Mood Disorders Across Our Lives

The health of our mind, which is linked intricately to that of our physical being, faces challenges at all ages and stages of life. As these vignettes show, psychiatrists and researchers at Sunnybrook are diving deep into these challenges to steer the course of care

Dr. Benjamin Goldstein

Dr. Benjamin Goldstein is searching for biomarkers in the blood to optimize diagnosis and treatment of youth with bipolar disorder.

Photo: Curtis Lantinga

Dr. Benjamin Goldstein, an international expert in youth bipolar disorder, is searching for biological markers in the blood that can guide treatment of bipolar disorder, a chronic illness that affects 2% to 5% of teenagers.

Bipolar disorder is characterized by alternating episodes of mania, pathological elation accompanied by high energy and other symptoms, and depression. These disturbances can impair work or school performance, damage relationships, and lead to suicide or substance abuse. It is the fourth most disabling medical condition among adolescents.

Goldstein is studying whether increased markers of inflammation and decreased levels of a protein called brain-derived neurotrophic factor coincide with acute depression or mania. “We’re trying to parse out how people look biologically when they’re well versus when they’re symptomatic,” he says.

Bipolar disorder is associated with reduced life expectancy. Although people with this illness have a relatively high risk of suicide, the leading cause of death is heart disease, which occurs at higher rates and earlier ages than among people without the disorder.

Goldstein notes that there are no biological tests that clinicians can use to guide their decisions; psychiatrists rely on patients’ recollections and their observations of patients during a session.

“You’re asking someone affected by their mood disorder to comment on their mood symptoms,” he says, noting the limitations of that. “We’re not looking to replace the clinical interaction, but to augment it—to have some biological validation that can add to our understanding of the activity of the illness,” he says.

Perhaps most promising is the potential use of biomarkers to predict and treat an episode of illness proactively.

Goldstein hopes the markers he is examining, like C-reactive protein (CRP), will shed light on the link between bipolar disease and heart disease. C-reactive protein, which is used clinically to assess risk of future cardiovascular disease in adults, has been shown to rise during bouts of mania and depression. “If you have high CRP when depressed or manic, you can see how over a period of months or years that this is not healthy.”

Detailing the biology of the disorder would not only validate patients’ self-reports, but could also help doctors tailor therapies to individuals. Perhaps most promising is the potential use of biomarkers to predict and treat an episode of illness proactively.

“[Now] we wait for symptoms to happen, then name them as symptoms and treat them. We’d like to be able to get ahead of the puck,” says Goldstein. “Teens with bipolar disorder spend more than 50% of the time with symptoms that negatively affect quality of life. Being able to shift that by 10%—making it 60/40 or 70/30 in favour of wellness—would have a meaningful effect.”

Teens: a Primary Focus

Like those of Goldstein, Dr. Amy Cheung’s patients are young—teens, and some younger than that. Against a backdrop of research showing people aged under 20 years have the highest rate of depression, Cheung wants to get more teens the help they need, and faster.

She notes about 20% of teens will have had an episode of depression by the time they finish high school. Depressed youth struggle academically and may abuse drugs or alcohol, or engage in reckless behaviour.

Family doctors are well positioned to screen for depression because they see patients regularly and, in general, patients feel comfortable with them. Unfortunately, it’s not standard practice, says Cheung. “We screen for all sorts of things in primary care, and yet there’s no standardized mental health screening when we know one in five kids has a mental health problem in Canada. It’s a lost opportunity.”

Barriers to mental health screening are considerable. Family doctors receive minimal mental health training and may feel unequipped to treat depression. Moreover, their practices can be unsuited to managing psychiatric illness because patients are booked back-to-back for short appointments. “How do you assess a child with depression in three minutes?” asks Cheung.

Through interviews with family doctors, Cheung uncovered that one obstacle to screening for depression is concern about mental health support. If a problem is discovered, then the family doctors are unsure what to do and to whom referrals should be made. To address the matter, she helped create an online resource that contains screening tools, educational material for families and information on medication.

As a next step, Cheung, newly bestowed with the Bell Canada Chair in Adolescent Mood & Anxiety Disorders, is evaluating whether a tool to help family doctors perform mental health check-ups enables earlier identification of depression. Through earlier diagnosis, she hopes to lessen the impact of illness on teenagers’ lives. “It’s such a significant disruption in their development. The quicker we catch it, the better.”

Dr. Sophie Grigoriadis

Dr. Sophie Grigoriadis is lead author of a study that analyzes the risks of antidepressant use during pregnancy.

Photo: Curtis Lantinga

The Pregnancy Blues

For a pregnant woman, depression takes a different cast. For starters, it’s often overlooked, says Dr. Sophie Grigoriadis, head of the women’s mood and anxiety clinic at Sunnybrook. Her research tackles a controversial topic: antidepressants during pregnancy.

She notes pregnant women are often told symptoms, including fatigue, and changes in sleep, appetite and sex drive, are part and parcel of having a baby. “The diagnosis is easily missed,” says Grigoriadis.

Between 8% and 15% of pregnant women experience depression. Left untreated, the risks are serious. These women are less likely to eat and sleep well, or seek prenatal care; they are more likely to smoke and drink alcohol, and may be at risk of suicide.

Advisories issued by Health Canada and the U.S. Food and Drug Administration warning of adverse effects of antidepressant use in pregnancy has generated worry on the part of women and confusion among clinicians, says Grigoriadis.

Seeking clarity, she and her team analyzed the evidence surrounding use of antidepressants in pregnancy. They led the first meta-analysis of outcomes after antidepressant exposure in utero, which looked at gestational age, birth weight, Apgar scores (rating of a newborn’s health after birth) and spontaneous abortion.

The results were intriguing: there were statistically significant increased risks of some adverse effects, but the differences found in the exposed group were small and typically within normal ranges.

For example, on average, the birth weight of babies whose mothers took antidepressants during pregnancy was 75 grams lighter. “When dealing with a 3,500-gram baby, what is 75 grams—clinically?” says Grigoriadis, who notes that although the effects weren’t large, they are worthy of consideration.

Results also showed the gestational age of babies exposed to antidepressants during pregnancy was about three days shorter, and their Apgar scores were within the range signifying normal to excellent health.

She has also studied the effects of untreated maternal depression and found it is associated with premature delivery and less breastfeeding initiation. “Untreated depression is not without its consequences. You have to weigh the risks and benefits and do what’s best for mom and baby,” she says.

Grigoriadis and her colleagues have created a guide that includes the results of this research for obstetricians, family doctors and psychiatrists. They are doing a pilot study to evaluate the usefulness of the tool in practice, and hope to make it available across Canada.

Worry Knot

As adults, we all fret—there’s the mortgage, children, aging parents, career—but there’s anxiety, and then there’s Anxiety. Obsessive-compulsive disorder (OCD) is a chronic illness that affects 2% of the population and is characterized by unwanted and intrusive thoughts that produce fear or worry. People with OCD perform repetitive acts to reduce obsession-related anxiety.

Drs. Peggy Richter and Neil Rector

Drs. Peggy Richter and Neil Rector are studying how to improve outcomes in obsessive-compulsive disorder.

Photo: Doug Nicholson

Although OCD has a strong genetic basis, its mechanisms are unclear. If you’re looking for a causal gene, you won’t find one, says Dr. Peggy Richter, head of the Frederick W. Thompson Anxiety Disorders Centre at Sunnybrook. “Psychiatric illnesses are complex. They’re thought to be related to a number of small genes of small effect that contribute to risk in interactive ways.”

Psychiatric illnesses are complex. They’re thought to be related to a number of small genes of small effect that contribute to risk in interactive ways.

Richter is exploring the biology of OCD. Her approach is to study the genes—specifically, those that encode for liver enzymes that break down psychiatric medicines—of people who respond well to a class of antidepressants. The aim is to shed light on mechanisms of the disease, and predict drug response and tolerance.

Medication is a first-line treatment for OCD, but its effectiveness is limited. Antidepressants work—partially—in roughly 60% of patients. Richter puts it into perspective: “If your rituals take four to six hours a day, you might be on a drug treatment, be deemed a ‘responder,’ and your rituals still take two-and-a-half to three hours a day.”

She led the first study showing the CYP (“sip”) family of genes, known to play a role in antidepressant response generally, may play a role in OCD. Richter found that patients with OCD who have extra copies of the CYP2D6 gene had to try more antidepressants before finding the right one. These people tried, on average, five drugs, versus patients with OCD who had two normal copies of the gene, who tried two.

Her goal is to be able to personalize treatment so that it works better. She imagines a scenario in which a doctor adjusts dosing or switches drugs based on a patient’s genetic make-up: “Wouldn’t it be lovely if we could do that, and your odds of response go up from 60%to maybe 80% or 90%?”

Richter, along with psychologist Dr. Neil Rector, head of research at the Thompson Anxiety Disorders Centre, is also investigating disgust processes in OCD. “We’re learning that disgust processes may be related to the development and maintenance of OCD for some. We also think the emotion of disgust may have important treatment implications, requiring more targeting than in the past,” says Rector.

In a study looking at facial recognition of disgust, they found people with OCD had impaired ability to identify the emotion compared with people who had other anxiety disorders. They also found that patients with OCD who responded well to cognitive-behavioural therapy (CBT) were much better at identifying expressions of disgust than were untreated patients; their ability was on par with that of people without an anxiety disorder. That, says Rector, is encouraging: “If this deficit exists, it appears to be something that can change in the context of treatment.”

This study is the first to look at whether facial recognition of disgust can improve among people with OCD. It provides evidence that successful CBT may lead to more accurate identification of disgust, which may have implications for the commonly observed exaggerated disgust reactions in OCD.

They plan to conduct a larger study to analyze changes in disgust in relation to ameliorating symptoms. “Does improvement of facial recognition of disgust correlate with symptom improvement?” asks Rector. “It’s the next step in this line of research.”

Dr. Ken Shulman

Dr. Ken Shulman is investigating the risks associated with lithium, a drug that stabilizes mood, but can have toxic side effects.

Photo: Curtis Lantinga

The Aging Mind Needs a Steady Hand

Later in life, a plethora of medical conditions can emerge, including those that affect the brain. “You have to be able to differentiate between a mood disorder like depression and the beginning of a dementia. That’s why careful assessment of elderly people needs to be conducted,” says Dr. Ken Shulman, a geriatric psychiatrist and head of the Hurvitz Brain Sciences Program at Sunnybrook.

Although depression is common among people aged 65 and older, experts warn it shouldn’t be viewed as a natural consequence of aging. It is estimated that symptoms, including persistent sadness and hopelessness, affect 15% of older adults in the community. Among seniors in long-term care facilities, the rate swells to about 40%, although this may be associated with the development of dementia and other medical conditions.

Mood stabilizers are a first-line therapy prescribed to stave off depression and mania. One of these, lithium, is a mainstay of treatment for bipolar disorder—and a double-edged sword, says Shulman. “It’s a very effective treatment, but it can also be toxic and cause significant side effects.”

One of his interests is lithium use and risk of kidney disease. Lithium is the only mood stabilizer that is removed solely by the kidney. With age, kidney function decreases, resulting in increased blood levels of the drug. “We need to make sure doctors are aware that as people age on lithium maintenance, the dosage needs to be lowered accordingly,” says Shulman.

Drug interaction is also a problem. Lithium poisoning can occur when used with medication commonly prescribed to older adults, including water pills, blood pressure medicine and anti-inflammatory drugs. Family doctors and specialists should therefore work together and be familiar with a patient’s medical conditions and the drugs she is taking, says Shulman, who adds it’s what they aim to do at Sunnybrook.

The goal of his research is to provide clinicians with greater knowledge of the risks associated with lithium, which, he says, “when used at the appropriate levels, is a drug that can keep people stable and well, and their quality of life is much improved.”

He is also looking at ways of improving guidelines for laboratory analysis of lithium levels in the blood. Establishing a therapeutic range specific to older adults could help prevent lithium intoxication. “An elderly person in their late 70s or 80s cannot tolerate the same lithium level that a 20- or 30-year-old can, but the labs don’t differentiate between a geriatric lithium level and a young adult lithium level,” says Shulman.

At play is a larger public health concern, he adds: “It’s one of the biggest problems we face in medicine: the effects drugs have on older adults. That’s not to say we can’t and shouldn’t use drugs in older adults; it [just] calls for a more careful approach.”

Suicide: Ageless, Stageless

Mood disorders present different challenges across the lifespan, but common across ages is that they increase the risk of suicide. Dr. Mark Sinyor is combing through coroners’ data to probe that risk.

Dr. Mark Sinyor

Dr. Mark Sinyor is mining coroner's data to identify patterns of suicide in Toronto. His aim is to develop targeted suicide prevention strategies.

Photo: Curtis Lantinga

“We want to understand who dies from suicide and the situations that surround it. How do specific health or psychiatric conditions change the risk of suicide? Do the events just prior to death give us a window into the minds of people thinking about suicide, and could they give us clues about how to stop it? We’re hoping this will be the start of a larger conversation on how to prevent suicide,” he says.

There are about 4,000 suicides in Canada annually. Although it is the 10th-leading cause of death overall, suicide is the second-leading cause of death among people aged 10 to 50 years, notes Sinyor.

In one study, Sinyor examined thousands of suicides that happened in Toronto between 1998 and 2010. Using statistical analysis, he identified five distinct clusters. The study, the largest of its kind in Canada, provides a clear snapshot of patterns of suicide in Toronto based on age, sex, mental illness and stressors such as bereavement and financial troubles.

Understanding these details is important, says Sinyor. For example, one group he uncovered was middle-aged men with depression and substance abuse problems. “That’s a very particular set of circumstances. If we know those people at that phase of life are at high risk, [then] we can target a strategy toward them.”

He also found that while suicide occurs at all ages, those at highest risk are elderly males. Targeted, thorough interventions, including education geared to specific groups, are therefore critical, says Sinyor, whose prior work showed erecting a bridge barrier at Toronto’s Bloor Street Viaduct didn’t change suicide rates.

“One of the lessons of [that study] is that you can’t think of an object, like a barrier, in and of itself being a suicide prevention strategy. It’s one component, but the strategy has to be comprehensive. We need to educate people about mental illness, suicide and the risks of suicide.”

Research Funding & Other Information

Cheung: Bell Canada, Canadian Institutes of Health Research (CIHR) and Ontario Mental Health Foundation (OMHF). Goldstein: CIHR, The Depressive and Bipolar Disorder Alternative Treatment Foundation, Heart and Stroke Foundation (Ontario), National Institute of Mental Health (NIMH) and OMHF. Grigoriadis: CIHR, OMHF, Ontario Ministry of Health and Long-Term Care (MOHLTC), Ontario Women’s Health Council and C. R. Younger Foundation. Rector: CIHR and Frederick W. Thompson. Richter: CIHR, International OCD Foundation, NIMH, OMHF and Frederick W. Thompson. Shulman: MOHLTC. Sinyor: Dr. Brenda Smith Bipolar Research Fund and Physicians’ Services Incorporated Foundation. Each holds an appointment within Sunnybrook Research Institute, and is a member of the department of psychiatry at the University of Toronto.

Dr. Benjamin Goldstein