Point of care assay for blood aripiprazole concentrations: development, validation and utility.

BACKGROUND: The antipsychotic aripiprazole is often used in the treatment of first-episode psychosis. Measuring aripiprazole blood levels provides an objective measure of treatment adherence, but this currently involves taking a venous blood sample and sending to a laboratory for analysis. AIMS: To detail the development, validation and utility of a new point of care (POC) test for finger-stick capillary blood concentrations of aripiprazole. METHOD: Analytical performance (sensitivity, precision, recovery and linearity) of the assay were established using spiked whole blood and control samples of varying aripiprazole concentration. Assay validation was performed over a 14-month period starting in July 2021. Eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Capillary blood samples were tested by the MyCare™ Insite POC analyser, which provided measurement of aripiprazole concentration in 6 min, and the venous blood sample was tested by the standard laboratory method. RESULTS: A total of 101 patients agreed to measurements by the two methods. Venous blood aripiprazole concentrations as assessed by the laboratory method ranged from 17 to 909 ng/mL, and from 1 to 791 ng/mL using POC testing. The correlation coefficient between the two methods (r) was 0.96 and there was minimal bias (slope 0.91, intercept 4 ng/ml). CONCLUSIONS: The MyCare Insite POC analyser is sufficiently accurate and reliable for clinical use. The availability of this technology will improve the assessment of adherence to aripiprazole and the optimising of aripiprazole dosing.

Cariprazine - an Alternative Treatment for Clozapine-resistant Schizophrenia?

Treatment-resistant schizophrenia (TRS) poses a significant therapeutic challenge in psychiatric practice. Clozapine is recognized as a treatment of choice in TRS but is not always effective in alleviating patients' symptoms. Additionally, clozapine therapy is associated with multiple side effects and monitoring requirements that often limit its use and negatively affect patients' compliance with the treatment. Although clozapine augmentation options are available, there is currently no alternative monotherapy proven to be effective in TRS. We present a case of a young man with TRS who failed to respond to appropriate trials of risperidone, aripiprazole and also clozapine, and who experienced impairing adverse effects of clozapine that made further clozapine treatment not only futile but also detrimental to his health. He was successfully treated with cariprazine monotherapy, which culminated in the remission of his both positive and negative symptoms of psychosis as well as in the marked improvement in social functioning. Cariprazine, a newer atypical antipsychotic endowed with a D3-preferring mode of action, may offer a better tolerated and more acceptable treatment option for patients with difficult-to-treat psychotic symptoms.

First Use of Clozapine Point of Care Testing in Acute Inpatient Psychiatry: Preliminary Report.

Clozapine is the antipsychotic of choice in treatment-resistant schizophrenia. Serum clozapine concentration testing is essential to monitor adherence, adjust dosing, and ensure treatment safety. However, patients who are acutely unwell are frequently reluctant to undergo blood testing requiring venipuncture. Also, conventional laboratory-based measurement of clozapine plasma levels can take days, thus contributing to the suboptimal use of clozapine when it is most needed. We pioneered clozapine whole-blood point of care (POC) testing in the acute inpatient setting in the treatment of a group of actively psychotic patients receiving clozapine during the outbreak of the COVID-19 pandemic. POC clozapine testing using automated homogenous immunoassay requires only finger prick blood sampling and is more acceptable to patients. As it produces results in minutes, clozapine POC testing serves to promptly ascertain adherence with treatment and inform therapeutic dosing. POC testing offered a more practical, less invasive, and quicker alternative to conventional methods of monitoring clozapine levels. Near immediate availability of clozapine levels expedited clinical decisions and helped ensure safe clozapine prescribing to our severely psychotic patients in a time of crisis. By facilitating patients' early safe discharge from the hospital, clozapine POC testing also reduced length of hospitalization.

COVID-19 and acute inpatient psychiatry: the shape of things to come.

Psychiatric services that provide acute inpatient care have to respond to the challenges brought about by the COVID-19 pandemic to consistently deliver high standards of treatment to patients and ensure the safety of staff. This can only be achieved by fostering a culture that rewards initiative and empowers inpatient teams to implement and comply with changes which everyone understands and benefits from. The experience of an inner London acute psychiatric unit has shown the value of combining proactive leadership, multidisciplinary decision making and good communication in adapting services to an everchanging environment. Practical solutions have emerged that have improved service delivery and patient care, and which will likely outlast the COVID-19 pandemic. These include changes to team work and routine, streamlining patient care with a focus on goal directed admissions, developing a healthier work environment and adopting novel technology in patient care and multidisciplinary collaboration.KEY POINTSPsychiatric inpatient units have to manage the COVID-19 crisis alongside the risk of acutely disturbed behaviour, while ensuring high standards of care and patient throughput.To respond to the COVID-19 crisis, inpatient units have to foster a culture that rewards initiative and empowers teams to implement and comply with changes that everyone understands and benefits from.Adaptive strategies should include good communication, a healthy work environment, flexible rules, dynamic infection control and adopting novel technology for clinical care and multidisciplinary work.Proactive leadership, multidisciplinary teamwork, transparency and a shared ethos of responsibility are the main tools to build effective inpatient teams.

Psychotic disorders and electrocardiogram abnormalities in the acute psychiatric setting: more than the metabolic syndrome alone.

Medical comorbidity in severe mental illness (SMI) is high and often severe, accounting for reduced life expectancy in this group. We assessed the rate and degree of electrocardiogram (ECG) abnormalities in acutely unwell SMI male patients by reviewing the case notes of 50 consecutive admissions to an inpatient psychiatric unit. 82% were admitted with a psychotic disorder with a median age of 35 (range 19 - 72 years). Of the 29 patients who had an ECG during admission or recently (<90 days) prior to admission, 21% had a clinically relevant abnormality. 42% of patients did not have an ECG during admission or recently. Results indicate that SMI patients requiring acute care, in addition to metabolic disorders, may also have significant ECG abnormalities from a young age. Comprehensive medical monitoring, including regular ECGs and use of preventive strategies, should be an integral part of management of SMI from the outset.KEY POINTSThis small study found that out of 50 patients admitted to an acute psychiatric unit, 29 (58%) had a recent (<90 days) electrocardiogram (ECG); 6 of them (21%) had clinically relevant ECG abnormalities.ECG abnormalities were found in 24% (n = 10) of patients who had at least 1 documented ECG ever performed (n = 41, 82%).42% of patients did not have an ECG performed in the 90 days prior to or during admission.Results indicate that patients with Severe Mental Illness (SMI) requiring acute care are at risk of metabolic disorders and ECG abnormalities from a young age.Comprehensive medical monitoring including regular ECGs and early preventive strategies should be part of SMI patients' management plans from the outset. Larger scale studies are needed to assess the impact of early intervention on cardiovascular risk in SMI.

Does Nicotine Prevent Cytokine Storms in COVID-19?

COVID-19 has a benign outcome in most cases, yet it can also be fatal and no specific treatment is available as of yet. Older age and several medical comorbidities are risk factors for COVID-19 complications. We report on an elderly man with a longstanding history of bipolar affective disorder associated with heavy smoking, alcohol abuse and multiple comorbidities, including severe chronic obstructive pulmonary disease and recurrent pulmonary sepsis, who contracted COVID-19 during his inpatient treatment of a manic episode, and who fully recovered from COVID-19 without any need for respiratory support. We discuss how his excessive use of nicotine replacement therapy may have contributed to his emerging unscathed from COVID-19. Nicotine, an α7-nACh receptor agonist, may boost the cholinergic anti-inflammatory pathway and hinder the uncontrolled overproduction of pro-inflammatory cytokines triggered by the SARS-CoV-2 virus, which is understood to be the main pathway to poor outcomes and death in severe COVID-19.

Clozapine in the Time of COVID-19.

Clozapine is the most effective antipsychotic for treatment resistant schizophrenia but adverse reactions to clozapine include neutropenia. The current COVID-19 pandemic may raise specific concerns for clinicians prescribing clozapine for patients who need it. We report on two actively psychotic patients with treatment resistant schizophrenia who required admission to our inner-London acute psychiatric unit during the COVID-19 pandemic and who were treated with clozapine. One was a young patient who developed COVID-19 symptoms and tested positive for the SARS-CoV-2 virus while receiving clozapine and the other was an aging man who tested negative for the SARS-CoV-2 virus but had contact with COVID-19 during initiation of clozapine treatment. Both responded to clozapine treatment and were safely discharged from hospital without any complication. These cases suggest that, in the absence of complications, exposure to COVID-19 per se and the onset of mild symptoms in those infected may not warrant withdrawal or postponement of clozapine treatment when this is indicated.

Focussing on the fundaments - assessing and treating Clozapine Induced Gastrointestinal Hypomotility.

Background: Clozapine is a second-generation antipsychotic used in treatment-resistant Schizophrenia (TRS). Clozapine Induced Gastrointestinal Hypomotility (CIGH) is the commonest cause of clozapine related death, yet remains under-recognised and under-monitored.Aims and hypothesis: To review the pharmacological management of CIGH. We hypothesised that pharmacological interventions would reduce the incidence of adverse outcomes associated with CIGH.Methods: We retrospectively reviewed consecutive patients treated on clozapine over a one year period on a male acute psychiatric ward. Information on patient demographics, CIGH symptomatology, treatment and outcome were extracted.Results: In total, 14 male patients with a mean age of 43 years (standard deviation 10 years) were included. Of these, 9 patients experienced CIGH during admission, in all cases presenting as constipation. Among patients experiencing CIGH, 8 of 9 (89%) patients received one or more interventions. This was most commonly a stimulant, or osmotic laxative. By discharge, the 8 patients treated were in full remission of CIGH symptoms.Conclusions: A high proportion of patients treated with clozapine experience CIGH, presenting most commonly as constipation. Whilst potentially life-threatening, CIGH can be successfully treated in an acute inpatient setting. Active monitoring of CIGH symptoms in patients initiated, or reinitiated on clozapine is recommended.Key pointsA high proportion of patients treated with Clozapine experience constipation, the cardinal feature of Clozapine Induced Gastrointestinal Hypomotility.Whilst potentially life-threatening, CIGH can be successfully treated in an acute inpatient setting with simple interventions.Active monitoring of CIGH symptoms in patients initiated, or reinitiated on clozapine is recommended.Future research on the potential benefit of prophylactic intervention would be beneficial.

Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: De-escalation and rapid tranquillisation.

The British Association for Psychopharmacology and the National Association of Psychiatric Intensive Care and Low Secure Units developed this joint evidence-based consensus guideline for the clinical management of acute disturbance. It includes recommendations for clinical practice and an algorithm to guide treatment by healthcare professionals with various options outlined according to their route of administration and category of evidence. Fundamental overarching principles are included and highlight the importance of treating the underlying disorder. There is a focus on three key interventions: de-escalation, pharmacological interventions pre-rapid tranquillisation and rapid tranquillisation (intramuscular and intravenous). Most of the evidence reviewed relates to emergency psychiatric care or acute psychiatric adult inpatient care, although we also sought evidence relevant to other common clinical settings including the general acute hospital and forensic psychiatry. We conclude that the variety of options available for the management of acute disturbance goes beyond the standard choices of lorazepam, haloperidol and promethazine and includes oral-inhaled loxapine, buccal midazolam, as well as a number of oral antipsychotics in addition to parenteral options of intramuscular aripiprazole, intramuscular droperidol and intramuscular olanzapine. Intravenous options, for settings where resuscitation equipment and trained staff are available to manage medical emergencies, are also included.

Mirtazapine treatment of a severe depressive episode and resolution of elevated inflammatory markers.

Depression has been shown to be associated with systemic inflammatory activity and the mode of action of several antidepressants appears to involve immunomodulation. Effects on immune system activity have also recently been observed in correlation with therapeutic response to mirtazapine in cardiac patients with depression, but no study has yet examined these effects in otherwise physically healthy depressed patients treated with mirtazapine. This report describes an association between a clinical antidepressant response and a decrease in markers of systemic inflammation observed during pharmacotherapy with mirtazapine in a severely depressed but physically well patient. This observation adds to the evidence that changes in inflammatory responses may be implicated in the mode of action of antidepressants. Further studies of antidepressant responses to mirtazapine and levels of inflammatory markers in depressed patients without medical comorbidity can help elucidate the role of the immune system in the pathophysiology of depression, and hence contribute to the development of novel antidepressant therapies.

Harnessing clinical psychiatric data with an electronic assessment tool (OPCRIT+): the utility of symptom dimensions.

Progress in personalised psychiatry is dependent on researchers having access to systematic and accurately acquired symptom data across clinical diagnoses. We have developed a structured psychiatric assessment tool, OPCRIT+, that is being introduced into the electronic medical records system of the South London and Maudsley NHS Foundation Trust which can help to achieve this. In this report we examine the utility of the symptom data being collected with the tool. Cross-sectional mental state data from a mixed-diagnostic cohort of 876 inpatients was subjected to a principal components analysis (PCA). Six components, explaining 46% of the variance in recorded symptoms, were extracted. The components represented dimensions of mania, depression, positive symptoms, anxiety, negative symptoms and disorganization. As indicated by component scores, different clinical diagnoses demonstrated distinct symptom profiles characterized by wide-ranging levels of severity. When comparing the predictive value of symptoms against diagnosis for a variety of clinical outcome measures (e.g. 'Overactive, aggressive behaviour'), symptoms proved superior in five instances (R(2) range: 0.06-0.28) whereas diagnosis was best just once (R(2):0.25). This report demonstrates that symptom data being routinely gathered in an NHS trust, when documented on the appropriate tool, have considerable potential for onward use in a variety of clinical and research applications via representation as dimensions of psychopathology.

A UK panel consensus on the initiation of aripiprazole for the treatment of bipolar mania.

OBJECTIVE: The objective of this consensus paper is to provide practical guidance on why and how aripiprazole, with its distinct pharmacological and side effect profile, should be used for treatment of acute bipolar mania. METHODS: An advisory panel of UK healthcare professionals, with extensive experience of prescribing aripiprazole for acute bipolar mania, met to discuss its use in this setting. RESULTS: The panel agreed that aripiprazole is effective in treating bipolar mania when prescribed and dosed appropriately, in both the short and long term, as monotherapy or in combination with a mood stabilizer. Unlike other atypical agents, aripiprazole has antimanic effects that are not associated with sedation, which is beneficial for patients, particularly in the long term. If rapid tranquillization is required when initiating aripiprazole in acutely disturbed patients, short-term coprescription of a benzodiazepine is recommended. Most side effects associated with aripiprazole occur within the first 1-3 weeks and are usually transient and easily treatable. Aripiprazole poses low risk of metabolic side effects, sexual dysfunction, and anhedonia, which can facilitate treatment adherence and help improve clinical outcomes. CONCLUSIONS: Aripiprazole is an effective first-line treatment for acute bipolar mania with a favorable safety/tolerability profile.

[The quest for the pharmacological treatment of schizophrenia: from conventional neuroleptics to atypical antipsychotics and beyond]. / La búsqueda del tratamiento farmacológico de la esquizofrenia: desde los neurolépticos convencionales a los antipsicóticos atípicos y más allá.

Schizophrenia is a common and impairing illness for which no treatment was available until the 2nd half of the last century. The introduction of antipsychotics changed forever the fate of sufferers. In addition to treating patients, antipsychotics have served as the main research tool in the effort to elucidate the neurochemistry of positive and negative symptoms of schizophrenia and thus foster the development of ever better therapeutic approaches. The dopaminergic theory of schizophrenia and insights on the role of serotonin and other neurotransmitters in psychosis have emerged as a result. However, none of these drugs is devoid of adverse effects, which can affect different systemic functions and present in varying degrees of severity and duration. From the advent of chlorpromazine and the conventional antipsychotics through the arrival of clozapine and other atypical antipsychotics, to the launch of newer compounds like aripiprazole and asenapine, clinicians have always had to carefully consider the inevitable trade-off between therapeutic efficacy and safety profile of the drugs they prescribe. Despite the decisive advances in the treatment of schizophrenia in the nearly sixty years since chlorpromazine was introduced, this is likely to remain the central tenet of psychiatric prescribing for many decades to come.

[The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness]. / El futuro de la depresión: una enfermedad sistémica, neuroendócrina, inflamatoria y neurodegenerativa compleja.

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioural therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimise clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.

El futuro de la depresión: una enfermedad sistémica neuroendócrina, inflamatoria y neurodegenerativa compleja / The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness

Los modelos neurobiológicos de la depresión han evolucionado más allá de la teoría monoaminérgica, que fue construida luego del advenimiento de las drogas antidepresivas en la década de 1950. Actualmente se considera que la depresión implica una amplia gama de neurotransmisores, incluyendo a la dopamina y el glutamato, y a prácticamente la totalidad del sistema nervioso central. La evidencia emergente está redefiniendo la depresión como una enfermedad crónica y sistémica que puede deteriorar la función neuroendocrina, los ritmos biológicos y las respuestas inmunes, y como una enfermedad que, de no ser tratada, puede conducir a la demencia. Diferentes abordajes de investigación, desde la biología molecular hasta los estudios clínicos, han ofrecido tanto nuevos conocimientos acerca de los mecanismos fisiológicos implicados como también indicios para desarrollar terapias antidepresivas efectivas en respuesta a los mismos. Además de los métodos ya bien establecidos, como los inhibidores de la recaptación de monoaminas y la terapia cognitivo-conductual, estos pueden incluir drogas anti-inflamatorias no esteroides, prescripción de ejercicio físico, tratamientos somáticos y toda una nueva generación de drogas antidepresivas dotadas de modos de acción originales. A medida que el manejo de la depresión se torna cada vez más multifacético, los médicos serán capaces de optimizar los resultados clínicos para sus pacientes integrando sinérgicamente las múltiples opciones terapéuticas disponibles.

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioral therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimize clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.

El futuro de la depresión: una enfermedad sistémica neuroendócrina, inflamatoria y neurodegenerativa compleja / The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness

Los modelos neurobiológicos de la depresión han evolucionado más allá de la teoría monoaminérgica, que fue construida luego del advenimiento de las drogas antidepresivas en la década de 1950. Actualmente se considera que la depresión implica una amplia gama de neurotransmisores, incluyendo a la dopamina y el glutamato, y a prácticamente la totalidad del sistema nervioso central. La evidencia emergente está redefiniendo la depresión como una enfermedad crónica y sistémica que puede deteriorar la función neuroendocrina, los ritmos biológicos y las respuestas inmunes, y como una enfermedad que, de no ser tratada, puede conducir a la demencia. Diferentes abordajes de investigación, desde la biología molecular hasta los estudios clínicos, han ofrecido tanto nuevos conocimientos acerca de los mecanismos fisiológicos implicados como también indicios para desarrollar terapias antidepresivas efectivas en respuesta a los mismos. Además de los métodos ya bien establecidos, como los inhibidores de la recaptación de monoaminas y la terapia cognitivo-conductual, estos pueden incluir drogas anti-inflamatorias no esteroides, prescripción de ejercicio físico, tratamientos somáticos y toda una nueva generación de drogas antidepresivas dotadas de modos de acción originales. A medida que el manejo de la depresión se torna cada vez más multifacético, los médicos serán capaces de optimizar los resultados clínicos para sus pacientes integrando sinérgicamente las múltiples opciones terapéuticas disponibles.(AU)

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioral therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimize clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.(AU)