Discovery of special proteins in brain opens new pathway to treating depression

From MAO-A to B, protein discoveries may lead to a new types of antidepressants

Discovery of special proteins in brain opens new pathway to treating depression

Neuroscientists at the Centre for Addiction and Mental Health (CAMH) have found that patients with depression may have elevated levels of a particular protein in the brain, opening a pathway for developing a new type of antidepressant medication.

The research team, led by Dr. Jeffrey Meyer, the Head Scientist of the Neurochemical Imaging Program in Mood and Anxiety Disorders at CAMH, found that the MAO-B protein — short for monoamine oxidase B — was found in heightened levels in the prefrontal cortex area of the brains of depressed patients.

How Meyer’s research team first discovered the protein

The breakthrough of Meyer’s research team that led to this study was the discovery of elevated levels of the MAO-A protein in women who had recently delivered a baby.

Originally, researchers considered both MAO-A and MAO-B as the same protein, MAO, as they both break down the molecule tyrosine. However, medications developed to treat early postpartum depression – a mood disorder associated with childbirth – revealed that despite a 70 per cent overlap in the structures of the two proteins, the medications only affected the MAO-A enzyme.

Neuroscientists have therefore since considered MAO-A and MAO-B to be different types of chemicals.

The link between MAO-B levels and clinical depression

The recent study by Meyer’s research team evaluated images taken from the brains of 40 patients over a period of four years. Half of the volunteers had experienced episodes of major depression, while the remaining 20 were considered healthy controls.

Through positive emission tomography, a type of brain imaging, the researchers discovered that 50 per cent of the patients with depression had elevated levels of MAO-B compared to the healthy individuals.

The patients with depression were found to have, on average, a 26 per cent increase in the volume of MAO-B in the prefrontal cortex region compared to those without the condition. This region is primarily responsible for complex cognitive behaviour, personality regulation, decision-making, and moderating social behaviour and emotions.

The researchers also found a positive correlation between MAO-B levels and the duration of depressive episodes. That is, the longer the depressive episode, the higher the detected level of MAO-B in the prefrontal cortex and other brain regions.

While MAO-A breaks down serotonin, MAO-B promotes cell turnover by breaking down old and excess neurotransmitters, such as dopamine and norepinephrine, chemicals that are responsible for pleasure and reward.

Although this process is essential in maintaining a healthy brain, increased levels of MAO-B can lead to removing too much of the feel-good chemicals, which may lead to depression.

The limitations of current antidepressant medications

Although there are already antidepressants in the pharmaceutical market, they mainly only target serotonin. Meyer pointed out, in an email to The Varsity, that the current medications and treatment options are not effective for everyone with depression.

“While some people respond well to SSRI [selective serotonin reuptake inhibitors] medications half do not. A key problem is that there are subtypes of depression and we need to match treatments to the subtypes of depression better,” wrote Meyer.

There are already drugs on the market that inhibit MAO-B used for Alzheimer’s and Parkinson’s disease. The research team is looking for ways to direct them towards treating depression.

“There are medications purposed for other illness that shut down MAO-B and could be repurposed for depression,” wrote Meyer.

“With this study now in hand, published in what is traditionally the top psychiatric research journal, I am asking the companies that own the patent rights to these medications to use them for depression.”

How the discovery of MAO-B can lead to new antidepressant research

After the discovery of MAO-A, Meyer’s lab has made progress in developing a dietary supplement that would compensate for the sudden rise of MAO-A in early postpartum depression.

They are currently seeking to create a blood test that could detect monoamine type illnesses. This would help identify individuals who would respond better to MAO-targeted drugs as opposed to the usual antidepressant treatments.

“The main steps are to test medications in development and those available for use, (even if indicated for other illnesses) for their ability to shut down MAO-B. Then I would like to see if matching a medication that shuts down MAO-B to the subtype of depression with greater MAO-B would help increase the chance of cure,” wrote Meyer.

“We are also looking for low cost approaches to predict the subtype of clinical depression with the highest MAO-B level.”

Approximately 15 per cent of people are affected by depression at some point in their life and it is the main cause of disability around the  world.

Meyer wrote, “There is great reason for hope because we are increasingly understanding how the brain changes in clinical depression which is creating new opportunities for cures.”

Psychotherapy affects depression differently than antidepressants

A personal exploration into the science behind antidepressants and CBT

Psychotherapy affects depression differently than antidepressants

Content warning: discussions of depression and suicide.

The first time I walked through the door of my psychiatrist’s office, I was full of doubt. I had been feeling low for quite a while, and I had trouble believing that any treatment would truly help me feel better.

I had just completed my second year of university, and I felt broken and exhausted. A blend of burning out, experiencing depressive episodes, disengaging from pastimes I used to enjoy, and fantasizing about dying drove me to seek treatment at U of T’s Health & Wellness Centre.

As part of my initial assessment, which occurred over the course of several sessions, my psychiatrist asked me questions about practically every aspect of my life: recent events, medical history, sleep patterns, appetite, suicidal ideations, and more. After considering all my symptoms, she prescribed me Prozac, an antidepressant medication, and recommended cognitive behavioural therapy (CBT). Both are common treatments for depression.

I gave them both a try. I was fortunate to be able to see a therapist for CBT, which was covered by my family’s health insurance. At first, I was skeptical that it would work, but I decided to commit myself to at least a few sessions.

CBT, as I learned, is a short-term form of psychotherapy that helps people build skills for staying healthy. In essence, it helps people identify, question, and change distorted thoughts and beliefs they might have about themselves and the world. By recording their thoughts during upsetting situations, people examine how their unhelpful thoughts might contribute to problems like depression.

Research on how CBT compares to antidepressants

Dr. Zindel Segal, a U of T psychology professor and an expert in CBT, said in an interview with me that “when people are in certain mood states, they tend to have thoughts that are very compatible with those mood states. So, when someone’s feeling depressed, they’re more likely to feel hopeless, judge themselves, and be very critical.”

According to Segal, CBT provides a way of treating people’s thoughts and assumptions as hypotheses that can be tested, rather than as hard facts. “That can help people alleviate the impact that some of these thinking styles can have on their moods,” he elaborated.

For me, CBT was extremely challenging more so than any math or biochemistry course I have ever taken. Perceptions are simply hard to change. At the time, for example, I felt incredibly worthless and undeserving of love. In the face of this, CBT helped me stay objective and not always accept my perceptions as truth. Psychotherapy made me stand back from my thinking to consider situations from different viewpoints.

“In the face of [critical challenges], CBT helped me stay objective and not always take my perceptions as truth.”

However, distorted thoughts and beliefs are often not the only culprits of depression. Much is still unknown about the causes of depression, but researchers suspect that chemical imbalances in the brain play a role in maintaining low moods. Antidepressant medications are designed to address these chemical imbalances by boosting concentrations of neurotransmitters namely serotonin and norepinephrine in the brain.

At first, I was very reluctant to try antidepressant medication because I was wary of possible side-effects. However, my psychiatrist assured me that the starting dose was low, that I would be closely monitored, and that we could always adjust my treatment if the medication was not right for me. In the end, I experienced only minor side-effects and really benefited from the resulting stability in my mood.

The differences between CBT and antidepressants

So, what are the differences between CBT and antidepressants in treating depression, according to experts? Researchers like Segal, who recently co-authored a paper comparing the efficacy of CBT versus antidepressants, are working hard to answer this question.

Segal’s research team found that CBT and antidepressants target different symptoms of depression. Antidepressants were found to be best for treating symptoms specifically related to depressed mood, feelings of guilt, suicidal thoughts, and psychic anxiety.

On the contrary, CBT and antidepressants were equally effective in treating patients who struggled with other specific symptoms of depression, like changes in sleep and appetite. “This paper tries to address more of a symptom-to-patient matching approach so that people are getting antidepressants if they have a symptom profile that might be more responsive to the drug,” said Segal.

In my case, CBT and antidepressants were temporary treatments that helped me bounce back from a bout of depression and develop long-term skills in staying healthy. Each treatment helped me in different ways: CBT helped me build emotional resilience, whereas antidepressant medication gave me the extra energy to ‘get back on my feet’ and return to doing the things I love to do.

But whichever treatment people are prescribed, Segal stressed that depression is treatable. “Whether you have hypertension or depression, it is possible to get treatment.”


If you or someone you know is in distress, you can call:

  • Canada Suicide Prevention Service phone available 24/7 at 1-833-456-4566
  • Good 2 Talk Student Helpline at 1-866-925-5454
  • Ontario Mental Health Helpline at 1-866-531-2600
  • Gerstein Centre Crisis Line at 416-929-5200
  • U of T Health & Wellness Centre at 416-978-8030.

Warning signs of suicide include:

  • Talking about wanting to die
  • Looking for a way to kill oneself
  • Talking about feeling hopeless or having no purpose
  • Talking about feeling trapped or being in unbearable pain
  • Talking about being a burden to others
  • Increasing use of alcohol or drugs
  • Acting anxious, agitated, or recklessly
  • Sleeping too little or too much
  • Withdrawing or feeling isolated
  • Showing rage or talking about seeking revenge
  • Displaying extreme mood swings

The more of these signs a person shows, the greater the risk. If you suspect someone you know may be contemplating suicide, you should talk to them, according to the Canadian Association for Suicide Prevention.

The promise of ketamine in overcoming treatment-resistant depression

Therapeutic potential of ketamine discussed in review by U of T medical researchers

The promise of ketamine in overcoming treatment-resistant depression

Content warning: Discussions of suicide in the context of treating major depressive disorder.

Ketamine is a promising medication that brings hope to patients struggling with severe depression, offering potential therapeutic effects for those who are non-responsive to standard antidepressants.

The dissociative anesthetic is currently used by physicians and veterinarians to cause fast-acting insensitivity to pain during medical procedures. It is also used illicitly as a recreational drug, causing feelings of disconnection and relaxation among users.

Yet in controlled settings, ketamine also shows potential as a medication to help patients who are suffering from major depressive disorder. In April, a research review by U of T researchers found that ketamine offers significant effects as an antidepressant.

The lead author of the paper, Dr. Joshua Rosenblat, discussed the review’s findings with The Varsity. As a clinician-scientist in the Department of Psychiatry, Rosenblat is currently studying the antidepressant effects of ketamine.

He explained three major effects that differentiate ketamine from standard antidepressants: a different mechanism of action, a rapid onset of effects, and a response in patients who are not positively affected by commonly prescribed antidepressants.

Ketamine affects depression via a novel mechanism of action

For the past several decades, standard antidepressants have worked by affecting levels of serotonin, norepinephrine, and dopamine, explained Rosenblat.

In generalized terms, serotonin is a chemical messenger thought to regulate mood, while norepinephrine controls alertness and arousal. Dopamine affects attention and emotion.

But ketamine affects the brain differently. Rather than targeting these neurotransmitters, it instead changes levels of glutamate – the main excitatory messenger in the brain.

Ketamine’s unique mechanism of action could therefore explain why it may positively affect patients suffering from treatment-resistant depression, who do not respond to standard antidepressants.

Ketamine could provide a more rapid onset of affects, versus standard antidepressants

Ketamine also provides a rapid onset of effects. Standard antidepressants, said Rosenblat, usually take two months of prescribed usage to take effect.

He explained that with ketamine, alleviation of depressive symptoms can appear within two hours of consumption. This is especially promising as an option for patients suffering from suicidal thoughts.

A decrease in suicidal thoughts can plausibly reduce the number of suicidal attempts; however, Rosenblat noted that the evidence is currently too limited to make a conclusion. He explained that studies are lacking, as only a small percentage of patients affected by such thoughts attempt to commit suicide.

Ketamine could also be used for special applications. Depression is very common among patients facing terminal cancer, explained Rosenblat.

“If you were to start them on an antidepressant and they only have one month left to live, for example, [the patients may] only experience the side effects, and never get the benefits.”

Rosenblat is currently leading a clinical trial at Princess Margaret Hospital to research the use of ketamine for improving the final months of life for patients affected by terminal cancer.

The risks and drawbacks of ketamine as an antidepressant

While the prospect of applying ketamine for treating depression is promising, there are several discouraging factors to its application.

To start, ketamine carries the risk of substance abuse. While ketamine is not strongly addictive, said Rosenblat, recreational users of the drug can develop a dependence.

Ketamine may also be prohibitively expensive for potential patients, as it is not covered by OHIP. Furthermore, as a medicine that is only available for research study or private use, it cannot currently be prescribed by most physicians.

There are also limited studies on the rare side effects of ketamine. In the short-term, the main known side effects are disassociation, a daydream-like state, and nausea which may occur during the administration of ketamine.

“We don’t know what we don’t know,” said Rosenblat. It is unclear whether ketamine may cause rare, adverse reactions in some patients. Long-term side effects of ketamine are also unclear.

Rosenblat therefore does not encourage self-medication for U of T students suffering from mental health challenges, as ketamine is not sufficiently studied.

Only a “very small percentage” would likely positively benefit from ketamine, explained Rosenblat, compared to standard treatment options supported by a much wider body of research.

The future of ketamine research

Although ketamine is not fully studied and is currently only used in special situations, it still brings “a message of hope,” said Rosenblat.

While ketamine is still not approved as an antidepressant, the U.S. Food and Drug Administration has approved esketamine, a structurally similar compound, as a nasal spray antidepressant. This became the first antidepressant of its kind to be used in the United States.

While Rosenblat notes that much more future research needs to be done with ketamine, he agrees that preliminary results are “very promising.” With a new avenue of research in treating severe depression, the future of research in the field seems optimistic.

Talks with impact

The Canadian Association for Neuroscience held Public Lectures at the 10th Annual Canadian Neuroscience Meeting

Talks with impact

Rowan Stringer, a high school student from Ottawa, got her first concussion on a Friday in 2013. On the following Monday, she got her second concussion, and on the Wednesday, her third. On the following Sunday, these head injuries ended the life of the 17-year-old rugby player.

Dr. Charles Tator shared Rowan’s story with the audience members of the 2016 Canadian Association for Neuroscience (CAN) Public Lectures. As the first of several events, these lectures heralded the 10th Annual Canadian Neuroscience Meeting, a symposium showcasing the top Canadian research in this field.

Leading neuroscientists Dr. Margot Taylor, Director of Functional Neuroimaging and Diagnostic Imaging at The Hospital for Sick Children, and Dr. Charles Tator, a neurosurgeon at Toronto Western Hospital, were invited to the Peter Gilgan Centre for Research and Learning to speak about their work with innate and acquired brain injury, respectively.

Dr. Taylor introduced the magnetic resonance imaging (MRI) and magnetoencephalography (MEG) brain imaging techniques currently being used in her studies. Her work centres on developmental differences in the pediatric population, comparing typically developing (TD) children with children born preterm or who have Autism Spectrum Disorder (ASD).

“MEG and fMRI are complementary in understanding the neural mechanism of cognitive function,” explained Dr. Taylor. “The main advantage of MEG is that it gives timing information,” whereas fMRI allows the researcher to “determine what brain regions are involved with cognitive ability.” Using these neuroimaging methods, she found that atypical working memory brain processes are found in the ASD group.

In addition to investigating working memory, a component of short-term memory that allows information storage during mental activity, Dr. Taylor explored a concept called theory of mind (ToM) in children with ASD. ToM is the ability to understand that other people have different perspectives from oneself. “People have to inhibit their own belief to understand what others believe,” said Dr. Taylor. “It is considered a key deficit in autism and is called ‘mind-blindness.’”

ASD is an innate disorder of brain development. On the flip side of the coin, Dr. Tator spoke about his research, activism, and experience with acquired brain injuries as a neurosurgeon.

“A concussion is a brain injury. In fact, it is the most common brain injury,” said Dr. Tator. Although the exact mechanism is unknown, experts believe that rotational head acceleration — rather than the tearing or bruising of the brain — causes concussions. The brain moves within the skull. “That’s why helmets don’t work. Helmets do prevent other types of brain injury but they don’t prevent concussions.”

Another concern with concussions is in its diagnosis. “We do not have a good biomarker,” said Dr. Tator. Concussions today are still diagnosed clinically, meaning they are dependent on the amalgamation of a clinician’s judgement with a patient’s self-reported symptoms. This requires the patient to be compliant and truthful. “Imagine having a major disorder that can only be diagnosed with autopsy,” Dr. Tator posited. A purposeful effort to hide the injury can fool the examiner. “We still witness this regularly in professional sports,” said Dr. Tator, recalling hockey player Sidney Crosby’s melee with concussions.

Beyond the NHL, this issue has blighted many lives, including Rowan Stringer’s. She lost her life after ignoring several symptoms of concussion. “This case alone indicates that concussion is a public health concern,” said Dr. Tator. “We are playing catch-up in this field. It’s been a completely neglected field for a long time, but not anymore.”

As a prelude to the 10th Annual Canadian Neuroscience Meeting, these lectures sparked discussion of current research by the neuroscience community.

A dangerous blow

U of T conducts the first study on the incidence of all-cause injury in the NFL

A dangerous blow

According to a new survey, nearly 1 in 5 Canadians have suffered a concussion from sports.

Recently, the effects of concussions have been in the media due to the release of the new blockbuster Concussion. The film stars will smith as Bennet Omalu, a Nigerian-American forensic pathologist faced with the challenge of proving that concussions from professional football may be more serious than was previously believed.

In the film, Omalu attempts to convince the NFL — and the many Americans who love professional football — that concussions from professional football may be linked to long-term depression and mental health issues.

Here in Toronto, research on the effects of concussions are ongoing and productive. Assistant Professor Michael Hutchison of the faculty of kinesiology and physical education is the director of the concussion program at U of T’s David l. Macintosh sport medicine clinic, and a prominent concussion researcher.

His most recent publication, “descriptive epidemiology of musculoskeletal injuries and concussions in the NFL, 2012-2014,” published in collaboration with Dr. David w. Lawrence and Dr. Paul Comper studies the effect of american football on concussions.

The paper, published in the Orthopeadic Journal of Sports Medicine, utilizes the weekly injury reports from the NFL to understand the epidemiology and frequency of concussions in the NFL. The paper found that head injuries or concussions accounted for nearly 7 per cent of all injuries by anatomical location in nfl players. It also determined that wide receivers suffered from the greatest rate of injury, while quarterbacks and kickers had the lowest. Equally startling is the fact that the incidence rate of concussions in the NFL in 2012-2014 has increased 1.61 times since 2002-2007. The paper also suggests that the incidence of concussions in american football is nearly three times as high as the incidence seen in professional rugby union.

Although the relatively high prevalence of concussions in football has been known for some time, it was the work of Bennet Omalu that inextricably linked the high prevalence of concussions in football to a disorder he named chronic traumatic encephalopathy, abbreviated as CTE. In linking the two, he discovered a link between the frequent brain trauma of football to depression and issues of mental health in a number of former professional football players. However, because CTE cannot be detected using traditional methods (such as cat scans), proving its existence was a challenge for Omalu, who initially faced ridicule for making the links that were later proven. The connection between concussions and repeated brain trauma and CTE is now nearly universally accepted. Furthermore, thanks to research at U of T, the relative prevalence of concussions in american football is being uncovered. In the future, we may be able to find safer ways to play the game that millions love without threatening the mental health of  its players.