Is there a relationship between morphological and functional platelet changes and depressive disorder?

BACKGROUND: Blood platelets, due to shared biochemical and functional properties with presynaptic serotonergic neurons, constituted, over the years, an attractive peripheral biomarker of neuronal activity. Therefore, the literature strongly focused on the investigation of eventual structural and functional platelet abnormalities in neuropsychiatric disorders, particularly in depressive disorder. Given their impact in biological psychiatry, the goal of the present paper was to review and critically analyze studies exploring platelet activity, functionality, and morpho-structure in subjects with depressive disorder. METHODS: According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to March 2020 with the search terms: (1) platelets in depression [Title/Abstract]"; (2) "(platelets[Title]) AND depressive disorder[Title/Abstract]"; (3) "(Platelet[Title]) AND major depressive disorder[Title]"; (4) (platelets[Title]) AND depressed[Title]"; (5) (platelets[Title]) AND depressive episode[Title]"; (6) (platelets[Title]) AND major depression[Title]"; (7) platelet activation in depression[All fields]"; and (8) platelet reactivity in depression[All fields]." RESULTS: After a detailed screening analysis and the application of specific selection criteria, we included in our review a total of 106 for qualitative synthesis. The studies were classified into various subparagraphs according to platelet characteristics analyzed: serotonergic system (5-HT2A receptors, SERT activity, and 5-HT content), adrenergic system, MAO activity, biomarkers of activation, responsivity, morphological changes, and other molecular pathways. CONCLUSIONS: Despite the large amount of the literature examined, nonunivocal and, occasionally, conflicting results emerged. However, the findings on structural and metabolic alterations, modifications in the expression of specific proteins, changes in the aggregability, or in the responsivity to different pro-activating stimuli, may be suggestive of potential platelet dysfunctions in depressed subjects, which would result in a kind of hyperreactive state. This condition could potentially lead to an increased cardiovascular risk. In line with this hypothesis, we speculated that antidepressant treatments would seem to reduce this hyperreactivity while representing a potential tool for reducing cardiovascular risk in depressed patients and, maybe, in other neuropsychiatric conditions. However, the problem of the specificity of platelet biomarkers is still at issue and would deserve to be deepened in future studies.

Lifetime evolution of ADHD treatment.

Attention-deficit hyperactivity disorder (ADHD), has been traditionally considered a neurodevelopmental disorder affecting children and adolescents characterized by inattention, hyperactivity, disruptive behavior, and impulsivity. Although still debated, it is evident that ADHD is also present in adulthood, but this diagnosis is rarely carried out, mainly for the frequent comorbidity with other psychiatric and/or substance abuse disorders. Given the need to shed more light on the pharmacological treatment of ADHD, we performed a naturalistic review to review and comment on the available literature of ADHD treatment across the lifespan. Indeed, stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants, although requiring some weeks to be fully effective, are useful when a substance abuse history is detected. In any case, the pharmacological management of ADHD appears to be still largely influenced by the individual experience of the clinicians. Further longitudinal studies with a careful and detailed characterization of participants across different phases of the lifespan are also required to provide relevant confirmations (or denials) regarding pharmacological treatments amongst the different age groups.

Potentially traumatic events, post-traumatic stress disorder and post-traumatic stress spectrum in patients with fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is defined as a severe, chronic, non-articular rheumatic condition characterised by widespread musculoskeletal pain, hyperalgesia and generalised tender points, in the absence of inflammatory or structural musculoskeletal abnormalities. Pain is the predominant symptom, allodynia and hyperalgesia are common signs. Extreme fatigue, impaired cognition and non-restorative sleeping difficulties coexist in addition to other somatic symptoms. Several studies suggest there is a meaningful relationship between FM and the psychological symptoms of depression and post-traumatic stress disorder (PTSD). PTSD is a mental disorder that can develop after a person has been exposed to a traumatic event, characterised by a specific set of symptoms including re-experiencing of the event, avoidance and numbing and arousal. The present study investigates the impact of lifetime potentially traumatic events, including losses, and of post-traumatic stress symptoms on the severity of illness in patients with fibromyalgia (FM). METHODS: Sixty-one patients with FM, diagnosed according to the American College of Rheumatology criteria, were consecutively enrolled at the Unit of Rheumatology, University of Pisa, Italy. Assessments included: the SCID-5 and the Trauma and Loss Spectrum Self-Report (TALS-SR) lifetime version. RESULTS: 21.3% of the subjects (n=13) met the criteria for "partial" PTSD: 57.4% criterion B, 42.6% criterion C, 31.1 criterion D and 44.3% criterion E. Fibromyalgia patients without PTSD reported significantly lower scores in all domains compared to the patients with partial PTSD, the latter ones reporting significantly lower scores in all domains compared to full PTSD with the exception of domain I. In particular, these differences were noticeable in Domain VI and Domain VIII. CONCLUSIONS: The results of the study show that fibromyalgic patients with PTSD report more potentially traumatic events, avoidance symptoms, numbing, arousal, maladaptive coping and personality characteristics compared to patients with partial or without PTSD; these results could indicate that loss and/or trauma events represent a risk factor for the development of symptoms of FM in genetically predisposed individuals.

Sex matters: The impact of oxytocin on healthy conditions and psychiatric disorders.

Oxytocin (OT) is involved in the regulation of physiological processes and emotional states, with increasing evidence for its beneficial actions being mediated by the autonomic and immune systems. Growing evidence suggests that OT plays a role in the pathophysiology of different psychiatric disorders. Given the limited information in humans the aim of this study was to retrospectively explore plasma OT levels in psychiatric patients, particularly focusing on sex-related differences, as compared with healthy controls. The patients studied here were divided into three groups diagnosed with obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). Plasma OT levels were significantly different between healthy men and women, with the latter showing higher values, while none of the three psychiatric groups showed sex-related differences in the parameters measured here. The intergroup analyses showed that the OT levels were significantly higher in OCD, lower in PTSD and even more reduced in MDD patients than in healthy subjects. These differences were also confirmed when gender was considered, with the exception of PTSD men, in whom OT levels were similar to those of healthy men. The present results indicated that OT levels were higher amongst healthy women than men, while a sex difference was less apparent or reversed in psychiatric patients. Reductions in sex differences in psychopathologies may be related to differential vulnerabilities in processes associated with basic adaptive and social functions.

Different Sides of Depression in the Elderly: An In-depth View on the Role of Aß Peptides.

BACKGROUND: Late-onset depression (LOD) is the most common neuropsychiatric disorder associated with Alzheimer's disease (AD), often associated with structural and functional brain changes, neuropsychological impairments and negative family history for affective disorders. LOD could be a risk factor or a prodromal phase of AD; this has led to the investigation of the link between depression and amyloid-ß (Aß) peptides by measuring Aß levels in plasma, cerebrospinal fluid (CSF) and brains of elderly depressed subjects. OBJECTIVE: This study aims to clarify the complex relationship between depression, Aß peptides and AD. METHODS: We evaluated all articles published up to 2019 in PubMed in which Aß was measured in serum (or plasma), CSF or brain in elderly with Major Depressive Disorder or depressive symptoms evaluated with standard scales. RESULTS: Low plasma Aß42 levels are strongly associated with depression severity. Plasma Aß40 levels are higher in younger depressed, drug-resistant and those with more severe symptoms. CSF Aß42 levels are lower in depressed than controls. PET-detected global and region-specific increases in Aß deposition are sometimes associated with LOD, cognitive impairment, anxiety but not with Cardiovascular Diseases (CVDs)/CVD risk factors. Elderly depressed with CVDs/CVD risk factors have more frequently high plasma Aß40 levels and drug-resistance; those without Conclusion: Two specific Aß profiles emerge in the depressed elderly. One is associated with Aß42 reductions in plasma and CSF, possibly reflecting increased brain amyloid deposition and prodromal AD. The other one is characterized by high plasma Aß40 levels, cerebrovascular disease and is clinically associated with increased AD risk.

Platelet APP Processing: Is It a Tool to Explore the Pathophysiology of Alzheimer's Disease? A Systematic Review.

The processing of the amyloid precursor protein (APP) is a critical event in the formation of amyloid plaques. Platelets contain most of the enzymatic machinery required for APP processing and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. The goal of the present paper was to analyze studies exploring platelet APP metabolism in Alzheimer's disease patients trying to assess potential reliable peripheral biomarkers, to offer new therapeutic solutions and to understand the pathophysiology of the AD. According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to June 2020 with the search terms: "((((((APP) OR Amyloid Precursor Protein) OR AbetaPP) OR Beta Amyloid) OR Amyloid Beta) OR APP-processing) AND platelet". Thirty-two studies were included in this systematic review. The papers included are analytic observational studies, namely twenty-nine cross sectional studies and three longitudinal studies, specifically prospective cohort study. The studies converge in an almost unitary way in affirming that subjects with AD show changes in APP processing compared to healthy age-matched controls. However, the problem of the specificity and sensitivity of these biomarkers is still at issue and would deserve to be deepened in future studies.

Can platelet activation result in increased plasma Aß levels and contribute to the pathogenesis of Alzheimer's disease?

One of the central lesions in the brain of subjects with Alzheimer's disease (AD) is represented by aggregates of ß-amyloid (Aß), a peptide of 40-42 amino acids derived from the amyloid precursor protein (APP). The reasons why Aß accumulates in the brain of individuals with sporadic forms of AD are unknown. Platelets are the primary source of circulating APP and, upon activation, can secrete significant amounts of Aß into the blood which can be actively transported to the brain across the blood-brain barrier and promote amyloid deposition. Increased platelet activity can stimulate platelet adhesion to endothelial cells, trigger the recruitment of leukocytes into the vascular wall and cause perivascular inflammation, which can spread inflammation in the brain. Neuroinflammation is fueled by activated microglial cells and reactive astrocytes that release neurotoxic cytokines and chemokines. Platelet activation is also associated with the progression of carotid artery disease resulting in an increased risk of cerebral hypoperfusion which may also contribute to the AD neurodegenerative process. Platelet activation may thus be a pathophysiological mechanism of AD and for the strong link between AD and cerebrovascular diseases. Interfering with platelet activation may represent a promising potential adjunct therapeutic approach for AD.

Protracted Hiccups Induced by Aripiprazole and Regressed after Administration of Gabapentin.

Hiccups are sudden, repeated, and involuntary contractions of the diaphragm muscle (myoclonic contraction). It involves a reflex arc that, once activated, causes a strong contraction of the diaphragm immediately followed by the closure of the glottis translating into the classic "hic" sound. Hiccups can be short, persistent, and intractable depending on the duration. The most disabling hiccups often represent the epiphenomenon of a medical condition such as gastrointestinal and cardiovascular disorders; central nervous system (CNS) abnormalities; ear, nose, and throat (ENT) conditions or pneumological problems; metabolic/endocrine disorders; infections; and psychogenic disorders. Some drugs, such as aripiprazole, a second-generation antipsychotic, can induce the onset of variable hiccups. We describe herein the cases of three hospitalized patients who developed insistent hiccups after taking aripiprazole and who positively responded to low doses of gabapentin. It is probable that aripiprazole, prescribed at a low dosage (<7.5 mg/day), would act as a dopamine agonist by stimulating D2 and D3 receptors at the "hiccup center" level-located in the brain stem-thus triggering the hiccup. On the other hand, gabapentin led to a complete regression of the hiccup probably by reducing the nerve impulse transmission and modulating the diaphragmatic activity. The present case series suggests the use of low doses of gabapentin as an effective treatment for aripiprazole-induced hiccups. However, our knowledge of the neurotransmitter functioning of the hiccup reflex arc is still limited, and further research is needed to characterize the neurotransmitters involved in hiccups for potential novel therapeutic targets.

Misperceptions and hallucinatory experiences in ultra-trailer, high-altitude runners.

BACKGROUND: The Mountain Activities Neuro-behavioural Research Programme is a research project born in the 2 nd Unit of Psychiatry, Department of Clinical and Experimental Medicine at the University of Pisa to investigate the effects of altitude on the mental and neuro-behavioural aspects of people performing activities in mountainous areas. METHODS: In this study, after elaborating a standardised data collection form, based on traditional psychopathology notions, to classify the misperceptions reported by the athletes taking part, we investigated the various types of these misperceptions in 21 athletes (including only one female), with a mean age of 44.90 ± 8.51 (min 33 and max 58). RESULTS: The athletes reported different kinds of misperceptions. It was possible to highlight three different clusters of athletes, based on the similarities between the kinds of misperceptions reported in each cluster: (a) anomalies in the intrinsic characteristics of perceptions (i.e. depersonalisation and derealisation), (b) illusions and (c) hallucinations. CONCLUSIONS: This study supports the concept that anomalous perceptual experiences may occur independently of the context of psychiatric or neurological disorders. The chance of observing hallucinatory phenomena outside the context of psychiatric disorders and in extreme environmental conditions among ultra-trail runners may offer a unique opportunity to those intending to study psychopathological conditions in a 'para-physiological' context.