Late Life Depression: When the Golden Years Turn Grey (and the SSRIs Don't Shine)

It never gets old to talk about late-life depression. Lets explore why growing older can sometimes mean growing sadder.

We prance through executive dysfunction, vascular woes, inflammatory fires, and amyloid beta blues. 

We’ll discuss why SSRIs might not be the golden ticket and what alternatives, like dopamine agonists, rTMS, and even ECT, can brighten those grey years.

Plus, we'll ponder if your patient is depressed, or if their brain is just throwing a vascular tantrum.

Tune in, turn up your hearing aids, and fluid restrict for the next 20 minutes if you have the worlds smallest bladder.

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Transcript

Dr. Amayo: So Dr. Handratta, why should we talk about depression in late life? Is it because you're getting old? 

That's true. That's one. That's one. That's one reason. Absolutely. Right. Like I need to be worried about it.

Thanh: Welcome to the Y in Psychiatry!

Dr. Amayo: Hi, this is Dr. Amayo consult and liaison fellow..

Thanh: Where we delve into the intricate nuances of psychiatric topics.

Dr. Handratta: My name is Dr. Handratta attending psychiatrist. I did my residency from University of Connecticut and then I did my fellowship from Georgetown University in consultation and liaison.

Thanh: Each episode features interview style discussions that explore the intersection of the mind medicine and the human experience. Together we'll uncover the hidden why and the groundbreaking discovery shaping the psychiatric landscape.


So grab a seat, warm beverage, tune in, [00:01:00] and let's embark on this journey to unlock the mysteries of the human psyche. Only on The Y in Psychiatry.

Dr. Amayo: 3, 2, 1. Welcome back to the Y in psychiatry, and as usual, it is your host, Dr.

Amayo. And I have, and this is Dr. Handratta. 

Dr. Handratta: Hello guys. 

Dr. Amayo: Hi. Hi. If you've forgotten, I'm a C/L Psychiatry fellow, and Dr. Handratta is a attending extraordinaire in psychiatry. And today is our last episode for this season, and we are gonna close it up as life closed up. With geriatric depression, so depression in late life.

So Dr. Handratta, why should we talk about depression in late life?

Dr. Handratta: So the reason we talk about late life depression is because late life depression is a huge risk factor for different medical causes, right? It can lead to obesity, which in turn lead to [00:02:00] hypertension. Patients can have hyperlipidemia, diabetes, which in turn increase the risk of cardiovascular and cerebrovascular disease.

So there's a huge link between depression and comorbid medical conditions, plus medical condition itself actually can lead to late life depression. 

Dr. Amayo: So it's a cycle? Yes. Yes. And do we know why? 

Dr. Handratta: Yeah, so there is some theories about late life depression, right? So the four prominent theory for late life depression, one is called as the depression executive dysfunction syndrome, right?

The second one is the vascular theory, the vascular pathology that leads to late life depression. The third is the inflammation. How inflammation plays an important role in onset of depression. And the fourth one is the amyloid beta deposits in the brain that leads to depression, which in turn increase the risk for Alzheimer's dementia in neuro car.

Dr. Amayo: Okay, so what's depression executive dysfunction syndrome. 

Dr. Handratta: So depression, executive [00:03:00] dysfunction syndrome. It's basically a problem in your frontal striatal white matter tracts. So it's a white matter tract that connects the frontal lobe. to your striatum or the basal ganglia. So patients with the depression executive dysfunction syndrome, they have increased in the white matter hyperintensity in these tracks.

Plus they also, during the depressive episode, showed decrease activation of your dorsal lateral prefrontal cortex, which is a part of your central executive network. As well as the dorsal anterior cingulate cortex, which is a part of your salience network.


And so this is the pathology that you see in depression executive dysfunction syndrome. But 30% of these patients will also have changes in their neuropsychological testing. And these patients usually don't respond to SSRI, they're more resistant to SSRI or they'll show a partial response and they're more likely to relapse actually quickly on an SSRI, 

Dr. Amayo: When you say changes in neuropsychological testing, are we talking [00:04:00] cognitive changes?

Dr. Handratta: Exactly, it's about cognitive changes. Like they can actually show a decrease in their verbal fluency. They show a decrease in the response inhibition. They can have problem with novel planning. They can have problem with working memory, they can have problem with idio motor planning.

They can have problem with cognitive flexibility. 

Dr. Amayo: Are we sure this is not like a presentation of a neurocognitive disorder in itself. 

Dr. Handratta: This is not actually like they, they don't present with depression. So if you look at the symptoms actually that are present, right? So they're not like typical major depressive disorder.

So these patients will have more suspiciousness. So paranoia, right? They will have more anhedonia. They'll show psychomotor retardation and decrease insight. But there are very minimal depressive symptoms and minimal neuro vegetative symptoms. So that's what actually differentiates it from melancholic depression or major depressive disorder.

But there's no cognitive domain in there. It's not like they're basically like forgetting things. Like how patients with Alzheimer's dementia, [00:05:00] but sometimes patients with dis depression, executed dysfunction may have Alzheimer's with infant. Yeah. 

Dr. Amayo: Yeah. Sounds a lot like front to temporal dementia, with the behavior change and paranoia.

Dr. Handratta: A bit paranoia. Yes, but they're not like disinhibited, like in frontotemporal dementia. Frontotemporal dementia if it, the behavioral variant. So frontotemporal, behavioral symptoms you basically see a lot of apathy. You see a lot of lack of empathy.

You see socially inappropriate behavior. Hyperphagia of frontotemporal dementia , behavioral type. Sometimes patients actually have never smoked in their life, never had alcohol in their life, and you see them actually smoking and drinking alcohol. 

Dr. Amayo: So this is remarkable. Bit different from that.

Dr. Handratta: Yes, exactly. 

Dr. Amayo: So this is more mood, apathy, right? Lack of insights and maybe some slight paranoia. Paranoia. Exactly okay. So if SSRIs doesn't work well with this medication, what do we do? 

Dr. Handratta: So one of the treatment that works with these patients like there's no placebo [00:06:00] controlled trial. But this is a medication that also helps in patients with Parkinson's disease who have depression.

It's a dopamine D2/D3 receptor agonist called pramipexole that we use for patients with restless leg syndrome and fibromyalgia. So you can add that to SSRI to make it work better. Yeah, because it's a problem with the dopamine system. 

Dr. Amayo: Would you use like a stimulant? 

Dr. Handratta: You can actually use stimulants, but I don't know whether it's been studied in depression, executive dysfunction syndrome, but it makes sense if you look at the neurobiology behind it.

Dr. Amayo: So this depression executive dysfunction, we call it DED. Does sound makes it sound cool? Yes. So it's dead. Dead. It's a, it's not funny. So it's a dysfunction between your striatum and your frontal lobe. 

Dr. Handratta: Yes.

Dr. Amayo: And that connection for some reason, it sounds like there's hyperintensity in MRI. Not, maybe there's a lack of connection. Yeah. It seems [00:07:00] but this syndrome usually presents with maybe some low insights, some paranoia, and they're not very responsive to SSRIs, and it seems like having a dopamine agonist helps with that .

Okay. And so another cause of late life depression is vascular causes. Yes. 

Dr. Handratta: So as, in the mid or the late life, you're more prone for hypertension and diabetes , right? Which increases your vascular risk. So patients can have multi-infarct dementia when they have multiple strokes.

And strokes at the right area of the brain can cause dysfunction. So here actually you'll see white matter lesions in the frontal temporal occipital parietal lobe. But white matter tracks are also affected for example, like the cing ular or the insulate fascicular or superior launch of fascicular.

Now patients, another risk factor is increase in the homocysteine, so you can check the homocysteine level. If it is increased, then these patients are more likely to develop late life depression. 

Dr. Amayo: [00:08:00] And secondary to vascular cause. 

Dr. Handratta: Exactly. Exactly. And again, these vascular dementias are also not very responsive to SSRIs.

Dr. Amayo: You say vascular dementia or vascular depression. 

Dr. Handratta: Oh, vascular cause for depression? Yeah. They're also pretty resistant to SSRIs unless the patient has had depression in the past. Which has responded to an SSRI then you can use SSRIs in these patients. 

Dr. Amayo: How can you differentiate this from vascular dementia?

Dr. Handratta: So vascular dementia is it's called multi impact dementia. 

So you see a step ladder pattern. So patient will have a stroke, they'll decline, and then they'll do fine for some time till they have one other stroke. 


And vascular dementia usually has involvement of the white matter as well as your deep gray matter. And you can see lacunar infarcts in the brain. They will have vascular risk factors, but you have to differentiate it from something called Binswanger's disease, which is just a subcortical white matter changes, but there's no gray matter involved. 

Dr. Amayo: So Binswanger's disease is vascular as well, right? 

Dr. Handratta: It's vascular. It's the same vascular risk factor like multi infarct dementia. Only thing is that [00:09:00] it's a subcortical white matter tract involvement. There is no gray matter involvement like multi-infarct dementia, and so slowly progressive dementia. 

Dr. Amayo: So Binswanger's will just be in your, subcortical. Okay. And this is different from vascular caused depression because there is no neurocognitive disorder involved. 

Dr. Handratta: Yes. 

Dr. Amayo: So it would just seem the mood aspect 

Dr. Handratta: Exactly. 

Of it.

Exactly. 

Dr. Amayo: But it sounds like. If you rode the dice enough, you can get either one. 

Yes, you can. If there a stroke is at the right area of the brain, then you can also develop dementia. So in multi infarct dementia, you will see a change in the personality of the patient. You can see patients will have ataxia. They will have incontinence and they can also have pseudo-bulbar symptoms. 



So how can you help with vascular cause depression? 

Dr. Handratta: So they have tried rTMS. rTMS has been found to be effective in patients with vascular dementia. Again, there's no randomized placebo controlled trials.

Dr. Amayo: So vascular depression basically depression in late life, most likely secondary [00:10:00] to chronic vascular diseases. Similar pathology to vascular dementia, except now the presentation or the syndrome that we're seeing is a depressive like syndrome. Yes. And I assume just like improving risk factors, so take care of the hypertension, take care of cholesterol and things like that will probably help and prevent worsening of the syndrome.

Dr. Handratta: Absolutely. And it's a good thing that you mentioned. So there have been trials actually where you can add angiotensin receptor blockers. So the trial that was done was using candesartan. The reason is that you can't use ACE inhibitor. ACE inhibitors will block both angiotensin one and two.

Angiotensin receptor blocker blocks only angiotensin one, not angiotensin two. Angiotensin two is required for vasodilatation, neuronal differentiation, and axonal regeneration. 

So when you don't block the angiotensin two, you actually help with neural growth and differentiation. 

Dr. Amayo: Interesting. 

Dr. Handratta: They've also used calcium channel blocker with fluoxetine. They have used nifedipine as well as verapamil 

Dr. Amayo: [00:11:00] Oh wow. 

Dr. Handratta: To improve depression in patients with vascular risk factors. 

Dr. Amayo: So with vascular, cause dementia, we can use it could, with the SI, with the SSRI. So it seems first line for most of these treatments are still SSRI. Just, you might need another agent to assist with it. Alright, so you also 

mentioned inflammation. Yes. 

Dr. Handratta: So inflammation is another important cause, right? So there's an enzyme that is stimulated by inflammation, right? It's called indoleamine 2 3-dioxygenase, that converts your tryptophan into kynureninic acid, which is toxic to the neurons. 

So what happens is now, since a tryptophan is converted into a toxic metabolite, you don't have enough tryptophan for production of serotonin, and you don't have enough serotonin.

You cannot produce enough melatonin, so you can have depression with the sleep disturbance. 


So plus if your cytokines are actually increased, it also actually causes glucocorticoid resistance. So these are some of the factors that can actually increase the risk for. Depression in patients who have chronic inflammation [00:12:00] that's going on.

Dr. Amayo: Is there a particular reason why the older population are more susceptible to this inflammatory driven depression? 

Dr. Handratta: This is also because your immune system is not as strong as you grow older and inflammation, theory of depression came into existence from hepatitis C infection, like when you used to give interferon to patients with Hepatitis C. 

These patients showed an increase in the amount of glutamate in the basal ganglia, and they were more prone for depression. So we used to treat those depression by using paroxetine at that time. But now you are better treatment for hepatitis C, so you don't use interferon.

Yeah. And plus, in inflammation can also increase the CRP level. So there's a study which shows that if the CRP is high, so if the CRP is less than one milligram per liter, they responded better to escitalopram. The CRP is more than one milligram per liter. They responded better to nortriptyline.

Then there was a study that was done where they used TNF alpha antagonist called Infliximab. It worked very well in patients who had depression, but the CRP level of more than five [00:13:00] milligram per liter. So the CRP was not elevated, infliximab was not effective. But if the CRP was elevated.

That population responded well to it. 

Dr. Amayo: And just for our listeners and to CRP is for C-reactive protein. 

Dr. Handratta: C-reactive protein

Dr. Amayo: And it's a marker for inflammation. So inflammatory driven depression, when there's high stress level, when there's high inflammation, there's an enzyme I already forgot, 

Dr. Handratta:  indoleamine 2 3-dioxygenase 

Dr. Amayo: That enzyme increases the use of tryptophan and therefore there's no tryptophan to make serotonin. And there's no tryptophan to make melatonin. And ultimately from the best that we know, more serotonin good, less serotonin depression. Yes. And that's what we think is going on for inflammatory depression. And so it sounds like SSRI. Can be effective with these patients? 

Dr. Handratta: Yes. SSR has been found to actually decrease those inflammation markers.

Dr. Amayo: Yes. Okay. 

Any other adjunct you had with that? 

Dr. Handratta: Nothing actually like, but we'll talk about like how we augment SSRIs in patients with late life depression. Yeah. 

Dr. Amayo: And then the last one, amyloid-beta. Yes. 

Dr. Handratta: So amyloid-beta we all know. [00:14:00] Yeah. It's a response which is seen in patients with Alzheimer's dementia.

It can also be seen in other conditions. So data actually shows that people who have long standing history of major depressive disorder. So we showed people who have major depressive disorder are more likely to have deposits amyloid beta in the hippocampus.

But patients who have late, like depression. How even more amyloid beta deposit in the hippocampus. And we know hippocampus is part of your default mode network. 

And these patients are more likely to develop depression. So when they looked at patients with amnestic, MCI, mild cognitive impairment, when they have late life depression, these patients actually convert into Alzheimer's dementia faster.

And there's more likely for them to convert. So amyloid-beta is a risk factor for the conversion of an MCI into a full flow blown dementia of Alzheimer's type plus depression along with it. 

Dr. Amayo: Okay. And I guess my is would amyloid better driven late life depression

wouldn't that just be like a precursor to Alzheimer's? 

Dr. Handratta: [00:15:00] Yes. 

Dr. Amayo: Cognitive disorder. 

Dr. Handratta: Absolutely, so if you have depression after the age of 65 years, it's a prodrome of dementia, basically. Yeah. Okay.


Dr. Amayo: Any hope for treatments with that? 

Dr. Handratta: Now they have the antibodies actually that they use for Alzheimer's dementia, and it works good with patients who have a mild cognitive impairment.

So if you pick those patient population early on in life. Yeah. You have treatment. 

Dr. Amayo: I wonder if, so before we have evidence of a neurocognitive disorder, but we have a high suspicion of a amyloid beta driven depression. Would you use like a rivastigmine or. Oh I, it, the cholinesterase inhibitor use with an SSRI something 

Dr. Handratta: you can use a cholinesterase inhibitor. There are some studies actually using cholinesterase inhibitor like donepezil with an SSRI. So cholinesterase inhibitor will not prevent depression. It'll not actually decrease the progression of the dementia. It does, but very mild. 

It's more effective to treating apathy, agitation, and psychosis in patients with dementia Alzheimer's type.

Dr. Amayo: Okay so [00:16:00] we talked briefly about the medications. It sounds like SSRI is the go-to for all of this four types of late life depression causes. And it sounds like with DED we want to use and dopamine agonist medication, anything else that we need. 

Dr. Handratta: So if the patient shows a partial response to SSRI or they do not respond to SSRI, you can augment with lithium where the data is pretty good. You can actually augment with aripiprazole where again, the data is actually shown to be pretty good. ECT is the most effective treatment for late light depression, where the remission rate is about 60 to 80%. And then there's another study where ECT was added to venlafaxine, where the response rate was about 70% and remission was 61%.

And then once the patient reaches remission, then you can add or ECT every month to a combination of venlafaxine and lithium, which actually improve the quality of life over the next 24 months. So ECT is the [00:17:00] best treatment to go with 

Dr. Amayo: Regardless of if we're thinking the pathology is driven by vascular versus inflammatory versus amyloid beta? 

Dr. Handratta: Exactly right. If they don't respond to SSRI and you want an immediate response. ECT is perfect. It works good for depression with psychosis. People, if they're not eating well, are not tolerating medications. 

Dr. Amayo: Okay. We should do a talk about ECT. Yes, we should. Do we do? We know why it works.

Dr. Handratta: ECT do not know exactly where it works and how it works, but we know that it increases BDNF. Okay. Brain derived neurotropic factor 

Dr. Amayo: Okay okay, that is it for late life depression. So late life depression. Depression. We said late life. So from 50 years old.

Yeah. And up. So these are times when there's a lot of stress. There's a lot of medical conditions that could be affecting it. And one of the causes, so we talked about depression, executive dysfunction, we talked about vascular causes, we talked about inflammation, and we talked about amyloid betas and how to take care of those.

Thank you for listening. And [00:18:00] again, this is the Y in psychiatry. 

Dr. Handratta: Thank you. Yes, sir. 

Thanh Nguyen: End of season one. Boom. End of season one. 

Dr. Amayo: Oh my God, sir, I forgot how smart you were. Oh no. Thank you. You quickly reminded me.

Thanh Nguyen: thank you for joining us on today's episode, our tireless team is already hard at work on the next season We're gonna cobble together another potpouri of fascinating discussions for the next season so be sure to tune in and listen again to this season if you want to. Remember to visit our website, give us some feedback on our podcast.

More than anything else, we really hope we're facilitating that curiosity about psychiatry or as we like to think about it, the the why in psychiatry. All right, until next time everyone, keep smiling, keep shining, stay curious out there.