An accurate diagnostic method using biological indicators is critically needed for bipolar disorder (BD) and major depressive disorder (MDD). The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a crucial regulator of synaptic function, and its dysregulation may play a central role in the pathophysiology of psychiatric disorders. Our recently developed positron emission tomography (PET) tracer, [11C]K-2, enables the quantitative visualization of AMPAR distribution and is considered useful for characterizing synaptic phenotypes in patients with psychiatric disorders. This study aimed to develop a machine learning-based method to differentiate bipolar disorder from major depressive disorder using AMPAR density. Sixteen patients with BD and 27 patients with MDD, all in depressive episodes, underwent PET scans with [11C]K-2 and structural magnetic resonance imaging. AMPAR density was estimated using the standardized uptake value ratio from 30 to 50 min after tracer injection, normalized to whole brain radioactivity. A partial least squares model was trained to predict diagnoses based on AMPAR density, and its performance was evaluated using a leave-one-pair-out cross-validation. Significant differences in AMPAR density were observed in the parietal lobe, cerebellum, and frontal lobe, notably the dorsolateral prefrontal cortex between patients with BD and patients with MDD during a depressive episode. The model achieved an area under the curve of 0.80, sensitivity of 75.0%, and specificity of 77.8%. These findings suggest that AMPAR density measured with [11C]K-2 can effectively distinguish BD from MDD and may aid diagnosis, especially in patients with ambiguous symptoms or incomplete clinical presentation.

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To compare the effects of placebo versus no treatment in people with schizophrenia.

Background: Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium. Methods: Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared. Results: Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n = 45) for trazodone and 89.1% (n = 41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups (P = 0.17 and P = 0.13, respectively). Conclusion: Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium.Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared.Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n = 45) for trazodone and 89.1% (n = 41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups ( P = 0.17 and P = 0.13, respectively).Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

Background: To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance. Results: We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic. Conclusion: The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.

OBJECTIVE:To compare efficacy and safety of single daily dosing (Single-DD) vs multiple daily dosing (Multiple-DD) regimens of psychotropic drugs, the authors conducted a systematic review and meta-analysis.DATA SOURCES:A systematic literature search of MEDLINE and Embase was conducted with keywords related to dosing regimens and psychotropic drugs (last search: December 30, 2019).STUDY SELECTION:Randomized controlled trials comparing clinical outcomes between Single-DD and Multiple-DD of the same formulation of the same psychotropic drugs in patients with psychiatric disorders were included.DATA EXTRACTION:Data on study discontinuation, psychopathology, and treatment-emergent adverse events (TEAEs) were extracted.RESULTS:A total of 32 studies with 34 paired comparisons involving 3,142 patients met the eligibility criteria and were included in the meta-analysis. Various types of psychotropic drugs were examined: antidepressants (22 comparisons), antipsychotics (7 comparisons), benzodiazepines (2 comparisons), mood stabilizers (2 comparisons), and antidepressant-benzodiazepine combination (1 comparison). There was no significant difference in study discontinuation due to all causes (30 comparisons, N = 2,883, risk ratio [RR] = 1.01, 95% CI = 0.94 to 1.09, P = .77), lack of efficacy (22 comparisons, N = 2,307, RR = 1.06, 95% CI = 0.84 to 1.33, P = .62), or adverse events (25 comparisons, N = 2,571, RR = 0.93, 95% CI = 0.75 to 1.14, P = .47) between the Single-DD and Multiple-DD groups. No significant difference was found in changes in psychopathology (8 comparisons, N = 1,337, standardized mean difference = 0.00, 95% CI = -0.11 to 0.11, P = .99) between the 2 groups. These results were also true for any type of psychotropic drugs. In terms of TEAEs, however, there were significant differences in anxiety (4 comparisons, N = 347, RR = 0.53, 95% CI = 0.33 to 0.84, P = .007) and sleepiness (3 comparisons, N = 934, RR = 0.82, 95% CI = 0.68 to 0.99, P = .04) in favor of the Single-DD group.CONCLUSIONS:The findings suggest Single-DD can be clinically adopted regardless of type of psychotropic drugs in patients with psychiatric disorders in general.

‘Mood stabilizers’ are collectively referred to as drugs used for the treatment of bipolar disorders, but they are fuzzy in concept. While some definitions, such as ‘drug that has efficacy in the treatment of acute manic and depressive episodes and in the prevention of recurrences,’ have been proposed,1, 2 Malhi and Chengappa recently proposed two opposite views on this term: (i) to define a mood stabilizer as ‘it must achieve sustained long-term functional mood stability and discernibly prevent future illness’; or (ii) ‘it is time to retire the term, mood stabilizer.’3 In reality, there has been no clear consensus on the definition of, and what constitutes, ‘mood stabilizers.’ Several ‘mood stabilizers’ are also used for various other conditions, including epilepsy. Moreover, some of the ‘antipsychotics’ used for schizophrenia also have mood-stabilizing effects and are often indicated for bipolar disorder. Thus, there is a significant gap between the disease-based nomenclature and clinical indications. To better appreciate the current complex conditions, we conducted a systematic examination of official indications of the drugs that have been approved for bipolar disorder and are available either in Japan or the USA. The approved indications of 17 drugs that have an indication for bipolar disorder are summarized in Table S1. In Japan, the approved indications other than bipolar disorder include schizophrenia, major depressive disorder, dysthymia, autistic disorder, epilepsy, migraine, trigeminal neuralgia, nausea and vomiting, restlessness and apprehension before surgery, tetanus, and hiccups. In the USA, the approved indications for these drugs besides bipolar disorder include schizophrenia, major depressive disorder, autistic disorder, epilepsy, Tourette's disorder, migraine, nausea and vomiting, restlessness and apprehension before surgery, tetanus, hiccups, psychotic disorders, porphyria, and severe behavioral problems in children. These results confirm the discrepancy between the term ‘mood stabilizers’ and their approved indications. This discrepancy is problematic and perplexes patients and their families; moreover, it leads to a misunderstanding of the rationale for the prescription, which in turn negatively impacts adherence to pharmacotherapy.4, 5 This disease-based nomenclature is confusing not only for patients but also for medical doctors. They prescribe ‘antidepressants’ for anxiety disorders and ‘antipsychotics’ for depression. Indeed, we recently reported on a significant gap between the generic terminology of ‘antipsychotics’ and ‘antidepressants’ and their actual approved indications.5 In general, more than half of ‘second-generation antipsychotics’ and ‘newer antidepressants’ were found to be approved not only for psychotic disorders and depression, respectively, but also for a variety of other psychiatric and psychological conditions. While generic names, such as ‘mood stabilizers,’ ‘antipsychotics,’ and ‘antidepressants’ may still be useful for communication purposes to some extent, a potential solution for this confused and confusing terminology is a proposal to move from disease-based to pharmacology-driven nomenclature. Along these lines and also in order to reflect the recent advances in neuroscience, the Neuroscience-based Nomenclature (NbN) has been proposed.4, 6, 7 This pharmacologically driven nomenclature provides a new platform to reflect up-to-date new scientific knowledge and may also be more useful and appropriate not only in clinical practice for both patients and clinicians but for basic and clinical research as well. This nomenclature aims to reflect the best of current pharmacological knowledge. It is true that our current knowledge is limited to adequately defining the primary target or to elucidating the exact mechanisms of action; the background on the efficacy of lithium remains obscure to date, for instance. However, the NbN is a platform that reflects up-to-date scientific evidence on the pharmaceutical compounds. With the accumulation of knowledge on these drugs, the NbN will become closer to perfection. J.Z. and H.U. are taskforce members of the Neuroscience-based Nomenclature as a representative of the Asian College of Neuropsychopharmacology. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.