Everything You Ever Wanted To Know About Depression

Since it’s different for everyone, your particular form of depression can make a difference in choosing the what the best treatment option is for you.

By Elizabeth Forbes, esperanza editor


There’s no such thing as “depression.”  Instead, experts say, we should get in the  habit of talking about “depressions” just  as we talk about infections or cancers.

There are variations in each individual’s constellation  of symptoms, how long the symptoms stick around, and how the illness plays out over time—and those variations matter when it comes to finding the best treatment options.

Some people with depression may be plagued by low self-esteem and feelings of worthlessness, yet function well on a day-to-day basis. Others may not be as affected by negative thinking, but buckle under  heavy fatigue and pervasive apathy. Sadness could be considered a defining symptom of depression, but even that’s not always present: A person with depression might be overly irritable or emotionally numb instead of profoundly unhappy.

The Diagnostic and Statistical Manual of Mental Disorders—the primary reference guide in North America for identifying a psychiatric condition—tries to take that variability into account. There are nine symptoms listed in the criteria for major depressive disorder, including some paired extremes: eating more than usual or hardly at all, for example. A combination of five from the list qualifies you for the diagnosis.

“There are physical, cognitive, mood and emotional symptoms that factor into a diagnosis of depression,” says Heather Flynn, PhD, an associate professor and vice chair for research at the Florida State University College of Medicine. “Two people with the same diagnosis can present completely differently.”



Some broad generalizations about differing breeds of the “black dog” can be made. Flynn, who is also co-chair of the National Network of Depression Centers’ task force for women and mood disorders, notes that men and women often manifest depression in dissimilar ways. As a population, women with depression tend to have more anxiety than men, report more fatigue and hypersomnia (excessive sleeping), and tend toward lethargy. A man would be more likely to exhibit insomnia and agitation.

Also characteristic of male depression: lashing out from irritability and anger, abusing alcohol and other substances, and turning inward—perhaps because guys are socialized to not show “weak” emotions. Underlying depression may go undetected because it doesn’t fit the stereotypical image of someone weeping on the couch for days on end.

Across the life span, depression in adolescence doesn’t look like depression in adulthood. And people reared within the Euro-American tradition may not “feel” depression the way people from other backgrounds would—another barrier to diagnosis.

“People from different cultures may present with physical symptoms such as headaches or stomachaches,” Flynn notes, rather than emotional distress.

Experts use the word “heterogeneity” to refer to the slippery nature of depressive disorders.

“Depression is not one single thing,” says Rudolf Uher, MD, PhD, a psychiatrist who holds the Canada Research Chair in Early Intervention in Psychiatry and is an associate professor at Dalhousie University.

“We see it every day. We make the same diagnosis of major depressive disorder in a number of people, we give them the same treatment, and we see very different outcomes.”



Major depression is just one of eight main options under depressive disorders in the latest edition of the Diagnostic and Statistical Manual, known as DSM-5. Published in May 2013, DSM-5 was the first significant update since 1994 and incorporates 20 years of accruing research. There are several new classifications for depression, including:

Persistent depressive disorder, which consolidates features of dysthymia and chronic major depression. It may have fewer symptoms than major depression, but they typically set in at an earlier age, never lift for long, and become a backdrop to existence rather than an interruption of regular life.

Premenstrual dysphoric disorder, which “graduated” to an official diagnosis. Disabling symptoms flare up during the second half of the menstrual cycle and improve quickly once flow starts. Along with the “usual” depressive signs, criteria for PMDD include moodiness, feeling on edge or overwhelmed, and physical symptoms such as breast tenderness or swelling, bloating, and joint or muscle pain.

Tweaks to major depressive disorder include adding “hopelessness” to the mood criteria and deleting the so-called bereavement exclusion. After all, someone may develop clinical depression in response to loss of a loved one as well as to loss of a job or a marriage, or some other major life change.

Two people with the same diagnosis can present completely differently.

It seems as if that kind of “reactive” depression, triggered by a stressful event, would be fundamentally different than the kind that just occurs out of the blue, for some “inborn” reason. When it comes to finding effective medication, however, the origin of an episode doesn’t seem to make much difference. The “time course” of the illness—whether it’s episodic or enduring—appears to be more relevant.

“There’s some indication that depression that lasts for years has different causes and may respond to different treatments,” Uher says.

And what might those causes be? The picture is not at all clear, except that some interplay of genetic susceptibility and environmental influence is at work.

For example, a history of childhood trauma has been strongly linked to greater risk for persistent depressive disorder—combined with “some genetic predisposition that makes you likely to get depressed after a bad childhood,” Uher says.

The situation is puzzling even for depressions tied to women’s hormonal shifts, whether premenstrual dysphoric disorder or depression that arises during or after a pregnancy (technically, “depression with peripartum onset”). It seems obvious the root would be the mother of all female hormones, right? Wrong.

“It’s actually been very difficult to pinpoint estrogen as a cause of depression despite lots and lots of research,” Flynn says. The drastic changes in estrogen levels during pregnancy may even protect some women against depression, while raising risk for others.

Large-scale genome studies haven’t fared any better. According to Uher, whose research specialties include psychiatric genetics, efforts to isolate which genes contribute to the risk for depression have identified exactly none.

That’s not to say they don’t exist, he notes: “A family history of depression or bipolar disorder still remains an important predictive factor. It’s just that we have not been able to pinpoint the exact genetic variants yet.”



Neuroscience doesn’t have any silver-bullet answers yet, either. The class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), introduced in the 1980s, was built on observations that people with depression often have low levels of the neurotransmitter serotonin. Turns out the interplay between depression and brain chemistry is not so straightforward.

SSRIs provide relief for a large subset of people with depression. Many others don’t respond, however, suggesting their depressions have some more complex basis.

“We know that serotonin is an important issue because the SSRIs work in a lot of depressions, but we can’t assume that’s all there is,” says Jan A. Fawcett, MD, a psychiatry professor at the University of New Mexico who chaired the panel tasked with revising the mood disorders section for the DSM-5.

Newer medications target other neurotransmitters associated with  regulating mood. Thus the class of SNRIs, named for serotonin and norepinephrine. Several of the atypical antipsychotics used as add-on treatments for depression act on the dopamine system, a key player in the brain’s pleasure centers.

So does ketamine, an anesthetic which is in the early stages of research for quick relief from unipolar and  bipolar depression. And Fawcett says patients with treatment-resistant depression who have profound anhedonia, or an inability to take pleasure in activities that are normally enjoyable, have responded well to medications for Parkinson’s disease that increase dopamine in the brain.

But wait, there’s more. Research has moved beyond brain chemistry to take in the organ’s functional circuitry and anatomical structure, too. Through brain imaging, researchers have found significant patterns in people with depression—reduced activity in the dorsolateral prefrontal cortex (involved in cognition), compromised function in the anterior cingulate gyrus (important in emotional processing), and thinning of the cerebral cortex (central to planning, reasoning and mood), to name a few.

Regulation of the amygdala, a structure deep in the brain that’s associated with primal emotions and memory, seems to misfire in a number of mental disorders. A study published in Neuron earlier this year found that how strongly the amygdala reacts to threats can predict who will develop depression or anxiety due to stressful life events.  Individuals who showed more brain activity in response to photos of angry or fearful faces proved to be more vulnerable when faced with conflict  in relationships or problems at work  or school.

Then there’s the inflammation theory of depression, which implicates the body’s “fight-or-flight” system more generally. When the brain perceives a threat (real or not) or another stressor, cortisol and other hormones go into overdrive. That affects a host of body processes: insulin production, blood flow, the digestive system, the immune system.

Ultimately, chronic stress contributes to systemic inflammation, which can be easily measured through a substance in the blood called C-reactive protein (CRP). There’s a strong connection between elevated levels of CRP and greater risk for psychological distress and depression.

The argument is that some depressions may essentially be a symptom of underlying inflammation, which would explain why people with depression have higher rates of cardiac disease and diabetes, are prone to gastrointestinal complaints, and frequently have co-occurring anxiety.

Recent studies provide support for this view. When researchers from Emory University looked at how people with treatment-resistant depression responded to an anti-inflammatory medication, they found individuals with elevated levels of C-reactive protein improved and those with more normal levels did not.

Uher led another study, published in the American Journal of Psychiatry in December 2014, comparing reactions to two antidepressants. In this case, blood levels of CRP roughly predicted “who is more likely to respond to Drug A than to Drug B,” he notes.



The ability to predict an individual’s likely response to a medication by measuring a biomarker—levels of some substance in the blood or activity in the brain—forms the basis of personalized medicine.

“It’s very advanced in areas like cancer, where you can get a piece of the tumor and measure different enzymes and decide how aggressive it is and what kinds of treatment will block the pathologic process,” Fawcett says. “People are just starting to talk about it in psychiatry.”

Heather Flynn, the clinical psychologist from Florida State University College of Medicine, notes that there are some useful starting points even in the absence of reliable biomarkers. If a close relative has depression, what medications worked for them? If this is not a first episode for the patient, what worked well in the past? Above all, what are the most troubling symptoms?

“The most important thing at this stage is understanding the person’s particular symptom profile and making sure the treatments are affecting those symptoms,” she says. “Some people might get better if you target their sleep, whereas other people, you might have to target their sense of worth.”

If the primary symptom doesn’t improve, she adds, “the depression is likely to not get better overall.”

Given that different depressions may spring from different roots, it’s not surprising that medication alone may not be enough to sustain recovery. Flynn says neuroimaging studies have shown that medication and psychotherapy affect different parts of the brain.

“If somebody has recurrent depression, which is more than two episodes, the best treatment option is a combination of medication and psychotherapy…. That’s one of the most robust findings we have for chronic depression,” Flynn says.



Mark Kopta, PhD, a psychology professor at the University of Evansville in Indiana, has spent years looking at the equivalent of personalized medicine for psychotherapy. Researchers in this field talk about “dose-response relationship”— what level of therapy will produce the best results, how long on average before improvements should be seen, and what patient characteristics make a difference in those results.

In one of his early studies, published in 1994, Kopta and colleagues “looked at outcomes for 90 symptoms and the probability of improving across sessions —predicting the number of sessions it takes a patient to get well based on their symptoms.”

Some of their findings: “Angry depression was much more difficult to treat than non-angry depression. It takes a lot more sessions…. Acute symptoms, like extreme crying or panic, tend to be easier to treat.”

There’s some indication that depression that lasts for years has different causes and may respond to different treatments.

(In fact, a long-term study launched by the U.S. National Institute of Mental Health found that the presence of irritability and anger may mark “a distinct subtype” of major depressive disorder.)

There are treatment choices among psychotherapies just as there are among antidepressants: cognitive behavioral therapy (CBT) and mindfulness-based CBT, dialectical behavior therapy, solution-focused therapy, positive psychology techniques, narrative therapy, psychoanalysis and other psychodynamic therapies that probe the past for insight. Many therapists don’t stick with one “pure” approach, but mix and match.

The 1994 study included both past-oriented and skills-oriented therapy approaches. Kopta says regardless of the theoretical basis, there are essential elements common to any type of successful counseling.

“One is a plausible interpretation of the problem, whether it’s the way your parents raised you or some other factor. Another is corrective experiences: You go out in life and you try things. Third is cognitive modification: You practice a change in your thinking. And do it with an accepting, empathic therapist.”

In his own practice, Kopta says, his treatment approach might differ based on whether someone has a pessimistic outlook that contributes to chronic depression or whether there’s been a life event, such as a divorce, job loss, or death. Although the distinction has not proved useful in prescribing medication, it can dictate what kind of problem-solving skills, cognitive recalibration and lifestyle changes will promote recovery.

For people with depression—and for the professionals who want to help them—that’s really what it boils down to: Figuring out which treatment will provide the most relief in the shortest amount of time.

Kopta is also executive director of a nonprofit research group that channeled two decades of findings into a computerized assessment tool which is being used by the U.S. Department of Defense. In addition to producing a graphic “behavioral health profile” weighing psychiatric symptoms, the CelestHealth System tries to predict how well the individual will respond to talk therapy.

Some people might get better if you target their sleep, whereas other people, you might have to target their sense of worth.

A “therapeutic bond scale” indicates how the client-therapist relationship will influence progress. The “psychotherapy readiness scale” gauges the likelihood of success based on factors like how far back the psychological issues date, whether the person thinks counseling will be helpful, and the level of belief that it’s possible to “eventually overcome your problems and have a satisfying life.”

Many scientists hope to do something similar for pharma-cotherapy by zeroing in on essential distinctions in the causes and course of depressions, as well as the qualities that aid in recovery. Fawcett foresees “different diagnostics … recognizing different subtypes of the illness” arriving within the next decade or so.

Advances in the past mean there’s an ever-wider range of medications available. Future research will take the guesswork out of selecting the best one for you—whether based on your symptoms, such as anger or anhedonia, or on some biological marker like C-reactive protein.

Those kinds of findings so far, Fawcett says, “are good examples of why we need to think in a more individualized way about depression.”


Read more:
A Guide For Diagnosing Major Depressive Disorder in Adults


Printed as “Depression: What breed is your black dog?”, Spring 2015

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