Differential Serum Levels of CACNA1C, Circadian Rhythm and Stress Response Molecules in Subjects with Bipolar Disorder: Associations with Genetic and Clinical Factors.

Background: Many patients with bipolar disorder (BD) do not respond to or have difficulties tolerating lithium and/or other mood stabilizing agents. There is a need for personalized treatments based on biomarkers in guiding treatment options. The calcium voltage-gated channel CACNA1C is a promising candidate for developing personalized treatments. CACNA1C is implicated in BD by genome-wide association studies and several lines of evidence suggest that targeting L-type calcium channels could be an effective treatment strategy. However, before such individualized treatments can be pursued, biomarkers predicting treatment response need to be developed. Methods: As a first step in testing the hypothesis that CACNA1C genotype is associated with serum levels of CACNA1C, we conducted ELISA measures on serum samples from 100 subjects with BD and 100 control subjects. Results: We observed significantly higher CACNA1C (p<0.01) protein levels in subjects with BD. The risk SNP (rs11062170) showed functional significance as subjects homozygous for the risk allele (CC) had significantly greater CACNA1C protein levels compared to subjects with one (p=0.013) or no copies (p=0.009). We observed higher somatostatin (SST) (p<0.003) protein levels and lower levels of the clock protein ARTNL (p<0.03) and stress signaling factor corticotrophin releasing hormone (CRH) (p<0.001) in BD. SST and PER2 protein levels were associated with both alcohol dependence and lithium response. Conclusions: Our findings represent the first evidence for increased serum levels of CACNA1C in BD. Along with altered levels of SST, ARNTL, and CRH our findings suggest CACNA1C is associated with circadian rhythm and stress response disturbances in BD.

A systematic review of clozapine-associated inflammation and related monitoring.

Clozapine is an effective antipsychotic medication used for treatment-resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life-threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: (i) the impact of clozapine on inflammatory markers, (ii) monitoring cardiac and other organ function during clozapine-associated inflammatory processes, and (iii) monitoring non-specific signs and symptoms of inflammation. Elevated levels of C-reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4-8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine-associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence-based guidelines for the monitoring of clozapine-associated inflammation.

Assessing Naltrexone Prescribing and Barriers to Initiation for Alcohol Use Disorder: A Multidisciplinary, Multisite Survey.

Objective: To survey barriers in prescribing naltrexone for alcohol use disorder. Methods: A 12-question survey related to naltrexone prescribing patterns, perceptions, and knowledge was sent to 770 prescribers in the departments of internal medicine, family medicine, and psychiatry across a health system with sites in Arizona, Florida, and Minnesota. Results: Responses were obtained and included for 146/770 prescribers (19.0% response rate). Most respondents were in the department of internal medicine (n = 94, 64.4%), but the departments of psychiatry (n = 22, 15.1%) and family medicine (n = 30, 20.5%) were also represented. Only 34 (23.3%) respondents indicated they had prescribed naltrexone in the previous 3 months. The most common reasons for not prescribing naltrexone were "unfamiliarity with naltrexone for treatment of alcohol use disorder" and "patients do not have appropriate follow-up or are not in a formal treatment program." Compared with those representing internal/family medicine, psychiatry respondents were more likely to prescribe naltrexone and answer knowledge questions correctly. Conclusion: In this survey among primarily non-addiction-trained prescribers, a disparity was shown for prescribing naltrexone and in knowledge barriers between staff in internal/family medicine and psychiatry. There exist opportunities for education and quality improvement that promote the prescribing of naltrexone for alcohol use disorder by non-addiction specialists.

Electroencephalogram (EEG) With or Without Transcranial Magnetic Stimulation (TMS) as Biomarkers for Post-stroke Recovery: A Narrative Review.

Stroke is one of the leading causes of death and disability. Despite the high prevalence of stroke, characterizing the acute neural recovery patterns that follow stroke and predicting long-term recovery remains challenging. Objective methods to quantify and characterize neural injury are still lacking. Since neuroimaging methods have a poor temporal resolution, EEG has been used as a method for characterizing post-stroke recovery mechanisms for various deficits including motor, language, and cognition as well as predicting treatment response to experimental therapies. In addition, transcranial magnetic stimulation (TMS), a form of non-invasive brain stimulation, has been used in conjunction with EEG (TMS-EEG) to evaluate neurophysiology for a variety of indications. TMS-EEG has significant potential for exploring brain connectivity using focal TMS-evoked potentials and oscillations, which may allow for the system-specific delineation of recovery patterns after stroke. In this review, we summarize the use of EEG alone or in combination with TMS in post-stroke motor, language, cognition, and functional/global recovery. Overall, stroke leads to a reduction in higher frequency activity (≥8 Hz) and intra-hemispheric connectivity in the lesioned hemisphere, which creates an activity imbalance between non-lesioned and lesioned hemispheres. Compensatory activity in the non-lesioned hemisphere leads mostly to unfavorable outcomes and further aggravated interhemispheric imbalance. Balanced interhemispheric activity with increased intrahemispheric coherence in the lesioned networks correlates with improved post-stroke recovery. TMS-EEG studies reveal the clinical importance of cortical reactivity and functional connectivity within the sensorimotor cortex for motor recovery after stroke. Although post-stroke motor studies support the prognostic value of TMS-EEG, more studies are needed to determine its utility as a biomarker for recovery across domains including language, cognition, and hemispatial neglect. As a complement to MRI-based technologies, EEG-based technologies are accessible and valuable non-invasive clinical tools in stroke neurology.

Clinical Phenotype of Tardive Dyskinesia in Bipolar Disorder.

PURPOSE: Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. MATERIALS AND METHODS: Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. RESULTS: The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. CONCLUSIONS: This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

Positive Urine Drug Screens and External Mortality in Teenagers Who Present for Medical Care.

Objective: To examine whether a positive urine drug of abuse screen in youth who receive medical care is associated with subsequent risk of external mortality (eg, overdose, suicide, homicide, accident).Methods: This was a population-based retrospective cohort study of all Olmsted County (Minnesota) residents who were 13-18 years of age at the time of urine drug screen (UDS) testing (January 1, 1999, to November 28, 2012). Cox regression models were used to examine the relationships between having a positive UDS and external mortality, adjusted for sex, race, age, alcohol exposure, psychiatric diagnoses as defined by the International Classification of Diseases (ICD-9/ICD-10), and medical setting of UDS testing. Separate analyses were done for (1) overall UDS results, (2) tetrahydrocannabinol (THC), and (3) cocaine.Results: Of the 2,772 teenagers included in this study (47.2% male), a total of 26 died of external causes during a median follow-up period of 11.8 years. Testing positive for any illicit substance was not associated with significantly increased risk of external mortality (hazard ratio [HR] = 1.9; 95% CI, 0.9-4.2). Testing positive for cocaine was associated with significantly increased risk of external mortality (HR = 7.0; 95% CI, 1.9-25.0). Testing positive for THC was associated with a marginally significantly increased risk of external mortality (HR = 2.1; 95% CI, 1.0-4.7); however, when cocaine was added as a covariate in the analysis, the relationship between THC-positive UDS and mortality was still elevated but was no longer statistically significant (HR = 1.8; 95% CI, 0.8-4.1).Conclusions: History of cocaine-positive UDS may help identify a population of young people who are at high risk of premature death.

Relative Age Effect on Problematic Alcohol Use in Adolescents.

Objective: Relative age refers to a difference in age between peers in the same academic year. Although younger age of alcohol use is associated with a higher risk of lifetime problematic alcohol use, the potential effects of relative age are poorly understood. We hypothesized that a younger relative age would be associated with a younger chronological age of testing positive for alcohol in a medical setting. Methods: Problematic alcohol use was operationalized and identified as a positive alcohol test (PAT) in a medical setting. This was a retrospective population study of all 12 to 18-year-old residents (n = 4610) of Olmsted County, Minnesota (USA), who were tested for alcohol in a medical care setting from 1998 through 2016. Cox regression models examined the relationship between relative age and the age at testing positive for alcohol. Results: Relative age was not associated with age at first PAT. Results remained nonsignificant after stratifying by gender, and after adjusting for race, number of nonalcohol-related psychiatric comorbidities, and type of alcohol testing. Conclusions: The results did not support a relative age effect as a risk factor for alcohol use in adolescents in Olmsted County, Minnesota. These results contrast with findings from previous studies on this topic, which suggested older relative age increases risk of alcohol use in adolescence.

Naltrexone Initiation in the Inpatient Setting for Alcohol Use Disorder: A Systematic Review of Clinical Outcomes.

Alcohol use disorder (AUD) is a highly prevalent health issue in the United States. The number of those receiving medication-assisted treatment (MAT) is limited, despite strong evidence for their effectiveness. The inpatient setting may represent an important opportunity to initiate MAT. The goal of this study was to summarize the data on naltrexone initiation in the emergency department or inpatient setting for the management of AUDs. We searched ClinicalTrials.gov, Ovid EBM Reviews, Ovid Embase, Ovid Medline, Ovid PsycINFO, Scopus, and Web of Science from inception through October 31, 2019. Search strategies were created using a combination of keywords (Supplemental Appendix 1, available online at http://www.mcpiqojournal.org) and standardized index terms related to naltrexone therapy for medically hospitalized patients with AUD. Two uncontrolled pre-post study designs evaluated naltrexone prescription rates, 30-day readmission rates, and rehospitalization rates. Two authors independently abstracted data on study characteristics, results, and study-level risk of bias. The research team collaborated to assess the strength of evidence across studies. Two studies reported that implementing a protocol for naltrexone initiation increased MAT rates, with one study noting a substantial decrease in 30-day hospital readmissions. Overall, we found that there is a paucity of data on naltrexone initiation in the inpatient setting for AUDs. This likely reflects the nature of current clinical practice and prescriber comfortability. There is a need for further studies evaluating MAT initiation in the inpatient setting. Furthermore, efforts to increase provider knowledge of these therapeutic options are in need of further exploration.

Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores.

Bipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic polygenic risk score (PRS) analysis using multiple PRSs from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank (N = 968) and Genetic Association Information Network (N = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p = 0.003) and BMI (OR = 0.87; p = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p = 7e-5) and MDD (OR = 1.23; p = 4e-5) and lower BD PRS (OR = 0.8; p = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p = 1e-6) and anhedonia (OR = 1.22; p = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity contributes to clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

Label-free proteomics differences in the dorsolateral prefrontal cortex between bipolar disorder patients with and without psychosis.

BACKGROUND: Psychosis is common in bipolar disorder (BD) and is related to more severe cognitive impairments. Since the molecular mechanism of BD psychosis is elusive, we conducted this study to explore the proteomic differences associated with BD psychosis in the dorsolateral prefrontal cortex (DLPFC; BA9). METHODS: Postmortem DLPFC gray matter tissues from five pairs of age-matched male BD subjects with and without psychosis history were used. Tissue proteomes were identified and quantified by label-free liquid chromatography tandem mass spectrometry and then compared between groups. Statistical significance was set at q < 0.40 and Log2 fold change (Log2FC) ≥ |1|. Protein groups with differential expression between groups at p < 0.05 were subjected to pathway analysis. RESULTS: Eleven protein groups differed significantly between groups, including the reduction of tenascin C (q = 0.005, Log2FC = -1.78), the elevations of synaptoporin (q = 0.235, Log2FC = 1.17) and brain-specific angiogenesis inhibitor 1-associated protein 3 (q = 0.241, Log2FC = 2.10) in BD with psychosis. The between-group differences of these proteins were confirmed by Western blots. The top enriched pathways (p < 0.05 with ≥ 3 hits) were the outgrowth of neurons, neuronal cell proliferation, growth of neurites, and outgrowth of neurites, which were all predicted to be upregulated in BD with psychosis. LIMITATIONS: Small sample size and uncertain relationships of the observed proteomic differences with illness stage and acute psychosis. CONCLUSIONS: These results suggested BD with psychosis history may be associated with abnormalities in neurodevelopment, neuroplasticity, neurotransmission, and neuromodulation in the DLPFC.

Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder.

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10-13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

Rehospitalization to a child and adolescent psychiatry unit: Role of trauma and bullying.

OBJECTIVE: Psychiatric rehospitalizations results in a significant burden to patients, families, and health care systems. Understanding psychiatric rehospitalizations offers an opportunity to identify weaknesses in current systems of care. The objective of this study was to test the hypothesis that a history of trauma or ongoing bullying increases the risk of psychiatric rehospitalization. METHOD: Retrospective cohort study of 366 individual patients (71% female) admitted to a pediatric psychiatry unit between 1/1/2015 and 12/31/2015. The primary outcome measure was rehospitalization to the same psychiatric hospital unit within one year of first discharge. Trauma was defined as having a history of Post-Traumatic Stress Disorder, Reactive Attachment Disorder, or a filed Suspected Abuse and Neglect of a Child report by the end of first hospitalization. Ongoing bullying was identified by medical record review. RESULTS: History of trauma (Odds Ratio (OR) = 3.2, 95% Confidence Interval (CI) = 1.8-5.6, p < 0.0001) and ongoing bullying (OR = 2.2, CI = 1.2-3.9, p = 0.009) were significantly associated with increased rates of rehospitalizations. We controlled for the following covariates: Patient Health Questionnaire-9 Modified (PHQ-9M) score, gender, age, relative age, initial length of stay, disrupted family system, and sexual orientation/identity. CONCLUSION: History of trauma or ongoing bullying are important risk factors for pediatric psychiatric rehospitalization.

Treatment of Generalized Anxiety Disorder with Gabapentin.

Gabapentin is frequently used in the treatment of anxiety disorders. However, there are no randomized controlled trials on the effectiveness of this medication in generalized anxiety disorder (GAD), and there are only a few case reports. We present a case of a 59-year-old female with a psychiatric history of GAD. The patient discontinued benzodiazepines after more than 7 years of daily treatment which led to rebound anxiety, benzodiazepine withdrawal symptoms, and suicidal ideation. She was psychiatrically hospitalized and started on gabapentin. Over the next 10 months of outpatient follow-up, she attempted to taper off gabapentin due to personal preference to limit medications. During this time, we observed a clear dose-response pattern of gabapentin on GAD symptoms. In the absence of controlled studies, these findings may offer important information about the effectiveness of gabapentin in GAD.

Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms.

BACKGROUND: Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder. METHODS: Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death was used to test associations with circadian rhythms. RESULTS: SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p = .003) and SZ (Nt, p = .02). In normal control subjects, Nt of SST-IR neurons varied according to time of death. This pattern was altered in BD subjects, characterized by decreases of SST-IR neurons selectively in subjects with time of death corresponding to the day (6:00 am to 5:59 pm). Numbers of neuropeptide Y-IR neurons were not affected. CONCLUSIONS: Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

Benzodiazepine Use in Older Adults: Dangers, Management, and Alternative Therapies.

Several major medical and psychiatric organizations, including the American Geriatrics Society, advise against using benzodiazepines or nonbenzodiazepine hypnotics in older adults. Despite these recommendations, benzodiazepines continue to be massively prescribed to a group with the highest risk of serious adverse effects from these medications. This article summarizes legitimate reasons for prescribing benzodiazepines in the elderly, serious associated risks of prescribing them, particularly when not indicated, barriers physicians encounter in changing their prescription patterns, and evidence-based strategies on how to discontinue benzodiazepines in older patients. Although more research is needed, we propose several alternatives for treating insomnia and anxiety in older adults in primary care settings. These include nonpharmacological approaches such as sleep restriction-sleep compression therapy and cognitive behavioral therapy for anxiety or insomnia, and as well as alternative pharmacological agents.

Highlights from the Biennial International Congress on Schizophrenia Research (ICOSR), March 28-April 1, 2015.

The 2015 International Congress on Schizophrenia Research, held in Colorado Springs, Colorado, attracted over 1,000 attendees from March 28-April 1, 2015. With the gracious assistance of Congress directors Carol Tamminga and Chuck Schulz, as well as meeting staff Dorothy Denton and Cristan Tamminga, we bring you the following reports on various Congress sessions concerning approaches to prevention in schizophrenia and social cognition.

Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia.

Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.