Perturbed iron biology in the prefrontal cortex of people with schizophrenia.

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness.

Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.

Use of antidepressants with pharmacogenetic prescribing guidelines in a 10-year depression cohort of adult primary care patients.

OBJECTIVE: To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. METHODS: Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. RESULTS: The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). CONCLUSION: One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.

Exploring Heterogeneity on the Wisconsin Card Sorting Test in Schizophrenia Spectrum Disorders: A Cluster Analytical Investigation.

OBJECTIVES: The Wisconsin Card Sorting Test (WCST) is a complex measure of executive function that is frequently employed to investigate the schizophrenia spectrum. The successful completion of the task requires the interaction of multiple intact executive processes, including attention, inhibition, cognitive flexibility, and concept formation. Considerable cognitive heterogeneity exists among the schizophrenia spectrum population, with substantive evidence to support the existence of distinct cognitive phenotypes. The within-group performance heterogeneity of individuals with schizophrenia spectrum disorder (SSD) on the WCST has yet to be investigated. A data-driven cluster analysis was performed to characterise WCST performance heterogeneity. METHODS: Hierarchical cluster analysis with k-means optimisation was employed to identify homogenous subgroups in a sample of 210 schizophrenia spectrum participants. Emergent clusters were then compared to each other and a group of 194 healthy controls (HC) on WCST performance and demographic/clinical variables. RESULTS: Three clusters emerged and were validated via altered design iterations. Clusters were deemed to reflect a relatively intact patient subgroup, a moderately impaired patient subgroup, and a severely impaired patient subgroup. CONCLUSIONS: Considerable within-group heterogeneity exists on the WCST. Identification of subgroups of patients who exhibit homogenous performance on measures of executive functioning may assist in optimising cognitive interventions. Previous associations found using the WCST among schizophrenia spectrum participants should be reappraised. (JINS, 2019, 25, 750-760).

Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV.

This investigation aimed to assess whether inhibition of cathecol-O-methyl transferase (COMT) by tolcapone could provide neuroprotection against HIV-associated neurodegenerative effects. This study was conducted based on a previous work, which showed that a single nucleotide polymorphism (SNP) at position 158 (val158met) in COMT, resulted in 40 % lower COMT activity. Importantly, this reduction confers a protective effect against HIV-associated neurocognitive disorders (HAND), which have been linked to HIV-associated brain changes. SH-SY5Y-differentiated neurons were exposed to macrophage-propagated HIV (neurotropic MACS2-Br strain) in the presence or absence of tolcapone for 6 days. RNA was extracted, and qPCR was performed using Qiagen RT2 custom array consisting of genes for neuronal and synaptic integrity, COMT and pro-inflammatory markers. Immunofluorescence was conducted to validate the gene expression changes at the protein level. Our findings demonstrated that HIV significantly increased the messenger RNA (mRNA) expression of COMT while reducing the expression of microtubule-associated protein 2 (MAP2) (p = 0.0015) and synaptophysin (SYP) (p = 0.012) compared to control. A concomitant exposure of tolcapone ameliorated the perturbed expression of MAP2 (p = 0.009) and COMT (p = 0.024) associated with HIV. Immunofluorescence revealed a trend reduction of SYP and MAP2 with exposure to HIV and that concomitant exposure of tolcapone increased SYP (p = 0.016) compared to HIV alone. Our findings demonstrated in vitro that inhibition of COMT can ameliorate HIV-associated neurodegenerative changes that resulted in the decreased expression of the structural and synaptic components MAP2 and SYP. As HIV-associated dendritic and synaptic damage are contributors to HAND, inhibition of COMT may represent a potential strategy for attenuating or preventing some of the symptoms of HAND.

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications.

Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.

Typologies of positive psychotic symptoms in methamphetamine dependence.

BACKGROUND AND OBJECTIVES: Understanding methamphetamine associated psychotic (MAP) symptom typologies could aid in identifying individuals at risk of progressing to schizophrenia and guide early intervention. METHODS: Latent class analysis (LCA) of psychotic symptoms collected from 40 (n = 40) methamphetamine dependent individuals with a history of psychotic symptoms but no history of a primary psychotic disorder. RESULTS: Three typologies were identified. In one, persecutory delusions dominated (Type 1), in another persecutory delusions were accompanied by hallucinations (Type 2), and in the third a high frequency of all the assessed hallucinatory and delusional symptoms was observed (Type 3). DISCUSSION AND CONCLUSION: MAP is a heterogeneous syndrome with positive symptom typologies. SCIENTIFIC SIGNIFICANCE: This study represents the first attempt at identifying typologies of MAP and highlights the potential utility of LCA in future large-scale studies.

Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees.

Methylenetetrahydrofolate reductase (MTHFR) genetic variation has been associated with the diagnosis of major depressive disorder (MDD) but no study to date has examined the effect MTHFR variation has on MDD prognosis. We sought to examine the prospective effects of two common MTHFR variants (C677T and A1298C) as well as seven haplotype-tagging single nucleotide polymorphisms (htSNPs) on MDD prognosis over a 5-year (60-month) period. Participants were 147 depressed primary care attendees enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) prospective cohort study. Prognosis of MDD was measured using three methods: (1) DSM-IV criteria, (2) Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9), and (3) Center for Epidemiologic Studies Depression Scale (CESD). DSM-IV criteria for MDD was assessed using the Composite International Diagnostic Interview at baseline and 24, 36, 48, and 60 months post-baseline; whereas, PHQ-9 and CESD measures were employed at baseline and 12, 24, 36, 48, and 60 months post-baseline. Repeated measures analysis of variance showed that PHQ-9 symptom severity trajectories differed by C677T genotype (F = 3.34, df = 2,144, P = 0.038), with 677CC genotype showing the most severe symptom severity course over the 60 months of observation. Neither the A1298C polymorphism nor any of the htSNPs were associated with MDD prognosis regardless of measure used. Our results suggest that the MTHFR C677T polymorphism may serve as a marker for MDD prognosis pending independent replication.

Increased CDK5 expression in HIV encephalitis contributes to neurodegeneration via tau phosphorylation and is reversed with Roscovitine.

Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3ß and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE.

Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders.

FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p < 0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p = 0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p = 0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.

Oestrogen alpha-receptor variant and two-year memory decline in midlife Australian women.

OBJECTIVE: To prospectively examine the influence of the oestrogen-α receptor (ESR1)PvuII polymorphism on changes in memory performance over a 2-year period among 80 midlife postmenopausal Australian women. METHODS: Healthy women aged 56-67 years were administered a battery of four memory (verbal and non-verbal) tasks at baseline and 2 years later. RESULTS: Carriers of the ESR1 p allele had significantly greater declines in logical memory compared to participants with the PP genotype, independent of demographic characteristics (e.g. age), chronic illness (e.g. hypertension), sleep aid usage, hormone levels, apolipoprotein E e4 status and prospective changes in mood, smoking and alcohol consumption. CONCLUSION: These findings provide preliminary evidence for larger and longer prospective trials that will be able to determine if the p allele of the ESR1PvuII polymorphism is a potential biomarker of logical memory decline among aging women.

Chronic illness histories of adults entering treatment for co-occurring substance abuse and other mental health disorders.

Little is known about the medical status of individuals entering treatment for co-occurring substance abuse and other mental disorders (COD). We analyzed the medical histories of 169 adults entering outpatient treatment for CODs, estimating lifetime prevalence of chronic illness and current smoking, comparing these rates to the general population, and examining psychiatric and substance-related correlates of chronic illness. Results revealed significantly higher prevalence of hypertension, asthma, arthritis, and smoking compared to the general US population, and showed an association between chronic illness and psychiatric symptom distress and substance use severity. Findings support integration of chronic illness management into COD treatment.

Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.

Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed in wild type injected with HCV core protein into the hippocampus. In vitro analysis in neuronal cells exposed to HCV core demonstrated retraction of the neuronal processes in an ERK/Signal Transducer and Activator of Transcription 3 (STAT3)-dependent manner dependent on toll-like receptor 2 (TLR2) signaling activation. These results indicate that HCV core protein neurotoxicity may be mediated by the sustained activation of ERK/STAT3 via TLR2-IRAK1 signaling pathway. These pathways provide novel targets for development of neuroprotective treatments for HCV involvement of the CNS.

Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings.

Macrophages are one of HIV-1's principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3's binding to DA, would be more likely to develop CI. Cochran-Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.

Clinical characteristics and impacts of HIV infection in people with bipolar disorders.

BACKGROUND: People with bipolar disorders (BD) may be at increased risk of Human Immunodeficiency Virus (HIV) infection but our understanding of the impacts of HIV infection on psychiatric outcomes is poor. This study aimed to examine the prevalence, temporal relationship, and clinical impact of HIV infection in people with BD. METHODS: In this retrospective case-control study, anonymised electronic case records of patients with BD who had been under the care of South London and Maudsley mental health services were used for data extraction. 54 HIV+ people with BD were identified and compared to a matched control group of 54 HIV- people with BD. RESULTS: The prevalence of HIV co-morbidity in the BD population was around 1%. 76% of HIV+ BD men identified as men who have sex with men (MSM). 65% of the HIV+ BD group were diagnosed with BD before becoming HIV+. The HIV+ BD group experienced significantly higher rates of stimulant, GBL/GHB and psychedelic use compared to the HIV- BD group. 85% of the HIV+ BD group were recorded as taking antiretroviral medications. LIMITATIONS: Retrospective and cross-sectional study design, and a relatively small sample size CONCLUSIONS: The prevalence of HIV comorbidity in BD was comparable to the local general population. HIV infection in BD is associated with MSM status and stimulant, GHB/GBL and psychedelics use suggesting that HIV prevention strategies should particularly target these groups. Lower use of antiretroviral medications by people with BD underlines the importance of engaging HIV+ BD people in HIV services.

Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals.

Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.

Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence.

Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations. Using a case-control design this study's purpose was to explore, among a population of methamphetamine-dependent Caucasians, six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations. A total of 193 non-psychotic males (117 methamphetamine-dependent and 76 controls) were genotyped for variants located in six genes (AKT1, ARRB2, BDNF, COMT, GSTP1, OPRM1). Genotypic and allelic frequencies, odds ratios, and 95% confidence intervals were calculated. None of the putative gene associations was significantly replicated in our sample of Caucasian men. Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 (ARRB2) and glutathione S-transferase P1 (GSTP1) and allelic convergence for brain-derived neurotrophic factor (BDNF). Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms (SNPs) for methamphetamine (METH) dependence reported among Asian populations across other ethnic/ancestral groups.

Homelessness and neuropsychological impairment: preliminary analysis of adults entering outpatient psychiatric treatment.

Homelessness has been associated with neuropsychological (NP) impairment, but few studies have adequately controlled for factors known to affect NP performance. We performed brief NP testing examining learning, recall, processing speed, executive functioning, and verbal fluency in 50 ever- and 22 never-homeless persons entering outpatient psychiatric treatment. Groups were matched a priori on key demographic, substance use, psychiatric, and premorbid intelligence quotient characteristics. Rates of NP impairment were high among both groups (46%-54%). There were no significant differences in global NP impairment. There were trends toward better levels of processing speed and executive functioning among never-homeless relative to ever-homeless. Among the ever-homeless group, NP test performance was unrelated to number of homelessness episodes (median 3). Findings confirm high prevalence of NP impairment among homeless individuals but provide little evidence for broad NP differences between ever- and never-homeless persons matched for coexisting conditions that have confounded interpretation of previous results in the literature.

Positive symptoms of psychosis correlate with expression of ubiquitin proteasome genes in peripheral blood.

Several brain- and blood-based gene expression studies in patients with psychotic disorders (e.g., schizophrenia) have identified genes in the ubiquitin proteasome system (UPS) pathway as putative biomarkers. However, to date an examination of the UPS pathway in the broader context of symptom severity in psychosis has not been conducted. The purpose of this study was to investigate the correlation between clinical scores on the Scales for the Assessment of Positive and Negative Symptoms (SAPS-SANS) and expression of 43 highly annotated genes within the UPS pathway in blood from patients with psychosis. A sample of 19 psychotic patients diagnosed with schizophrenia (n = 13) or bipolar disorder (n = 6) were recruited. Pearson's partial correlations, adjusting for gender, ethnicity, age, education, medication, smoking, and past 6-month substance use, were performed between each of the selected UPS genes and both scales. Significant Bonferroni-adjusted positive associations were observed between SAPS scores and two ubiquitin conjugation genes (i.e., UBE2K, SIAH2), while a negative association was observed with one deubiquitination gene (i.e., USP2). No gene expression levels were significantly associated with scores on the SANS after correction for multiple testing. Our findings suggest that dysregulation of the UPS, specifically ubiquitin conjugation and deubiquitination, may point to a possible underlying biological mechanism for severity of positive but not negative symptoms.