Background:
Despite an increasing body of research highlighting their efficacy to treat a broad range of medical conditions, psychedelic drugs remain a controversial issue among the public and ...politicians, tainted by previous stigmatisation and perceptions of risk and danger.
Objective:
This narrative review examines the evidence for potential harms of the classic psychedelics by separating anecdotes and misinformation from systematic research.
Methods:
Taking a high-level perspective, we address both psychological and psychiatric risks, such as abuse liability and potential for dependence, as well as medical harms, including toxicity and overdose. We explore the evidence base for these adverse effects to elucidate which of these harms are based largely on anecdotes versus those that stand up to current scientific scrutiny.
Results:
Our review shows that medical risks are often minimal, and that many – albeit not all – of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context.
Conclusions:
This highlights the importance for clinicians and therapists to keep to the highest safety and ethical standards. It is imperative not to be overzealous and to ensure balanced media reporting to avoid future controversies, so that much needed research can continue.
Abstract Neurocognitive impairment predicts disability in schizophrenia, making intervention theoretically attractive as a means to minimise chronic disability. Many trials confirm that cognitive ...remediation (CR) produces meaningful, durable improvements in cognition and functioning but fewer focus on the early stages. We systematically reviewed CR trials in early schizophrenia to determine its efficacy on global cognition, functioning and symptoms. Two reviewers independently searched electronic databases to identify randomised controlled trials investigating CR following a first episode of psychosis. Eleven trials with 615 participants were identified. Random effect models revealed a non-significant effect of CR on global cognition (effect size = 0.13, 95% CI − 0.04, 0.31; p0.14), p < 0.05 in sensitivity analysis (effect size 0.19; CI 0.00, 0.38). One of seven neurocognitive domains showed a significant positive effect (verbal learning and memory) and five others showed borderline significant benefits. There was a significant effect on functioning (0.18; CI 0.01, 0.36; p < 0.05) and symptoms (0.19; CI 0.02, 0.36; p < 0.05). CR's effect on functioning and symptoms was larger in trials with adjunctive psychiatric rehabilitation and small group interventions. CR's effect sizes in early illness were smaller than those in chronic schizophrenia, perhaps because of participants' reduced scope for improvement, though trials' small number and size produces uncertain estimates of effect. However, significant benefits were seen in functioning and symptoms and moderator analyses indicate factors that may increase CR's effect. Findings here, theoretical considerations and trials in chronic schizophrenia suggest that targeting social cognition might also enhance its efficacy.
Abstract Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. ...Cariprazine is a dopamine D3 /D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2 mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25 mg/kg, PO) or risperidone (0.16 or 0.1 mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1 mg/kg and 0.25 mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.
•Object recognition memory decays to 0 after a 6h ITI in female hL rats.•Activation of nicotinic α7 and α4b2 receptors restores this memory.•Donepezil restores this memory while risperidone is ...ineffective.
Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer’s disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need.
In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female Hooded Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.
N-methyl-
d
-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist,
d
-serine, in clinical ...trials has shown positive effects in patients. Therefore, inhibition of
d
-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases
d
-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.
Rationale
Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute ...treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder.
Objectives
Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia.
Methods
Female-hooded Lister rats received vehicle or PCP (2 mg/kg, i.p.) for 7 days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001–0.1 mg/kg, s.c.) alone or in combination with the D
1
receptor antagonist SCH-23390 (0.05 mg/kg, i.p.) or 5-HT
1A
receptor antagonist WAY100635 (1 mg/kg, i.p.). Time spent exploring two identical objects during a 3-min acquisition trial (followed by a 1-min intertrial interval) and then a familiar and a novel object for another 3 min (retention trial) were recorded onto videotape and scored blind.
Results
In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (
p
< 0.001). Asenapine (0.01–0.075 mg/kg) reversed PCP-induced deficits in NOR (
p
< 0.01–0.001) in a dose-related manner. This effect was antagonised by SCH-23390 but not by WAY100635.
Conclusions
These results demonstrate a role for D
1
but not 5-HT
1A
receptor mechanisms in mediating the cognitive effects of asenapine in this rodent model.
Rationale
Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the ...cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the γ-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA
A
receptor sub-units, such as α1, α4 and δ is reduced in the dorsolateral prefrontal cortex of schizophrenia patients.
Objectives
The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA
A
receptors in alleviating the PCP-induced deficit.
Results
Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA
A
receptors.
Conclusion
The present study shows that extrasynaptic GABA
A
receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.
Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric ...disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic alpha 7 and alpha 4 beta 2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female Hooded Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.
It is well documented that schizophrenia patients exhibit dysfunction in various cognitive domains, including attention/vigilance, as demonstrated by impaired performance in the myriad of Continuous ...Performance Tests (CPTs). NMDA receptor antagonists provide a pharmacological model in animals of the cognitive disruption presented in the disorder. We therefore examined the effects of a sub-chronic PCP treatment regimen (5.0mg/kg 7-days bi-daily) in the recently developed rodent test of vigilance, the 5-Choice Continuous Performance Test (5C-CPT). We assessed the effects of this regimen after at least a 7-day washout period on both baseline performance and when the attentional load was increased. Sub-chronic PCP treatment impaired 5C-CPT performance in a manner consistent with impaired vigilance in patients with schizophrenia, with reduced hit rate and impaired signal sensitivity. These effects were only evident when performance was challenged following parameter manipulations. These data demonstrate that attention/vigilance is sensitive to disruption following sub-chronic PCP treatment in a pre-clinical task that may demonstrate increased analogy to human vigilance tasks. Although the PCP-induced attentional deficits are not as large as those deficits observed in other domains, these data provide evidence that this pharmacological model can affect multiple cognitive domains and may be useful for assessing putative pro-cognitive therapeutics for schizophrenia.
This article is part of a Special Issue entitled ‘Schizophrenia’.
► Sub-chronic PCP treatment had no impact on the ability to conduct the 5C-CPT under baseline conditions following a 7-day washout period. ► Following an increase in the attentional load, animals sub-chronically treated with PCP exhibited an attentional impairment in the drug-free state. ► Sub-chronic PCP treatment induced a baseline-dependent attentional impairment in rats.
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