Antidepressants

Peter Johnson

Historical Perspective

Depression and antidepressants: molecular and cellular aspects

Cell. Mol. Life Sci. (2009) 66:29853008

Treatment Flow Chart

Selective Serotonin Reuptake Inhibitors (SSRIs)

Most commonly prescribed antidepressant Examples: Paxil, Zoloft, Prozac, Celexa Side effects: drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, weight gain, and sexual dysfunction

Prevents reuptake of serotonin (HT-5) and subsequent degradation. This leads to accumulation of serotonin in synaptic cleft and concentration returns to normal range. Upregulation of p11 and CREB (cyclic-AMPresponse element-binding protein)

SSRI Mechanism

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

SSRI Problems
Only effective in 60-70% of patients

Side effects
Discontinuation symptoms (brain zaps, nausea, insomnia, confusion, vertigo, and sexual dysfunction)

Serotonin syndrome (aka too much or interactions)

confusion, agitation, mania, anxiety, coma, irregular heartbeat, high or low blood pressure, nausea, diarrhea, abdominal pain, muscle contractions or rigidity, restlessness, shaking, loss of coordination, shivering, seizures

Increase chance of suicide?

Time Lag

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, 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. Several weeks more to achieve full effect. Longer signaling pathways?

5-HT Receptor Subtypes

http://www.cnsforum.com

What if SSRIs do not work?

 Other class of antidepressant -TCAs- block reuptake of neurotransmitters such as norepinephrine and serotonin -MAOIs- block degradation of dopamine, serotonin, and norepinephrine by inhibiting monoamine oxidase -NDRIs- 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. Mol. Life Sci. (2009) 66:29853008

Activity of antidepressants

Depression and antidepressants: molecular and cellular aspects Cell. Mol. Life Sci. (2009) 66:29853008

Dual Treatment?
Results: Only 30-40% of patients remit after 8 weeks of antidepressant therapy Bupropion and Escitalopram (BUP and ESC) vs. SSRI 33% remission by Week 2 (13% is SSRI), 63% by Week8 Problems: 29% had severe adverse effect, 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, which should increase serotonin neurotransmission

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

Ketamine, 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 (Erics presentation and LTP)

Lower levels of S845 phosphorylated Glu-R1

Phosphorylated state implicated in AMPA desensitization

Ketamine

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

Ketamine Vs. SSRIs

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

Problems with NMDA therapy options

Long term affects still undetermined
Scrutinized for long term toxicology, carcinogenicity and reproductive toxicity studies

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

Molecular pathway analysis of genes regulated in the NAc by the HDAC inhibitor MS-275

Covington III et al. (2009). Antidepressant Actions of Histone Deacetylase Inhibitors. Journal of Neuroscience. 29(37): 11451-11460.

References
Agam G, Bersudsky Y, Berry G, Moechars D, Lavi-Avnon Y, Belmaker RH (2009)
Knockout mice in understanding the mechanism of action of lithium. Biochemical Society Transactions. Vol. 37, part 5.

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