The 10 most-cited articles in American Journal of Psychiatry, 2021

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex…

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of…

OBJECTIVE: The authors sought to identify scalable evidence-based suicide prevention strategies. METHODS: A search of PubMed and Google Scholar identified 20,234 articles published between September 2005 and December 2019, of which 97 were randomized controlled trials with suicidal behavior or ideation as primary outcomes or epidemiological studies of limiting access to lethal means, using educational approaches, and the impact of antidepressant treatment. RESULTS: Training primary care physicians in depression recognition and treatment prevents suicide. Educating youths on depression and suicidal behavior, as well as active outreach to psychiatric patients after discharge or a suicidal crisis, prevents suicidal behavior. Meta-analyses find that antidepressants prevent suicide attempts, but individual randomized controlled trials appear to be underpowered. Ketamine reduces suicidal ideation in hours but is untested for suicidal behavior prevention. Cognitive-behavioral therapy and dialectical behavior therapy prevent suicidal behavior. Active screening for suicidal ideation or…

OBJECTIVE: It is estimated that childhood attention deficit hyperactivity disorder (ADHD) remits by adulthood in approximately 50% of cases; however, this conclusion is typically based on single endpoints, failing to consider longitudinal patterns of ADHD expression. The authors investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood. METHODS: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) underwent eight assessments over follow-ups ranging from 2 years (mean age, 10.44 years) to 16 years (mean age, 25.12 years) after baseline. The authors identified participants with fully remitted, partially remitted, and persistent ADHD at each time point on the basis of parent, teacher, and self-reports of ADHD symptoms and impairment, treatment utilization, and substance use and mental disorders. Longitudinal patterns of remission and persistence were identified that considered context and timing. RESULTS: Approximately 30% of children with ADHD experienced full remission at some point during the…

Obsessive-compulsive disorder (OCD) is a common, chronic, and oftentimes disabling disorder. The only established first-line treatments for OCD are exposure and response prevention, and serotonin reuptake inhibitor medications (SRIs). However, a subset of patients fails to respond to either modality, and few experience complete remission. Beyond SRI monotherapy, antipsychotic augmentation is the only medication approach for OCD with substantial empirical support. Our incomplete understanding of the neurobiology of OCD has hampered efforts to develop new treatments or enhance extant interventions. This review focuses on several promising areas of research that may help elucidate the pathophysiology of OCD and advance treatment. Multiple studies support a significant genetic contribution to OCD, but pinpointing the specific genetic determinants requires additional investigation. The preferential efficacy of SRIs in OCD has neither led to discovery of serotonergic abnormalities in OCD nor to development of new serotonergic medications for OCD. Several lines of preclinical and clinical…

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. METHODS: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the…

Schizophrenia is a complex neuropsychiatric syndrome with a heterogeneous genetic, neurobiological, and phenotypic profile. Currently, no objective biological measures—that is, biomarkers—are available to inform diagnostic or treatment decisions. Neuroimaging is well positioned for biomarker development in schizophrenia, as it may capture phenotypic variations in molecular and cellular disease targets, or in brain circuits. These mechanistically based biomarkers may represent a direct measure of the pathophysiological underpinnings of the disease process and thus could serve as true intermediate or surrogate endpoints. Effective biomarkers could validate new treatment targets or pathways, predict response, aid in selection of patients for therapy, determine treatment regimens, and provide a rationale for personalized treatments. In this review, the authors discuss a range of mechanistically plausible neuroimaging biomarker candidates, including dopamine hyperactivity, N-methyl-d-aspartate receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, and…

The authors examine U.S.-based evidence that connects characteristics of the social environment with outcomes across the psychosis continuum, from psychotic experiences to schizophrenia. The notion that inequitable social and economic systems of society significantly influence psychosis risk through proxies, such as racial minority and immigrant statuses, has been studied more extensively in European countries. While there are existing international reviews of social determinants of psychosis, none to the authors' knowledge focus on factors in the U.S. context specifically-an omission that leaves domestic treatment development and prevention efforts incomplete and underinformed. In this review, the authors first describe how a legacy of structural racism in the United States has shaped the social gradient, highlighting consequential racial inequities in environmental conditions. The authors offer a hypothesized model linking structural racism with psychosis risk through interwoven intermediary factors based on existing theoretical models and a review of the literature. Neighborhood…

OBJECTIVE: The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank. METHODS: This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status. RESULTS: CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than…