SAGE ELEVATE PRESENTATION ENDURING RESOURCE Slide Transcript - - PDF document

SAGE ELEVATE PRESENTATION ENDURING RESOURCE Slide Transcript Slide 1

• e. 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
• f 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

• r, 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

• bviously, 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

• bserved. 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

• f 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

• ut 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

• f 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

• ver 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,

• r 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

• f 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
• f having depression then I think our task is to establish

that diagnosis and to disambiguate the diagnosis from

• ther 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,

• r 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

• r 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

• ccurring 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

• ngoing? 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

• mega 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

• f 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

• ut 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.