Men Are From Mars, Women Are from VenusGender Differences in Psychiatry

Presenter : Sukhmani Kaur Sadana, MD PGY-3 Psychiatry Resident, UND

• Schizophrenia

• Depression

• PTSD

• Alcohol Use Disorder

Overview

Upon completion of this program, the learner will be able to

• Understand the gender based differences that exist in some of the major psychiatric disorders• Understand the reasons that explain the same differences• Examine the recent evidence on gender based pharmacological treatment options

Objectives

Schizophrenia• Affects about 23 million people worldwide • 1.2% Americans (3.2 million) affected• Male: Female incidence = 1.4:1 ( Aleman et al ), ( Mc Grath J et al )

• Female onset is 3-5 years later than men• Men have a single peak of onset between 21 to 25 years

while women have bimodal presentations, one between 25 to 30 and the other one after 45 years

• Women make up up to 66-87% of late onset schizophrenia

Rina Li et al, PubMed

M Afsal Javed et al, Journal Of Pakistan Medical Association, February 2000

But Why????Structural TheoryOverview of structural neuroimaging abnormalities in schizophrenia• Cortical tissue loss• Smaller thalamus• Enlarged caudate nucleus• Small medial temporal lobes, volume reduction in superior

temporal gyrus• Reversed cerebral asymmetry

Abnormal Lateralization in Schizophrenia

• Schizophrenic brains have abnormal patterns of lateralization notably in hemispheres controlling language function (temporal lobes)

• Similar asymmetry in unimpaired relatives of schizophrenics.

• Large rightward asymmetry in major portion of temporal lobe (inferior and medial) and inferior frontal gyri. Stronger rightward lateralization in men than women in superior temporal lobe. (Tomasi et al)

• Males noted to have less normal asymmetry than females in the superior temporal lobe. Also noted to have reduced volumes than women

• Males noted to have reversal of normal left > right inferior parietal lobes as well. Schizophrenic females did not differ from healthy females in respect to inferior parietal lobe volume.

Role of Estrogen

• ER-alpha mRNA expression is reduced in schizophrenic patients

• SNP in intron 1 of ESR1 gene in schizophrenics- lower expression of ER-alpha receptors in prefrontal cortex

• 46% (sample 276) of hospital admissions in females were during menstruation or just prior to menstruation.

(Dalton K et al)

• Female schizophrenic patient’s have more severe symptoms in low estrogen phase of their menstruation cycle.

Hormonal Theory

• Psychotic symptoms improved during pregnancy and worsen in postpartum period.

• Premenopausal women have better course of illness and respond better to neuroleptics than menopausal women.

• Symptom severity scores were less in mid luteal phase than early follicular phase.

Mode of Action

Estrogen modulates the dopaminergic system- competes with dopamine at receptor sites, therefore decreases the level of dopamine in schizophrenics.

Estrogen has neuroprotective effects• promotes neuronal sprouting• myelination• enhances synaptic density and plasticity• facilitates neuronal connectivity• anti-inflammatory, antioxidant • improves cerebral blood flow

Role of Oxytocin• Increasing evidence of oxytocin as regulator of human social behaviors (social decision making, evaluating

and responding to social stimuli)mediating social interactions forming social memories.• Preclinical mouse models show oxytocin has potential

antipsychotic effect through inhibitory regulation of mesolimbic dopamine

• Conflicting results of association between oxytocin levels in schizophrenia patients and potential protective role in women.

Treatment OptionsEstrogen• 5 RCTs found significant weighted effect size for the efficacy of

estrogen on total symptom severity in women with schizophrenia.

• All RCTs provided estrogens for 4-8 weeks and no long term studies could be done because of the side effects of long term estrogen therapy.

SERMS• Currently raloxifene is the only SERM approved for long term

treatment• Janna D Boer et al– a meta analysis of raloxifene augmentation in

men and women with schizophrenia (9 double blind RCTs included)

Study N Group Mean age in years +/- SDRaloxifene Placebo

Dose (mg) Duration(weeks)

Kulkarni et al (2010)

21 F (post) 53.3 +/- 8 50.9+/- 4.2 120 12

Kulkarni et al (2010)

14 F (post) 54.6 +/- 4.6 50.9+/-4.2 60 12

Ussall et el(2010)/ Huerta Ramos et al(2014)

33 F (post) 60.1 +/- 6.41 62.7+/4.54 60 12

Kianimehr et al (2014)

46 F (post) 62 +/- 4.49 60.44+/5.28 120* 8

Khodaie- Ardakaniet al(2014

42 M 32.4 +/- 7.8 31.4 +/-5.9 120 8

Weickert et al(2015)

79 M, F (pre + post)

37.4 +/-7.3 34+/- 8.4 120 6

Kulkarni et al (2016)

56 F(per + post) 52.9 +/- 8.07 53.1+/7.43 120 12

Usall et al(2016) 70 F(post) 62+/-9.39 61.3+/-10.41 60 24

Weiser et al (2017) 200 F(post) 55.8+/-4.7 56.6+/- 4.6 120 16

Oxytocin

• Bakharave et al- IV or intranasal oxytocin 5 IU daily for 2 weeks to men with schizophrenia vs placebo for 2 weeks . Improved negative scores in treatment group

Depression• Affects 16.2 million Americans.• Global annual prevalence is 5.5 %and 3.2% in women and men

respectively• Most common types of depression are

1.MDD 2.PDD3.Bipolar depression 4.Seasonal depression5.Postpartum depression 6.Psychotic depression

• Women are twice as likely to suffer from depression• 10-15% women suffer from postpartum depression• 3:1 -female: male for seasonal depression

But Why????Biological TheoryOverview of structural brain abnormalities in MDD • Reduction in volume of subiculum of hippocampus• Abnormal reduction in the glial cells in prefrontal cortex and

amygdala

Sex based structural differences• Males- Increase in the GMV in left cerebellum and GMV

reduction in the bilateral middle temporal gyrus, left ventromedial prefrontal gyrus

Females- GMV reduction in left lingual gyrus and dorsal medial prefrontal gyrus

( Xiao Yang et al 2017 )

Genetic Factors• Heritability of depression is 40% with 2-3 times increased risk of

depression if first degree relative has depression.• GWAS studies

no single gene is responsible each susceptibility gene(SLC 6A4; polymorphism at 5-

HTTLPR, 5-TPH2, BDNF) contributes a small fraction to the overall genetic riskOverlapping sets of susceptibility gene that interact with

the environment

Sex Based Difference- Girls show higher incidence of a variant of serotonin transporter gene 5-HTTLPR

HPA Axis Dysfunction- Elevated cortisol, CRH, non suppression of dexamethasone suppression test, blunted ACTH response to CRH

Sex Based differences in HPA dysfunction• Female rats have higher number glucocorticoid receptors

• Female rats are more sensitive to the low levels of CRF and less adaptable to high levels of cortisol. This means that females more easily enter a state of hyperarousal.

• No consistent gender based difference in the response to stress found in humans.

Response to Stress

• Stressor specific differences in HPA axis dysfunction found. Women have higher cortisol with stressors like marital conflict; social rejection challenges while men responded to difficulties with achievement challenges (mathematic or verbal challenges)

• Women ruminate more than men while men are better able to distract themselves.

Hormonal Hypothesis

Role of Estrogen• Inconsistent studies on polymorphism of estrogen receptor genes

and risk of depression.• Estrogen modulates the serotonin levels in the brain. Site of

action is raphe nucleus. Beta estrogen receptors found , localization of ER- beta mRNA in raphe nuclei

• Estrogen induces the expression of tryptophan hydroxylase, increases the density of 5HT2a receptors in the brain.

• Female depression often occurs during periods of changes in hormones including prior to menses, immediately after pregnancy or shortly after menopause.

• The prevalence of depression in children is low(<5%) and rises drastically in pre adolescence stages(20%). Most notable in adolescent girls.

Role Of Oxytocin• Conflicting results on oxytocin levels in MDD. • Frasch et al- compared nocturnal plasma oxytocin level in

patients with MDD and healthy control. 83% showed a decrease in oxytocin when compared to age matched control.

• Anderberg and Uvnas Moberg- lower levels of oxytocin in women with MDD and fibromyalgia as compared to females with fibromyalgia without MDD.

• Other studies contradict these results.

Treatment Options• PMDDHormone replacement using OCPs, GnRH agonists and danzol

have been used. Various OCPs tested in open and controlled trial . General

consensus is OCPs are used to treat the physical symptoms associated with PMDD rather than the depression.

• Postpartum depressionSichel et al-Open trial demonstrating benefit of estradiol

therapy in postpartum women. 21 out of 23 women responded to sublingual 17-b estradiol therapy (4.8 mg/day) for 8 weeks.

Gregoire et al- Controlled trial where women received a higher dose of estradiol (200 mg/day) for 6 months in addition to antidepressants

had higher benefits with depression.Ahokas et al- Study with 23 women revealed 83% women reached

remission within 2 weeks of sublingual estradiol.• Postmenopausal/Peri-menopausal Depression Schmidt et al; Schneider et al- 2 out of 3 controlled trials

demonstrated efficacy of estrogen replacement (3 weeks) for physical and depressive symptoms.

• No randomized controlled trial demonstrating benefit of oxytocin in treatment of MDD.

PTSD•70% of the adult population in U.S has experienced some kind of traumatic event once in their lifetime.

•20% of this population goes on to develop PTSD (44.7 million people)

•Lifetime prevalence of PTSD in women is 10-12% while in men is 5-6%.

•One out of 9 women develop PTSD which makes them twice as likely as men.

•Women experience more numbing, avoidance, anxiety and affective disorders while men present with irritability, impulsiveness and substance use.

•PTSD sub cluster scores like re-experiencing and hyper arousal have been higher in women

But Why????Rate Of ExposureWomen are exposed to more high impact trauma (sexual trauma) at

a younger age than men. Trauma early in life has more impact especially type 2 trauma

(prolonged and repeated trauma) on neurobiological development and personality.

Biological Factors Evidence of HPA axis dysfunction in PTSD is inconsistent. Some studies reveal hypo activity while others report hyperactivity. Stressor specific differences in stress response noted. Women have

more sensitized HPA axis response to stress.

Hormonal Theory

Oxytocin is the “tend and befriend hormone”. Associated with decreasing the stress response to trauma. Higher oxytocin is associated with faster HPA recovery in

women.Early exposure to trauma is associated with disruption of

oxytocin system in children and plays role in development of emotional behaviors.

Response To Stress

Women more likely to report acute emotional responses-intense fear, helplessness, horror, intrusive thoughts, avoidance, panic and anxiety.Women are prone to develop peri-traumatic disassociation

(one of the strongest predictors of PTSD)Women show more sensitization to dissociative system while

men show more sensitization to hyper-arousal.

Cognitive AppraisalFemales more likely to report threat and loss appraisals than

males. Difference in “control appraisal” .Men show higher level of

perceived control which is associated with lower reliance on blaming others and lower risk of developing PTSDHigher perception of threat and loss of control in women

may explain the gender differences.

Treatment OptionsOxytocin for PTSD• Jessie L Frijling - repeated intranasal oxytocin administration

early post trauma reduced subsequent development of PTSD development

• Further studies required.

Alcohol Use Disorder

• 2015 National Survey on Drug Use and Health reported, more than 15.1 million adults ages >18 have AUD. Alcohol poisoning kills six adults every day.

• Of these 9.8 million are men and 5.3 million are women. • 20% of males have alcohol abuse while on 5-6% women

abuse alcohol.

Definition for AUD differ for men and women. • Drinking at low risk for developing AUD is >3 drinks in a

single day and no more than 7 drinks in a week for women while for men it is no more than 4 drinks in a single day and no more than 14 drinks in a week.

• Binge drinking for women is >4 drinks for women and >5 drinks for men on at least 1 day per month.

• The difference in the prevalence can be explained by both biological and social influences but the mechanism is unclear

Genetic Influences• Male adoption studies- the risk of men developing alcoholism with

a positive family history is 1.6-3.6 times higher• Women adoption studies- inconsistent data.• Twins studies- Genetic variability accounts for 50-60% of variation

in risk for alcoholism in males while the data is inconsistent for women.

• Candidate gene studies reveal multiple susceptibility gene involvement.

• Polymorphism of ADH1B and ALDH2 are strong genetic determinants of alcohol dependence

• Significant gender based differences in polymorphism of ALDH2 gene. Age of onset of alcoholism lower in females with inactive ALDH2 while no difference in male

But Why????

Pharmacokinetics• Women have reduced gastric ADH activity than men .• Women have lower body water content leading higher BAC in

women after absorption from GI• Women eliminate the same amount of alcohol as men do in an

hour but have higher elimination rate per volume of blood per hour. May lead to faster recovery

Dose Related Impairment• Women more susceptible to alcohol’s effect on cognition( memory

and divided attention)• Psychomotor performance (eye-brain-hand coordination and body

sway) not affected by gender

Questions