Background The Departments of Veterans Affairs (VA) and Defense (DOD) provide care each year for approximately 75,000 people with first-episode psychoses or schizophrenia, but neither has formal, evidence-based guidance for treating these conditions. Recognition of this gap, together with guidance from Congress, led the Departments to develop clinical practice guidelines for first-episode psychosis and schizophrenia. This synopsis summarizes the psychopharmacological and other somatic treatment recommendations. Study Design An interdisciplinary panel of VA and DOD mental health and primary care providers was created following methods specified by the VA/DOD Evidence-Based Practice Guideline Work Group. The panel formulated key questions that guided a comprehensive search of the intervention literature from November 2011 to December 2021, with evidence limited to findings from randomized clinical trials. Recommendations were based on evaluation of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. Study Results The VA/DOD guideline panel developed 15 pharmacological and somatic treatment recommendations, including those on antipsychotic medication use for the treatment of first-episode psychosis and schizophrenia, use of clozapine for treatment-resistant schizophrenia, treatment of clozapine non-responders, and side effect management. There was insufficient evidence to provide recommendations for or against the use of non-antipsychotic medications or somatic treatments to treat negative or cognitive symptoms. Conclusions The VA/DOD guideline panel developed 15 pharmacological and somatic treatment recommendations to promote optimal, evidence-based care for active service members and Veterans. However, there remain multiple treatment planning decision points for which there is a lack of data and/or effective treatments.

Background Despite the large number of people treated for first-episode psychosis and schizophrenia within the Departments of Defense (DOD) and Veterans Affairs (VA), neither the DOD nor VA had established formal recommendations for the treatment of these conditions. This gap led Congress to require the development of clinical practice guidelines (CPG) for the treatment of schizophrenia. This paper reports on the psychosocial and rehabilitative recommendations presented in the VA/DOD Clinical Practice Guidelines for Management of First-Episode Psychosis and Schizophrenia. Study Design The CPG was developed by an interdisciplinary panel of mental health and primary care providers from DOD and VA following methods specified by the VA/DOD Evidence-Based Practice Guideline Work Group. The panel formulated key questions and identified critical outcomes that guided a comprehensive search of the literature published from November 2011 to December 2021. The evidence considered was limited to systematic reviews, meta-analyses, and randomized clinical trials. Recommendations were based on the evaluation of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. Study Results The review process produced 4 psychosocial/rehabilitative treatment recommendations for first-episode psychosis (early intervention services, family interventions, individual placement and support (IPS), and cognitive behavioral therapy for psychosis) and 11 recommendations for schizophrenia (family and caregiver services, assertive community treatment, IPS, smoking cessation, skills training, cognitive training, psychotherapies, aerobic exercise, yoga, weight management, and telephone-based care management). Conclusions The VA/DOD CPG reflects the expansion of treatments for first-episode psychosis and schizophrenia and highlights the challenges in developing clinical practice guidelines.

BackgroundCurrent literature does not thoroughly examine the development or treatment of first episode psychosis (FEP) among active duty service members.MethodsWe conducted a rapid review on demographics, epidemiology, assessment, and intervention for FEP among service members. The final dataset contained eight peer-reviewed articles published between 2011 and 2021.ResultsIncidence of FEP among service members ranged from 1.4 to 2.3 for schizophrenia and 5.6 to 9.3 for other psychotic disorders per 10,000 person-years. Risk factors for developing psychosis during active duty service included distance of the place of service to home, multiple substance use, birthplace or place of residence in small towns or large cities, psychosocial stress, placement in an Army service branch or motor transport occupation, and more than one visit to mental health providers in the year before diagnosis. Racial minority status, younger age, less education, lower military grade, less time spent in service, and never-married status were also associated with higher risk of FEP.ConclusionEnhancing screening procedures before and after military entrance, reducing the impact of psychosocial stress during military initiation, and providing early, multimodal treatment for FEP would likely improve health outcomes for service members and reduce burden on the Military Health System.

Supplemental Digital Content is Available in the Text.Results demonstrated that both opioid and benzodiazepine prescriptions 30 days before case onset were independently associated with subsequent injuries in US service members. Given the high rates of physical trauma and pain among service members, opioid-prescribing practices and use patterns have significant implications for the well-being of service members and can affect military medicine and personnel readiness. This study measured the association between prescribed opioid and benzodiazepine medications and subsequently reported injuries (accidental, alcohol and drug related, self-inflicted, and violence related) among active duty military members. Participants were service members who entered the military between January 1, 2005, and June 30, 2010. In a nested case-control design, we compared individuals with injuries to individuals without injuries with respect to their opioid and benzodiazepine prescriptions in the 30 days before the injury of an index case. We used a multiintercept, logistic regression model to compare coefficient estimates by injury type. Overall, approximately 17% of individuals with an injury and 4% of individuals without an injury had a recorded opioid prescription. Individuals with an injury of any type had greater odds of prior exposure to opioid prescriptions than controls. Although a dose-response effect was observed for all injury types, it reached a plateau sooner for natural or environmental accidents and self-inflicted injuries relative to alcohol-related and drug-related injuries, violence-related injuries, vehicle accidents, accidental falls, and other accidents. Benzodiazepine prescriptions were found in 3.5% of individuals with an injury and 0.5% of individuals without an injury. The association between benzodiazepine prescriptions and injuries was strongest for natural and environmental accidents.

Description: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations. Methods: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis. Recommendations: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.

Repetitive transcranial magnetic stimulation (rTMS) as a treatment for posttraumatic stress disorder (PTSD) has gained interest over the past two decades. However, it has yet to be recommended in major treatment guidelines. We conducted a systematic review of randomized controlled trials to examine the efficacy of rTMS for PTSD. Thirteen studies with 549 participants were included in this review. We compared the effects of (1) rTMS versus sham, and (2) high-frequency (HF) versus low-frequency (LF) rTMS, on posttreatment PTSD scores and other secondary outcomes. We calculated the standardized mean differences (SMD) to determine the direction of effects, and unstandardized mean differences to estimate the magnitude of efficacy. At post-treatment, rTMS was superior to sham comparison in reducing PTSD (SMD = -1.13, 95% CI: -2.10 to -0.15) and depression severity (SMD = -0.83, 95% CI: -1.30 to -0.36). The quality of evidence, however, was rated very low due to small samples sizes, treatment heterogeneity, inconsistent results, and an imprecise pooled effect. HF rTMS was associated with slightly improved, albeit imprecise, outcomes compared to LF rTMS on PTSD (SMD = -0.19, 95% CI: -1.39 to 1.00) and depression (SMD = -1.09, 95% CI: -1.65 to -0.52) severity. Further research is required to advance the evidence on this treatment.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1–2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

OBJECTIVE:To demonstrate the prevalence of opioid use disorder (OUD) in the military health system (MHS), geographically map OUD patients and providers, and offer policy recommendations to help increase buprenorphine waiver prescribing.DESIGN:This study was a retrospective review of data from the MHS records. Deidentified records of MHS OUD patients receiving buprenorphine were utilized. Secondary data with nonpersonally identifiable information (PII) were used for pulling records of buprenorphine prescribing providers within the direct care system (MHS providers) and providers from the purchased care system (civilian facilities accepting TRICARE beneficiaries).SETTING:This study reviewed records of individuals within the MHS, in the United States, and its territories.PATIENTS AND PARTICIPANTS:Patients within the MHS system with a diagnosis of OUD. Providers, within the MHS or purchased care, who had prescribed buprenorphine were selected.MAIN OUTCOME MEASURED:The number of OUD patients in the MHS and providers caring for these OUD patients. In addition, geographical maps illustrating the dispersion of OUD patients, and prescribers were created.RESULTS:The vast majority of MHS OUD patients receive their care from purchased care. Between 2015 and 2018, there has been a shift in the number OUD diagnosed patients by region, and the number of OUD prescribers.CONCLUSION:The MHS population, particularly active duty, is a transient population. As such, it is not a surprise that the population of OUD patients or prescribers varied by region during that time period. Furthermore, results demonstrate that there is a need to increase the number of buprenorphine-waivered prescribers within the MHS. Changes in policy may encourage more providers to obtain the waiver or increase patient load.

This paper presents data from the United States Department of Defense Suicide Event Report System for years 2012-2015 to detail descriptive, longitudinal rate data and risk factor profiles associated with military suicide. The annual findings were aggregated from all U.S. military suicide deaths and suicide attempts. Data elements included the most common method of suicide (firearms), most common behavioral health diagnoses (substance abuse/dependence), common life stressors (failed intimate-partner relationships), and an individual's history of operational deployment. Age- and sex-adjusted rates for the Services were compared with rates for the U.S. adult population. Results showed that the current reporting period (2015) is similar to patterns that have been observed over the preceding years and to patterns reported in the overall U.S. adult population. Suicide rates remain elevated but stable for both the Active and Reserve Components of the Military Services compared to historical levels observed prior to 2003. Finally, we discuss common errors and misinterpretations that can occur when analyzing surveillance data.

Neural cell adhesion molecule (N-CAM) is a cell recognition molecule, four major isoforms (180: 140, 120, and 105-115 kDa) of which are present in brain. N-CAM has several roles in cellular organization and CNS development. Previously we have found an elevation in CSF N-CAM 120 kDa in the CSF of patients with schizophrenia, bipolar disorder, and depression. We now report an increase in the variable alternative spliced exon (VASE), a 10 amino acid sequence inserted into the fourth N-CAM domain, in the CSF of patients with schizophrenia, but not in bipolar disorder or depression. VASE-immunoreactive (VASE-ir) bands were measured in CSF from patients with schizophrenia (n = 14), bipolar disorder I (n = 7), bipolar disorder II (n = 9), unipolar depression (n = 17) and matched controls (n = 37) by Western immunoblotting. Three VASE-ir bands were distinguished in lumbar CSF corresponding to heavy (165 kDa), medium (155 kDa) and low (140 kDa) MW. A logarithmic transformation was applied to the VASE protein units and analyzed with a MANOVA. There was a 51% and 45% increase in VASE heavy (p = 0.0008) and medium (p = 0.04) MW protein, respectively, in patients with schizophrenia as compared with normal controls. Current neuroleptic treatment in patients with schizophrenia had no effect on CSF VASE concentrations. VASE concentration correlated significantly with behavioral ratings in patients with schizophrenia but not affective disorders. Thus, VASE immunoreactivity is increased in schizophrenia but not in affective disorders. These results provide further evidence of an abnormality of N-CAM protein in chronic schizophrenia and suggest differences between schizophrenia and affective disorders in regulation of N-CAM. Published by Elsevier Science Ltd.

Clonidine is a centrally acting antihypertensive and has been prescribed widely for more than 20 years. Because it decreases central norepinephrine activity, clonidine has been investigated as an antipsychotic. In most of the preliminary studies, clonidine was tested as the sole antipsychotic agent. We performed a double-blind, placebo-controlled, crossover study to compare a placebo plus a neuroleptic to clonidine plus a neuroleptic in a group of 16 chronically psychotic patients. Of these 16, 3 dropped out secondary to side effects of the clonidine and 1 withdrew from the study. The clonidine dosage varied from 0.2 to 0.6 mg per day. The concurrent neuroleptic (one of the following: haloperidol, thiothixene, thioridazine, mesoridazine, or fluphenazine) averaged 34 mg per day of haloperidol equivalents. Symptoms were monitored using the Psychiatric Symptoms Assessment Scale. The data provided evidence that a clonidine/neuroleptic combination was not more effective than a neuroleptic alone in this group of patients. These data suggest that the central antino-repinephrine activity of a neuroleptic is not potentiated further by clonidine.

Transforming growth factor betas (TGFβs) are potent immunosuppressive molecules released in the brain after injury. We hypothesized that TGFβ levels in cerebrospinal fluid (CSF) of schizophrenic patients would be altered because TGFβ can influence neural cell adhesion moelecule (N-CAM) expression in vitro. The levels of TGFβ1 and β2 in CSF of patients with schizophrenia and normal controls measured by ELISA showed no differences. There was evidence that the stability of TGFβ in CSF may be altered in schizophrenia. For a limited sample, TGFβ1 and N-CAM concentrations were significantly correlated in normal patients (r = 0.98) but not in schizophrenics. The results do not support an active neurodegeneration or anti-inflammatory response in the central nervous system, which is reflected in the CSF of chronic schizophrenics.

While schizophrenia has a genetic component, its pathogenesis is unknown. Abnormal concentrations of two cell recognition molecules (CRMs), neural-cell adhesion molecule (N-CAM) and L1 antigen have been described in the cerebrospinal fluid (CSF) of patients with schizophrenia. Studies of monozygotic twins discordant for schizophrenia may help separate genetic and environmental contributions to the disease. In the present study of monozygotic twins discordant for schizophrenia, the affected twins had increased N-CAM and decreased L1 antigen in their CSF. Non-affected twins were not different from normals. Although processes related to genetic instability cannot be entirely ruled out, these results suggest that these abnormalities are not a part of the genetic predisposition to become schizophrenic. Thus the changes in N-CAM and L1 antigen may reflect either the events which precipitated the onset of schizophrenia, or events which are associated with the experience of having the disease.

Recent hypotheses and findings indicate that measurements of interactions between cerebrospinal fluid (CSF) biogenic amine systems, rather than measurement of CSF biogenic amine metabolites, better correlate with clinically important findings in schizophrenia. To test these hypotheses, we used a recent technological advance in high performance liquid chromatography with electrochemical detection and combined it with multivariate statistical analyses to study biogenic amine concentrations in CSF in schizophrenia. This approach enabled the study of the interactions of several metabolites of each of the three major neurotransmitter pathways (dopaminergic, noradrenergic, and serotonergic) to test existing hypotheses regarding the neurobiochemical basis of schizophrenia. Twenty biogenic amines, their metabolites, and other compounds from 24 medication-free schizophrenic patients and 12 normal control subjects were simultaneously measured using a recently developed technique of gradient high performance liquid chromatography coupled with a 16-channel electrochemical array detector. After covariation for storage time, results of a stepwise discriminant function analysis comparing the control and patient groups identified tryptophan, tryptophol, and epinephrine as discriminating variables. Hotelling's paired T-2 test from a subgroup of schizophrenic patients studied while they were and were not receiving neuroleptic treatment did not yield any significant differences between subgroups. A discussion of the findings and a comparison with previous studies of CSF biogenic amines in schizophrenia are presented.

We conducted an MRI pilot study of three schizophrenic patients with the syndrome of polydipsia-hyponatremia. Paired MRI scans were obtained at baseline and in the water-loaded state to study the acute effects of water loading and accompanying changes in serum sodium and osmolality on brain structures. We report the pilot data on the observed individual MRI changes of reduced volume of the lateral ventricles in all three patients, and the third ventricles in two patients, in the water-loaded state. These changes were not statistically significant possibly because of small sample size.

As part of a multidimensional study of cerebrospinal fluid biogenic amine metabolites in schizophrenia, the relationship between neurochemical measures and psychopathology assessed using the Psychiatric Symptom Assessment Scale (PSAS) was analyzed. In a group of 20 unmedicated patients, 3,4-dihydroxyphenylacetic acid (DOPAC) was a predictor of symptom severity in a stepwise multiple regression model. Values of 3-hydroxykynurenine and metanephrine in the unmedicated state predicted clinical response in a stepwise multiple regression model, as measured by improvement in PSAS mean item score following 6 weeks on a standard dose of neuroleptic. In a subgroup of 14 patients in whom both off- and on-medication concentrations of cerebrospinal fluid biogenic amines and metabolites were measured, change in 3-hydroxykynurenine predicted clinical outcome in a multiple regression model. These findings point toward the need to examine the role of the kynurenine pathway of tryptophan metabolism in the pathophysiology of schizophrenia.

The exact role of azodye reductase, a liver microsmal enzyme, and its influence on the hepatocarcinogenicity of 4-dimethylaminoazobenzene (DAB) are uncertain. The effect of DAB is depressed by many nutritional factors, including trytophan. Therefore, the effects of o-aminophenol and of L-tryptophan and its metabolites L-kynurenine, anthranilic acid, kynurenic acid, quinaldic acid, 3-hydroxy-DL-kynurenine, 3-hydroxyanthranilic acid, xanthurenic acid, quinolinic acid, N-methylnicotinamide, and N′-methylnicotin-amide on rat liver azoreductase activity were determined, using DAB as substrate. Only 3-hydroxyanthran- ilic acid, 3-hydroxykynurenine and o-aminophenol decreased enzyme activity. The inhibition was greater if the buffered solutions (pH 7.4) of these three compounds were kept overnight before use, but the effect was prevented if these compounds were prepared in solutions of L-ascorbic acid and/or L-cysteine HCl. This observation indicates that the autoxidation products were probably responsible for inhibition of the enzyme. Further study of the oxidation products including the phenylquinoneimine formed from the oxidation of 3-hydroxyanthranilic acid in air, cinnabarinic acid, xanthommatin, 2-amino-3H-isophenoxazin-3-one, 1,9-dimethyl-2-amino-3H-phenoxazin-3-one and actinomycin D showed that all these compounds inhibited enzyme activity. A non-competitive type of inhibition was observed in the presence of cinnabarinic acid and xanthommatin. Cinnabarinic acid, xanthommatin, 2-amino-3H-isophenoxazin-3-one, 1,9-dimethyl-2-amino-3H-phenoxazin-3-one, a nd actinomycin D all have the same phenoxazinone ring system, suggesting that the driving factor in the inhibition of the azoreductase is the presence of the phenoxazinone chromophore. The chemical resemblance of these phenoxazinones to the coenzyme riboflavine further supports this supposition.