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Depression Antidepressants

Depression Antidepressants

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Antidepressants

Peter Johnson

Historical Perspective

Depression and antidepressants: molecular and cellular aspects

Cell. Mol. Life Sci. (2009) 66:2985–3008

Treatment Flow Chart .

and sexual dysfunction • • Prevents reuptake of serotonin (HT-5) and subsequent degradation.Selective Serotonin Reuptake Inhibitors (SSRIs) • • Most commonly prescribed antidepressant Examples: Paxil. Celexa Side effects: drowsiness. This leads to accumulation of serotonin in synaptic cleft and concentration returns to normal range. weight gain. decreased appetite. anxiety. Prozac. Zoloft. Upregulation of p11 and CREB (cyclic-AMPresponse element-binding protein) . nervousness. insomnia. dry mouth.

cnsforum.png .SSRI Mechanism http://www.com/content/pictures/imagebank/hirespng/Drug_SSRI_2.

shivering. nausea. anxiety. seizures • Increase chance of suicide? • Time Lag… . shaking. agitation. restlessness. abdominal pain. and sexual dysfunction) • Serotonin syndrome (aka too much or interactions) – confusion. coma. muscle contractions or rigidity. insomnia.SSRI Problems • Only effective in 60-70% of patients • Side effects • Discontinuation symptoms (“brain zaps”. nausea. mania. loss of coordination. vertigo. high or low blood pressure. irregular heartbeat. confusion. diarrhea.

limiting ability of SSRI to enhance 5-HT expression early on in treatment – Future direction: Studies show that 5-HT1A and 5-HT1B receptor antagonists augment the effect of SSRIs on 5-HT function without blocking associated antidepressant effects • 2-3 weeks to increase sensitivity of receiving cell to serotonin. • Longer signaling pathways? .SSRI: The “time lag” • Role of 5-HT receptors – SSRIs indirectly activate 5-HT1A and 5-HT1B autoreceptors which has a inhibitory effect on 5-HT cell firing and release. Several weeks more to achieve full effect.

cnsforum.5-HT Receptor Subtypes http://www.com .

What if SSRIs do not work? .

Mol.inhibit the neuronal uptake of dopamine and norepinephrine -And even more… Other Strategies • Lithium augmentation – Inhibits IMPase (inositol monophosphatase) activity and inositol transporter function – Depressed subjects have increased IMPase activity Figure 1: “Depression and antidepressants: molecular and cellular aspects” Cell. serotonin. and norepinephrine by inhibiting monoamine oxidase -NDRIs.block reuptake of neurotransmitters such as norepinephrine and serotonin -MAOIs.block degradation of dopamine. (2009) 66:2985–3008 .• Other class of antidepressant -TCAs. Life Sci.

Activity of antidepressants “Depression and antidepressants: molecular and cellular aspects” Cell. Life Sci. Mol. (2009) 66:2985–3008 .

Dual Treatment? Results: • Only 30-40% of patients remit after 8 weeks of antidepressant therapy • Bupropion and Escitalopram (BUP and ESC) vs. which should increase serotonin neurotransmission . while 89% had “moderate to severe” adverse effects • Required close moderating and readiness to dosage control • Studies that show already superior drugs than SSRIs Possible Explanations: • An immediate increase in firing of rat dorsal raphe serotonin neurons. 63% by Week8 Problems: • 29% had “severe” adverse effect. SSRI • 33% remission by Week 2 (13% is SSRI).

Future Directions: NMDA Receptors Antagonists .

Ketamine • Noncompetitive binding to NMDA receptor and induces glutamate release by increasing firing rate of glutamatergic neurons • Rapid improvement in symptoms – 1st study of 17 treatment-resistant patients: 71% saw response (50% reduction in HAM-D score) and 29% saw remission (HAMD score <7) with 35% seeing response for at least 1 week – 2nd study: patients with family history of alcohol abuse saw higher response (67%) and remission (42%) than patients with no family history (18% and 9%) • glutamate system appears to play a major role in both conditions= sensitivity of NR2A – 3rd study: Within 24 hrs. 22 point reduction in MADRS score and significant reduction of suicidal ideation in 28 treatmentresistance patients .

a NMDA Receptor Antagonist • The rapid onset and the prolonged effects of ketamine are due to an increase in AMPA receptors. which makes the postsynaptic cell become more sensitive to action potentials (Eric‟s presentation and LTP) • Lower levels of S845 phosphorylated Glu-R1 – Phosphorylated state implicated in AMPA desensitization .Ketamine.

. Ketamine and the next generation of antidepressants with a rapid onset of action.Ketamine Machado-Viera et al. 123: 143-150. Pharmacology and Therapeutics.

123: 143-150. Pharmacology and Therapeutics. SSRIs Machado-Viera et al. . Ketamine and the next generation of antidepressants with a rapid onset of action.Ketamine Vs.

carcinogenicity and reproductive toxicity studies .Problems with NMDA therapy options • Long term affects still undetermined – Scrutinized for long term toxicology.

Genetic effects on treatment • Genetic polymorphisms play a role in determining response to SSRI treatment – Polymorphism of FKBP5 (co-chaperone of HSP90 regulating glucocorticoid receptor function)= rapid response to anti-depressants – 5HT2a –Receptor gene 102 T/C C variant= less antidepressant response – CRF gene= antidepressants affect expression .

Epigenetic Affects • Increased H3 acetylation and reduced levels of HDAC2 expression in the NAc • Antidepressant-like effects of HDAC inhibition occur by increasing histone acetylation at certain gene promoters and thereby exerting complex effects on gene expression .

29(37): 11451-11460. Antidepressant Actions of Histone Deacetylase Inhibitors. (2009).Molecular pathway analysis of genes regulated in the NAc by the HDAC inhibitor MS-275 Covington III et al. Journal of Neuroscience. .

Mol. Pharmacology and Therapeutics. DiazGranados N. Cerebrospinal Fluid Inositol Monophosphatase: Elevated Activity in Depression and Neuroleptic-treated Schizophrenia.References • Agam G. (2009). Journal of Neuroscience.. Govoni S. Biochemical Society Transactions. No. Zarate C. Lucchelli A. Du J. Manji H. Queree P (2008) Important messages in the „post‟: recent discoveries in 5-HT neurone feedback control. Lanni C. 66: 2985-3008 Machado-Viera R. (2009) Ketamine and the next generation of antidepressants with a rapid onset of action. Cell. Trends in Pharmacological Sciences. 29(37): 11451-11460. Biol Psychiatry 63: 349-352 Sharp T. Antidepressant Actions of Histone Deacetylase Inhibitors. 123: 143-150. Maeng S. • • • • • • Atack J. Boothman L. Vol. 37. Chen G. Berry G. Lavi-Avnon Y. Bersudsky Y. Salvadore G. Vol. Life Sci. McCammon J. Biol Psychiatry 44: 433-437 Covington III et al. Schloesser R. 12 . (2008) Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine.. Belmaker RH (2009) Knockout mice in understanding the mechanism of action of lithium. part 5.. Moechars D. Zarate C. 28. Raley J. Levine J. Boselli C (2009) Depression and antidepressants: molecular and cellular aspects. Belmaker RH (1998).

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