Small conductance Ca2+-activated K+ (SK) channels are expressed throughout brain regions important for long-term memory. They constrain the intrinsic excitability of neurons by enhancing afterhyperpolarization, shape glutamatergic synaptic potentials and limit induction of NMDA receptor-dependent synaptic plasticity. Behaviorally, SK channels modulate learning and memory encoding. It is hypothesized that SK channels influence cognitive symptoms of psychosis including executive functioning, working memory, and selective attention. Theories of psychosis currently posit that symptoms of psychosis are a result of dopaminergic hyperfunction, and glutamatergic dysregulation which can be induced following administration of the NMDA receptor antagonist, ketamine. Initial experiments confirmed that sub-chronic treatment with KET produced significant impairment of object recognition memory, trace fear memory, and latent inhibition compared to SAL mice. A comparison of ketamine dosing regimens revealed the necessity for sub-chronic/chronic dosing on a consistent schedule with a wash out period, to obtain long-lasting attention and memory impairment. These experiments revealed for the first time that sub-chronic KET treatment elicited a new phenotype in male C57BL/6J mice: audible vocalizations. KET mice emitted audible vocalizations within 10 min of receiving KET injections, and vocalizations were detected up to 30 min after injection. Experiments conducted to determine the efficacy of SK channel agonists and antagonists on SK channels to modulate attention and memory in the ketamineinduced model of psychosis in C57BL/6J mice demonstrated for the first time that the SK2 channel activator, CyPPA, significantly reduced memory impairment and decreased the attention deficit of KET mice. A new method of analysis for trace fear conditioning freezing responses permitted a more accurate measurement of the ability of mice to discriminate the predicted delivery of shock during trace versus CS intervals. The application of the novel analytical method further demonstrated that KET mice failed to accurately discriminate these intervals, due to their impaired attention and acquisition of the trace conditioned response. This study examined the efficacy of SK channel drugs to rescue cognitive impairments in a pharmacological mouse model of schizophrenia. The results indicate that SK2 subunit activators and blockers, may provide a new therapeutic treatment for memory impairment and attention deficits seen in schizophrenic disorders. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Several trials have reported rapid antidepressant response from the anesthetic drug ketamine although the mechanism behind this effect is not fully understood. Research has focused mainly on ketamine’s action in the brain, including its effects on chemical balance, connections between brain cells and networks, and cognition. Trials with psychedelic drugs have had similar antidepressant results as ketamine, and the quality of the subjective psychedelic experience seems to mediate antidepressant action. Ketamine causes similar alterations of consciousness, which have been viewed as side effects. This thesis examines whether ketamine works in a similar way as psychedelics, where the ketamine-induced dissociative-like experience has a relationship to antidepressant response. Leading theories of depression and ketamine’s action in the brain are presented, and eight studies examining the relationship between ketamine-induced subjective experience and antidepressant response are reviewed. Three included studies found a relationship between psychedelic- and dissociative-like symptoms and reduction in depression, while five did not. The supposed relationship between psychedelic- and dissociative-like symptoms and antidepressant action has not been adequately explored and needs further examination in clinical trials.

An increasing amount of research suggests Ketamine in subanaesthetic doses to be an effective antidepressant for Major Depressive Disorder (MDD) and Treatment-Resistant Disorder (TRD). After the finding that NMDA-receptor antagonists may hold antidepressant effect, several studies have suggested Ketamine to have great effect in relief of depressive symptoms. A time lag between biological and behavioural effects have been shown in currently available antidepressants and are not guaranteed to be efficient; only 30% of patients reach adequate response. The aim for this thesis is to systematically review available studies on the efficiency of Ketamine's antidepressant effects in patients with TRD. Scopus, Web of Science, and PubMed were the databases searched for relevant research regarding the subject. Six articles were included in the analysis. A compilation of the results presented a moderate to large effect size for Ketamine compared to placebo at 24 hours through day seven. It is of immense weight that prolonged adverse effects and possible abuse are taken into consideration for future research, as well as how to sustain the dramatic acute antidepressant effect of Ketamine.

Depression är en psykisk sjukdom som kan drabba ungdomar, vuxna och äldre individer. Sjukdomen kännetecknas av en eller flera episoder med en minskad förmåga och negativa tankar. Andra symtom som är också vanligt förekommande kan vara bland annat känsla av värdelöshet, sömnstörningar och självmordstankar. Depression förekommer i tre olika svårighetsgrader; lätt-, medelsvår - och svår depression. Tillståndet kan behandlas med en psykologisk -, farmakologisk - eller ECT-behandling beroende på svårighetsgrad och symtombild. En tredjedel av patienterna uppfyller dock fortfarande kriterierna för en depression och uppvisade symtom trots att de försökte med de olika behandlingsmetoderna. Dessa patienter kännetecknas av terapiresistent-depression (TRD), och de har även en högre suicidrisk. Läkemedlet ketamin tillhör gruppen anestesiläkemedel, men senare har det upptäcktes att den kan verka antidepressivt i låga doser. Det förekommer som två enantiomerer, (S)-ketamin och (R)-ketamin. S-enantiomeren är den isomer med högst potens och R-enantiomeren är den med lägre potens. (S)-ketamin (esketamin) leder till mindre hallucinationer jämfört med (R)-ketamin. Ketamin är en N-metyl-D-aspartat (NMDA) – receptorantagonist, den verkar genom att blockera NMDA-receptorer i hjärnan. Tidigare studier har visat att ketamin kan ge en snabb antidepressiv effekt vid behandling av personer med TRD. Syftet med detta examensarbete var att genom litteraturstudier undersöka effekter av ketamin i behandling av deprimerade personer. Det eftersöktes efter randomiserade kontrollerade studier (RCT) i databasen Pubmed, där fem RCT valdes att analyseras vidare i syfte med att svara på frågeställningen. Två studier var dose-response studier, en studie undersökte och jämförde effekten av intravenöst administrerad ketamin med ett annat läkemedel, midazolam, en studie jämförde intravenös esketamin med placebo och en studie undersökte effekten av intranasal esketamin med placebo. Sammanfattningsvis, resultatet visade statistiskt signifikanta förbättringar avseende depressionens svårighetsgrad hos patienterna med TRD efter 24 timmar i jämförelse med placebo. Resultatet inkluderade även behandlingsrespons (definierat som > 50 % minskning från start i symtompoäng). Behandling med ketamin och esketamin gav statistisk signifikanta skillnader i behandlingsrespons i samtliga studier. Andelen patienter som visade respons på behandling med ketamin av någon form var mellan 38 % – 67 % jämfört med 0 – 18 % för placebo och 28 % för midazolam. Dessutom var en lägre dos av ketamin eller esketamin bättre när det gäller tolerans och orsakade mindre biverkningar jämfört med högre doser. Enligt resultat, så visade ketamin en bra behandlingseffekt mot TRD, men det krävs mer forskning med större antal deltagare och under längre perioder för att kunna säkrare bedöma dess antidepressiva effekter och besvara syftet med arbetet. (R)-ketamin har en viss antidepressiv effekt men kan leda till en högre incidens av hallucinationer jämfört med (S)-ketamin som verkar vara bättre alternativ då racemisk ketamin ju innehåller 50 % (R)-ketamin som även har narkotisk effekt. / Depression is a mental illness that can affect young people, adults and the elderly population. The disease is characterized by one or more episodes with negative thoughts and reduced cognitive function. Other symptoms that are also common can include feelings of worthlessness, sleep disorders and suicidal thoughts. Depression occurs in three different degrees of severity; mild-, moderate – and severe depression. The condition can be treated with psychological-, pharmacological – or ECT-treatment depending on the severity and type of symptoms. About one third of patients are still diagnosed as suffering from depression despite trying the different available treatment methods. These patients have treatment-resistant depression (TRD), and they have a higher risk of committing suicide. The drug ketamine belongs to the group of anesthetic drugs, but later it has been discovered that it can act as an antidepressant in low doses. It occurs as two enantiomers, (S)-ketamine and (R)-ketamine. The (S)-enantiomer is the isomer with the highest potency and the (R)-enantiomer is the one with the lower potency. (S)-ketamine (esketamine) leads to less hallucinations compared to (R)-ketamine. Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist. It acts by blocking NMDA receptors in the brain. Previous studies have shown that ketamine can provide a rapid antidepressant effect in the treatment of people with TRD. The purpose of this study was to investigate whether ketamine is effective enough in the treatment of people with TRD. Randomized controlled trials (RCTs) were searched for in the Pubmed database. Five RCTs was selected to be further analyzed in order to answer the question. Two studies were dose-response tests, one study examined the effect of intravenous ketamine in comparison with another drug, midazolam, one study examined the effect of intranasal esketamine with placebo and one study compared intravenous esketamine with placebo. In summary, the results showed statistically significant improvement and the severity of the depression in patient with TRD was reduced after 24 hours compared with placebo. The treatment response was defined as > 50 % reduction in symptom score using the MADRS. The effect of the treatment with ketamine and esketamine was compared with placebo, and the results were statistically significant in the five selected studies. The proportion of patients that showed response to treatment varied between 38 % - 67 %. This was compared to the response in the placebo group that varied between 0 % - 18 %, and with the response for midazolam that was 28 %. In addition, a lower dose of ketamine or esketamine was better in terms of tolerance and caused fewer side effects compared to higher doses. According to the results, ketamine was shown to have a good treatment effect against TRD, but more research is needed with a larger number of participants and for longer periods of time in order to be able to more reliably assess its antidepressant effects and to be able to answer the question regarding the effectiveness of treatment. (R)-ketamine has a certain antidepressant effects but can lead to higher incidence of hallucinations compared to (S)-ketamine, which seems to be a better alternative as racemic ketamine contains 50 % (R)-ketamine which also has a narcotic effect.

Enhancing stress resilience could prevent a variety of stress-induced disorders and thus reduce the global burden of psychiatric disease. It was previously reported that a single administration of the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine prior to stress could prevent stress-induced fear and behavioral despair in male mice, suggesting the possibility of developing prophylactic drugs to prevent psychiatric disorders. However, it was still unknown whether prophylactic agents could be effective in female mice, if other drugs could exert prophylactic actions, and how prophylactics could alter mechanisms in the brain to increase stress resilience. We hypothesized that targeting different receptors that could significantly alter neuroplasticity in the hippocampus (HPC) would be protective against stress. We first sought to determine whether stereospecific metabolites of (R,S)-ketamine, (2S,6R)-hydroxnorketamine ((2S,6S)-HNK) and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), could attenuate stress-induced behaviors in male and female mice. Next, we aimed to test the prophylactic efficacy of fluoroethylnormemantine (FENM), a novel-composition NMDAR antagonist derived from memantine. Subsequently, we examined the protective effects of 3 different serotonin type IV receptor (5-HT4R) agonists against stress. Finally, we sought to determine whether dual targeting of the NMDAR and 5-HT4R could exert additive effects in enhancing resilience to stress against a wide variety of stress-induced behaviors. Drug efficacy was assayed in male and female mice using a battery of stress models and behavioral tests including: contextual fear conditioning (CFC), cued fear conditioning, contextual fear discrimination (CFD), learned helplessness (LH), chronic immobilization stress (CIS), paired-pulse inhibition (PPI), the forced swim test (FST), sucrose splash test (SST), open field (OF), elevated plus maze (EPM), marble burying (MB), and novelty-suppressed feeding (NSF). Liquid chromatography-mass spectrometry (LC-MS), immunohistochemistry, Western blotting, patch clamp electrophysiology, ovariectomy (OVX), and hormone replacement techniques were used to examine how prophylactic drugs alter brain function and test whether ovarian hormones mediate the protective effects of prophylactic compounds in female mice. We show that (R,S)-ketamine, (2S,6S)-HNK, (2R,6R)-HNK, FENM, and 3 different 5-HT4R agonists are protective against specific stress-induced behaviors when administered in both male and female mice. We demonstrate that multimodally targeting NMDARs and 5-HT4Rs can broadly enhance resilience to protect against a variety of stressinduced maladaptive behaviors in both sexes. Finally, we determine a common mechanism by which various prophylactic compounds, despite targeting different receptors, attenuate bursts of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated activity to exert their protective effects. Together, these data: 1) uncover a variety of novel drug candidates for further preclinical and clinical development, 2) indicate a potential neural substrate underlying resilience to stress, and 3) reveal neurobiological mechanisms contributing to the psychopathology of psychiatric disease.

BACKGROUND: Major Depressive Disorder (MDD) is a common mental health illness, characterized by persistent feelings of sadness, diminished interests, guilt, low-self esteem, and disturbances in sleep and appetite. A significant percentage of patients with MDD are treatment resistant. Electroconvulsive Therapy (ECT) is a biological procedure utilized for treatment resistant illnesses. Diagnosis and clinical conditions primarily dictate when ECT is the appropriate treatment modality for an individual. Circumstances requiring rapid clinical response, risks affiliated with alternative treatments, resistance to pharmacotherapy, and medical history are all factors that designate ECT as the treatment of choice. METHODS: The objective of this systematic review was to examine how different anesthetics or combinations of agents affect ECT’s therapeutic efficacy in depressed, adult patients. Electroencephalography (EEG) and motor seizure durations and Hamilton Depression Rating Scale (HDRS) scores were used as primary measures of clinical outcomes. Two rounds of literature searches were conducted in the PubMed, Web of Science, and Google Scholar databases to identify randomized controlled trials and crossover trials that examined the effects of different intravenous sedatives and hypnotic agents on ECT. Two reviewers independently evaluated the internal validity and quality of studies, extracted data, and analyzed statistics. Utilizing all relevant data, standardized mean differences (SMD) with 95% confidence intervals (CIs), and heterogeneity measures were calculated. Ten studies with 373 participants were included. RESULTS: Thiopental only anesthesia was associated with longer EEG seizure duration when compared to propofol only treatment. The pooled effect size from studies with propofol anesthesia also suggests that this agent is associated with shorter seizure durations. If assessed individually with thiopental, the combination of ketamine and thiopental is correlated with increased motor as well as EEG seizure durations. When pooled; however, studies with patient groups assigned to anesthesia consisting of ketamine and another primary agent do not show significant differences either in EEG or motor seizure durations. Additionally, no difference exists in HDRS score reductions between propofol and methohexital. Of note; however, ketamine combined with either propofol or thiopental had significantly greater decreases in HDRS scores. CONCLUSION: Choice of anesthetic should be determined based on anticipated clinical outcome, adverse effect profile, reemergence, and patient preference. If long seizures are preferred, thiopental may be a reasonable option. However, if significantly larger decreases in depression score are preferred, then the combinations of ketamine and propofol or ketamine and thiopental appear to be the therapies of choice. Small sample sizes and insufficient clinical data limit the interpretations of these variables that determine therapeutic efficacy. Larger randomized control trials and crossover trials would provide greater insight into the optimal use of intravenous anesthetic agents with minimal adverse effects.

No description available.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA)-channel blocker that has recently shown promise in the treatment of major depressive disorder, distinguishing itself from classical anti-depressants through its rapid and lasting effects when given at sub-anaesthetic doses. Animal models of depression are commonly used to research individual mechanisms of action and this literature review aimed to investigate how ketamine influences BDNF-TrkB neurotransmission in the hippocampus and prefrontal cortex within animal models of depression. Reduced levels of BDNF and TrkB-transmission, as well as downstream signalling, are common in both humans experiencing depression and in rodent models of depression, and ketamine was found to counteract this reduction in the majority of studies reviewed. In the majority of studies ketamine’s anti-depressant actions were viewed to be at least partially connected to its effects on BDNF-TrkB neurotransmission. This was supported by the anti-depressant effects being readily blocked by pharmacological inhibition of TrkB. Inhibition also blocked the downstream neurobiological changes associated with ketamines anti-depressant effects. / Ketamin är en icke-kompetitiv N-methyl-D-aspartate (NMDA)-kanal antagonist som nyligen har visat lovande resultat i behandling av depression. Substansen särskiljer sig från klassiska antidepressiva läkemedel genom att dess effekt infinner sig snabbt och kvarstår under en längre period om det ges i låga doser. Djurmodeller av depression används för att undersöka individuella mekanismer relaterade till depression och denna litteraturstudie ämnade att undersöka hur ketamin påverkar BDNF-TrkB signallering inom hippocampus och prefrontala cortex i djurmodeller av depression. Minskade nivåer av BDNF och TrkB-signalering är vanligt förekommande både hos männsikor med depression och i djurmodeller av depression. I majoriteten av studierna återställde ketamin nivåerna av BDNF och TrkB-signalering till normala värden. Dess antidepressiva effekt kopplades till denna signalväg eftersom farmakologisk inhibering av TrkB i majoriteten av studierna resulterade i att den anti-depressiva effekten uteblev. Inhiberingen blockerade även nedströms neurobiologiska förändringar som anses kopplade till ketamins antidepressiva effekter.

<p>In this case study research project I have determined that multidrug sedation in children younger than eight years are possible.<br /> Conscious sedation [or sedation where verbal contact with the patient is possible] can be used successfully to decrease anxiety and fear for unpleasant experiences, like dental procedures.</p> <p><br /> Behaviour therapy in conjunction with one or more drugs can be used to depress the central nervous system in order to decrease the patient&rsquo / s awareness of unpleasant stimuli. This enables treatment to be carried out without patient interference. Extensive literature surveys were done to determine the ideal drugs as well as the ideal route for conscious sedation in dental treatment for children. In this study project drugs like midazolam, propofol, alfentanyl and ketamine were titrated intravenously to achieve conscious sedation.</p>

The dissociative anesthetic ketamine has been subject to growing abuse worldwide, particularly in adolescents. This project compared the effects of ketamine in conditioned place preference and intravenous self-administration in adolescent (PND 28-50) and adult (>PND70) Sprague-Dawley rats. Cocaine served as a positive control. In CPP, adolescents demonstrated preferences for ketamine, while adults developed an aversion. In the self-administration procedure, adults acquired the behavior more rapidly, but there was no difference in the percentage of subjects reaching acquisition nor in responding under a progressive ratio schedule for either drug. The CPP results suggest that adolescents have a greater sensitivity to the rewarding and tolerance to the aversive effects of ketamine. The divergent results for ketamine in the adults may reflect differences in the two procedures. However, because cocaine produced only hedonic effects in both age groups, it also suggests unique characteristics of ketamine and differences in its effects based on age.