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.

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.

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.

In vivo evidence of lower synaptic vesicle density in schizophrenia.

Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [11C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [11C]UCB-J binding, an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using [11C]UCB-J and high-resolution research tomography (HRRT). [11C]UCB-J distribution volume (VT) and binding potential (BPND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [11C]UCB-J BPND with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen's d = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85) and temporal cortex (-11%, Cohen's d = 1.23). These differences remained significant after partial volume correction. [11C]UCB-J BPND did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that [11C]UCB-J PET is a sensitive tool to detect lower synaptic density in SCZ and holds promise for future studies of early detection and disease progression.

Preliminary in vivo evidence of lower hippocampal synaptic density in cannabis use disorder.

Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [11C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BPND) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [11C]UCB-J BPND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BPND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study.

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.

Identifying brain networks in synaptic density PET (11C-UCB-J) with independent component analysis.

BACKGROUND: The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. 11C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI. METHODS: The aim of this study was to identify maximally independent brain source networks, i.e., "spatial patterns with common covariance across subjects", in 11C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex. RESULTS: Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison. CONCLUSION: This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.

Grey Matter Volume Differences Associated with Extremely Low Levels of Cannabis Use in Adolescence.

Rates of cannabis use among adolescents are high, and are increasing concurrent with changes in the legal status of marijuana and societal attitudes regarding its use. Recreational cannabis use is understudied, especially in the adolescent period when neural maturation may make users particularly vulnerable to the effects of Δ-9-tetrahydrocannabinol (THC) on brain structure. In the current study, we used voxel-based morphometry to compare gray matter volume (GMV) in forty-six 14-year-old human adolescents (males and females) with just one or two instances of cannabis use and carefully matched THC-naive controls. We identified extensive regions in the bilateral medial temporal lobes as well as the bilateral posterior cingulate, lingual gyri, and cerebellum that showed greater GMV in the cannabis users. Analysis of longitudinal data confirmed that GMV differences were unlikely to precede cannabis use. GMV in the temporal regions was associated with contemporaneous performance on the Perceptual Reasoning Index and with future generalized anxiety symptoms in the cannabis users. The distribution of GMV effects mapped onto biomarkers of the endogenous cannabinoid system providing insight into possible mechanisms for these effects.SIGNIFICANCE STATEMENT Almost 35% of American 10th graders have reported using cannabis and existing research suggests that initiation of cannabis use in adolescence is associated with long-term neurocognitive effects. We understand very little about the earliest effects of cannabis use, however, because most research is conducted in adults with a heavy pattern of lifetime use. This study presents evidence suggesting structural brain and cognitive effects of just one or two instances of cannabis use in adolescence. Converging evidence suggests a role for the endocannabinoid system in these effects. This research is particularly timely as the legal status of cannabis is changing in many jurisdictions and the perceived risk by youth associated with smoking cannabis has declined in recent years.

Psychosis-Relevant Effects of Intravenous Delta-9-Tetrahydrocannabinol: A Mega Analysis of Individual Participant-Data from Human Laboratory Studies.

INTRODUCTION: There is increasing interest in the relationship between cannabinoids and psychosis. While individual human laboratory studies have been critical in demonstrating that cannabinoids (e.g., delta-9-tetrahydrocannabinol [THC]) can induce acute transient psychosis-like effects in healthy human volunteers, combining data from multiple studies offers a fine-grained view of these effects. METHODS: THC-induced psychosis-relevant effects were examined using a data repository of 10 double-blind, randomized, placebo-controlled, crossover studies with 400 i.v. THC infusions in healthy human volunteers. The Positive and Negative Syndrome scale was used to measure psychotomimetic effects. The profile of symptoms, frequency of a response, its relationship to THC dose and substance use, latent structure in Positive and Negative Syndrome scale response, and the relationships between psychotomimetic and perceptual alteration symptoms were evaluated. RESULTS: Clinically meaningful increases in positive symptoms were noted in 44.75% infusions; conceptual disorganization, hallucinations, blunted affect, somatic concern, motor retardation, and poor attention were the items most frequently altered by THC. The increase in Positive and Negative Syndrome scale positive symptoms was positively associated with THC dose (beta = 11.13, SE = 4.94, Wald χ 2 = 19.88, P < .001) and negatively associated with frequent cannabis use (beta = -0.575, SE = 0.14, Wald χ 2 = 18.13, P < .001). Furthermore, positive symptoms were strongly correlated with Clinician Administered Dissociative States Scale perceptual alterations score (rs = 0.514, P < .001). CONCLUSION: Intravenous administration of THC consistently induces psychotomimetic effects that include symptoms across Positive and Negative Syndrome scale domains. Moreover, healthy individuals who frequently use cannabis have a blunted psychotomimetic response.

Interaction between environmental and familial affective risk impacts psychosis admixture in states of affective dysregulation.

BACKGROUND: Evidence suggests that cannabis use, childhood adversity, and urbanicity, in interaction with proxy measures of genetic risk, may facilitate onset of psychosis in the sense of early affective dysregulation becoming 'complicated' by, first, attenuated psychosis and, eventually, full-blown psychotic symptoms. METHODS: Data were derived from three waves of the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). The impact of environmental risk factors (cannabis use, childhood adversity, and urbanicity) was analyzed across severity levels of psychopathology defined by the degree to which affective dysregulation was 'complicated' by low-grade psychotic experiences ('attenuated psychosis' - moderately severe) and, overt psychotic symptoms leading to help-seeking ('clinical psychosis' - most severe). Familial and non-familial strata were defined based on family history of (mostly) affective disorder and used as a proxy for genetic risk in models of family history × environmental risk interaction. RESULTS: In proxy gene-environment interaction analysis, childhood adversity and cannabis use, and to a lesser extent urbanicity, displayed greater-than-additive risk if there was also evidence of familial affective liability. In addition, the interaction contrast ratio grew progressively greater across severity levels of psychosis admixture (none, attenuated psychosis, clinical psychosis) complicating affective dysregulation. CONCLUSION: Known environmental risks interact with familial evidence of affective liability in driving the level of psychosis admixture in states of early affective dysregulation in the general population, constituting an affective pathway to psychosis. There is interest in decomposing family history of affective liability into the environmental and genetic components that underlie the interactions as shown here.

Reasoning bias, working memory performance and a transdiagnostic phenotype of affective disturbances and psychotic experiences in the general population.

BACKGROUND: The jumping to conclusions (JTC) reasoning bias and decreased working memory performance (WMP) are associated with psychosis, but associations with affective disturbances (i.e. depression, anxiety, mania) remain inconclusive. Recent findings also suggest a transdiagnostic phenotype of co-occurring affective disturbances and psychotic experiences (PEs). This study investigated whether JTC bias and decreased WMP are associated with co-occurring affective disturbances and PEs. METHODS: Data were derived from the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Trained interviewers administered the Composite International Diagnostic Interview (CIDI) at three time points in a general population sample (N = 4618). The beads and digit-span task were completed to assess JTC bias and WMP, respectively. CIDI was used to measure affective disturbances and an add-on instrument to measure PEs. RESULTS: Compared to individuals with neither affective disturbances nor PEs, the JTC bias was more likely to occur in individuals with co-occurring affective disturbances and PEs [moderate psychosis (1-2 PEs): adjusted relative risk ratio (RRR) 1.17, 95% CI 0.98-1.41; and high psychosis (3 or more PEs or psychosis-related help-seeking behaviour): adjusted RRR 1.57, 95% CI 1.19-2.08], but not with affective disturbances and PEs alone, whereas decreased WMP was more likely in all groups. There was some evidence of a dose-response relationship, as JTC bias and decreased WMP were more likely in individuals with affective disturbances as the level of PEs increased or help-seeking behaviour was reported. CONCLUSION: The findings suggest that JTC bias and decreased WMP may contribute to a transdiagnostic phenotype of co-occurring affective disturbances and PEs.

Marijuana Legalization: Impact on Physicians and Public Health.

Marijuana is becoming legal in an increasing number of states for both medical and recreational use. Considerable controversy exists regarding the public health impact of these changes. The evidence for the legitimate medical use of marijuana or cannabinoids is limited to a few indications, notably HIV/AIDS cachexia, nausea/vomiting related to chemotherapy, neuropathic pain, and spasticity in multiple sclerosis. Although cannabinoids show therapeutic promise in other areas, robust clinical evidence is still lacking. The relationship between legalization and prevalence is still unknown. Although states where marijuana use is legal have higher rates of use than nonlegal states, these higher rates were generally found even prior to legalization. As states continue to proceed with legalization for both medical and recreational use, certain public health issues have become increasingly relevant, including the effects of acute marijuana intoxication on driving abilities, unintentional ingestion of marijuana products by children, the relationship between marijuana and opioid use, and whether there will be an increase in health problems related to marijuana use, such as dependence/addiction, psychosis, and pulmonary disorders. In light of this rapidly shifting legal landscape, more research is urgently needed to better understand the impact of legalization on public health.

A Meta-analytic Review of Non-specific Effects in Randomized Controlled Trials of Cognitive Remediation for Schizophrenia.

Cognitive remediation (CR) has been found to improve cognitive performance among adults with schizophrenia in randomized controlled trials (RCTs). However, improvements in cognitive performance are often observed in the control groups of RCTs as well. There has been no comprehensive examination of change in control groups for CR, which may inform trial methodology and improve our understanding of measured outcomes for cognitive remediation. In this meta-analysis, we calculated pre-post change in cognitive test performance within control groups of RCTs in 32 CR trials (n = 794 participants) published between 1970 and 2011, and examined the association between pre-post change and sample size, duration of treatment, type of control group, and participants' age, intelligence, duration of illness, and psychiatric symptoms. Results showed that control groups in CR trials showed small effect size changes (Cohen's d = 0.12 ± 0.16) in cognitive test performance over the trial duration. Study characteristics associated with pre-post change included participant age and sample size. These findings suggest attention to change in control groups may help improve detection of cognitive remediation effects for schizophrenia.

Thyroid dysfunction in major psychiatric disorders in a hospital based sample.

BACKGROUND & OBJECTIVES: Abnormalities in thyroid hormonal status is common in major psychiatric disorders. Although the relevance of thyroid dysfunction to bipolar disorder is well-recognized, yet the association between thyroid dysfunction and schizophrenia-spectrum disorders is under-emphasized. The aim of this study was to examine and compare the rates of abnormal thyroid hormonal status in patients with schizophrenia-spectrum disorders and mood disorders in an inpatient tertiary care general hospital psychiatry unit. METHODS: This was a retrospective hospital-based study on 468 inpatient samples. Data on serum thyroid stimulating hormone (TSH), T3 (triiodothyroxine), T4 (L-thyroxine), free unbound fractions of T3 and T4 (FT3 and FT4) were obtained from records of 343 patients, 18 patients were anti-TPO (anti thyroid peroxidase antibody) positive. The rates of abnormal thyroid hormonal status were compared using the chi square test. RESULTS: Abnormal thyroid hormonal status in general, and presence of hypothyroidism and hyperthyroidism, in particular were seen in 29.3, 25.17 and 4.08 per cent patients with schizophrenia spectrum disorders, respectively. These were comparable to the rates in patients with mood disorders (23.24, 21.62 and 1.62%, respectively). Eleven of the 18 patients with antiTPO positivity had a schizophrenia-spectrum disorder. There were no gender differences. INTERPRETATION & CONCLUSIONS: Thyroid dysfunction was present in patients with schizophrenia-spectrum disorder as well as mood disorders. Autoimmune thyroid disease was more commonly seen in patients with schizophrenia-spectrum disorders compared to mood disorders. The findings reiterate the relevance of screening patients with schizophrenia-spectrum disorders for abnormal thyroid hormonal status.

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.

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.

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.

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.