- Selective serotonin reuptake inhibitors (SSRIs) block the serotonin transporter on the pre-synaptic neuron, increasing the serotonin available to bind to the post-synaptic 5-HT receptors.
- SSRIs have very weak affinity for other mono-amine transporters (norepinephrine and dopamine reuptake transporters).
The delay in onset of action of SSRIs is the result of presynaptic and postsynaptic adaptive mechanisms.
- 5-HT1A receptor is a post-synapitc autoreceptor, which down-regulates 5-HT in response to higher 5-HT concentrations in the synapse. Blockade of 5-HT1a is hypothesized to enhance and speed up the therapeutic effect of SSRIs.
- Pindolol, a 5-HT1a antagonist, was studied in several placebo-controlled trials with promising results. 
- The blockade of 5-HT2A receptors (Mirtazapine, aripiprazole) also seems to improve the clinical effects of SSRIs. 
SSRIs inhibit platelet aggregation, which can lead to bleeding in patients with von Willibrand desease, hemophilia, thrombocytopenia, or gastric ulcer.
- While SSRIs do not decrease platelet count, they inhibit platelet reuptake of 5-HT from serum, leading platelet 5-HT depletion.
- 5-HT is an important pro-coagulant involved in primary hemostasis (platelet adhesion/aggregation/secretion of procagulants).
- Short-term SSRI use (7-28 days) is significantly associated with upper gastrointestinal bleeding. Gender differences may exist in the relationship between SSRI use and upper gastrointestinal bleeding, M>F, with OR >1.6 at 7 days 
- Risk of GI bleed increases 12-fold with concominant use of SSRIs and NSAIDs 
Drug-induced liver injury
Although an infrequent event, DILI from antidepressant drugs may be irreversible, and clinicians should be aware of it. Aminotransferase surveillance is the most useful tool for detecting DILI, and prompt discontinuation of the drug responsible is essential. 
- The antidepressants associated with greater risks of hepatotoxicity are iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine.
- The antidepressants that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine.
SSRIs and Sleep
- Non-responders to citalopram (Ci) (n=565) alone were randomized to Ci+Bupropion ER and Ci+Buspirone. Roughly 30% achieved remission in both groups. Bupropion ER group had fewer side effects and and greater reduction in symtpoms severity (NEJM 2006)
 The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci. Jul 2004; 29(4): 252–265
 Wang YP, Chen YT, Tsai CF, et.al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014 Jan 1;171(1):54-61.
 Dalton, SO. Use of serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding. Arch Inter Med. 2003; 163:59-64
 Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014 Apr 1;171(4):404-15.