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• Loss of pleasure (anhedonia).
• Too few positive emotions and too many negative ones.
• Accompanying major depression are great grief and great guilt. Sometimes this can take on the quality of a delusion "things are terrible and getting worse"
• Primarily a disorder of thought rather than emotion, in that sufferers tend to see the world in a distorted, negative way.
• Psycho-motor retardation -- the person moves and speaks slowly.
• Eating declines, sleeping does as well and the architecture of sleep is different as well.
• Elevated levels of glucocorticoids.
• Problems with hippocampal dependent memory.

• Unipolar depression: fluctuates from feeling extremely depressed to feeling reasonably normal.
• Manic depression: fluctuates between deep depression and wild, disorganized hyperactivity.
• This is not just a single disease, but a heterogeneity of diseases that have different underlying biologies.

Depression involves abnormal levels of the neurotransmitters norepinephrine, serotonin, and dopamine.

• Tricyclics: stops the recycling of these neurotransmitters into the axon terminals. The neurotransmitter remains in the synapse longer and is likely to hit tis respective receptor a second or third time.
• MAO inhibitors: blocks the degradation of these neurotransmitters in the synapse by inhibiting the action of a crucial enzyme in that degradation MAO. More of the messenger remains in the synapse to stimulate the dendrite of the receiving neuron.
• These work on all three neurotransmitter systems, making it impossible to tell which one is critical to the disease.

• Neurotransmitters in the synapses changes within hours. However give that same drug to a depressed person, and it takes weeks for the person to feel better.
• Revisionist 1: it's not too little neurotransmitter, it's actually too much. When you give a depressive drugs, there is a down regulation in the receptors which compensates for the increased neurotransmitter signal, the depressive problem of excessive neurotransmitter signaling goes away and the person feels better.
• Revisionist 2: It really is too little neurotransmitter. There is downregulation of the autoreceptors. Underestimating the amount of neurotransmitter it has released, the neuron will inadvertently start increasing the amount it synthesizes and discharges. ECT decreases the number of norepinephrine autoreceptors, at least in experimental animal models.

• Serotonin: thought to have something to do with incessant ideation in depression, the uncontrollable wallowing in those dark thoughts.
• Norepinephrine: that major pathway that utilizes norepinephrine is an array of projections from a brain region called the locus ceruleus. Plays a role in alerting the other brain regions. A shortage of norepinephrine in this pathway might begin to explain the psychomotor retardation.
• Dopamine: Has something to do with pleasure.
• The attention these days is the most for serotonin and the least for depression.
• Perhaps substance P is involved: plays a role in pain perception, with a major role in activating the spinal cord pathways.

Cortex thinks an abstract negative thought and manages to convince the rest of the brain that this is as real as a physical stressor.

• Part of the brain that is very concerned with negative emotions.
• Its resting level of activity tends to be elevated in people with a depression.

• The ACC and the amygdala
• The right PFC.

• Chronic illness that involves overactivation of the immune system is more likely to cause depression than other equally severe and prolonged illnesses that don't involve the immune system.
• Cytokines can get into the brain where they can stimulate CRH release. They can also interact with norepinephrine, dopamine, and serotonin systems. Critically, cytokines can cause depression.

• Abnormal levels of a number of different hormones often go hand in hand with depression.
• People with too little thyroid hormone can develop major depressions.
• The incidence of unipolar depression differs greatly with women suffering far more than men.

• Cognitive Psychologists: When something upsetting happens, women are more likely to ruminate over it. Men are more likely to want to think about something else. A ruminative tendency makes you more likely to become depressed.
• Psychosocial theory: Because women in many societies have less control over the circumstances of their lives than do men, they are at greater risk for depression.
• Other theory: Men really do have as high a rate of depression, but they are simply more likely to mask it with substance abuse.
• All of these run into trouble because men and women have the same rate of bipolar depression.
• Women are particularly at risk for depression at certain reproductive points: mensturation, menopause, and the weeks immediately after giving birth.
• Estrogen and progesterone regulate neurochemical events in the brain, including the metabolism of neurotransmitters such as norepinephrine and serotonin.

• People who are prone to depression tend to experience stressors at a higher than expected rate.
• Much of this appears to be stressors built around lack of social support. This raises the potential for a vicious cycle to emerge.
• But the major way the link is thought about is that people who undergo a lot of life stressors are more likely than average to succumb to a major depression.
• Have lots of glucocorticoids in the bloodstream and the risk of a depression increases.

Glucocorticoid levels are typically abnormal in people who are clinically depressed. The elevated levels appear to be due to too much of a stress signal from the brain. The excessive secretion of glucocorticoids is due to what is called feedback resistance.

• Sustained stress will deplete dopamine from those pleasure pathways, and norepinephrine from that alerting locus ceruleus part of the brain. Moreover, stress alters all sorts of aspects of the synthesis, release, efficacy, and breakdown of serotonin.
• Elevated glucocorticoid levels appear to play a role in the fact that depressives are at least mildly immunosuppressed, and are more prone to osteoporosis. Prolonged major depression increases the risk of heart disease about three to fourfold even after controlling for smoking and alcohol consumption.
• Glucocorticoids damage the hippocampus.