Affective Disorders Flashcards
Monoamine Hypothesis
Reduced Levels of 5HT and NE are responsible for depression –> reserpine effect (blood pressure medication creates depression as side effect)
Enhanced levels of 5HT and NE are responsible for mania (manic activity correlates with cocaine use and is caused by increase of cats by reuptake blockades or enhanced release)
Unlcear in this model which monos/nts are actually the most important (still debate over 5HT vs NE)
Problems: time gap between antidepressant action and clinical therapeutic effects wouldn’t exist if depleted monoamines were the cause of depression.
- -> Also: little human evidence that depressed people have altered levels of 5ht except for decreased 5HIAA levels and decreased tryptophan.
- -> now considered overly simplified
5HT Dysfunction in Mood Disorders: Human Evidence
- Measure 5HT turnover via 5HIAA
- Tryptophan blood levels: tryptophan depletion challenge (trypt deficient amino acid cocktail that temporarily decreases 5HT in the brain) - can cause relapse of depressive symptoms or decreased mood in controls.
- –> takeaway: just having low 5HT doesn’t cause depression: only those who are vulnerable to depression by having a decreased 5HT sensitivity will develop.
- –> patients being treated with AD’s show temporary relapse of symptoms with the tryp challenge:: therefore 5HT must be available for these drugs to work…
- SERT: S vs L alleles
- –> s allele = decreased functionality of transporter - correlated with depression when also experience stressful life event; also associated with increased amgydala activity to threatening stimuli and score higher on negative emotionality tests.
- Receptor Binding Studies:
- -> depressed have increased 5HT2c receptors (compensating for low levels?)
- Challenge Studies -
- -> measuring the magnitude of biological responses to agonists and antagonists… the magnitude is an indicator of the sensitivity and functionality of the receptor..
- -> Depressed: 5HT Receptors are less sensitive
- Imaging Technology -
- -> PET measure bloodflow differences between healthy vs depressed individuals (increased amygdala activity and increased OFC activity - maybe reflects attempts to control negative thoughts)
Antidepressants, 5HT, Animal Studies
Acute Effects: Most AD’s increase 5HT by blocking reuptake or inhibiting MAO.
…but…. increased synaptic 5HT activates auto receptors that then decrease cell firing and decrease 5HT synthesis release so overall NEUTRAL response…..
CHRONIC: treatment with AD’s creates tolerance: decreased action of auto receptors so gradually increase the amount of 5HT in the synapse (because no tolerance to reuptake blockade)
NE Role in Depression and AD’s
NE is also altered by AD’s
–> metabolite MHPG has shown mixed results with patients but is usually elevated in treated patients.. – suggesting the medication increases NE turnover
- Medicated ppl see down regulation of both beta and alpha2 auto receptors — chronic AD admin decrease the responsiveness of alpha2 autos and increases NE turnover.
- Treatment with NE reuptake inhibitors can help and relapse can be seen by preventing NE synthesis by depleting NE precursor tyrosine.
NE-5HT Modulation in Depression
Evidence:
– Destroying 5HT terminals with neurotoxin prevents the down regulation of beta receptors seen with AD admin.
–5HT agonists can indirectly stimulate NE system and down regulate beta receptors
–Increasing NE function can increase electrophys activity of the raphe nuclei.
“GC Hypothesis” and “Neurotrophic Hypothesis” of Depression
Based on stress related neuroendocrine problems.
–Problem = dysregulated HPA Axis::
increased GCs caused by increased ACTH caused by increased CRF from the hypothalamus – CRF neurons are controlled by the amyg… and inhibit the hippocampus to stop the HPA axis activation.
—> Stress keeps gc levels high - and damages the hippo causing atrophy and decreased neurogenesis… the damaged hippo causes a loss in inhibition over the HPA.
- -> dysregulation of HPA possibly due to decreased BDNF in the brain: “Neurotrophic Hypothesis” –
- —-neurotrophics are necessary for normal brian development and also regulate changes in synapses and cell survival as adults…
- low BDNF may cause atrophy in PFC and hippo and decreased neurogenesis in hippo too.
- AD’s may prevent low BDNF
- —-> evidence: chronic stress decreases BDNF in hippo, chronic but NOT acute AD admin increases BDNF in animals and humans, and ADS prevent stress induced decreases in BDNF and atrophy.
- BDNF synthesis is dependent on cAMP 2nd mess system. Chronic AD’s up regulate cAMP in hippo and frontal cortex (despite down regulating beta and 5HT receptors)
MAOi’s
Nardil, Marplan - now mostly used for patients who show resistance to other medications
: Inhibit MAO to increase the amount of monos available for release in the terminal
- Side Effects are many and can be dangerous:
–> Synergistic effects with other over the counter drugs that also increase NE peripherally can be dangerous (like nasal sprays and cold medications)
–> Inhibition of MAO in the liver lease to dietary restrictions – no tyramine metabolism in the liver (no cheese!)
–> Inhibition of cytochrome p450 enzymes in liver enhances effects of other drugs (increased alcohol and barbiturate)
TCA’s
Imipramine
: Inhibit reuptake of (mostly) monoamines by binding to transporter proteins
- -> Side Effects:
- block other monoamines too and also Ach and histamine and sometimes Epinephrine.
- Anticholinergic Side Effects: (recall: blocking reputake in Ach system actually just decreases amount of Ach transmission because of AchE and need for choline)
- ——> dry mouth, dizziness, confusion, constipation, blurred vision, impaired memory
- Toxicity with overdose - heart problems, delirium, coma, respiratory suppression.
2nd Generation AD’s
Fluoxetine (prozac) - SSRI, Zoloft, Paxil/paroxetine
– safest but take weeks to work..
: more selective than TCA’s to 5HT than NE; may also agonize 5HT2b receptors on astrocytes which could increase glucose downstream for the post synaptic cell.
- -> Side Effects: don’t alter NE, histamine, or Ach, so different from TCA’s:
- anxiety, restlessness
- movement disorders
- headaches, nausea, insomnia
- Serotonin Syndrome - fatal effects when combined with other 5HT agonists.
- X can cause physical dependence and withdrawal
Dual NE/5HT modulators
Cymbalta
Remeron - blocks alpha 2 autoreceptors and increases synaptic NE, and alpha2 hetero receptors on 5HT cells, which increases 5HT release.
3rd Generation AD’s
1) Ketamine (dissociative anesthetic); NMDA antagonist and indirectly increases AMPA transmission; admin subanesthic doses has shown rapid onset of symptom relief with prolonged effects. Doesn’t create dependence but is considered an abused substance.
2) Galanin - a neuropeptide colocalized with NE in the LC, and 5HT in the Raphe. Inhibitory modulator by hyper polarizing the cell and decreasing NT release at projection areas like the limbic system and PFC.
- -SSRI’s show up regulation of galanin and GalR2 receptor with the clinical effects.
- -Nonselective galanin antagonists can prevent SSRI fluoxetine’s effects during FST.
Lithium Carbonate
Most effective treatment for Bipolar - works on mania without causing depression or sedation. (less effective with depression)
: Increases 5HT and decreases cat activity (by increasing reuptake and decreasing release) –> most likely modifying synapse via 2nd messenger activity..
- -> Side Effects:
- excreted via kidneys (not metabolized) low sodium in the system can cause toxicity
- Mild thirst, fatigue, tremor, weight gain,
Tegretol
Bipolar Medication but also developed as anti convulsive
- inhibit NE reuptake, blocks adenosine receptors; an
- stabilizes inactive Na+ channels
- May also agonize Gaba
