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Byline: DJ Smith (Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK, smithdj3@cardiff.ac.uk); SN Ghaemi (Bipolar Disorders Research Program, Emory University, Atlanta, GA, USA.); N. Craddock (Department of [...]

Byline: DJ Smith (Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK, SmithDJ3@Cardiff.ac.uk); SN Ghaemi (Bipolar Disorders Research Program, Emory University, Atlanta, GA, USA); N Craddock (Department of [...]

In this conceptual review we argue that by certifying some of the atypical neuroleptics (or, if one prefers, antipsychotics) as indicated for the 'maintenance' treatment of bipolar disorder, the US FDA has created confusion in the field. These maintenance indications are based on studies using a 'relapse prevention' design, a design that does not address whether the agents tested can prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis. We found that the relapse prevention design fails to prove that these agents are mood stabilizers because patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). We believe that this represents withdrawal into the same mood episode that patients experienced before the maintenance study began, rather than prevention of a new mood episode, as research into the natural history of bipolar disorder indicates that such new episodes typically are of the opposite polarity. Thus, the inability of neuroleptics to prevent depression in such maintenance studies reflects the general inability to prevent any new mood episode recurrence (which we believe should be defined as 6 months or longer after the index episode). If one defines a mood stabilizer, as we do, as a drug that prevents new episodes of mania and depression in monotherapy, then these studies do not show that atypical neuroleptics are mood stabilizers. Future maintenance research studies in bipolar disorder should use the prophylaxis design (i.e. without pre-selection of drug responders), rather than the relapse prevention design. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study assessed patterns of psychopharmacological treatment for bipolar disorder. METHOD: Intake treatment data were examined for the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1998 to 1999). Diagnoses were assessed by using the Structured Clinical Interview for DSM-IV mood modules. Data on treatments were obtained by interviewing patients during the initial psychiatric examination. RESULTS: Of the 500 participants, 73.6 percent had bipolar I disorder, 23.0 percent had bipolar II disorder, and 3.4 percent had bipolar disorder not otherwise specified. Upon examination, 63.4 percent were euthymic, 24.6 percent were depressed, and 12.0 percent were experiencing manic, hypomanic, or mixed states. Standard mood stabilizers (lithium, valproate, or carbamazepine) were the most commonly prescribed class of drugs that participants were taking at intake (71.9 percent). The next most common class of agents was antidepressants (40.6 percent), followed by novel anticonvulsants (31.8 percent), second-generation neuroleptics (27.2 percent), and benzodiazepines (25.0 percent). Eleven percent of patients were treated with standard mood stabilizer monotherapy. These prescribing patterns were further analyzed by subtype of illness and compared with patterns in other clinical and community settings. CONCLUSION: In a large, well-characterized cross-sectional analysis of prescription patterns in the U.S. psychiatric academic setting, patients with bipolar disorder were primarily treated with standard mood stabilizers, followed by moderate use of antidepressants, novel anticonvulsants, and second-generation neuroleptics. Results can be useful in understanding the current clinical standard of care, as well as in guiding research studies toward areas in which there is a relative absence of evidence to inform clinical practice. Studies of longitudinal prescribing patterns in bipolar disorder are also needed. [ABSTRACT FROM AUTHOR]

What are the effects of lamotrigine and lithium for maintenance treatment in recently depressed people with bipolar I disorder?METHODSDesign: Randomised controlled trial.Allocation: Unclear.Blinding: Double blind.Follow up period: 18 months.Setting: 79 centres in 15 countries; 1997 to 2001.Patients: 463 adults with bipolar I disorder(mean age range 42. to 44 years), who were stabilised with lamotrigine during an 8-16 week open label phase (n.966). Main inclusion criteria: current or recent (past 60 days) DSM-IV major depressive episode; >/= 1 manic or hypomanic episodes, and >/= 1 depressive episodes within 3 years of enrolment. Exclusions: >6 DSM-IV mood episodes in the past year; significant psychiatric or medical comorbidity; epilepsy or suicidal. All other psychotropic medicines were discontinued before randomisation.Intervention: Maintenance treatment with lamotrigine (50, 200, or 400 mg/day), lithium (serum levels 0.8-1.1 mEq/l) or placebo.Outcomes: Time to intervention for any mood episode; adverse: events.Patient follow up: 95%.MAIN RESULTSBoth lamotrigine (200 or 400 mg/day) and lithium significantly increased the time to intervention for any mood episode compared with placebo (200 days with lamotrigine v 170 days with lithium v 93 days with placebo; p = 0.029 for both comparisons v placebo). There was no significant difference in the time to intervention between lamotrigine and lithium (p = 0.915). 11% of participants withdrew due to adverse effects (see table for most common adverse events).CONCLUSIONSLamotrigine and lithium are better than placebo for preventing mood episodes in people with bipolar I disorder.NOTEThere were initially three lamotrigine treatment groups; enrolment was stopped in the 50mg/day and 400 mg/day groups during the study because of poor enrolment. Efficacy data for lamotrigine was pooled for the 200 mg and 400 mg/day groups, a decision that had been made a priori. Authors point out that participants who were intolerant or unresponsive to lamotrigine would have been excluded during the prerandomisation stabilisation period, and this may have biased results. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The cognitive deterioration of politicians is a critical emerging issue. As professions including law and medicine develop and implement cognitive assessments, their insights may inform the proper strategy within politics. The aging, lifetime-appointed judiciary raises legal and administrative questions of such assessments, while testing of older physicians experiencing cognitive decline provides real-life examples of implementation. In politics, cognitive assessment must contend with the field's unique challenges, also taking context-dependent interpretations of cognitive-neuropsychological status into account. These perspectives, from legal and medical experts, political scientists, and officeholders, can contribute toward an equitable, functioning, and non-discriminatory system of assessing cognition that educates the public and enables politicians to maintain their public responsibilities. With proper implementation and sufficient public knowledge, we believe cognitive assessments for politicians, particularly political candidates, can be valuable for maintaining properly functioning governance. We offer recommendations on the development, implementation, and execution of such assessments, grappling with their democratic and legal implications.

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 AUC inf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the C max 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 AUC inf was 708 h ng/mL and the geometric mean C max 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., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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.

Background: Current psychiatric drug discovery and development has not produced very effective medications in the past few decades. Conventional wisdom provides reasons for failure that do not address major structural obstacles to true innovation for psychiatric drugs., Method: Narrative review based on analysis of the scientific literature augmented by personal experience in academic clinical research as well as in the pharmaceutical industry., Results: The largest obstacles to drug discovery and development are the biological invalidity of most DSM diagnoses, the economic incentives to produce short-term symptomatic treatments with blockbuster profit potential, and very low thresholds set by the FDA for ending drug discovery due to toxicity. Since these larger structural socio-economic obstacles to drug development will be difficult to change, a new proposal is made for a parallel non-profit drug discovery paradigm, to be funded by governments, akin to the development of vaccines for the Covid-19 pandemic. The key public health implications are highlighted in the example of developing new drugs for Alzheimer dementia, and the potential utility of an anti-tau agent like lithium, currently ignored in drug development in favor of much more expensive and questionably effective amyloid-reducing agents., Conclusions: Given the key structural problems of psychiatric drug discovery and development, a parallel non-profit drug discovery paradigm is needed to meet all public health needs, as well as to reinvigorate truly innovative and transformative research., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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., (© 2022. The Author(s).)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Clinicians and patients often try a treatment for an initial period to inform longer-term therapeutic decisions. A more rigorous approach involves N-of-1 trials. In these single-patient crossover trials, typically conducted in patients with chronic conditions, individual patients are given candidate treatments in a double-blinded, random sequence of alternating periods to determine the most effective treatment for that patient. However, to date, these trials are rarely done outside of research settings and have not been integrated into general care where they could offer substantial benefit. Designating this classical, N-of-1 trial design as type 1, there also are new and evolving uses of N-of-1 trials that we designate as type 2. In these, rather than focusing on optimizing treatment for chronic diseases when multiple approved choices are available, as is typical of type 1, a type 2 N-of-1 trial tests treatments designed specifically for a patient with a rare disease, to facilitate personalized medicine. While the aims differ, both types face the challenge of collecting individual-patient evidence using standard, trusted, widely accepted methods. To fulfill their potential for producing both clinical and research benefits, and to be available for wide use, N-of-1 trials will have to fit into the current healthcare ecosystem. This will require generalizable and accepted processes, platforms, methods, and standards. This also will require sustainable value-based arrangements among key stakeholders. In this article, we review opportunities, stakeholders, issues, and possible approaches that could support general use of N-of-1 trials and deliver benefit to patients and the healthcare enterprise. To assess and expand the benefits of N-of-1 trials, we propose multistakeholder meetings, workshops, and the generation of methods, standards, and platforms that would support wider availability and the value of N-of-1 trials., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: 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., Objective: 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., Methods: 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., Results: 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., Conclusions: 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., Trial Registration: ClinicalTrials.gov NCT03751280; https://clinicaltrials.gov/ct2/show/NCT03751280., (©S Nassir Ghaemi, Oleksandr Sverdlov, Joris van Dam, Timothy Campellone, Robert Gerwien. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.03.2022.)

Objectives: Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research., Method: A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library., Results: Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone., Conclusions: The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy., (© 2021 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

While serotonin reuptake inhibitors are sometimes used in clinical practice to treat acute bipolar depression, the neurophysiological substrates underlying their efficacy are little studied. In the context of a larger clinical efficacy trial, the present study explored neural mechanisms associated with citalopram versus placebo treatment for bipolar depression. FDG-PET imaging examined whole-brain metabolic changes before and after treatment. Clinical efficacy was similar for citalopram versus placebo. Neuroimaging results demonstrated greater glucose metabolism in the left orbitofrontal cortex (OFC) before treatment (combined citalopram and placebo subjects) relative to after treatment, but did not correlate with clinical recovery. Glucose metabolism in the left OFC was also a predictor of depression severity when baseline scans were regressed with baseline MADRS scores. Despite of our small sample size and possibly underpowered whole-brain analysis approach, these preliminary results suggest the OFC, a key region involved in reward circuity, may be a neural substrate for depressive symptom improvement in bipolar depression, regardless of whether due to active treatment or placebo., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Depression is a leading cause of disability. International guidelines recommend screening for depression and the Patient Health Questionnaire 9 (PHQ-9) has been identified as the most reliable screening tool. We reviewed the evidence for using it within the primary care setting., Methods: We retrieved studies from MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library that carried out primary care-based depression screening using PHQ-9 in populations older than 12, from 1995 to 2018., Results: Forty-two studies were included in the systematic review. Most of the studies were cross-sectional (N=40, 95%), conducted in high-income countries (N=27, 71%) and recruited adult populations (N=38, 90%). The accuracy of the PHQ-9 was evaluated in 31 (74%) studies with a two-stage screening system, with structured interview most often carried out by primary care and mental health professionals. Most of the studies employed a cut-off score of 10 (N=24, 57%, total range 5 - 15). The overall sensitivity of PHQ-9 ranged from 0.37 to 0.98, specificity from 0.42 to 0.99, positive predictive value from 0.09 to 0.92, and negative predictive value from 0.8 to 1., Limitations: Lack of longitudinal studies, small sample size, and the heterogeneity of primary-care settings limited the generalizability of our results., Conclusions: PHQ-9 has been widely validated and is recommended in a two-stage screening process. Longitudinal studies are necessary to provide evidence of long-term screening effectiveness., (Copyright © 2020. Published by Elsevier B.V.)