December 15, 2010

Commentary by Nicholas J. Brandon

Abazyan B, Nomura J, Kannan G, et al (2010). Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 68:1172-1181 

The interaction of a prenatal environmental stressor, polyinosinic:polycytidylic acid (poly I:C) with hDISC1 truncation resulted in increased "affective symptoms" in male transgenic mice. Mice exposed to the combination of environmental and genetic stressors showed increased anxiety and depression-like symptoms as well as altered social behavior, compared with mice exposed to either stressor alone. These findings have potential implications for "two-hit" theories of psychiatric illness.

Commentary by Lawrence Scahill and George M. Anderson

Bedi G, Hyman D, de Wit H (2010). Is ecstasy an "empathogen"? Effects of ±3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biol Psychiatry 68:1134-1140 

Exposure to 3,4-Methylenedioxymethamphetamine (MDMA), particularly at higher doses was associated with reports of increased "loving" and "friendly" feelings but decreased recognition of fearful facial expressions. Contrary to the authors' expectations, methamphetamine exposure was associated with subject's feeling "sociable" and "playful." The combination of positive effects on the emotional component of empathy with decrements in performance on cognitive aspects raises questions as to the utility of MDMA for the treatment of disorders characterized by poor social relatedness, such as autism.  

January 1, 2011

Commentary by Francesco Papaleo and Daniel R. Weinberger

Karlsgodt K, Robleto K, Trantham-Davidson H, et al (2010). Reduced dysbindin expression mediates N-Methyl-D-Aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry 69(1):28-34 

The authors examined N-methyl-d-aspartate (NMDA) function and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor function in prefrontal cortical pyramidal neurons in conjunction with spatial working memory in dysbindin mutant ("sandy") mice. Dysbindin is encoded by dystrobrevin-binding protein one gene (DTNBP1), a candidate gene for schizophrenia, and plays a role in both glutamate and dopamine signaling. The prefrontal pyramidal neurons from affected mice showed decreased expression of the NMDA receptor complex NR1 and decreased NMDA-evoked currents; the former correlated with working memory performance. While genetic background and environmental factors no doubt play a role in moderating the effects of dysbindin mutations, these findings further support the role of dysbindin in modulating aspects of neuronal signaling implicated in psychosis.

Commentary by Robert W. Buchanan and Robert Schwarcz

Tregellas JR, Tanabe J, Rojas DC, et al (2010). Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 69:7-11 

Castner SA, Smagin GN, Piser TM, et al (2010). Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors. Biol Psychiatry 69(1):12-18 

Two papers in this issue separately examine the effects of two partial agonists at the α7 nicotinic acetylcholine receptor in preclinical and clinical populations. Nicotinic agonists have shown only limited success in treating cognitive impairments in patients with schizophrenia despite a wealth of promising animal data. Castner and colleagues report their findings that in rhesus macaques cognitive improvement is observed only at AZD0328 doses significantly lower than those found to be cognitively enhancing in rodents- and that in a subset of the macaques, improvement in working memory performance was evident for a month or more after administration. In schizophrenic patients, Tregellas and colleagues found that administration of 3-(2,4-dimethoxybenzylidene)-anabaseine (DXMB-A) altered default network activity. The change in activity was moderated by the genotype of a subunit gene of the α7 nicotinic acetylcholine receptor previously associated with schizophrenia. Taken together, and in the context of previous findings, these studies suggest the potential clinical utility of nicotinic agonists while emphasizing the importance of dosing considerations in evaluating the effects of nicotinic agonists on clinical function.

January 15, 2011

Commentary by Paul J. Harrison 

The commentator reviews both the importance and potential impediments to research using post-mortem brains. The size of post-mortem studies has grown over the last two decades, and quality controls have significantly improved. Post-mortem studies now employ a wide range of research techniques that may serve to advance the field of biological psychiatry.

Februrary 1, 2011

Commentary by Bruce E. Wexler

Bickel WK, Yi R, Landes RD, et al (2011). Remember the future: working memory training decreases delay discounting among stimulant addicts. Biol Psychiatry 69(3):260-265 

Increased delay discounting has been noted in a variety of psychiatric conditions including substance use disorders. The authors discuss the observed association between high rates of discounting and poor working memory, and propose that increasing working memory might improve delay discounting. Stimulant-addicted subjects in treatment showed improved delayed discounting when trained on tasks of executive function while a control group who received the same rewards showed decreased delay discounting. While it is not entirely clear that the changes were driven by training on the cognitive tasks, these findings have potential implications across a range of psychiatric disorders.

Commentary by Stephen Rayport

Okvist A, Fagergren P, Whittard J, et al (2011). Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry 69(3):245-252 

Preclinical studies have suggested that glutamatergic plasticity in the forebrain is involved in aspects of drug seeking and taking  behaviors, but there has been little equivalent data in human subjects. The authors examined amygdalae of deceased drug users and found relationships between a post-synaptic scaffolding  protein and GluA1 glutamate receptors, and between other molecules involved in GluR trafficking to the post-synaptic membrane. These findings support suggestions that the strengthening of glutamatergic synaptic transmission in the amygdala represents a shared mechanism in drug addiction.

Februrary 15, 2011

Commentary by Joel E. Kleinman

Choi KH, Higgs BW, Wendland JR, et al (2011). Gene expression and genetic variation data implicate PCLO in bipolar disorder. Biol Psychiatry 69(4):353-359 

The authors identified 367 genes (400 transcripts) that were differentially expressed in post-mortem prefrontal brain tissue taken from bipolar patients versus controls. They found 45 cis SNP pairs with an association between gene expression and SNP genotype. One, an intro in the PCLO gene was associated with bipolar disorder. This study demonstrates the potential utility of combining genome-wide association studies (GWAS) and post-mortem data.

Commentary by Emra Bora and Christos Pantelis

Hallahan B, Newell J, Soares JC, et al (2011). Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 69(4): 326-335 

Benedetti F, Yeh PH, Bellani M, et al (2011). Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. Biol Psychiatry 69(4): 309-317 

Two papers examine different aspects of structural imaging in bipolar disorder. In the first, Hallahan and colleagues report on the findings of a mega-analysis combining structural imaging results from a large number of bipolar and healthy subjects. They find areas of difference, as well as noting effects of lithium and illness duration on brain morphometry. In the second, Benedetti and colleagues utilized diffusion tensor imaging (DTI) tract-based spatial statistics to compare  fractional anisotropy (FA), and mean and redial diffusivity between depressed bipolar and healthy subjects on a voxel-wise basis. They report evidence of white matter pathology in the bipolar patients. Together the studies highlight the growing evidence of neuroanatomic abnormalities in bipolar disorder but also show that many of the findings do not mirror those seen in schizophrenia.

March 1, 2011

Commentary by David L. Braff

Popov T, Jordanov T, Rockstroh B, et al (2011). Specific cognitive training normalizes auditory sensory gating in schizophrenia: a randomized trial. Biol Psychiatry 69(5): 465-471

Roussos P, Giakoumaki SG, Adamaki E, et al (2011). The influence of schizophrenia-related neuregulin-1 polymorphisms on sensorimotor gating in healthy males. Biol Psychiatry 69(5): 479-486 

Roussos and colleagues present data showing a correlation between neuregulin-1 (NRG1) SNPs and reduced pre-pulse inhibition (PPI) in a large group of healthy men. NRG1 has previously been hypothesized to be involved in the symptomatology of schizophrenia. In a separate study, Popov and colleagues report that both performance in specific cognitive areas, and deficits in PPI improved in schizophrenic patients who participated in an auditory-focused cognitive exercise program.

Commentary by David A. Lewis

Buchanan RW, Keefe RS, Lieberman JA, et al (2011). A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry 69(5): 442-449 

The authors test the effects of MK-0777, a (GABA)a partial agonist on cognition in a  group of schizophrenic patients. MK-0777 was previously found in a pilot study to improve selected measures of prefrontal cortical function. The intervention was not found to be effective in this larger, follow-up study, failing to improve cognitive performance in the treated group. Potential explanations for the lack of findings and future directions are discussed.