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Monoamine hypothesis Of approx. 30 neurotransmitters that have been identified, researchers have discovered associations between clinical depression and the function of three major neurochemicals. These substances are serotonin, norepinephrine, and dopamine. Antidepressants influence the overall balance of these three neurotransmitters within structures of the brain that regulate emotion, reactions to stress, and the physical drives of sleep, appetite, and sexuality.[medical citation needed]Most antidepressant medications increase the levels of one or more of the monoamines — the neurotransmitters serotonin, norepinephrine and dopamine — in the synaptic cleft between neurons in the brain. Some medications affect the monoamine receptors directly. Serotonin is hypothesized to regulate other neurotransmitter systems; decreased serotonin activity may allow these systems to act in unusual and erratic ways.[33] According to this "permissive hypothesis", depression arises when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter.[34] Some antidepressants enhance the levels of norepinephrine directly, whereas others raise the levels of dopamine, a third monoamine neurotransmitter. These observations gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that a deficiency of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life."[35] The proponents of this theory recommend the choice of an antidepressant with mechanism of action that impacts the most prominent symptoms. Anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and those experiencing a loss of energy and enjoyment of life with norepinephrine- and dopamine-enhancing drugs.[35] Besides the clinical observations that drugs that increase the amount of available monoamines are effective antidepressants, recent advances in psychiatric genetics indicate that phenotypic variation in central monoamine function may be marginally associated with vulnerability to depression. Despite these findings, the cause of depression is not simply monoamine deficiency.[36] In the past two decades, research has revealed multiple limitations of the monoamine hypothesis, and its explanatory inadequacy has been highlighted within the psychiatric community.[37] A counterargument is that the mood-enhancing effect of MAO inhibitors and SSRIs takes weeks of treatment to develop, even though the boost in available monoamines occurs within hours. Another counterargument is based on experiments with pharmacological agents that cause depletion of monoamines; while deliberate reduction in the concentration of centrally available monoamines may slightly lower the mood of unmedicated depressed patients, this reduction does not affect the mood of healthy people.[36] The monoamine hypothesis, already limited, has been further oversimplified when presented to the general public as a mass marketing tool, usually phrased as a "chemical imbalance".[38] In 2003 a gene-environment interaction (GxE) was hypothesized to explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR);[39] a 2009 meta-analysis showed stressful life events were associated with depression, but found no evidence for an association with the 5-HTTLPR genotype.[40] Another 2009 meta-analysis agreed with the latter finding.[41] A 2010 review of studies in this area found a systematic relationship between the method used to assess environmental adversity and the results of the studies; this review also found that both 2009 meta-analyses were significantly biased toward negative studies, which used self-report measures of adversity.[42] Other hypothesesMRI scans of patients with depression have revealed a number of differences in brain structure compared to those who are not depressed. Recent meta-analyses of neuroimaging studies in major depression, reported that compared to controls, depressed patients had increased volume of the lateral ventricles and adrenal gland and smaller volumes of the basal ganglia, thalamus, hippocampus, and frontal lobe (including the orbitofrontal cortex and gyrus rectus).[43][44] Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.[45] There may be a link between depression and neurogenesis of the hippocampus,[46] a center for both mood and memory. Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood. Drugs may increase serotonin levels in the brain, stimulating neurogenesis and thus increasing the total mass of the hippocampus. This increase may help to restore mood and memory.[47][48] Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior.[49] One of the neurotrophins responsible for neurogenesis is brain-derived neurotrophic factor (BDNF). The level of BDNF in the blood plasma of depressed subjects is drastically reduced (more than threefold) as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although decreased plasma BDNF levels have been found in many other disorders, there is some evidence that BDNF is involved in the cause of depression and the mechanism of action of antidepressants.[50] There is some evidence that major depression may be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that results in an effect similar to the neuro-endocrine response to stress. Investigations reveal increased levels of the hormone cortisol and enlarged pituitary and adrenal glands, suggesting disturbances of the endocrine system may play a role in some psychiatric disorders, including major depression. Oversecretion of corticotropin-releasing hormone from the hypothalamus is thought to drive this, and is implicated in the cognitive and arousal symptoms.[51] The hormone estrogen has been implicated in depressive disorders due to the increase in risk of depressive episodes after puberty, the antenatal period, and reduced rates after menopause.[52] On the converse, the premenstrual and postpartum periods of low estrogen levels are also associated with increased risk.[52] Sudden withdrawal of, fluctuations in or periods of sustained low levels of estrogen have been linked to significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized or restored.[53][54] Other research has explored potential roles of molecules necessary for overall cellular functioning: cytokines. The symptoms of major depressive disorder are nearly identical to those of sickness behavior, the response of the body when the immune system is fighting an infection. This raises the possibility that depression can result from a maladaptive manifestation of sickness behavior as a result of abnormalities in circulating cytokines.[55] The involvement of pro-inflammatory cytokines in depression is strongly suggested by a meta-analysis of the clinical literature showing higher blood concentrations of IL-6 and TNF-α in depressed subjects compared to controls.[56] These immunological abnormalities may cause excessive prostaglandin E₂ production and likely excessive COX-2 expression. Abnormalities in how indoleamine 2,3-dioxygenase enzyme activates as well as the metabolism of tryptophan-kynurenine may lead to excessive metabolism of tryptophan-kynurenine and lead to increased production of the neurotoxin quinolinic acid, contributing to major depression. NMDA activation leading to excessive glutamatergic neurotransmission, may also contribute.[57] Finally, some relationships have been reported between specific subtypes of depression and climatic conditions. Thus, the incidence of psychotic depression has been found to increase when the barometric pressure is low, while the incidence of melancholic depression has been found to increase when the temperature and/or sunlight are low.[58] Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.[59] PsychologicalVarious aspects of personality and its development appear to be integral to the occurrence and persistence of depression,[60] with negative emotionality as a common precursor.[61] Although depressive episodes are strongly correlated with adverse events, a person's characteristic style of coping may be correlated with his or her resilience.[62] In addition, low self-esteem and self-defeating or distorted thinking are related to depression. Depression is less likely to occur, as well as quicker to remit, among those who are religious.[63][64][65] It is not always clear which factors are causes and which are effects of depression; however, depressed persons that are able to reflect upon and challenge their thinking patterns often show improved mood and self-esteem.[66] American psychiatrist Aaron T. Beck, following on from the earlier work of George Kelly and Albert Ellis, developed what is now known as a cognitive model of depression in the early 1960s. He proposed that three concepts underlie depression: a triad of negative thoughts composed of cognitive errors about oneself, one's world, and one's future; recurrent patterns of depressive thinking, or schemas; and distorted information processing.[67] From these principles, he developed the structured technique of cognitive behavioral therapy (CBT).[68] According to American psychologist Martin Seligman, depression in humans is similar to learned helplessness in laboratory animals, who remain in unpleasant situations when they are able to escape, but do not because they initially learned they had no control.[69] Attachment theory, which was developed by English psychiatrist John Bowlby in the 1960s, predicts a relationship between depressive disorder in adulthood and the quality of the earlier bond between the infant and the adult caregiver. In particular, it is thought that "the experiences of early loss, separation and rejection by the parent or caregiver (conveying the message that the child is unlovable) may all lead to insecure internal working models ... Internal cognitive representations of the self as unlovable and of attachment figures as unloving [or] untrustworthy would be consistent with parts of Beck's cognitive triad".[70] While a wide variety of studies has upheld the basic tenets of attachment theory, research has been inconclusive as to whether self-reported early attachment and later depression are demonstrably related.[70] Depressed individuals often blame themselves for negative events,[71] and, as shown in a 1993 study of hospitalized adolescents with self-reported depression, those who blame themselves for negative occurrences may not take credit for positive outcomes.[72] This tendency is characteristic of a depressive attributional, or pessimistic explanatory style.[71] According to Albert Bandura, a Canadian social psychologist associated with social cognitive theory, depressed individuals have negative beliefs about themselves, based on experiences of failure, observing the failure of social models, a lack of social persuasion that they can succeed, and their own somatic and emotional states including tension and stress. These influences may result in a negative self-concept and a lack of self-efficacy; that is, they do not believe they can influence events or achieve personal goals.[73][74] An examination of depression in women indicates that vulnerability factors—such as early maternal loss, lack of a confiding relationship, responsibility for the care of several young children at home, and unemployment—can interact with life stressors to increase the risk of depression.[75] For older adults, the factors are often health problems, changes in relationships with a spouse or adult children due to the transition to a care-giving or care-needing role, the death of a significant other, or a change in the availability or quality of social relationships with older friends because of their own health-related life changes.[76] The understanding of depression has also received contributions from the psychoanalytic and humanistic branches of psychology. From the classical psychoanalytic perspective of Austrian psychiatrist Sigmund Freud, depression, or melancholia, may be related to interpersonal loss[77][78] and early life experiences.[79] Existential therapists have connected depression to the lack of both meaning in the present[80] and a vision of the future.[81][82] SocialPoverty and social isolation are associated with increased risk of mental health problems in general.[60] Child abuse (physical, emotional, sexual, or neglect) is also associated with increased risk of developing depressive disorders later in life.[83] Such a link has good face validity given that it is during the years of development that a child is learning how to become a social being. Abuse of the child by the caregiver is bound to distort the developing personality and create a much greater risk for depression and many other debilitating mental and emotional states. Disturbances in family functioning, such as parental (particularly maternal) depression, severe marital conflict or divorce, death of a parent, or other disturbances in parenting are additional risk factors.[60] In adulthood, stressful life events are strongly associated with the onset of major depressive episodes.[84] In this context, life events connected to social rejection appear to be particularly related to depression.[85][86] Evidence that a first episode of depression is more likely to be immediately preceded by stressful life events than are recurrent ones is consistent with the hypothesis that people may become increasingly sensitized to life stress over successive recurrences of depression.[87][88] The relationship between stressful life events and social support has been a matter of some debate; the lack of social support may increase the likelihood that life stress will lead to depression, or the absence of social support may constitute a form of strain that leads to depression directly.[89] There is evidence that neighborhood social disorder, for example, due to crime or illicit drugs, is a risk factor, and that a high neighborhood socioeconomic status, with better amenities, is a protective factor.[90] Adverse conditions at work, particularly demanding jobs with little scope for decision-making, are associated with depression, although diversity and confounding factors make it difficult to confirm that the relationship is causal.[91] Depression can be caused by prejudice. This can occur when people hold negative self-stereotypes about themselves. This "deprejudice" can be related to a group membership (e.g., Me-Gay-Bad) or not (Me-Bad). If someone has prejudicial beliefs about a stigmatized group and then becomes a member of that group, they may internalize their prejudice and develop depression. For example, a boy growing up in the United States may learn the negative stereotype that gay men are immoral. When he grows up and realizes he is gay, he may direct this prejudice inward on himself and become depressed. People may also show prejudice internalization through self-stereotyping because of negative childhood experiences such as verbal and physical abuse.[59] EvolutionaryMain article: Evolutionary approaches to depression From the standpoint of evolutionary theory, major depression is hypothesized, in some instances, to increase an individual's reproductive fitness. Evolutionary approaches to depression and evolutionary psychology posit specific mechanisms by which depression may have been genetically incorporated into the human gene pool, accounting for the high heritability and prevalence of depression by proposing that certain components of depression are adaptations,[92] such as the behaviors relating to attachment and social rank.[93] Current behaviors can be explained as adaptations to regulate relationships or resources, although the result may be maladaptive in modern environments.[94] From another viewpoint, a counseling therapist may see depression not as a biochemical illness or disorder but as "a species-wide evolved suite of emotional programs that are mostly activated by a perception, almost always over-negative, of a major decline in personal usefulness, that can sometimes be linked to guilt, shame or perceived rejection".[95] This suite may have manifested in aging hunters in humans' foraging past, who were marginalized by their declining skills, and may continue to appear in alienated members of today's society. The feelings of uselessness generated by such marginalization could in theory prompt support from friends and kin. In addition, in a manner analogous to that in which physical pain has evolved to hinder actions that may cause further injury, "psychic misery" may have evolved to prevent hasty and maladaptive reactions to distressing situations.[96] Drug and alcohol useSee also: Substance-induced mood disorders Very high levels of substance abuse occur in the psychiatric population, especially alcohol, sedatives and cannabis. Depression and other mental health problems can have a substance induced cause; making a differential or dual diagnosis regarding whether mental ill-health is substance related or not or co-occurring is an important part of a psychiatric evaluation.[97] According to the DSM-IV, a diagnosis of mood disorder cannot be made if the cause is believed to be due to "the direct physiological effects of a substance"; when a syndrome resembling major depression is believed to be caused immediately by substance abuse or by an adverse drug reaction, it is referred to as, "substance-induced mood disturbance". Alcoholism or excessive alcohol consumption significantly increases the risk of developing major depression.[98][99] Like alcohol, the benzodiazepines are central nervous system depressants; this class of medication is commonly used to treat insomnia, anxiety, and muscular spasms. Similar to alcohol, benzodiazepines increase the risk of developing major depression. This increased risk of depression may be due in part to the adverse or toxic effects of sedative-hypnotic drugs including alcohol on neurochemistry,[99] such as decreased levels of serotonin and norepinephrine,[32] or activation of immune mediated inflammatory pathways in the brain.[100] Chronic use of benzodiazepines also can cause or worsen depression,[101] or depression may be part of a protracted withdrawal syndrome.[102][103] About a quarter of people recovering from alcoholism experience anxiety and depression, which can persist for up to 2 years.[104] Methamphetamine abuse is also commonly associated with depression.[105] |
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