Psyc 4130 1nd Edition Lecture 34 Outline of Last Lecture I. Disorders of AffectII. Bipolar DisorderIII. DepressionIV. Diagnostic Criteria Highlights V. Signs and SymptomsVI. Common ComorbiditiesVII. Monoamine Hypothesis VIII. Evidence for MA Hypothesis IX. Resolving Lagtime IssuesX. BDNFXI. MAR BDNF Signaling CascadeXII. MA AutoR OverexpressionOutline of Current Lecture I. Tigerring MDDII. Autoreceptor DownregulationIII. HeritabilityIV. 5-HTT PolymorphismsV. Counterintuitive Case of 5-HTTVI. 5-HTT and DepressionVII. Anatomy of MMDVIII. MAOIsIX. “Cheese Effect”X. TCAsXI. TCA OverdoseXII. 2nd GenerationCurrent Lecture Triggering MDD- Relentlessly elevated levels of cortisol lead to hippocampal desentization/atrophy and amygdalar sensitization.- Common endpoint: Decreased MA activity Autoreceptor Downregulation - RX may lead to autoreceptor downregulation.These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- In turn, the signaling cascade leading to monoamine synthesis is normalized. - Other interventions can do this as well!o White box therapy, exerciseo Figure 16.21 exercise and neurogenesis o Electroshock therapy (ECD)o sgACC (Figure 16.19/20 Subgenual ACC) Heritability- Close relatives of people with severe disorders are ten TIMES(!) more likely to be affected.- Nearly 70% concordance rate for MZ twins (vs. 13% for DZ)- RORA gene (involved in circadian rhythm regulation) has strongest association with MDD. 5-HTT Polymorphisms- Responsible for reuptake, promoter region for 5-HTT- The allele for the promoter region for 5-HTT comes in two forms: “long” and “short”.- (Promoter regions are “upstream” regulatory DNA which control _____ ________.) - Individuals with one or two short alleles display greater amygdala activation when viewing pictures of fearful or angry faces. Counterintuitive Case of 5-HTT- Short alleles code for transporter that is less effective in removing 5-HT from synapse.- What happens to 5-HT levels over time?- This is the type associated with depression. - Too much synaptic 5-HT during development *may* tend to predispose people to depression later in life. - Abnormal sleep patterns, reduced motivation, et cetera. 5-HTT and Depression- A longitudinal study conducted by Caspi and colleagues (2003) followed 847 people for more than twenty years, beginning at age three.- Recorded major negative life events (e.g. child abuse, deaths of family members, romantic disasters, major illnesses, employment crises, et cetera)- MDD and suicide go up as a function of the number of negative events: Expected- But…this association was much stronger in people with two short alleles for the 5-HTT promoter. - Gene X environment INTERACTION!- MDD sufferers with two long alleles are more likely to respond to SSRIs…- …and drug efficacy is more likely to last!- And they even respond better to PLACEBO! Anatomy of MDD- Overactive amygdala:- Drevets (1992) and Links (1996) showed that MDD is associated with increased regional blood flow and metabolism in the amygdala.- Abercrombie (1998) showed a positive correlation between depression severity and amygdala activation.- Underactive medial PFC- The subgenual ACC is overractive in depressed patients (Drevets et al., 1997)- This same region is hyper-responsive during dipolar mania - The dorsal ACC (not the subgenual) and amygdala are reciprocally-connected and mutually-inhibitory. - dACC inhibition of the amygdala is stronger in individuals with two long alleles for 5-HTT.- It’s suggested that the dACC is, in essence, providing the amygdala with a “reality check”o Amygdala in freak out panic mode, dorsal ACC is like “chill out” inhibits it- The reality check bounces in MDD, leading to escalating: MAOIs- MAOIs were first deployed in the late 1950s.- The first MAOI, iproniazid, was being used to treat tuberculosis, when it was serendipitously discovered to have mood-elevating effects. - MAO is an enzyme that acts in the presynaptic axon terminal to deaminate DA, NE and 5-HT. - MAOIs block this activity, typically irreversibly.- It takes several weeks to biomanufacture more MAO. “Cheese Effect”- Foods containing large amounts of ___________ (a derivative of tyrosine) while on a MAOI may lead to hypertensive crisis. - Common culprits: Cheese, wine, most dairy products (e.g. yogurt), pickled, smoked or marinated meats, sour cream, soy sauce, teriyaki sauce, tofu, avocados, bananas, pineapple, peanuts, raspberries, yeast, et cetera. TCAs- Tricyclic Antidepressants - Introduced in 1950s_____- Mechanism of Action: RI of ____ and ____- How do they work TCA Overdose- Toxic effects are observed at about 10 times the normal therapeutic dose.- May include severe hypertension, cardiac arrythmias (abnormal electrical activity of the heart), seizure, and death. 2nd Generation- Thirty years after the introduction of the TCAs, a reuptake inhibitor that selectively engage 5-HTT was deployed following a decade of drug research.- 1986 saw the deployment of prozac- first SSRI
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