Clinical depression is a serious condition that negatively affects how a person thinks, feels, and behaves. In contrast to normal sadness, clinical depression is persistent, often interferes with a person’s ability to experience or anticipate pleasure, and significantly interferes with functioning in daily life. Untreated, symptoms can last for weeks, months, or years; and if inadequately treated, depression can lead to significant impairment, other health-related issues, and in rare cases, suicide.

A person is diagnosed with a major depression when he or she experiences at least five of the symptoms listed below for two consecutive weeks. At least one of the five symptoms must be either (1) depressed mood or (2) loss of interest or pleasure.

Symptoms include:

• Depressed mood most of the day, nearly every day
• Markedly diminished interest or pleasure in activities most of the day, nearly every day
• Changes in appetite that result in weight losses or gains unrelated to dieting
• Changes in sleeping patterns
• Loss of energy or increased fatigue
• Restlessness or irritability
• Feelings of anxiety
• Feelings of worthlessness, helplessness, or hopelessness
• Inappropriate guilt
• Difficulty thinking, concentrating, or making decisions
• Thoughts of death or attempts at suicide

The first step to being diagnosed is to visit a doctor for a medical evaluation. Certain medications, and some medical conditions such as thyroid disorder, can cause similar symptoms as depression. A doctor can rule out these possibilities by conducting a physical examination, interview and lab tests. If the doctor eliminates a medical condition as a cause, he or she can implement treatment or refer the patient to a mental health professional.

Once diagnosed, a person with depression can be treated by various methods. The mainstays of treatment for depression include various antidepressant medications, various forms of psychotherapy, or rTMS (repetitive transcranial  magnetic stimulation), a non-invasive, outpatient procedure that uses magnetic pulses to stimulate brain areas involved in mood regulation.

For severe, treatment-resistant depression, options include: enhanced non-invasive brain stimulation (for instance, the rapid-acting SAINT protocol); electroconvulsive theapy (ECT)or magnetic seizure therapy (MST); and esketamine, a medicine derived from the ketamine molecule and marketed under the brand name Spravato, a rapid-acting nasal spray often used with oral antidepressants for adults with treatment-resistant depression with or without suicidal ideation.

Watch this BBRF webinar: What’s New with TMS for Depression and Other Brain Diseases, featuring Dr. Mark S. George, a TMS pioneer.

Depression is significantly more common in women than in men (lifetime prevalence of major depression in women may be twice as high as in men). An estimated 20 percent of women will experience at least one episode of depression in their lifetime. Scientists are examining many potential causes and contributing factors relating to women’s increased depression risk. Biological, life-cycle, hormonal, and psychosocial factors unique to women may be linked to women’s higher depression rates. Researchers have shown, for example, that hormones affect brain chemistry, impacting emotions and mood. Postpartum depression is a major risk for women who have children,  An estimated 5 percent to 10 percent of women who experience postpartum depression have what doctors classify as a severe form of the disorder, posing a direct threat to the life of the mother, and, of course, to the welfare of her newborn. Both severe and less severe forms of postpartum depression are thought to be triggered by abrupt changes in hormone levels after childbirth, and are regarded as medically serious. The rapid-acting medicines Brexanolone and Zuranolone, both FDA-approved, treat postpartum depression by modifying activity at the brain’s GABA receptors, inhibitory or signal-dampening receptors whose function is sensitive to shifting hormone levels.

Before adolescence, girls and boys experience depression at about the same frequency. By adolescence, however, girls become more likely to experience depression than boys. Research points to several possible reasons for this imbalance. The biological and hormonal changes that occur during puberty likely contribute to the sharp increase in rates of depression among adolescent girls.

Menopause is defined as the state of an absence of menstrual periods for 12 months. Menopause is the point at which estrogen and progesterone production decreases permanently to very low levels. The ovaries stop producing eggs and a woman is no longer able to get pregnant naturally. During the transition into menopause, some women experience an increased risk for depression. Scientists are exploring how the cyclical rise and fall of estrogen and other hormones may affect the brain chemistry that is associated with depressive illness.

For older adults who experience depression for the first time later in life, other factors, such as changes in the brain or body, may be at play. For example, older adults may suffer from restricted blood flow, a condition called ischemia. Over time, blood vessels become less flexible. They may harden and prevent blood from flowing normally to the body’s organs, including the brain. If this occurs, an older adult with no family or personal history of depression may develop what some doctors call “vascular depression.” Those with vascular depression also may be at risk for a coexisting cardiovascular illness, such as heart disease or a stroke.

The ability of ketamine to produce a rapid and effective antidepressant response is considered by most experts an important finding in depression research. Originally developed as an anesthetic, ketamine is an antagonist of the NMDA receptor on a subset of brain cells. It often produces rapid (within hours) and dramatic antidepressant actions in patients who have failed to respond to conventional antidepressants (i.e., are considered treatment-resistant). Ketamine's therapeutic effects are not long-lasting; in most people they fade within 1-2 weeks. Ketamine is psychoactive and has potentially dangerous side effects; it has a past history of being abused as a street drug, although when used as an antidepressant it is delivered in "sub-anesthetic" doses.  Another potential ketamine side effect is dissociation, the sensation of having an out-of-body experience.  The FDA has approved esketmaine (Spravato), which is based on the ketamine molecule, for treatment of severe, treatment-resistant depression.  Studies aimed at characterizing the mechanisms by which ketamine works rapidly and effectively in severely depressed individuals may lead to novel targets and agents that are safer and more long-lasting (ketamine's antidepressant effect usually fades after a week or two), and could revolutionize the treatment of depression. Numerous BBRF Grants support this work, including a number that are attempting to develop ketamine analogs – compounds that act like ketamine but lack its undesirable side effects.

Treatment-resistant depression (TRD) is a term used in clinical psychiatry to describe cases of major depressive disorder that do not respond to standard treatments (two or more courses of standard antidepressant treatments). For many people, antidepressant treatment and/or ‘talk’ therapy (such as Cognitive Behavioral Therapy) ease symptoms of depression, but with treatment-resistant depression, there is either little or no impact or antidepressant effects are not sustained. Treatment-resistant depression symptoms can range from mild to severe and may require trying a number of approaches to identify what helps.

Treatment of resistant depression has most commonly been treated, historically, with electroconvulsive therapy (ECT). ECT has been modified to avoid or reduce serious side-effects associated with it, notably short-term memory-loss. The downside is that it works by inducing a brief therapeutic brain seizure, which likely is related to its impact in some patients upon short-term memory. Its therapeutic benefits can fade over a period of months, requiring additional treatments, each of which, involving anesthesia, carries some risk. Magnetic seizure therapy (MST) is one method that has been developed (in part by Dr. Sarah Lisanby, with the help of BBRF grants) that may be safer than ECT. A trial comparing ECT and MST found that they were equally effective in significantly reducing major depression symptoms. Both treatments, which induce brief therapeutic seizures under anesthesia, brought relief within weeks that endured over 6 months. MST appeared to be safer, with fewer side effects including what appeared to be less if any impact on memory.

New methods of non-invasive brain stimulation also offer the possibility of relief from treatment-resistant depression. Repetitive transcranial magnetic stimulation (rTMS), pioneered by Dr. Mark George with the support of BBRFgrants, was approved by the FDA in 2008 as a treatment for TRD. In its evolved form, rTMS (repetitive TMS) is now used to treat not only TRD but also as a first-line depression treatment. It is a noninvasive method that works through a coil held over the target area of the brain. A magnetic field passes through the skull to activate depression-linked brain circuitry (no seizures are induced and it is offered on an outpatient basis). Rapid-acting protocols based on iTBS, a technology that grew out of rTMS, is now approved under the SAINT protocol developed at Stanford University, and has demonstrated the ability to induce remissions after only 5 days of accelerated non-invasive brain stiumulation. Deep brain stimulation (DBS) is a technique adapted for treating depression tested by Dr. Helen Mayberg with the support of BBRF grants. Requiring an invasive procedure (brain surgery) and still used only on an experimental basis in severe cases of TRD, DBS works through electrodes surgically implanted deep in the brain. Another method, vagus nerve stimulation (VNS), stimulates the vagus nerve in the neck to therapeutically activate brain function.

Variations in genes--different kinds of DNA mutations, both common and rare--have been robustly linked to a number of serious psychiatric disorders including schizophrenia, bipolar disorder and autism. In depression, after a slow beginning, important progress on the genetics front is being made. Researchers have published the largest probe to date of genetic factors associated with the depression, using a sample of over 1 million people for the first time. It reveals 223 genome locations ("loci") that are often perturbed in the illness and likely to have impacts on causation, and suggests links between depression and other psychiatric diagnoses and behavioral traits.

Depression’s Genetic Links Probed in 1 Million People in a Single Study for the First Time