 In modern parlance, people can say they’re depressed when they’re unhappy or disappointed or feel thwarted or defeated. It’s almost become a synonym for sadness or disappointment. But in clinical practice, the term refers to a syndrome, or a group of signs and symptoms that have hung together and come on together over some period. And so, the term 

 refers to a syndrome that’s at least 2 weeks in duration and includes at least 5 key symptoms. There are 9, more or less, symptoms that are possible to define an episode of major depression, and you need to have 5 of them, including a depressed mood and/or a loss of interest or a sense of inability to experience pleasure as one of the defining symptoms; and then at least 4 more. And to meet the syndrome or criteria, these symptoms need to be experienced almost every day across a several-week period.

Now, some people oversleep when they’re depressed, but more people have trouble falling asleep or staying asleep, or waking up early in the morning. Similarly, some people overeat, and a few even gain weight with an episode of depression. But more often, depression blunts your repetitive desires. People will lose appetite, and then more severe depression will have an impact of significant weight loss.

Before 1980, the definitions of the depressive disorders were relatively brief and almost stereotypic. Many depressions experienced by people in the outpatient world were thought to be part of a neurotic condition. Since 1980, we’ve gone from thinking about neurosis to thinking about disorders. And so, a major depressive disorder would be defined when someone has a major depressive episode that’s not caused by some other medical condition, or is not part of having schizophrenia, and our person who’s suffering from this depressive episode does not have a past history of mania or hypomania. Then, their major episode would be part of bipolar disorder.

I mentioned 1980 as a touchstone, because that was when the 

Diagnostic and Statistical Manual of Mental Disorders, Third Edition

] was published, and that’s when the fully spelled out ways of diagnosing the illness became part of our standard nomenclature. Since then, there have been 2 major revisions, and some smaller revisions in between. And so, since 2013, we’ve had the 

, the basic definition of a major depressive episode has stayed pretty much the same as it was in 1980, although some of the subtypes, some of the subsets of classification have changed over time.

For example, whether the depression is seasonal or whether it’s associated with postpartum onset, and so forth, the instances are now called 

. These were subtypes of depression 20, 30 years ago. It’s just a way in which the nomenclature has evolved.

Over the last 20 years, so much more of depression treatment has fallen under the purview of primary care providers, including primary care physicians and primary care advanced nurse practitioners. And even physician’s assistants are involved in patient care outside of the psychiatric setting. Psychiatrists spend more time taking care of patients with more serious and complex illnesses, including people who aren’t responding to standard treatment.

It’s not that hard to make the diagnosis of a depressive episode, but you do need some time. And so, ways of streamlining, or ways of improving efficiency have evolved to make primary care providers more efficient. A really useful scale called the PHQ-9 [Patient Health Questionnaire, depression module] has the 9 common signs and symptoms of depression with a little 3-item rating scale for each one. It enables you to quickly explore the presence or absence of each of the potential symptoms. And so, you can at least weigh the syndrome and determine if the cardinal symptoms are there, often with the patient’s help using the checklist even before they see you.

Now, it’s not foolproof. Sometimes there will be mistakes, and the person may have another condition. You may miss a complicating condition like a substance abuse disorder, for which withdrawal from the substance is actually causing the depressive symptoms. But, it’s a good starting place. With the average follow-up visit for primary care somewhere south of 10 minutes, having this checklist repeated at each visit gives you a way, again, of weighing how heavy the syndrome is and whether the patient’s making progress with treatment.

Depression is a condition that exists within a social matrix. And so, it not only affects the sufferer, but it also affects their family. It’s certainly valuable to have the input of family in terms of whether this illness is causing a problem, even whether it’s an illness or not. Is this an extreme example of normal grief, or has it gone beyond that? So a family member’s input and observations can be helpful. This is particularly helpful when the differential diagnosis is bipolar disorder or recurrent depression. In bipolar disorder, patients often see the hypomanias, sometimes even the manias, as their best self and not a sign of illness. Whereas the family members appreciate this is different in magnitude and in level of impairment or dysfunction from the patient’s best self.

Defining and Diagnosing Clinical Depression

 Most psychiatric illnesses are best understood as biopsychosocial phenomena, meaning that there are multiple pathways of causation. It’s not caused by a single gene. There is no depression gene. But if you have a first-degree relative who has depression—a parent, for example&mdash;your chances of having depression yourself are somewhere between 2 and 5 times greater than the average person of your age and socioeconomic group. So, it is familial.

And when you try to look at the different factors that go into causality, the familial relationship does account for a significant proportion of the variants. But it’s not perfectly familial, and it’s certainly not under single-gene heredity. For example, if I had an identical twin who suffered from depression, I wouldn’t have 100% certainty of suffering from depression myself, maybe only 70% to 80%.

Even when the genetics are identical, life experience, what you’ve gone through, can influence whether you’re at higher risk or lower risk. Now, it may well be that resilience factors are also inherited or acquired or taught. And so, one thing that might differentiate people who seem to be more depression-prone from people who are hardier in the face of depressogenic kinds of things—setbacks like losses, and disappointments, and bereavement, and so forth&mdash;may be how you’ve learned to handle your behavior and your feelings when you’re in a potentially depressogenic circumstance. When I got into this business 40 years ago, the notion that the activity of your genes could actually be modified for the rest of your life by things that you experienced seemed almost like science fiction. But we now know that there are these epigenetic factors that do influence whether genes are easily turned on or not able to be turned on. For example, early adversity, early trauma, in particular child abuse, or child neglect, or even sexual abuse can actually have stress-modifying effects on the activity of genes that may haunt or plague a person’s stress response for the rest of their life, or through key periods like adolescence and in young adults.

Another good example in terms of biopsychosocial factors is the value of social support in resilience. Having a loving significant other in your life who’s watching your back and who cares for you and who can hear your complaints and be a sounding board and so forth reduces your chances of getting depressed during a time of stress. Having no such person increases your chances.

Interestingly, one reason that women have a higher risk of depression versus men is that having a caring woman in your life is a protective factor. Having a caring man in your life doesn’t hurt, but it doesn’t offer quite the same protection. So heterosexual men have a relative advantage in this regard. There are many other factors that also explain sex differences in depression, including hormonal factors. Men are much less likely to have a depression after childbirth. Postpartum depression is a risk mostly carried by women, probably in part because of hormonal changes. There may be some increased risk at other reproductive times in a woman’s life. For example, during or following menopause. Men don’t have the same kind of age-dependent risks that women have.

Economic power and being on the receiving end of abusive behavior are other factors that partly account for gender differences and depression rates. Having economic power is somewhat protective against the risk of depression. Being on the receiving end of abuse and neglect is a risk factor and our society, at least, is not there in that regard.

Interestingly, if you look at the Old Order Amish around Lancaster, Pennsylvania, there is no gender difference related to the risk of depression. There are many reasons for this, but it does suggest that in some alternate kinds of social settings, some of the sex-risk differences are explainable or understandable in terms of the social circumstances that you grow up and live in.

In our culture, we grow up with some sense of what’s proper to be talked about, and when to ask for help and when not to ask for help. And although depression is not a synonym for weakness, there is some general view that if you were strong enough or tough enough, or more resilient, or more resourceful, you wouldn’t need to ask for help. And so, there is some tendency for people to suffer in silence. They have certain perspectives about going to the psychologist or going to a therapist or going to a psychiatrist, or even going to a primary care physician to talk about having depression. You just hope it will go away. And often, initial episodes of depression can be relatively short-lived and they do go away. So you don’t seek help. But then, sadly, if your depression doesn’t go away, it begins to have a life of its own.

And so, one thing that caring others can do if they see a loved struggling or in trouble is talk with them about it. And if it sounds like it’s starting to get in the way of their life—if it’s affecting their parenting, or if it’s affecting their workplace performance&mdash;encourage them to get some help.

Risk Factors and the Stigma of Depression

 If we talk about a syndrome and the syndrome having a weight, the weight can be measured by the number of symptoms and the intensity of each symptom. And so, you can use a standard rating scale to basically estimate the severity that the person is suffering from. Now, obviously some symptoms are more severe and worrisome than others. Strong suicidal ideation, for example.

Nevertheless, the more symptoms, the stronger the symptoms, the more likely it is that the person is not functioning well. And so, when you initiate a treatment, you want to have a baseline measure of the weight of the depressive syndrome, and then at key time points—ideally every other week, but even if that’s not possible, monthly. The same measure of the same signs and symptoms to see what progress has been made. Almost always, you need to have about a 50% reduction in the weight of the symptoms to declare that the person is significantly better. A little better isn’t good enough. Significantly better is a starting place, because then you know you’re on the right track with the treatment. Ideally, you’re aiming to help the person achieve what we call a 

, which basically means an almost complete reduction of the signs and symptoms of the depressive episode.

When you’re initiating a treatment, you want symptom relief to occur pretty quickly. But even before that, if the treatment’s a medication, you want to make sure that the treatment is reasonably well tolerated.

A first time-limited goal in a management plan would be to pick a medication that is affordable, can be taken without worrisome adverse effects or annoying adverse effects, and can start to put the antidepressant treatment process into motion. That’s a goal for the first 2 weeks of treatment, to accomplish those things. That’s the first time-limited goal.

A second time-limited goal would be to get that first substantial symptom relief. And so, let’s aim to see that by 4 weeks. Ideally, we’d want to see it at 2 weeks, if we could. Some treatments work a little faster than others, but generally, if you’re not seeing that kind of reduction in the first 4 weeks, you may have to pick a different treatment for the depression.

To get to the end of the acute phase of treatment, that would be the third time-limited goal, that’s generally between the 6th and 12th week of treatment. That’s when you’ve declared victory with this particular treatment plan, or turn to another treatment plan, for which you’re resetting your time-limited goals.

There are all sorts of different guidelines to help physicians stay on track with their treatment efforts, and there are guidelines for various different kinds of disorders. For the depressive disorders in the United States, the American Academy of Family Physicians and the American Psychiatric Association have practice guidelines, as does the [US Department of] Veterans Affairs medical system. So depending where you’re practicing, there is a coherent set of guidelines available for you. I think the first American Psychiatric Association practice guidelines came out in 1993. I’m pretty sure they were revised again around the year 2000, and I think the third edition came out in 2010. The third edition is the most recent one, in part because the American Psychiatric Association has slowed its efforts with guideline development. It’s still weighing the impact of their experts’ relationships with the pharmaceutical industry. They’re very concerned and cautious that patients perceive that their treatment is being guided as much by experts’ opinions as experts’ relationships with pharmaceutical companies. This is a controversial area. You can’t have guidelines written by people who aren’t experts, but if you limit the guidelines to only people who have no relationships with the pharmaceutical industry, you have few experts left to write the guidelines. So we’ve not come to a good peace with that.

My favorite current practice guideline is the one that our Canadian colleagues, from their mood disorders consortium, does. There’s a 2016 version that is almost perfectly well suited for practitioners in the United States.

If we were going to take the Canadian guidelines and use them to update the American Psychiatric Association practice guidelines, we’d have the newest antidepressants. Medications like vortioxetine and vilazodone would be added. The whole value of using newer-generation antipsychotic medication for adjunctive therapy of major depressive disorder, that has mostly come online since the last edition of the American Psychiatric Association practice guidelines. But even the Canadian guidelines don’t have a full, up-to-date assessment of the newest therapies that have been introduced in the United States, including Spravato, which is the intranasal form of esketamine. And then the newest medicine approved for postpartum depression, brexanolone, which is a very interesting GABA [gamma-aminobutyric acid]-acting medicine called a neurosteroid, basically, which is another kind of rapid novel treatment for a condition that previously we had no specific medications indicated for.

Advances in the Management of Depression

EP 1: Defining and Diagnosing Clinical Depression

EP 2: Risk Factors and the Stigma of Depression

EP 3: Clinical Depression and Treatment Planning