You've probably come out of a particularly sad movie and said something like, "Man, that was depressing." In this case, you're talking about how, at that moment, the movie made you feel sad, discouraged, hopeless, or anxious. You probably wouldn't say something like, "Man, that movie was clinically depressing." The latter expression refers to a much different state of depression. Clinical depression, sometimes called major depressive disorder or unipolar depression, is a serious mental disorder that has a lifetime incidence of up to 20% in women and 12% in men. This makes it one of the most common reasons people seek out mental health services. As well as being relatively common, clinical depression is, in fact, very serious. It's so serious that it interferes with someone's day-to-day life, like working, studying, eating, and sleeping, essentially leading to this overall feeling that life isn't enjoyable. But what causes someone to feel this way? Well, we don't exactly know what specifically causes clinical depression, especially since it can be so different between patients. It's probably a combination of factors, though, like genetic factors, biological factors, environmental factors, and psychological factors. It's been shown that people with family members who have depression are three times more likely to have it themselves, and this link seems to increase with how closely related family members are. Biologically, though, most medications focus specifically on neurotransmitters. Neurotransmitters are signaling molecules in the brain that are released by one neuron and received by receptors of another neuron. When that happens, essentially a message is relayed from one neuron to the next. Regulation of how many of these neurotransmitters are being sent between neurons at any given time is thought to play a super important role in the development of symptoms of depression, since they're likely involved in regulating a lot of brain functions like mood, attention, sleep, appetite, and cognition. The three main neurotransmitters that we focus on for depression are serotonin, norepinephrine, and dopamine. Why do we focus on these three? Well, because medications that cause there to be more of these neurotransmitters in the synaptic cleft, this space between the neurons, are shown to be effective antidepressants. And this finding led researchers to develop the monoamine deficiency theory, which says that the underlying basis of depression is low levels of serotonin, norepinephrine, or dopamine, which are all called monoamines because they have one amine group. Additionally, it's thought that each of these might have an impact on certain sets of symptoms with depression, like norepinephrine on anxiety or attention, or serotonin on obsessions and compulsions, or dopamine on attention, motivation, and pleasure. So if one of these is down, then that could lead to a set of specific symptoms being felt by the patient. Serotonin in particular is thought to be a major player, some theories suggest it's even capable of regulating the other neurotransmitter systems, although evidence supporting this theory is still pretty limited. Some hard evidence implicating serotonin in depression has to do with tryptophan depletion, which is the amino acid the body uses to make serotonin. So if you take it away, you can't make as much serotonin, and it's been shown that when the body can't make as much serotonin, patients start getting symptoms of depression. So that's all well and good, but unfortunately the reasons why serotonin or other neurotransmitters might be lost or decreased in depressed patients in the first place isn't well known, and research remains ongoing. Ultimately, development of depression is complicated, right? It involves these biological components in combination with the genetic components as well as environmental factors, which could be specific events like a death or a loss, or sexual and physical abuse. In order to diagnose clinical depression, patients must meet certain criteria that are outlined in the Diagnostic and Statistical Manual for Mental Disorders, the 5th edition. First, they must be affected by at least 5 of the following 9 symptoms most of the day nearly every day: depressed mood, diminished interest or pleasure in activities, significant weight loss or gain, inability to sleep or oversleeping, psychomotor agitation, like pacing or wringing one's hands, or psychomotor impairment, like this overall slowing of thought and movements, fatigue, feelings of worthlessness or guilt, lowered ability to think or concentrate, and finally recurrent thoughts of death or suicidality, including suicidal thoughts, with or without a specific plan, as well as suicide attempts. And these symptoms must cause significant distress to the patient's daily life. Also, the depressive episode can't be due to a substance or other medical condition, the symptoms can't be better explained by another mental disorder like schizoaffective disorder, and finally the patient can't have had a manic or hypomanic episode at any point. Additionally, sometimes major depressive disorder can be divided into subtypes, or closely related conditions. Postpartum depression is a subtype that can happen following childbirth, although studies have shown that in many cases onset of depression occurs prior to childbirth as well, so it's now diagnosed as depressive disorder with peripartum onset, in other words the onset happens during pregnancy or 4 weeks following delivery. It's not quite understood why this happens, although hormonal changes likely play a role, especially estrogen and progesterone. Also though, an abrupt change in lifestyle might be an important causal factor, especially because this can happen in men as well as women. Atypical depression is another important subtype that's characterized by an improved mood when exposed to pleasurable or positive events, called mood reactivity, and this is in contrast to other subtypes like melancholic depression, even during what used to be pleasurable events. Also, atypical depression often includes symptoms like weight gain or increased appetite, oversleeping, heavy feeling limbs also known as leaden paralysis, and rejection sensitivity, essentially feeling anxiety at the slightest evidence of rejection. Finally, dysthymia, now known as persistent depressive disorder, is sometimes used to describe milder symptoms of depression that happen over longer periods of time, specifically two or more years with two or more of the following symptoms, a change in appetite, a change in sleep, fatigue or low energy, reduced self-esteem, decreased concentration or difficulty making decisions, and feelings of hopelessness or pessimism. Knowing that so many factors are probably involved in depression, it can be a challenge to treat, although with the right treatment, 70-80% of patients with clinical depression can significantly reduce their symptoms. Treatment can come in many forms and are most commonly grouped into one of two major categories, one, non-pharmacologic approaches, in other words, things other than medications, and two, pharmacologic approaches, either a single medication or combinations of medications. Starting with the non-medication approach, a number of studies have shown the benefits of physical activity in helping with depression. There are various reasons why it's thought to work, ranging from the release of neurotransmitters, endorphins, and endocannabinoids, to raising the body temperature and relaxing tense muscles. Regardless of the exact mechanisms, data suggest that exercising for 20 minutes three times a week can help alleviate depression symptoms. There's also a lot of research exploring the relationship between diet and depression, and although there are no silver bullet foods, many experts suggest healthy eating habits like more fruits and veggies. Beyond physical activity and healthy eating, which is more helpful for a number of reasons, another major non-pharmacologic approach is psychotherapy, or talk therapy, which is definitely preferred for young patients and for those with milder symptoms. There are a few popular approaches including cognitive behavior therapy and interpersonal therapy, and the most important thing here is that these approaches depend heavily on the relationship between the patient and the therapist, as well as the clinical skills of the therapist. If patients have more severe depression, or mild depression for a longer period of time, then antidepressant medication might be prescribed along with the therapy. The most commonly prescribed medications are selective serotonin reuptake inhibitors, or SSRIs. In the synaptic cleft, after neurotransmitters get released, those neurotransmitters are normally reabsorbed. SSRIs block the reabsorption, or inhibit the reuptake, of serotonin, which means that there's going to be more serotonin in the synaptic cleft. Other classes of antidepressants that are less commonly prescribed are monoamine oxidase inhibitors, or MAOIs, and tricyclics. As a final, last line treatment for severe depression, ECT might be performed, under written consent. ECT stands for electroconvulsive therapy, and is when a small and controlled amount of electric current is passed through the brain while patients are under general anesthesia, and this induces a brief seizure. Although ECT has been used for decades, and actually does seem to be effective for about 50% of patients, the reason why electrically induced seizures seem to improve symptoms is not well understood. Alright, clinical depression is tough, both for those experiencing it and for those trying to help treat it. Unlike many other illnesses, depression carries with it a lot of social stigma, and can lead to moral judgments that can make a person with depression feel even worse. Love and support from friends and family helps tremendously, and having a strong social support network has been proven to lead to better outcomes.