Exam 2 Lecture 21, Antidepressant I

Continuous depression: Become and stay depressed Recurrent depression: Bounce between depression and “normal”

Cycle of depression and mania: Bounce between elation and depression

denotes 1 type of mood disorder, unipolar depression Symptoms maybe secondary to adverse, distressing events in patients life (reactive) or may have no clear precipitating cause (endogenous) lifetime prevalence in US is 17%, one of most common psych disorders Associated with other med conditions; high co-morbidity with heart disease, diabetes, chronic pain and anxiety disorders Economic cost $70 Billion 3.4% commit suicide

applied to recurrent cyclic episodes of mania and depression, used to be called “manic-depressive illness” Form of psychotic disorder distinct from schizophrenia 1-3% prevalence in adult pop

Percentage of people using antidepressant has increased Females tend to take more then men

5 or more symptoms should have been present during at least a 2 week period and represent a change from previous functioning

severely depressed mood for most of day Anhedonia Loss of interest or pleasure in normally enjoyable things Feelings of extreme sadness, hopelessness, etc Lost of self esteem; self depreciation change in appetite with weight gain or loss Suicidal thoughts fatigue, decreased energy early waking with trouble sleeping

3 or more of the following symptoms for >1 week and interfering with job or relationships

inflated self-esteem and grandiosity Extreme elation, tinged with dysphoria and irritability Marked insomnia Increased verbal and motor activity, increased goal-directed activities Poor judgment Mania alternates with depression, transition or “switch” can occur over a period of minutes to hours to days

Bipolar I disorder: at least 1 episode of mania Bipolar II disorder: at least 1 episode of hypomania and 1 episode of depression

symptoms traditionally sought to be associated with deficiencies of CNS monamine transmitters, specifically NE and/or 5HT. Maybe disruption in linkage between the NE and 5HT systems

In bipolar disorder, were thought to be due to excessive monoaminergic transmission….especially by NE and DA

Controversial, not all evidence fits Current drug therapies based on this theory

Depression due to deficiency of monamine transmission by NE or 5-HT or both Mania is due to an excess of monoamine neurotransmission

Reserpine (which depletes catecholamines) causes depression MAO inhibitors (which prevent catecholamine and serotonin metabolism) are antidepressants Drugs that block NE and 5HT reuptake (TCA and SSRIs) are antidepressants Depressed patients excrete less catecholamine metabolites in urine, suggesting lower CNS catecholamine neuronal activity Theory is based on mechanism of action of 1st effective antidepressant drugs….MAO inhibitors and TCA

Rostral raphe nuclei and Caudal raphe nuclei

Locus cerulean and Lateral tegmental NA cell system

Some effective antidepressants do not block either NE or 5HT uptake by nerve terminals Some drugs that do block catecholamine and serotonin uptake (blow and amphetamine) are poor antidepressants clinically There is poor temporal correlation between the onset of the clinical antidepressants effect (3-4 weeks) and the blockade of re-uptake or MAO inhibition in brain (immediate)

suggests depression maybe due to loss of brain-derived neurotrophic factor (BDNF) in critical brain areas such as hippocampus and frontal cortex BDNF normally promotes neurogenesis (birth of new neurons) in these regions, and BDNF deficiency is associated with fewer new neurons Stress and pain = decrease BDNF levels, MDD patient have decreased hippocampal volume

BDNF critical for neural plasticity, exert neural growth via RTK B, Hippocampus to HPA (hypothalamus, pituitary, adrenal) axis, anterior cingulate, orbitofrontal cortex. In animal models, direct infusion of BDNF alleviates major depression BDNF in cerebral spinal fluid decreased in human with major depression

chronic administration of antidepressants causes autoreceptor subsensitivity thereby increasing release of NE or 5HT from nerve terminals…. Dumbed down: When NE reuptake blocked, more NE is in synapse that binds to alpha 2 auto receptors. These receptors control negative feedback. Since there is more NE to bind to the alpha 2, they become bound excessively and then they become internalized thereby reducing alpha 2 receptor density at presynaptic end. Reduced density allows for more NE release since they would usually inhibit it but there are less alpha 2 auto receptors to inhibit release

Due to decreased Monoamines and BDNF acting on CREB dependent transcription, making less BDNF Also Gluccocorticoids causes reduce in transcription that leads to neural development

Chronic stress and/or genetic susceptibility overwhelms normal neuroplasticity and causes a decrease in neurogenesis in the hippocampus BDNF is up-regulated with antidepressant use (in hippocampus) BDNF and its receptor (TrkB) are required for antidepressant efficacy and hippocampal neurogenesis Stress decreases BDNF production and neurogenesis

Depression results from chronic inflammatory event Increased cytokine levels damage glia and cause tryptophan to turn into the neurotoxin quinolic acid (QUIN) intreat of 5-HT QUIN causes glutamate receptor activation and glutamate release, leading to excitotoxicity and decreased BDNF production May explain why glutamate blockers (iu ketamine) have strong antidepressant effects