Dual disorder: does expert clinical experience support the rationale for cariprazine use?

Comorbid substance use disorder (SUD) in patients with schizophrenia (dual disorder, DD) is a frequent occurrence in the psychiatric clinical practice and is positively associated with poorer outcomes. Despite a very high co-prevalence, clinical guidelines for SUD and severe mental illnesses tend to give limited consideration to co-existing disorders regarding diagnosis and management. This article is the result of a meeting held in February 2023 to discuss common challenges and best clinical practice initiatives for patients with schizophrenia and DD in different treatment settings. The authors identified issues in the clinical approach to DD in schizophrenia spectrum disorders and suggested the most suitable management based on their experience as a group of experts, identifying possible improvement areas. In conclusion, the panel recommends that individuals with DD should be cared for in a single center. Pharmacologic treatment in individuals with DD needing both control of symptoms related to schizophrenia spectrum disorders and substance withdrawal should ideally be based on using a non-sedative antipsychotic with anti-craving activity.

Psychosis after buprenorphine, heroin, methadone, morphine, oxycodone, and tramadol withdrawal: a systematic review.

OBJECTIVE: This study's main objective is to carry out a systematic review of the onset of psychotic symptoms after opioid withdrawal. The opiate dependence correlated to psychiatric symptoms has been well described. MATERIALS AND METHODS: Following the PRISMA methodology. The consecutive search strategy was applied: (morphine OR buprenorphine OR oxycodone OR tramadol OR fentanyl OR remifentanil OR opioids OR heroin OR methadone) AND (Psychosis OR psychotic symptoms OR schizophrenia). RESULTS: 12 case reports, 3 series of cases, 2 clinical studies, and 2 reviews were found. It seems that the time association is present in all of them; symptoms appear days after the interruption of the opioid. Most of the articles reported are case reports that describe symptoms that appear after the suspension of the opioid substance; in most cases, the reintroduction of the opioid had therapeutic effects and provoked a remission of these symptoms. These preliminary findings indicate that opiates could have an antipsychotic effect; however, the literature is scarce. It is critical to consider, if needed, in opioid-dependent patients who start with psychosis after the opioid withdrawal the possible replacement or reintroduction of opioids to prevent further deterioration in the patient's mental status. CONCLUSIONS: This study encompasses a comprehensive description of the literature concerning the possible not well-studied outcome of opioid withdrawal. There are some reports of temporal association between withdrawal and psychotic symptoms that improved after the reintroduction of the opioid; it could be taken into consideration in the clinical practice.

Exploring the prevalence of substance-induced neurocognitive disorder among polysubstance users, adding subjective and objective evidence of cognitive impairment.

The objective of this study was to explore the prevalence of substance-induced neurocognitive disorder (NCD) in a sample of polysubstance users, adding both objective- and subjective cognitive impairment. METHOD: We collected cross-sectional data from 33 community-based residential facilities in Mexico City. Montreal Cognitive Assessment was used for measurement of objective cognitive impairment, and a DSM-5-based interview for subjective impairment. Years and days of recent use of alcohol, marijuana, cocaine and inhalants were collected for regression analyses. RESULTS: 753 participants were analyzed; from these, 50.5% show objective impairment, 71% and 58.5% self-reported any cognitive deficit and cognitive decline, respectively. Between 21.8%-36.5% would qualify for NCD when integrating both objective- and subjective impairment (deficit or decline). Significant weak associations were found between objective impairment and subjective deficits in all cognitive domains except social cognition. Regression models adding both objective- and subjective measures explained more variation in the years of alcohol, inhalant and cocaine use, and in recent marijuana use, than the objective measure alone, but associations were inconsistent. CONCLUSION: Though significant in proportion, the prevalence of NCD in this population can only be partially related to substance use. Further integrative approaches are needed to refine the epidemiology of this disorder.

Benefits of EEG-Neurofeedback on the Modulation of Impulsivity in a Sample of Cocaine and Heroin Long-Term Abstinent Inmates: A Pilot Study.

The aim of this pilot study was to assess whether neurofeedback (NFB) can be useful in the treatment of impulsive behavior in long-term abstinent cocaine and heroin addicts. A single-blind sham-controlled NFB protocol was carried out to assess the effects of NFB on impulsivity in 20 (10 + 10) cocaine and heroin long-term abstinent addicts (Diagnostic and Statistical Manual of Mental Disorders [4th ed., text rev.; DSM-IV-TR]). Psychotic and neurologic diseases were excluded. Participants underwent 40 NFB sessions based on the very slow cortical potential range. Inhibitory deficits were specifically addressed through right and left prefrontal training. Clinical improvement was measured with Likert-type scales, the Hamilton Depression Rating Scale, and the State-Trait Anxiety Inventory, and impulsivity was assessed using the Barratt Impulsiveness Scale and the Continuous Performance Test. Although the results are preliminary due to the small sample size, the NFB-treated group showed a significant clinical improvement, including symptoms of anxiety and depression, with two differentiated time periods. No significant clinical improvement was found in the control group. A significant decrease in the post- versus pre-treatment measures of global impulsivity, nonplanning impulsivity, and error commission measures was found in the NFB-treated group; effect size (dKorr) in the pre-post control design was moderate. No significant change was found in the control group. Despite the limitations of this study, the results suggest that NFB is better than placebo in improving impulsivity and clinical symptoms of anxiety and depression in long-term abstinent cocaine- and heroin-dependent individuals.

Psychotic symptoms following oxycodone withdrawal, case report and update.

Opiate withdrawal-induced psychosis is an uncommon clinical manifestation. We present a 36-year-old male patient, with no prior personal or familiar psychiatric history, in treatment with several analgesic drugs (including oxycodone) for non-inflammatory chronic rachialgia. The patient is hospitalized after exhibiting psychotic symptomatology (delusions of harm and contamination, olfactory hallucinations, and aberrant behavior). This psychotic symptomatology first manifested after abruptly interrupting his prescribed oxycodone intake. It had a fluctuating course over time (alternating between lucid states and delusional ones) and eventually subsided after the prescription of antipsychotic drugs. In this case report, we describe the follow-up of the patient and discuss the influence and relevance of oxycodone withdrawal on the psychotic symptomatology.

Pharmacological Treatment of Insomnia Symptoms in Individuals with Substance Use Disorders in Spain: A Quasi-Experimental Study.

INTRODUCTION: Pharmacological treatment of insomnia in patients with addictions has been hardly investigated and there are few researches about it in an inpatient detoxification. The aim of this study was to describe the outcomes of the pharmacological treatment of insomnia in SUD patients admitted to a detoxification unit in Spain, with a focus on the primary substance of abuse and co-occurring mental disorders. METHODS: A quasi-experimental study was conducted in 481 addicted in patients, who were admitted for substances detoxification in Vall d´Hebron University Hospital, Barcelona, Spain, from 2010 to 2015. The patients underwent systematic evaluation of axes I and II psychiatric disorders (SCID-I, SCID-II, and CAADID). Insomnia was evaluated using a night time sleep log. Substance-dependent patients, who had insomnia during hospital detoxification, received a psychotropic medication with hypnotic effect, keeping the regular clinical practice without randomization. RESULTS: At discharge, insomnia was considered to have been alleviated in 63.8% (n = 204) of patients while 36.2% (n = 116) of patients remained with insomnia disturbances. Comparing hypnotic treatments it was observed that mirtazapine and clotiapine were the treatment that corrected the insomnia more frequently. DISCUSSION: Since insomnia is not corrected in all patients, it should be further investigated in medications with hypnotic purpose. Based on the results of this work, randomized clinical trials might be proposed.

Buenos usos y riesgos de los fármacos opiáceos / Good use and risks of opioid drugs

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Higher severity of cocaine addiction is associated with tactile and somatic hallucinations.

BACKGROUND: The aim of this study is to describe the features of cocaine-dependent patients who have had cocaine-induced tactile/somatic hallucinations (CITSH), and to analyze the association with addiction-related variables and psychiatric comorbidity, comparing patients with CITSH, patients with cocaine psychotic symptoms (CIP) and no CITSH, and patients without any psychotic symptom. METHOD: A cross-sectional study was conducted in 767 cocaine-dependent patients in an outpatient treatment center for addictions. The following data were obtained: sociodemographic characteristics, CIP information, addiction-related variables and psychiatric comorbidity. A bivariate and multivariate analysis was performed. RESULTS: Of the whole sample, 6.6% reported CITSH at some point of their lives, 48.4% had suffered some CIP other than CITSH, and 45% had not experienced any psychotic symptom. According to multivariate analysis, risk of overdose increases by 12.1 (OR) times the probability of having had CITSH compared patients with CIP-no-CITSH. Other variables associated to patients with CITSH were: age of drug use onset, presence of episodes of overdose, prevalence of psychotic disorder induced by cocaine. In general, in all variables studied, patients with CITSH presented worse clinical features (addiction variables and psychiatric comorbidity) than patients with CIP without CITSH and non-CIP group. CONCLUSION: CITSH are usually associated with other psychotic symptoms induced by cocaine. The patients who experienced CITSH are more severe cases compared both with patients with CIP without CITSH and patients without CIP. Increased risk of overdose is an important issue in this type of patients.

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence.

Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 µM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 µM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.

HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model.

Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, a process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration.

Glutamate triggers neurosecretion and apoptosis in bovine chromaffin cells through a mechanism involving NO production by neuronal NO synthase activation.

Previous work from our group stated that nitric oxide (NO), via cytokines, induces apoptosis in chromaffin cells by a mechanism involving iNOS, nNOS, and NF-κB. In this paper the involvement of glutamate as a possible intracellular trigger of neurosecretion and NO-mediated apoptosis has been evaluated. We show that chromaffin cells express different ionotropic and metabotropic glutamate receptors, this exerting different effects on the regulation of basal and glutamate-induced catecholamine secretion, via NO/cGMP. In addition, we studied the effects of endogenously generated NO, both basal and glutamate-stimulated, on apoptosis of chromaffin cells. Our results show that glutamate agonists are able to induce cell death and apoptosis in bovine chromaffin cells, parallel to an increase in NO production. Such effects were reversed by NOS inhibitors and glutamate receptor antagonists. Under basal conditions, iNOS inhibitors did not have any effect on apoptosis, whereas nNOS inhibitors induced apoptosis, indicating a neuroprotective effect of constitutive nNOS-generated NO. In contrast, glutamate-induced apoptosis was strongly reversed by nNOS inhibitors and weakly by iNOS inhibitors, thus indicating nNOS involvement in glutamate-mediated apoptosis. These results were confirmed by the fact that nNOS expression, but not iNOS, is specifically activated by glutamate. Finally, our results suggest the participation of PKG, PKA, PKC, and MAPK pathways in glutamate-mediated nNOS activation in chromaffin cells and point out the involvement of both PKA and PKC signaling pathways in the apoptotic effect of glutamate.

Síndrome de Wolfram y trastornos psiquiátricos: A propósito de un caso / Wolfram syndrome and psychiatric disorders: a case report

Presentamos el caso de un varón de 15 años con Síndrome de Wolfram que es una entidad neurodegenerativa poco prevalente caracterizada por la presencia de diabetes mellitus y atrofia óptica bilateral progresiva que ingresa en la Unidad de Hospitalización de Psiquiatría Infanto - Juvenil por presentar una anorexia nerviosa restrictiva que es una enfermedad que hasta el momento no había sido descrita como asociada a este síndrome en el que, sin embargo sí se ha descrito un mayor riesgo de presentar psicopatología depresiva y suicidio

We report the case of a teenage 15 year old male with Wolfram syndrome, which is a less prevalent neurodegenerative condition characterized by the presence of diabetes mellitus and progressive bilateral optic atrophy. The patient was hospitalized in the child and adolescent psychiatry unit presenting restrictive anorexia nervosa that is a disease that until now, had never been associated with this syndrome. However, The Wolfram Syndrome has been related to a greater risk of suicide and depressive psychopathology

Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence.

Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine-related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case-control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine-dependent patients and 482 sex-matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P-value adjusted for age = 1.9e-04, odds ratio = 1.72 (1.29-2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.

Risk factors for cocaine-induced psychosis in cocaine-dependent patients.

Cocaine consumption can induce transient psychotic symptoms, expressed as paranoia or hallucinations. Cocaine induced psychosis (CIP) is common but not developed in all cases. This is the first European study on the relationship between CIP, consumption pattern variables and personality disorders. We evaluated 173 cocaine-dependent patients over 18 years; mostly males, whose average age was 33.6 years (SD=7.8). Patients attending an outpatient addictions department were enrolled in the study and subsequently systematically evaluated using SCID I and SCID II interviews for comorbid disorders, a clinical interview for psychotic symptoms and EuropASI for severity of addiction. A high proportion of cocaine dependent patients reported psychotic symptoms under the influence of cocaine (53.8%), the most frequently reported being paranoid beliefs and suspiciousness (43.9%). A logistic regression analysis was performed, finding that a model consisting of amount of cocaine consumption, presence of an antisocial personality disorder and cannabis dependence history had 66.2% sensitivity 75.8% specificity predicting the presence of CIP. In our conclusions, we discuss the relevance of evaluating CIP in all cocaine dependent-patients, and particularly in those fulfilling the clinical profile derived from our results. These findings could be useful for a clinical approach to the risks of psychotic states in cocaine-dependent patients.

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells.

Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Met(flx/flx) and Met(-/-) oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-ß)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Met(flx/flx) cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Met(flx/flx) and Met(-/-) oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in normal, untransformed oval cells, c-Met and EGFR represent critical molecular players to control proliferation and survival that function independent of one another.

Abordaje terapeútico en el TDAH, TUS y psicosis tóxica / Therapeutic approach in ADHD, SUD and toxic psychosis

El trastorno por déficit de atención e hiperactividad (TDAH) es un factor de riesgo independiente para el desarrollo gradual del uso de sustancias en la adolescencia y la adultez. Así se observan altas tasas de TDAH en personas con diagnóstico de TUS, consumidores de diferentes clases de sustancias, incluidos los opiáceos, alcohol, cannabis, estimulantes y nicotina. Así, estudios longitudinales prospectivos sugieren que el diagnóstico de TDAH en la infancia o la adolescencia aumenta el riesgo de TUS en la vida adulta. El abuso de sustancias puede modificar los síntomas, la rapidez de la progresión y la respuesta al tratamiento en el TDAH. Del mismo modo, el TDAH puede modificar el curso del trastorno de consumo de sustancias. Esta es la razón por la que tenemos que diagnosticar y tratar esta comorbilidad, y conocer todos los posibles síntomas de psicosis que pueden surgir en el abuso de sustancias y el tratamiento con estimulantes

Attention deficit hyperactivity disorder (ADHD) is an independent risk factor for the gradual development of substance use disorders (SUD) in adolescence and adulthood. High rates of ADHD are found in people diagnosed with SUD, who consume different classes of substances, including opioids, alcohol, cannabis, stimulants and nicotine. Thus, prospective longitudinal studies suggest that the diagnosis of ADHD in childhood or adolescence increases the risk of SUD later in adult life. Substance abuse may modify the symptoms, rapidity of progression, response to treatment, and long-term outcome of ADHD. Similarly, ADHD may modify the course of the SUD. This is the reason that we need to diagnose and treat this comorbidity, and have the knowledge of all possible symptoms of psychosis that can emerge in substance abuse and stimulant treatment