The Efficacy of Mobile Phone-Based Interventions for the Treatment of Depression: A Systematic Meta-Review of Meta-Analyses of Randomized Controlled Trials.

BACKGROUND: Depression is ranked by the World Health Organization as the single largest contributor to global disability. The shortage of health care resources, conditions of social distancing during the present pandemic, and the continuing need of patients with subclinical depression and in remission for supportive therapies, all together motivate a search for new approaches to deliver appropriate and timeous treatment for depression. SUBJECTS AND METHODS: We conducted a systematic literature search of meta-analyses and systematic reviews on the topic of mobile apps for the treatment of depression using the Medline (Pubmed) database during the period ending March 30th, 2022. This review was managed following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and entailed a search strategy using key-words related to depressive states and mobile phone apps for depression treatment and management. RESULTS: A total of 15 full-text articles met the inclusion criteria for the current systematic review. 13 of the 15 studies reported on the effectiveness of mobile apps for treating depression, finding a significant reduction in depressive symptoms with small-to-medium positive effect size. Patients with severe depression experienced greater benefits from a behavioral activation app, whereas those with mild depression responded better to a mindfulness app. The impact of clinicians' support is difficult to isolated completely from the particular interventions' effects. CONCLUSIONS: Mobile-based intervention apps present a convenient tool for prevention and supportive therapy of depression. The use of mobile apps may act as an efficient intervention to reduce depression in adult patients regardless the potential contributing factors of gender or co-morbidities, but the role of mobile apps should be contrasted with other digital interventions.

Monoamine Oxidase Inhibition by Plant-Derived ß-Carbolines; Implications for the Psychopharmacology of Tobacco and Ayahuasca.

The monoamine oxidases (MAOs) are flavin-containing amine oxidoreductases responsible for metabolism of many biogenic amine molecules in the brain and peripheral tissues. Whereas serotonin is the preferred substrate of MAO-A, phenylethylamine is metabolized by MAO-B, and dopamine and tyramine are nearly ambivalent with respect to the two isozymes. ß-Carboline alkaloids such as harmine, harman(e), and norharman(e) are MAO inhibitors present in many plant materials, including foodstuffs, medicinal plants, and intoxicants, notably in tobacco (Nicotiana spp.) and in Banisteriopsis caapi, a vine used in the Amazonian ayahuasca brew. The ß-carbolines present in B. caapi may have effects on neurogenesis and intrinsic antidepressant properties, in addition to potentiating the bioavailability of the hallucinogen N,N-dimethyltryptamine (DMT), which is often present in admixture plants of ayahuasca such as Psychotria viridis. Tobacco also contains physiologically relevant concentrations of ß-carbolines, which potentially contribute to its psychopharmacology. However, in both cases, the threshold of MAO inhibition sufficient to interact with biogenic amine neurotransmission remains to be established. An important class of antidepressant medications provoke a complete and irreversible inhibition of MAO-A/B, and such complete inhibition is almost unattainable with reversible and competitive inhibitors such as ß-carbolines. However, the preclinical and clinical observations with synthetic MAO inhibitors present a background for obtaining a better understanding of the polypharmacologies of tobacco and ayahuasca. Furthermore, MAO inhibitors of diverse structures are present in a wide variety of medicinal plants, but their pharmacological relevance in many instances remains to be established.

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans.

Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood-brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.

Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET.

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0-60min after pre-treatment with α-CCA-Na in mice (-47%) and in piglets (-66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

Effects of acute detoxification of the herbal blend 'Spice Gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study.

We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.

Validation of the octamouse for simultaneous 18F-fallypride small-animal PET recordings from 8 mice.

UNLABELLED: Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D(2/3) ligand (18)F-fallypride serving as a test substance for brain receptor imaging. METHODS: The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the (18)F-fallypride binding potential (BP(ND)) in the striatum were tested in groups of mice receiving (18)F-fallypride at 2 different specific activities (140 and 50 GBq/µmol), with and without scatter correction. Finally, the relationship between BP(ND) and injected dose of (18)F-fallypride (3.5-17 MBq/mouse) was tested. RESULTS: Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of (18)F-fallypride BP(ND) in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BP(ND) by a mean of 6%; covariances of the inter- and intraoperator variability of BP(ND) were 10%. There was a positive correlation between radiochemical dose and BP(ND) with (R(2) = 0.53) and without (R(2) = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum. CONCLUSION: The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of (18)F-fallypride BP(ND) was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BP(ND) on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify (18)F-fallypride BP(ND) in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of diverse radioligands.

FDG-PET mapping the brain substrates of visuo-constructive processing in Alzheimer's disease.

The anatomical basis of visuo-constructive impairment in AD is widely unexplored. FDG-PET can be used to determine functional neuronal networks underlying specific cognitive performance in the human brain. In the present study, we determined the pattern of cortical metabolism that was associated with visuo-constructive performance in AD. We employed two widely used visuo-constructive tests that differ in their demand on visual perception and processing capacity. Resting state FDG-PET scans were obtained in 29 probable AD patients, and cognitive tests were administered. We made a voxel-based regression analysis of FDG uptake to scores in visual test performance, using the SPM5 software. Performance in the CERAD Drawing test correlated with FDG uptake in the bilateral inferior temporal gyri, bilateral precuneus, right cuneus, right supramarginal gyrus and right middle temporal gyrus covering areas of dorsal and ventral visual streams. In contrast, performance in the more complex RBANS Figure Copy test correlated with FDG uptake in the bilateral fusiform gyri, right inferior temporal gyrus, left anterior cingulate gyrus, left parahippocampal gyrus, right middle temporal gyrus and right insula, encompassing the ventral visual stream and areas of higher-level visual processing. The study revealed neuronal networks underlying impaired visual test performance in AD. The extent of involvement of visual and higher order association cortex increased with greater test complexity. From a clinical point of view, both of these widely used visual tests evaluate the integrity of complementary cortical networks and may contribute complementary information on the integrity of visual processing in AD.

Synthesis, radiolabeling and in vivo evaluation of [11C]RAL-01, a potential phosphodiesterase 5 radioligand.

Very few tracers are available for imaging studies of second messenger systems. We developed a radiosynthesis for the phosphodiesterase (PDE) 5 inhibitor [(11)C]RAL-01. Whole body distribution studies using positron emission tomography (PET) revealed a time-dependant passage through the liver and accumulation of radioactivity in the bile of the Landrace pig. Displaceable binding was readily discerned in the myocardium, and traces of binding were seen in pulmonary tissue, consistent with the use of this class of drug in the treatment of pulmonary hypertension and heart failure. [(11)C]RAL-01 readily entered the brain and obtained an equilibrium distribution volume of 4-5 ml g(-1). Mean parametric images suggested the presence of a small displaceable binding component, but this binding was not significant in the present group of three pigs. Thus, [(11)C]RAL-01 shows considerable promise for PET studies of biliary elimination and of PDE5 binding in the cardiovascular system. However, analogues of higher affinity may be required for investigations of central nervous system binding sites.

MDMA-evoked changes in cerebral blood flow in living porcine brain: correlation with hyperthermia.

3,4-Methylenedioxymethamphetamine (MDMA) acutely releases intraneuronal dopamine and serotonin and evokes hyperthermia which is linked to toxicity for serotonin fibers. The acute effects of MDMA on cerebral blood flow (CBF) in living brain have not been described in an animal model of MDMA intoxication. We predicted that MDMA-induced hyperthermia should correlate with increased CBF in the hypothalamus, a serotonin-rich brain region subserving thermoregulation. To test this prediction, we used positron emission tomography with statistical parametric mapping for exploratory analysis of the focal changes in the magnitude of CBF in the anesthetized female Landrace pig (n = 9) at 30 and 150 min after acute challenge with MDMA-HCl (1 mg/kg, i.v.). The MDMA treatment was followed by increased CBF in the occipital cortex and in the medial mesencephalon overlapping the dorsal raphé nucleus, and reduced CBF in the cerebellar vermis and in a cluster in the medulla encompassing the left locus coeruleus. The individual increase of body temperature correlated positively with increased CBF in the vicinity of the raphé nucleus, in the hypothalamus (regions linked to thermoregulation), and also in the medial frontal cortex, which together comprise the regions receiving the most dense serotonin innervations in pig brain. Thus, individual differences in the susceptibility to MDMA-induced hyperthermia in this population correlated with the magnitude of focal increases in CBF within specific brain regions endowed with a dense serotonin innervation, including regions linked to thermoregulation.