Mood, Metabolism, and Cognition: An Interview with Rodrigo Mansur

Table of Contents

Today – how the body influences the brain in mood disorders, an app to measure cognition, and a run down of treatments for cognitive decline in bipolar disorder.

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From Brain to Body and Back

In 1980, the Society for Neuroscience began lobbying Congress to increase funding for neuroscience research, and on July 18, 1990 their efforts paid off. President George HW Bush signed a formal proclamation designating the 1990’s as the “Decade of the brain.” At the time I had just started working at the National Institutes of Mental Health, and the excitement was palpable. You could not go to a meeting or lecture without hearing a reference to the initiative and the promise it held. And by the end of the decade, most people judged it a success. Here’s a few of the accomplishments:

  1. The discovery of neural plasticity. Before the 1990’s, students were taught in psychology 101 that the brain was a static organ that became kind of set in its ways by age 25. Now they are given a more empowering message: Through neuroplasticity, the brain changes throughout life – “use it or lose it” as the mantra goes, or as Dr. Amen put it in his bestselling book, Change Your Brain, Change Your Life. Thanks to these ideas, older adults are taking up musical instruments, aerobics, and dexterity games in hopes of reshaping their brain and staving off dementia. But we also learned that some periods of neural development were more critical than others, such as early childhood, which lead many states to launch pre-school education programs.
  2. The discovery of genetic mutations responsible for Huntington’s Disease, amyotrophic lateral sclerosis, and Rett Syndrome. Genetic advances like these have now entered clinical practice – and no, I’m not talking about pharmacogenetic testing – but testing for neurodevelopmental disorders with a genetic basis is now a routine part of the work up for autism and intellectual disabilities. If you’re not already doing that, look for it in our upcoming June issue this year – we’ll show you how.
  3. The discovery of the neural origins of alcohol use disorders
  4. And of course, a rush of new anticonvulsants and second-generation antidepressants and anti-psychotics

Psych Disorders Caused – or Kinda Caused – by Medical Conditions

That decade has long past, and if we had to anoint the research of the current day, I’d call it the decade of the body-and-brain. The DSM continues to uphold a firm line in the sand between the brain and the body with the exclusionary clause that the symptoms of most disorders cannot be “due to the physiological effects of another medical condition.” That line, which looks so clean and sensible in the textbook, is getting increasingly blurred as we learn about the multitude of ways that physical health impacts mental health.

KELLIE NEWSOME: It looks like they blurred the line a bit already in the transition from DSM-IV to DSM-5. In the old DSM we had to exclude symptoms that were due to a general medical condition, while in DSM-5 the wording is another medical condition, that word – “another” – suggests that psychiatric disorders are medical conditions as well.

CHRIS AIKEN: In reality, I’m hard pressed to think of a patient whose psychiatric disorder was not impacted in part by their physical health, and outside of delirium and neurologic illnesses, it’s equally rare to see a patient whose mental health problems are 100% due to a medical problem. It’s often said that when a patient has treatment resistant depression that you should go back to square one and look at whether any medical conditions like hypothyroidism, anemia, or vitamin deficiencies are causing the depression. And I hope our listeners will diligently run a lab panel like that – check out our June 2018 issue on treatment resistant depression for a list of what to include. But I don’t think our listeners are very excited to hear this advice, because they’ve learned from experience that those tests are fairly low yield. In fact endocrinologists are currently debating whether we should routinely test for thyroid problems in depressed patients, because the false-positive rate is high and we end up treating a lot of cases of subclinical hypothyroidism that – in the view of our endocrinology colleagues – do not need to be treated.

Hormones, Inflammation, and Metabolic Health

KELLIE NEWSOME: So you may not find that elusive general medical condition that explains all your patients symptoms, but you can make a big difference by pausing to consider how their physical health is impacting their brain, particularly in depression. That boils down to at least three categories, all of which overlap and influence each other in some way:

  1. Hormones. That includes the hypothalamic pituitary axis, through which so-called stress hormones like cortisol flow, as well as reproductive hormones.
  2. Inflammation. On this one we have numbers. Inflammation contributes to 30% of cases of depression, and when it comes to treatment resistant depression that number jumps to 50%.  The causes of inflammation are many, here’s a short list:
  3. Stress…. From childhood trauma to recent stressful life events
  4. Infection, whether active or recently like within the past 6-12 months
  5. Chronic medical illness, especially arthritis, autoimmune diseases, chronic pain, asthma, diabetes, cancer, and heart disease.
  6. Obesity (particularly a BMI above 30)
  7. Recent chemotherapy or radiation
  8. Recent bodily injury or surgery

One of those – recent infection – has become particularly relevant in the COVID era. This month a new study found that 52% of COVID-19 patients developed a full depressive episode within 4 months of the infection.

  • Metabolic health. It’s not uncommon to see a psychiatric patient with obesity, diabetes, or high cholesterol, or with the vascular diseases from high blood pressure to coronary artery disease. Each of these metabolic problems has an independent effect on both mood and cognition, and in this month’s Carlat Report we featured an interview with Rodrigo Mansur who is leading some of the research in this area.
Rodrigo Mansur, MD

Insulin Resistance in the Brain

CHRIS AIKEN: In medical school I was taught about all the end-organ damage that diabetes causes, from the retina to the toes. But the brain was never on that list, which never made sense to me – why would it be spared the same kind of damage? Dr. Mansur’s discoveries suggest it is not spared – that diabetes increases the risk of depression, cognitive problems, and dementia. The brain, it turns out, develops insulin resistance much as the rest of the body does, but insulin plays a different role in the brain.

Dr. Mansur: It’s the idea that insulin signaling in the brain is dysfunctional. Now insulin signaling in the brain has important differences from peripheral insulin metabolism. So the brain relies less than the muscle cells or the liver. It depends less on insulin to absorb glucose. The brain, specifically certain areas, can absorb glucose independently of insulin.

Insulin is going to mediate in the brain a lot of the usual suspects there in terms of feeding, ingesting behavior, but we have evidence that insulin’s role goes beyond that, so insulin receptors are expressed in a variety of areas that are interesting for psychiatry. It’s expressed in the prefrontal cortex. It’s expressed in the nucleus accumbens, the ventral striatum areas there that are relevant for combination for reward behaviors. And there is evidence now both from preclinical and clinical work that insulin modulates actually behaviors not just expressed in these regions, but it modulates how these regions are activated, and that results in differences in behavior. We have evidence that that’s the case in obese populations, and we have done some work as well in individuals with depression.

CHRIS AIKEN: The result of these physiologic changes is not just depression but cognitive problems as well.

Dr. Mansur: So individuals with type 2 diabetes, even if they do not have comorbid depression, they have a high risk of having cognitive impairment and it may eventually progress to dementia.

CHRIS AIKEN: And diabetes is not the only cause here – vascular disease and elevated lipids have been independently linked to depression and cognitive problems.

Dr. Mansur: There is very interesting data showing that even in the early stages of mental illness our patients already have some level of cardiovascular dysfunction there. It’s a well-established fact that there is excessive and premature mortality in individuals with mental health issues. So individuals with depression, bipolar disorder, for example, they have a life expectancy that is approximately 15 years lower than their peers in the general population. The number one cause of death in this population is cardiovascular disease. No question that suicide is a key problem there, right, but in terms of overall absolute numbers they are more likely to die prematurely from a cardiovascular condition. So, there is no question that this is an also important mediator in the association between metabolic health and mood disorders.

Meds for Metabolism and Mood

CHRIS AIKEN: Dr. Mansur went on to describe clinical studies where various anti-diabetic medications are being used to improve mood and cognition, including metformin, intranasal insulin, and the new class of medications that are being used for diabetes and weight loss – the glutides.

KELLIE NEWSOME: The glutides – mainly liraglutide – have controlled trial evidence to reduce weight gain on antipsychotics, and more preliminary evidence to improve cognition. Some are available oral, and some, like liraglutide, are used as injections – but it’s a very small needle and patients usually don’t have problems with it. Liraglutide goes by the brand name Victoza when it’s used for diabetes, and Saxenda when used for weight loss. In the article, Dr. Mansur talks about how and when to use these drugs, but emphasizes they are not first line in psychiatric practice.

Thinc-IT: An App for Cognition

CHRIS AIKEN: Dr. Mansur is hard to keep up with. I arranged the interview to focus on this metabolic research, but after scheduling a software app was released that – to my knowledge – is the first free and validated app that measure cognitive functioning in patients, and Dr. Mansur played a role in validating it. It’s called Thinc-It, and Think is spelled THINC hyphen IT.  You can google that for the download or the link is in the notes for this show. Hint: the website is as in Mary.

Dr. Mansur: So THINC-it is a tablet-based tool to measure cognition. So it’s a tool that we validated a few years ago. Validation means we compared how it performed with the traditional pen-and-paper tests, and it performed quite well. And we also tested how reliable it was for repeated measures like if you have to track someone over time with or without treatment if we could do that, if we could detect meaningful changes. And the validation results are quite good, and again it is not a perfect tool; there is no such thing. Cognition is extremely complex in heterogeneous domains, right. You have multiple domains: attention, memory, processing speed, working memory, cognitive control, so it’s hard for a single tool or a single test to capture it all. But there is a need in clinical practice for something that is easy to use and affordable, and that is why the THINC-it tool comes in. It is free. It takes 5 minutes and gives clinicians useful results for decision making.

KELLIE NEWSOME: Here’s what it looks like. First, you should use a tablet or laptop with a touch-screen – an iphone is probably too small to do the problems. You could use a mouse but that will be a little more challenging as it involves tasks like connecting the dots that are easier to do with your finger, but hey the test is only meant to measure change so a mouse would still be valid.

There are 5 tests. The first one is purely subjective – it asks the patient to rate their cognitive functioning. Next is Spotter, which measures reaction time, and for those neuropsychologists in the audience it’s based on the Choice reaction time task. So, Dr. Aiken, how’d you do on that?

CHRIS AIKEN: The computer flashes a right or left arrow, and you have to press the corresponding right or left arrow on the keyboard as quickly as possible. At first, I thought this would be easy, I mean, at least they are not asking you to press the opposite arrow like the go-no-go test where you have to inhibit your instinctual response. But here’s the catch – sometimes they put that right arrow on the left side of the screen, and it’s moments like that when you really feel the hemispheric split of your brain, as your left eye registers the arrow but your right hand has to press the button.

KELLIE NEWSOME: Next comes Symbol Check, which measures working memory – the ability to hold a bunch of information in your head while you work. For those of you who caught last week’s podcast, this is also known as the notorious N-Back test that might raise IQ if you have the patience to regularly practice it. Let’s see how Dr. Aiken did.

CHRIS AIKEN: When you do this one, expect to fail the first few times. It takes a little while to get the gist of it. There’s a long line of 5 different shapes moving across the screen – triangle, square, hexagon, circle, and X. You have to memorize the upcoming shapes – you use your working memory for that – and when a shape hits the middle of the screen it disappears – but you have to quickly name the shape that disappeared by touching a symbol on the screen. So it’s a bit like the Memory card game children play – where the cards are revealed and then turned over and you have to remember them – only here there is a time element as well.

KELLIE NEWSOME: Next is Code Breaker, which you might recall from our podcast on cognition last winter is the famed Digit symbol substitution test. It measures processing speed and a whole lot else. It’s like those decoder rings that have enchanted children since the time of little orphan Annie – where you have a ring with a series of numbers that correspond to letters, and they use it to interpret coded messages like 49112. Let’s see how Dr. Aiken fared.

CHRIS AIKEN: This one is also hard, but it goes a lot better if you start by memorizing the 6 numbers on the decoder – then you can breeze through as the symbols pass before your eye because you’ll know which number the correspond to without having to cross reference it all the time.

KELLIE NEWSOME: And finally, the trail making test. If you’ve ever used the Montreal Cognitive Assessment Test – which has taken the place of the mini mental status exam as a popular screening test for dementia – you’ll recognize this one. There’s a bunch of numbers and letters scattered on the screen, and you have to connect them like connect-the-dots, but you have to do it in order alternating letters and numbers, so A-1 B-2 C-3 D-4 and so forth. This is the only test that really benefits from a touch screen, although you could do it with a mouse.

At the end of the test, it gives you a visual display of your score, and it graphs that over time as you – hopefully – improve. Dr. Aiken these scores are confidential, so you don’t have to share yours.

CHRIS AIKEN: Well, I was average on most of them, except the dang Digit symbol substitution test – below average on that. But there was one I was above average on.

KELLIE NEWSOME: What was that?

CHRIS AIKEN: Ah, the self-assessment – you know, the subjective one.

KELLIE NEWSOME: Well, keep up the good work there. And have you used it with any patients?

CHRIS AIKEN: Yes I’ve used it to measure cognition in patients as they recover from depression, and it’s very encouraging because they can see they are getting better. And sometimes their self-assessment gets worse even as their objective score is improving – which tells us something about self-awareness.

KELLIE NEWSOME: Hmmm… it says a lot about self-awareness.

CHRIS AIKEN: Well, anyway the test is particularly useful there. And it’s useful when you recommend an intervention that might improve cognition, like aerobic exercise, Mediterranean diet, or just getting better sleep through a behavioral program.

KELLIE NEWSOME: Or when starting a medication that improves cognition, like starting or switching stimulants. And we should mention this app is free because it is sponsored by the makers of vortioxetine (Trintellix). This antidepressant improved scores on the digit symbol substitution test – the one that Dr. Aiken bombed on – and though this test is very simple it’s actually a good predictor of work functioning. The digit symbol substitution test has been used for over a hundred years, so it’s well validated, and how well you score on it is unrelated to your IQ or educational level.

CHRIS AIKEN: The creation of the app was sponsored by the pharmaceutical company, but the tests themselves were developed long ago. So Thinc-IT is in a position much like a lot of the free rating scales we use – you know many of the free ones like the Mood Disorder Questionnaire for bipolar and the Physicians Health Questionnaire for depression are only free because a pharmaceutical company bought the rights to them and made them freely available. Dr. Mansur has never received funding from Lundbeck, the maker of vortioxetine. Here’s how he recommends using it.

THINC-it TestMeasuresBased on
SpotterReaction timeChoice reaction time task
Symbol CheckWorking memoryn-Back test
Code BreakerProcessing speedDigit symbol substitution test
TrailsExecutive functioningTrail Making Test Part B

Dr. Mansur: So you can use it as an assessment tool. Cognitive complaints are extremely common in our clinical practice. And the cognitive domain there it’s important to emphasize is a key determinant of functional outcomes. So very frequently we have a situation in clinical practice where we are treating someone with depression is that their mood improves but their cognitive function doesn’t improve, at least not as much, and that makes it particularly hard for them to return to the previous level of functioning.

We have more than a few studies now showing that one of the main determinants of functional disability in depression is actually cognitive dysfunction. It seems to have a stronger effect even more than depressed mood, for example. So it’s an extremely important domain to monitor and/or assess. The assessment, however, as we talked before can be quite complicated because there are a lot of variables there. You have numerous tests. You have cognitive batteries that take a lot of time that can be quite costly. The THINC-it has the advantage of being very simple to use; again it’s free and can give clinicians useful information in terms of you know in terms of how their patients are performing cognitively in a certain period of time.

Treatments for Cognition in Bipolar

CHRIS AIKEN: As I said, Dr. Mansur is hard to keep up with, and just as our interview went to press he published a systematic review of treatments for cognitive impairment in bipolar disorder. It included 11 medications, about half of which are not available in general practice like methylene blue and erythropoietin – there were also a few studies of mifepristone, which is used to induce abortions shortly after insemination. But some of them are more usable, like lurasidone (Latuda), and sensoril which is a proprietary extract of an Indian form of ginseng – the only problem with these is they only had one positive controlled trial. The review also looked at transcranial magnetic stimulation (TMS), transcranial direct current stimulation – which is unrelated to TMS and is an electrical stimulation device patients use at home – and cognitive remediation therapy – which is an active, behavioral intervention for cognitive dysfunction. The summary was that most of these are promising but the data is too preliminary to say. Some of the failures – which did not turn out so well even in the small controlled trials that were published – were pramipexole and n-acetyl cysteine – both of which have positive data in bipolar depression, and the dementia medication galantamine, which seemed to work worse than placebo.

KELLIE NEWSOME: Rodrigo Mansur, MD is Assistant Professor in the Division of Brain and Therapeutics at University of Toronto

Rapid cycling

And now for the word of the day….Rapid cycling

Rapid cycling is a DSM specifier for bipolar disorder that mans the patient has had 4 or more mood episodes in the past year. Often those episodes involve mania, depression, and mixed states, but a patient with bipolar disorder could cycle in and out of depression and still have rapid cycling. The term was coined in 1974 by David Dunner and Ronald Fieve when they observed that rapid cycling patients do not respond well to lithium. Actually, they don’t respond very well to any medications, and although anticonvulsants were often touted as the preferred treatment for rapid cycling, recent analyses suggest they respond just as poorly to anticonvulsants as they do to lithium. Rapid cycling has responded to atypical antipsychotics like quetiapine and olanzapine, but it’s not clear if this response is better than other options.

Risk factors for rapid cycling include female gender, thyroid disorders, trauma history, substance use, and antidepressant use. Keep that in mind for our next episode, where we’ll look at what mood experts do with antidepressants in bipolar disorder in their own practice.

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