TCAs acts on many other transmitter systems in the CNS and periphery, eg, the histaminergic or acetylcholinergic systems,62 leading to sedation, hypotension, blurred vision, dry mouth, and other unwanted effects. In addition, TCAs may be life -threatening and fatal in overdose, especially due to their effects on the cardiovascular system.63 Also, the

irreversible MAOIs have their own problems, such as an interaction with tyramine (the so-called “cheese effect”), which causes potentially lethal hypertension.62 The main problem with the less severe side effects is a reduction in compliance, patients often do not take a sufficient dosage Inhibitors,research,lifescience,medical for an adequate period of time and thus remain in an “undertreated” state. The development of newer antidepressants has aimed to improve the safety and tolerability of the TCAs and reuptake inhibitors, and selectivity for a single monoamine seemed to be the key to this goal. Since the introduction of fluoxetine as the first selective serotoninreuptake inhibitor Inhibitors,research,lifescience,medical (SSRI), a great number of similarly acting drugs have followed and SSRIs

are now applied in the treatment of several psychiatric disturbances, such as anxiety, panic, or obsessive compulsive disorder, where altered Inhibitors,research,lifescience,medical serotonergic transmission is assumed.62 Because preclinical and clinical studies have shown that chronic stimulation of the 5-HT system also affects the NE system and vice versa,64 there has been renewed interest in the role of

neurotransmitters other than serotonin. The development of the newest generation of antidepressants, including reboxetine (a selective NE-reuptake inhibitor), venlafaxine Inhibitors,research,lifescience,medical (a dual reuptake inhibitor), or the multiple receptor-acting substances mirtazepine, nefazodone, bupropion, and trazodone, may positively influence therapeutic potentials with reduced incidence of side effects due to reduced affinities for other systems.62 Interestingly, one drug, tianeptine, shows a quite atypical mechanism, Inhibitors,research,lifescience,medical namely an increase in 5-HT uptake, Mephenoxalone but most probably this substance predominantly counteracts stress effects in the hippocampus.65 With the use of these new drugs, the incidence of severe side effects was certainly reduced, but there are rather severe, treatment-resistant types of depression, which may not adequately be treated with these drugs. A new drug regimen, augmentation therapy, was CHIR-99021 purchase introduced some years ago, which is defined as the addition of a second agent to an existing antidepressant to achieve improved clinical response. Popular strategies are augmentation of TCA drugs with Li+, or SSRIs with pindolol. Although the results of these strategies in relieving depressive symptoms are encouraging, more prospective, well-controlled studies will have to clarify the benefits and risks of augmentation strategies.