteal phase treatment with SSRIs

Gonadal steroids

GnRH agonists (e.g., Lupron)

Post-partum Depression (PPD)

Slide 12

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

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

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.

Episodes During 12 Months Follow Up

Gender and Episode Frequency

Slide 18

Slide 19

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

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?

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%

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?

"Estimated 7%"

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”

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.

Slide 27

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

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.

Slide 30

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

Menstrual Phase Effects

Slide 34

Slide 35

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.

Slide 37

Perimenstrual Mood Changes
Possible Pathophysiology

"Is estrogen an antidepressant?"

Is estrogen an antidepressant?

Clinical trials

Neurotransmitter effects: 5HT

Is progesterone a mood stabilizer?

Neurosteroids

Neurotransmitter effects: glutamate, GABA

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.

Slide 41

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.

Estrogen Effects on 5HT

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

Progesterone metabolites :

Allopregnanolone (3a, 5a TH Progesterone)

3a, 5a TH deoxycorticosterone

Pregnanolone (3a, 5b 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 μM concentrations, produce Chloride influx without GABA

Slide 46

Slide 47

Slide 48

Neurosteroid Effects

Effects of Neurosteroids

Antidepressant

Anxiolytic

Anticonvulsant

Neuroprotective / neurotrophic

Mood Stabilizer Effects on GABA and Glutamate

Slide 52

Treatment

Slide 54

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.


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


	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


	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


	Serotonin Specific Reuptake Inhibitors (SSRIs)
	Luteal phase treatment with SSRIs
	Gonadal steroids
	GnRH agonists (e.g., Lupron)


	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.


	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


	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.


	Increased depressive episodes in women with BPD leading to increased anti-depressant use.
	Hormonal fluctuations acting to drive episode frequency.


	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.


	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%


	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.


		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”


	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.


	Mood should fluctuate in relation to the menstrual cycle in women with RCBD.
	Episodes may preferentially originate in particular phases of menstrual cycle.


	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.


	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.


	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.


	Is estrogen an antidepressant?
		Clinical trials
		Neurotransmitter effects: 5HT

	Is progesterone a mood stabilizer?
		Neurosteroids
		Neurotransmitter effects: glutamate, GABA


	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.


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


	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


		Progesterone metabolites :
			Allopregnanolone (3a, 5a TH Progesterone)
			3a, 5a TH deoxycorticosterone
			Pregnanolone (3a, 5b 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 μM concentrations, produce Chloride influx without GABA


	Antidepressant
	Anxiolytic
	Anticonvulsant
	Neuroprotective / neurotrophic


	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.