Current Pharmaceutical Design - Volume 18, Issue 36, 2012

Depression is one of the most common psychiatric conditions affecting numerous individuals in the world. However, the currently available antidepressant medication shows low response and remission rates. Thus, new antidepressants need to be discovered or developed. Aiming to describe the current neurobiological hypotheses regarding the pathophysiology of depression and in order to give an overview of novel possible antidepressant drug targets, we reviewed publications and studies referring to the neurobiology of depression. This review included genetics, epigenetics and gene expression, neuroanatomy and structural anatomy, neurochemistry, neuroendocrinology, neuroimmunology and novel drug targets using a MEDLINE/Pubmed search. The search was augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings. On the one hand, the literature reveals in part contradictory information, but on the other hand, it shows convergent information regarding the relevance of research targets apart from the monoamine deficiency hypothesis of depression such as epigenetic phenomena and changes in neuronal and glial function and structure. Recent neurobiological findings in these areas of research provide multidimensional perspectives for the progress in the psychopharmacological treatment of depression.

The aim of this review was to describe the sleep anomalies in depression, the effects of antidepressants on sleep, the usefulness of antidepressants in the treatment of primary insomnia and insomnia in other psychiatric disorders. Depression is associated with abnormalities in the sleep pattern that include disturbances of sleep continuity, diminished slow-wave sleep (SWS) and altered rapid eye movement (REM) sleep parameters. Although none of the reported changes in sleep are specific to depression, many of them, for example increased REM density and reduced amount of SWS in the first sleep cycle, are used as biological markers for research on depression and in the development of antidepressant drugs. An antidepressant should reverse abnormalities in the sleep pattern. However, many antidepressants can worsen sleep. Because of the activating effects of some drugs, for example imipramine, desipramine, fluoxetine, paroxetine, venlafaxine, reboxetine and bupropion, many patients who take them have to be co-prescribed with sleep-promoting agents to improve sleep. Even in maintenance treatment with activating antidepressants as many as 30-40%; of patients may still suffer from insomnia. Antidepressants with sleep-promoting effects include sedative antidepressants, for example doxepin, mirtazapine, trazodone, trimipramine, and agomelatine which promotes sleep not through a sedative action but through resynchronization of the circadian rhythm. Sedative antidepressants are frequently used in the treatment of primary insomnia, although not many double-blind studies have been provided to support such an approach to insomnia treatment. One exception is doxepin, which has been approved for the treatment of insomnia characterized by difficulties in maintaining sleep.

The aim of antidepressant drug treatment is to produce remission without causing adverse effects during the acute phase of the illness and to prevent relapses or recurrences during continuation or maintenance therapy. To achieve these goals, drug choice and dosage must be optimized for each patient individually. Therapeutic drug monitoring (TDM), which is based on the assumption that clinical effects correlate better with blood levels than doses, can be helpful. When using tricyclic antidepressant drugs TDM enhances safety and efficacy. For newer antidepressant drugs, however, it is a matter of debate to which extend TDM can have beneficial effects. For many antidepressants there exist carefully designed studies concerning the relationship between plasma concentration and clinical effects that allow the definition of recommended therapeutic ranges of the plasma concentration. In some drugs however, concentration-effect studies are lacking so far, but target ranges resulting from clinically relevant plasma concentrations or from pharmacokinetic studies could be provided. During the last years, knowledge on therapeutic references ranges in blood towards TDM guided treatment has markedly improved for new antidepressant drugs, and many specific indications have been defined for useful TDM. Recently published guidelines describe the best practice of TDM for neuropsychiatric drugs. The aim of this review is to summarize the current status of TDM for antidepressant drugs and discuss the literature with regard to response optimization, pharmacovigilance and economic benefits and with regard to needs for further research.

The prevalence of depression in patients with epilepsy (PWE) is high. To elucidate the nature of depression in PWE, a comparison was made between PWE and patients with idiopathic depression (PWID), applying 3 test batteries: Beck Depression Inventory II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D) and Buss–Perry Aggression Questionnaire (BAQ). The former 2 rating scales were developed to measure depressive symptoms, while the latter was designed to detect anger and aggressive states. As a result, the group of patients with PWE showed significantly higher BAQ scores in comparison to those with PWID. Further, the BAQ and BDI scores were closely related within a group of PWE, while BAQ and BDI scores were not correlated with each other within a group of PWID. With regard to pharmaceutical therapy, the safety of antidepressants, especially SSRIs, is well established. However, there has been only one randomized controlled trial (RCT) thus far, which failed to show a significant difference in efficacy between placebo and various antidepressants. In contrast, there are two RCTs regarding the efficacy of LTG. The clinical profile of the depressiolytic effects of LTG in PWE may be different from that of antidepressants in patients with idiopathic depression, in that BAQ is more sensitive measure than BDI or CES-D. It is now widely recognized that the failure to treat depression in PWE can result in serious consequences. However, even a fundamental question, such as whether antidepressants are as effective in this population as in PWID, remains to be answered.

Stress constitutes a risk factor for diseases where the immune system plays a significant role. Stress is recognized as a possible trigger for flare ups during the course of multiple sclerosis (MS). The disclosure to the patient of the diagnosis of MS, the commencement of immunomodulatory therapy, and the unpredictability and vagaries of disease progression are all sources of stress. Biological stress systems such as the hypothalamic-pituitary-adrenal system and the sympathetic nervous system may influence the pathogenesis and the disease course of MS. The ability to cope with stress may also be impaired, mediated for example by cognitive deficits or loss of abilities and resources as disease progresses or by the high prevalence of concurrent mood disturbances such as depression and chronic fatigue. Psychiatric comorbidities of MS disease or therapy as well as impairments of coping strategies are underrecognized in clinical practice. Treatment plans for depression among MS patients, as the most common psychiatric comorbidity, should be individualized with integrated approaches. Antidepressants are effective for the treatment of depression in MS patients although further clinical research into the neurobiological and psychological bases of depressive disorders in MS patients is clearly needed. In therapy, coping strategies can be enhanced through multidisciplinary assessment of the various challenges and restrictions imposed by the disease and assisting and supporting the patient in addressing these. Exercise, as a form of positive stress (eustress), also has a role in therapy.

Major depressive disorder (MDD) is a prevalent mental illness associated with significant impairment in quality of life and treatment resistance in as many as 50% of patients. Few alternatives to psychopharmacological and electroconvulsive therapy (ECT) exist. Transcranial magnetic stimulation (TMS) is one such alternative with demonstrated efficacy in the treatment of both MDD and treatment- resistant depression (TRD). Accrued evidence from meta-analyses suggests that rTMS has moderate effect sizes in both MDD and TRD, comparable, though less robust, to those seen in ECT treated patients, and similar to those seen with antidepressant treatment in TRD. To date, rTMS has been used in adult, pediatric, and geriatric populations with success. Predictors of response include lower age, lower degrees of treatment resistance, and the absence of comorbid anxiety or psychotic symptoms. rTMS is cost-effective when compared to existing treatments for TRD including psychopharmacological interventions and ECT. More research, however, is needed to determine the most optimal stimulation parameters. Accelerated treatment over a short duration of time, sequential bilateral stimulation, extended number of pulses per session are potential methods of optimizing efficacy over current unilateral stimulation protocols. The extent to which rTMS can be pushed to engender the greatest possible clinical effects while avoiding seizure induction remains unknown.

Background: Antidepressant medication is a major cornerstone in treatment of mood and anxiety disorders. Numerous substances are available on the market; however, only 60% of treated patients show sufficient response to medication and side effects are common. Lengthy trials are not uncommon until the optimized drug and dose is found and unfortunately, no valid predictors to match the ‘right’ drug to the ‘right’ patient exist nowadays. Genetic factors are thought to be involved as evidenced by numerous pharmacogenetic studies. This comprehensive review summarizes the most interesting findings and discusses clinical implications of pharmacogenetic results. Methods: We reviewed available literature on pharmacogenetics of antidepressant response and side effects until summer 2011 using the PubMed database. Results: Promising findings exist for several variants in candidate genes involved in the pharmacokinetics or pharmacodynamics of antidepressants. These include association findings in the serotonin transporter gene (5-HTT), serotonin receptor genes, a gene coding an efflux pump in the blood-brain-barrier (ABCB1), and genes involved in the HPA axis. Promising candidate genes increasing risk for side effects include some of the genes associated with treatment response and cytochrome P450 genes. Conclusion: A high number of studies on pharmacogenetics of antidepressants have been published during the past decades. However, contradictory results still limit clinical use of these findings. Future studies should include functional analyses and consider gene-gene and gene-environment interactions. This will aid in facilitating a future use of pharmacogenetics in clinical practice, likely leading to improved patient care.

The heritability of major depression has been documented in a number of epidemiologic studies. Twin studies have estimated the heritability at about 37% and these estimation can rise up to 70% if severity, relapse rate and age of onset are considered. Despite the relative importance of genetic risk factors in the pathogenesis of this disease, molecular genetic studies, including large genome-wide association studies, only a very small number of candidate genes, explaining little of the variance have been identified. This fact has been termed “missing heritability” and could be accounted by a number of factors including that the presumed causal variants are not tagged by the current genetic approaches, that major depression is truly polygenic, with each polymorphism only contributing very small increases in risk, unaccounted environmental influences and complex epigenetic factors. Epigenetics refers to the regulation of DNA transcription without alteration of the original sequence and is controlled by DNA methylation, histone modifications and non-coding RNAs and can be transmitted through generations. A number of clinical and preclinical studies suggest that epigenetic mechanisms could play an important role in the pathogenesis and treatment of major depression. So far, most studies investigated genes within the hypothalamicpituitary- adrenal (HPA) axis or the neurotrophin system. It is also of interest that current psychopharmacologic drugs including antidepressants, antipsychotics and mood stabilizers may exert some of their effects by inducing epigenetic changes. Most notably, epigenetic alterations are potentially reversible and accessibe for drug treatment, which lead to the development of novel classes of antidepressant drugs.

Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research. Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression. Methods: We have carried out a medline search “oxidative stress depression”, “oxidative stress affective disorders”, “free radicals and depression”, “free radicals and affective disorders” “antidepressants oxidative stress” “antidepressants and free radicals”. We found numerous reports elaborating depressive disorder and oxidative stress. Most of the previous studies concentrated on investigating antioxidants in human blood as well as in animal models. However, few of these reports were able to show correlations of reduced oxidative stress with antidepressant treatment and clinical outcome measures. Fewer studies elaborated the concentrations of antioxidants in the human brain and some pro-oxidative enzymes in depression. However, more studies are needed to elucidate the complex role of oxidative stress in the aetiology of depression.

Impaired glucose tolerance is observed in depressed patients, and patients suffering from depression have an increased risk to develop diabetes mellitus. In depressed and diabetic patients, studies have shown both a beneficial effect of antidepressants on glucose homeostasis and the opposite. This review aims to structure the conflicting data and focuses on the question, which effect specific antidepressants have on glucose homeostasis. We therefore performed a systematic review of all available studies referenced in Medline from 1960 to 2011. We included antidepressant agents indexed in the Anatomical Therapeutic Chemical (ATC) classification system of the WHO in 2011 and searched for studies investigating their effects on glucose metabolism in clinical samples as well as in healthy subjects. Of 876 studies screened we included 66. Most studies had small sample sizes and lacked a placebo group limiting conclusions about antidepressant effects on glucose tolerance. However, some evidence points to beneficial effects on glucose homeostasis of hydrazine-type monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). In case of SSRIs, the effect is more pronounced in diabetic patients or patients with comorbid depression and diabetes mellitus. Noradrenegic substances (and possibly also dualacting antidepressants), in contrast, may deteriorate glucose tolerance. They can be used in depressed patients when favorable effects on mood outweigh adverse metabolic effects, but in depressed diabetics this can be at the expense of worsening of glycemic control. The effects of other antidepressants, like bupropione, mirtazapine or newer agents, require further investigation before reliable conclusions can be made. The synthesis of the findings is discussed in light of the specific pharmacodynamic properties of the antidepressants as well as the pathophysiological changes in depression and impaired glucose homeostasis, including animal studies.

There is a plausible role for cytokines, brain-derived neurotrophic factor (BDNF), and their interaction in major depressive disorder's (MDD) etiology. This review includes (i) briefly defining cytokines, (ii) a discussion of theories for why they may affect brain function, (iii) cross-sectional associations between cytokines and MDD, (iv) the effect of antidepressants on cytokines, (v) the behavioral effects of cytokines administration to humans, (vi) the behavior effects of their administration to animal models, and (vii) potential neurochemical systems influenced by cytokines. The role of BDNF is then briefly examined, along with a review of several studies that have examined a Val/Met polymorphism in the BDNF gene. The bidirectional relationship between BDNF and cytokines is subsequently discussed. Potential ramifications for MDD treatment that are appraised include (i) use of cytokine biomarkers for identifying specific populations for targeted MDD therapy, (ii) the use of medications that directly antagonize the role of inflammatory cytokines, (iii) potential indirect modifiers of cytokine activity, and (iv) possible downstream intracellular second messenger targets.

Objective: The objective of the study is to systematically analyze and summarize research literature regarding health service use and costs of depressive symptoms in late life. Design: Relevant articles were identified by systematically searching the databases MEDLINE, Web of Science, PSYNDEXplus, PsycINFO, and Cochrane Library. Keywords were ‘depression’ or ‘depressive*’, and ‘cost’ or ‘economic burden’ or ‘utilization’ or ‘use’ and ‘old age’ or ‘elderly’. Studies based on representative samples of elderly individuals aged 55 years and older were included. Results: 55 studies were found, 34 studies determined health service utilization, 10 studies reported costs, and 11 studies reported both. Studies of health service utilization and costs showed homogeneously that depressive elderly individuals have an increased service use compared to non-depressive, and a one-third increase of outpatient, inpatient, and total healthcare costs of depressive individuals. The majority of studies reported antidepressant (AD) use between 20 and 45% by depressive individuals. Mean annual costs for AD ranged from 108 to 305 US$ PPP (purchasing power parities). Increased service use and costs are only to a small proportion related to depression treatment. Conclusions: Depressive symptoms in late life lead to a high economic burden for nations which is not explained by costs for depressive symptom treatment. Strategies for improvement of diagnostic validity and treatment success of depressive symptoms in late life may have an effect on economic burden for societies.

Depressive disorders place a large burden on patients and on society. Although efficacious treatment options for unipolar depressive disorders exist, substantial gaps in care remain. In part, the challenge lies in the matching of individual patients with appropriate care. This is complicated by the steady increases in the variety of antidepressants available in the market. The goal of this study is to highlight the decision processes in the selection of antidepressants by clinicians, given that most treatments have similar clinical effectiveness profiles. We conducted a systematic literature review of studies that referred to the decisions surrounding treatment with antidepressants for the treatment of non-psychotic unipolar depression. Our analysis of the literature reveals that the choice of treatment is based on a variety of factors, of which clinical evidence is only one. These factors can be categorized into clinical factors such as illness and treatment characteristics, individual factors such as patient and physician characteristics, and contextual factors such as setting characteristics, decision supports and pharmacoeconomic aspects. Illness characteristics are defined by the type and severity of depression. Treatment characteristics include drug properties, efficacy, effectiveness and favorable as well as unintended adverse effects of the drug. Examples for patient characteristics are co-morbidities and individual preferences, and physician characteristics include knowledge, experience, values and beliefs, and the relationship with the patient. Treatment guidelines, algorithms, and most recently, computational supports and biological markers serve as decision supports.

Identifying biological and clinical markers of treatment response in depression is an area of intense research that holds promise for increasing the efficiency and efficacy of resolving a major depressive episode and preventing future episodes. Collateral benefits include decreased healthcare costs and increased workplace productivity. Despite research advances in many areas, efforts to identify biomarkers have not revealed any consistently validated candidates. Studies of clinical characteristics, genetic, neuroimaging, and various biochemical markers have all shown promise in discrete studies, but these findings have not translated into a personalized medicine approach to treating individual patients in the clinic. We propose that an integrated study of a range of biomarker candidates from across different modalities is required. Furthermore, advanced mathematical modeling and pattern recognition methods are required to detect important biological signatures associated with treatment outcome. Through an informatics-based integration of the various clinical, molecular and imaging parameters that are known to be important in the pathophysiology of depression, it becomes possible to encompass the complexity of contributing factors and phenotypic presentations of depression, and identify the key signatures of treatment response.