Background: Mood disorders [bipolar disorder (BD) and recurrent unipolar depression] are among the most common mental health conditions worldwide, and are recognized as significant risk factor for development of mild cognitive impairment (MCI) and dementia. Lithium, the gold standard treatment for these mood disorders, has also been suggested as a potential neuroprotective agent, even at trace doses. This study aims to evaluate the effect of trace doses of lithium in preventing cognitive decline in individuals with mood disorders. Methods: This is randomized, double-blind, placebo-controlled trial involving 250 participants aged 55 to 75 years, all of whom have mood disorders and are not currently receiving lithium therapy. Participants will be randomized into either trace dose lithium (50 mg oral tablets daily) or placebo group, with 125 subjects in each group. All participants will continue their usual clinical treatment and will be followed every six month for five years. The primary outcome measure will be the incidence of MCI or worsening of pre-existing MCI, defined as change from baseline clinical dementia rating scale (CDR) score of 0 to 0.5 (MCI). Conclusions: If this research demonstrates that trace doses of lithium can prevent the onset or progression of MCI or dementia in patients with mood disorders, it could offer a new therapeutic approach for addressing cognitive decline in this high-risk population, with significant public health implications. Trial registration: clinicaltrials.gov: NCT06662526.

By manipulating inclusion criteria, one can prove whatever point one wishes in meta-analysis. This critique examines a recent meta-analysis claiming lithium ineffectiveness for suicidality, based on three biased features: inclusion of many large studies specifically designed to exclude suicidality, producing zero suicide outcomes in all groups (n = 1856), thereby artificially decreasing statistical significance; arbitrary exclusion of all trials prior to the year 2000, thereby excluding two randomized clinical trials which demonstrated benefit for lithium; and underreporting of placebo suicide events in a recent randomized trial. It thereby created a smaller effect size (two suicides with lithium versus five with placebo = RR = 0.42), though still beneficial for lithium, and a larger denominator of no events (total n for included studies = 2578), leading to the claim of statistical non-significance (95% confidence intervals (CIs) 0.1-4.5). The same literature can be analyzed including the two excluded older studies, and including the two placebo deaths in the recent trial, producing a larger effect size (two suicides with lithium versus nine with placebo, RR = 0.25). Furthermore, uninformative studies with no events could be excluded (total n for included studies = 1203), as is standard practice in meta-analysis, producing statistically significant results (95% CIs 0.05, 0.83). This more complete, more accurate, and less biased meta-analysis is provided in this article.In short, including all studies with non-zero suicide outcomes, there is clear benefit for lithium. The recent meta-analysis is a classic example of pseudoscience, using scientific technique superficially to confirm, rather than refute, one's own opinions.

Background: The exploration of metacognition in relation to anxiety has received considerable attention in recent decades. Research indicates that it plays a role in the development and maintenance of anxiety disorders while also providing benefits, including the ability to assess situations, modify behaviors, and make informed decisions. Summary: We propose that having an awareness of a disorder, also known as insight, is related to metacognition in anxiety. This relationship stems from the ability it provides individuals to recognize their mental state through reflection on personal experiences. We discuss the impact of insight and metacognition on decision-making, treatment-seeking behaviors, and coping strategy selection. Key Messages: Understanding the concept of insight in anxiety disorders, as compared to other mental disorders like psychosis, requires exploring its complexities while carefully considering the balance of harms and benefits. While the medicalization of symptoms in psychosis is widely regarded as clearly beneficial, evaluating the role of insight in anxiety disorders demands a more nuanced understanding. Gaining a fuller perspective on patients’ beliefs can impact their behaviors and decision-making. Clinicians can achieve this by encouraging active self-reflection to increase awareness, which includes evaluating both severity and impact on daily functioning. This also involves expressing experiences and exploring attributions of anxiety. This practical approach enables clinicians to understand engagement and treatment-seeking behaviors, allowing them to tailor treatment plans and develop effective coping and management strategies. Ultimately, this knowledge promotes a deeper comprehension of insight into anxiety disorders.

Abstract S. Nassir Ghaemi, MD, MPH, is a psychiatrist with expertise in mood illnesses and training in philosophy and public health. He is Professor of Psychiatry at Tufts University and Lecturer in Psychiatry at Harvard Medical School, and also has worked in clinical drug discovery research in psychiatry at Novartis Institutes for Biomedical Research in Cambridge, MA. He is the author of multiple books including Clinical Psychopharmacology (Oxford University Press, 2019), The Concepts of Psychiatry (Johns Hopkins University Press, 2003), The Rise and Fall of the Biopsychosocial Model (Johns Hopkins University Press, 2009), and A First-Rate Madness (Penguin, 2011). This interview explores his views on depression, antidepressants, the biopsychosocial model, DSM, diagnostic validity, and many other conceptual issues of concern to the field. A common refrain in his work is that psychiatry has lost its way by pursuing a putatively atheoretical nosology for understanding mental illness in the form of DSM and by prioritizing pragmatic considerations over scientific evidence.

Background: Bipolar disorder (BD) and obsessive–compulsive disorder (OCD) comorbidity is an emerging condition in psychiatry, with relevant nosological, clinical, and therapeutic implications. Methods: We updated our previous systematic review on epidemiology and standard diagnostic validators (including phenomenology, course of illness, heredity, biological markers, and treatment response) of BD-OCD. Relevant papers published until (and including) 15 October 2023 were identified by searching the electronic databases MEDLINE, Embase, PsychINFO, and Cochrane Library, according to the PRISMA statement (PROSPERO registration number, CRD42021267685). Results: We identified 38 new articles, which added to the previous 64 and raised the total to 102. The lifetime comorbidity prevalence ranged from 0.26 to 27.8% for BD and from 0.3 to 53.3% for OCD. The onset of the two disorders appears to be often overlapping, although the appearance of the primary disorder may influence the outcome. Compared to a single diagnosis, BD-OCD exhibited a distinct pattern of OC symptoms typically following an episodic course, occurring in up to 75% of cases (vs. 3%). Notably, these OC symptoms tended to worsen during depressive episodes (78%) and improve during manic or hypomanic episodes (64%). Similarly, a BD course appears to be chronic in individuals with BD-OCD in comparison to patients without. Additionally, individuals with BD-OCD comorbidity experienced more depressive episodes (mean of 8.9 ± 4.2) compared to those without comorbidity (mean of 4.1 ± 2.7). Conclusions: We found a greater likelihood of antidepressant-induced manic/hypomanic episodes (60% vs. 4.1%), and mood stabilizers with antipsychotic add-ons emerging as a preferred treatment. In line with our previous work, BD-OCD comorbidity encompasses a condition of greater nosological and clinical complexity than individual disorders.

This new journal is a challenge to conventional wisdom. Contemporary psychiatry provides average clinical care in the best of circumstances, and poor care in many cases. It lives on failed theories of a past century, and pretends it is avant-garde. The profession’s system of diagnosis, the Diagnostic and Statistical Manual, 5th edition (DSM-5), published by the American Psychiatric Association (APA), is mostly false, and demonstrably so. Yet it is accepted and practiced worldwide as if it was proven true. The profession’s medication treatment approach is based on DSM-5 definitions, and thus is also false and weak in its effects. Yet it is accepted by government regulators and pharmaceutical companies worldwide. Most psychiatric drugs only improve symptoms short-term, at best, like aspirin for a headache or ibuprofen for a fever, yet they are given and assumed to be effective long-term, though few are proven so (such as lithium) and many are disproven long-term. Its psychotherapies are eclectic, and applied more often based on the preferences of practitioners than the needs of patients.

William Osler (1849-1919) is often considered the most influential physician in the emergence of science-based medicine. However, his approach to clinical medicine tends to be misunderstood, and its relevance to psychiatry has not been explored systematically. Osler's approach to the patient had four components: biological reductionism about disease, a scientific approach to clinical diagnosis, therapeutic conservatism, and a humanistic approach to the person. These concepts conflict with the pragmatic, eclectic, anti-reductionistic assumptions of contemporary psychiatry, as codified in its interpretation of a "biopsychosocial" model. This model leads to unscientific practice, with excessive use of medications given for symptoms, and inattention to identifying and treating diseases. This article suggests that implementing Osler's philosophy of medicine in psychiatry would greatly benefit the latter. It would inaugurate a new "biohumanistic" approach to psychiatry.

Why do we not have better drugs? This question is the core concern of this paper, based on an assessment of the scientific literature and personal experience inside and outside the pharmaceutical industry. I will examine standard and alternate explanations for the challenges of psychiatric drug discovery and development (Table 1) and provide my interpretation based on scientific studies and historical processes.

The second edition of a clear and accessible guide to the application of statistics in psychiatric practice. The book expertly describes statistical concepts in clear and simple terms, with minimal mathematical content, making it the ideal resource for busy mental health professionals. Fully revised throughout, it features five new chapters covering key advances in the field and important topics in greater detail. Amongst the key concepts discussed in this edition are the logic of randomization, clinical trials, the overuse of p-values, understanding effect sizes, meta-analysis and why clinical experience is limited by observational confounding bias. Featuring a wealth of clinical examples, on topics of high importance or controversy in psychiatry, plus explanations and reasoning, to give clinicians a better understanding of how to apply research to their practice.

Abstract Adult attention-deficit disorder (ADD) is a common diagnosis, and amphetamine medications are increasingly used. Recent reports suggest high prevalence of affective temperaments, such as cyclothymia, in adult ADD. This study reexamines prevalence rates as reflecting misdiagnosis and reports for the first time on the effects of amphetamine medications on mood/anxiety and cognition in relation to affective temperaments. Among outpatients treated at the Tufts Medical Center Mood Disorders Program (2008–2017), 87 cases treated with amphetamines were identified, versus 163 non–amphetamine-treated control subjects. Using the Temperament Scale of Memphis, Pisa, Paris and San Diego–Autoquestionnaire, 62% had an affective temperament, most commonly cyclothymia (42%). In amphetamine-treated cases, mood/anxiety symptoms worsened notably in 27% (vs. 4% in the control group, risk ratio [RR] 6.2, confidence interval [CI], 2.8–13.8), whereas 24% had moderate improvement in cognition (vs. 6% in the control group; RR, 3.93; CI, 1.9–8.0). Affective temperaments, especially cyclothymia, are present in persons about one-half of persons diagnosed with adult ADD and/or treated with amphetamines.

Despite the unprecedented wave of research and publications sparked by the recent pandemic, only few studies have investigated the impact of COVID-19 on the Italian community-based system of mental health care. We aimed to summarize the available evidence from the literature also considering what we have learned from our daily clinical practice. As hospital care was restricted by COVID-19, although reducing their opening hours and activities, Community Mental Health Centers promoted continuity of care for at-risk populations, supporting them to cope with loneliness and hopelessness during quarantine and self-isolation. Ensuring continuity of care also remotely, via teleconsultation, lowered the risk of psychopathological decompensation and consequent need of hospitalization for mental health patients, with satisfaction expressed both by patients and mental health workers. Considering what we have learned from the pandemic, the organization and the activity of the Italian community-based system of mental health care would need to be implemented through 1) the promotion of a "territorial epidemiology" that makes mental health needs visible in terms of health care workers involved, 2) the increase of mental health resources in line with the other European high-income countries, 3) the formalization of structured initiatives of primary care and mental health cooperation, 4) the creation of youth mental health services following a multidimensional and multidisciplinary approach and encouraging family participation, 5) the promotion of day centers, to build competence and self-identity within a more participatory life, and programs geared to employment as valid models of recovery-oriented rehabilitation.

Abstract This single‐center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40‐min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose‐proportional manner across the dose range 0.016–0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048–0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1‐h post‐dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose‐dependent.

Abstract Background In the 1970 s, scientific research on psychiatric nosology was summarized in Research Diagnostic Criteria (RDC), based solely on empirical data, an important source for the third revision of the official nomenclature of the American Psychiatric Association in 1980, the Diagnostic and Statistical Manual, Third Edition (DSM-III). The intervening years, especially with the fourth edition in 1994, saw a shift to a more overtly “pragmatic” approach to diagnostic definitions, which were constructed for many purposes, with research evidence being only one consideration. The latest editions have been criticized as failing to be useful for research. Biological and clinical research rests on the validity of diagnostic definitions that are supported by firm empirical foundations, but critics note that DSM criteria have failed to prioritize research data in favor of “pragmatic” considerations. Results Based on prior work of the International Society for Bipolar Diagnostic Guidelines Task Force, we propose here Clinical Research Diagnostic Criteria for Bipolar Illness (CRDC–BP) for use in research studies, with the hope that these criteria may lead to further refinement of diagnostic definitions for other major mental illnesses in the future. New proposals are provided for mixed states, mood temperaments, and duration of episodes. Conclusions A new CRDC could provide guidance toward an empirically-based, scientific psychiatric nosology, and provide an alternative clinical diagnostic approach to the DSM system.

Second messenger systems, like the cyclic nucleotide, glycogen synthase kinase-3β, phosphoinositide, and arachidonic acid cascades, are involved in bipolar disorder (BD). We investigated their role on the development of novel therapeutic drugs using second messenger mechanisms. PubMed search and narrative review. We used all relevant keywords for each second messenger cascade combining it with BD and related terms and combined all with novel/innovative treatments/drugs. Our search produced 31 papers most were reviews, and focussed on the PI3K/AKT-GSK-3β/Nrf2-NF-ĸB pathways. Only two human randomized clinical trials were identified, of ebselen, an antioxidant, and celecoxib, a cyclooxygenase-2 inhibitor, both with poor unsatisfactory results. Despite the fact that all second messenger systems are involved in the pathophysiology of BD, there are few experiments with novel drugs using these mechanisms. These mechanisms are a neglected and potentially major opportunity to transform the treatment of bipolar illness.

OBJECTIVE:Drugs can be divided into two major categories, symptomatic and disease modifying. This review explores whether and how psychiatric drugs fall into one or the other of those categories, and the implications of those results for clinical practice and research in psychopharmacology.METHOD:Narrative review.RESULTS:Most psychiatric drugs have only short-term effects of improving active symptoms. They do not show long-term benefits for the underlying disease, such as improving the course of illness and improving mortality. Evidence is provided for this claim in the treatment literature of antidepressants for depressive illness and antipsychotics for schizophrenia. Developing truly beneficial drugs for disease modification also is limited by the poor clinical and biological validity of Diagnostic and Statistical Manual diagnoses as well as the use of invalid falsely positive maintenance efficacy randomized discontinuation trial designs.CONCLUSIONS:Current psychopharmacology is limited mostly to symptomatic effects, not transformative treatments for the diseases underlying those symptoms. A change in approach is needed in psychopharmacology practice and research, focusing on long-term disease modification rather than short-term symptom improvement.

Antipsychotic medications have limited benefits in schizophrenia, and cognitive behavioral therapy may be beneficial as an adjunct. There may be potential for implementing mobile cognitive behavioral therapy–based treatment for schizophrenia in addition to standard antipsychotic medications. This study aims to determine whether PEAR-004, a smartphone-based investigational digital therapeutic, improves the symptoms of an acute psychotic exacerbation of schizophrenia when it is added to standard treatments. This was a 12-week, multicenter, randomized, sham-controlled, rater-blinded, parallel group proof‑of‑concept study of 112 participants with moderate acute psychotic exacerbation in schizophrenia. This study was conducted in 6 clinical trial research sites in the United States from December 2018 to September 2019. The primary outcome, change in Positive and Negative Syndrome Scale (PANSS) from baseline to week 12 or the last available visit, was analyzed using the mixed-effects regression model for repeated measures, applied to an intent-to-treat sample. The total PANSS scores slightly decreased from baseline over the study period in both groups; the treatment difference at day 85 between PEAR-004 and sham was 2.7 points, in favor of the sham (2-sided P=.09). The secondary scales found no benefit, except for transient improvement in depressive symptoms with PEAR-004. Application engagement was good, and patient and clinical investigator satisfaction was high. No safety concerns were observed. There was some evidence of study site heterogeneity for the onboarding processes and directions on PEAR-004 product use at baseline and throughout the study. However, these differences did not affect the efficacy results. In the largest-to-date randomized, sham-controlled study of a digital therapeutic in schizophrenia, PEAR-004 did not demonstrate an effect on the primary outcome—total PANSS scores—when compared with a nonspecific digital sham control. The secondary and exploratory results also did not demonstrate any notable benefits, except for possible temporary improvement in depressive symptoms. This study provided many useful scientific and operational insights that can be used in the further clinical development of PEAR-004 and other investigational digital therapeutics. ClinicalTrials.gov NCT03751280; https://clinicaltrials.gov/ct2/show/NCT03751280