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European Archives of Psychiatry and... Oct 2023Cognitive impairment has been observed in patients with various psychiatric disorders, including schizophrenia, major depressive disorder (MDD), and bipolar disorder... (Review)
Review
Cognitive impairment has been observed in patients with various psychiatric disorders, including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BD). Although modern therapeutic drugs can improve certain symptoms (i.e., psychosis, depression) in these patients, these drugs have not been found to improve cognitive impairment. The N-methyl-D-aspartate receptor antagonist (R,S)-ketamine has attracted attention as a rapidly acting antidepressant. In addition to its robust antidepressant effects, (R,S)-ketamine has been suggested to improve cognitive impairment in patients with MDD and BD, despite causing cognitive impairment in healthy control subjects. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Arketamine has been found to have more potent antidepressant-like actions than esketamine in rodents. Interestingly, arketamine, but not esketamine, has been suggested to improve phencyclidine-induced cognitive deficits in mice. Furthermore, arketamine has been suggested to ameliorate cognitive deficits in rodent offspring after maternal immune activation. In the current article, it is proposed that arketamine has therapeutic potential for treating cognitive impairment in patients with psychiatric disorders. Additionally, the potential role of the gut-microbiome-brain axis in cognitive impairment in psychiatric disorders is discussed.
Topics: Animals; Mice; Ketamine; Depressive Disorder, Major; Cognitive Dysfunction; Antidepressive Agents
PubMed: 36786865
DOI: 10.1007/s00406-023-01570-5 -
Physiology & Behavior May 2023Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with...
Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.
Topics: Rats; Female; Animals; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Cognition Disorders; Cognition; Disease Models, Animal
PubMed: 36781093
DOI: 10.1016/j.physbeh.2023.114117 -
ACS Pharmacology & Translational Science Jan 2023We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321...
Identification and Characterization of ML321: A Novel and Highly Selective D Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity.
We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptional selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit ″atypical″ antipsychotic activity in humans with significantly fewer side effects than observed with the currently FDA-approved D2R antagonists.
PubMed: 36654757
DOI: 10.1021/acsptsci.2c00202 -
The American Journal of Emergency... Mar 2023
Topics: Humans; Phencyclidine; Lamotrigine; Anticonvulsants; Substance Abuse Detection; False Positive Reactions; Phencyclidine Abuse
PubMed: 36604235
DOI: 10.1016/j.ajem.2022.12.016 -
International Journal of Molecular... Dec 2022Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having... (Review)
Review
Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains ( and ), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms.
Topics: Humans; Schizophrenia; Gastrointestinal Microbiome; Antipsychotic Agents; Olanzapine; Clozapine; Probiotics; Prebiotics
PubMed: 36555774
DOI: 10.3390/ijms232416129 -
International Journal of Molecular... Dec 2022Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine,... (Review)
Review
Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. First used mainly for their pharmacological properties in anesthesia, their recreational use is increasing. ACH derivatives have an antagonistic activity against the N-methyl-D-aspartate receptor, which leads to dissociative effects (dissociation of body and mind). Synthetic ketamine derivatives produced in Asia are now arriving in Europe, where most are not listed as narcotics and are, thus, legal. These structural derivatives have pharmacokinetic and pharmacodynamic properties that are sometimes very different from ketamine. Here, we describe the pharmacology, epidemiology, chemistry and metabolism of ACH derivatives, and we review the case reports on intoxication.
Topics: Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Asia; Europe
PubMed: 36555217
DOI: 10.3390/ijms232415574 -
Cureus Nov 2022Most patients with advanced cancer experience debilitating pain, which significantly affects their quality of life and has both physical and psychological implications....
Most patients with advanced cancer experience debilitating pain, which significantly affects their quality of life and has both physical and psychological implications. Opioids have been the mainstay of treatment for chronic cancer pain, but some people develop serious adverse effects or may become refractory to opioid use. There is always a need and search for alternative non-opioid analgesics with an acceptable safety profile, and one such drug is ketamine. In this era of evolving analgesic therapeutics, ketamine has been noted to have favourable results. Ketamine, a phencyclidine analogue, is an N-methyl-D-aspartate antagonist (NMDA), and it has been shown to have an analgesic effect at sub-anaesthetic doses by blocking NMDA-induced pain sensitization and enhancing opioid receptor sensitization. This is a case report of a 46-year-old Indian female with recurrent metastatic adenocarcinoma endometrium (International Federation of Obstetrics and Gynecology (FIGO) Grade II) involving the vaginal vault, rectum, and adrenal glands, along with para-rectal, bilateral iliac, and retroperitoneal nodal metastases, in which ketamine infusion was used successfully to alleviate the pain that was initially not controlled with an incremental dose of opioids. The patient presented with progressive pain in the peri-anal region, rated 8/10 on the Numerical Pain Rating Scale (NRS), following which she was treated with escalating doses of intravenous (IV) fentanyl, but with little to no relief. In view of the patient's opioid-resistant pain, she was started on a low-dose ketamine IV infusion (50 mg in 50 ml of 0.9% NS) as "burst therapy," at infusion rates of 0.02 mg/kg/hr-0.08 mg/kg/hr, with adequate pain relief occurring at 0.08 mg/kg/hr. Literature suggests weight-based dosing of ketamine ranging from 0.06 mg/kg/hr to 0.8 mg/kg/hr was previously used to achieve satisfactory results. In this patient, even lower doses were effectively used to achieve optimum long-term analgesia, cause an upliftment in the patient's overall mood and quality of life, and cause a significant reduction in opioid usage. However, further research is required to assess the efficacy of ketamine at such doses and its effect on opioid consumption. This case report will promote further study regarding optimum IV ketamine dosing and administration in the management of opioid-refractory pain in cancer patients, especially in the Indian population.
PubMed: 36545179
DOI: 10.7759/cureus.31662 -
Neuropsychopharmacology : Official... Aug 2023The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including...
The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including schizophrenia, are associated with impairments in flexible decision making that can be evaluated using the probabilistic reversal learning (PRL) task. The PRL task has been reverse-translated for use in rodents. Disrupting glutamate neurotransmission during early postnatal neurodevelopment in rodents has induced behavioral, cognitive, and neuropathophysiological abnormalities relevant to schizophrenia. Here, we tested the hypothesis that using the NMDA receptor antagonist phencyclidine (PCP) to disrupt postnatal glutamatergic transmission in rats would lead to impaired decision making in the PRL. Consistent with this hypothesis, compared to controls the postnatal PCP-treated rats completed fewer reversals and exhibited disruptions in reward and punishment sensitivity (i.e., win-stay and lose-shift responding, respectively). Moreover, computational analysis of behavior revealed that postnatal PCP-treatment resulted in a pronounced impairment in the learning rate throughout PRL testing. Finally, a deep neural network (DNN) trained on the rodent behavior could accurately predict the treatment group of subjects. These data demonstrate that disrupting early postnatal glutamatergic neurotransmission impairs flexible decision making and provides evidence that DNNs can be trained on behavioral datasets to accurately predict the treatment group of new subjects, highlighting the potential for DNNs to aid in the diagnosis of schizophrenia.
Topics: Animals; Rats; Phencyclidine; Schizophrenia; Reversal Learning; Synaptic Transmission; Reward
PubMed: 36509858
DOI: 10.1038/s41386-022-01514-y