Current Neuropharmacology (v.13, #4)

Meet Our Editorial Board Member by K. Suk (419-419).

Brain Structural Effects of Antipsychotic Treatment in Schizophrenia: A Systematic Review by Roberto Roiz-Santiañez, Paula Suarez-Pinilla, Benedicto Crespo-Facorro (422-434).
The findings about the progressive brain changes in schizophrenia are controversial, and the potential confounding effect of antipsychotics on brain structure is still under debate. The goal of the current article was to review the existing longitudinal neuroimaging studies addressing the impact of antipsychotic drug treatment on brain changes in schizophrenia. A comprehensive search of PubMed was performed using combinations of key terms distributed into four blocks: “MRI”, “longitudinal”, “schizophrenia” and “antipsychotic”. Studies were considered to be eligible for the review if they were original articles. Studies that examined only changes in brain density were excluded. A total of 41 MRI studies were identified and reviewed. Longitudinal MRI studies did not provide a consistent notion of the effects of antipsychotic treatment on the pattern of brain changes over time in schizophrenia. Overall, most of the included articles did not find a linear relationship between the degree of exposure and progressive brain changes. Further short- and longterm studies are warranted to a better understanding of the influence of antipsychotics in brain structural changes in schizophrenia and also to verify whether first and second generation antipsychotics may differentially affect brain morphometry.

Psychopharmacological treatments for schizophrenia have always been a matter of debate and a very important issue in public health given the chronic, relapsing and disabling nature of the disorder. A thorough understanding of the pros and cons of currently available pharmacological treatments for schizophrenia is critical to better capture the features of treatment-refractory clinical pictures and plan the developing of new treatment strategies. This review focuses on brain functional changes induced by antipsychotic drugs as assessed by modern functional neuroimaging techniques (i.e. fMRI, PET, SPECT, MRI spectroscopy). The most important papers on this topic are reviewed in order to draw an ideal map of the main functional changes occurring in the brain during antipsychotic treatment. This supports the hypothesis that a network-based perspective and a functional connectivity approach are needed to fill the currently existing gap of knowledge in the field of psychotropic drugs and their mechanisms of action beyond neurotransmitter systems.

Bipolar disorder is associated with subtle neuroanatomical deficits including lateral ventricular enlargement, grey matter deficits incorporating limbic system structures, and distributed white matter pathophysiology. Substantial heterogeneity has been identified by structural neuroimaging studies to date and differential psychotropic medication use is potentially a substantial contributor to this. This selective review of structural neuroimaging and diffusion tensor imaging studies considers evidence that lithium, mood stabilisers, antipsychotic medication and antidepressant medications are associated with neuroanatomical variation. Most studies are negative and suffer from methodological weaknesses in terms of directly assessing medication effects on neuroanatomy, since they commonly comprise posthoc assessments of medication associations with neuroimaging metrics in small heterogenous patient groups. However the studies which report positive findings tend to form a relatively consistent picture whereby lithium and antiepileptic mood stabiliser use is associated with increased regional grey matter volume, especially in limbic structures. These findings are further supported by the more methodologically robust studies which include large numbers of patients or repeated intra-individual scanning in longitudinal designs. Some similar findings of an apparently ameliorative effect of lithium on white matter microstructure are also emerging. There is less support for an effect of antipsychotic or antidepressant medication on brain structure in bipolar disorder, but these studies are further limited by methodological difficulties. In general the literature to date supports a normalising effect of lithium and mood stabilisers on brain structure in bipolar disorder, which is consistent with the neuroprotective characteristics of these medications identified by preclinical studies.

Brain Structural Effects of Antidepressant Treatment in Major Depression by Nicola Dusi, Stefano Barlati, Antonio Vita, Paolo Brambilla (458-465).
Depressive disorder is a very frequent and heterogeneous syndrome. Structural imaging techniques offer a useful tool in the comprehension of neurobiological alterations that concern depressive disorder. Altered brain structures in depressive disorder have been particularly located in the prefrontal cortex (medial prefrontal cortex and orbitofrontal cortex, OFC) and medial temporal cortex areas (hippocampus). These brain areas belong to a structural and functional network related to cognitive and emotional processes putatively implicated in depressive symptoms. These volumetric alterations may also represent biological predictors of response to pharmacological treatment. In this context, major findings of magnetic resonance (MR) imaging, in relation to treatment response in depressive disorder, will here be presented and discussed.

In the last two decades, neuroimaging research has reached a much deeper understanding of the neurobiological underpinnings of major depression (MD) and has converged on functional alterations in limbic and prefrontal neural networks, which are mainly linked to altered emotional processing observed in MD patients. To date, a considerable number of studies have sought to investigate how these neural networks change with pharmacological antidepressant treatment. In the current review, we therefore discuss results from a) pharmacological functional magnetic resonance imaging (fMRI) studies investigating the effects of selective serotonin or noradrenalin reuptake inhibitors on neural activation patterns in relation to emotional processing in healthy individuals, b) treatment studies in patients with unipolar depression assessing changes in neural activation patterns before and after antidepressant pharmacotherapy, and c) predictive neural biomarkers of clinical response in depression. Comparing results from pharmacological fMRI studies in healthy individuals and treatment studies in depressed patients nicely showed parallel findings, mainly for a reduction of limbic activation in response to negative stimuli. A thorough investigation of the empirical findings highlights the importance of the specific paradigm employed in every study which may account for some of the discrepant findings reported in treatment studies in depressed patients.

Herbal Medicine for Anxiety, Depression and Insomnia by Lei Liu, Changhong Liu, Yicun Wang, Pu Wang, Yuxin Li, Bingjin Li (481-493).
The prevalence and comorbidity of psychiatric disorders such as depression, anxiety and insomnia are very common. These well-known forms of psychiatric disorders have been affecting many people from all around the world. Herb alone, as well as herbal formula, is commonly prescribed for the therapies of mental illnesses. Since various adverse events of western medication exist, the number of people who use herbs to benefit their health is increasing. Over the past decades, the exploration in the area of herbal psychopharmacology has received much attention. Literatures showed a variety of herbal mechanisms of action used for the therapy of depression, anxiety and insomnia, involving reuptake of monoamines, affecting neuroreceptor binding and channel transporter activity, modulating neuronal communication or hypothalamic-pituitary adrenal axis (HPA) etc. Nonetheless, a systematic review on herbal pharmacology in depression, anxiety and insomnia is still lacking. This review has been performed to further identify modes of action of different herbal medicine, and thus provides useful information for the application of herbal medicine.

The Effects of Psychological Stress on Depression by Longfei Yang, Yinghao Zhao, Yicun Wang, Lei Liu, Xingyi Zhang, Bingjin Li, Ranji Cui (494-504).
Major depressive disorder is a serious mental disorder that profoundly affects an individual's quality of life. Although the aetiologies underlying this disorder remain unclear, an increasing attention has been focused on the influence imposed by psychological stress over depression. Despite limited animal models of psychological stress, significant progress has been made as to be explicated in this review to elucidate the physiopathology underlying depression and to treat depressive symptoms. Therefore, we will review classical models along with new methods that will enrich our knowledge of this disorder.

Zinc in the Glutamatergic Theory of Depression by Katarzyna Mlyniec (505-513).
Depression is a serious psychiatric illness that affects millions of people worldwide. Weeks of antidepressant therapy are required to relieve depressive symptoms, and new drugs are still being extensively researched. The latest studies have shown that in depression, there is an imbalance between the main excitatory (glutamatergic) and inhibitory (GABAergic) systems. Administration of antagonists of the glutamatergic system, including zinc, has shown an antidepressant effect in preclinical as well as clinical studies. Zinc inhibits the NMDA receptor via its binding site located on one of its subunits. This is thought to be the main mechanism explaining the antidepressant properties of zinc. In the present review, a link between zinc and the glutamatergic system is discussed in the context of depressive disorder.

Research on the Pathological Mechanism and Drug Treatment Mechanism of Depression by Guo-jiang Peng, Jun-sheng Tian, Xiao-xia Gao, Yu-zhi Zhou, Xue-mei Qin (514-523).
Depression is one of the prevalent and persistent psychiatric illnesses. It brings heavy socioeconomic burden such as healthcare expenditures and even higher suicide rates. Despite many hypotheses about its mechanism have been put forward, so far it is still unclear, not to mention the precise and effective diagnostic or therapeutic methods. In this paper, the current conditions of pathological and pharmacological mechanism of depression were reviewed systematically. Firstly, the most recent hypotheses and metabolomics based research including hereditary, neurotransmitter systems, brain derived neurotrophic factor (BDNF), hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and inflammatory as well as metabolomics were summarized. Secondly, the present situation and development on antidepressant drugs at home and abroad were reviewed. Finally, a conclusion and prospect on the pathological and pharmacological mechanism of depression were provided primarily.

The Antidepressant-like Effects of Estrogen-mediated Ghrelin by Pu Wang, Changhong Liu, Lei Liu, Xingyi Zhang, Bingzhong Ren, Bingjin Li (524-535).
Ghrelin, one of the brain-gut peptides, stimulates food-intake. Recently, ghrelin has also shown to play an important role in depression treatment. However, the mechanism of ghrelin's antidepressant-like actions is unknown. On the other hand, sex differences in depression, and the fluctuation of estrogens secretion have been proved to play a key role in depression. It has been reported that women have higher level of ghrelin expression, and ghrelin can stimulate estrogen secretion while estrogen acts as a positive feedback mechanism to up-regulate ghrelin level. Ghrelin may be a potential regulator of reproductive function, and estrogen may have additional effect in ghrelin's antidepressantlike actions. In this review, we summarize antidepressant-like effects of ghrelin and estrogen in basic and clinical studies, and provide new insight on ghrelin's effect in depression.

The Effects of Calorie Restriction in Depression and Potential Mechanisms by Yifan Zhang, Changhong Liu, Yinghao Zhao, Xingyi Zhang, Bingjin Li, Ranji Cui (536-542).
Depression, also called major depressive disorder, is a neuropsychiatric disorder jeopardizing an increasing number of the population worldwide. To date, a large number of studies have devoted great attention to this problematic condition and raised several hypotheses of depression. Based on these theories, many antidepressant drugs were developed for the treatment of depression. Yet, the depressed patients are often refractory to the antidepressant therapies. Recently, increasing experimental evidences demonstrated the effects of calorie restriction in neuroendocrine system and in depression. Both basic and clinical investigations indicated that short-term calorie restriction might induce an antidepressant efficacy in depression, providing a novel avenue for treatment. Molecular basis underlying the antidepressant actions of calorie restriction might involve multiple physiological processes, primarily including orexin signaling activation, increased CREB phosphorylation and neurotrophic effects, release of endorphin and ketone production. However, the effects of chronic calorie restriction were quite controversial, in the cases that it often resulted in the long-term detrimental effects via inhibiting the function of 5-HT system and decreasing leptin levels. Here we review such dual effects of calorie restriction in depression and potential molecular basis behind these effects, especially focusing on antidepressant effects.

The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression by Yi-Qun Wang, Rui Li, Meng-Qi Zhang, Ze Zhang, Wei-Min Qu, Zhi-Li Huang (543-553).
Most depressed patients suffer from sleep abnormalities, which are one of the critical symptoms of depression. They are robust risk factors for the initiation and development of depression. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. REM sleep alterations include a decrease in REM sleep latency, an increase in REM sleep duration and REM sleep density with respect to depressive episodes. Emotional brain processing dependent on the normal sleep-wake regulation seems to be failed in depression, which also promotes the development of clinical depression. Also, REM sleep alterations have been considered as biomarkers of depression. The disturbances of norepinephrine and serotonin systems may contribute to REM sleep abnormalities in depression. Lastly, this review also discusses the effects of different antidepressants on REM sleep disturbances in depression.

Erratum: (554-554).