Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles.

There is still a lack in the molecular comprehension of major depressive disorder (MDD) although this condition affects approximately 10% of the world population. Protein phosphorylation is a posttranslational modification that regulates approximately one-third of the human proteins involved in a range of cellular and biological processes such as cellular signaling. Whereas phosphoproteome studies have been carried out extensively in cancer research, few such investigations have been carried out in studies of psychiatric disorders. Here, we present a comparative phosphoproteome analysis of postmortem dorsolateral prefrontal cortex tissues from 24 MDD patients and 12 control donors. Tissue extracts were analyzed using liquid chromatography mass spectrometry in a data-independent manner (LC-MSE). Our analyses resulted in the identification of 5,195 phosphopeptides, corresponding to 802 non-redundant proteins. Ninety of these proteins showed differential levels of phosphorylation in tissues from MDD subjects compared to controls, being 20 differentially phosphorylated in at least 2 peptides. The majority of these phosphorylated proteins were associated with synaptic transmission and cellular architecture not only pointing out potential biomarker candidates but mainly shedding light to the comprehension of MDD pathobiology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00406-012-0301-3) contains supplementary material, which is available to authorized users.

Concomitant consumption of caffeine with recreational psychostimulant drugs of abuse can provoke severe acute adverse reactions in addition to longer term consequences. The mechanisms by which caffeine increases the toxicity of psychostimulants include changes in body temperature regulation, cardiotoxicity and lowering of the seizure threshold. Caffeine also influences the stimulatory, discriminative and reinforcing effects of psychostimulant drugs. In this review, we consider our current understanding of such caffeine-related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), which has been most recently described and characterized. Co-administration of caffeine profoundly enhances the acute toxicity of MDMA in rats, as manifested by high core body temperature, tachycardia and increased mortality. In addition, co-administration of caffeine enhances the long-term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug-induced toxicity comprising MDMA-related enhancement of dopamine release coupled to a caffeine-mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine-related drug interactions with cocaine, d-amphetamine and ephedrine where similar mechanisms are implicated. Understanding the underlying mechanisms will guide appropriate intervention strategies for the management of severe reactions and potential for increased drug-related toxicity, resulting from concomitant caffeine consumption. AbbreviationsBAT, brown adipose tissue; BP, blood pressure; CPP, conditioned place preference; CREB, cAMP response element binding protein; CVS, cardiovascular system; CYP, cytochrome P450 enzyme; DARPP-32, cAMP-regulated phosphoprotein of 32 kDa; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; MDA, methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; PDE, phosphodiesterase; UCP, uncoupling protein IntroductionIn recreational drug use settings, caffeine is found in a range of commercially available products such as energy drinks that may be consumed with other drugs (Reissig et al., 2009). In addition, forensic analyses of seized illicit drug samples have reported quantities of caffeine mixed with other stimulants, including cocaine and amphetamines (Cole et al., 2011). BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 946 British Journal of Pharmacology (2012) Such combinations may influence the toxicity of these stimulants and, consequently, investigations regarding the potential for adverse interactive effects are warranted. Interactive effects have led to concern that caffeine could have a role to play in the acute, often idiosyncratic, and long-term adverse consequences associated with the consumption of a range of psychostimulant drugs, including some agents in clinical use. Risks associated with caffeine use in recreatio...

Background and purpose: Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction. Experimental approach: Adult male Sprague-Dawley rats were treated with caffeine (10 mg·kg ) exacerbated MDMA-induced hyperthermia. Conclusions and implications:A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A2A receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Future studies on the molecules identified here may lead to new insights into schizophrenia pathophysiology and pave the way for translation of novel diagnostics for use in a clinical setting.