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Psychotropic Agent

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Psychotropic Agent

Psychotropic medications are used to treat mental health disorders. There are five main types of psychotropic medications, and each type has its own specific uses, benefits, and side effects. Your doctor can help you decide which psychotropic medication is right for you.

Many psychotropic medications work by adjusting the number of major chemicals in the brain. These chemicals are called neurotransmitters. Increasing or decreasing certain neurotransmitters can counter the effects of certain mental health disorders.

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.

A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition, or behavior.[1]

Psychoactive drugs are often prescribed to manage pain. The subjective experience of pain is primarily regulated by endogenous opioid peptides. Thus, pain can often be managed using psychoactives that operate on this neurotransmitter system, also known as opioid receptor agonists. This class of drugs can be highly addictive, and includes opiate narcotics, like morphine and codeine.[19] NSAIDs, such as aspirin and ibuprofen, are also analgesics. These agents also reduce eicosanoid-mediated inflammation by inhibiting the enzyme cyclooxygenase.

Myristica remained official in the United States Pharmacopeia through U. S. P. XIII (1947). Myristica oil was kept on for several more editions, principally as a flavouring agent, but was finally dropped from U. S. P. XVII (1965).

"The minor aromatic ethers, eugenol and safrol, have been suggested as possible active components. This seems unlikely, as the amounts ingested from a 5 g nutmeg (0.001 g and 0.003 g respectively) are much below the usual therapeutic levels of these substances (3.0 ml and 0.5 ml respectively). The only component, aside from the myristicin fraction, of the volatile oil from nutmeg that deserves serious consideration as an active agent is the pinenedipentene fraction. Many descriptions of the toxic syndromes of representative terpene medicines parallel the common toxic manifestations of nutmeg (i.e., nausea, cyanosis, stupor, cold extremities, often delirium). [However] actual toxic dosages of oils that are of make-up similar to the hydrocarbon fraction of nutmeg (such as oil of turpentine) are as a rule 20 to 60 times higher than that which would be encountered in nutmeg intoxication."

At the same time, there is an impressive amount of anecdotal evidence suggesting that many people througout the world consume nutmeg as a psychoactive agent. One hears persistent rumours, for instance, that Myristica serves as a narcotic in the Orient, that it is commonly taken by prison inmates, and that it has become a popular hallucinogenic drug among bohemians and students in the United States.

Shulgin, who has tried to work out the biochemistry of nutmeg's hallucinogenic action, has assumed [22] for the moment that the myristicin fraction of the oil (with its more than 25 per cent content of elemicin) is, indeed, the active principle. He has noted that the metabolism of the aromatic ethers found in essential oil is "virtually unknown" except for a detoxication mechanism by which safrol is converted to piperonylic acid. This reaction indicates a capacity to oxidize an olefinic side chain. Shulgin has suggested that, if this degradative process is "applicable to myristicin, or especially to elemicin, a theoretical intermediate, a vinyl alcohol, could undergo transamination producing the known psychotomimetic drug, 3,4,5-trimethoxy amphetamine (TMA) ". The recent description of the new synthetic hallucinogen - 3-methoxy-4, 5-methylenedioxy amphetamine (MMDA) - which might be derived by an analogous process from myristicin, itself, is even more suggestive of a psychotropic function for this component of nutmeg (fig. 3 b) [5] .

Thus far, human pharmacological data are inadequate to support the contention that myristicin is psychoactive or that it is an active principle of whole nutmeg. Shulgin has written [22] : "... some combination of factors in total nutmeg is capable of producing a psychotropic response: the structure of elemicin or myristicin wanting only an ammonia molecule to become a recognized mental agent must be accepted as at least an intriguing coincidence."

The seeds and arils of M. fragrans have powerful narcotic properties. In man, they have frequently caused serious but almost never fatal intoxications. Most Westerners are ignorant of these toxic properties and know nutmeg and mace only as flavouring agents.

Both spices are used as narcotics, probably by significant numbers of people, although information on this use of Myristica is scarce. When taken deliberately as psychotropics, nutmeg and mace often cause reactions quite unlike those described in classical accounts of Myristica poisoning and much more like experiences with Cannabis or other hallucinogenic drugs. Law enforcement officers and governmental authorities are not aware of the importance of nutmeg as a narcotic.

Since exploding rates of mental diseases, as well as subsequent increasing application of psychotropic agents, more and more evidences emerge on their liver-toxic effects. Previous studies have shown that more than 160 psychotropic drugs, including antidepressants and antipsychotics, can cause liver-side effects [5]. As the most common psychotropic drugs, almost all antidepressants are generally considered to cause unpredictable, dose-independent liver injury, even at therapeutic doses, and this hepatotoxicity usually develops between several days and six months during drug intake [6]. Antipsychotics, another common psychotropic drugs, also have been shown to be closely associated with the risk of DILI. The common first-generation antipsychotics, like chlorpromazine, and second-generation antipsychotics, such as risperidone and olanzapine, evidence of hepatotoxicity have been provided in both cases and animal studies [7,8,9,10,11]. Simultaneously, it is worth noting that multiple psychotropic drugs are strongly related to adverse metabolic effects such as diabetes and obesity, which further highlighting the need to recognize the hepatotoxic potential of psychotropic drugs [12, 13]. However, the psychotropic drug-induced DILI is a challenging not only in terms of diagnosis, but also in terms of management.

NLRP3 inflammasome, one of the most representative immune multiprotein platforms, is composed of a sensor NLRP3, adapter ASC, and inflammatory protease caspase-1. This platform is activated in response to diverse molecular patterns [14]. Studies have shown that the NLRP3 inflammasome activation requires two sequential signals: a priming signal and an activation signal. After sensing danger signals, the activated caspase-1 triggers maturation and secretion of proinflammatory cytokine IL-1β and, under certain conditions, to induction of gasdermin D (GSDMD)-mediated pyroptosis [15,16,17]. As an essential component of host defense, however, the dysregulated NLRP3 inflammasome activity causes uncontrolled inflammation, which underlies multiple diseases, such as gout [18], type 2 diabetes [19], atherosclerosis [20], and idiosyncratic drug-induced liver injury (IDILI) [21]. Growing evidences suggest that excessive activation of the NLRP3 inflammasome is a key risk factor for hepatotoxicity [22], and have been reported that application of the NLRP3 inflammasome blockade can reduce hepatic inflammation and fibrosis in mice [23]. Additionally, studies also have shown the role of NLRP3 inflammasome in hepatic injury driven by antiepileptic agents such as carbamazepine [24] and antituberculosis drugs such as isoniazid [25]. 59ce067264


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