Current Pharmaceutical Design - Volume 24, Issue 22, 2018

Depression is a mental disorder with serious negative health outcomes. Its main clinical manifestations are depressed mood, slow thinking, loss of interest, and lack of energy. The rising incidence of depression has a major impact on patients and their families and imposes a substantial burden on society. With the rapid development of imaging technology in recent years, researchers have studied depression from different perspectives, including molecular, functional, and structural imaging. Many studies have revealed changes in structure, function, and metabolism in various brain regions in patients with depressive disorder. In this review, we summarize relevant studies of depression, including investigations using structural magnetic resonance imaging (MRI), functional MRI (task-state fMRI and resting-state fMRI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), brain network and molecular imaging (positron emission tomography [PET] and single photon emission computed tomography [SPECT]), which have contributed to our understanding of the etiology, neuropathology, and pathogenesis of depressive disorder.

Major depressive disorder (MDD) has been a prominent topic in recent years due to its unknown etiology and pathology, high prevalence rate, and the high cost of treatment. Due to its high resolution for soft tissue, magnetic resonance imaging (MRI) has become an essential noninvasive tool for the evaluation of the brain substrates underlying mental disorders. MRI enables characterization of brain morphology and function in MDD patients. Compared to healthy controls, MDD patients have structural changes in certain brain regions such as the prefrontal cortex, cingulate cortex, precuneus, thalamus, and hippocampus. Abnormal brain functions as indicated by various MRI measurements including region homogeneity, the amplitude of low-frequency fluctuation, functional connectivity, and mean kurtosis may also contribute to the pathogenesis of MDD. This mini-review summarizes recent MRI findings on the neural manifestations of MDD. We discuss the potential of MRI biomarkers that may prove clinically useful for early diagnosis and evaluation of treatment outcomes for depression.

Depression is a highly prevalent disorder that affects more than 300 million adults worldwide in 2015. Depression also frequently coexists with many other conditions such as osteoporosis and one-third of the Intensive Care Unit (ICU) survivors had depressive symptoms. Antidepressants have become the most commonly prescribed drugs in the United States. In addition to the regular process, drug discovery and development (R) for depression presents extra challenges because of the heterogeneity of the symptoms and various co-occurring disorders. Botanical medicine with multi-functional nature has been proposed to be more effective, providing rapid control of core and comorbid conditions of depression. With the technical advances in analytical instruments, metabolomics is entering into a “new generation”. Next-generation metabolomics (NGM) has the capability to comprehensively characterize drug-induced metabolic changes in the biological systems. NGM has demonstrated great potential in all the stages of pharmaceutical R in the last 10 years. Albiflorin isolated from Peony roots is a promising drug candidate with multi-target for depression and is currently under development by Beijing Wonner Biotech. In this work, we summarized the common analytical platforms for NGM and its main applications in drug R We used albiflorin as an example to illustrate how NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation. Future directions on how to expand the use of NGM for new antidepressant development in pharmaceutical industry were also discussed.

Conventional serotonin-enhancing antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have shown effectiveness in the treatment of major depression, but their significant limitations such as slowness of action have led to intensive research efforts to develop new antidepressants. Increased synaptic neurotransmission of serotonin (5-hdroxytryptamine; 5-HT) through orchestration of stimulation and blockade of various subtypes of 5-HT receptors is involved in the mechanisms of action of SSRIs. Agonists at the 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors and antagonists at the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5- HT6, and 5-HT7 receptors have shown antidepressant properties in clinical and preclinical studies. However, paradoxical antidepressant-like effects of both agonists and antagonists at particular 5-HT receptors suggest the need to consider the neurochemical mechanisms of each 5-HT receptor subtype. Therefore, better knowledge of the involvement of individual 5-HT receptors in the mechanisms of action of currently used antidepressants as well as antidepressant effects of selective ligands of 5- HT receptor subtypes will provide opportunities for the development of future antidepressants with more rapid onset of action, fewer side effects, and better efficacy than SSRIs.

Background: Circadian rhythm disruption underlies the pathophysiology of psychiatric disorders, especially depression. Both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms have been developed with specificity to alter the circadian dysfunction. The current management strategy with antidepressants is far from being satisfactory in addressing this issue. In recent years, attempts at discovering new antidepressants focused on a melatonergic system which is known to be altered in depression have led to a potential option for treatment of depression. Methods: We reviewed all recently published relevant articles on melatonin and its analogues to look for their implication in the treatment of circadian rhythm disruption and depression. Results: Melatonin, a pleiotropic regulator molecule and its analogues (ramelteon, agomelatine, TIK-301, Neu- P11 and tasimelteon) have been observed to resynchronize the circadian rhythm and some were said to alleviate depressive symptoms in depressed subjects. Conclusion: This review focuses on substantial advances in the melatonin-based chronobiologic intervention and its responses in the treatment of depression.

Background: Conventional antidepressants are thought to produce their impact on clinical symptoms by increasing the central availability of biogenic amine neurotransmitters (the monoamine hypothesis of depression). These drugs continue to be the primary medicines used in major depressive disorder. Although they have biological effects after acute dosing, full antidepressant response generally takes weeks of daily administration. Lack of rapid onset is a large limitation in antidepressant therapy (e.g., suicide, lack of medication compliance, difficulty switching medications). Methods: The present review of the literature discusses the preclinical and clinical findings on compounds that can produce immediate symptom relief. Results: These compounds include ketamine, scopolamine, and mechanistically-related drugs. Newer additions to the list of potential rapid-acting agents include antagonists of metabotropic (mGlu) 2/3 receptors, negative allosteric modulators of α5-containing GABAA receptors, and psychedelic compounds. An additional benefit of these compounds is that they have demonstrated large effect sizes and, importantly, demonstrated efficacy in patient's refractory to other treatments. A drawback of some of these compounds, to date, is finding ways to expand the duration of clinical efficacy. In addition, for some compounds, the side-effect profile requires management. A primary mechanism by which rapid effects might be produced is through the amplification of excitatory neurotransmission through activation of AMPA receptors. The extracellular efflux of glutamate induced by these drugs has been documented and provides the hypothesized triggering mechanism for AMPA receptor amplification. Conclusion: The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the current focus of antidepressant drug discovery. Promising clinical findings exist for several compounds including ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin. Two compounds are in late stage clinical development: GLYX-13 (Rapastinel) and eskekamine.

Depression is a common mental disease, and it is one of the most crippling diseases in the world. Although current pharmacotherapies contribute to the treatment of depression, the high incidence of a partial responses or no responses, and delayed onset of the antidepressants, make many patients to experience unsatisfactory results from treatment. In view of the high suicide rate during the period of drug onset, it is critical to find antidepressant drugs with rapid onset for the treatment of depression. This paper mainly reviews some drugs that have rapid antidepressant effect and their mechanisms, including monoaminergic receptor drugs, glutamate receptor drugs, mammalian target of rapamycin (mTOR) signaling agonist, gamma-aminobutyric acid energy (GABAergic) agonist and drug combinations. In addition, we introduce several rodent models currently used to assess antidepressant onset in this review: chronic unpredictable mild stress (CUMS), forced swimming test (FST) and tail suspension test (TST), olfactory bulbectomy (OBX) and other models, which provide a methodological approach for assessing the rapid onset of antidepressant drugs.

Parkinson's disease (PD) is standout amongst the most common neurodegenerative malady with unpredictable dynamic pathology. At present, accessible traditional choices for PD have certain impediments of their own, and subsequently persistent consistence and fulfillment are low. Current contemporary treatment options just give symptomatic alleviation constrained control to anticipate malady progression, bringing about poor patient consistence and fulfilment. Numerous rising pharmacotherapies for PD are in various phases of medical improvement. Treatments incorporate adenosine A2A receptor antagonists, anti-apoptotic agents, monoamine oxidase inhibitors, glutamate receptor antagonists, and antioxidants for example, N-acetyl cysteine, edaravone, and coenzyme Q10. Other rising nonpharmacotherapies incorporate microRNAs, viral vector gene therapy, stem cells transglutaminases, RTP801, and glial derived neurotrophic factor (GDNF). Furthermore, surgeries including profound pallidotomy, deep brain stimulation, thalamotomy and gamma knife surgery have developed as elective mediations for cutting edge PD patients who have totally used common medications and still suffer from unrelenting motor symptoms. Complementary and Alternative medicine (CAM) modalities, such as Yoga, acupuncture, Tai Chi, Music therapies are highly practiced in several countries, offer some of the safer and effective treatment modalities for PD. While a few of these treatments hold much assurance in postponing the beginning of ailment and moderating its progression, more pharmacotherapies and careful mediations should be examined in various phases of PD. Therefore, the main objective of our review is to fill the gap between the researches and provide updated and productive information about the research reported in the last couple of years and can fulfil the most reassuring plausibility for encourage treatment of Parkinson Disease.

Depression is one of the leading causes of disability in the world. Current pharmaceutical treatment for depression remains unsatisfactory due to its limited therapeutic efficacy and undesirable side effects. There is increasing interest in looking for alternative strategies from diet for the treatment of depressive disorder. The nutrition factors have the potential to regulate several neurochemical pathways implicated in depression. This review gives an overview of the recent advances in depression treatment using nutrition factors including vitamins, polyunsaturated fatty acid, elements and natural products. The review covers most recent publications from 2016 to mid-2018. The results of basic experimental and clinical studies were summarized. The risk of deficiency and effect of intervention using nutrition factors for the depression were also discussed. Although the results are controversial in some cases due to the experimental design, the relationship has been observed between deficiency of certain nutrition factors and incidence of depression in the majority of studies. The dietary nutrition supplements may play significant or synergic role in treating or improving depressive disorders.

The incidence of malignant tumors has been increasing year by year worldwide. Psychological problems related to cancer development have also received increasing attention from the public, especially cancerrelated depressive disorders. Depression in cancer patients which reduces patient quality of life, treatment compliance, and seriously affects patients' recovery. This article discussed the significance of psychotherapy for the treatment of cancer-related depression in patients with regard to the epidemiology, etiology, screening and the current methods of psychotherapy for malignancies complicated by depressive disorders. Data Sources: Pubmed, using the keywords "tumor/cancer/depression/ psychotherapy" to search related literature. Data Selection: Studies were selected which had cancer-related depression or psychotherapy for cancerrelated depression as their original subjects. Data Synthesis: Cancer-related emotional disorders include mainly cancer-related depression, anxiety, and sleep disorders. Psychological problems brought about by malignant tumors have become increasingly prominent and its mortality rate has risen significantly. Studies have shown that malignant tumors and depression are actually comorbid. The absence of special screening tools has led to a low rate of diagnosis of cancer-related depression. The current psychotherapy methods for cancer complicated by depressive disorders in China and abroad include cognitive behavioral intervention, social support, adaptive behavior training and antidepressant drug treatment. Psychotherapy can alleviate the negative emotions of cancer patients, reduce the related harm, and improve the quality of life for patients with malignant tumors. Conclusion: Psychotherapy can reduce the psychological burden on patients, and improve their quality of life. More work is still needed to determine whether or not the psychological treatment can extend the overall survival of the cancer patients.

Neuropsychiatric and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, depression and anxiety pose a sizable global health problem, accompanying substantial burden of disorders, suicides, physical comorbidities, high fiscal expenses, and poor quality of life. There is a recent upsurge in global interest toward the area of traditional therapies and phytomedicines are widely admired by researchers owing to their natural source and fewer side effects. On the contrary, conventional synthetic drugs have been reported with undesirable but inevitable ill effects having poor patient compliance. Thus, herbal medicines are being preferred over synthetic drug therapies as an effective remedy for many brain disorders. Ayurveda provides a holistic approach to treatment along with several nootropic herbs having multi-dimensional bioactivities in various disorders. Scattered information is available pertaining to traditional Ayurvedic remedial options for various mental disorders. Present review encompasses: (i) common brain disorders and the associated changes (ii) Ayurvedic holistic approach to manage neurodegenerative and depressive disorders, and (iii) important Ayurvedic single herbs and polyherbal formulations with description of their traditional usage and administration. Concomitantly, it opens up for future investigations and standardization on Ayurvedic nootropic herbs.

There is enough data available now to believe that nature has provided cure of almost every ailment through herbal medicine or management. Therefore, now there is lot of emphasis on identification, evaluation, development and characterization of numerous plants and their active constituents against several diseases including depression. Depression is not only one of the most common ailments but also a highly complex condition to study. Even though several antidepressant drugs are available now, yet their effectiveness and usefulness are highly questionable especially because of their side effects. As herbal remedies are generally associated with favourable safety profiles therefore they have the possible potential to deliver effective replacements to currently available synthetic antidepressants. More recently, efforts have been focused on characterization of pharmacologically active ingredients and to identify the mode of action of herbal antidepressant medicines. This review describes a brief introduction of different animal models for depression and discusses the advantages and disadvantages for each approach. Then we have summarized possible plant phytochemicals as antidepressant drug and their underlying mechanisms. In the main body of the review, we have discussed in detail the most frequently used plants (21) being investigated for the treatment of depression. Additionally, we have provided the list of medicinal plants (92) representing their origin, parts used, extraction method, evaluation method and possible active ingredient. In the final part of the review we have presented the summary of clinical trials on the use of medical plants for depression and their active constituents.

Background The application of an ion selective technique for the determination of analyte concentrations is considered one of the most economical techniques for quality control purposes. Objective To elaborate and investigate the construction and general performance characteristics of potentiometric PVC membrane sensors for venlafaxine cation (Ven+). Method The sensors are based on the use of the ion association complexes of the venlafaxine cation with phosphotungstate (PT) and silicotungstate (ST) counter anions as ion exchange sites in the plasticized PVC matrix. They are characterized by potentiometric and conductimetric measurements, performed under various conditions. Results The electrodes showed a fast (response time around 15 s), stable (life span 45 days) and linear (r2 0.995) response for venlafaxine over the concentration range of 5x10-5 - 1x10-2 M venlafaxine hydrochloride. The solubility product of the ion pair and the formation of the precipitation reaction leading to the ion pair, were determined conductimetrically. The electrodes were found to be very selective, precise (RSD < 1%) and applicable to the potentiometric determination of venlafaxine hydrochloride in pure solutions or in pharmaceutical preparation and in biological fluid (serum), without any interference. Validation of the method shows the suitability of the proposed electrodes for use in the quality assessment of venlafaxine hydrochloride. Conclusion Using only a pH meter in combination with the selective electrodes, drug substance or drug product could be determined accurately in a few seconds. In addition, the in-house made electrodes were tested to monitor venlafaxine in serum. Acceptable results were achieved using the standard addition technique.