Important information the literary view is on the the article “Mechanism of disease, Major Depressive Disorder” (Belmaker, 2008). Which is attached. The four domains are COGNITIVE, BIOLOGICAL, SOC
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 55 review article Mechanisms of Disease Major Depressive Disorder R.H. Belmaker, M.D., and Galila Agam, Ph.D. From Ben Gurion University of the Negev, Beersheba, Israel. Address reprint requests to Dr. Belmaker at Beersheba Mental Health Center, P.O. Box 4600, Beersheba, Israel, or at [email protected].
N Engl J Med 2008;358:55-68.Copyright © 2008 Massachusetts Medical Society. D epression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emo - tions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is diff icult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sex - ual desire; constipation; loss of the abilit y to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These chang - es must last a minimum of 2 weeks and interfere considerably with work and fam - ily relations. On the basis of this broad def inition, the lifetime incidence of depres - sion in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower def inition of severe depression, which they call melan - cholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking.
Although some pathogenetic mechanisms in these cases and in cases of major depres - sive disorder overlap, a history of mania defines a distinct illness termed bipolar dis - order. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsis - tent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major de - pression. G e n e t i c s Studies comparing concordance rates for major depression between monozygotic and dizygotic twins suggest a heritability of about 37%, 5 which is much lower than the heritability of bipolar disorder or schizophrenia. Some aspects of the normal person - ality, such as avoidance of harm, anxiousness, and pessimism, are also partly heritable. 6 Kendler et al. 7 showed that although depression is due in part to heritable depression- prone personality traits, it is also the result of heritable factors that are independent of personality. Early-onset, severe, and recurrent depression may have a higher heri - tability than other forms of depression. 8 It is clear from studies of families that major depression is not caused by any single gene but is a disease with complex genetic fea - tures. Studies of pedigrees with multiple cases of major depression have identif ied chromosomal regions with linkage to the disorder, and some of these loci have been replicated in more than one study, although no single chromosomal region has been replicated in every family study of genetic linkage in depression. Holmans et al. 9 found T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 56 evidence of linkage of recurrent, early-onset de - pression to chromosome 15q25-q26, but the pop - ulation attributable risk was small. No specif ic molecular risk factor has been reli - ably identif ied. One common polymorphic variant of the serotonin-transporter–linked polymorphic region ( 5-HTTLPR ), which affects the promoter of the serotonin-transporter gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. 10 Some studies have shown that this polymorphism confers a predis - position to depression, 11 but it also confers a pre - disposition to an anxious and pessimistic person - ality. 10 Brain imaging reveals functional differences in emotion-related areas of the brain among car - riers of the different common polymorphisms of 5-HTTLPR ,12 although a direct relation to depres - sion is unclear. In a large, prospective epidemio - logic study, Caspi et al. 13 found that 5-HTTLPR predicted depression only in association with de - f ined life stresses. Some environmental factors could confer a predisposition to depression by af - fecting the genome epigenetically — for example, increased maternal care in rodents causes an epi - genetic change in the promoter region of the glu - cocorticoid-receptor gene. 14 T h e M o n o a m i n e - D e f i c i e n c y H y p o t h e s i s The noradrenergic and serotonergic systems orig - inate deep in the brain and fan out over almost the entire brain, suggesting a system capable of modulating many areas of feeling, thinking, and behaving. The early antidepressants blocked the reuptake of norepinephrine and serotonin by the presynaptic neuron. The immediate effects of this pharmacologic action are to increase the availabil - ity of norepinephrine and serotonin in the synapse and to increase stimulation of the postsynaptic neuron. Inhibitors of the enzyme monoamine oxi - dase were also discovered to have antidepressant properties. This enzyme catabolizes norepineph - rine and serotonin in their respective presynaptic neurons, and such inhibition could be expected to increase the availability of neurotransmitters. These discoveries led to a major theor y of depression known as the monoamine-def iciency hypothesis.
Numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal f luid, as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably. However, a newly dis - covered form of the enzyme tryptophan hydroxy - lase, designated TPH-2, is specif ic to the brain 15 and could explain why previous postmortem stud - ies of total enzyme activity did not show differ - ences in tryptophan hydroxylase activity between patients with depression and controls. 16 A recent positron-emission tomographic study using a li - gand for brain monoamine oxidase showed a 30% increase of the enzyme in a subgroup of patients with depression. 17 A study measuring differences in monoamine metabolites between the internal jugular vein and the brachial artery showed lower production by the brain of norepinephrine metabo - lites in patients with depression than in controls. 18 The monoamine-def iciency hypothesis continues to stimulate research whenever a new technical window into the brain is opened. Serotonin and norepinephrine can be depleted experimentally in humans by oral treatments. 19 A drink containing all amino acids except trypto - phan stimulates the liver to synthesize proteins and rapidly depletes the plasma (and therefore the brain) of tryptophan. Tryptophan is rate-limiting for serotonin synthesis in the brain. Such oral tryptophan depletion does not induce depression in healthy subjects but will cause a relapse of de - pression in patients who have been successfully treated with a serotonin-reuptake inhibitor. 19 Sim - ilarly, α-methyl paratyrosine inhibits tyrosine hy - droxylase, the rate-limiting step in catecholamine synthesis. Treatment with α-methyl paratyrosine does not induce depression in normal subjects but will induce a relapse in patients who have been treated successfully with a norepinephrine-reup - take inhibitor. 19 These f indings suggest that nor - epinephrine and serotonin have critical roles in the mechanisms of these treatments of depression but that additional neurochemical factors are neces - sary to cause depression. Because direct measurements of monoamine neurotransmission did not yield definitive findings in relation to depression, the downstream effects of monoamine neurotransmission were explored (Fig. 1). The serotonin-1B receptor is located pre - synaptically and regulates the release of serotonin by feedback inhibition. Postmortem studies show that the levels of p11, a protein that enhances the eff iciency of serotonin-1B receptor signaling, are decreased in the brains of patients with depres - sion. 20 The serotonin-1A receptor is located both presynaptically and postsynaptically to regulate me ch a nisms of dise a se n engl j med 358;1 www.nejm.org january 3, 2008 57 serotonin function (Fig. 1). The receptor can be evaluated in patients with depression by injecting specif ic agonists and measuring specif ic neuro - endocrine responses, such as elevation of the pro - lactin level. 21 Results suggest that the sensitivity of this receptor is reduced in patients with depres - sion. 21 The α 2-noradrenergic receptor, which is usually presynaptic, modulates norepinephrine re - lease by feedback inhibition (Fig. 1). Heightened receptor sensitivity has been described in patients with depression, 22 which is consistent with re - duced norepinephrine release. It is conceivable that the second-messenger sys - tems for serotonergic and noradrenergic neuro - transmission malfunction in depression, and for this reason the phosphatidylinositol and cyclic AMP second-messenger systems have been exten - sively evaluated. Reduced inositol levels have been found in postmortem studies of the brains of per - sons who have died by suicide 23 and in magnetic resonance spectroscopic studies of the frontal cor - tex in patients with depression. 24 A blunted cyclic AMP response to stimulation was found in post - mortem studies of the brains of patients with de - pression. 25 These reductions in second-messenger function may impair neurotransmitter function even without changes in monoamine levels or re - ceptor numbers. These data indirectly support elaborations of the original monoamine-deficiency hypothesis of depression (Fig. 1). G proteins that mediate signaling between re - ceptors and second-messenger systems have also been investigated in patients with depression, both in postmortem studies of the brain 26 and in stud - ies of peripheral-blood cells. 27 Although these systems are clearly affected, no consistent picture has emerged because there are numerous forms of G proteins that vary in different areas of the brain. The cyclic AMP response element–binding protein (CREB) is a transcription factor affected by cyclic AMP in the cell. In an animal model of de - pression, rats with overexpression of CREB in the dentate g yrus behaved similarly to rats treated with antidepressants, but the opposite effect was found when CREB was overexpressed in the nu - cleus accumbens. 26,28 Thus, the role of CREB in depression is specif ic to the region of the brain.
Most but not all studies show that long-term treat - ment with antidepressants stimulates CREB func - tion, possibly depending on the type of drug and the dosage. 28 Levels of CREB and phospho-CREB were reduced in postmortem studies of the cor - texes of patients who had a major depressive disorder and had not taken antidepressants, as compared with controls. 26,28 Many studies of sec - ond-messenger systems and transcription factors in depression were inspired by the belief that it takes several weeks before antidepressant treat - ment has an effect; consequently, the studies were designed to detect time-dependent biochemical changes in the cell. New meta-analyses suggest that antidepressant effects begin rapidly, howev - er, 29 thereby supporting the classic monoamine- def iciency hypothesis. A strong point of the monoamine theory has been its predictive power. Almost every compound that has been synthesized for the purpose of in - hibiting norepinephrine or serotonin reuptake has been proved to be a clinically effective antidepres - sant. A behavioral model of depression has been developed in which a rodent is placed in a glass cylinder f illed with water, the sheer wall offering no chance of escape. The animal struggles for a while and then f loats passively (the forced swim test). A single prior injection of antidepressant in - creases the struggling time; results in this model have excellent predictive validity for new antide - pressants. Other animal models have been devel - oped by selective breeding of rats for depression- like behavior, and these genetically susceptible rodents also have a response to antidepressants. 30 Still other models that can be studied biochemi - cally induce depression with the use of long-term mild stress or learned helplessness. However, no animal model of depression captures the periodic change of behavior into and out of depression that is seen in patients with depression. Molecular techniques such as gene knockout partially support the monoamine theory of depres - sion. The serotonin-reuptake–transporter knock - out mouse is excessively anxious and characterized by increased immobility in the forced swim test. 31 This effect is similar to that of the low-activity polymorphic variant of the serotonin receptor on human personality 10 but is the opposite of the ex - pected effects of serotonin-reuptake–inhibitor an - tidepressants. However, this inconsistency could be explained by the difference between a chron - ic monoamine abnormality during brain develop - ment 31 and the hypothesized acute monoamine depletion in an adult with depression. Table 1 shows the effects in mice of knocking out genes related to monoamine neurotransmitters. The effects of stimulants on mood indirectly T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 58 support the monoamine-def iciency hypothesis of depression and show that mood can be altered rapidly. Cocaine and amphetamines are powerful releasers of monoamines into the synapse as well as inhibitors of reuptake. Their mood-elevating effects are immediate, but in patients with severe depression they have often been reported to cause agitation rather than relief of depression. This finding could ref lect the ability of these stimulants to deplete the presynapse of monoamines and thus cause a “crash” into depression. Recent studies support the theor y that an acute response to a single dose of amphetamine predicts a patient’s longer-term response to monoamine-reuptake in - hibitors. 46 The role of dopamine def iciency in depression is suggested by the frequency of depression in pa - tients with Parkinson’s disease and the effect of reserpine, which depletes serotonin, norepineph - rine, and dopamine, causing a hypoactive state in animals. The antidepressant agent buproprion in - hibits the reuptake of dopamine. Some direct do - pamine-receptor agonists, such as pramipexole, have been reported to be eff icacious in the treat - ment of depression, even though they were devel - oped for Parkinson’s disease. 47 A major liability of the monoamine-def iciency hypothesis is its derivation from the mechanism of currently available antidepressants. Approxi - mately two thirds of patients have a clinical re - sponse to these agents, whereas one third have a response to placebo. 48 Perhaps the mechanism of depression is not related to monoamines in two of three cases. S t r e s s , t h e H y p o t h a l a m i c –P i t u i t a r y – A d r e n a l A x i s , a n d G r o w t h F a c t o r s Stress 49 is perceived by the cortex of the brain and transmitted to the hypothalamus, where cortico - tropin-releasing hormone (CRH) is released onto pituitary receptors. This stimulus results in the se - cretion of corticotropin into plasma, stimulation of corticotropin receptors in the adrenal cortex, and release of cortisol into the blood. Hypothalam - ic cortisol receptors respond by decreasing CRH production to maintain homeostasis (Fig. 2). There is considerable evidence that cortisol and its central releasing factor, CRH, are involved in depression. 50,51 Patients with depression may have elevated cortisol levels in plasma, 38 elevated CRH levels in cerebrospinal f luid, 50 and increased levels of CRH messenger RNA and protein in limbic brain regions. 50 In studies using dexa - methasone to evaluate the sensitivity of the hypo - thalamus to feedback signals for the shutdown of CRH release, the normal cortisol-suppression re - sponse is absent in about half of the most se - Figure 1 (facing page). The Monoamine-Def iciency Hypothesis Extended.
The monoamine hypothesis of depression postulates a def iciency in serotonin or norepinephrine neurotrans - mission in the brain. Monoaminergic neurotransmis - sion is mediated by serotonin (5-hydroxytryptamine 1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or norepinephrine (noradrenaline) released from presyn - aptic neurons (serotonergic neuron, shown on the left side, and noradrenergic neuron, shown on the right side [condensed virtually]). Serotonin is synthesized from tryptophan, with the f irst step in the synthetic pathway catalyzed by tryptophan hydroxylase; norepi - nephrine is synthesized from tyrosine, with the f irst step catalyzed by tyrosine hydroxylase. Both mono - amine transmitters are stored in vesicles in the presyn - aptic neuron and released into the synaptic cleft, there - by affecting both presynaptic and postsynaptic neurons. Cessation of the synaptic action of the neu - rotransmitters occurs by means of both reuptake through the specif ic serotonin and norepinephrine transporters and feedback control of release through the presynaptic 5-HT1A and 5-HT1B regulatory autore - ceptors for serotonin and the α2-noradrenergic autore - ceptors for norepinephrine. Monoamine oxidase A (MAO-A) catabolizes monoamines presynaptically and thereby indirectly regulates vesicular content. The pro - tein p11, which interacts with 5-HT1B receptors, in - creases their function. Postsynaptically, both serotonin and norepinephrine bind two kinds of guanine nucleo - tide triphosphate –binding protein (G protein)– coupled receptors: cyclic AMP (cAMP)– coupled receptors, which activate adenylate cyclase (AC) to generate cAMP, and phosphatidylinositol (PI)– coupled recep - tors, which activate phospholipase C (PLC). PLC gener - ates inositol triphosphate (IP 3) and diacylglycerol (DAG); cAMP activates protein kinase A (PK A), and IP 3 and DAG activate protein kinase C (PKC). The two pro - tein kinases affect the cAMP response element–bind - ing protein (CREB). Findings in patients with depres - sion that support the monoamine-def iciency hypothesis include a relapse of depression with inhibi - tion of tyrosine hydroxylase or depletion of dietary tryptophan, an increased frequency of a mutation af - fecting the brain-specif ic form of tryptophan hydroxy - lase ( TPH-2), increased specif ic ligand binding to MAO-A, subsensitive 5-HT1A receptors, malfunction - ing 5-HT1B receptors, decreased levels of p11, poly - morphisms of the serotonin-reuptake transporter asso - ciated with depression, an inadequate response of G proteins to neurotransmitter signals, and reduced lev - els of cAMP, inositol, and CREB in postmortem brains.
me ch a nisms of dise a se n engl j med 358;1 www.nejm.org january 3, 2008 59 verely depressed patients. 52 Antidepressant-induced clinical remission is accompanied by reversal of some of these abnormalities. 52 Adults with a histor y of physical or sexual abuse as children have increased levels of CRH in cerebrospinal f luid. 53 Adult rodents that were sepa - rated from their mothers or abused as pups show increased immobilit y in the forced swim test, which is reversed by antidepressant treatment. 54 Mice with region-specif ic knockout of the gluco - corticoid receptor at an adult age have increased activity of the hypothalamic–pituitary–adrenal axis and increased immobility in the forced swim test, both of which are reversed by antidepressants. 55 Increased levels of monoamines in the synapse affect the hypothalamic–pituitary–adrenal axis 56 and reverse some of the long-term effects of stress. 56 It is possible that antidepressants relieve depression by reducing the secondary stress caused by a painfully dispirited mood rather than by di - rectly elevating mood. An antistress mechanism could explain the general usefulness of antidepres - T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 60 Table 1. Monoamine-Related Gene Knockouts That Affect Depression-Related Behavior in Mice.* Gene or Protein Function Depression-Related Changes Corroboration of Monoamine-Deficiency Hypothesis Other Behavior Elicited by Knockout of Gene sert Serotonin transporter Increased depressive behavior, reduced se - rotonin level, desensitized postsynaptic 5-HT1AR, and reduced presynaptic 5-HT1AR function 32 No Excessive anxiety 32 net Norepinephrine transporter Reduced depressive behavior, prolonged norepinephrine clearance, elevated ex - tracellular norepinephrine levels 33 Yes Increased locomotion response to amphetamines and co - caine 33 5-ht1ar Serotonergic 1A receptor (presynaptic autorecep - tor and postsynaptic) Reduced depressive behavior, normal sero - tonin level and release, impaired SSRI-induced neurogenesis 32 No Excessive anxiety,impaired hippocampal learn - ing 32 5-ht1br Serotonergic 1B receptor (presynaptic autorecep - tor and postsynaptic) Reduced response to SSRI in forced swim test, reduced serotonin level and in - creased serotonin release, increased SSRI-induced serotonin release, de - creased serotonin-transporter expres - sion 32 Yes Increased aggressiveness, re - duced anxiety, increased ex - ploration, increased use of cocaine 32 p11 (protein) Interacts with and enhanc - es signaling efficiency of 5-HT1BR Increased depressive behavior, increased serotonin turnover 20 No Not reported 20 5-ht2ar Serotonergic 2A receptor No change 34 No Reduced inhibition in conflict- anxiety paradigms 34 5-ht7 Serotonergic 7 receptor (possibly presynaptic autoreceptor and post - synaptic) Reduced depressive behavior and REM sleep duration 35 No Normal locomotion 35 α2aar α2A-Adrenergic receptors (presynaptic autorecep - tor) Reduced norepinephrine levels, presynaptic inhibition of release, 36 increased depres - sive behavior 37 No Altered sympathetic regula - tion, 36 impaired motor coor - dination α2car α2c-Adrenergic receptors (presynaptic autorecep - tor restricted to central nervous system) Reduced depressive behavior 38 Yes Increased aggressiveness, 32 increased locomotion re- sponse to amphetamines 36 mao-a Monoamine oxidase A Increased brain serotonin and epinephrine levels 39 No Increased aggressiveness and response to stress, 30 de- creased exploration 32 ac VII (hetero- zygotes) Adenylyl cyclase type 7 Reduced depressive behavior 40 No Unchanged anxiety 40 impa1 Inositol monophos- phatase 1 Reduced depressive behavior, unaltered brain inositol levels 41 Yes Increased hyperactivity and sensitivity to pilocarpine- induced seizures 41 smit1 Sodium- myo -inositol trans - porter 1 Reduced depressive behavior and brain ino - sitol levels 42 Yes Increased sensitivity to pilocar - pine-induced seizures 42 creb Cyclic AMP–response ele - ment–binding protein Reduced depressive behavior, normal anti - depressant-induced behavior 43 No No increase in BDNF after long- term use of antidepres - sants 43 bdnf Male mice Brain-derived neurotrophic factor No depressive behavior 44 No Increased aggressiveness, hy - perphagia, 45 hyperactivity 44 Female mice Brain-derived neurotrophic factor Increased depressive behavior 44 Yes Increased aggressiveness, hy - perphagia 45 * BDNF denotes brain-derived neurotrophic factor, 5-HT1AR 5-hydroxytryptamine 1A receptor, 5-HT1BR 5-hydroxytryptamine 1B receptor, REM rapid eye movement, and SSRI selective serotonin-reuptake inhibitor.
me ch a nisms of dise a se n engl j med 358;1 www.nejm.org january 3, 2008 61 sants for a wide variety of psychiatric conditions, including panic disorder, post-traumatic stress disorder, bulimia, premenstrual syndrome, and obsessive–compulsive disorder. CRH-receptor an - tagonists show antidepressant activity in animal models, 57 but the results of large clinical trials have been disappointing. A compound that blocks the glucocorticoid receptor has been reported to be eff icacious in depression, but only the most severe and psychotic type. 58 A single test for the cortisol level in blood does not contribute to the diagnosis of depression, since levels of cortisol var y markedly in a circadian rhythm 38 and because the overlap between values in patients and those in controls is considerable.
Mild stress induced in the laborator y, such as Figure 2. The Hypothalamic–Pituitary– Cortisol System in Depression. The hypothalamic–pituitary– cortisol hypothesis of depression postulates that abnormalities in the cortisol response to stress may underlie depression. The black arrows show that in response to stress, which is perceived by the brain cortex and the amygdala and transmitted to the hypothalamus, corticotropin-releasing hormone (CRH) is released, inducing the anterior pituitary gland to secrete corticotropin into the bloodstream. Corticotropin stimulates the ad - renal cortexes to secrete the glucocorticoid hormone cortisol. The red lines show that cortisol, in turn, induces feed - back inhibition in the hypothalamus and the pituitary, suppressing the production of CRH and corticotropin, respec - tively. Findings in patients with depression that support the hypothalamic–pituitary– cortisol hypothesis include the following: cortisol levels are sometimes increased in severe depression, the size of the anterior pituitary and adrenal cortex is increased, and CRH levels in the cerebrospinal f luid and CRH expression in the limbic brain regions are in - creased. Hippocampal size and the numbers of neurons and glia are decreased, possibly ref lecting reduced neuro - genesis due to elevated cortisol levels or due to reduced brain-derived neurotrophic factor.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 62 Table 2.
Additional Biologic Theories of the Pathophysiology of Depression.* Theory Supporting Evidence Contradictory Evidence Altered glutamatergic neurotransmission Glutamate and glutamine levels in the prefrontal cortex are reduced 91 Glutamate levels in the occipital cortex are increased 92,93 Intravenous ketamine, an NMDA antagonist, induces rapid, sustained anti - depressant effect 94 Ketamine binds to high-affinity-state D2 dopamine receptors 95 Cortical messenger RNA levels of glutamate transporters and of the enzyme that converts glutamate to glutamine are reduced 96 It is not clear whether antidepressants affect AMPA receptors in the brain 97 Reduced GABAergic neurotransmission Levels of GABA in plasma, cerebrospinal fluid, the dorsolateral prefrontal cortex, and the occipital cortex are reduced 91-93 GABA occurs in more than 30% of brain synapses, suggesting nonspecificity GABA-modulating agents have effects in animal models of depression 98 There is a lack of difference in prefrontal cortex GABA levels on MRS in de - pression 99 Antidepressants affect GABAergic function 98 GABA neurotransmission may be related to symptoms of anxiety in depression GABA neuron immunoreactivity is reduced in the prefrontal cortex 100 Abnormal circadian rhythms Sleep deprivation and light therapy have antidepressant effects 101,102 The association between clock-related genes and depression is inconsis - tent 103 Some patients with depression have circadian abnormalities of mood, sleep, temperature, and neuroendocrine secretion 104 Rodents active during the day become depressed when daylight is short - ened 105 Deficient neurosteroid synthesis Cholesterol levels are low in plasma and the brain during depression 106 The findings in schizophrenia are similar 107 DHEA has antidepressant effects in patients with depression 108 Neurosteroids (neuroactive steroids in the brain that modulate neurotrans - mitter receptors) mostly affect memory and sleep Impaired endogenous opi - oid function δ-Opioid–receptor agonists have antidepressant-like effects in rodents and up-regulate levels of BDNF in the brain 109 Although early reports suggested that opiates may be effective in treating de - pression, 110 data from large, controlled, randomized trials are lacking Capacity for cortical μ-opioid–receptor binding is decreased in response to sustained sadness 111 Monoamine–acetylcholine imbalance Depressed mood can be induced in humans by administration of physostig - mine, an acetylcholinesterase inhibitor 112 Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduced symp - toms of depression 113 Nicotinic acetylcholine receptor antagonists potentiate antidepressants 114 Many antidepressants are not anticholinergic Cytokine-mediated cross- talk between the im - mune system and the brain Depression is common in infectious and autoimmune diseases 115 Most studies are correlative 116 Exposure to cytokines induces depressive symptoms, and cytokine secretion is increased in major depression 115 Cytokine-induced depressive symptoms are temporary and not replicated in all studies 117 Antidepressants have antiinflammatory effects 115 Substance P antagonists are not therapeutic in depression Cytokines affect the hypothalamic–pituitary–adrenal axis and mono - amines 115 me ch a nisms of dise a se n engl j med 358;1 www.nejm.org january 3, 2008 63 stress associated with mental arithmetic calcula - tions or simulated public speaking, results in greater changes in plasma cortisol levels than most reported differences between the values in patients with depression and those in controls. 38 It is possible that chronic mild elevations of cor - tisol, especially at night, when cortisol levels in normal subjects are very low, have a pathogenic role in depression. It is also possible that periph - eral cortisol elevations are only a ref lection of central disturbances in CRH signaling, which me - diate the effects of environmental stress on mood. 59 A major liability of the hypothalamic–pituitary– adrenal axis theory of depression is the diff iculty of def ining the relationship of stress to depres - sion. Some patients have a single lifetime depres - sive episode, whereas a larger proportion have a recurrent or even chronic course. Various types of acute stress, early childhood trauma, or long- term psychosocial problems may be involved and may lead to different responses of the stress sys - tem. Stress may be causative in some cases and secondary to depressed mood in others. Severe stress in rodents does not necessarily model the common stresses of childhood. The association of abuse in childhood with psycho - pathologic disorders, including depression, in adulthood could be due to common factors link - ing family perpetrators of abuse and their victims, including not only shared genes but also a shared environment of poverty, poor nutrition, and poor prenatal care. Depression is not uncommon in people with no psychosocial risk factors. Most patients treated for depression have no evidence of hypothalamic–pituitary–adrenal dysfunction, just as most such patients have no direct evidence of brain monoamine def iciency. The classic teaching is that neurons do not di - vide in the adult mammalian brain, but studies have shown that neurogenesis occurs in several areas of the brain, especially the hippocampus.
Neurogenesis is more prominent in rodents than in primates, 60 and some have questioned whether it occurs in the human cortex. 61 Elevated levels of glucocorticoids can reduce neurogenesis, and this has been suggested as a mechanism for the de - creased size of the hippocampus on magnetic resonance images of the brain in many patients with depression. 62 In postmortem studies of pa - tients with depression, cell loss in the subgenual prefrontal cortex, atrophy in the dorsolateral pre - frontal cortex and the orbitofrontal cortex, and Thyroxine abnormalities Levels of transthyretin are reduced in the cerebrospinal fluid in patients with depression 118 Thyroid hormones modulate the serotonergic system in the brain 119 Thyroxine monotherapy is ineffective Brain neurogenesis is decreased after the administration of thyroxine in adult rats with hypothyroidism 120 Hypothyroidism is not manifested in most patients with depression Rate of response to triiodothyronine is increased during depression 121 Dysfunction of specific brain structures and circuits Transcranial magnetic stimulation of the prefrontal cortex 122 and deep-brain stimulation of the anterior cingulate affect mood 123 Implicated brain areas differ from study to study Glucose use is reduced in the prefrontal cortex 124 and subgenual prefrontal cortex 125 Inconsistent findings with respect to blood flow, volumetric, glucose utiliza - tion, and postmortem methodologies 63,124,126 Circuit dynamics in the hippocampus are altered in a rat model of depression 127 * AMPA denotes alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, BDNF brain-derived neurotrophic factor, DHEA dehydroepiandrosterone, GA BA γ-aminobutyric acid, MRS magnetic resonance spectroscopy, and NMDA N-methyl- d-aspartic acid.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 64 increased numbers of cells in the hypothalamus and the dorsal raphe nucleus have been reported. 63 These effects resemble the atrophic changes in the brain in patients with Cushing’s disease 64 and in rodents treated with glucocorticoids. 65 However, cortisol elevations in depression are much lower than in Cushing’s disease. Restraint in a small container induces stress in rodents, suppressing neurogenesis, and this effect is countered by antidepressant treatment. 66 An - tidepressants also enhance neurogenesis in non - human primates. 67 Santarelli et al. 68 irradiated the hippocampus in mice and abolished neurogene - sis. They found that the radiation also abolished the ability of the animals to respond behaviorally to antidepressant treatment in the forced swim test, but this phenomenon does not occur in every mouse strain studied. 69 Henn and Vollmayr sum - marized other studies providing evidence that de - creased neurogenesis is a result of stress and anxiety but may not be behaviorally relevant. 70 The relevance of animal models of neurogenesis to clinical studies of depression has been questioned by analogy with studies of neuroprotection strat - egies in stroke, for which numerous f indings in animal models have not been replicated in hu - man studies. 71 Brain-derived neurotrophic factor (BDNF), a neurotrophic peptide, is critical for axonal growth, neuronal survival, and synaptic plastic - it y, 72 and its levels are affected by stress 73 and cortisol. 74 A postmortem study of patients with depression who had committed suicide showed that BDNF was reduced in the hippocampus. 75 Antidepressant drugs and electroconvulsive thera - py up-regulate BDNF and other neurotrophic and growth factors 75,76 ; a single bilateral infusion of BDNF into the dentate gyrus has antidepressant- like effects. 77 One study showed that the hippo - campus was smaller than normal in patients with depression who carried a met166 BDNF allele. 78 In an animal model of depression, epigenetic his - tone methylation mediated down-regulation of BDNF transcripts and antidepressant treatment reversed this effect. 79 These studies suggest that BDNF is the link among stress, neurogenesis, and hippocampal atrophy in depression. However, a genetic association of the BDNF val166met poly - morphism with depression has not been replicated in most studies, 74 and BDNF may be related not only to depression but to multiple psychiatric dis - orders. 74 BDNF-knockout mice have behaviors un - related to depression. 45 Reduced BDNF levels in the peripheral blood of patients with depression seem to derive almost entirely from blood plate - lets, 80 and many artifacts must therefore be con - sidered in interpreting these f indings. Inf lamma - tion in the brain and some neurotoxins increase brain BDNF levels, suggesting that the actions of BDNF are not uniformly therapeutic. 81 Castrén 82 has proposed that antidepressant treatments may increase synaptic sprouting and allow the brain to use input from the environment more effec - tively to recover from depression. This hypothe - sis highlights the role that cognition may play in depression and suggests that biochemical mech - anisms may be nonspecif ic. Strong epidemiologic data point to an associa - tion between major depressive disorder and in - creased cardiovascular morbidity and mortality. 83 In many patients, cardiovascular disorders precede depression, and in others, depression precedes the cardiovascular disorder. Both n−3 fatty acid def i - ciency 84 and elevated plasma homocysteine levels 85 have been implicated in cardiovascular disease and in depression. Elevated cortisol levels in depres - sion could increase the risk of coronar y arter y disease, since cortisol increases visceral fat. 64,86 Antidepressant treatment increases the sur vival rate among patients who become depressed after coronary occlusion. 86 Endothelial-cell signaling plays a crucial role in brain neurogenesis, 87 and these cells secrete BDNF; thus, both depression and cardiovascular disease could be examples of an endothelial disorder. Signs of inf lammator y processes have been described in major depres - sion 88 and in cardiovascular disease. Some data suggest that exercise has protective or therapeu - tic effects in depression. 89 Rodent models support this possibility. 90 O t h e r P o s s i b l e M e c h a n i s m s Table 2 summarizes possible pathophysiological mechanisms of depression other than those based on the monoamine-def iciency hypothesis or the roles of stress, cortisol, and neurogenesis. Many of these other proposed mechanisms have also been implicated in psychiatric and neurologic dis - orders other than depression. Since the compo - nents of the brain are highly interconnected, it is not diff icult to f ind possible integrative frame - works between two or more of the various theo - ries. Testing the theories in a manner that can re - me ch a nisms of dise a se n engl j med 358;1 www.nejm.org january 3, 2008 65 R e fe r enc e s Wakef ield JC, Schmitz MF, First MB, Horwitz AV. Extending the bereavement exclusion for major depression to other losses: evidence from the National Co - morbidit y Survey. 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Research in depression has sometimes been se - quentially imitative of dominant ideas in related fields, such as neurogenesis, glutamate neurotrans - mission, and nicotinic receptors, instead of pro - gressing on its own path. S u m m a r y It would be appealing to attempt to categorize de - pression in terms of monoamine-depletion forms that are perhaps related to genes coding for en - zymes involved in neurotransmission and cortisol- related forms that are characterized by a more long-term course, hippocampal atrophy, and a his - tory of psychosocial stress. However, the clinical data do not fall into such neat categories, since monoamine-based antidepressants are most effec - tive in patients with severe depression when cor - tisol levels remain high after the administration of dexamethasone. Major depressive disorder is likely to have a number of causes. Middle-aged or elderly patients presenting with depression may have a disorder related to cardiovascular disease and originating from endothelial dysfunction. 128 Patients in their late teens or early 20s who have severe depression may have important genetic risk factors and a high risk of manic episodes. 8 In patients with an anx - ious and depressive personality, depression may be due to genetically determined personality fac - tors 11 or adverse childhood experiences. 129 Avoidance of premature closure on any one scientif ic theory of the mechanism of depression will best serve the search for new, more effective treatments. It is likely that the pathogenesis of acute depression is different from that of recurrent or chronic depression, which is characterized by long-term declines in function and cognition.
Mood can be elevated (by stimulants, 46 by brain stimulation, 123 or by ketamine 94) or depressed (by monoamine depletion 19 in recovered patients) for short periods, but longer-term improvement may require reduction of the abnormal glucocorticoid function induced by stress or increases in brain neurotrophic factors.
No potential conf lict of interest relevant to this article was reported.We thank Herman van Praag, who inspired our work on de - pression over the course of three decades.
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129. posting presentations at medical meetings on the internet Posting an audio recording of an oral presentation at a medical meeting on the Internet, with selected slides from the presentation, will not be considered prior publication. This will allow students and physicians who are unable to attend the meeting to hear the presentation and view the slides. If there are any questions about this policy, authors should feel free to call the Journal ’s Editorial Offices.
