GSK-163090 is potent, selective, and orally active 5-HT1A/B/D receptor antagonist. GSK163090 was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic. GSK-163090 had been in phase II clinical trials by GlaxoSmithKline for the treatment of major depressive disorder (MDD) and anxiety disorders. However, this research has been discontinued.

Radafaxine (GW353162, ( )-(2S,3S)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) or S,S-hydroxybupropion) is an active metabolite of bupropion. It acts as an inhibitor of the dopamine transporter. Radafaxine was investigated for the treatment of depression however, development was discontinued.

DOV 216,303 [(+/-)-1-(3, 4-dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride] is the prototype of a class of compounds referred to as "triple" reuptake inhibitors. DOV 216,303 were licensed from Wyeth in 1998. This compound inhibits the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. In August 2004, DOV entered into a development and commercialization partnership for the triple reuptake inhibitors (DOV 21,947 and DOV 216,303) with Merck for depression.

Fananserin is a potential antipsychotic compound with a high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Fananserin has been researched for the treatment of schizophrenia. Fananserin was the first selective D4/5-HT2A antagonist to undergo clinical trials for schizophrenia. It has a high affinity for D4 (Ki 2.9 nM) and 5-HT2A (Ki 0.37 nM) receptors and is over 100-fold selective versus H1, a1 adrenergic, 5-HT1A and D2 dopamine receptors. Development of this compound was halted following phase II clinical trials due to lack of efficacy.

Eptapirone is a potent, selective and efficacious 5-HT1A receptor agonist. In rats, it is readily bioavailable after oral administration. Likely, because of its high efficacy at 5-HT1A receptors, Eptapirone exerted powerful antidepressant- and anxiolytic-like activity in animal models. Eptapirone given in the evening suppresses REM (rapid eye movement) sleep more than buspirone and implies a greater central effect on serotonin receptors, which is consistent with the preclinical data that indicate it has greater efficacy than buspirone. It has little effect on other sleep stages. Eptapirone has been in phase I clinical trials for the treatment of anxiety and major depressive disorder. However, this research has been discontinued.

Nefiracetam is a cyclic derivative of gamma-aminobutyric acid (GABA). It is thought to act by normalising dysfunctional acetylcholine, GABA and possibly monoamine neurotransmitter systems, but it may also facilitate N/L-type calcium channel opening. Nefiracetam has received attention as a treatment for seizures, depression, and dementia. Nefiracetam was found to be extremely testicular toxic in both rats and dogs; it was found to significantly decrease the levels of testicular testosterone leading to atrophy and malformation of sperm.

Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms. Once ingested, psilocybin is rapidly metabolized to the psilocin, which then acts on serotonin receptors in the brain. Psilocybin was identified as the active hallucinogenic compound in magic mushrooms in 1959, but humans have used assorted psilocybin mushrooms in religious ceremonies since prehistoric times. In the 1960's psilocybin was marketed for use as a treatment for various psychoses, however, it was withdrawn from the market when the regulatory environment changed. Recently there has been as renewed interest in studying the medicinal uses of psilocybin for treatment of anxiety, depression, migraine headaches, addictions, and other neuropsychiatric conditions.

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.

McN-5652 is one of a series of substituted pyrrolo-isoquinolines that, as a group, potently inhibit the uptake of one or more of the monoamines, norepinephrine, serotonin and dopamine. Receptor binding experiments indicated that McN-5652 has a weak affinity for serotonin 5-HT2 and alpha-1 adrenergic receptors. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.

Protopanaxadiol (PPD, Yuxintine) is an organic compound characterizing a group of ginsenosides. It is a dammarane-type tetracyclic terpene sapogenin found in ginseng (Panax ginseng) and in notoginseng (Panax pseudoginseng). Protopanaxadiol has a wide range of pharmacologic activities, including antiestrogen, anti-inflammatory, antitumor, vasodilating, cardioprotection, and antidepressant effects. The antidepressant effect of oral Protopanaxadiol had been confirmed by several different animal models, such as forced swimming test tail suspension test, and rat olfactory bulbectomy depression models. Protopanaxadiol was found to have much fewer adverse drug reactions than currently-used first-line antidepressants. It is almostdevoid of sedation, sexual dysfunction, weight gain, cardiovascular complications, and anticholinergic effects. Protopanaxadiol was in phase II clinical trials as a novel antidepressant in China.