The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.

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Cochrane Handbook for Systematic Reviews of Interventions

The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance.

Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154

A method for estimating the probability of adverse drug reactions

Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m, $847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.

https://www.bmj.com/content/bmj/329/7456/15.full.pdf

Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients

Adverse drug reactions: definitions, diagnosis, and management.

The Mesolimbic Dopamine Reward Circuit in Depression

A shortened 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome has been developed. This scale offers an increase in efficiency while at the same time retaining clinical usefulness, validity and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal.

Assessment of Alcohol Withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar)

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Withdrawal Reaction after Long-Term Therapeutic Use of Benzodiazepines

Context The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neurotransmitter systems. The challenge is to elucidate the brain mechanisms of MDD behavioral symptoms, chiefly those of anhedonia. Objectives To visualize the neuroanatomical substrates implicated in altered reward processing in MDD, using functional magnetic resonance imaging in combination with a dopaminergic probe (a 30-mg dose of oral dextroamphetamine sulfate) to stimulate the brain reward system; and to test the hypothesis that a hypersensitive response to dextroamphetamine in MDD involves the prefrontal cortex and the striatum. Design and Interventions Among subjects with MDD and healthy control subjects, functional magnetic resonance imaging data were collected before and after single-blind administration of dextroamphetamine. Setting Subjects were recruited through local newspaper advertisements and by word of mouth. Participants Twelve depressed subjects (mean age, 34.83 years; male-female ratio, 6:6) met criteria for MDD according to the DSM-IV , were not taking antidepressants, and had no comorbid Axis I disorders. Twelve control subjects (mean age, 29.33 years; male-female ratio, 5:7) were healthy volunteers without a history of Axis I disorders. Main Outcome Measures Functional magnetic resonance imaging blood oxygen level–dependent activation was measured during a controlled task, and dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory. Results Subjects with MDD had a hypersensitive response to the rewarding effects of dextroamphetamine (2-fold increase; t 21  = 2.74, P  = .01), with altered brain activation in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F 1,44  = 11.93, P  = .001). Conclusion Dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, shedding light on the neurobiology of the anhedonic symptoms in MDD and suggesting these substrates as future therapeutic targets.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209040/yoa40146.pdf

Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe.

The goal of this review is to familiarize the reader about the potential involvement of the brain reward system (BRS) in symptoms of Major Depressive Disorder (MDD). The authors introduce a novel approach to study the pathophysiology of MDD that includes pharmacological probing of BRS pathways (e.g. d-amphetamine, hydromorphone) together with an elicited and measurable behavioral component (e.g. pleasant effects, increased energy, altered cognition). To this date, the major focus of MDD pathophysiology studies has been to characterize biological differences between healthy subjects and depressed patients such as alteration in the monoaminergic and endocrine systems. The relative importance of the various biological changes has not been elucidated, that is, linking these with specific behavioral manifestations in MDD have rarely been attempted. One core symptom of MDD is a decreased experience of pleasure or interest in previously enjoyed activities (i.e. anhedonia) such as work or hobbies, and is accompanied by decreased motivation or drive. The BRS consists of the neural pathways involved in eliciting rewarding experiences in animals and humans. The hypothesis is that altered BRS function may be an underlying brain mechanism of the loss of pleasure/interest experienced in MDD, and will be manifested through an altered response to a BRS probe. The authors have examined BRS function in MDD by introducing a pharmacological probe (i.e. d-amphetamine/d-amph). Amphetamine is defined as a probe due to its ability to release dopamine within major components of the BRS (i.e. the mesocorticolimbic dopamine system.) In addition to the objective pharmacological effects (e.g. altered heart rate), BRS probes like d-amph elicit reliable and measurable behavior, that is, the hedonic effects. A review of the neurobiology of MDD, the BRS, the rationale for implicating the BRS in depressive symptoms, and preliminary data, are presented in this article.

Claudio A. Naranjo

Papers

A method for estimating the probability of adverse drug reactions

Assessment of Alcohol Withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar)

Withdrawal Reaction after Long-Term Therapeutic Use of Benzodiazepines

Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe.

The role of the brain reward system in depression