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The principle of pragmatism in clinical trials has been broadly recognised as a way to close the gap between research and practice. In this contribution, we argue that the conduct of pragmatic clinical trials in Europe may be hampered by poor implementation of current European Union's Clinical Trial Regulation No. 536/2014.
Maju et al. provided clarifications on important and controversial issues related to esketamine clinical trial data, in response to a vivid debate triggered by the marketing authorisation recently granted by this new medicine. In this commentary, we reply to their comments attempting to critically discuss the evidence base needed to obtain regulatory approval.
In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.
Impairments in neuro and social cognition are considered core features of schizophrenia (SCZ) since they affect patients' functioning and contribute to poor socio-occupational outcomes. Therefore, the improvement of cognitive performances has become a primary goal in the care of patients with SCZ, especially in the first phases of the disease, as early interventions may favour better long-term outcomes. Cognitive remediation (CR) is a behavioural training aimed at improving cognitive functions with the goal of durability and generalisation in everyday life. Neuroimaging studies suggest that CR leads to neuroplasticity in chronic SCZ, whereas only a few studies tested the neural effects of CR in the early phase of the disease. Thus, in this review, we aimed at summarising CR-induced structural and functional brain changes in early SCZ. Existing evidence showed a protective effect of CR on grey matter volume in selected medial-temporal (i.e. hippocampus, parahippocampus and amygdala) and thalamic regions whereas functional changes affected mostly dorsolateral prefrontal and insular cortices both associated with improvements in cognitive performance and emotion regulation. Overall, CR in early SCZ appears to be associated with neural adaptations mostly allocated in prefrontal and limbic regions, however future longitudinal studies are needed to clarify whether the positive effects of cognitive training persist over time. It may also be interesting to investigate whether the application of CR in the early v. the late stage of the disease may lead to incremental benefits.
Since its development and theorisation in the 60s, attachment theory has greatly influenced both clinical and developmental psychology suggesting the existence of complex dynamics based on the relationship between an infant and its caregiver, that affects personality traits and interpersonal relationships in adulthood. Many studies have been conducted to explore the association between attachment styles and psychosocial functioning and mental health. By contrast, only a few studies have investigated the neurobiological underpinnings of attachment style, showing mixed results. Therefore, in this review, we described current evidence from structural and functional imaging studies with the final aim to disentangle the neural correlates of attachment style in healthy individuals. Overall, different attachment styles have been correlated with volumetric alterations mainly in the cingulate cortex, amygdala, hippocampus and anterior temporal pole. Consistently, functional imaging studies suggested patterns of activations in fronto-striatal-limbic circuits during the processing of social and attachment-related stimuli. Further studies are needed to clarify the neurobiological signature of attachment style, possibly taking into consideration a wide range of demographic, psychosocial and clinical factors that may mediate the associations between the style of attachment and brain systems (e.g., gender, personality traits, psychosocial functioning, early-life experience).
Hostility and related dimensions like anger, urgency, impulsivity and aggressiveness have been described in non-clinical populations and various serious mental illnesses including schizophrenia. Although representing a mental healthcare challenge, the investigation of such constructs is often limited by the presence of complex and multi-factorial causes and lack of agreement in their conceptualisation and measurement. In this review, we aim to clarify the anatomical basis of hostility-related dimensions in schizophrenia. Imaging studies suggest malfunctioning of a neural circuitry including amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula and hippocampus to modulate hostile thoughts and behaviours, at least in the subgroup of patients with schizophrenia who exhibit high levels of urgency, impulsivity and aggressiveness.
In individuals with coronary artery disease and concurrent depressive symptomatology, the evidence on the beneficial and harmful effects of antidepressants is very limited. Recently, a study was carried out to describe depressive symptoms and the treatments provided under real-world circumstances to cardiac patients who entered the Mayo Clinic cardiac rehabilitation program. Antidepressant use was associated with reductions in depressive symptoms, but also with poorer cardiovascular outcomes. In this commentary, the results of this study are discussed in view of their clinical implications for everyday clinical practice and for the production of knowledge.
A recent meta-analysis of antidepressant trials is the largest conducted to date. Although it claims to prove antidepressant effectiveness beyond dispute, the main outcome is response rates, which are derived from continuous data in a process that can inflate differences between groups. The standardised mean difference of 0.3 is in line with other meta-analyses that show small differences between antidepressants and placebo that are unlikely to be clinically significant. Other factors likely to exaggerate the effects are discussed, and evidence on associations between antidepressant effects and severity and outcomes of long-term treatment is considered. Clinicians need to have open discussions with patients about the limitations of antidepressant research, the lack of evidence that antidepressants correct a chemical imbalance or other brain abnormality, and the range of adverse effects and mental and physical alterations they can produce.
Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.
A substantial proportion of people with mental health conditions do not adhere to prescribed pharmacological treatments. Poor adherence is probably one of the most critical elements contributing to relapse in people with schizophrenia and other severe mental disorders. In order to tackle this global issue, in November 2017 the Food and Drug Administration approved a tablet formulation of the atypical antipsychotic aripiprazole embedded with a novel digital adherence-assessment device. In this commentary, we critically appraised the potential beneficial and harmful consequences of this new digital formulation of aripiprazole, and we highlighted expected implications for clinical practice.
Research evidence guiding the identification of pragmatic and effective actions aimed at improving the selection, availability, affordability and rational prescribing of medicines for mental disorders is sparse and inconsistent. In order to boost the development of new research, in this commentary we suggest to organise and classify all the activities in this area under a common theoretical framework and nomenclature, adopting the term ‘public health psychopharmacology’. Public health psychopharmacology is proposed as a research discipline, based on contributions from the fields of regulatory science, health services research and implementation science. Implementing the term public health psychopharmacology may offer advantages, as the scientific community would be more focused on common goals and objectives, with, likely, an increasing body of research evidence of practical use.
Generalised anxiety disorder (GAD) is a common psychiatric illness characterised by selective morpho-functional brain alterations. The breath of neuroimaging studies investigating the neural basis of GAD is extensive; however, its pathophysiology is still largely unknown. Specifically for proton Magnetic Resonance Spectroscopy (¹H MRS) investigations, which have the aim of identifying differences in metabolite levels between conditions in key brain areas, often showed contrasting results. Indeed, there are selected ¹H MRS studies reporting deficits of key metabolites in GAD patients; however, collectively the literature remains mixed with respect to consistency of major findings. In this review, we evaluate published ¹H MRS studies on GAD with the final aim of providing a comprehensive overview of the extent of neurometabolic dysfunctions associated with GAD. Interestingly, the majority of the studies reviewed showed altered metabolite levels in the dorsolateral prefrontal cortex and hippocampus suggesting regional specificity. These results also provide evidence of the utility of ¹H MRS not only for elucidating the pathophysiology of neuropsychiatric diseases, but also for the identification of more beneficial and targeted pharmacological interventions. Additionally, future studies are warranted to overcome methodological differences observed across the studies.
In the treatment of resistant schizophrenia, a number of meta-analyses attempted to quantify the efficacy and tolerability of antipsychotic (AP) polypharmacy v. monotherapy with contradictory results. Recently, a systematic review and meta-analysis of randomised controlled trials investigated the efficacy and tolerability of AP combination v. monotherapy in schizophrenia. It included 31 studies: 21 double-blind (considered high-quality studies) and 10 open-label (considered low-quality studies). The meta-analysis showed that, overall, the combination of two APs was more effective than monotherapy in terms of symptom reduction (standardised mean difference (SMD) = −0.53, 95% confidence interval (CI) −0.87 to −0.19); however, this result was confirmed only in the subgroup of low-quality studies. Negative symptoms improved when combining a D2 antagonist with a D2 partial agonist (SMD = −0.41, 95% CI −0.79 to −0.03) both in double-blind and open-label studies. In the present commentary, the results of this systematic review are critically discussed in terms of their clinical and research implications.
Although bipolar disorder (BD) is traditionally conceptualised as one diagnostic entity, the heterogeneity of pathophysiological manifestations in BD suggests the need to classify the subtypes of the illness based on neural markers. Specifically, the presence of psychotic symptoms seems to be relevant for the clinical outcome and may have specific neuroanatomical bases. The main objective of the present review was to assess whether the distinction between psychotic BD (PBD) and non-psychotic BD (NPBD) can improve the identification of the neurobiological markers of this complex illness. To this end, we summarised the findings from the magnetic resonance imaging studies that explored the cerebral correlates of psychosis in BD in terms of grey matter volume (GMV). Overall, the results suggest the presence of peculiar GMV differences between PBD and NPBD. Specifically, psychosis in BD seems to be associated with cortical GMV deficits compared with both healthy controls and NPBD, mainly in the frontal region. Conversely, NPBD patients showed GMV deficits in selective regions of the basal ganglia when compared with the other groups. Taken together, this evidence confirms the importance to classify BD based on the psychotic dimension, which may have a specific neurobiological architecture that partially overlaps across multiple psychotic disorders.
Relevant biochemicals of the brain can be quantified in vivo, non-invasively, using proton Magnetic Resonance Spectroscopy (¹H MRS). This includes metabolites associated with neural general functioning, energetics, membrane phospholipid metabolism and neurotransmission. Moreover, there is substantial evidence of implication of the frontal and prefrontal areas in the pathogenesis of psychotic disorders such as schizophrenia. In particular, the anterior cingulate cortex (ACC) plays an important role in cognitive control of emotional and non-emotional processes. Thus the study of its extent of biochemistry dysfunction in the early stages of psychosis is of particular interest in gaining a greater understanding of its aetiology. In this review, we selected ¹H MRS studies focused on the ACC of first-episode psychosis (FEP). Four studies reported increased glutamatergic levels in FEP, while other four showed preserved concentrations. Moreover, findings on FEP do not fully mirror those in chronic patients. Due to conflicting findings, larger longitudinal ¹H MRS studies are expected to further explore glutamatergic neurotransmission in ACC of FEP in order to have a better understanding of the glutamatergic mechanisms underlying psychosis, possibly using ultra high field MR scanners.
Three-month long-acting paliperidone is a new, recently marketed, formulation of paliperidone, characterised by the longest available dosing interval among long-acting antipsychotics. The clinical profile of 3-month long-acting paliperidone was recently summarised by the European Medicines Agency (EMA) in a public assessment report, released in April 2016. In this commentary, the main strengths and limitations of the EMA assessment report were appraised and discussed, in order to highlight possible implications for clinical practice, future research and regulatory practices for drug approval.
Patients experiencing psychoses and in need of antipsychotic agents may be exposed to a higher risk of myocardial infarction (MI) than the general population. As there have been no randomised studies investigating this association, a recent systematic review and meta-analysis included all observational studies that compared the incidence of MI among patients receiving antipsychotics v. no treatment. It found nine studies and calculated that the odds (risk) for developing MI were 1.88-fold higher in antipsychotic users compared with individuals who had not taken antipsychotic drugs. In this commentary, the results of this systematic review are discussed in view of their clinical implications for everyday clinical practice.
The pathogenesis of bipolar disorder (BD) is to date not entirely clear. Classical genetic research showed that there is a contribution of genetic factors in BD, with high heritability. Twin studies, thanks to the fact that confounding factors as genetic background or family environment are shared, allow etiological inferences. In this work, we selected twin studies, which focus on the relationship between BD, genetic factors and brain structure, evaluated with magnetic resonance imaging. All the studies found differences in brain structure between BD patients and their co-twins, and also in respect to healthy controls. Genetic effects are predominant in white matter, except corpus callosum, while gray matter resulted more influenced by environment, or by the disease itself. All studies found no interactions between BD and shared environment between twins. Twin studies have been demonstrated to be useful in exploring BD pathogenesis and could be extremely effective at discriminating the neural mechanisms underlying BD.
Until recently, no comprehensive guidance specifically on the conduction of systematic reviews and meta-analyses of pharmacoepidemiological studies of safety outcomes was available. In December 2015, the European Network of Centres for Pharmacoepidemiology and Pharamacovigilance (ENCePP), a network coordinated by the European Medicines Agency, published their ‘Guidance on conducting systematic reviews and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes’, filling an important gap in the field. This paper highlights the ENCePP recommendations in terms of study identification, data extraction, study quality appraisal and analytical plan. Although the ENCePP document should not be considered as definitive, since it will likely be refined following researchers’ feedback, it is expected that it will be highly influential and useful for the field, with the ultimate goal to improve and standardise the conduction and reporting of systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes.