Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT_1A, 5-HT_1B, α₂-adrenoceptors) and postsynaptic receptors (e.g., 5-HT₃). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT_1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT_1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT₃ receptors located in cortical and hippocampal GABA interneurons. 5-HT₃ receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.     

Can we estimate the accuracy of ADME-Tox predictions?

There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.     

Can osteoporosis increase the incidence of heart failure in adults?

Background: Recent studies have suggested shared comorbidities between heart failure and osteoporosis. In addition, patients with osteoporosis are associated with increased risks of developing cardiovascular disease.

Methods: A retrospective cohort analysis was conducted to determine the association between osteoporosis and heart failure. Data was from the Longitudinal Health Insurance Database 2000 (LHID 2000), Taiwan. Patients with newly diagnosed osteoporosis were identified, and osteoporosis-free controls were randomly selected from the general population and frequency matched according to age, sex, and index year using the LHID 2000. We analyzed the risks of heart failure using Cox proportional-hazards regression models.

Results: During the mean follow-up of 7.1?±?3.5 years, the cumulative incidence of heart failure was 2.24% higher in the osteoporosis cohort than in the comparison cohort (p?Conclusion: We observed a higher incidence of developing heart failure in Taiwanese adults with osteoporosis, especially in those with chronic comorbidities. There might be linking pathophysiology and mechanisms from osteoporosis to heart failure.     

Is the prophylactic antidepressant efficacy of lithium in bipolar I disorder dependent on study design and lithium level?

In the 1970s, several randomized controlled trials demonstrated significant antimanic and antidepressant properties of lithium in the prophylactic treatment of bipolar disorder. However, a recent meta-analysis of randomized, placebo-controlled trials of lithium in bipolar disorder found that its protective effect against depressive relapse/recurrence was equivocal. By examining potentially relevant parameters of recent randomized controlled trials with regard to lithium's prophylactic antidepressant efficacy, we try to identify factors which might help to explain these discrepant results across the different trials. Lithium's efficacy against manic relapse/recurrence appears rather robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment. Furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response. A lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence. To provide evidence-based guidelines on this issue, large prospective, randomized, double-blind, placebo-controlled trials are needed comparing the efficacy of lithium at different plasma levels against manic and depressive relapse/recurrence. In these trials, factors previously associated with predicting response to lithium should also be assessed.     

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy?

Since neither angiotensin-converting enzyme inhibitors (ACE-I) nor angiotensin II receptor blockers (ARB) can completely suppress aldosterone levels, there is a need for alternative/supplementary antihypertensive medications, such as the selective aldosterone blocker eplerenone (Inspra). This multicenter study measured the safety and efficacy of add-on eplerenone therapy to reduce blood pressure not controlled by ACE-I or ARB monotherapy. An ad hoc analysis evaluated whether active plasma renin or serum aldosterone levels could predict blood pressure response to eplerenone therapy. Patients (N = 341) with a diastolic blood pressure > 95 mmHg on a fixed dose of ACE-I or ARB were randomized to 8 weeks of double-blind treatment with eplerenone 50 mg qd or placebo. If blood pressure remained uncontrolled following 2, 4, or 6 weeks of treatment, the eplerenone dose was increased to 100 mg qd. In a combined cohort analysis of these patients, the placebo-adjusted change in systolic and diastolic blood pressure was -5.9/-2.4 mmHg (p< 0.001 and p = 0.006, respectively). While adding eplerenone to an ACE-I or ARB is safe and effective for blood pressure reduction, there was no baseline value or range of values of active plasma renin, serum aldosterone, or their ratio that predicted a favorable response to either of these drug combinations.     

The Causes of Heroin Addiction—A Review of the Literature. Part II

Theories on the causes of heroin addiction are reviewed in this two part article. Part II reviews the literature that considers the family of the addict and the stepping stone theory.     

Can we improve the treatment of congestion in heart failure?

Introduction: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes.

Areas covered: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide – and its doses – with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed.

Expert opinion: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need.     

Can we improve the treatment of congestion in heart failure?

INTRODUCTION: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes. AREAS COVERED: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed. EXPERT OPINION: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need.     

Are we going to increase the use of antidepressants up to that of benzodiazepines?

Objective The present study compared recent trends in benzodiazepine and antidepressant consumption in Italy and projected their global sales in the future. We investigated whether the increasing use of antidepressants is associated with a progressive reduction in benzodiazepine use.Methods Data concerning actual quantities of benzodiazepines and antidepressants dispensed in Italy from 1995 to June 2003 were obtained from IMS Health. For each agent, the number of defined daily doses (DDDs) per 1000 inhabitants per day and the annual expenditure in Euros was calculated.Results During the 9-year period, benzodiazepine consumption remained substantially stable, accounting for 50 DDDs/1000 per day in 2003. In the same period, antidepressant consumption dramatically rose, from 9 DDDs/1000 per day in 1995 to 26 DDDs/1000 per day in 2003, an increase of nearly three times. While the use of tricyclic antidepressants declined by one-third and that of other older agents remained substantially stable, the use of selective serotonin-reuptake inhibitors and newer agents (venlafaxine, mirtazapine, reboxetine) increased by 623%. Global consumption of antidepressants was projected to increase still further, and, in 2007, the total sales of antidepressants were projected to be similar to the total sales of benzodiazepines. The value of benzodiazepine sales increased from 322 million to 565 million Euros, an increase of 43%; similarly, the value of antidepressant sales increased from 186 million to 569 million Euros, an increase of 67%.Conclusions In Italy, the consumption of benzodiazepines was not affected by the increased prescribing of selective serotonin-reuptake inhibitors and newer antidepressants.     

Preparing for an era of weapons of mass destruction (WMD)--are we there yet? Why we should all be concerned. Part II

September 11, 2001 demonstrated dramatic voids in national preparedness, and catalyzed massive efforts to identify and remedy vulnerabilities. Since Part I of this series appeared in August 2002, significant improvements have been achieved especially in bioterrorism and chemical terrorism for first responders and emergency medicine, law enforcement, and public health (surveillance). Such efforts manifested benefits during the SARS outbreaks and monkeypox cases of 2003. Nevertheless, emerging infectious diseases will continue to pose a threat if we do not remain vigilant and continue to invest in training, surveillance, and treatments. As expected, many poison centers and toxicologists have taken leadership roles nationwide. In regions where such leadership existed, preparedness levels are strong and collaborations resulted in the development of valuable response plans and training, including the Advanced Hazardous Life Support (AHLS) and Basic Disaster Life Support (BDLS) courses. Early success notwithstanding, experts suggest that current national preparedness has improved slightly from "1" (9/11) to "3" out of "10". Increasingly it has become evident that the nuclear threat, including radiation terrorism, is significant, against which the US remains inadequately prepared. Arguably the nuclear threat-whether accidental or planned-remains our highest consequence vulnerability, and we must rapidly improve our readiness across disciplines. Special populations including the elderly and children remain marginalized in preparedness protocols. Local vulnerabilities including chemical manufacturing and transportation--not just a risk for terrorism but industrial accidents--continue unabated. Our early success is not an endpoint; much work remains and time is fleeting. This report examines vulnerabilities that must be addressed to enhance preparedness.     

Can side effects of steroid treatments be minimized by the temporal aspects of delivery method?

Introduction: Glucocorticoids are commonly prescribed medications associated with significant mortality and morbidity, even when used at physiological dosages. The endogenous glucocorticoids are secreted in a complex rhythm consisting of both a daily circadian rhythm and a more rapid and dynamic ultradian rhythm that is highly conserved in nature. Current therapeutic options attempt to target the circadian aspects of this rhythm but do not take into account the oscillating ultradian pulsatility.

Areas covered: This article analyzes English-language literature on Pubmed and discusses the physiology and evidence behind the importance of different patterns of glucocorticoid presentation on gene regulation, animal responses and clinical significance.

Expert opinion: There is compelling evidence for pulsatility being an important factor in hypothalamic pituitary adrenal (HPA) axis regulation and tissue responses to glucocorticoids. Different patterns of gene regulation and neural and behavioral responses are seen dependent upon the pattern of glucocorticoid presentation. Disease states are associated with disordered HPA ultradian activity. Glucocorticoid treatments have significant risk/benefit issues. It is now time to go back to first principles and think about the physiology and patterns of drug presentation in glucocorticoid-based therapeutics.     

Can we develop neurally acting drugs for the treatment of migraine?

Serotonin (5-HT)(1B/1D) receptor agonists, which are also known as triptans, represent the most important advance in migraine therapeutics in the four millennia that the condition has been recognized. The vasoconstrictive activity of triptans produced a small clinical penalty in terms of coronary vasoconstriction but also raised an enormous intellectual question: to what extent is migraine a vascular problem? Functional neuroimaging and neurophysiological studies have consistently developed the theme of migraine as a brain disorder and, therefore, demanded that the search for neurally acting antimigraine drugs should be undertaken. The prospect of non-vasoconstrictor acute migraine therapies, potential targets for which are discussed here, offers a real opportunity to patients and provides a therapeutic rationale that places migraine firmly in the brain as a neurological problem, where it undoubtedly belongs.     

Multisite effectiveness trials of treatments for substance abuse and co-occurring problems: Have we chosen the best designs?

Multisite effectiveness trials such as those carried out in the National Drug Abuse Treatment Clinical Trials Network (CTN) are a critical step in the development and dissemination of evidence-based treatments because they address how such treatments perform in real-world clinical settings. As Brigham et al. summarized in a recent article (G. S. Brigham, D. J. Feaster, P. G. Wakim, & C. L. Dempsey C. L., 2009), several possible experimental designs may be chosen for such effectiveness trials. These include (a) a new treatment intervention (Tx) is compared to an existing mode of community based treatment as usual (TAU): Tx versus TAU; (b) a new intervention is added to TAU and compared to TAU alone: Tx + TAU versus TAU; or (c) a new intervention is added to TAU and compared to a control condition added to TAU: Tx + TAU versus control + TAU. Each of these designs addresses a different question and has different potential strengths and weaknesses. As of December 2009, the primary outcome paper had been published for 16 of the multisite randomized clinical trials conducted in the CTN, testing various treatments for drug abuse, HIV risk behavior, or related problems. This paper systematically examines, for each of the completed trials, the experimental design type chosen and its original rationale, the main findings of the trial, and the strengths and weaknesses of the design in hindsight. Based on this review, recommendations are generated to inform the design of future effectiveness trials on treatments for substance abuse, HIV risk, and other behavioral health problems.     

Can thermodynamic measurements of receptor binding yield information on drug affinity and efficacy?

The present commentary surveys the methods for obtaining the thermodynamic parameters of the drug-receptor binding equilibrium, DeltaG degrees, DeltaH degrees, DeltaS degrees, and DeltaC degrees (p) (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the binding of agonists and antagonists to several G-protein coupled receptors (GPCRs) and ligand-gated ion channel receptors (LGICRs). In particular, thermodynamic data for five GPCRs (beta-adrenergic, adenosine A(1), adenosine A(2A), dopamine D(2), and 5-HT(1A)) and four LGICRs (glycine, GABA(A), 5-HT(3), and nicotinic) have been collected and analyzed. Among these receptor systems, seven (three GPCRs and all LGICRs) show "thermodynamic agonist-antagonist discrimination": when the agonist binding to a given receptor is entropy-driven, the binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TDeltaS degrees (kJ mol(-1); T = 298.15 K) = 40.3 (+/- 0.7) + 1.00 (+/-0.01) DeltaH degrees (kJ mol(-1)); N = 184; r = 0.981; P < 0.0001 - which is of the form DeltaH degrees = beta. DeltaS degrees, revealing the presence of the "enthalpy-entropy compensation" phenomenon. This means that any decrease of binding enthalpy is compensated for by a parallel decrease of binding entropy, and vice versa, in such a manner that affinity constant values (K(A)) of drug-receptor equilibrium (DeltaG degrees = -RT ln K(A) = DeltaH degrees - TDeltaS degrees ) cannot be greater than 10(11) M(-1). According to the most recent hypotheses concerning drug-receptor interaction mechanisms, these thermodynamic phenomena appear to be a consequence of the rearrangement of solvent molecules that occurs during the binding.     

Evaluation of the performance of elastomeric pumps in practice: are we under-delivering on chemotherapy treatments?

Background and aims: Elastomeric pumps are widely used to facilitate ambulatory chemotherapy, and studies have shown that they are safe and well received by patients. Despite these advantages, their end of infusion time can fluctuate significantly. The aim of this research was to observe the performance of these pumps in real practice and to evaluate patients’ satisfaction.

Methods: This was a two-phase study conducted at three cancer units over 6 months. Phase-1 was an observational study recording the status of pumps at the scheduled disconnection time and noting remaining volume of infusion. Phase-2 was a survey of patients and their perception/satisfaction. Ethical approval was granted.

Results: A total of 92 cases were observed covering 50 cases disconnected at hospital and 42 disconnected at home. The infusion in 40% of hospital disconnection cases was slow, with patients arriving at hospital with unfinished pumps; 58% of these had an estimated remaining volume which exceeded 10?mL with 35% exceeded 20?mL. In 73% of these cases, and regardless of the remaining volume, the patient was disconnected and the pump was discarded.

Conclusions: The performance of pumps varied, which affected nurse workload and patients’ waiting-times. A smart system is an option to monitor the performance of pumps and to predict their accuracy.     

Treatment of thyrotoxicosis — the current position Part II: Drug therapy and thyroidectomy

Summary

Antithyroid drugs such as carbimazole and propylthiouracil prevent iodination of thyroglobulin and reduce hormone formation, storage and secretion. Carbimazole is the most favoured and should be given 8-hourly, initially in daily doses of 45 to 60?mg. decreasing to 15?mg. or less when the thyrotoxicosis is controlled. Patients with mild thyrotoxicosis and a small goitre and satisfactory response should have carbimazole for 18 months. The decision to continue antithyroid drugs for longer than 6 months may be easier if a 20-minute radioiodine uptake is suppressed by T3 given for a week or more (T3 suppression test), although this test of remission is not infallible.

Patients with large glands, and who are difficult to bring under control with drugs, should have an operation or radioactive iodine (¹³¹I) therapy depending on age and fertility. Likewise people who have a relapse after stopping drug treatment (and this may be increased by iodide) can have another course or alternatively operation or radioiodine therapy.

In general, antithyroid drugs are very safe; occasionally, (1 in 30) a maculopapular rash is seen or the patient has nausea. A granulopenia is very rare, never complete, occurs suddenly and is nearly always reversible if drugs are stopped. Potassium per chlorate is only used when other treatment is not feasible since it might cause aplastic anaemia. Studies with ³⁵S labelled antithyroid drugs show that they differ in distribution, and rate and mode of metabolism.

Partial thyroidectomy is reserved for patients with obvious goitres, severe or relapsing thyrotoxicosis and always provided there is a skilled surgical team and an agreeable and fit patient. In experienced hands the outcome is good, but occasionally the patient is left with hoarseness, or parathyroid insufficiency, or a bad scar. There is also a risk of hypothyroidism and sometimes patients relapse. The incidence of complications is related to many factors but it is known that the more evidence there is of thyroid autoimmunity the higher the risk of post-operative hypothyroidism; and there is an inverse relationship between risk of hypothyroidism and recurrence, probably related to the amount of tissue resected.