_______________________________________________________________________ Depression and Suicide
After the initial onset of MDD, around 15% of patients have a chronic and unremitting course. An additional 35% recover but experience one or more future recurrent episodes, and roughly 50% of first lifetime onsets recover and do not have future MDE episodes [10; 37]. The risk of recurrence becomes progressively lower over time as the duration of remission increases. Preceding severe depressive episodes, younger age, and previous multiple depressive episodes increase the risk of recurrence [10]. Antidepressant medication can alter the disease course by reducing relapse rates, while premature antidepressant dis- continuation is associated with marked increases in risk of relapse [38; 39; 40]. Relapse prevention is a clinical priority, and a collaborative care model with ongoing pharmacotherapy and/or psychotherapy and regular follow-up can improve treat- ment adherence and reduce the risk of depressive relapse [21; 41]. A single episode of major depression is associated with a 50% chance of a subsequent episode, two episodes with a 70% chance, and three or more episodes with a 90% chance [42]. A greater number of depressive episodes predicts poor treatment response [22]. Depression is an illness with a potentially fatal outcome. Among persons with a mood disorder, 12% to 20% will ultimately die by suicide. The first three months is the period of highest risk for a first attempt, with the three months fol- lowing the first attempt being the highest risk period for a second attempt [43]. DEFINITIONS Several similar but distinct terms are used to describe depres- sion. The DSM-5-TR states the common feature of depressive disorders is the “presence of a sad, empty, or irritable mood, accompanied by somatic and cognitive changes that signifi- cantly affect a person’s ability to function” [10]. Depressive disorder is an umbrella term that includes MDD (including major depressive episode), persistent depressive disorder, pre- menstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspeci- fied depressive disorder. A new diagnosis, disruptive mood dysregulation disorder (a chronic, severe, persistent irritability), is included in the DSM-5-TR to address concerns of potential overdiagnosis and treatment of bipolar disorder in children 12 years of age and younger [10]. MDD, formerly called major depression or clinical depression, is the classic condition in this group of disorders, characterized by discrete episodes of at least two weeks’ duration involving clear-cut changes in affect, cognition, and functioning, with inter-episode remissions [10]. Persistent depressive disorder is a chronic, lower-grade depression that does not have the level of severity of MDD. A depressed mood (i.e., feeling sad) that occurs for most of the day, for more days than not, and for at least two years (or at least one year for children and adolescents) is the essential feature of this disorder [10].
PATHOPHYSIOLOGY OF DEPRESSION AND SUICIDE
PATHOPHYSIOLOGY OF DEPRESSION The understanding of MDD pathophysiology and treatment is substantially changing. Until recently, the explanatory model of depressive illness and antidepressant drug efficacy was the monoamine hypothesis. Modern antidepressants were introduced in the 1950s following serendipitous discovery of anti-depressant effects with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Selective sero- tonin reuptake inhibitors (SSRIs) were introduced in the late 1980s, followed by atypical antidepressants and serotonin- noradrenaline reuptake inhibitors (SNRIs) [44]. The mono- amine hypothesis, proposed to explain the unexpected effects of TCAs/MAOIs in the 1950s, posits that depression results from deficient brain serotonin (5-HT) and/or norepinephrine levels. This remained the dominant paradigm of depression and the basis of nearly all FDA-approved antidepressants for the next five decades [45; 46]. Limitations of the monoamine hypothesis and mechanistic homogeneity of standard antide- pressants are now understood. MDD is vastly more complex and diverse than previously assumed, and novel pathways that underlie its pathophysiology have been identified [47; 48]. Inflammatory Pathways “Inflammation” broadly describes immune-related processes within the body, a protective immunovascular response involv- ing immune cells, blood vessels, and molecular mediators. Inflammatory response is activated by external (microbial infection) or internal (atherosclerosis) causes to maintain homeostasis, by eliminating initial cause of injury, clearing dead and damaged cells, and initiating tissue repair. A normal immune system produces pro- and anti-inflammatory media- tors. When anti-inflammatory mediators cannot inhibit the pro-inflammatory immune response, a chronic inflammatory state may develop. Acute inflammation is adaptive (for clearing infection), but chronic inflammation is usually maladaptive and destructive and may persist for years as a low-grade state without clinical symptoms [49]. An inflammatory response produces prostaglandins, white blood cells, and cytokines that generate other inflammatory molecules, including tumor necrosis factor-alpha, interleukins, and C-reactive protein. These mediators communicate with other immune system elements. Central nervous system (CNS) inflammation (neuroinflammation) involves diverse cell types, microglia, and astrocytes that both induce and limit brain inflammatory processes [49]. Peripheral and central immune systems communicate through bidirectional pathways [50]. Inflammation is a core component of chronic mood disorders.
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