rCBF and prefrontal abnormalities in depressives: 1. Clear reduction in bloodflow in left prefrontal cortex, focused on orbitofrontal and cingulate regions 2. Often, these abnormalities extend to anatomically-linked areas of the striatum Structural abnormalities in depressives 1. Mixed reports of lateral ventricular enlargement, prefrontal cortical shrinkage 2. Interesting reduction in size of cerebellum, especially the vermis 3. Increased size of pituitary, reduced size of hippocampus DEPRESSION IN THE ELDERLY: Atrophy, focal abnormalities and global reductions in blood flow are seen BIPOLAR DEPRESSION: Cerebellar atrophy Focal abnormalities Reduced global cerebral blood flow in depression, increased in mania Possible temporal shrinkage MORE ON MONOAMINES AND DEPRESSION ANTIDEPRESSIVES CAUSE CHANGES IN MANY NT SYSTEMS DRUGS AFFECTING A SINGLE SYSTEM HAVE COMPARABLE EFFICACY! Thus drugs with fairly specific effects on JUST the dopamine, or norepinephrine, or serotonin systems can all work THESE SYSTEMS ARE LINKED: Changes in any one, but especially serotonin and norepi, can induce changes in the others LACK OF ALTERATIONS IN CSF/BLOOD MONOAMINE LEVELS, FOR ANY NEUROTRANSMITTER THE SEROTONIN HYPOTHESIS SEROTONIN RECEPTORS REVISITED 5-HT1 RECEPTORS: These are autoreceptors, and there are two types: 1. 5-HT1A: Somatodendritic autoreceptors which shut down FIRING 2. 5-HT1D: Terminal autoreceptors which shut down serotonin RELEASE 5-HT2: A major post-synaptic receptor SSRIs AND RECEPTOR DOWN-REGULATION SSRIs, TCAs, MAOIs and ECT all down-regulate the 5-HT2 receptor This down-regulation is slow (weeks not days), and this time-course parallels the rise of anti- depressive effects Many therefore believe that it is this effect which accounts for the antidepressant effects, over all drug classes OR perhaps that this is a secondary effect, indicating that a chronic reduction in serotonin caused up- regulation, and that treatment restores serotonin levels and hence causes down-regulation PLATELETS: Some depressives have reductions in platelet response to 5-HT, suggesting an abnormality in the 5-HT2 receptor Some studies report reduced 5-HT uptake sites in platelets of depressives BRAIN SCANS AND 5-HT ABNORMALITIES Binding studies suggest a lowering of 5-HT uptake sites In normal patients, serotonin INCREASES activity in left prefrontal cortex, maybe decreases activity in right prefrontal cortex No such effects are seen in depressives SAD AND SEROTONIN: Seasonal Affective Disorder (SAD) seems linked to melatonin deficiencies in the pituitary Melatonin is synthesized from serotonin SEROTONIN AND SUICIDE 5-HIAA is lower in CSF of suicides 5-HT2A receptor density is increased in prefrontal cortex of suicide However, cortisol can up-regulate 5-HT2 receptors TRYPTOPHAN DEFICIENCY AND DEPRESSION: Depressive in remission due to SSRIs or TCAs can be tipped back into depression within days of an experimentally-induced tryptophan deficiency Some studies report decreased plasma tryptophan concentrations in depressives THE NOREPI HYPOTHESIS TCAs CAN BE RATHER SPECIFIC ADRENERGIC REUPTAKE BLOCKERS TCAs AND -ADRENERGIC RECEPTOR DOWN- REGULATION: This effect is quite comparable to that seen with the 5-HT2 down-regulation But may be correlative not causal THERE IS INCREASED à2 BINDING IN PLATELETS OF DEPRESSIVES ENDOCRINE ABNORMALITIES IN DEPRESSIVES MAY BE A FUNCTION OF NOREPI ABNORMALITIES OR NOREPI REUPTAKE BLOCKERS MAY INDIRECTLY AFFECT THE SEROTONIN SYSTEM THE DOPAMINE HYPOTHESIS DOPAMINE MODULATES REWARD AND EUPHORIA BUPROPION, A SPECIFIC DOPAMINE REUPTAKE BLOCKER, HAS ANTIDEPRESSIVE PROPERTIES COCAINE-INDUCED D2 RECEPTOR DOWN- REGULATION SEEMS TO TRIGGER DEPRESSION DEPRESSIVES SELF-ADMINISTER DOPAMINE AGONISTS BUT: Parkinson's not always depressive Increased cortisol enhances dopamine, and cortisol is enhanced in depression SSRIs may normalize dopamine in prefrontal cortex CONCLUSION: Nothing is as yet certain, but my bets are on: DEPRESSION RESULTS FROM A NEUROCHEMICAL IMBALANCE IN PREFRONTAL CORTEX THIS IMBALANCE MAY BE DUE TO AN ABNORMAL SEROTONERGIC REGULATION OF PREFRONTAL DOPAMINE INTERNET ANTIDEPRESSANT COSTS CATEGORY COMPOUND DAILY DOSAGE (mg) COST/ MONTH (Generics in parentheses) TCA Amitriptyline 150 mg $ 27 Desimipramine 150 mg $ 150 ($ 45) Imipramine 250 mg $ 125 ($ 25) Doxepin 125 mg $ 7 SSRI Fluvoxamine 200 mg $ 150 Paroxetine 30 mg $ 67 Fluoxetine 20 mg $ 72 Sertraline 100 mg $ 68 Citalopram 40 mg $ 62 NON- TRADITIONAL Buspirone 10 mg $ 40 Venlafaxine 125 mg $ 145 Trazadone 300 mg $ 300 ($ 21) Nefazodone 500 mg $ 67 Bupropion 300 mg $ 84