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Rationale: Withdrawal syndrome (WDS) has been described after discontinuation of antipsychotics. WDS could be the consequence of an over-activation of the dopaminergic pathway. Antipsychotics with a higher affinity for dopamine D2 receptors could be associated with a higher risk of WDS. This study aims to address this statement and evaluate the risk difference for withdrawal syndrome between antipsychotics based on pharmacovigilance data. Methods: We collected individual reports registered in Vigibase® between 01/01/2000 and 31/12/2022 of patients treated with antipsychotics and who had presented WDS. A disproportionality analysis was performed to evaluate the risk of reporting WDS with each antipsychotic compared to all other antipsychotics. We performed a correlation analysis to assess the correlation between the risk of reporting WDS for each antipsychotic in relation with their pKi for D2 and 5HT2A receptors. Results: The most frequent psychiatric withdrawal symptoms after antipsychotic discontinuation were insomnia, anxiety and depression. Tremor, headache and dizziness were among the most frequently reported neurologic withdrawal symptoms. Tiotixene had the highest risk of reporting WDS (ROR 7.08; 95%CI 3.49 – 14.35) followed by pimozide (ROR 4.35; 95%CI 1.93 – 9.77), quetiapine (ROR 4.24; 95%CI 3.87 – 4.64), thioridazine (ROR 4.17; 95%CI 2.50—6.98) and ziprasidone (ROR 2.98; 95%CI 2.41—3.67). We found a poor correlation between D2/5HT2A binding affinity and the risk of reporting withdrawal syndrome (R2 = 0,094). Conclusion: Our results suggest that there might be a risk difference for WDS between antipsychotics. Tiotixene, pimozide and quetiapine were associated with a higher risk of reporting a WDS whereas this risk was lower with chlorpromazine, clozapine and fluphenazine. We could not address the issue of withdrawal psychosis, withdrawal dyskinesia, rebound psychosis or supersensitivity psychosis due to the lack of specific WHO medDRA coded terms to identify potential cases. [ABSTRACT FROM AUTHOR]

Purpose of Review: With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing. The TRED-HF trial confirmed that heart failure remission rather than complete recovery is typical in patients with dilated cardiomyopathy who respond to therapy. The present review outlines key points related to the management and knowledge gaps of this growing patient group, focusing on patients with non-ischaemic dilated cardiomyopathy. Recent Findings: There is substantial heterogeneity among patients with normalized ejection fraction. The specific etiology is likely to affect the outcome, although a multiple-hit phenotype is frequent and may not be identified without comprehensive characterization. A monogenic or polygenic genetic susceptibility is common. Ongoing pathophysiological processes may be unraveled with advanced cardiac imaging, biomarkers, multi-omics, and machine learning technologies. There are limited studies that have investigated the withdrawal of specific heart failure therapies in these patients. Diuretics may be safely withdrawn if there is no evidence of congestion, while continued therapy with at least some disease-modifying therapy is likely to be required to reduce myocardial workload and sustain remission for the vast majority. Summary: Understanding the underlying disease mechanisms of patients with normalized ejection fraction is crucial in identifying markers of myocardial relapse and guiding individualized therapy in the future. Ongoing clinical trials should inform personalized approaches to therapy. [ABSTRACT FROM AUTHOR]

Purpose: To establish whether a slow or a rapid withdrawal of antiepileptic monotherapy influences relapse rate in seizure-free adults with epilepsy and calculates compliance and differences in the severity of relapses, based on the occurrence of status epilepticus, seizure-related injuries, and death. Methods: This is a multicentre, prospective, randomized, open label, non-inferiority trial in people aged 16 + years who were seizure-free for more than 2 years. Patients were randomized to slow withdrawal (160 days) or rapid withdrawal (60 days) and were followed for 12 months. The primary outcome was the probability of a first seizure relapse within the 12-months follow-up. The secondary outcomes included the cumulative probability of relapse at 3, 6, 9, and 12 months. A non-inferiority analysis was performed with non-inferiority margin of − 0.15 for the difference between the probabilities of seizure recurrence in slow versus rapid withdrawal. Results: The sample comprised 48 patients, 25 randomized to slow withdrawal and 23 to rapid withdrawal. Median follow-up was 11.9 months. In the intention-to-treat population, 3 patients in the slow-withdrawal group and 1 in the rapid withdrawal group experienced seizure relapses. The corresponding probabilities of seizure recurrence were 0.12 for slow withdrawal and 0.04 for rapid withdrawal, giving a difference of 0.08 (95% CI − 0.12; 0.27), which is entirely above the non-inferiority margin. No patients developed status epilepticus and seizure-related injuries or died. Risks were similar in the Per-Protocol population. Conclusions: Seizure-relapse rate after drug discontinuation is lower than in other reports, without complications and unrelated to the duration of tapering. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to analyze the characteristics of brain function and microstructure linked to epilepsy relapse after drug withdrawal in patients with focal epilepsy. Methods: Resting-state functional magnetic resonance imaging and high-resolution T1-weighted images were acquired within 1 month prior to drug withdrawal from 15 patients who did not have epilepsy relapse (PER − group) and 16 patients who subsequently had epilepsy relapse (PER + group). Additionally, 23 healthy participants undergoing the same scanning protocol were included as controls. Fractional amplitude of low-frequency fluctuation (fALFF) and gray matter density (GMD) were compared among groups. Subgroup and correlation analyses were also performed. Results: There were no significant differences in fALFF between patient groups, but the PER + group showed lower GMD in the bilateral calcarine, left precuneus, and right superior temporal gyrus than the PER − group (Gaussian random field correction, voxel-level P < 0.001 and cluster-level P < 0.05). Both increased seizure number and polytherapy were associated with lower GMD; also, patients using other antiseizure medications showed lower GMD than those using only levetiracetam (Gaussian random field correction, voxel-level P < 0.001, and cluster-level P < 0.05). The active period and disease duration showed both positive and negative correlations with GMD, while the seizure-free period mainly showed positive correlations with GMD (uncorrected, P < 0.001). Conclusion: Gray matter microstructure, but not local functional activity, showed distinct characteristics between patients with and without epilepsy relapse and may serve as a potential biomarker for predicting seizure recurrence upon drug withdrawal. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to compare outcomes of dose reduction, withdrawal, and continuation of tofacitinib in patients with rheumatoid arthritis (RA) and to examine effectiveness of rescue with an original treatment regimen for disease flare. Methods: We prospectively enrolled 100 patients who had high or moderate disease activity and treated them with tofacitinib at 5 mg twice daily for 1 year. All patients achieving remission or low disease activity (LDA) were assigned to a withdrawal, dose-reduction, or continuation group, then followed until disease flare or end of the study. For flare cases, the original treatment regimen was reintroduced. Results: During the first year, 68 patients achieved remission or LDA (median sustained time 49.0 weeks). Subsequently, disease flare occurred at the following crude incidence rates per person-year (95% confidence interval [CI]): 0.73 (0.43–1.22) after withdrawal, 0.44 (0.25–0.77) after dose reduction, and 0.04 (0.01–0.27) during continuation. Kaplan-Meier estimates of median flare-free time (95% CI) were 7.0 months (2.8–11.2) for withdrawal and 21.0 months (4.1–37.9) for dose reduction. In the Cox regression analysis, adjusted hazard ratios (95% CIs) were 18.11 (2.38–138) for withdrawal and 9.13 (1.19–70.4) for dose reduction compared with continuation. Restart of the original treatment regimen led to rapid remission in flare cases (93% for withdrawal and 100% for dose reduction). Conclusion: After achievement of remission or LDA, the dose-reduction strategy seems preferable to immediate withdrawal of tofacitinib. Restart of the original regimen can reinduce RA control in flare cases. Key Points • During the 1-year tofacitinib therapy, two-thirds of RA patients with high or moderate disease activity achieved rapid and sustained remission or low disease activity. • During subsequent years, the incidence rate and adjusted hazard ratio for disease flare were significantly higher following tofacitinib immediate withdrawal than following dose reduction. • Half of the patients were estimated to remain flare-free for 21 months after dose reduction and for 7 months after withdrawal of tofacitinib. • Restart of the original treatment regimen rapidly restored disease control in almost all flare cases. [ABSTRACT FROM AUTHOR]

Introduction: Although non-melanoma skin cancers (NMSCs) are associated with a very low mortality risk, they have been reported to have a major impact on patients' health-related quality of life (HRQoL). Vismodegib is a therapy for patients who are affected by locally advanced basal cell carcinoma (BCC) or metastatic BCC who are ineligible for surgery and/or radiotherapy. The aim of the present clinical study was to assess the long-term efficacy of vismodegib after its withdrawal by evaluating the recurrence rate of advanced BCC, assessing also patients' HRQoL after 3 and 6 months from drug withdrawal. Methods: A retrospective study was performed to analyze patients with advanced and/or multiple BCCs that had been treated with vismodegib (150 mg daily) at the Non-Melanoma Skin Cancer Unit of the University of Naples Federico II (Italy) and had obtained a complete regression in 6 months. At the end of the 6-month treatment cycle, patients that reported total remission of the skin tumor were visited monthly in order to assess their therapeutic response. Moreover, to assess the specific impact of vismodegib on HRQoL, DLQI was administered before vismodegib treatment (baseline), at the end of the therapy cycle (6 months), as well as after 3 and 6 months from vismodegib discontinuation. Results: Thirty-five patients (27 male, 8 female), with a complete regression of their advanced BCC after vismodegib treatment, were included in the study. The duration of treatment for all patients was 6 months as set by study inclusion criteria. A BCC recurrence rate of 31% (11/35) was reported after a 6-month follow-up. The average reported Dermatology Life Quality Index (DLQI) score increased from a value of 0 at the end of the 6-month vismodegib treatment to a mean value of 2.4 after 3 months from drug withdrawal and 3.6 after 6 months from treatment discontinuation. Conclusion: The results of this exploratory analysis of vismodegib withdrawal are consistent with a substantial link between treatment response and patients' HRQoL. Furthermore, 11 out of 35 (31%) patients that reported a complete remission of the disease after 6 months of vismodegib treatment reported BCC recurrence. These data highlight the importance of continuous follow-up and perhaps different regimens of treatment, such as an alternate dose regimen to maintain disease control and reduce the adverse events as previously described in the literature. [ABSTRACT FROM AUTHOR]

Purpose: Dopamine agonist (DA) therapy is recommended as the first-line treatment for prolactinomas. However, it requires long treatment duration, and a high recurrence rate after DA withdrawal has been reported. We aimed to elucidate the predictors for long-term remission following DA withdrawal and propose the best candidates who can achieve complete remission after DA withdrawal. Methods: In a retrospective cohort study, we included 89 patients with prolactinoma who have withdrawn DAs with normal prolactin (PRL) levels at Seoul National University Hospital, from 2000 to 2016. Patient's data were retrieved from the electronic medical records. Results: The median age and median treatment duration of the study patients were 33 (15-73) years and 69.5 (8.3-277.4) months, respectively. The recurrence rate after drug withdrawal was 57.3% during the 23.9 (3.0-176.8) month follow-up period. Age, gender, baseline PRL level, and baseline maximum tumor diameter were similar between the remission and recurrence group. In the Cox-proportional hazard model analysis, the significant predictors for remission were nadir PRL level of <1 ng/dL (hazard ratio [95% confidence interval] = 0.37 [0.18-0.74]), invisible tumors on magnetic resonance imaging (MRI) (0.42 [0.24-0.74]), and treatment duration of >72 months (0.54 [0.30-0.96]). Of the subjects who met all the three criteria, 66.7% achieved long-term remission. Conclusions: Patients who have no tumor visible on MRI, have a nadir PRL level <1 ng/dL during drug treatment, and received drug treatment for >6 years may be the best candidates for DA withdrawal. [ABSTRACT FROM AUTHOR]

Purpose of Review: Despite the excellent treatment response in autoimmune hepatitis (AIH), relapse after drug-withdrawal remains an unsolved dilemma and relapse rates as high as 90-95% are reported. A clear recommendation, when and in which patients to offer drug withdrawal is lacking. Moreover, there are no data on outcome in patients with mild disease activity in which therapy was withheld. Recent Findings: In recent years , only a small number of studies addressed the question when and in which patients to stop treatment. Nevertheless, several potential predictors for early relapse could be identified including a prior relapse after drug withdrawal, dual immunosuppressive therapy at withdrawal, the presence of SLA/LP antibodies, and concomitant autoimmune diseases. Moreover, recent studies highlighted the relevance of complete biochemical remission defined as repeatedly normal serum transaminases and IgG levels. Summary: Patients qualifying for treatment cessation should be in stable biochemical remission (complete normal serum transaminases and IgG levels) on immunosuppressive monotherapy for at least 2 years before an attempt of drug withdrawal is performed. An even longer treatment duration might be associated with a lower relapse risk. Patients with advanced liver disease should be advised against drug withdrawal, since a flare might cause hepatic decompensation. Finally, many patients strongly wish to perform a trial of drug withdrawal and in any case, it is more advisable to perform a controlled trail than having the patient is doing it secretly and thereby putting him at considerable risk. AIH is characterized by a fluctuating, relapsing disease course. Therefore, in our opinion, withholding treatment appears only defensible in very few patients with mild inflammatory activity on liver histology (mHAI < 4) and without relevant fibrosis. These patients must be closely followed up. [ABSTRACT FROM AUTHOR]

Rationale: Despite substantial research efforts the aetiology of major depressive disorder (MDD) remains poorly understood, which is due in part to the heterogeneity of the disorder and the complexity of designing appropriate animal models. However, in the last few decades, a focus on the development of novel stress-based paradigms and a focus on using hedonic/anhedonic behaviour have led to renewed optimism in the use of animal models to assess aspects of MDD. Objectives: Therefore, in this review article, dedicated to Athina Markou, we summarise the use of stress-based animal models for studying MDD in rodents and how reward-related readouts can be used to validate/assess the model and/or treatment. Results: We reveal the use and limitations of chronic stress paradigms, which we split into non-social (i.e. chronic mild stress), social (i.e. chronic social defeat) and drug-withdrawal paradigms for studying MDD and detail numerous reward-related readouts that are employed in preclinical research. Finally, we finish with a section regarding important factors to consider when using animal models. Conclusions: One of the most consistent findings following chronic stress exposure in rodents is a disruption of the brain reward system, which can be easily assessed using sucrose, social interaction, food, drug of abuse or intracranial self-stimulation as a readout. Probing the underlying causes of such alterations is providing a greater understanding of the potential systems and processes that are disrupted in MDD. [ABSTRACT FROM AUTHOR]

Zusammenfassung Das NADA-Protokoll ist eine beliebte und schnell wachsende komplementäre Therapieform für Menschen mit Abhängigkeiten, Menschen unter Druck, in psychosozialen Notsituationen sowie psychiatrischen Erkrankungen. Die Studienlage zum NADA-Protokoll ist uneinheitlich. Dies hat drei Hauptgründe: Inadäquate Forschungsmethodik, eingeschränktes Verständnis über die Wirkweise des NADA-Protokolls, sowie eingeschränktes Verständnis über die Komplementarität des NADA-Protokolls. Aus einer Bewertung der wichtigsten Studien heraus wird eine Forschungsstrategie abgeleitet. Die Zukunft der Evaluation des NADA-Protokolls liegt in der Forschung unter Bedingungen der Normalversorgung (Comparative Effectiveness Research = Untersuchung der effectiveness statt der efficacy ). Als Kontrollgruppen sollten keine vermeintlichen Plazebo- oder Sham-Techniken dienen, sondern validierte und gut eingeführte Therapieformen. Diese Forschung sollte auch die sich entwickelnde Akupressur im Rahmen des NADA-Protokolls einschließen. The NADA-protocol is an acclaimed and rapidly expanding complementary form of therapy suited to treat individuals suffering from dependencies, pressure, psychosocial emergencies, and psychiatric disorders. The study situation with regard to the NADA-protocol is inconsistent for three main reasons: inadequate research methodology, a limited comprehension of the mode of action of the NADA-protocol, as well as a limited understanding of the NADA-protocol complementarity. Successive to an evaluation of the major studies, a research strategy is derived. The future of evaluating the NADA-protocol arises from research performed under conditions according to general standards of care (comparative effectiveness research = study of effectiveness instead of efficacy). Alleged placebo or sham-techniques should not be used as controls, rather validated and well introduced forms of therapy should be applied. This research approach should integrate the evolving acupressure within the context of the NADA-protocol. [ABSTRACT FROM AUTHOR]

Rationale: Preclinical studies have shown that cocaine exposure and withdrawal are associated with cellular oxidative stress damage. However, the impact of crack-cocaine dependence on oxidative stress biomarkers remains unclear. Here, we assessed peripheral oxidative stress and antioxidant defences during two periods of crack-cocaine detoxification treatment and associated these changes with psychological morbidity. Methods: Thirty female inpatients were recruited, and plasma samples were collected at the 4th and 18th days of abstinence; 30 healthy controls were also recruited. Plasma levels of protein carbonyl, protein thiol content, superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced reduced (GSH) and total reactive antioxidant potential (TRAP) were measured by standard methods; the questionnaires Cocaine Selective Severity Assessment, Beck Depressive Inventory and the Addiction Severity Index were applied. Results: We report higher oxidative stress damage after 4 days of detoxification, as shown by increased total thiol content and protein carbonylation when compared with control group and after 18 days of detoxification. After 18 days of treatment, we observed a recovery of the oxidative stress damage and increase of the antioxidant defences, as shown by higher levels of SOD, GPx, GSH and TRAP. There was a positive correlation between protein carbonylation and psychological variables; in contrast, there was a negative correlation between TRAP levels and clinical assessments. Conclusions: Taken together, these results suggest that drug rehabilitation treatment was effective in decreasing oxidative damage represented by the reduction in biological markers, which are closely related to the severity of withdrawal symptoms. [ABSTRACT FROM AUTHOR]

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Some psychiatric illnesses involve a learned component. For example, in posttraumatic stress disorder, memories triggered by trauma-associated cues trigger fear and anxiety, and in addiction, drug-associated cues elicit drug craving and withdrawal. Clinical interventions to reduce the impact of conditioned cues in eliciting these maladaptive conditioned responses are likely to be beneficial. Extinction is a method of lessening conditioned responses and involves repeated exposures to a cue in the absence of the event it once predicted. We believe that an improved understanding of the behavioral and neurobiological mechanisms of extinction will allow extinction-like procedures in the clinic to become more effective. Research on the role of glutamate-the major excitatory neurotransmitter in the mammalian brain-in extinction has led to the development of pharmacotherapeutics to enhance the efficacy of extinction-based protocols in clinical populations. In this review, we describe what has been learned about glutamate actions at its three major receptor types (N-methyl--aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and metabotropic glutamate receptors) in the extinction of conditioned fear, drug craving, and withdrawal. We then discuss how these findings have been applied in clinical research. [ABSTRACT FROM AUTHOR]

AbstractThe κ-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of μ-opioid receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward, and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug addiction. However, KOR agonists also produce several severe undesirable side effects such as dysphoria, water diuresis, salivation, emesis, and sedation in nonhuman primates, which may limit the clinical utility of KOR agonists for pain and drug abuse treatment. This article will review the role of KOR activation in mediating antinociception and addiction. The possible therapeutic application of κ-agonists in the treatment of pain and drug addiction is also discussed. [ABSTRACT FROM AUTHOR]

Presents a study that measured the effects of caffeine and caffeine withdrawal on psychomotor and cognitive performance, mood, blood pressure and heart rate in sleep-restricted participants. Methodology; Results; Conclusions.

Rationale: Many studies have found that caffeine consumed after overnight caffeine abstinence improves cognitive performance and mood. Much less is known, however, about the effects of caffeine after shorter periods of caffeine abstinence. Objectives: The aim of this study was to measure the effects on psychomotor and cognitive performance, mood, hand steadiness, blood pressure and heart rate of caffeine administration after periods of 4, 6, and 8 h of caffeine abstinence. Methods: Participants (n=49, 27 female) were moderate to moderate-high caffeine consumers (mean daily intake 370 mg/day). Following overnight caffeine abstinence, a 'pre-dose' of caffeine (1.2 mg/kg) was administered at 9 A.M., 11 A.M. or 1 P.M. The participants started a baseline battery of measurements at 4 P.M. before receiving caffeine (1.2 mg/kg) or placebo at 5 P.M. They then performed the battery of tests again, starting at 5:30 P.M. This was a double-blind, placebo-controlled, randomised study. Results: Performance and mood measurements confirmed a psychostimulant action of caffeine (versus placebo), but only after 8 h of caffeine abstinence. Caffeine also increased blood pressure after 8-h abstinence, whereas hand steadiness was decreased and perception of task demand was increased by caffeine after 4 h, but not after 6- and 8-h abstinence. Conclusions: A second cup-of-coffee equivalent dose of caffeine only reliably affected cognitive performance and mood after an 8-h interval between doses, but not after shorter intervals (when caffeine had some adverse effects). These results show that, apart from caffeine consumption soon after waking, the daily pattern of caffeine intake of many typical caffeine consumers is not well explained by the short-term psychostimulant effects of caffeine. [ABSTRACT FROM AUTHOR]

Recent studies in rodents have shown that withdrawal from chronic drug abuse is associated with a significant decrease in dopamine (DA) release in mesolimbic structures, especially in the shell region of the nucleus accumbens. Since the DA system is known to play an important role in reward processes, a withdrawal-associated impairment in mesolimbic DA-mediated transmission could possibly implicate reward deficit and thus enhance vulnerability to drug craving and relapse. We have previously demonstrated that acute repetitive transcranial magnetic stimulation (rTMS) has a modulatory effect on DA release in several areas of the rat brain, including dorsal striatum, hippocampus, and nucleus accumbens shell. In the present study, we investigated the possible use of rTMS as a tool in re- establishing the dysregulated DA secretion observed during withdrawal in morphine-sensitized male Sprague-Dawley rats. Using intracerebral microdialysis, we monitored the effects of acute rTMS (20 Hz) on the intra-accumbal release-patterns of DA in freely moving animals that were subjected to a morphine sensitization scheme for a period of 8 days. We provide first evidence that acute rTMS (20 Hz) is able to increase DA concentration in the shell region of the nucleus accumbens in both control animals and morphine- sensitized rats during abstinence. The DA release in morphine-sensitized rats was significantly higher than in controls. rTMS, therefore, might gain a potential therapeutic role in the treatment of dysphoric and anhedonic states during drug withdrawal in humans. [ABSTRACT FROM AUTHOR]

Millions of patients undergo surgery each year and an increasing proportion of these patients are consuming therapeutic drugs. Drug therapy is often withheld in the immediate perioperative period and after major surgery, in particular, there is often a prolonged period of fasting. This may lead to withdrawal effects including recurrence or worsening of patients' disease symptomatology. These effects will occur during a period of physiological and pathophysiological stresses and render patients more vulnerable to drug withdrawal phenomena. Thus, patients may be exposed to greater and sometimes unnecessary risks in the perioperative period. There are relatively few studies that have investigated this problem. The ones that have, however, confirm that drug abstinence in the perioperative period is a relatively common phenomenon and one study has demonstrated an association between duration of drug abstinence and adverse outcomes. The pathophysiological effects of major surgery on gastrointestinal function, neuro-humoral and cytokine adaptive responses to surgical stress are under-appreciated. These responses can reduce the effectiveness of oral administration and exacerbate co-existing disease processes. These problems are compounded by a fragmented approach to perioperative drug therapy with no one group of healthcare professionals assuming responsibility for this aspect of care. This may in part be a consequence of the complexities of rationalising drug therapy in the perioperative period together with the lack of readily available and evidence based information strategies for individual drugs or drug classes. An additional problem relates to the formulations, inherent pharmacokinetics and limited routes of administration of many prescribed drugs. These can prevent a ‘seamless’ transition from preoperative to postoperative management. Consumers, health professionals, pharmaceutical companies and drug regulatory agencies must all play a part in rectifying this problem. There remains a need for further research to clarify the effects of abstinence on patient outcomes and also to identify optimum strategies to avoid unwanted drug abstinence. [ABSTRACT FROM AUTHOR]

Objective: Many authors have reported discontinuation symptoms associated with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to investigate the incidence and characteristics of the discontinuation syndrome in patients who stopped treatment with the SSRIs paroxetine and fluoxetine under the usual conditions of clinical practice, and to identify clinical predictors of the syndrome.Methods: Ninety-seven outpatients who received an initial diagnosis of dysthymic disorder, who responded to >or=8 weeks treatment with paroxetine (n = 52) or fluoxetine (n = 45), and who discontinued the SSRI according to their psychiatrist's instructions were included. They were assessed at the time of discontinuation using a semi-structured interview for clinical and treatment characteristics, the Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS). Patients were then assessed 4 weeks later using a checklist for discontinuation symptoms, a semi-structured interview for discontinuation symptom characteristics, and the HAM-D and the MADRS.Results: A discontinuation syndrome was found in 26 patients (26.8% of our sample); of this group, 22 patients (84.6%) had received paroxetine, and 4 patients (15.4%) had received fluoxetine. The mean time at onset of symptoms was 2 days after drug discontinuation and the mean duration was 5 days. The statistical comparison between the groups with and without a discontinuation syndrome found two significant differences - a discontinuation syndrome was more common in patients treated with paroxetine and in patients with an earlier onset of dysthymic disorder. Multiple regression analysis confirmed that these two factors were related to the duration of discontinuation symptoms, while the number of symptoms was associated with three factors, including use of paroxetine, age at onset of dysthmia and female gender.Conclusions: A discontinuation syndrome is common after treatment with SSRIs is stopped in patients with dysthymia, and it appears to be more common in patients receiving paroxetine than in those receiving fluoxetine. The syndrome is related both to drug and clinical characteristics. The features of the syndrome in patients with different Axis I diagnoses should be compared in further investigations. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is now the leading cause of death in transplant recipients. This is due, in part, to the vulnerability of these patients to a complicated set of conditions including hypertension, diabetes mellitus, and post-transplant hyperlipidaemia (PTHL). PTHL is characterised by persistent elevations in total serum cholesterol, low density lipoprotein cholesterol and triglyceride levels. The causes of PTHL are complex and not fully understood, however several classes of immunosuppressants including the corticosteroids, rapamycins and calcineurin inhibitors, appear to play a role. PTHL has been observed in most studies in which patients received calcineurin inhibitor-based regimens, and has been observed with both tacrolimus and cyclosporin. Comparing these calcineurin inhibitors with regard to the relative incidence or severity of PTHL occurring during treatment is difficult because of the use of higher doses of corticosteroids in cyclosporin-based regimens, as compared with tacrolimus-based regimens. However, current expert opinion suggests that the discrepancies in the relative incidence and severity of PTHL are largely accounted for by this difference in corticosteroid dose. At this point in time, evidence for potential differences is scant and inconclusive. Further study is needed, not only to investigate differences in lipid profile, but also of the relative effects of these immunosuppressants on long term graft function as well as on cardiovascular morbidity and mortality. PTHL can be successfully managed with a combination of dietary management, reduction and, if appropriate, withdrawal of corticosteroids, and the administration of lipid-lowering drugs. With this combination of therapeutic options, the threats to long term health posed by PTHL may be effectively addressed. [ABSTRACT FROM AUTHOR]

Objective: To assess the cost effectiveness of tapered versus abrupt discontinuation of a microemulsion formulation of cyclosporin in patients with chronic plaque psoriasis. Methods: A cost-effectiveness analysis was performed in parallel with a nonblind, multicentre, international clinical trial of the safety and efficacy of intermittent short courses of cyclosporin. Direct and indirect costs were considered within a 1-year period following randomisation. Patients: Patients with chronic plaque psoriasis inadequately controlled with topical treatment. Study perspective: The study was conducted from a societal perspective and was performed using data from Canada, Spain, Turkey and the UK. Main outcomes measures: The health outcome used was the total number of systemic therapy-free days (STFDs) over the first year. The mean incremental cost-effectiveness ratio (ICER) was determined by dividing the differences in average cost per patient by the differences in average STFDs per patient. Results: The overall ICER was dominant because tapered discontinuation was associated with both lower costs and improved efficacy in comparison with abrupt discontinuation. Further analyses showed that tapered discontinuation was a cost-effective alternative to abrupt discontinuation therapy, even when a conservative definition for cost effectiveness was adopted. Conclusion: This cost-effectiveness analysis demonstrated that tapering cyclosporin was more cost effective than abruptly stopping cyclosporin in patients with chronic plaque psoriasis. [ABSTRACT FROM AUTHOR]

Discontinuation symptoms are recognised with tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and miscellaneous antidepressants. A wide variety of symptoms have been described, differing somewhat between antidepressant classes, and several symptom clusters or discontinuation syndromes appear to exist. A common feature is onset within a few days of stopping the antidepressant or, less commonly, reducing the dosage. Discontinuation syndromes are clinically relevant as they are common, can cause significant morbidity, can be misdiagnosed leading to inappropriate treatment and can adversely effect future antidepressant compliance. Preventative strategies include tapering antidepressants prior to stoppage and educating patients and healthcare professionals to ensure that antidepressants are taken consistently and not stopped abruptly. Most reactions are mild and short-lived and require no treatment other than patient reassurance. Severe cases can be treated symptomatically or the antidepressant can be reinstated before being gradually withdrawn. Reinstatement usually leads to symptom resolution within 24 hours. Some individuals require very conservative tapering schedules to prevent the re-emergence of symptoms. With SSRIs and venlafaxine another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself. Neonatal discontinuation symptoms can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and doctor must take this into consideration when making prescribing decisions. Discontinuation symptoms have received little systematic study with the result that most of the recommendations made here are based on anecdotal data or expert opinion. Research is needed to provide a firm evidence base for future recommendations. [ABSTRACT FROM AUTHOR]

The antiandrogen withdrawal syndrome is a well established phenomenon in prostate cancer. It is widely accepted that a subset of patients will benefit from the withdrawal of antiandrogen or steroidal hormone from hormonal therapy, exhibiting decreasing prostate-specific antigen (PSA) values and clinical improvement. The pathophysiology of antiandrogen withdrawal syndrome is not completely understood, although androgen receptor gene mutations seem to be the likely explanation. Currently, it is not possible to identify the subset of patients whose tumours will respond to antiandrogen or steroid withdrawal. Tumours that will respond may be classified as androgen-independent and hormone-sensitive tumours as opposed to androgen-independent and hormone-insensitive tumours that do not respond. Patients who respond to antiandrogen withdrawal experience approximately 6 months with improved quality of life; however, it is unknown if this translates into prolonged survival. At the very least, antiandrogen withdrawal offers a therapeutic modality that is not associated with adverse effects and improves quality of life even if only for a very limited time. Recent reports suggest that adding a secondary hormonal therapy such as amino- glutethimide, ketoconazole or steroidal hormones may enhance the response rate and prolong response time to the antiandrogen withdrawal syndrome. However, unless there is proof that this secondary hormonal manipulation prolongs survival, maintenance of quality of life is mandatory because of the possible adverse effects from these potent drugs. The fact that about 30% of patients will respond to antiandrogen or steroid withdrawal in hormone refractory prostate cancer must be taken into account in clinical trials of new cytotoxic agents which have been and will be conducted. Cessation of flutamide for at least 4 weeks and, in the case of bicalutamide, even 8 weeks, is mandatory before antiandrogen withdrawal syndrome can be excluded as the cause of decreasing PSA values. The antiandrogen withdrawal syndrome offers another piece of the puzzle of prostatic carcinoma, but at the same time it demonstrates how different advanced prostate cancer cells may react to therapeutic strategies and, therefore, hormone refractory prostate cancer remains a difficult challenge which must be solved in the future. [ABSTRACT FROM AUTHOR]

The current management of hepatic allograft rejection after liver transplantation in children requires effective baseline immunosuppression to prevent rejection and rapid diagnosis and treatment to manage acute rejection episodes. The subsequent impact on chronic rejection is dependent on the combination of adequate prevention and the treatment of acute rejection. Tacrolimus is a macrolide lactone that inhibits the signal transduction of interleukin-2 (IL-2) via calcineurin inhibition. Introduced in 1989, tacrolimus was first used in the salvage of refractory acute or chronic rejection under cyclosporin or to rescue patients with significant cyclosporin-related complications. The majority of paediatric transplant centres use a combination of steroids with tacrolimus as a basic immunosuppressant regimen following paediatric liver transplantation. This combination has allowed the acute cellular rejection-free rate to increase to between 30 and 60%, while lowering the rate of refractory rejection to less than 5%. Corticosteroid-resistant rejection is commonly treated with monoclonal (muromonab CD3) or polyclonal preparations. Although most episodes of acute cellular rejection occur during the first 6 weeks after liver transplant, the appearance of late acute liver allograft rejection must raise the question of noncompliance, especially in the adolescent population. Chronic rejection is becoming increasingly rare under tacrolimus-based immunosuppression. Tacrolimus is effective in reversing refractory acute cellular rejection or early chronic rejection in patients initially treated with cyclosporin-based regimens. Patients with a history of noncompliance as well as children with autoimmune liver disease are at risk of chronic rejection. Retransplantation therapy for chronic rejection has, fortunately, become more rare in the tacrolimus era with only 3% of retransplants being performed for this indication. Newer immunosuppressive agents are further modifying the long term management of liver allograft rejection. These include mycophenolate mofetil, rapamycin and IL-2 antibodies such as daclizumab. The development of these agents is allowing patient-specific immunosuppressive management to minimise rejection as well as the complications related to immunosuppression. [ABSTRACT FROM AUTHOR]

Zusammenfassung Eine junge Patientin mit einer Borderline-Persönlichkeitsstörung wird zusätzlich zu einer psychiatrischen tagesklinischen Behandlung mit dem NADA-Protokoll behandelt. Es stellen sich viele positive Therapieeffekte ein, die im Vorfeld mit jahrelanger psychiatrischer Behandlung nicht erzielt werden konnten. Bei dem NADA-Protokoll handelt es sich um eine standardisierte Ohrakupunkturmethode, welche sich gut als zusätzliche Behandlungsmethode bei psychisch schwerkranken Patienten eignet. Generell besteht keine direkte Kontraindikation in der Behandlung von Menschen mit emotional-instabilen Persönlichkeitsstörungen. Es ist jedoch hilfreich, einige krankheitsspezifische Aspekte zu beachten, vor allem den Umgang mit Selbstverletzungen, Suizidalität und einer gestörten Nähe-Distanz-Beziehung. A young female patient inflicted with Borderline-personality disorder receives psychiatric treatment in a day-care clinic and in addition treatment according to the NADA-protocol. A number of positive therapeutic effects emerged, which had failed to be obtained during years of psychiatric therapy. The NADA-protocol is characterized by a standard method of ear acupuncture being well suited as an additional treatment mode in psychological critically ill patients. In general, there is no immediate contraindication in treating patients with an emotionally instable personality disorder. However, it is helpful to consider some aspects specific to the illness. In particular, this refers to dealing with self-injury, suicidal tendencies and a disturbed proximity and distance relation. [ABSTRACT FROM AUTHOR]

In 39 patients who had been treated with metoprolol 100-200 mg daily or placebo for three years after acute myocardial infarction, serum lipids and lipoproteins were studied while the patients were on treatment as well as after its withdrawal. Withdrawal was performed over 1 week. Treatment had to be reinstituted in 6 patients (1 ex placebo and 5 ex metoprolol) because of aggravated symptoms. During the entire study period total cholesterol was significantly higher in the metoprolol withdrawal group and LDL cholesterol tended to be higher. HDL cholesterol in both groups increased significantly during the initial 28-day period following withdrawal of treatment. In both groups VLDL triglycerides tended to decrease during the first 28 day without treatment. Other lipoprotein fractions in both groups were unchanged. Overall, in patients who tolerated the ending of 3 years of treatment with metoprolol after myocardial infarction, there was no significant effect on lipoprotein fractions as compared to a placebo group. [ABSTRACT FROM AUTHOR]

Different kinds of physiological response to stimuli which have been associated with alcohol ingestion have been observed in human subjects. A literature review shows that when subjects are exposed to alcohol associated stimuli without consuming the drinks then increases in arousal, as indexed by skin conductance and heart rate increases, tend to occur. If subjects consume drinks which have been associated with alcohol ingestion, then decreases in arousal tend to occur. Forty non-dependent drinkers were asked to either consume or hold drinks which either had a history of alcohol association or did not. Interactions were observed between the activities subjects engaged in with the drinks and the degree of alcohol association of the drinks. Presentation of alcohol associated drinks produced smaller increases in arousal than non-alcohol associated drinks if the drinks were consumed but vice versa if the drinks were just held. The results support the conclusions drawn from the literature review and have implications for current theories of conditioned responses to drug cues and the related theories of the motivational processes involved in the regulation of drug intake. [ABSTRACT FROM AUTHOR]

There have been few attempts to model subjective symptoms of drug withdrawal using animals as subjects. Two approaches for developing such models are reviewed. First, using drug discrimination methodology, it may be possible to train animals to detect the effects of withdrawal. This method has two difficulties: 1) the only discriminations trained to date involve precipitated withdrawal, and 2) the stimulus controlling behavior is difficult to specify. Second, withdrawal from many drugs of abuse produces the symptom of anxiety, and it seems likely that animal models of anxiety could be useful for studying drug withdrawal. This hypothesis has been explored most fully using subjects trained to detect the discriminative stimulus properties of the putative anxiogenic drug pentylenetetrazole (PTZ). Withdrawal from benzodiazepines or ethanol substitutes fully for PTZ, and withdrawal from cocaine, morphine, and nicotine substitutes partially for PTZ. Emerging data suggest that other animal models of anxiety may also be useful for detecting drug withdrawal. The final portion of this review examines a behavioral test that is very sensitive for detecting physical signs of withdrawal in animals. In subjects maintained on an operant baseline using food as a reinforcer, withdrawal from a drug of dependence frequently is associated with disruption of that operant behavior. For example, tetrahydrocannabinol and cocaine, drugs that are not traditionally seen as having significant withdrawal signs, produce disruption of operant responding when high-dose administration is terminated, and their readministration reverses this behavioral disruption. Based on the observation that withdrawal is associated with anxiogenic stimuli, we suggest a method to determine if disruption of operant behavior may be related to these stimuli. [ABSTRACT FROM AUTHOR]

Seventy male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 schedule of reinforcement on the basis of whether they were injected subcutaneously with 0.75 mg/kg diazepam or 10.0 mg/kg pentylenetetrazol. Following discrimination acquisition, a dose-response function was generated for each drug during 5-min extinction periods. Subjects were then assigned to one of seven groups on the basis of their per cent responding during saline testing. Each group was injected with 5 mg/kg diazepam and then given a 5-min extinction test at intervals of 2, 4, 6, 8, 12, 16, 20, or 24 h subsequent to injection. The results indicated that at the shorter time intervals the animals responded on the diazepam lever. However, as the time interval between injection and testing lengthened, responding on the PTZ bar gradually increased until by 12 h following injection with diazepam the animals were responding as though they had received an injection of 5 mg/kg PTZ. Following this period of rebound, choice behavior returned to baseline by 24 h post-injection. [ABSTRACT FROM AUTHOR]

The pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity was studied in adult male rats that were given access to either caffeine solution (0.5 or 1.0 mg/ml) or plain water for 10 min every 6 h on a chronic daily basis; daily caffeine intake averaged 41 and 62 mg/kg, respectively. Dose-effect curves were determined for behavioral stimulant and depressant drugs in control and caffeine-treated groups. Drugs were injected IP and locomotor activity was measured for 30 min beginning 35 min later. Rats tolerant to stimulation of locomotor activity by caffeine were also tolerant to theophylline and 7-(2-chloroethyl)theophylline, but not to any of six nonxanthine stimulants, including cocaine, methylphenidate, and d-amphetamine. The adenosine analogs, R(−)-N-2-(phenylisopropyl)adenosine(R(−)-PIA) and 5′-(N-ethyl)carboxamidoadenosine (NECA), decreased locomotor activity of control and caffeine-treated (0.5 mg/ml) rats; dose-effect curves in rats consuming caffeine chronically were displaced to the right of the control curves by 10-fold for R(−)-PIA and 100-fold for NECA. Dose-effect curves for the nonadenosine behavioral depressants chlorpromazine and diazepam were unchanged by chronic treatment with caffeine, but the curve for pentobarbital, which is thought to inhibit adenosine receptor binding, was shifted to the right by a factor of 3. Rats withdrawn from chronic caffeine for 24 h were still completely tolerant to caffeine-induced stimulation of locomotor activity. Dose-effect curves for R(−)-PIA and d-amphetamine in rats withdrawn from chronic caffeine for 24 h were not different from curves in control animals. These results indicate that tolerance to caffeine-induced stimulation of locomotor activity is specific to the methylxanthine class of stimulants and is not a property of nonxanthine psychomotor stimulants. Furthermore, the adenosine-antagonist activity of caffeine remains evident even in rats completely tolerant to the stimulant effect of caffeine. These results provide no support for the view that caffeine tolerance is due to enhanced sensitivity of central adenosine systems. [ABSTRACT FROM AUTHOR]

The effects of single and long-term haloperidol administration on rat open field behavior was studied. Withdrawal from long-term haloperidol treatment induced a significant increase in all parameters of activity recorded, expcept rearing. There was a direct relationship between the impairment of motor function induced by the single haloperidol administration and the increment of general activity observed after withdrawal from repeated drug administration. The results were considered to be a consequence of the supersensitivity of central dopaminergic receptors probably, of the mesostriatal pathway, that occurred in order to maintain the animal's homeostasis. [ABSTRACT FROM AUTHOR]

The development of tolerance and dependence has traditionally been considered an integral aspect of the drug addiction process, and opiate dependence has been studied extensively as a model system in this regard. However, recent emphasis on the positive reinforcing properties of drugs has led to the suggestion that tolerance, dependence, and withdrawal may be of secondary or even negligible importance in motivating compulsive drug use. The current article argues for an integrated view of addiction in the form of a homeostatic neuroadaptation model which emphasizes the motivational significance of both the positive affective state produced by opiates and the negative affective state characteristic of drug withdrawal. The model is supported by evidence at both the behavioral and neural systems levels of analysis. Understanding the important distinction between somatic and affective components of opiate withdrawal is key to recognizing the factors which contribute to the motivational significance of opiate dependence and withdrawal. In addition, the critical role of conditioning processes in the maintenance of compulsive drug use and relapse after periods of abstention is discussed. Finally, it is argued that both the positive reinforcement produced by acute administration of a drug and the negative affective state produced by withdrawal are common to multiple classes of abused drugs, suggesting that an understanding of homeostatic neuroadaptation within motivational systems provides a key to the etiology, treatment and prevention of drug addiction. [ABSTRACT FROM AUTHOR]

Objective: Withdrawal of a drug from the market for safety reasons is a serious and sometimes complex decision. The scientific evidence supporting drug withdrawals in the past years is critically appraised. Methods: With data provided by the Spanish Medicines Agency, all drugs withdrawn from the Spanish market for safety reasons from January 1990 to December 1999 were identified. The adverse drug reactions (ADRs) were classified by the year of withdrawal, by the organ/system affected and by the alleged type of reaction (Rawlins and Thompson classification). A systematic review of the literature was performed. Results: A total of 22 drugs were withdrawn from the market due to safety reasons. In 18 of 22 cases (82%), the evidence supporting the drug withdrawal came from individual case reports, cases series or the combination of data provided by randomised clinical trials and case reports. Hepatic (eight cases) and cardiac (five cases) reactions accounted for 59% (13 of 22) of the total withdrawals. In 10 of 22 (45%) cases, drug withdrawal was clearly due to type-B reactions. Only four withdrawals were based on evidence from observational studies including a comparison group. Conclusion: Case reports are the main source of information used to withdraw a drug from the market for safety reasons. It is necessary to improve the quality of evidence supporting the withdrawal process of drugs linked to unexpected and severe ADRs. The use of large databases to perform cohort or nested case-control analyses is the most efficient and reliable method to study type-A class effect ADRs. The implementation of such databases in different countries could increase the quality of the information on ADRs by allowing researchers to conduct efficiently these type of studies. [ABSTRACT FROM AUTHOR]

The article presents a summary of the study about the cognitive benefits of withdrawing antiepileptic drugs (AEDs) in seizure-free patients. The study evaluates the effect of AED withdrawal on attention, reaction time, and speed of information processing. Comments by Emilio Perucca regarding the study are offered.