SAGE ELEVATE PRESENTATION

ENDURING RESOURCE

Slide

Transcript

Slide 1

I'm Roger McIntyre. Dr McIntyre: I'm a psychiatrist. I am a professor of

psychiatry in Toronto. I'll give a very brief and pithy

introduction to my colleague, Dr. Jamie Maguire, who

is very local - Tufts University associate professor of

psychiatry. And we're going to be sharing with you in

this very brief presentation the topic of postpartum

depression. It's a topic I don't think I need to spend a lot

of time on in pressing upon you how important this is.

For the last 20 years I have been running a very large

mood disorders program with the University of

Toronto. We have had several thousand patients over

the years who have first presented with postpartum

depression. I would say in the last five to 10 years

we've learned more about this topic and the

pathoetiology of this topic than we have in the previous

two or three decades combined. This information is

now guiding us towards very novel ways of helping

people who have this condition.

Slide 2

Now, the company who is supporting this presentation

is Sage Therapeutics, and both Jamie and myself are

supported by this company so you should know who

your spokespersons are today and who they are

working with so we have these conflicts to disclose.

Slide 3

This is a brief resume. I'm in Toronto. Jamie is very

local here in Boston at Tufts University.

Slide 4

Let's, if we can, just begin to set the stage or really

describe the topology of the land here. We want to talk

about postpartum depression. You're going to see this

acronym, PPD, throughout the slides. We're going to

talk about the prevalence of this condition. We're going

to talk about some of the disease models that have been

put forward to help us understand postpartum

depression. Then we're going to move in to some very

nice data that, frankly, Jamie has been leading this area

scientifically - helping us understand the molecular as

well as some of the endocrine aspects that are

subserving this phenomenology. Then we'll get into the

treatment.

Slide 5

Let's talk about facts and figures.

Slide 6

The DSM-5 does not have postpartum depression as a

discrete entity but has it listed as a specifier. In other

words, if you have depressive symptoms during

pregnancy or within four weeks of delivery that would

meet the criteria for puerperal depression or postpartum

depression. Other documents like the ICD-10 have

longer windows. Up to six weeks in the case of the

ICD. The World Health Organization extends it out to

12 months, but the point is that we have this entity

described in the DSM-5.

With respect to differential diagnosis the key

differential diagnosis is, in my view, bipolar disorder.

So any patient you see who presents with syndromal

depression in that postpartum period, you've got to be

thinking about bipolarity given the very high

probability that many individuals with postpartum

depression do have bipolar.

Slide 7

The differential diagnosis is what I call the trifecta.

You've got postpartum depression, you've got the

postpartum blues, and you have this postpartum distress

or, in some cases, a full-blown trauma that can be

recapitulated. Postpartum blues is very common. Fifty

to 80 percent of women will have this. It tends to start

after birth and usually resolves within a couple of

weeks. That is very different than a syndromal

depression that persists and is often accompanied by

very severe levels of impairment. That's the part that

I've been quite struck by.

Slide 8

But here is what I think is the takeaway message. When

asked, "What is the most common complication of

pregnancy or postpartum?" It's depression. It's

estimated that between 8 and 20 percent of women

experience postpartum depression. Statewide rates have

varied. Most rates coming in, in this 10 to 12 percent

range. It's more common than diabetes during

pregnancy. More common than hypertension. More

common than eclampsia. All these conditions that we

hear about, we've been trained about, we're paying

attention to are less common than postpartum

depression despite the high prevalence in its rank order

as being the most common problem of pregnancy

postpartum.

It is often the case that women are not accessing care

specifically for this problem. Only 10 to 12 percent of

women actually access care for this problem.

Slide 9

Now, this is a statewide look. This is a portrait

obviously, of the U.S. The point is, is that this is a

cross-national phenomenon. It's an international

phenomenon cutting across sociodemographic

categories. All cultures, all races regardless of

education. This is an enormous statistic that almost half

a million women will be affected by postpartum

depression.

Slide 10

Now, the implications to mom are obvious. You have

this condition which is a serious brain-based disorder.

That being depression, and that's often associated with

suicidality and, obviously, impairment in quality of life

and function. Along with that there's often maladaptive

behaviors that are recognized as increasing during this

time. Not only smoking of cigarettes, but more

commonly the misuse of alcohol. We also know that

because of postpartum depression or associated with it

we see much more pre-term delivery. Small for

gestational age and certainly, underweight infants.

Certainly, this is a serious issue indeed.

Slide 11

Now, in a larger forum, in perhaps, a less distracting

environment we would have had a lot more time to go

through this slide which I think is really, an incredibly

educational slide. The message for me is trajectory.

Whether it's the short-term meaning in the first month

to two months where attachment begins to be realized.

In the more intermediate term, that is, within the first

few years of life around emotional development,

cognitive development, and certainly, behavioral

development. What we recognize in children of moms

with postpartum depression is they begin to exhibit

what we call off-trajectory. There's abnormalities

observed. These could be interfering with function, and

this can be manifested way out until the teenage years

with respect to a higher risk of mental illness. Said

differently, there's implications for mom, that

mom/child dyad, and that unfortunately, creates a

scenario for the child increasing the risk for off-

trajectory development.

Slide 12

I'm going to stop there, pass the podium over to Jamie,

and Jamie is going to take us through what mice can tell

us. At least the data around mice. So Jamie….

Dr Maguire: Thank you so much. My name is Jamie

Maguire, and I am an associate professor at Tufts

University right down the street. The goals of my lab

are to study how stress and GABAergic dysfunction

can contribute to neurological and neuropsychiatric

disorders. One of the major focuses of my lab is

postpartum depression and major depression.

Slide 13

The reason that we're interested in the GABAergic

system is it's the primary inhibitory nerve transmitter in

the brain. It is mediated by GABA receptors that have

unique pharmacology. Many of the drugs that we use

act on these specific receptors. There's unique receptors

that are sensitive to neuroactive steroids, derivatives of

steroid hormones that can act on specific subtypes of

GABA receptors and potentiate the inhibitory effects of

GABA. Other separate subsets of the GABA receptors

are sensitive to benzodiazepines. These inhibitory

actions can inhibit neuronal function but can also

coordinate activity across brain regions. We are

interested in how these GABA receptors play a role in

coordinating activity across brain regions including

limbic regions that are important for affect. We're

interested in the amygdala, prefrontal cortex,

hippocampus - brain regions that have been implicated

in mediating affective behaviors - as well as the

paraventricular nucleus of the hypothalamus. The

paraventricular nucleus of the hypothalamus regulates

the stress response. It coordinates the hypothalamic-

pituitary adrenal axis and CRH neurons. Corticotropin

releasing hormone neurons reside in this area. They're

at the apex of HPA axis control. We're really interested

in how the GABA system can regulate stress reactivity

and therefore, also influence circuits that are important

for affective disorders. These neurons, these CRH

neurons that control stress reactivity are tightly

controlled by GABAergic signaling. Over 50 percent of

the inputs on to those neurons are GABAergic so

they're really tightly fine-tune controlled by

GABAergic signaling. These can coordinate the stress

response, but again, can also coordinate the activity

between different brain regions.

Slide 14

We're studying the role of GABA receptors in the

regulation of neuro networks involved in affect. One of

the things that we discovered about 10 years ago was a

mouse model that exhibited abnormal postpartum

behaviors. Mice that lack the receptors that are

neurosteroid sensitive, these GABAergic receptors, the

delta-receptor knock out animals. These mice exhibit

deficits in maternal care, and they exhibit depression-

like behaviors restricted to the postpartum period. We

were interested in studying these animals to determine

the underlying neurobiology of PPD. Through a series

of studies we were able to discover that these animals

have altered stress reactivity during the peripartum

period. Typically, during the peripartum period the

stress-induced activation of the stress response and

elevations of stress hormones are suppressed. What we

find is that in this animal model they have the inability

to suppress the stress response. We think that this

inability to suppress the stress reactivity may trigger an

increased vulnerability to abnormal postpartum

behaviors.

Slide 15

What we did was we generated another mouse model

which lacks a transporter that's critical for GABAergic

signaling, but specifically in these CRH neurons that

control the HPA axis and control stress reactivity. What

we found is that those animals also had the inability to

suppress the stress response during this peripartum

period. They had the exact same phenotype as the

initial mouse model. They have depression-like

behaviors restricted to the postpartum period, and they

have deficits in maternal care. We think that these

abnormal behaviors are tied to these neuroendocrine

abnormalities and changes in stress reactivity. We think

that this change in stress reactivity during the

peripartum period increases vulnerability to PPD, but

that the changes are downstream of that initial

triggering change. That there's changes in neuro

networks that are important for affect. And so, we've

been focusing our research recently on looking at how

neuro networks that are important for affect change

during the peripartum period, focusing in on areas like

the amygdala, prefrontal cortex, hippocampus - again,

these limbic regions that are involved in mediating

affective behaviors. These are also regions that come

out of clinical studies so fMRI in patients with

postpartum depression often show changes in reactivity

in these areas under default mode network, also, in

response to stimuli like their own infants’ cry or faces

of their infants - suggesting that clinically these regions

are important, and they're altered in PPD. We've been

limited in studying these underlying biological

mechanisms in patients. What we can do in

experimental models is try to learn more about how

these networks become dysfunctional and can

precipitate some of these postpartum behaviors.

Slide 16

I mentioned that our two preclinical models share some

features such as the inability to suppress the stress

response during the peripartum period. They also

exhibit these abnormal postpartum behaviors. You may

be wondering how do we assess these in experimental

models. One of the things that we look at is depression-

like behavior using the forced swim test. This is a

learned helplessness test where mice are placed into a

pool of water, and the latency to give up swimming and

remaining immobile is used as a measure for

depression-like phenotype. The reason that that test is

used is because it is responsive to antidepressant

treatment. And so, if we look at the depression-like

phenotype in our animals we see no difference in the

virgin animals. These animals are completely healthy in

the virgin condition. However, during the postpartum

period we see the manifestation of these abnormal

postpartum behaviors. We see that there's a decreased

latency to immobility and an increased total time

immobile in the forced swim test. This is indicative of

depression-like behavior. We also see profound deficits

in maternal care. And so, in the top of the images you

can see normal nesting behavior of mice. In the delta-

receptor knockout animals and in our two preclinical

models they exhibit abnormal nesting behavior in

addition to these depression-like phenotypes. That is

associated with an increase in pup mortality. We see

over a 50 percent increase in pup mortality due to either

cannibalism or neglect in both of these models. And so,

they have these profound deficits in postpartum

behaviors and maternal care. We can also do a test

called the maternal approach test. You introduce the

dam to her litter. You measure the amount of time it

takes for them to approach the litter and the amount of

time that they actually spend engaging in normal

maternal care. Again, these animals have profound

deficits in maternal care so they have an increased time

to approach their offspring, and they spend very little

time actually engaging in maternal care. Again, this is

associated with an increase in pup mortality. We are

using these preclinical models to better understand the

underlying neurobiology of postpartum depression

which gives us a little insight in to the mechanisms

leading to this disorder. We can explore experimental

models that we're unable to do in the patient population.

We also have the ability to use these models to test the

therapeutic effects of novel compounds.

Slide 17

We have partnered with Sage Therapeutics to look at

the effects of a neuroactive steroid again, that acts on

these specific subtypes of GABA A receptors and

coordinate network activity in limbic regions. What we

find is that both the chronic treatment during the

peripartum period with the Sage compound, SGE-516,

or an acute treatment right before testing can decrease

depression-like behavior in these animal models and

can also improve maternal care. We see that we can

utilize these preclinical models to better understand the

underlying neurobiology of PPD and to test compounds

that might be useful.

I hope I've convinced you that there's some utility in

what we can learn from animal models related to PPD,

both the underlying neurobiology as well as screening

novel compounds. I'm going to pass it back over to Dr

McIntyre who is going to tell you about what we can

learn from moms as well as mice.

Slide 18

Okay, thank you, Jamie. Just to pick up on that I want

to highlight a certain point. For seven decades we have

actually pressed the point that monoaminergic

dysregulation is critical if not to the pathogenesis also

to the treatment of depression. This is the first time, as

Jamie just walked us through that we're looking at a

female type of depression. In this case, postpartum

depression and attempting to suss out a neurobiology

that is perhaps unique to that condition and then with

that information guide a very novel treatment avenue.

So rather than discovering antidepressants by accident

which has been our directive for seven decades we're

trying to develop treatments based on an understanding

of the disease model.

Slide 19/Video

This is the very first time we're talking about

neurosteroids as critical to this phenotype. Let's, if we

can now, look at a video.

[Video plays]

Slide 20

Okay, the message is we need to be asking patients

about symptoms that are commensurate with depression

in that postpartum period. That would begin clearly

with screening questions. Just verbalizing those

questions with patients. Most would know typical

screening questions and/or using a screening instrument

like the Edinburgh screening tool for postpartum

depression. Once a patient has a high level of suspicion

of having depression then I think our task is to establish

that diagnosis and to disambiguate the diagnosis from

other differentials that we talked about including, but

not limited to, bipolar disorder. Who are we particularly

vigilant in terms of the assessment for postpartum

depression? In other words, what are the risk factors?

These are women who have depression during

pregnancy or high levels of anxiety during pregnancy.

Women with a previous puerperal-related depression,

or postpartum depression, or nonpostpartum depression

clearly, are at higher risk. It won't surprise us that

psychosocial stressors serve as a general risk whether

they be stressors in the relationship, general stressors

like economics, and/or the absence of appropriate

partner support, as a non-specific risk factor

socioeconomics. The U.S Preventative Services Task

Force along with other groups has really made this

point many, many times that we need to be screening

for postpartum depression in all women who have

recently given birth. You can see the statistic here in

terms of how common this risk actually is in women.

Slide 21

Now, with respect to the mechanisms that are at play in

postpartum depression I think we need to ask two

related questions. Is this a distinct neurobiological

entity? Yes? No? And then the second question is what

are the points of commonality with other types of

depression, and what's the point of differentiation?

Well, there's many points of commonality. We know

that there's disturbances in the so-called stress axis - the

hypothalamic-pituitary adrenal axis. There is an

emerging story that up to half of people with depression

exhibit what we call proinflammatory balance. There's

something wrong with the innate immune inflammatory

system. Again, this is seen across different

subpopulations of depression. Epigenetics brings

together the stressor whether distal stressors like trauma

or more proximate stressors like a recent loss, and this

is transmuted at the genetic level. That's been described

in many different types of depression. But what Jamie, I

think, eloquently described is the neurosteroids’ aspect.

In neurosteroids in their role in the pathogenesis, maybe

the treatment of depression has been a story that has

really emerged informed by some of the preclinical, but

also now, some of the clinical evidence in postpartum

depression. That's something that we have been very

intrigued by - particularly, the possibility of targeting

that system. Then what happens is we have this

occurring at the molecular level. We zoom out just like

a Google map, and as you zoom out and you look at the

circuits we begin to see alterations at the circuit level

that Jamie spoke to that subserves the disturbance in

thinking, the disturbance in vegetative function, the

disturbance in mood that is so common in women who

have postpartum depression.

Slide 22

Now, with pregnancy you won't be surprised. There's

changes in the endocrine milieu, not just the stress

milieu - the so-called cortisol axis, but also sex steroids

like progesterone as well as neurosteroids,

allopregnanolone. Allopregnanolone is derived, in part,

from progesterone. It's also produced de novo from

cholesterol. These types of steroids increase during

pregnancy and then with parturition there's a

precipitous decline. Now, no surprise…it’s

pharmacology 101 when the hormones are increasing,

there are adaptive changes occurring at the receptor.

Jamie brought our attention to the GABA system, and

you have down-regulation of the GABA system. Then

what happens with that precipitous decline postpartum,

this interaction between neurosteroids modulation and

GABA seems to be abnormal in some women who have

postpartum depression.

Slide 23

If we look at some of the noninvasive imaging studies,

we're finding convergent evidence. In other words, if

we look at magnetic resonance spectroscopy studies

some studies are reporting now alterations region-

specific in GABA being decreased in the brain in some

women with postpartum depression. With the converse

that is an elevation of glutamate in other regions of the

brain, for example, the prefrontal cortex. We are also

seeing changes in the circuitry in the brain that have

been replicated now in subpopulations of women with

postpartum depression. Again, this is an ongoing

question. Is this unique to postpartum depression or

does it cut across other subpopulations and that's

ongoing? And finally, we see some region-specific

alterations in blood flow.

Slide 24

So to bring this together what we would say is as

follows: we have at the molecular level points of

commonality with subtypes or subphenotypes of

depression. What's emerging and what I would call the

suspect in the center of the line is this alteration in

neurosteroids GABA activity that Jamie spoke to

creating what we call an inhibitory, excitatory

imbalance. At the circuit level we're seeing alterations,

neurochemical changes, as well as brain reactivity

changes that collectively create the so-called

endophenotype that leads to postpartum depression.

Slide 25

What are the management options?

Slide 26

Well, it's pretty dark in terms of what's out there, but

the management options being with what's in the

guidelines. We've got relatively few guidelines. The

Florida Medicaid Group,

www.medicaidmentalhealth.org has got a very nice,

free of charge updated set of recommendations in this

area. Antidepressants in psychotherapy emerge

immediately to mind. Unfortunately, we don't have as

much evidence really evaluating antidepressants.

Slide 27

We have certainly plenty of evidence for manualized-

based psychotherapies. IPT, CBT, mindfulness. Maybe

to some extent these treatments can be given in the

individual and group level which has cost advantages.

And more recently technology…it turns out that

computer-based or Internet-based CBT, for example,

can be very effective in postpartum depression. Some

emerging evidence for some of these alternative

therapies -- I don't know if that's the right word, but

omega 3s as well as yoga.

Slide 28

Now, for me to summarize the worldwide literature for

antidepressants in postpartum depression in this one

slide is concerning. This is it. We don't have a lot of

evidence for antidepressants in the postpartum. These

are positive studies. Some data here reported in this

case for sertraline, and we have some negative data

here including some very large aggregate analysis like

some systematic reviews and meta-analysis.

Slide 29

The message is that we really have a woeful body of

evidence supporting antidepressants in postpartum

depression. The guiding principles are no different.

Start low. Use the lowest effective dose but use an

effective dose. Use what previously worked. Obviously,

patient involvement is relevant. Comorbidity

sometimes guides what we choose. We don't have a

gold standard because the evidence is so woeful, quite

frankly, but this is a point worth mentioning that some

of the SSRIs, sertraline, paroxetine, fluvoxamine have

lower breast milk concentration.

Slide 30

So to summarize postpartum depression is common. It's

the most common complication of pregnancy and

postpartum. Most of these women are not actually

being detected. Most are not being specifically probed

for this common phenotype. The implications for mom

and the child, I think, are abundantly obvious. In the

academic world where Jamie and I spend a lot of our

time, in that ecosystem many questions about sussing

out the neurobiology, but this emerging story that

alterations in neurosteroids may be playing a unique

role in this phenotype…that's guiding potential novel

treatments. In the interim screen for it, ask about it,

diagnosis it when present. Differential diagnosis is

warranted and consider some of the available

treatments we have so that we can not only help lives

for moms, but also evidence indicates we'll set that

young child on a better life trajectory.

Slide 31

So with that, folks we're going to stop there. Thank you

very much for your attention.