Abstract: 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.