Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors. The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials. Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK(1)) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK(1) receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems. In the authors' view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.     

Cannabis and psychosis: what is the link?

Growing evidence supports the hypothesis that cannabis consumption is a risk factor for the development of psychotic symptoms. Nonetheless, controversy remains about the causal nature of the association. This review takes the debate further through a critical appraisal of the evidence. An electronic search was performed, allowing to identify 622 studies published until June 1st 2005. Longitudinal studies and literature reviews were selected if they addressed specifically the issues of the cannabis/psychosis relationship or possible mechanisms involved. Ten epidemiological studies were relevant: three supported a causal relationship between cannabis use and diagnosed psychosis; five suggested that chronic cannabis intake increases the frequency of psychotic symptoms, but not of diagnosed psychosis; and two showed no causal relationship. Potential neurobiological mechanisms were also identified, involving dopamine, endocannabinoids, and brain growth factors. Although there is evidence that cannabis use increases the risk of developing psychotic symptoms, the causal nature of this association remains unclear. Contributing factors include heavy consumption, length and early age of exposure, and psychotic vulnerability. This conclusion should be mitigated by uncertainty arising from cannabis use assessment, psychosis measurement, reverse causality and control of residual confounding.     

Vitamins and cognition: what is the evidence?

Vitamin supplements are consumed for their purported health benefits by a large segment of the populations of developed countries. Several indirect strands of evidence suggest that increasing levels of vitamins may improve brain function. These include evidence that individual vitamins are intrinsically involved in the cellular and physiological processes underpinning brain function; that small proportions of the population exhibit biochemical deficiencies in each individual vitamin, suggesting that a much larger proportion have less than optimal overall micronutrient status; and that epidemiological research suggests a relationship between individual vitamins (or the potentially neurotoxic amino acid homocysteine, which is related to B vitamin status), and cognitive function and mood. The related question as to whether direct supplementation with vitamins can therefore improve psychological functioning in cognitively intact individuals has been addressed in a number of studies. The evidence reviewed here suggests that, whereas studies involving supplementation with single vitamins, or restricted ranges of vitamins, have demonstrated equivocal results, evidence from studies involving the administration of broader ranges of vitamins, or multivitamins, suggest potential efficacy in terms of cognitive and psychological functioning. In contrast to the literature investigating restricted ranges of vitamins, most of the evidence regarding multivitamins was collected from healthy, non-elderly samples, suggesting that more research in this population is warranted.     

Pitavastatin and carbohydrate metabolism: what is the evidence?

Statins are the cornerstone of hypolipidemic treatment but recently have been associated with increased risk of developing diabetes mellitus. However, the risk of incident diabetes is not the same among statins. Pitavastatin lowers low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol but also seems to be neutral in terms of risk of incident diabetes. Clinical and experimental evidence shows that pitavastatin increases adiponectin levels and reduces oxidative stress, effects that seem to be implicated in the beneficial effect of the drug on carbohydrate metabolism variables. Pitavastatin is a useful hypolipidemic drug, which is promising for patients with increased diabetes risk or established diabetes.     

Human epicardial fat: what is new and what is missing?

1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD.     

Food Intolerance and childhood asthma: what is the link?

Food allergies and asthma are increasing worldwide. It is estimated that approximately 8% of children aged <3 years have food allergies. Foods can induce a variety of IgE-mediated, cutaneous, gastrointestinal, and respiratory reactions. The most common foods responsible for allergic reactions in children are egg, milk, peanut, soy, fish, shellfish, and tree nuts. Asthma alone as a manifestation of a food allergy is rare and atypical. Less than 5% of patients experience wheezing without cutaneous or gastrointestinal symptoms during a food challenge. In addition to acute respiratory symptoms, a food allergy may also induce airway hyper-responsiveness beyond the initial reaction. This process can occur in patients who do not demonstrate a decrease in lung function during the reaction. Inhalation of aerosolized food particles can cause respiratory symptoms in selected food-allergic individuals, particularly with fish and shellfish during cooking and aerosolization. However, this has not been demonstrated with the smelling of, or casual contact with, peanut butter. Rarely, food additives such as sulfating agents can cause respiratory reactions. This reaction occurs primarily in patients with underlying asthma, particularly in patients with more severe asthma. In contrast, there is no convincing evidence that tartrazine or monosodium glutamate can induce asthma responses. Although food-induced asthma is rare, it is common for patients and clinicians to perceive that food can trigger asthma. Avoidance of specific foods or additives has not been shown to improve asthma, even in patients who may perceive that a particular food worsens their asthma.However, patients with underlying asthma are more likely to experience a fatal or near-fatal food reaction. Food reactions tend to be more severe or life threatening when they involve the respiratory tract. The presence of a food allergy is a risk factor for the future development of asthma, particularly for children with sensitization to egg protein.The diagnosis of a food allergy includes skin or in vitro testing as an initial study when the history suggests food allergy. While negative testing generally rules out a food allergy, positive testing should be followed by a food-challenge procedure for a definitive diagnosis. The CAP-RAST FEIA (CAP-radioallergosorbent test [RAST] fluoroenzyme immunoasssay system [FEIA]) is an improved in vitro measure that in some cases may decrease the need for food challenges. However, similar to skin testing and the RAST, there is good sensitivity but poor specificity, such that specific challenges are often warranted.     

Glucocorticoid resistance - what is known?

It has become apparent in recent years that the glucocorticoid receptor is not a simple on/off switch, but instead orchestrates subtle and complex interactions between large numbers of proteins. This more sophisticated understanding awaits a unifying concept that will explain mechanisms of glucocorticoid resistance and allow new approaches to enhancing sensitivity.     

Tricyclic antidepressants and fibromyalgia: what is the mechanism of action?

Fibromyalgia is a chronic pain disorder of which other clinical features, such as persistent fatigue and disordered sleep, may be a secondary consequence. The initial pharmacological approach to treating the disorder is the management of the pain. Tricyclic antidepressants are the most effective drugs in use so far, especially when administered in combination with other therapies (e.g., selective serotonin re-uptake inhibitors), which suggests modulation of the neurotransmitters serotonin and noradrenaline. The effectiveness of amitriptyline and related tricyclic antidepressants, however, is consistent with the involvement of mechanisms, such as potassium channel modulation and NMDA receptor antagonism, in addition to or in place of the modulation of monoamine neurotransmitters. Investigation of the importance of each of the pharmacological properties of amitriptyline and related molecules in the management of fibromyalgia could provide clues for the rational design of new drugs.     

Tricyclic antidepressants and fibromyalgia: what is the mechanism of action?

Fibromyalgia is a chronic pain disorder of which other clinical features, such as persistent fatigue and disordered sleep, may be a secondary consequence. The initial pharmacological approach to treating the disorder is the management of the pain. Tricyclic antidepressants are the most effective drugs in use so far, especially when administered in combination with other therapies (e.g., selective serotonin re-uptake inhibitors), which suggests modulation of the neurotransmitters serotonin and noradrenaline. The effectiveness of amitriptyline and related tricyclic antidepressants, however, is consistent with the involvement of mechanisms, such as potassium channel modulation and NMDA receptor antagonism, in addition to or in place of the modulation of monoamine neurotransmitters. Investigation of the importance of each of the pharmacological properties of amitriptyline and related molecules in the management of fibromyalgia could provide clues for the rational design of new drugs.     

COPD: what is the unmet need?

Chronic obstructive pulmonary disease (COPD) is now recognized as a major source of ill health around the world with an important impact on both developed and developing economies. The emphasis in research has shifted from a purely physiological focus that mainly considered how airway smooth muscle tone can be modulated to improve lung emptying. Although long-acting inhaled beta-agonist and antimuscarinic antagonists have improved clinical management for many symptomatic patents, there is increasing attention being paid to the inflammatory component of COPD in the airways and lung parenchyma and to its close association with other diseases, which cannot simply be attributed to their having a common risk factor such as tobacco smoking. This clinical review is intended to identify not only those areas where pharmacological treatment has been successful or has offered particular insights into COPD but also to consider where existing treatment is falling short and new opportunities exist to conduct original investigations. A picture of considerable complexity emerges with a range of clinical patterns leading to several common end points such as exacerbations, exercise impairment and mortality. Defining subsets of patients responsive to more specific interventions is the major challenge for the next decade in this field.     

Sudden hearing loss subsequent to diarrhea: what is the missing link?

Sudden sensorineural hearing loss (SSNHL) is a debilitating condition with an incidence of nearly 20 per 100,000 in populations. Metronidazole-induced ototoxicity is an extremely rare etiology of SSNHL. In this report, we describe a young female with bilateral SSNHL due to oral use of metronidazole. A 23 years old female presented to the emergency department with acute bilateral hearing loss. We found out that her hearing loss had started 4 days after initiation of metronidazole which was administered for treatment of diarrhea. This case report shows that physicians should be aware of the uncommon side effects while prescribing metronidazole to patients in order to manage the possible adverse events on time.     

Drug transfer to the fetus and to the breastfeeding infant: what do we know?

The pregnant patient with inflammatory bowel disease presents a number of challenges to the clinician. In addition to the management of the patient's disease activity and the potential effects of disease on pregnancy, the clinician must also take into consideration any iatrogenic complications that may arise from the medical management of these conditions. Furthermore, should the patient elect to breastfeed her infant, the effect of drugs that may be passed through the breast milk must also be considered. This article focuses specifically on the issues of drug transfer to the fetus and to the breastfeeding infant. Meperidine is the sedative of choice for endoscopic procedures on pregnant patients, while benzodiazepines and propofol may be used with certain caveats. Amoxicillin/clavulanic acid and metronidazole are preferred if antibiotics are indicated for perianal Crohn's disease or pouchitis. The majority of medications used in the treatment of luminal IBD in pregnancy are not associated with significant adverse effects, and thus can generally be used safely. Certain medications, such as aminosalicylates, corticosteroids, and cyclosporine, appear low risk, while others such as methotrexate and thalidomide are clearly contraindicated. The role of other immunomodulators and biologics remains to be clearly defined, although early experience with infliximab and similar agents appear to be low risk. Safety in breastfeeding varies considerably among medications. There are many issues to address when considering pharmaceutical intervention in the pregnant patient, and patients should be carefully counseled regarding potential teratogenicity or adverse outcomes of medication used during pregnancy and breastfeeding.     

Early-onset cannabis use and cognitive deficits: what is the nature of the association?

BACKGROUND: Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life. METHODS: We analyzed neuropsychological test results from 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure, all of whom had undergone a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. We compared early-onset cannabis users with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin. RESULTS: The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late-onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, when we adjusted for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant. CONCLUSIONS: Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1). innate differences between groups in cognitive ability, antedating first cannabis use; (2). an actual neurotoxic effect of cannabis on the developing brain; or (3). poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture.     

Antiangiogenesis and radiotherapy: what is the role of combined modality treatment?

The formation of new blood vessels is a prerequisite for the growth of primary and metastatic tumour. Thus, strategies that aim at the inhibition of tumour angiogenesis have gained considerable interest in recent years. Furthermore, there is a need to identify the role of antiangiogenic agents in conjunction with conventional anticancer modalities like chemotherapy or radiotherapy. It is the objective of this review to summarise experimental data for different antiangiogenic agents used for combined modality experiments with radiotherapy. Promising data have been reported for a series of antiangiogenic agents for combined modality treatment with radiotherapy using tumour growth delay as the primary end-point. Yet, the results from different agents with various tumour lines are contradictory in part. Furthermore, enhancement of local tumour control, the main objective of curative radiotherapy, has so far been demonstrated for only two agents (DC101 and CA4DP), while experiments using TNP-470 even revealed a reduction of local tumour control when combined with irradiation. Finally, detailed studies investigating the modulation of normal tissue reactions for the combination of radiotherapy and inhibitors of angiogenesis are pending so far. Thus, experimental data currently available do not consistently support the beneficial effects of combined modality treatment with inhibitors of angiogenesis and radiotherapy. We therefore conclude that there is still a long way to go until we know which antiangiogenic agent will clinically be suitable for what tumour entity for combined treatment of radiotherapy and inhibitors of angiogenesis.     

Opioids and the immune system: what is their mechanism of action?

There is a significant amount of literature showing that morphine and other opioids modulate immune responses. The findings support many mechanisms by which this may occur. In vitro experiments provide evidence for direct actions of opioids on immune cells using a variety of functional end points. When these drugs are given in vivo, a plethora of immune parameters are also altered. The paper in this issue of the journal by Zhang et al. provides new information on morphine alteration of immune cell subsets in the spleen and thymus of mice and the potential role of glucocorticoids in these observed phenomena. This Commentary reviews the in vitro activities of morphine on leucocytes, as well as other documented mechanisms by which morphine can alter immune function in vivo.     

Accounting for induced-fit effects in docking: what is possible and what is not?

Proteins can undergo a variety of conformational changes upon ligand binding. Although different mechanisms may play a role, the phenomenon is commonly referred to as induced fit to indicate that the tight structural complementarity of the interaction partners is a consequence of the binding event. Docking methods need to take into account this ability of the ligand and the protein to mutually adapt to each other when forming a complex. Handling the ligand as flexible is already common practice in docking applications. This is not yet the case for the protein. In fact, the accurate prediction of protein conformational changes upon ligand binding is still a major challenge, even more if computational speed is an issue, as for example in virtual screening applications. However, significant progress has been made over the past years and many valuable approaches have become available to address the protein flexibility problem and to provide more reliable docking predictions for complexes governed by significant induced-fit effects. This review provides a brief overview of the current situation, the most recent advances, and the remaining limitations of flexible protein docking, with particular focus on approaches handling protein flexibility simultaneously with ligand placement in the docking process.