Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that delivers a low amount of electrical energy to targeted brain regions. Recently, a tDCS device was approved by the U.S. Food and Drug Administration for treatment of major depressive disorder. Although this is an important step forward, the observed effect size was modest, and finding ways to improve tDCS efficacy is important. One way to do so is to leverage contextual dependence of tDCS effects. tDCS modulates neuronal excitability in a state-dependent manner, and concurrent cognitive, emotional, or behavioral engagement are important contextual factors that might further improve acute and longer-lasting outcomes. The authors outline the theoretical rationale for integrating therapeutic engagement with tDCS and the need for longer follow-up to assess efficacy, drawing on mechanistic insights, and describe a prior use case of tDCS concurrent with a virtual reality context to underscore this use.
The use of digital therapeutics in psychiatry is rapidly expanding. From internet-based psychotherapy to cognitive training modules, digital therapeutics have the potential to scale evidence-based psychiatric care. Concurrently, biological treatments that modulate neuroplasticity are reshaping expectations for the speed and durability of symptom change. This review describes clinical evidence for integrating digital and biological interventions to leverage treatment-induced windows of enhanced neuroplasticity. It provides an overview of existing digital therapeutics and then reviews synergistic combination treatments, outlining evidence that pairing approaches may improve the efficacy of one or both components. Finally, it discusses clinical implications for psychiatrists, including current use cases, practical limitations, and evolving regulatory and reimbursement pathways for digital therapeutics. Overall, integrated digital and biological treatments have promise for enhancing treatment outcomes and improving access. Future directions include adequately powered, well-controlled randomized trials, mechanistic studies of neuroplasticity, and real-world effectiveness research.
Background:Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods:We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings:We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation:All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding:National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.Appeared originally in Lancet 2018; 391:1357-1366.
Over the past 25 years, the field of psychiatry has seen a rapid expansion of ketamine treatment services offered for the off-label management of depression, anxiety, and other psychiatric disorders as well as the U.S. Food and Drug Administration's approval of intranasal esketamine, the S-enantiomer of ketamine, for treatment-resistant depression and suicidal depression. In this review, the authors describe recent advances in the use of ketamine and esketamine for the treatment of depression and other psychiatric disorders, new research on novel treatment targets, and emerging evidence about ketamine's potential as a prophylactic intervention. Key outstanding issues and limitations of current ketamine treatment also are discussed.
Tardive dyskinesia (TD) is characterized by involuntary movements that develop in association with chronic use of antipsychotic medications. While second-generation antipsychotics are associated with lower risk of TD compared with first-generation antipsychotics, their widespread use across a range of chronic mental health conditions (such as psychotic disorders, autism, and mood disorders) has resulted in substantial public health burden of TD. The therapeutic landscape of managing TD has been transformed by the U.S. Food and Drug Administration (FDA) approval of two selective vesicular monoamine transporter 2 (VMAT2) inhibitors in 2017. This report reviews efficacy and safety considerations for the two FDA-approved VMAT2 inhibitors, deutetrabenazine and valbenazine, which are recommended as first-line treatment for troublesome TD in current practice guidelines. Overall, these VMAT2 inhibitors offer significant benefit to patients experiencing TD through improved health and quality of life.
Pediatric posttraumatic stress disorder (PTSD) is a debilitating condition that is associated with significant functional impairment, diagnostic complexity, and limited evidence-based treatment options. Among its core features, trauma-related sleep disturbances-particularly nightmares-are highly prevalent, profoundly impairing, and contribute to the chronicity and severity of the disorder. Prazosin, a selective alpha1-adrenergic antagonist, has demonstrated efficacy in adults for reducing nightmares and improving sleep, but pediatric data remain limited. This case report describes an adolescent male patient with chronic PTSD who achieved full symptomatic remission and functional recovery with prazosin monotherapy. The patient had previously failed to respond to multiple psychotropic classes, including antidepressants, mood stabilizers, and antipsychotics. After initiating prazosin and titrating to 3 mg nightly, he experienced rapid and sustained resolution of nightmares, improvement in sleep quality, and overall reduction of PTSD symptomatology. His UCLA Child/Adolescent PTSD Reaction Index scores declined from 61 to 11 over 20 weeks. This case is contextualized within a narrative review of the pediatric prazosin literature, and highlights pharmacologic rationale, safety considerations, and clinical utility. The findings underscore the central role of sleep disturbances as a pivotal treatment target in pediatric PTSD and support further research into prazosin's therapeutic potential in this population.
Ketamine is a well-established anesthetic agent that is gaining increasing recognition for its diverse therapeutic applications, including the management of chronic pain, refractory status epilepticus, major depressive disorder, and suicidality. Although it has been used clinically since the 1960s, multiple clinical trials with ketamine and esketamine in adults and pediatric populations are ongoing. There has been recent growing interest in ketamine and esketamine for psychiatric conditions in children and adolescents. The clinical use of ketamine is complex, in part because of the numerous available formulations and administration routes. Ketamine has different bioavailability depending on the route of administration: intravenous (100%), intramuscular (64%-93% in adults, 41% in pediatric populations), intranasal (43%-48% in adults, 50% in pediatric populations), sublingual (29%-32%), rectal (25%-30%), epidural (77%), and oral (17%-18%), which is due to extensive first-pass hepatic metabolism. Differences in dosing also produce distinct clinical effects. The challenges associated with ketamine use are further magnified in pediatric populations, for which developmental stage, pharmacokinetics, and neurodevelopmental factors play critical roles in guiding safe and effective treatment. In this review, the authors summarize the pharmacodynamics, pharmacokinetics, adverse effects and contraindications, and clinical applications of ketamine and esketamine among adult and pediatric populations.
Continuous antipsychotic treatment is crucial for relapse prevention in schizophrenia. This article reviews the literature comparing long-acting injectable antipsychotics (LAIs) with oral formulations in various outcomes, including relapse prevention, recovery, and mortality reduction. LAIs ensure consistent medication delivery and are increasingly valued especially for patients in the early phase of schizophrenia, in which they help prevent the irreversible consequences of relapse. The reconceptualization of LAIs underscores their role as proactive rather than as last-resort interventions, which positions them as essential tools in early treatment stages. It is vital for clinicians to communicate effectively with patients and their families about the benefits and practicalities of LAIs. Conversations should begin early in treatment to normalize LAI use by addressing potential misconceptions and emphasizing the role of LAIs in maintaining psychiatric stability and reducing hospitalizations. Engaging family members in discussions enhances support networks, which can then aid the patient's adherence to treatment. Clinicians should provide detailed comparisons between available pharmacologic treatment options, including their dosing intervals, administration methods, and side-effect profiles, that are tailored to patient needs and health care settings. Practical considerations such as storage requirements, insurance coverage, and administration logistics must be addressed. By framing LAIs as valuable components of schizophrenia management, particularly in early phases, clinicians can optimize patient adherence and outcomes. This review highlights the growing recognition of the role of LAIs in contemporary mental health care and advocates for their strategic implementation to enhance patient quality of life.
Neurocognitive disorders (NCDs) encompass various conditions that affect cognition and functioning in activities of daily living. Although many types of NCDs lack curative therapy, medications may be used to ameliorate cognitive as well as behavioral and psychological symptoms of dementia (BPSD). Medications classified as acetylcholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and antiamyloid monoclonal antibodies target cognitive symptoms. For BPSD, antidepressants, antipsychotics, mood stabilizers, anxiolytics, and stimulants have been studied. Selection of pharmacotherapies requires careful risk-benefit analysis for individual patients. This review discusses available evidence to guide these discussions and clinical decisions.
Psilocybin, a serotonergic psychedelic, has gained attention as a potential treatment for various psychiatric conditions. In this review, the authors summarize current clinical evidence related to psilocybin's efficacy, safety, and mechanisms of action across psychiatric disorders. Findings from early-phase and small-scale clinical trials suggest rapid but variable reductions in depressive symptoms, with some studies reporting sustained effects. Psilocybin has also shown preliminary benefits in alleviating anxiety related to life-threatening illness and in reducing substance use, including alcohol and tobacco dependence. Emerging but limited evidence supports possible therapeutic effects in the treatment of obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, and posttraumatic stress disorder. Reported adverse events, such as headache, nausea, and short-lived anxiety, are typically transient and mild; however, notable adverse reactions have occurred in larger randomized trials. Mechanistically, psilocybin may act by modulating limbic-prefrontal circuits, promoting synaptic plasticity, and enhancing emotional and cognitive flexibility, in particular when administered alongside structured psychotherapeutic support. Although the existing data are encouraging, the evidence base remains limited by small sample sizes, highly selective populations, and short follow-up durations. Larger, rigorously designed trials are required to confirm efficacy, establish long-term safety, and refine therapeutic protocols. Overall, psilocybin represents a promising but still experimental intervention that warrants further systematic investigation under controlled conditions.
Over the past two decades, ketamine has emerged as a rapid-acting antidepressant, especially among patients with treatment-resistant depression. As an N-methyl-d-aspartate glutamate receptor antagonist, ketamine has reshaped the understanding of the underlying neurobiological mechanisms of depression treatment. Ketamine induces a transient state of enhanced neuroplasticity and likely potentiates metaplasticity-the brain's increased capacity to undergo future plastic changes. These effects suggest a posttreatment window during which patients are more cognitively flexible and responsive to other interventions. This theoretical framework has led to increasing interest in pairing ketamine with psychotherapies, such as cognitive-behavioral therapy (CBT), to enhance response and reduce relapse after ketamine treatment. This combined approach differs conceptually from ketamine-assisted psychotherapy, which is modeled after psychedelic-assisted therapy and emphasizes the consciousness-altering experience of ketamine as being integral to the therapeutic process. Multiple early studies suggest that CBT or other cognitive therapies delivered after ketamine treatment may leverage the neurobiological changes and cognitive flexibility ketamine induces to produce an enhanced and more durable antidepressant effect. However, the evidence remains limited, and critical parameters such as optimal timing and structure for combined treatment remain undefined. This review summarizes the theoretical rationale for and emerging empirical evidence supporting the integration of ketamine or esketamine with cognitive therapies. The authors evaluate recent clinical trials and highlight gaps in the literature, and conclude with a proposed framework for interventional psychiatrists seeking to incorporate CBT into ketamine-based treatment programs.
Psychedelic-assisted therapies (PATs) are emerging as novel combination treatments for selected stress- and trauma-related psychiatric conditions, particularly in cases where existing pharmacologic and psychotherapeutic approaches have provided limited benefit. Although current mechanistic models emphasize neuroplasticity, large-scale network changes, and modulation of neurotransmitter systems, these are insufficient to explain how therapeutic change emerges within the broader context of preparation, altered states of consciousness, interpersonal relationships, meaning-making, and integration. The authors introduce a non-neuroreductionist, multilevel framework that distinguishes mechanisms of action from mechanisms of change, highlighting how neuroplasticity, memory updating, relational processes, contextual factors, and meaning-making may interact to support therapeutic change. They draw on relevant evidence and clinical theory to describe how these treatments may create time-limited windows that support experiential relearning. Ethical considerations; limitations; and implications for practice, including the possibility that vulnerability may be increased when safeguards are inadequate, are discussed. Guidance is provided for clinicians who encounter PATs in practice.
