Affective Temperaments Misdiagnosed as Adult Attention Deficit Disorder: Prevalence and Treatment Effects.

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.

In the Tradition of William Osler: A New Biohumanistic Model of Psychiatry.

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.

The Need for Non-profit Psychiatric Drug Discovery and Development.

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.

Symptomatic versus disease-modifying effects of psychiatric drugs.

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.

Second messengers and their importance for novel drug treatments of patients with bipolar disorder.

Second messenger systems, like the cyclic nucleotide, glycogen synthase kinase-3ß, 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-3ß/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.

Polypharmacy as maintenance treatment in bipolar illness: A systematic review.

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.

Lurasidone Efficacy in Mixed Depressive States: A Comparison of Standard Rating Scales to the Koukopoulos Mixed Depression Rating Scale.

INTRODUCTION: A new mood rating scale for mixed states of depression along with manic-like excitatory symptoms, the Koukopoulos Mixed Depression Rating Scale (KMDRS), was assessed in a post hoc analysis of a randomized clinical trial of lurasidone versus placebo in major depressive disorder (MDD) with mixed features. METHODS: The KMDRS was compared with the Montgomery Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Item weighting was performed and compared with an original KMDRS validation data set. Weighting was used to provide imputed KMDRS scores in the lurasidone study, based on observed MADRS and YMRS scores. RESULTS: Standardized effect sizes were larger for MADRS (0.61) and YMRS (0.79) than for KMDRS (0.44, Cohen d). CONCLUSIONS: This analysis did not find that the KMDRS produced a larger effect size than the MADRS in Diagnostic and Statistical Manual for Mental Disorder-5 (DSM-5) defined MDD with mixed features. The lower utility of KMDRS may be due to the imputed nature of this analysis, or also to the DSM-5 defined patient population, which may reflect mixed hypomania rather than mixed depression.

A New Nomenclature for Psychotropic Drugs.

INTRODUCTION: Current classifications of psychotropic drugs, developed in the 1960s, are based on beliefs about clinical effectiveness. This article evaluates the scientific validity of current drug terms and possible alternative classifications. METHODS: A historical, conceptual, and empirical review of the psychopharmacology literature is provided. Consistency of classification is examined by 3 major categories: chemical structure, pharmacodynamic mechanism, and clinical efficacy. RESULTS: Current drug terms based on clinical effectiveness are not valid scientifically, either claiming efficacy which is disproven or ignoring other areas of clinical efficacy. Hence, clinical efficacy is not a consistent and scientifically valid way of classifying psychotropic drugs. Chemical structures are also heterogeneous for drugs with similar clinical efficacy. The most consistent way to define drug classes is pharmacodynamic mechanism. Specific drug groups identified are: monoamine agonists ("antidepressants" and "stimulants"), dopamine blockers ("antipsychotics"), second messenger modifiers ("mood stabilizers), and gabaergic agonists ("anxiolytics" or "hypnotics"). CONCLUSIONS: Consistent with a recent proposal of psychopharmacology organizations, this article proposes a new nomenclature based mainly on biological pharmacodynamic mechanisms. Specific terms that are scientifically valid and clinically practical are suggested. It is hoped that this new language would allow for more meaningful and accurate communication between clinicians and patients.

A 13-week, randomized double-blind, placebo-controlled, cross-over trial of ziprasidone in bipolar spectrum disorder.

OBJECTIVE: Features of bipolarity in a major depressive disorder sample were used to define a "bipolar spectrum disorder" population for treatment with a neuroleptic agent, ziprasidone. METHODS: Forty-nine acutely depressed patients were randomized to ziprasidone-washout-placebo or placebo-washout-ziprasidone in this double-blind, prospective, 13-week crossover trial. All patients met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for a major depressive episode and were positive for at least 3 predictors of bipolarity: family history of bipolar disorder, antidepressant-induced mania, highly recurrent depressive episodes (>5), atypical depression, early onset of depression (

Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial.

BACKGROUND: We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. RESULTS: In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. CONCLUSIONS: The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

Carcinogenicity of psychotropic drugs: A systematic review of US Food and Drug Administration-required preclinical in vivo studies.

OBJECTIVE: The US Food and Drug Administration approval process for psychotropic drugs requires safety studies of carcinogenicity in animals. These studies are consistently conducted and provide a database for assessment of potential biological risk of carcinogenicity in humans. This report is a systematic review of that database for psychotropic drugs. METHOD: US Food and Drug Administration-approved registration data ('package inserts') were examined, where available, for all psychotropic drugs in the following classes: antidepressants, antipsychotics, benzodiazepines/sedative-hypnotics, amphetamines and anticonvulsants. RESULTS: Overall, new generation (atypical) antipsychotics (90%, 9/10 agents) and anticonvulsants (85.7%, 6/7 agents) showed the highest evidence of carcinogenicity among psychotropic drugs classes assessed. Antidepressants (63.6%, 7/11) and benzodiazepines/sedative-hypnotics (70%, 7/10) were next, and stimulants (with the exception of methylphenidate) were last (25%, 1/4 agents). Overall, 71.4% of all drugs examined (30/42) showed evidence of carcinogenicity in 43.2% (38/88) of specific experimental studies. CONCLUSIONS: US Food and Drug Administration-based analyses demonstrate that almost all atypical antipsychotics and anticonvulsants are carcinogenic in animals, as are the majority of antidepressants and benzodiazepines and methylphenidate. These animal-based results are not sufficient to draw definitive conclusions in humans, but they provide data that could be acknowledged in the informed consent process of clinical treatment.

The bipolar spectrum: conceptions and misconceptions.

OBJECTIVE: This review aims to address concerns about the potential overinclusiveness and vagueness of bipolar spectrum concepts, and also, concerns about the overlap between bipolar illness and borderline personality. METHOD: Narrative review based on historical and empirical studies. RESULTS: Bipolar disorder (BD) and major depressive disorder (MDD) came to be separate entities with the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM III), in contrast to the Kraepelinian manic-depressive insanity (MDI) concept, which included both. The bipolar spectrum concept is a return to this earlier Kraepelinian perspective. Further, very different features differentiate the disease of bipolar illness (family history of bipolar illness, severe recurrent mood episodes with psychomotor activation) from the clinical picture of borderline personality (dissociative symptoms, sexual trauma, parasuicidal self-harm). The term 'disorder' obfuscates an ontological difference between diseases, such as manic-depressive illness, and clinical pictures, such as hysteria/post-traumatic stress disorder/dissociation/borderline personality. CONCLUSIONS: Bipolar spectrum concepts are historically rooted in Kraepelin's manic-depressive illness concept, are scientifically testable, and can be clearly formulated. Further, they differ in kind from traumatic/dissociative conditions in ways that can be both historically and scientifically established.

Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits.

OBJECTIVE: Dementia is a major public health issue, with notably high rates in persons with mood illnesses. Lithium has been shown to have considerable neuroprotective effects, even in trace or low doses. The aim of this review is to summarize the current understanding of lithium benefits in trace or low doses in dementia prevention and for other behavioral or medical benefits. METHODS: A systematic review identified 24 clinical, epidemiological, and biological reports that met inclusion criteria of assessing lithium in standard or low doses for dementia or other behavioral or medical benefits. RESULTS: Five out of seven epidemiological studies found an association between standard-dose lithium and low dementia rates. Nine out of 11 epidemiological studies, usually of drinking water sources, found an association between trace-dose lithium and low suicide/homicide/mortality and crime rates. All four small randomized clinical trials of lithium for Alzheimer's dementia have found at least some clinical or biological benefits versus placebo. Only one small randomized clinical trial (RCT) of trace lithium has been conducted, assessing mood symptoms in former substance abusers, and found benefit with lithium versus placebo. CONCLUSIONS: Lithium, in both standard and trace doses, appears to have biological benefits for dementia, suicide, and other behavioral outcomes. Further RCT research of trace lithium in dementia is warranted.

Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV).

The DSM system has never acknowledged a central position for mixed states; thus, mixed depressions have been almost completely neglected for decades. Now, DSM-5 is proposing diagnostic criteria for depression with mixed features that will lead to more misdiagnosis and inadequate treatment of this syndrome. Different criteria, based on empirically stronger evidence than exists for the DSM-5 criteria, should be adopted.

Effectiveness of short-term olanzapine in patients with bipolar I disorder, with or without comorbidity with substance use disorder.

OBJECTIVES: Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. METHODS: Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. RESULTS: SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02-2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). CONCLUSIONS: The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

Postmodern medicine: an analysis of the pharmaceutical industry and its critics.

The relationship between physicians and the pharmaceutical industry has been the subject of extensive debate in the last decade or so. This analysis offers some personal observations and suggestions on this discussion from the perspective of psychiatry. The article analyzes a number of critiques of the pharmaceutical industry-the free market myth, the drug price myth, the academic-pharmaceutical complex, lack of innovation, ghost authorship, and the profit motive-in relation to the ethics of medical practice and suggests some public policy solutions. While the focus here is on psychiatry, many of the concepts and principles discussed should apply generally to the medical profession as a whole.

MIJ821 (onfasprodil) in healthy volunteers: First-in-human, randomized, placebo-controlled study (single ascending dose and repeated intravenous dose).

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.