Obsessive-compulsive disorder The serendipitous discovery that cl

Obsessive-compulsive disorder The serendipitous discovery that clomipramine (CMI), a more serotonergic tricyclic, is effective for obsessive-compulsive disorder (OCD) was important in giving impetus to a serotonin hypothesis of OCD.47 Subsequent work found that the more selective SSRIs were not only efficacious but also well-tolerated.48 More recent psychobiological Inhibitors,research,lifescience,medical research has focused on

delineating the role of neurotransmitters other than serotonin; dopaminergic augmentation strategies have been used clinically for some time now,49 and a range of other molecular treatment targets are being pursued.50,51 Anecdotal reports of the efficacy of CMI in OCD were followed by rigorous randomized controlled trials. Such work demonstrated Inhibitors,research,lifescience,medical that clomipramine was more efficacious than both placebo and noradrenergic tricyclic agents such as desipramine, and that it was efficacious in both adults as well as in children and adolescents with OCD.52 Such work led to the first FDA approval for OCD pharmacotherapy.15 The use of intravenous (IV) CMI for refractory OCD has also been investigated,53,54 as this route of administration avoids first-pass hepatic metabolism which breaks CMI down to its less potent form, desmethyl-clomipramine. Inhibitors,research,lifescience,medical With the introduction of the SSRIs, several studies of these

agents were undertaken in OCD, and these generally showed efficacy and safety.55 Fluoxetine, fluvoxamine, paroxetine, and sertraline have all been FDA-approved for OCD.56 While several meta-analyses have suggested that CMI may be more effective Inhibitors,research,lifescience,medical than SSRIs (Table II),57 this finding may reflect the fact that earlystudies were characterized by a lower placebo response rate. Flead-to-head comparisons of CMI and SSRIs have shown equal efficacy and superior tolerability for the SSRIs.58 Thus, the SSRIs are now typically viewed as the first-line choice for OCD.8,9,11,56,59 Table II. VX-765 supplier Selected meta-analyses of obsessive-compulsive disorder treatment. CMI, clomipramine; SSRI, selective serotonin reuptake Inhibitors,research,lifescience,medical inhibitor;

OCD, obsessive-compulsive disorder A meta-analysis of medication dosage findings in OCD suggests that patients who fail to respond to low-dose therapy should be increased to a higher and dose.60 An adequate trial in OCD should be at least 12 weeks in length.61 Although there is less published work on the longer-term treatment of OCD, a number of studies have demonstrated that early discontinuation often leads to relapse.58 Guidelines therefore suggest that patients who respond to initial acute treatment should then be continued for at least 1 year, and withdrawn gradually.8,9,56,59 It has been suggested that efficacy can be maintained even after a reduction in dosage of long-term treatment, with the benefits of improved tolerability and adherence.

However, if the intrinsic oscillator prefers certain frequencies,

However, if the intrinsic oscillator prefers certain frequencies, the rational design of tACS paradigms is more complex (and interesting). The selective preference of certain stimulation frequencies is called resonance, a well-known phenomenon that can be observed in many physical and biological systems. Technically, resonance can be easily determined by application of periodic stimulation with identical amplitude, but different frequencies. Any Inhibitors,research,lifescience,medical measure of oscillatory structures will reveal the degree to which the system prefers a given

frequency. In fact, one can look for two fundamental properties that delineate the resonance properties of the system: (i) the presence of so-called

“Arnold tongues”; and (ii) the presence of harmonics. Arnold tongues delineate the areas of entrainment for parameter pairs of stimulation amplitude and frequency. The tongueshaped areas derive from the fact Inhibitors,research,lifescience,medical that the stronger the amplitude of the periodic stimulation, the broader the range of frequencies to which an intrinsic oscillator can be entrained (Figure 4.) This corresponds to the intuitive concept Inhibitors,research,lifescience,medical that weak forces can only amplify the intrinsically present dynamics whereas stronger forces can—to a certain extent—override/modulate the frequency of the intrinsic oscillator. Harmonic frequencies refer to the phenomenon that stimulation Inhibitors,research,lifescience,medical at multiples of the intrinsic frequencies has a privileged effect on the amplitude of the ongoing oscillation. Computational simulations of large-scale cortical networks demonstrated that such resonance

effects indeed mediate the modulatory effects of tACS19; yet detailed experimental demonstration of resonance at the www.selleckchem.com/products/ph-797804.html network level has remained elusive. Likely, the discovery of such a phenomenon will build on the well-documented intrinsic resonance of individual neurons,67,68 especially layer V pyramidal cells that are interestingly very sensitive to electric fields due to their Inhibitors,research,lifescience,medical elongated somatodendritic axis.69 Figure 4. Arnold’s tongues. Effects of periodic perturbations are limited to stimulation frequencies close to the intrinsic (fundamental) frequency and its harmonics. Inverted triangles (“tongues”) delimit areas where for increasing else stimulation … Feedback stimulation: the future? In this review, I have discussed the recent evidence for: (i) a modulatory effect of endogenous electric fields that likely provide a synchronizing network signal by feedback; and (ii) network resonance as the putative mechanistic principle by which rhythmically active neuronal networks are sensitive to periodic perturbations by both endogenous and exogenous electric fields. Together, these recent discoveries provide fertile grounds for the development of novel noninvasive brain stimulation paradigms.

The annual rate of change in cognitive performance on each test w

The annual rate of change in cognitive performance on each test was calculated using linear mixed models. Overall differences in baseline (year 1) and annual rates of change were compared across all groups, followed by pairwise group comparisons. Neuropathologic assessment At autopsy, the right hemibrain was coronally sliced and frozen, and the whole left hemibrain was fixed in 10% buffered formaldehyde for at least 2 weeks and subsequently sectioned in the coronal plane. Routine diagnostic sections were obtained from the middle frontal Inhibitors,research,lifescience,medical gyrus (MFG), the superior and middle temporal gyri (SMTG),

the inferior GW9662 in vitro parietal (IP) lobule, the primary visual cortex, the anterior cingulate, the amygdala, the hippocampus

and entorhinal cortex, basal ganglia and basal forebrain, the thalamus, midbrain including the substantia nigra, pons, medulla, spinal cord, and cerebellum. Tissues were processed, embedded in paraffin, cut at 10 μm, and stained with Inhibitors,research,lifescience,medical hematoxilyn and eosin and with silver Hirano method (Yamamoto and Hirano 1986). Lewy body (LB) pathology was assessed in the brain stem and anterior cingulate cortex with alpha-synuclein immunohistochemistry (Synuclein 1 Transduction Laboratories, Palo Alto, CA, Inhibitors,research,lifescience,medical USA; dilution, 1:500). Silver stained Inhibitors,research,lifescience,medical sections were used in the standard assessment of AD pathology according to CERAD guidelines (Mirra et al. 1993). NP density was determined in the MFG, SMTG, and IP lobule and a CERAD age-related plaque score was assigned: 0 = none, A = sparse, B = moderate, C = frequent (Mirra et al. 1993). In combination with the clinical data, a pathological diagnosis Inhibitors,research,lifescience,medical of normal with respect to AD, possible AD, probable AD, or definite AD was rendered according to CERAD guidelines. As an additional

approach to assessing the severity of neurodegeneration, the distribution of NFTs was assessed and graded on a scale of 0–VI according to Braak (Braak and Braak 1991). As an adjunct to the standard means of assessing and diagnosing AD, stereologic analysis was performed PAK6 using 10 μm sections of the MFG, middle temporal gyrus (MTG), IP, and precuneus (PreCu) were stained with an antibody for Aβ-amyloid (6E10, Covance, Emeryville, CA, USA, dilution 1:500) and phosphorylated tau (PHF-1 antibody; gift of Dr. P. Davies, dilution, 1:100). Stereological measurements were performed using a Zeiss light microscope equipped with a 100´, NA 1.30, oil Plan neofluor ∞/0.10 objective, and interfaced with a Stereo-Investigator system (MBF bioscience, Williston, VT, USA). The fractional area of immunoreactivity was measured utilizing the area fraction fractionator probe.

Mechanism of action of anticonvulsants with respect to bipolar di

Mechanism of action of anticonvulsants with respect to bipolar disorder Until the discovery of neuroleptics and lithium in the treatment

of BD, electroconvulsive therapy (ECT) was the only available-and still is the most effective- treatment of mania. The antimanic response is estimated to be approximately 80%11 Although the decisive cellular mechanisms for response remain speculative, it appears that with every #Dapagliflozin keyword# application of ECT the seizure threshold increases. Thus, ECT has, paradoxically, an anticonvulsant effect. Interestingly, manic patients show an increase in seizure tiireshold with fading manic symptomatology.12 These observations may supply a clinical rationale for using anticonvulsants in the acute treatment of mania. When considering the cellular mode of action of anticonvulsants, we have to distinguish between three different Inhibitors,research,lifescience,medical levels: synaptic transmission, intracellular signaling, and, finally, gene activation. Following this hierarchy, we will first consider the impact of anticonvulsants on the metabolism and

the synaptic action of biogenic amines. GABA Both established mood stabilizers, CBZ and VPA, exhibit Inhibitors,research,lifescience,medical agonistic effects on the GABAergic system. CBZ is a positive modulator of the GABA A receptor that increases the GABA A receptor-mediated chloride current.13 VPA increases GABA release in different areas of the brain.14 This action of VPA was one of the supporting arguments leading to a GABA hypothesis of

BD.15-17 However, we are now facing a situation where we have to note that the most specific GABAergic anticonvulsants appear Inhibitors,research,lifescience,medical not to be as efficacious in BD as drugs with a wider range of Inhibitors,research,lifescience,medical action such as CBZ and VPA. A double-blind randomized trial of gabapentin18 could not support antimanic efficacy previously observed in open trials19, 20 and a first open trial for the y-aminobutyric acid plasma membrane transporter – 1 (GAT 1) inhibitor tiagabine also showed no benefit in manic patients.21 Another highly specific GABAergic compound, vigabatrine, is even suspected of inducing affective disorders and psychosis in epileptic PD184352 (CI-1040) patients.22 Excitatory amino acids Inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated currents have been reported for CBZ.23 In addition, a decrease in aspartate release was observed for VPA.24 As far as the new antiepileptic drugs are concerned, much thought has been given to the inhibition of glutamate and aspartate release by LTG.25, 26 However, this appears to be more an effect mediated by the blockade of sodium channels rather than a direct effect on synthesis and release of excitatory amino acids.

101 The neurosteroids The neurosteroids are a novel, interesting

101 The neurosteroids The neurosteroids are a novel, interesting class of neuromodulators synthesized in the brain directly from cholesterol.102 They appear to act essentially via an allosteric modulation of the GABAA receptor, although other receptors may also be involved.102,103 As early as 1987, Majewska suggested that neurosteroids could play an important role in mood regulation.104 Several studies have shown that positive allosteric modulators (which potentiate GABA action), such as progesterone and allopregnanolone, have anxiolytic effects in various animal models.103

Neurosteroid synthesis is regulated by a peripheral NVP-BEZ235 price benzodiazepine receptor (PBR) located on the outer mitochondrial membrane,105 Inhibitors,research,lifescience,medical and part of the anxiolytic effects of benzodiazepine could in fact involve increased neurosteroid synthesis. Compounds with a selective affinity for the PBR, such as FGIN-1-27, have shown an anxiolytic action in rats.106 Neurosteroids are currently attracting a lot of interest because of their potential role as natural, endogenous Inhibitors,research,lifescience,medical anxiolytics. Inhibitors,research,lifescience,medical Hormones of the HPA axis Hormones of the HPA axis, such as

Cortisol, or corticosterone (in rodents), ACTH, and CRF are usually increased in a state of fear and anxiety. They also appear to modulate the response to threatening events. Corticotropin-releasing factor Intracerebral administration of CRF has been shown to Inhibitors,research,lifescience,medical elicit anxious-like behavior in rats.107 More recent pre-clinical studies suggest that CRF and its receptors play a pivotal, integrative role in the stress response and anxiety-related behaviors.108,109 There are two major CRF systems in the brain: the neuroendocrine system in the PVN, and another system with CRF cells

located in the amygdala (CeA) and BNST, which would be more directly related to the physiological and behavioral responses associated with fear and anxiety. Whereas glucocorticoids restrain CRF Inhibitors,research,lifescience,medical production in the PVN (the neuroendocrine negative feedback loop), they appear to increase CRF expression in the amygdala and BNST, thus promoting fear- and anxiety-related behavior.110 CRF neurons originating from the amygdala project onto the LC (Figure 1) and contribute to increased arousal in fear and anxiety states.111 In a rat model, a full postsynaptic CRF agonist, CRF(1-41), increased arousal at low dosage and had an anxiogenic action at higher doses.112 This suggests to that progressively increasing levels of CRF in the brain may ensure the transition from the initial state of increased arousal to the anxious state of expectancy in stressful situations. Transgenic mice overexpressing CRF show a behavioral and neuroendocrine profile consistent with an increased level of stress and anxiety, including elevated plasma ACTH and corticosterone levels, and generally exhibit the same behavioral changes as those observed in mice following exogenous CRF administration.

Meanwhile, the eye is a very unique vital organ that is poorly ac

Meanwhile, the eye is a very unique vital organ that is poorly accessible to drugs/therapeutics following systemic or local administration. It is reported that only less than 5% of topically administered drug enters the eye as a result of poor permeation and extensive drug loss do occur through various mechanisms such as lacrimation, tear dilution, and tear turnover [3, 4]. Achieving the desired therapeutic outcomes from topical drug administration may

be further hampered by (a) poor patient Inhibitors,research,lifescience,medical adherence to daily medication dosing instructions; (b) difficulties in accurately administering drug to the eye; and (c) variable drug efficacy. Particularly, treatment of diseases affecting posterior segment Inhibitors,research,lifescience,medical of the eye will pose another layer of challenges because of the barriers to drug distribution

to the retina either from the anterior segment or through blood circulation across the tight junctions of blood-retinal barrier (BRB) [5–7]. In general, conventional drug delivery systems like eye drops, suspensions, and ointments are associated with poor drug penetration Inhibitors,research,lifescience,medical and are less likely to be effective in treating the posterior segment diseases of the eye [8]. In most protracted ocular disease/disorder, it is desirable to limit the frequency of drug administration to COX inhibitor ensure patient acceptance of drug delivery platforms while maximizing ocular drug bioavailability. Considering the posterior segment diseases, a logical approach to achieving high intraocular drug concentrations will be through intravitreal injections [6]. However, routine application of intravitreal injections has many drawbacks which include (i) the potential fast drug elimination from the posterior chamber which will shorten duration of Inhibitors,research,lifescience,medical drug action; (ii) repeated intravitreal injections may cause complications such as vitreous hemorrhage, retinal detachment, and ocular trauma [8–10], and (iii) the invasive nature of administration. A potential

viable strategy of reducing the frequency of drug administration Inhibitors,research,lifescience,medical as well as ensuring substantial drug delivery to the posterior segment in chronic ocular diseases is implantable drug delivery systems. The general trend is that patients are less likely to embrace ocular delivery platforms with associated invasiveness the paper will critically assess the progress and challenges in the these design, development, and application of polymeric ocular implants for glaucoma while offering our perspectives on the future trend. With the classification of glaucoma as a neurodegenerative disorder, effective drug delivery strategies especially to the posterior eye segments will be important in achieving the desired therapeutic outcomes. Although there are many clinically approved intravitreal delivery systems for other ocular diseases/disorders, none is currently approved for glaucoma at the time of writing. 2.

It provides more information about agomelatine’s role as a potent

It provides more information about agomelatine’s role as a potential adjuvant to other antidepressants and antipsychotics and suggests that agomelatine in combination with other medications is being used routinely in clinical practice. Footnotes This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts

Inhibitors,research,lifescience,medical of interest in preparing this article.
Blockade of the dopamine D2 receptor is a key mechanism in the antipsychotic treatment of patients diagnosed with a psychotic disorder but has also been associated with Tyrphostin AG-1478 nmr emotional impairments [Artaloytia et al. 2006; Carlsson, 1988; Van Putten et al. 1981]. Evidence for a negative impact of D2 blockade on emotional experience, however, has been based mainly on results from data collected with medication-related, cross-sectional questionnaires in semi-experimental environments, lacking ecological validity. In a previous study [Lataster Inhibitors,research,lifescience,medical et al. 2010] the association between D2 receptor occupancy and experience of emotions in daily life reality was investigated using the experience sampling method (ESM), a fine-grained Inhibitors,research,lifescience,medical momentary assessment technique for collecting emotional experiences in the flow of daily life [Myin-Germeys et al. 2009; Delespaul, 1995]. Results from this study showed that occupancy of the

D2 receptor, Inhibitors,research,lifescience,medical occasioned by the antipsychotics haloperidol and risperidone, was associated with impaired emotional experience [Lataster et al. 2010]. In the current experiment, the same method was used to investigate the effects of aripiprazole treatment on psychotic symptoms and emotional

Inhibitors,research,lifescience,medical experience in a sample of 13 patients with schizophrenia who were switched from treatment with traditional dopamine antagonist antipsychotics to treatment with the partial dopamine agonist aripiprazole. Aripiprazole has been shown to be adequate in reducing psychotic symptoms [Kim et al. 2009] and may, because of its partial D2 agonistic properties, have preferential effects on the dopaminergic motivation and reward system compared with pure dopamine antagonist antipsychotics, possibly resulting in a different subjectively experienced side-effects profile. Indeed, despite very high levels of D2 occupancy, aripiprazole treatment has been associated with better scores Histone demethylase on the Subjective Well-being under Neuroleptics (SWN) scale compared with traditional D2 antagonist antipsychotics [Mizrahi et al. 2009]. The current study aimed at adding ecological validity to these results by monitoring emotional experience and psychotic symptoms in daily life reality. Method Patients The sample consisted of 13 patients with a diagnosis of schizophrenia, displaying insufficient therapeutic response to antipsychotic treatment.

Because loving kindness overlaps with other forms of meditation f

Because loving kindness overlaps with other forms of INCB024360 clinical trial meditation from the Theravada/insight tradition in the practice of “letting go” of the conceptual self, it is likely and difficult to ascertain how experience in these other practices influences loving kindness. Even with a smaller number of reported hours of loving

kindness, meditators may practice loving kindness in a selfless manner as compared to novices based on their many hours spent practicing other forms of meditation from this tradition. This finding may be of particular relevance to understanding the commonalities between different meditation practices, and is supported empirically by the findings Inhibitors,research,lifescience,medical of this study. These confounds can be addressed in studies comparing the neural substrate of different meditation

practices in meditators; this study was underpowered to make such comparisons. Future studies should also track changes in the Inhibitors,research,lifescience,medical neural substrate of loving kindness and other meditation practices across training. Future work may also test the relationship between these findings and behavioral or clinical measures such as compassionate behavior (Condon et al. 2013). Acknowledgments We thank our participants Inhibitors,research,lifescience,medical for their time and effort; Joseph Goldstein and Ginny Morgan for input on meditation instructions; Jeremy Gray and Hedy Kober for input on study design; Thomas Thornhill IV for study coordination; Susan Whitfield-Gabrieli and Carlo de los Angeles for their input on data analysis; Aneesha Ahluwalia for her input on the manuscript; and Hedy Sarofin and Inhibitors,research,lifescience,medical staff of the Yale Magnetic Resonance Research Center for their contributions.

Conflict of Interest None declared. Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. All slices are displayed for the comparison of BOLD signal during loving kindness meditation between meditators and novices, corresponding to Fig. ​Fig.1.1. Brain regions in blue/cold show reduced BOLD signal during loving kindness meditation in meditators as compared Inhibitors,research,lifescience,medical to novices (P < 0.05 FWE, cluster corrected; slices displayed left to right). Figure S2. All slices are displayed for the comparison of intrinsic connectivity during loving kindness meditation between meditators and novices, corresponding to Fig. ​Fig.2.2. Brain regions in blue/cold show less intrinsic connectivity during PAK6 loving kindness meditation in meditators as compared to novices (P < 0.05 FWE, cluster corrected; slices displayed left to right). Figure S3. All slices are displayed for the comparison of seed-based functional connectivity during loving kindness meditation for novices greater than meditators. Brain regions in yellow/hot show greater functional connectivity with the posterior cingulate cortex/precuneus during loving kindness meditation in novices than meditators (P < 0.

At the crossroad of medical, psychological, philosophical and mor

At the crossroad of medical, psychological, philosophical and moral selleck chemical reflection, this involves complex and fundamental

questioning on respect for life and for the person [1,2]. How can a happy medium be found between abandon and excessive therapeutic intervention? [3,4] How can a decision be reached which respects the person and which may require us to administer additional treatment, or to continue or withdraw treatment already in place? [5] When confronted with a compulsory choice, all doctors, care teams and families then Inhibitors,research,lifescience,medical face the double difficulty of responsibility and doubt. Concerning the determinants of decision-making, besides applying the main ethical principles [6], several Inhibitors,research,lifescience,medical publications [1,2,4,5,7-10] focus on taking directives into account, the role of the person of trust, the need to coordinate teamwork and the participation of carers in the decision-making process, and some others show the need to take into account the religious and moral beliefs of people as well as the cost of care and treatments [11,12]. Benett & al. recently Inhibitors,research,lifescience,medical highlighted the lack of emphasis on research which informs clinical decisions in end of life care [13]. In a recent review of the

different methods used by researchers in the end of life domain [14], the predominant Inhibitors,research,lifescience,medical use of qualitative or mixed methods which called on social science tools

was highlighted (interview, focus group, Arts/drama, Quality of life tools/surveys, Storytelling, Narratives/diaries, Mixed methods). The role of caregivers (healthcare professionals and family) Inhibitors,research,lifescience,medical in the decision-making process must be understood before designing a research protocol on this topic. Their role depends on socio-cultural aspects, organisational aspects, professional guidelines and legislation. In France, if a patient is in an advanced or terminal phase of a severe and incurable disease, or if a patient receives only artificial unless life sustaining treatment, French law (Code of Public Health, Law No. 2005-370 of 22 April 2005 on patients’ rights and end of life) allows the clinician caring for the patient to limit or stop unnecessary or disproportionate treatment. The decision is purely the responsibility of the clinician in charge of the patient, but it must be made after discussion with the care team and with a medical consultant outside the department. The patient’s physician must seek and take into account any previous directives made by the patient, and obtain the opinion of the family or relatives.

” This may also occur with TCAs and some nonpharmacological thera

” This may also occur with TCAs and some nonpharmacological therapies such as sleep deprivation or electroconvulsive therapy. Bupropion is thought to be less dangerous in this respect, but this needs confirmation. Overall, as many as about one fifth of bipolar I patients develop iatrogenic hypomania or mania during treatment for a depressive episode. However, the exact relation between ADs and the “iatrogenic switch” is controversial, because bipolar mood disorders have such a high rate of recurrence anyway. There is also a minor form of AD-induced Inhibitors,research,lifescience,medical euphoria that would not qualify for hypomauia or mania according to the judgement of most clinicians, in which, for example, the patient

comes to the consultation saying that he or she feels really well and has no more problems. This wonderful improvement should alert the clinician to a possible loss of empathy or neglect of justified preoccupations. Indeed, Inhibitors,research,lifescience,medical such patients may stop worrying about their children’s education, blithely stating that they are not gifted enough to continue studies, or may fail to undertake the necessary steps to address a difficult professional situation. One patient, known previously to

be much preoccupied about environmental issues, found that global warming was no longer a matter of concern to him. Such “subsyndromic” forms of mania may be either an Inhibitors,research,lifescience,medical adverse drug reaction seen with the newer ADs, or a behavioral change resulting from patients enjoying a psychological balance they had Inhibitors,research,lifescience,medical been unable to achieve for years or even decades. The differential diagnosis can be difficult, A minority of activists in the United States contend that the effects of the SSRIs, in particular fluoxetine, on the mental state of patients are similar to those experienced by Sigmund Freud when he started taking cocaine,

or those induced by the amphetamines, when their supposed merits in the treatment of depression Inhibitors,research,lifescience,medical or fatigue were much vaunted 50 years ago. A detailed literature search carried out by us disclosed no evidence of addictive potential with either the old or the recent ADs, with the possible exception of the nonselective irreversible monoamine oxidase inhibitors (MAOIs) or the dopaminergic antidepressants, for which a very low risk may exist in some predisposed subjects. ADs, all therefore, do not appear to be addictive: for example, drug addicts who are capable of recognizing psychostimulants or benzodiazepines, fail to discriminate between ACY-1215 in vitro sertraline and placebo.6 The rare cases of addiction to ADs concern subjects who were previously addicted to many other substances. Furthermore, recent ADs have been prescribed to psychostimulant addicts and other addicts, with a somewhat debatable rate of success, but certainly without the occurrence of massive and frequent addiction.