What is the neurobiology of schizophrenia?

Schizophrenia spectrum disorders are brain diseases that are developmental dementias (dementia praecox). Their pathology begins in utero with psychosis most commonly becoming evident in adolescence and early adulthood. It is estimated they afflict the U.S. population at a prevalence rate of approximately 0.8%. Genetic studies indicate that these brain diseases are about 80% determined by genes and about 20% determined by environmental risk factors. Inheritance is polygenic with some 270 gene loci having been identified as contributing to the risk for schizophrenia. Interestingly, many of the identified gene loci and gene polymorphisms are involved in brain formation and maturation. The identified genetic and epigenetic risks give rise to a brain in which neuroblasts migrate abnormally, assume abnormal locations and orientations, and are vulnerable to excessive neuronal and synaptic loss, resulting in overt psychotic illness. The illness trajectory of schizophrenia then is one of loss of brain mass related to the number of active psychotic exacerbations and the duration of untreated illness. In this context, molecules such as dopamine, glutamate, and serotonin play critical roles with respect to positive, negative, and cognitive domains of illness. Acutely, antipsychotics ameliorate active psychotic illness, especially positive signs and symptoms. The long-term effects of antipsychotic medications have been debated; however, the bulk of imaging data suggest that antipsychotics slow but do not reverse the illness trajectory of schizophrenia. Long-acting injectable antipsychotics (LAI) appear superior in this regard. Clozapine remains the "gold standard" in managing treatment-resistant schizophrenia.

Stroke death in patients receiving radiation for head and neck cancer in the modern era.

Objectives: Head and neck cancer is a common malignancy frequently treated with chemotherapy and radiotherapy. Studies have shown an increased risk of stroke with the receipt of radiotherapy, but data on stroke-related mortality are limited, particularly in the modern era. Evaluating stroke mortality related to radiotherapy is vital given the curative nature of head and neck cancer treatment and the need to understand the risk of severe stroke in this population. Methods: We analyzed the risk of stroke death among 122,362 patients (83,651 patients who received radiation and 38,711 patients who did not) with squamous cell carcinoma of the head and neck (HNSCC) diagnosed between 1973 and 2015 in the SEER database. Patients in radiation vs. no radiation groups were matched using propensity scores. Our primary hypothesis was that radiotherapy would increase the hazard of death from stroke. We also examined other factors impacting the hazard of stroke death, including whether radiotherapy was performed during the modern era when IMRT and modern stroke care were available as well as increased HPV-mediated cancers of the head and neck. We hypothesized that the hazard of stroke death would be less in the modern era. Results: There was an increased hazard of stroke-related death in the group receiving radiation therapy (HR 1.203, p = 0.006); however, this was a very small absolute increase, and the cumulative incidence function of stroke death was significantly reduced in the modern era (p < 0.001), cohorts with chemotherapy (p=0.003), males (p=0.002), younger cohorts (p<0.001) and subsites other than nasopharynx (p=0.025). Conclusions: While radiotherapy for head and neck cancer increases the hazard of stroke death, this is reduced in the modern era and remains a very small absolute risk.

Patterns of recurrence after intracranial stereotactic radiosurgery for brain-only metastases from non-small cell lung cancer and the impact of upfront thoracic therapy with synchronous presentation.

Background: We characterized long-term organ-specific patterns of recurrence, time to progression (TTP) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) with brain-only metastases treated with single-fraction stereotactic radiosurgery (SRS) and analyzed the impact of upfront thoracic therapy (UTT) in those with synchronous presentation of primary NSCLC and brain metastases. Methods: The clinical records of 137 patients with brain metastases from NSCLC treated with intracranial SRS, and no other metastatic sites, were retrospectively reviewed. Patients with available follow-up imaging (n=124) were analyzed for patterns of recurrence; all were analyzed for OS. Results: The majority of first distant recurrences were in brain and thoracic sites, while extra-thoracic sites were relatively uncommon. After median follow-up of 16.0 months, 24.8% did not develop recurrence outside of brain and/or thoracic sites and 43.5% were free of distant extracranial recurrence. Whole brain radiotherapy (WBRT) and UTT, but not systemic therapy, altered patterns of recurrence and intracranial or extracranial TTP. Multivariable analysis revealed UTT, but not systemic therapy or WBRT, was associated with more favorable OS [hazard ratio (HR) 0.515, P=0.029] among 88 patients with synchronous presentation. Within the subgroup of thoracic stage III patients (n=69), those treated with UTT experienced remarkable median extracranial TTP and OS of 19.3 and 22.7 months, respectively. Conclusions: First and cumulative recurrences in patients treated with intracranial SRS for NSCLC metastases limited to brain are most often in the brain and thorax. Long-term survival is possible, regardless of thoracic stage, and is dependent on UTT among other factors.

Squamous cell carcinoma of the head and neck with unknown primary: trends and outcomes from a hospital-based registry.

BACKGROUND: Squamous cell carcinoma of unknown primary of the head and neck region is a known entity described mainly by retrospective reports. We searched a hospital-based registry to better describe the changing incidence, and to assess diagnostic and treatment strategies. METHODS: The National Comprehensive Cancer Database was queried for head and neck cancers from oropharynx, tonsil, tongue, larynx, hypopharynx primary sites with a designation of clinical T0, representing an unknown primary. Kaplan Meier, Cox multivariate models, and propensity matched cohorts were used to assess significant factors for overall survival. RESULTS: There were 964 cases that met the criteria, and 468 cases with known treatments, staging, and survival data. The incidence increased over time, with the highest rates supported in the last 5 years. In patients who underwent HPV testing, 72% were positive. Patients with AJCC 7th clinical N2c or N3 disease had significantly worse outcomes despite the majority receiving neck dissection, radiation, and chemotherapy. Local surgery, compared to incisional or excisional biopsy, had the highest diagnostic yield of finding a primary tumor. In multivariate models, no combination of surgical approach, radiation, or systemic therapy was significantly associated with improved survival. This remained true in 1:1 propensity matched cohorts for age, comorbidities, and clinical nodal burden. In a subset of cN1 patients, combined chemoradiation therapy after excisional biopsy or local surgery was associated with (not statistically significant) improved survival compared to radiation alone (P=0.054). CONCLUSIONS: The incidence of unknown primary head and neck carcinoma is increasing, and current cases have a high proportion of HPV positivity. HPV positivity predicts strongly for a tonsil primary. Local surgery was associated with the highest diagnostic yield. Clinical nodal burden strongly predicts for overall outcome, and type of treatment facility is an important driver of survival. A subset of cN1 patients may benefit from the addition of chemotherapy to radiation.

Long-Term Maintenance of Acinar Cells in Human Submandibular Glands After Radiation Therapy.

PURPOSE: In a combined retrospective and prospective study, human salivary glands were investigated after radiation treatment for head and neck cancers. The aim was to assess acinar cell loss and morphologic changes after radiation therapy and to determine whether irradiated salivary glands have regenerative potential. METHODS AND MATERIALS: Irradiated human submandibular and parotid salivary glands were collected from 16 patients at a range of time intervals after completion of radiation therapy (RT). Control samples were collected from 14 patients who had not received radiation treatments. Tissue sections were analyzed using immunohistochemistry to stain for molecular markers. RESULTS: Human submandibular and parotid glands isolated less than 1 year after RT showed a near complete loss of acinar cells. However, acinar units expressing functional secretory markers were observed in all samples isolated at later intervals after RT. Significantly lower acinar cell numbers and increased fibrosis were found in glands treated with combined radiation and chemotherapy, in comparison to glands treated with RT alone. Irradiated samples showed increased staining for duct cell keratin markers, as well as many cells coexpressing acinar- and duct cell-specific markers, in comparison to nonirradiated control samples. CONCLUSIONS: After RT, acinar cell clusters are maintained in human submandibular glands for years. The surviving acinar cells retain proliferative potential, although significant regeneration does not occur. Persistent DNA damage, increased fibrosis, and altered cell identity suggest mechanisms that may impair regeneration.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis.

AIM: Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC). METHODS: From the Surveillance, Epidemiology and End Results registry, patients with pathologically confirmed T1-3N0 NSCLC were identified. Risks of brain metastases at time of initial diagnosis were analyzed. RESULTS: Patients selected to not undergo primary NSCLC resection had approximately tenfold greater incidence of brain metastases versus those who did. Younger age, adenocarcinoma histology, higher tumor stage and higher histologic grade were all significantly (p < 0.0001) associated with greater likelihood of presenting with brain metastases. CONCLUSION: Given the morbidity and mortality of brain metastases, routine brain screening after NSCLC diagnosis (particularly adenocarcinoma) may be justifiable, though more refined cost-benefit analyses are warranted.

Dopamine antagonist antipsychotics in diverted forensic populations.

In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals suffering from schizophrenia-spectrum disorders. In contrast, however, positive psychotic symptoms (e.g., command hallucinations and persecutory delusions) often drive behavior which serves as the gateway to arrest and criminalization. Historically, the keystone of treatment for positive psychotic symptoms has been antagonism of dopamine D2 receptors in the mesolimbic tract. In this article, we review and explore the principles underlying dopamine antagonism for the treatment of psychosis; optimization of dopamine antagonists in treating positive psychotic symptoms; the advantages of depot dopamine antagonist antipsychotics in forensic settings; the concepts of pharmacokinetic and pharmacodynamic treatment failures; and the role of medication plasma concentrations in optimizing and managing treatment.

Short course radiation therapy for rectal cancer in the elderly: can radical surgery be avoided?

Rectal cancer in elderly patients can be difficult to manage. Short course radiation therapy (SCRT) has shown to be effective when given immediately prior to surgery. Here we report outcomes of elderly patients who underwent SCRT either alone or prior to resection. Between 2010 and 2015, elderly patients with rectal cancer and no distant metastatic disease were identified. Symptoms at diagnosis, therapies, toxicities, and pathologic and clinical response were recorded from patient charts. The SCRT prescription dose was 5 Gy ×5 to the rectal tumor and 4 Gy ×5 to the mesorectum, omitting the iliac nodes. Twenty patients were identified with median age of 85 years (range, 71-93 years). No patient received systemic therapy. Sixty percent of patients were cT3 at diagnosis. Half underwent resection post SCRT and half received SCRT as definitive therapy. The 1- and 2-year overall survival was 75% and 54%. Overall survival did not differ between patients treated with SCRT and surgery compared to SCRT alone (P=0.8). Of the 10 surgical patients, 3 had a complete pathologic response at time of resection and 3 patients died within 2 weeks due to perioperative complications. Of patients treated with SCRT alone, 8 were symptomatic at presentation and 5 had a clinician defined symptomatic response. No patient treated with SCRT monotherapy required additional palliative measures for outflow obstruction, but 2 progressed locally and died. SCRT is well tolerated, results in pathologic complete responses in a small percentage of patients, and achieves 63% symptom improvement rate as monotherapy. A high peri-operative complication rate was observed in this small series. In elderly patients, SCRT as initial treatment with a watch and wait approach for surgery is feasible and should be evaluated prospectively.

Inoperable Pulmonary Carcinoid Tumors: Local Control Rates With Stereotactic Body Radiotherapy/Hypofractionated RT With Image-Guided Radiotherapy.

INTRODUCTION: Surgery is the standard of care for pulmonary carcinoid tumors; however, options for inoperable patients are few. We report the outcomes of inoperable pulmonary carcinoid patients treated with stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: From an institutional database, we retrospectively identified patients treated with SBRT for pulmonary carcinoid tumors from 2007 to 2017. Additional inclusion criteria were previous histopathologic diagnosis, age older than 18 years and Karnofsky performance status ≥ 70. RESULTS: Ten patients were treated for 12 pulmonary carcinoid lesions with 5 to 10 fractions of SBRT. Their median age was 66.5 years (range, 40-83 years) and most presented with nonspecific symptoms of cough, shortness of breath, or hemoptysis. Pathology revealed typical carcinoid for 9 patients, with the 10th with atypical histology. The median prescription dose for all patients was 50 Gy in 5 to 10 fractions (range, 40-60 Gy) with SBRT/hypofractionated radiation with daily image-guided radiotherapy (IGRT) delivered using a linear accelerator with respiratory monitoring. Four patients received 10-fraction hypofractionated radiation with daily IGRT and 6 others received 5-fraction SBRT. The follow-up after SBRT/hypofractionated IGRT ranged from 6 to 56 months (median, 25 months). Four patients were alive with stable disease at their last follow-up. Two patients died from disease progression in the mediastinal lymph nodes as well as in the lung. Both opted for palliative treatment. The other 4 patients died from their comorbid medical conditions, but had stable disease at their last follow-up. Median overall survival was 27.1 months (range, 5.5-56 months). CONCLUSION: Pulmonary carcinoid tumors treated with SBRT have a promising tumor control rate and survival.

Predicting intracranial progression following stereotactic radiosurgery for brain metastases: Implications for post SRS imaging.

PURPOSE: Follow-up imaging after stereotactic radiosurgery (SRS) is crucial to identify salvageable brain metastases (BM) recurrence. As optimal imaging intervals are poorly understood, we sought to build a predictive model for time to intracranial progression. METHODS: Consecutive patients treated with SRS for BM at three institutions from January 1, 2002 to June 30, 2017 were retrospectively reviewed. We developed a model using stepwise regression that identified four prognostic factors and built a predictive nomogram. RESULTS: We identified 755 patients with primarily non-small cell lung, breast, and melanoma BMs. Factors such as number of BMs, histology, history of prior whole-brain radiation, and time interval from initial cancer diagnosis to metastases were prognostic for intracranial progression. Per our nomogram, risk of intracranial progression by 3 months post-SRS in the high-risk group was 21% compared to 11% in the low-risk group; at 6 months, it was 43% versus 27%. CONCLUSION: We present a nomogram estimating time to BM progression following SRS to potentially personalize surveillance imaging.

Comparison of Single- and Five-fraction Regimens of Stereotactic Body Radiation Therapy for Peripheral Early-stage Non-small-cell Lung Cancer: A Two-institution Propensity-matched Analysis.

PURPOSE: To evaluate differences in local control (LC), disease-specific (DC), and overall survival (OS) of patients with early-stage non-small-cell lung cancer (NSCLC) treated with single- (SF) versus 5-fraction (FF) stereotactic body radiation therapy (SBRT) at 2 institutions. PATIENTS AND METHODS: Peripheral early-stage NSCLC cases treated with a median dose of 30 Gy in SF or a median dose of 50 Gy in FF were included per institutional practice. Kaplan-Meier and Cox models were used to assess survival. A matched-pair analysis was performed to account for imbalances. Toxicities including Common Terminology Criteria for Adverse Events (CTCAE) grade 3 pneumonitis, chest wall pain requiring long-acting narcotics, and hospitalization for respiratory events 6 months posttreatment were recorded. RESULTS: A total of 163 lesions were treated between 2007 and 2015; 65 received SF SBRT and 98 received FF SBRT. Most tumors were T1 (n = 92) and T2 (n = 34) lesions and had adenocarcinoma (n = 77) and squamous cell carcinoma (n = 46) histologies, respectively. In the matched cohort, there were no differences in OS, LC, DC, or progression-free survival between the groups. LC and OS at 1 year in the matched cohort was 95% and 88%, and 87% and 84% in the SF and FF cohorts, respectively. There was 1 grade 3 pneumonitis in the FF group, and 9 total hospitalizations post-SBRT, 3 (5%) in the SF group and 6 (6%) in the FF group. CONCLUSIONS: No statistically significant differences were seen in LC or DC following SF or FF SBRT in this matched cohort of peripheral lesions. No grade 4 or higher toxicities were reported.

Deuterium Tetrabenazine for Tardive Dyskinesia.

Tardive dyskinesia remains a significant, potentially stigmatizing or crippling adverse effect for any patient treated with an antipsychotic medication. While second- and third-generation antipsychotics have exhibited lower annual incidence rates for tardive dyskinesia than classic or first-generation agents, 3.9% versus 5.5%, the estimated incidence rate is only modestly lower. When coupled with the fact that second- and third-generation antipsychotic medications have come to be employed in treating a wider range of disorders (e.g., autism spectrum disorders, mood disorders, personality disorders, etc.), it is clear that the population of patients exposed to the risk of tardive dyskinesia has expanded. On April 3, 2017, the U.S. Food and Drug Administration (FDA) approved a deuterated version of tetrabenazine (Xenozine®) for the treatment of the involuntary choreic movements associated with Huntington's disease. More recent data, however, have indicated that deuterium tetrabenazine or deutetrabenazine (Austedo®) is effective in treating tardive dyskinesia. Moreover, like the other derivative of tetrabenazine, valbenazine (Ingrezza®), deutetrabenazine offers less frequent dosing and a better short-term adverse effect profile than that of tetrabenazine. Longer use in a broader range of patients, however, will be required to identify risks and benefits not found in short-term trials, as well as optimal use parameters for treatment of tardive dyskinesia.

Augmentation of phenelzine with aripiprazole and quetiapine in a treatment-resistant patient with psychotic unipolar depression: case report and literature review.

Irreversible monoamine oxidase inhibitor (MAOI) antidepressants have significant efficacy in treatment-resistant unipolar depression, but in some instances patients may not achieve remission. Among the adjunctive and augmentation strategies, certain second-generation antipsychotics (SGAs) have approval for inadequate responders to antidepressant therapy, including aripiprazole, brexpiprazole, and quetiapine, with lurasidone and the olanzapine/fluoxetine combination indicated for bipolar depression. Clinicians may eschew SGA options in part due to the limited literature on SGA-MAOI combinations, with only one published case involving aripiprazole, and none for olanzapine, lurasidone, or brexpiprazole. In addition to the limited publication history on SGA-MAOI treatment, clinicians may also be deterred by uncertainty regarding SGA mechanisms and the risk of serotonin syndrome or other adverse outcomes. This paper describes the case of a 54-year-old male with a history of psychotic unipolar depression treated with a combination of phenelzine, aripiprazole, and quetiapine, and reviews the 12 published cases of SGA-MAOI combination therapy with a focus on the pharmacological basis for serotonin syndrome, and the SGA mechanisms that should not be associated with a risk for this syndrome.

Psychopharmacology of Persistent Violence and Aggression.

Persistent violence not due to acute psychosis or mania can be managed only after appropriate characterization of the aggressive episodes (psychotic, impulsive, or predatory/planned/instrumental). The type of violence combined with the psychiatric diagnosis dictates the evidence-based pharmacologic approaches for psychotically motivated and impulsive aggression, whereas instrumental violence mandates forensic/behavioral strategies. For nonacute inpatients, schizophrenia spectrum disorders, traumatic brain injury, and dementia comprise the majority of individuals who are persistently aggressive, with impulsive actions the most common form of violence across all diagnoses. Neurobiological considerations combined with empirical data provide a comprehensive framework for systematic medication trials to manage persistently aggressive patients.

Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction.

Objective. Clozapine provides a 50%-60% response rate in refractory schizophrenia but has a narrow therapeutic index and is susceptible to pharmacokinetic interactions, particularly with strong inhibitors or inducers of cytochrome P450 (CYP) 1A2. Case Report. We report the case of a 28-year-old nonsmoking female with intellectual disability who was maintained for 3 years on clozapine 100 mg orally twice daily. The patient was treated for presumptive urinary tract infection with ciprofloxacin 500 mg orally twice daily and two days later collapsed and died despite resuscitation efforts. The postmortem femoral clozapine plasma level was dramatically elevated at 2900 ng/mL, and the cause of death was listed as acute clozapine toxicity. Conclusion. Given the potentially fatal pharmacokinetic interaction between clozapine and ciprofloxacin, clinicians are advised to monitor baseline clozapine levels prior to adding strong CYP450 1A2 inhibitors, reduce the clozapine dose by at least two-thirds if adding a 1A2 inhibitor such as ciprofloxacin, check subsequent steady state clozapine levels, and adjust the clozapine dose to maintain levels close to those obtained at baseline.

The neurobiology of psychopathy: recent developments and new directions in research and treatment.

Psychopathic individuals account for substantial predatory and impulsive violence. To the present, the principal intervention used to decrease the harm inflicted by psychopaths has been confinement. Nevertheless, most confined psychopathic persons return to the community. Recent advances in the understanding of the neurobiology of psychopathy hold promise for new research directions and more effective treatments. In this article, we will explore recent advances in genetics, electrophysiology, brain imaging, and psychopharmacology, as well as, in brief, their implications for new directions in research and treatment.

"Meta-guidelines" for the management of patients with schizophrenia.

Guidelines for treating various conditions can be helpful in setting practice standards, but the presence of several sets of guidelines from different countries, experts, and settings, written at different times, can also create confusion. Here we provide a "guideline of guidelines" for the treatment of schizophrenia, or "meta-guidelines, which not only reconcile the various existing standards but also update them to include the use of several newer agents, most of which were marketed following the publication of existing standards.

TP0326, a Treponema pallidum ß-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein.

Definitive identification of Treponema pallidum rare outer membrane proteins (OMPs) has long eluded researchers. TP0326, the sole protein in T. pallidum with sequence homology to a Gram-negative OMP, belongs to the BamA family of proteins essential for OM biogenesis. Structural modelling predicted that five polypeptide transport-associated (POTRA) domains comprise the N-terminus of TP0326, while the C-terminus forms an 18-stranded amphipathic ß-barrel. Circular dichroism, heat modifiability by SDS-PAGE, Triton X-114 phase partitioning and liposome incorporation supported these topological predictions and confirmed that the ß-barrel is responsible for the native protein's amphiphilicity. Expression analyses revealed that native TP0326 is expressed at low abundance, while a protease-surface accessibility assay confirmed surface exposure. Size-exclusion chromatography and blue native polyacrylamide gel electrophoresis revealed a modular Bam complex in T. pallidum larger than that of Escherichia coli. Non-orthologous ancillary factors and self-association of TP0326 via its ß-barrel may both contribute to the Bam complex. T. pallidum-infected rabbits mount a vigorous antibody response to both POTRA and ß-barrel portions of TP0326, whereas humans with secondary syphilis respond predominantly to POTRA. The syphilis spirochaete appears to have devised a stratagem for harnessing the Bam pathway while satisfying its need to limit surface antigenicity.