Substance use and spine density: a systematic review and meta-analysis of preclinical studies.

The elucidation of synaptic density changes provides valuable insights into the underlying brain mechanisms of substance use. In preclinical studies, synaptic density markers, like spine density, are altered by substances of abuse (e.g., alcohol, amphetamine, cannabis, cocaine, opioids, nicotine). These changes could be linked to phenomena including behavioral sensitization and drug self-administration in rodents. However, studies have produced heterogeneous results for spine density across substances and brain regions. Identifying patterns will inform translational studies given tools that now exist to measure in vivo synaptic density in humans. We performed a meta-analysis of preclinical studies to identify consistent findings across studies. PubMed, ScienceDirect, Scopus, and EBSCO were searched between September 2022 and September 2023, based on a protocol (PROSPERO: CRD42022354006). We screened 6083 publications and included 70 for meta-analysis. The meta-analysis revealed drug-specific patterns in spine density changes. Hippocampal spine density increased after amphetamine. Amphetamine, cocaine, and nicotine increased spine density in the nucleus accumbens. Alcohol and amphetamine increased, and cannabis reduced, spine density in the prefrontal cortex. There was no convergence of findings for morphine's effects. The effects of cocaine on the prefrontal cortex presented contrasting results compared to human studies, warranting further investigation. Publication bias was small for alcohol or morphine and substantial for the other substances. Heterogeneity was moderate-to-high across all substances. Nonetheless, these findings inform current translational efforts examining spine density in humans with substance use disorders.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Effects of Buprenorphine, Methadone and Substance-Use on COVID-19 Morbidity and Mortality.

Objectives: Substance use disorder has been associated with increased morbidity in COVID-19 infection. However, less is known about the impact of active substance use and medications for opioid use disorder (MOUD) on COVID-19 outcomes. We conducted a retrospective cohort study to evaluate the impact of substance use, namely cannabis, cocaine, alcohol, sedative and opioid use as well as buprenorphine or methadone = on COVID-19 morbidity and mortality. Methods: Using electronic-health record data at a large urban hospital system, patients who tested positive for COVID-19 between January 1, 2020 to December 31, 2021 were included. Substance use was identified from urine toxicology and MOUD prescriptions within 90 days prior to admission. COVID-19 outcomes included mortality, ICU admission, need for ventilatory support, number and duration of hospitalizations. Multivariable logistic regression was performed controlling for variables such as age, sex, medical comorbidity, tobacco use, and social disadvantage. Results: Among COVID-19 positive patients (n=17,423), sedative, cannabis, cocaine, and opioid use was associated with statistically significant increases in need for ICU care, need for ventilatory support, number of hospitalizations and duration of hospitalization. Substance use was not associated with an increase in all-cause mortality. There were no statistically significant differences between methadone, buprenorphine and other opioids on COVID-19 outcomes. Conclusions: Active substance use were associated with increased morbidity in COVID-19 infection. MOUD was not associated with worse COVID-19 outcomes compared to OUD. Future studies focused on MOUD treatments that reduce morbidity may help improve clinical outcomes in COVID-19.

Characterization of an extreme phenotype of schizophrenia among women with homelessness.

Background: Studies of schizophrenia and homelessness are often confounded by comorbid substance use. Women with schizophrenia and homelessness in India have very low rates of substance use and provide a unique opportunity to disentangle the effects of illness from that of substance use. We examined the clinical characteristics of women with schizophrenia and homelessness and compared it to an age-matched group of women with schizophrenia living with their family. Methods: 36 women with schizophrenia and homelessness, and 32 women with schizophrenia who were illness living with family were evaluated for psychopathology using Scale for Assessment of Positive Symptoms (SAPS)/ Scale for assessment of negative symptoms (SANS) scales, cognitive difficulties using Montreal Cognitive Assessment (MOCA)/Rowland Universal Dementia Scale (RUDAS), and Frontal Assessment Battery(FAB), disability using World Health Organization - Disability assessment Scale (WHO-DAS) and psychosocial factors using a semi-structured proforma. The groups were compared using t-tests and chi-square for continuous and categorical variables respectively. Results: Women with schizophrenia and homelessness were found to have significantly higher scores on measures of psychopathology, significantly lower cognitive functioning, and much higher disability, and were also on higher doses of antipsychotics. The mean scores on measures of psychopathology, cognition and disability for women with schizophrenia and homelessness differed by 2-3 standard deviations with the mean for women living with family (i.e. z scores) suggesting that they represented an extreme phenotype. Rates of past employment were higher among women with schizophrenia and homelessness. Hence these differences were not accounted for by premorbid functioning. Conclusions: The study raises the possibility of an extreme phenotype of schizophrenia with severe and persistent psychopathology non-responsive to dopamine blocking drugs, cognitive impairment, and disability, which needs further exploration.

International perspective on physician knowledge, attitude and practices related to medical cannabis.

Background: The trends of recreational use of cannabis and use of cannabis for medical indications (i.e. "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there's growing evidence for negative health outcomes related to use of cannabis. In this rapidly shifting landscape, the role of physician's attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis. Methods: We conducted a cross-sectional survey of physicians from 17 countries between 2016-2018. The survey comprised of 28 questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify predictors of physician willingness to recommend medical cannabis. Results: A total of 323 physicians responded to the survey. Mean age was 35.4± 9.5 years, with 10.04 ±8.6 years of clinical experience. 53 percent of physicians were women. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis; 33% noted inadequate knowledge regarding medical cannabis). Overall willingness to recommend medical cannabis was highest for chemotherapy-induced nausea, refractory chronic neuropathic pain, and spasticity in amyotropic lateral sclerosis (ALS). Conclusion: This international study examining knowledge, attitudes and practices related to medical cannabis among physicians revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is wide variability in willingness to recommend medical cannabis that is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.

Role of Psychedelics in Treatment-Resistant Depression.

There is increasing interest in exploring the therapeutic potential of psychedelics in treatment-resistant depression (TRD). Classic psychedelics (such as psilocybin, LSD, ayahuasca/DMT), and atypical psychedelics (such as ketamine) have been studied in TRD. The evidence for the classic psychedelics TRD is limited at the present time; early studies however show promising results. There is also recognition that psychedelic research may be subject to a "hype bubble" at the present time. Future studies focused on delineating necessary ingredients of psychedelic treatments and the neurobiological basis of their effects, will help pave the way for the clinical use of these compounds.

Bidirectional relationships between cannabis use, anxiety and depressive symptoms in the mediation of the association with psychotic experience: further support for an affective pathway to psychosis.

BACKGROUND: Empirical evidence suggests that people use cannabis to ameliorate anxiety and depressive symptoms, yet cannabis also acutely worsens psychosis and affective symptoms. However, the temporal relationship between cannabis use, anxiety and depressive symptoms and psychotic experiences (PE) in longitudinal studies is unclear. This may be informed by examination of mutually mediating roles of cannabis, anxiety and depressive symptoms in the emergence of PE. METHODS: Data were derived from the second longitudinal Netherlands Mental Health Survey and Incidence Study. Mediation analysis was performed to examine the relationship between cannabis use, anxiety/depressive symptoms and PE, using KHB logit in STATA while adjusting for age, sex and education status. RESULTS: Cannabis use was found to mediate the relationship between preceding anxiety, depressive symptoms and later PE incidence, but the indirect contribution of cannabis use was small (for anxiety: % of total effect attributable to cannabis use = 1.00%; for depression: % of total effect attributable to cannabis use = 1.4%). Interestingly, anxiety and depressive symptoms were found to mediate the relationship between preceding cannabis use and later PE incidence to a greater degree (% of total effect attributable to anxiety = 17%; % of total effect attributable to depression = 37%). CONCLUSION: This first longitudinal cohort study examining the mediational relationship between cannabis use, anxiety/depressive symptoms and PE, shows that there is a bidirectional relationship between cannabis use, anxiety/depressive symptoms and PE. However, the contribution of anxiety/depressive symptoms as a mediator was greater than that of cannabis.

A systematic review of approaches to improve medication adherence in homeless adults with psychiatric disorders.

Introduction: Medication non-adherence is a significant problem among homeless individuals with psychiatric disorders in the United States. We conducted a systematic review to identify strategies to improve psychiatric medication adherence among homeless individuals with psychiatric disorders, including substance use disorders. Methods: We searched seven databases (MEDLINE, Embase, PsychInfo, Scopus, Web of Science, CDSR, and CENTRAL) and screened 664 studies by title and abstract followed by full-text review. Our inclusion criteria were studies that: involved an intervention for homeless adults with psychiatric disorders, reported a quantitative outcome of medication adherence, and were published in English in a peer-reviewed journal. We rated the relative effectiveness of strategies described in each study using a self-designed scale. Results: Eleven peer-reviewed studies met criteria for inclusion in this review. Within these studies, there were seven different approaches to improve medication adherence in this population. Three studies were randomized controlled trials (RCTs) and the remaining were observational studies. Outpatient interventions included Assertive Community Treatment, Cell Phone-Assisted Monitoring, Customized Adherence Enhancement plus Long-Acting Injectable Medications, and Homeless-Designated Pharmacy Clinics. Residential, shelter-based, and inpatient interventions included use of the Housing First model, Modified Therapeutic Communities, and Homeless-Designated Inpatient Care. The approaches described in four of the eleven studies were rated as scoring a 3 or higher on a 5-point scale of effectiveness in improving medication adherence; none received 5 points. Discussion: The interventions with the strongest evidence for improving medication adherence in this population were Assertive Community Treatment, Customized Adherence Enhancement plus Long-Acting Injectable Medications, and Housing First. Overall, studies on this topic required more rigor and focus on medication adherence as an outcome in this population. This review highlights several promising strategies and the need for larger RCTs to determine effective and diverse ways to improve medication adherence among homeless adults with psychiatric disorders.

Age, gender and body-mass-index relationships with in vivo CB1 receptor availability in healthy humans measured with [11C]OMAR PET.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Schizophrenia is frequently accompanied with social cognitive disturbances. Cannabis represents one established environmental factor associated with the onset and progression of schizophrenia. The present cross-sectional study aimed to investigate the association of facial emotion recognition (FER) performance with cannabis use in 2039 patients with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). FER performance was measured using the Degraded Facial Affect Recognition Task (DFAR). Better FER performance as indicated by higher DFAR-total scores was associated with lifetime regular cannabis use in schizophrenia (B = 1.36, 95% CI 0.02 to 2.69), siblings (B = 2.17, 95% CI 0.79 to 3.56), and HC (B = 3.10, 95% CI 1.14 to 5.06). No associations were found between DFAR-total and current cannabis use. Patients with schizophrenia who started to use cannabis after the age of 16 showed better FER performance than patients who started earlier (B = 2.50, 95% CI 0.15 to 4.84) and non-users (B = 3.72, 95 CI 1.96 to 5.49). Better FER performance was found also in siblings who started to use cannabis after 16 compared to non-users (B = 2.37, 95% CI 0.58 to 4.16), while HC using cannabis performed better than non-users at DFAR-total regardless of the age at onset. Our findings suggest that lifetime regular cannabis use may be associated with better FER regardless of the psychosis risk, but that FER might be moderated by age at first use in people with higher genetic risk. Longitudinal studies may clarify whether there is a cause-and-effect relationship between cannabis use and FER performance in psychotic and non-psychotic samples.

Impact of Cannabis Use, Substance Use Disorders, and Psychiatric Diagnoses on COVID-19 Outcomes: A Retrospective Cohort Study.

Objective: While psychiatric disorders have been recognized as a risk factor for COVID-19 outcomes, the impact of substance use disorders (SUD) on COVID-19 outcomes has not, to date, been examined in a systematic manner. We examined the association between SUD (cannabis, cocaine, alcohol, opioid, and benzodiazepine) as well as psychiatric diagnoses (schizophrenia, mood disorders, anxiety disorders) and COVID-19 outcomes in a large, retrospective cohort study.Methods: COVID-19-positive patients admitted to a large health care system in the US between January and December 2020 were included in this study. SUD and psychiatric diagnoses were identified from urine toxicology reports and ICD-10 diagnosis codes in the electronic medical record, respectively. Multivariable logistic regression was performed controlling for potential confounders such as age, race, sex, smoking status, and medical comorbidities. COVID-19-relevant outcomes included mortality, need for intensive care unit (ICU) admission, need for ventilatory support, length of hospitalization, and number of hospitalizations.Results: Among COVID-19 patients (N = 6,291), those with SUD were more likely to require ICU admission (adjusted odds ratio [AOR] = 1.46, P = .003) and ventilatory support (AOR = 1.49, P = .01). The association between SUD and ICU admission was driven by alcohol use disorder (AUD), whereas that between SUD and ventilatory support was driven by both AUD and opioid use disorder (OUD). Patients with SUD were more likely to have a longer mean maximum length of hospitalization (11.32 vs 8.62 days, P < .0001) and a greater mean number of hospital admissions in 2020 (2.96 vs 2.33, P < .0001). These associations were significant for cannabis use disorder, AUD, OUD, and benzodiazepine use disorder. The association with greater number of admissions was also significant for cocaine use disorder. Patients with psychiatric diagnoses were also more likely to have a greater maximum length of hospitalization (11.93 vs 8.39 days, P < .0001) and hospital admissions (2.72 vs 2.31, P < .0001). These associations were significant for schizophrenia, mood disorders, and anxiety disorders.Conclusions: COVID-19 patients with SUD had greater likelihood of requiring critical interventions, such as ICU admission and ventilatory support. SUD and psychiatric diagnoses were also associated with a longer duration of hospitalization and greater number of hospital admissions. These findings identify COVID-19 patients with SUD and psychiatric comorbidities as a high-risk group.

Analysis of circulating exosomes reveals a peripheral signature of astrocytic pathology in schizophrenia.

OBJECTIVES: Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. This study aimed to examine neuropathology-relevant protein biomarkers in circulating plasma-derived exosomes from patients with schizophrenia and age- and sex-matched healthy controls. METHODS: Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo protein (glial fibrillary acid protein[GFAP], synaptophysin, and α-II-Spectrin) immunopositivity was examined using Western blot analyses with band intensity quantified. Methods were consistent with the 'Minimal information for studies of extracellular vesicles 2018' (MISEV2018) guidelines. RESULTS: Exosomal GFAP concentration was significantly higher and α-II-Spectrin expression significantly lower in plasma obtained from schizophrenia patients. No group differences were observed between in plasma exosomal concentration and size or in CD9, calnexin, or synaptophysin levels. CONCLUSIONS: Our results demonstrate a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesised astroglial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.

Lower prefrontal cortical synaptic vesicle binding in cocaine use disorder: An exploratory 11 C-UCB-J positron emission tomography study in humans.

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.

Selective Serotonin Reuptake Inhibitors: How Long Is Long Enough?

Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications. They are among the first-line medications for several chronic or relapsing-remitting psychiatric conditions, including major depressive disorder and anxiety disorders. The advantages of SSRI use include ease of titration and their tolerability and safety profile. Guidelines for the short-term use of SSRIs are widely available, but there is no well-organized guidance on how and whether to maintain a patient on SSRIs for the long-term. In this article, we discuss the benefits and possible adverse consequences of long-term SSRI use, as well as clinical practice considerations when using SSRIs chronically. The major benefit of long-term SSRI use is relapse prevention. The current literature suggests that the general health risks of long-term SSRI use are low; however, further research, particularly in special populations including youth and the elderly, is needed. Long-term SSRI use increases the risk of tachyphylaxis and discontinuation syndrome. Recognizing that many patients may remain on SSRIs for many years, there are several factors that prescribers should consider if they choose to use an SSRI when initiating treatment and during long-term monitoring. The decision to continue or to discontinue an SSRI should be an active one, involving both the patient and prescriber, and should be revisited periodically. Patients who remain on SSRIs for the long-term should also have periodic monitoring to reassess the risk-benefit ratio of remaining on the SSRI, as well as to assess the safety, tolerability, and efficacy of the medication.

The Networked Computer Metaphor: A Novel Tool for Psychiatric Trainees to Enhance Utility of the Biopsychosocial Model of Health and Illness.

The biopsychosocial (BPS) model proposed by George Engel posited that a disease developed through a complex interaction of biological, psychological and social factors. This popular model, despite its limitations, continues to influence the practice and treatment of illness and service delivery worldwide. We propose the networked computer metaphor as a novel and pragmatic tool to help psychiatric trainees appreciate and enhance the utility of the BPS model as it pertains to psychiatric disorders. We also propose that the application of this metaphor would help provide some clues to answer the question of achieving the goal envisioned by Engel of providing holistic and comprehensive patient-centered care. We also discuss the utility of this metaphor from trainee, teacher and patient perspectives and describe various examples of the application of this metaphor so as to deepen our understanding of the BPS model. We discuss the criticisms of this model, summarize the applications of this metaphor and outline future directions for research.