Symptoms and circuits in depression

Symptoms and circuits in depression

Currently, the monoamine hypothesis of depression is now being applied to understanding how monoamines regulate the efficiency of information processing in a wide variety of neuronal circuits that may be responsible for mediating the various symptoms of depression. Obviously, there are numerous symptoms required for the diagnosis of a major depressive episode ( ). EachFigure 6-44 symptom is hypothetically associated with inefficient information processing in various brain circuits, with different symptoms topographically localized to specific brain regions ( ).Figure 6-45

Figure 6-41. . Prolonged activation of circuits due to repeated exposureDevelopment of stress sensitization to stressors can lead to a condition known as “stress sensitization,” in which circuits not only become overly activated but remain overly activated even when the stressor is withdrawn. Thus, an individual with severe stress in childhood will exhibit transient symptoms during stress exposure, with resolution of the symptoms when the stressor is removed. The circuits remain overly activated in this model, but the individual exhibits no symptoms because these circuits can somehow still compensate for this additional load. However, the individual with “stress-sensitized” circuits is now vulnerable to the effects of future stressors, so that the risk for developing psychiatric symptoms is increased. Stress sensitization may therefore constitute a “presymptomatic” state for some psychiatric symptoms. This state might be detectable with functional brain scans of circuits but not from psychiatric interviews or patient complaints.

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Figure 6-42. . It may be that the degree of stress oneProgression from stress sensitization to depression experiences during early life affects how the circuits develop and therefore how a given individual responds to stress in later life. No stress during infancy may lead to a circuit that exhibits “normal” activation during stress and confers no increased risk of developing a psychiatric disorder. Interestingly, mild stress during infancy may actually cause the circuits to exhibit reduced reactivity to stress in later life and provide some resilience to adult stressors. Overwhelming and/or chronic stress from child abuse, however, may lead to stress-sensitized circuits that may become activated even in the absence of a stressor. Individuals with stress sensitization may not exhibit phenotypic symptoms but may be at increased risk of developing a mental illness if exposed to future stressors.

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Figure 6-43. . Genetic research has shown that the type of serotoninSerotonin genetics and life stressors transporter (SERT) with which you are born can affect how you process fearful stimuli and perhaps also how you respond to stress. Specifically, individuals who are carriers of the s variant of the gene for SERT appear to be more vulnerable to the effects of stress or anxiety, whereas those who carry the l variant appear to be more resilient. Thus, s carriers exhibit increased amygdala activity in response to fearful faces and may also be more likely to develop a mood or anxiety disorder after suffering multiple life stressors. The higher risk of depression may also be related to increased likelihood of cognitive symptoms, brain atrophy, increased cortisol, and, if depressed, poor response to selective serotonin reuptake inhibitors (SSRIs).

Not only can each of the nine symptoms listed for the diagnosis of a major depressive episode be mapped onto brain circuits whose inefficient information processing theoretically mediates these symptoms ( ), but the hypothetical monoaminergic regulation of each of these variousFigure 6-45 brain areas can also be mapped onto each brain region they innervate ( through ).Figures 6-31 6-33 This creates a set of monoamine neurotransmitters that regulates each specific hypothetically malfunctioning brain region. Targeting each region with

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Figure 6-44. . According to the Symptoms of depression Diagnostic and Statistical Manual of Mental Disorders , a major depressive episode consists of either depressed mood or loss of interest and at least four of the following: weight/appetite changes, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of guilt or worthlessness, executive dysfunction, and suicidal ideation.

Figure 6-45. . Alterations in neuronal activity and in the efficiencyMatching depression symptoms to circuits of information processing within each of the eleven brain regions shown here can lead to symptoms of a major depressive episode. Functionality in each brain region is hypothetically associated with a different constellation of symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

drugs that act on the relevant monoamine(s) that innervate those brain regions potentially leads to reduction of each individual symptom experienced by a specific patient by enhancing the efficiency of

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information processing in malfunctioning circuits for each specific symptom. If successful, this targeting of monoamines in specific brain areas could even eliminate symptoms, and cause a major depressive episode to go into remission.

Figure 6-46. . Mood-related symptoms of depression can be characterized by theirPositive and negative affect affective expression – that is, whether they cause a reduction in positive affect or an increase in negative affect. Symptoms related to reduced positive affect include depressed mood; loss of happiness, interest, or pleasure; loss of energy or enthusiasm; decreased alertness; and decreased self-confidence. Reduced positive affect may be hypothetically related to dopaminergic dysfunction, with a possible role of noradrenergic dysfunction as well. Symptoms associated with increased negative affect include depressed mood, guilt, disgust, fear, anxiety, hostility, irritability, and loneliness. Increased negative affect may be linked hypothetically to serotonergic dysfunction and perhaps also noradrenergic dysfunction.

Many of the mood-related symptoms of depression can be categorized as having either too little positive affect, or too much negative affect ( ). This idea is linked to the fact that there areFigure 6-46 diffuse anatomic connections of monoamines throughout the brain, with diffuse dopamine dysfunction in this system driving predominantly the reduction of positive affect, diffuse serotonin dysfunction driving predominantly the increase in negative affect, and norepinephrine dysfunction being involved in both. Thus, reduced positive affect includes such symptoms as depressed mood but also loss of happiness, joy, interest, pleasure, alertness, energy, enthusiasm, and self-confidence ( , left). Enhancing dopamine function, and possibly also norepinephrine function mayFigure 6-46 improve information processing in the circuits mediating this cluster of symptoms. On the other hand, increased negative affect includes not only depressed mood but guilt, disgust, fear, anxiety, hostility, irritability and loneliness ( , right). Enhancing serotonin function, and possibly alsoFigure 6-46 norepinephrine function, may improve information processing in the circuits that hypothetically mediate this cluster of symptoms. For patients with symptoms of both clusters, they may require triple-action treatments that boost all three of the monoamines.

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