Effects of quetiapine on anhedonia induced by withdrawal from chronic amphetamine administration

Contexte: L’anhédonie, un état caractérisé par une capacité réduite d’éprouver du plaisir. Des études cliniques récentes montrent qu’un médicament antipsychotique atypique, la quétiapine, est bénéfique pour le traitement de la toxicomanie qui est supposé d’atténuer les symptômes de sevrage associés à l’usage abusif des drogues psychotropes. Le but de la présente étude était d’étudier les effets de l'administration aiguë de quétiapine sur la récompense chez des animaux en état de sevrage après un traitement chronique avec l’amphétamine. Notre hypothese est que la quetiapine va diminuer l’anhedonie causer par le sevrage. Méthodes: Les expériences ont été effectuées avec des rats mâles de la souche Sprague-Dawley entraînés à produire une réponse opérante pour obtenir une courte stimulation électrique au niveau de l'hypothalamus latéral. Des mesures du seuil de récompense ont été déterminées chez différents groupes de rats avant et pendant quatre jours après le traitement avec des doses croissantes (1 à 10 mg/kg, ip toutes les 8 heures) de d-amphétamine sulfate, ou de son véhicule, au moyen de la méthode du déplacement de la courbe. L’effet de deux doses de quétiapine a été testé 24 h après le sevrage chez des animaux traités avec l’amphétamine ou le véhicule. Résultats: Les animaux traités avec l’amphétamine ont montré une augmentation de 25% du seuil de récompense 24 h après la dernière injection, un effet qui a diminué progressivement entre le jour 1 et le jour 4, mais qui est resté significativement plus élevé en comparaison de celui du groupe contrôle. La quétiapine administrée à 2 et 10 mg/kg pendant la phase de sevrage (à 24 h) a produit une augmentation respective de 10 % et 25 % du seuil de recompense; le meme augmentation du seuil a été observe chez les animaux traitées avec le véhicule. Un augmentation de 25 % du seuil de recompense a aussi été observés chez les animaux en état de sevrage à l'amphétamine. Un test avec une faible dose d’amphétamine (1 mg/kg) avant et après le sevrage a révélé une légère tolérance à l’effet amplificateur de cette drogue sur la récompense, un phénomène qui pourrait expliquer l’effet différent de la quétiapine chez les animaux traités avec le véhicule et ceux traités avec l’amphétamine. Conclusions: Ces résultats reproduisent ceux des études précédentes montrant que la quétiapine produit une légère atténuation de la récompense. Ils montrent également que le sevrage à l’amphétamine engendre un léger état d'anhédonie et que dans cet état, une dose élevée de quetiapine et non pas une dose faible accentue l’état émotionnel négatif. Ils suggèrent qu’un traitement à faibles doses de quétiapine des symptômes de sevrage chez le toxicomane devrait ni aggraver ni améliorer son état émotionnel.Background: Anhedonia, a condition in which the capacity of experiencing pleasure is reduced, is observed in patients that are under withdrawal from drugs of abuse. Recent clinical studies show that quetiapine may be beneficial in the treatment of substance abuse by alleviating the withdrawal-negative affect stage of addiction. This study investigated the effects of acute quetiapine on reward in animals under withdrawal from d-amphetamine. Methods: Experiments were performed on male Sprague-Dawley rats trained for intracranial self-stimulation. Measures of reward threshold were determined with the curve-shift method in different groups of rats before, and during four days after treatment with escalating doses (1 to 10 mg/kg, i.p) of d-amphetamine sulphate or its vehicle. At 24h after withdrawal, the effects of two doses of quetiapine (2 and 10 mg/kg ip) were tested in all the animals. Results: Animals treated with d-amphetamine showed 25% reward attenuation at 24h of withdrawal, an effect that decreased over the next three days. Quetiapine administered acutely at 2mg/kg and 10mg/kg on the first day of withdrawal produced 10% and 25% reward attenuation, respectively, in the vehicle-control animals, an effect also observed in the animals under withdrawal from d-amphetamine but only at the high dose. Conclusions: These results show that quetiapine produced a mild attenuation of reward in normohedonic and in anhedonic animals. They suggest that quetiapine should be used at low doses for the treatment of substance abusers under withdrawal from psychostimulant drugs to avoid enhancement of the anhedonic state

Psychiatric and neurological symptoms in schizophrenia and substance use disorder patients treated for 12-weeks with quetiapine

Contexte Autant dans une population schizophrène que non schizophrène, l‘abus de substance a pour conséquence la manifestation de symptômes psychiatriques et neurologiques. Dans les présentes études cas-témoins, nous avons examiné les différences initiales ainsi que les changements suite au traitement de 12 semaines à la quetiapine au niveau de la sévérité de la toxicomanie et des symptômes psychiatriques et neurologiques chez 3 groupes distincts. Ces 3 groupes sont: des patients schizophrènes avec une toxicomanie (double diagnostic: DD), des patients schizophrènes sans toxicomanie concomittante (SCZ) et finalement, des toxicomanes non schizophrènes (SUD). Parallèlement, afin de nous aider à interpréter nos résultats, nous avons mené deux revues systématiques: la première regardait l‘effet d‘antipsychotiques dans le traitement de troubles d‘abus/dépendance chez des personnes atteintes ou non de psychoses, la deuxième comparait l‘efficacité de la quetiapine et sa relation dose-réponse parmi différents désordres psychiatriques. Méthodes Pour nos études cas-témoins, l‘ensemble des symptômes psychiatriques et neurologiques ont été évalués via l‘Échelle du syndrome positif et négatif (PANSS), l‘Échelle de dépression de Calgary, l‘Échelle des symptômes extrapyramidaux (ESRS) ainsi qu‘avec l‘Échelle d‘akathisie de Barnes. Résultats À la suite du traitement de 12 semaines avec la quetiapine, les groupes SCZ et DD recevaient des doses de quetiapine significativement plus élevées (moyenne = 554 et 478 mg par jour, respectivement) par rapport au groupe SUD (moyenne = 150 mg par jour). Aussi, nous avons observé chez ces mêmes patients SUD une plus importante baisse du montant d‘argent dépensé par semaine en alcool et autres drogues, ainsi qu‘une nette amélioration de la sévérité de la toxicomanie comparativement aux patients DD. Par conséquent, à la fin de l‘essai de 12 semaines, il n‘y avait pas de différence significative dans l‘argent dépensé en alcool et drogues entre les deux groupes de toxicomanes iv or, les patients DD présentait, comme au point de départ, un score de toxicomanie plus sévère que les SUD. Étonnamment, aux points initial et final de l‘étude, le groupe DD souffrait de plus de symptômes parkinsoniens et de dépression que le groupe SCZ. Par ailleurs, nous avons trouvé qu‘initiallement, les patients SUD présentaient significativement plus d‘akathisie, mais qu‘en cours de traitement, cette akathisie reliée à l‘abus/dépendance de cannabis s‘est nettement améliorée en comparaison aux patients SCZ. Enfin, les patients SUD ont bénéficié d‘une plus grande diminution de leurs symptômes positifs que les 2 groupes atteints de schizophrénie. Conclusions Bref, l‘ensemble de nos résultats fait montre d‘une vulnérabilité accentuée par les effets négatifs de l‘alcool et autres drogues dans une population de patients schizophrènes. Également, ces résultats suggèrent que l‘abus de substance en combinaison avec les états de manque miment certains symptômes retrouvés en schizophrénie. De futures études seront nécessaires afin de déterminer le rôle spécifique qu‘a joué la quetiapine dans ces améliorations.Background Psychiatric and neurological symptoms are consequences of substance abuse in schizophrenia and non-schizophrenia patients. The present case-control studies examined differences in substance abuse/dependence, and psychiatric symptoms and neurological symptoms in substance abusers with [dual diagnosis (DD) group] and without schizophrenia [substance use disorder (SUD) group] and in non-abusing schizophrenia patients (SCZ group) –undergoing 12-week treatment with quetiapine. Furthermore, two systematic reviews were conducted in order help explain our results. The first examined the usefulness of antipsychotics for the treatment of substance abuse/dependence in psychosis and non-psychosis patients. The second examined the dose-response and comparative efficacy of quetiapine across psychiatric disorders. Methods Psychiatric symptoms and neurological symptoms were evaluated with the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Extrapyramidal Symptoms Rating Scale, and the Barnes Akathisia Rating Scale. Results DD and SCZ patients were receiving significantly higher doses of quetiapine (mean = 554 and 478 mg per day, respectively), relative to SUD patients (mean = 150 mg per day). We found that SUD patients showed greater improvement in weekly dollars spent on alcohol and drugs and SUD severity, compared to DD patients. At endpoint, there was no significant difference in dollars spent, but DD patients still had a higher mean SUD severity. Interestingly, DD patients had significantly higher parkinsonism and depression than SCZ patients at baseline and endpoint. On the other hand, we found that SUD patients had significantly more akathisia at baseline, improved more than SCZ patients, and this was related to cannabis abuse/dependence. Finally, SUD patients improved more in Positive and Negative Syndrome Scale positive scores than DD and SCZ patients. Conclusions Taken together, our results provide evidence for increased vulnerability to the adverse effects of alcohol and drugs in schizophrenia patients. They also suggest that substance abuse/withdrawal may mimic some symptoms of schizophrenia. Future studies will need to determine the role quetiapine played in these improvements

The future of multiple sclerosis treatments

Introduction. There are not many conditions in which the last few decades have brought such a major change in the landscape of treatments as is the case of multiple sclerosis (MS). A number of disease modifying treatments (DMTs) are presently available for the treatment of the inflammatory phase of this disabling disease; however, the need for treating neurodegeneration and halting the progression of disability is still unmet. Areas covered: In this paper we review the available information on existing and emerging DMTs and we discuss their place within the context of different treatment strategies in MS. Expert Commentary: The future of MS treatments should include the development of new treatment strategies tackling disease progression, together with a better understanding of the side-effects and the best sequential strategy of implementation of available and emerging drugs

Resting State Functional Connectivity of the Lateral and Medial Hypothalamus in Cocaine Dependence: An Exploratory Study

The role of dopamine in cocaine misuse has been extensively documented for the mesocorticolimbic circuit. Preclinical work from earlier lesion studies to recent multidisciplinary investigations has suggested that the hypothalamus is critically involved in motivated behavior, with the lateral and medial hypothalamus each involved in waking/feeding and resting/satiety. However, little is known of hypothalamus function and dysfunction in cocaine misuse. Here, we examined resting state functional connectivity of the lateral and medial hypothalamus in 70 individuals with cocaine dependence (CD) and 70 age as well as gender matched healthy controls (HC). Image pre-processing and analyses followed published work. Compared to HC, CD showed increased lateral hypothalamic connectivity with dorsolateral prefrontal cortex and decreased functional connectivity with the ventral precuneus. CD showed increased medial hypothalamic connectivity with the inferior parietal lobule and decreased connectivity with the ventromedial prefrontal cortex, temporal gyrus, fusiform gyrus, and ventral striatum. Further, at trend level significance, the connectivity strength between lateral hypothalamus and dorsolateral prefrontal cortex was positively correlated with total amount of cocaine use in the past month (p = 0.004, r = 0.35) and the connectivity strength between medial hypothalamus and ventral striatum was negatively correlated with cocaine craving as assessed by the Tiffany Cocaine Craving Questionnaire (p = 0.008, r = −0.33). Together, the findings demonstrated altered resting state functional connectivity of the hypothalamus and may provide new insight on circuit level deficits in cocaine dependence

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review

BackgroundKetamine and psychedelics have abuse liability. They can also induce “transformative experiences” where individuals experience enhanced states of awareness. This enhanced awareness can lead to changes in preexisting behavioral patterns which could be beneficial in the treatment of substance use disorders (SUDs). Preclinical and clinical studies suggest that ketamine and psychedelics may alter markers associated with synaptic density, and that these changes may underlie effects such as sensitization, conditioned place preference, drug self-administration, and verbal memory performance. In this scoping review, we examined studies that measured synaptic markers in animals and humans after exposure to ketamine and/or psychedelics.MethodsA systematic search was conducted following PRISMA guidelines, through PubMed, EBSCO, Scopus, and Web of Science, based on a published protocol (Open Science Framework, DOI: 10.17605/OSF.IO/43FQ9). Both in vivo and in vitro studies were included. Studies on the following synaptic markers were included: dendritic structural changes, PSD-95, synapsin-1, synaptophysin-1, synaptotagmin-1, and SV2A.ResultsEighty-four studies were included in the final analyses. Seventy-one studies examined synaptic markers following ketamine treatment, nine examined psychedelics, and four examined both. Psychedelics included psilocybin/psilocin, lysergic acid diethylamide, N,N-dimethyltryptamine, 2,5-dimethoxy-4-iodoamphetamine, and ibogaine/noribogaine. Mixed findings regarding synaptic changes in the hippocampus and prefrontal cortex (PFC) have been reported when ketamine was administered in a single dose under basal conditions. Similar mixed findings were seen under basal conditions in studies that used repeated administration of ketamine. However, studies that examined animals during stressful conditions found that a single dose of ketamine counteracted stress-related reductions in synaptic markers in the hippocampus and PFC. Repeated administration of ketamine also counteracted stress effects in the hippocampus. Psychedelics generally increased synaptic markers, but results were more consistently positive for certain agents.ConclusionKetamine and psychedelics can increase synaptic markers under certain conditions. Heterogeneous findings may relate to methodological differences, agents administered (or different formulations of the same agent), sex, and type of markers. Future studies could address seemingly mixed results by using meta-analytical approaches or study designs that more fully consider individual differences

Cannabidiol in Humans—The Quest for Therapeutic Targets

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington’s disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed