Biology of depression
Encyclopedia
Scientific studies have found that numerous brain areas show altered activity in depressed patients. It has not been possible to determine a single cause of depression.
Most antidepressant
s increase synaptic
levels of the monoamine neurotransmitter
serotonin
. They may also enhance the levels of two other neurotransmitters, norepinephrine
and dopamine
. This observation gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that the deficit 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." The proponents of this hypothesis recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. The anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitor
s, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs.
Consistent with the monoamine hypothesis, a longitudinal study
uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow stressful life events, but even more so for people with one or two short allele
s of the 5-HTT gene. Serotonin may help to regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties
of this dysregulation.
In the past two decades, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The antidepressants that do not act through the monoamine system, such as tianeptine
and opipramol
, have been known for a long time. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people nor does it worsen the symptoms in depressed patients. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.
An offshoot of the monoamine hypothesis suggests that monoamine oxidase A
(MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET
study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with the depressive symptoms in youth. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression.
Depression may be related to abnormalities in the circadian rhythm
, or biological clock. For example, rapid eye movement (REM) sleep—the stage in which dream
ing occurs—may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem
, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation
activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.
Research on the effects of light therapy
on seasonal affective disorder
suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy
both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in hospitalized patients.
are a group of small nuclei in the upper brain stem
, located directly at the midline of the brain. They are the sole source of serotonin
in the brain. Despite their small size, they project very widely, and are involved in a very diverse set of functions. Most antidepressants are serotonergic. Serotonin system dysfunction cannot be the sole cause of depression, though: antidepressant
s usually bring serotonin levels up to normal very quickly, but it often takes at least two to four weeks before mood improves significantly. The 5-HTT gene regulates a chemical called serotonin. Serotonin works as the neurotransmitter and helps with the modulation of things such as anxiety, anger, appetite, sexuality, sleep, mood, and several other things. People with depression often have impaired 5-HTT genes. There are two forms of the 5-HTT gene and everyone has two 5-HTT genes. (Levinson) There is a long form of 5-HTT and a short form of 5-HTT. Research shows that people with both 5-HTT genes being the long form are less likely to become depressed while people with one short and one long or two short forms are more likely to develop depression. Research is still being conducted to find more information. The functions of serotonin are difficult to describe in a simple way. In some circumstances serotonin seems to act as a signal of "repletion" or "satisfaction". Thus, satiation after eating, and orgasm following sex, both produce release of serotonin. In animals that have hierarchical social structures, dominant individuals show higher levels of serotonin metabolites than lower-status individuals. In the brain, serotonin exerts a suppressive effect on both the reward system
and punishment system, and therefore is likely to reduce the intensity of motivation whether aversive or appetitive. (One of the most common but least-discussed side effects of antidepressants is to reduce sex drive).
(SCN) is the control center for the body's "biological clock". It contains neurons whose activity waxes and wanes throughout the day. The output from the SCN controls the sleep/wake cycle as well as a number of other biological rhythms, such as fluctuations in body temperature. Disturbances of these cycles are a consistent symptom of depression, especially of the melancholic type. The "classic" pattern is for depressed people to have great difficulty falling asleep at night, and then to wake bolt upright at around 3 AM. The waking is usually preceded by a rise in body temperature, which in non-depressed people does not usually occur until several hours later. It is a common observation that antidepressants produce a return to normal sleep patterns before they produce an improvement in mood: if good sleep does not return, it is a strong sign that the treatment is not going to be effective. Conversely, disruptions to sleep are often the first indication of impending relapse.
There is a powerful interaction between the Raphe nuclei and the SCN. On one hand, the Raphe nuclei send a strong serotonergic projection to the SCN. In animal studies, this input has been shown to modulate the ability of light to reset the timing of the biological clock: the more serotonin, the stronger the effects of light. On the other hand, the biological clock exerts a strong influence on the Raphe nuclei: serotonin levels drop during sleep, and fall almost to nothing during REM (dreaming) sleep. It is worth noting that one of the characteristics of sleep in depressed people is that REM tends to appear very soon after sleep onset, whereas in non-depressed people it does not usually dominate sleep until the last hours, in the early morning. Antidepressants are powerful suppressors of REM.
(or ventral tegmental area) is a small area in the basal midbrain which is a critical part of the brain's reward system. It sends projections to the nucleus accumbens
that use the neurotransmitter dopamine
. Addictive drugs universally increase the effects of dopamine in this system, whereas drugs that oppose dopamine produce anhedonia
of the sort seen in depressed people. Dopamine-enhancers such as cocaine often relieve the lack-of-pleasure in depression, but the effects only last as long as a drug is present in the body: that is, they temporarily alleviate one of the main symptoms, but do not help to cure the disease.
shell, as it was shown in the forced swimming test, an animal model of depression.
is activated by negative experiences of many types, and consistently shows higher levels of activity in depressed people than in non-depressed people. The functions of the ACC are controversial, but one proposal is that it mediates the conscious experience of suffering. Several decades ago, trials were made of ablating parts of the ACC in an attempt to relieve intolerable pain in patients who were terminally ill. These patients reported that after the surgery, they could still perceive the physical sensations of pain, but they no longer found them distressing. (The effects of heroin and morphine are sometimes described in the same way.) Very recently, clinical experiments were made in using deep brain stimulation
to temporarily inactivate the ACC in severely depressed patients. This was not effective in all cases, but in some patients very striking results were achieved, with a perceptible lifting of mood immediately apparent to the patient as soon as the stimulus was applied.
s and is considered as a governor for a vast network involving areas like hypothalamus
and brain stem
, which influences changes in appetite and sleep; the amygdala
and insula
, which affect the mood and anxiety; the hippocampus
, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep Brain Stimulations of this area have been successful in reducing its elevated activity and thus curing depression in patients that could not be cured by anti-depressants.
in depression. Pittenger and Duman have reviewed extensive research, demonstrating a convergence of three phenomena:
They conclude that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.
is a chain of endocrine structures that are activated during the body's response to stressors of various sorts. It often shows increased activation in depressed people, and drugs that reduce its activity are sometimes effective in reducing symptoms. The HPA influences many parts of the brain, including the Raphe nuclei.
published an influential study of Avshalom Caspi et al. who found that a gene-environment interaction
(GxE) may 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
). Soon after, the results were replicated by Kenneth Kendler
's group, raising hopes in the psychiatric genetics
community. By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of the largest studies were negative. Two 2009 meta-analyses
were also negative; one included 14 studies, the other just five, owing to different study selection criteria. A 2010 review of studies in this area found 17 replications, 8 partial replications (interaction only in females or only with one of several types of adversity), and 9 non-replications (no interaction or an interaction in the opposite direction). It also found a systematic relationship between the method used to assess environmental adversity and the results of the studies; all studies using objective indicators or structured interviews to assess stress replicated the gene–environment interaction fully or partially, whereas all non-replications relied on brief self-report measures of adversity. This review also found that both 2009 meta-analyses were significantly biased toward negative studies.
Other hypothesized genomic influences are BDNF polymorphisms, but the replications studies have been mixed and insufficient as of 2005 for a meta-analysis. Studies also indicate an association of BDNF to suicidal behavior. However, findings from the gene-environment interactions studies suggest that the current BDNF models of depression are too simplistic. A 2008 study found interactions (biological epistasis
) in the signaling pathways of the BDNF and the serotonin transporter
; the BDNF Val66Met allele, which was predicted to have reduced responsitivity to serotonin, was found to exercise protective effects in individuals with the short 5-HTTLPR allele that is otherwise believed to predispose individuals to depressive episodes after stressful events. Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.
associated with reduced plasma tryptophan
, due to Fructose malabsorption
Monoamine hypothesis
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s increase synaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
levels of the monoamine neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
. They may also enhance the levels of two other neurotransmitters, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. This observation gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that the deficit 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." The proponents of this hypothesis recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. The anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
s, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs.
Longitudinal study
A longitudinal study is a correlational research study that involves repeated observations of the same variables over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the...
uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow stressful life events, but even more so for people with one or two short allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s of the 5-HTT gene. Serotonin may help to regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties
Emergence
In philosophy, systems theory, science, and art, emergence is the way complex systems and patterns arise out of a multiplicity of relatively simple interactions. Emergence is central to the theories of integrative levels and of complex systems....
of this dysregulation.
In the past two decades, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The antidepressants that do not act through the monoamine system, such as tianeptine
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....
and opipramol
Opipramol
Opipramol is an antidepressant and anxiolytic used in Germany and other European countries. Although it is a member of the tricyclic antidepressants, opipramol's primary mechanism of action is much different in comparison...
, have been known for a long time. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people nor does it worsen the symptoms in depressed patients. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.
An offshoot of the monoamine hypothesis suggests that monoamine oxidase A
Monoamine Oxidase A
Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAO-A gene. Monoamine oxidase A is an isozyme of monoamine oxidase. It preferentially deaminates norepinephrine , epinephrine , serotonin, and dopamine...
(MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with the depressive symptoms in youth. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression.
Circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
, or biological clock. For example, rapid eye movement (REM) sleep—the stage in which dream
Dream
Dreams are successions of images, ideas, emotions, and sensations that occur involuntarily in the mind during certain stages of sleep. The content and purpose of dreams are not definitively understood, though they have been a topic of scientific speculation, philosophical intrigue and religious...
ing occurs—may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation
Sleep deprivation
Sleep deprivation is the condition of not having enough sleep; it can be either chronic or acute. A chronic sleep-restricted state can cause fatigue, daytime sleepiness, clumsiness and weight loss or weight gain. It adversely affects the brain and cognitive function. Few studies have compared the...
activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.
Research on the effects of light therapy
Light therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
on seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy
Light therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in hospitalized patients.
Abnormalities by brain region
Research on the brains of depressed patients usually shows disturbed pattern of interaction between multiple parts of the brain. Here are the areas that are most strongly affected:Raphe nuclei
The raphe nucleiRaphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...
are a group of small nuclei in the upper brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, located directly at the midline of the brain. They are the sole source of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in the brain. Despite their small size, they project very widely, and are involved in a very diverse set of functions. Most antidepressants are serotonergic. Serotonin system dysfunction cannot be the sole cause of depression, though: antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s usually bring serotonin levels up to normal very quickly, but it often takes at least two to four weeks before mood improves significantly. The 5-HTT gene regulates a chemical called serotonin. Serotonin works as the neurotransmitter and helps with the modulation of things such as anxiety, anger, appetite, sexuality, sleep, mood, and several other things. People with depression often have impaired 5-HTT genes. There are two forms of the 5-HTT gene and everyone has two 5-HTT genes. (Levinson) There is a long form of 5-HTT and a short form of 5-HTT. Research shows that people with both 5-HTT genes being the long form are less likely to become depressed while people with one short and one long or two short forms are more likely to develop depression. Research is still being conducted to find more information. The functions of serotonin are difficult to describe in a simple way. In some circumstances serotonin seems to act as a signal of "repletion" or "satisfaction". Thus, satiation after eating, and orgasm following sex, both produce release of serotonin. In animals that have hierarchical social structures, dominant individuals show higher levels of serotonin metabolites than lower-status individuals. In the brain, serotonin exerts a suppressive effect on both the reward system
Reward system
In neuroscience, the reward system is a collection of brain structures which attempts to regulate and control behavior by inducing pleasurable effects...
and punishment system, and therefore is likely to reduce the intensity of motivation whether aversive or appetitive. (One of the most common but least-discussed side effects of antidepressants is to reduce sex drive).
Suprachiasmatic nucleus (SCN)
The suprachiasmatic nucleusSuprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
(SCN) is the control center for the body's "biological clock". It contains neurons whose activity waxes and wanes throughout the day. The output from the SCN controls the sleep/wake cycle as well as a number of other biological rhythms, such as fluctuations in body temperature. Disturbances of these cycles are a consistent symptom of depression, especially of the melancholic type. The "classic" pattern is for depressed people to have great difficulty falling asleep at night, and then to wake bolt upright at around 3 AM. The waking is usually preceded by a rise in body temperature, which in non-depressed people does not usually occur until several hours later. It is a common observation that antidepressants produce a return to normal sleep patterns before they produce an improvement in mood: if good sleep does not return, it is a strong sign that the treatment is not going to be effective. Conversely, disruptions to sleep are often the first indication of impending relapse.
There is a powerful interaction between the Raphe nuclei and the SCN. On one hand, the Raphe nuclei send a strong serotonergic projection to the SCN. In animal studies, this input has been shown to modulate the ability of light to reset the timing of the biological clock: the more serotonin, the stronger the effects of light. On the other hand, the biological clock exerts a strong influence on the Raphe nuclei: serotonin levels drop during sleep, and fall almost to nothing during REM (dreaming) sleep. It is worth noting that one of the characteristics of sleep in depressed people is that REM tends to appear very soon after sleep onset, whereas in non-depressed people it does not usually dominate sleep until the last hours, in the early morning. Antidepressants are powerful suppressors of REM.
Ventral tegmental area (VTA)
The ventral tegmentumVentral tegmentum
The ventral tegmentum , better known as the ventral tegmental area , is a group of neurons located close to the midline on the floor of the midbrain...
(or ventral tegmental area) is a small area in the basal midbrain which is a critical part of the brain's reward system. It sends projections to the nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
that use the neurotransmitter dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. Addictive drugs universally increase the effects of dopamine in this system, whereas drugs that oppose dopamine produce anhedonia
Anhedonia
In psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....
of the sort seen in depressed people. Dopamine-enhancers such as cocaine often relieve the lack-of-pleasure in depression, but the effects only last as long as a drug is present in the body: that is, they temporarily alleviate one of the main symptoms, but do not help to cure the disease.
Nucleus accumbens (NAc)
Long-term exposure to various unavoidable stress factors decreases dopamine release in the NAcNucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
shell, as it was shown in the forced swimming test, an animal model of depression.
Anterior cingulate cortex (ACC)
The anterior cingulate cortexAnterior cingulate cortex
The anterior cingulate cortex is the frontal part of the cingulate cortex, that resembles a "collar" form around the corpus callosum, the fibrous bundle that relays neural signals between the right and left cerebral hemispheres of the brain...
is activated by negative experiences of many types, and consistently shows higher levels of activity in depressed people than in non-depressed people. The functions of the ACC are controversial, but one proposal is that it mediates the conscious experience of suffering. Several decades ago, trials were made of ablating parts of the ACC in an attempt to relieve intolerable pain in patients who were terminally ill. These patients reported that after the surgery, they could still perceive the physical sensations of pain, but they no longer found them distressing. (The effects of heroin and morphine are sometimes described in the same way.) Very recently, clinical experiments were made in using deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
to temporarily inactivate the ACC in severely depressed patients. This was not effective in all cases, but in some patients very striking results were achieved, with a perceptible lifting of mood immediately apparent to the patient as soon as the stimulus was applied.
Subgenual cingulate
Recent studies have shown that Brodmann area 25, also known as Subgenual cingulate is metabolically overactive in treatment-resistant depression. This region is extremely rich in serotonin transporterSerotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
s and is considered as a governor for a vast network involving areas like hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
and brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, which influences changes in appetite and sleep; the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
and insula
Insular cortex
In each hemisphere of the mammalian brain the insular cortex is a portion of the cerebral cortex folded deep within the lateral sulcus between the temporal lobe and the frontal lobe. The cortical area overlying it towards the lateral surface of the brain is the operculum...
, which affect the mood and anxiety; the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep Brain Stimulations of this area have been successful in reducing its elevated activity and thus curing depression in patients that could not be cured by anti-depressants.
Altered neuroplasticity
Recent studies have called attention to the role of altered neuroplasticityNeuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
in depression. Pittenger and Duman have reviewed extensive research, demonstrating a convergence of three phenomena:
- Chronic stress reduces synaptic and dendritic plasticity
- Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees)
- Anti-depressant medications enhance neuroplasticity at both a molecular and dendritic level.
They conclude that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.
Hypothalamic-Pituitary-Adrenal (HPA) axis
The Hypothalamic-pituitary-adrenal axisHypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
is a chain of endocrine structures that are activated during the body's response to stressors of various sorts. It often shows increased activation in depressed people, and drugs that reduce its activity are sometimes effective in reducing symptoms. The HPA influences many parts of the brain, including the Raphe nuclei.
Genetic factors
In 2003 ScienceScience (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
published an influential study of Avshalom Caspi et al. who found that a gene-environment interaction
Gene-environment interaction
Gene–environment interaction is the phenotypic effect of interactions between genes and the environment....
(GxE) may 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
5-HTTLPR
5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,...
). Soon after, the results were replicated by Kenneth Kendler
Kenneth Kendler
Kenneth S. Kendler is an American psychiatrist best known for this pioneering research in psychiatric genetics, particularly the genetic causes of schizophrenia. Kendler is one of the highest cited psychiatry researchers. Between 1990 and 1998 he was the 2nd highest cited psychiatrist. For the...
's group, raising hopes in the psychiatric genetics
Psychiatric genetics
Psychiatric genetics, a subfield of behavioral neurogenetics, studies the role of genetics in psychological conditions such as alcoholism, schizophrenia, bipolar disorder, and autism. The basic principle behind psychiatric genetics is that genetic polymorphisms, as indicated by linkage to e.g...
community. By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of the largest studies were negative. Two 2009 meta-analyses
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
were also negative; one included 14 studies, the other just five, owing to different study selection criteria. A 2010 review of studies in this area found 17 replications, 8 partial replications (interaction only in females or only with one of several types of adversity), and 9 non-replications (no interaction or an interaction in the opposite direction). It also found a systematic relationship between the method used to assess environmental adversity and the results of the studies; all studies using objective indicators or structured interviews to assess stress replicated the gene–environment interaction fully or partially, whereas all non-replications relied on brief self-report measures of adversity. This review also found that both 2009 meta-analyses were significantly biased toward negative studies.
Other hypothesized genomic influences are BDNF polymorphisms, but the replications studies have been mixed and insufficient as of 2005 for a meta-analysis. Studies also indicate an association of BDNF to suicidal behavior. However, findings from the gene-environment interactions studies suggest that the current BDNF models of depression are too simplistic. A 2008 study found interactions (biological epistasis
Epistasis
In genetics, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic...
) in the signaling pathways of the BDNF and the serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
; the BDNF Val66Met allele, which was predicted to have reduced responsitivity to serotonin, was found to exercise protective effects in individuals with the short 5-HTTLPR allele that is otherwise believed to predispose individuals to depressive episodes after stressful events. Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.
Fructose malabsorbtion
A series of 50 subjects examined in an Australian study showed increased depressive scores on Beck Depression InventoryBeck Depression Inventory
The Beck Depression Inventory , created by Dr. Aaron T. Beck, is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression...
associated with reduced plasma tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
, due to Fructose malabsorption
Fructose malabsorption
Fructose malabsorption, formerly named "dietary fructose intolerance," is a digestive disorder in which absorption of fructose is impaired by deficient fructose carriers in the small intestine's enterocytes. This results in an increased concentration of fructose in the entire intestine.Fructose...