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February 28, 2005
Working memory: a new target?
Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction.
Lewis DA, Volk DW, Hashimoto T.
Psychopharmacology (Berl). 2004 Jun;174(1):143-50. Epub 2003 Dec 09.
This article is about research being done to identify other potential targets in the brain for medications for schizophrenia. The authors focus on an aspect of schizophrenia that is often overlooked, but is of paramount importance in understanding the disorder fully. Namely, the loss of working memory and deficit in executive function that is associated with schizophrenia often can be severely limiting when people with schizophrenia are attempting to reintegrate into society. Working memory refers to what is needed to remember and complete a task. Executive function regards the mental processes involved in planning and executing a task. Both of these are often disturbed in schizophrenia. The parts of the brain that are typically considered important for these processes is called the DLPFC or dorsolateral prefrontal cortex. That breaks down to dorsolateral (dorso = back, lateral=side) prefrontal (just behind the frontal lobe) cortex (outer layers of the brain matter). There have been many studies that have demonstrated a decrease in blood flow to the DLPFC in people with schizophrenia, particularly in these types of memory tasks. The neurons thought to be responsible for these changes utilize a neurotransmitter called GABA (gamma aminobutyric acid). This is a neurotransmitter that is utilized by the brain for inhibitory functions and it can control the on/off switch of important cells called pyramidal cells. These cells are vital for the processing of these types of memory. The GABA neurons are themselves turned on or off by receptors that respond to local conditions. To make it even more complicated, there are several parts of the receptor that finesse the neuron to respond in different ways. The subunit that has been shown to be most critical for this process is the GABA-A receptor. Therefore, the authors postulate that action at that part of the receptor may be able to alter how those neurons fire and by doing that may alter the dysfunctional cells that are in the DLPFC that causes the functional impairment in working memory and executive function.
While this paper delves into many complex issues regarding the genetics of the receptors, the proteins that may/may not be involved, I will discuss the possible pharmacological implications that they discuss rather than focusing on the complex basic science.
The chandelier cell (named for its chandelier-like appearance) is a cell that responds to the GABA-A subunit and is responsible for impacting the initial segments of the pyramidal cells. Brain cells, or neurons, work by an electrical impulse that is generated at the beginning of the cell (axon initial segment) and that moves quickly to the end (synapse) where it releases neurotransmitter that impacts and starts the process in the next neuron. Since these chandelier cells work in the important initial segment, they are of particular interest. The authors postulate, and are studying, whether a medication that works at the GABA-A receptor (an agonist or drug that increases activity at the receptor) would be beneficial in working memory and may impact this core schizophrenia symptom. In particular, there is a subunit of the subunit called the alpha-2 subunit that is even more specific for this process and that is what the authors are testing with a new medication. It should be noted that medications called benzodiazepines (like ativan/lorazepam, klonipin/clonazepam or valium/diazepam) work more generally on the GABA system. The medication being proposed would be like a cousin of these but much more specific (hopefully.) The research on such a medication is being done now, and it remains to be seen if it will have the theorized benefit in actuality, but the results should be available in the not too distant future though it might be a much longer time until such a medication is available widely on the market.
February 21, 2005
Genetic blood test for sz?
Assessing the Validity of Blood-Based Gene Expression Profiles for the Classification of Schizophrenia and Bipolar Disorder: A Preliminary Report
Ming T. Tsuang, Nadine Nossova, Tom Yager, Min-Min Tsuang, Shi-Chin Guo, Kou Ge Shyu, Stephen J. Glatt, and C.C. Liew
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 133B:1–5 (2005)
In this paper, the authors are describing a new technique for doing genetic testing. Traditionally, DNA tests are done on tissues, particularly the tissue that shows evidence of the disease being queried. In psychiatric illness however, that is difficult or impossible because one cannot do a brain biopsy without significant risk of harm to the patient. It has been hypothesized that blood may be a “sentinel” marker for disease in the body. That means that if there is a problem somewhere in the body, it may show evidence in the blood in addition to the location where the problem has occurred. Using blood is helpful also because there is a large supply in the body, it is reproduced rapidly so multiple samples are possible, and it is easy and safe to obtain with little pain or risk to the patient. These authors specifically were looking at RNA in the blood to help differentiate between people with bipolar disorder, schizophrenia and the normal population.
This study showed some very exciting and interesting results. While it is limited by a small sample size and a very homogenous population, the possibilities raised by this work are significant. They were able to look at a large number of genes, including many that would not have been thought to have a relation to schizophrenia. They used an “unbiased” approach which utilized a more wide ranging view to look for potential markers. They found that they could differentiate between schizophrenia and bipolar and healthy control with approximately 95% reliability. One of the major markers noted in schizophrenia had to do with genes that are turned on in inflammatory diseases (like rheumatoid arthritis, cystic fibrosis and myocarditis.) This may mean that schizophrenia has an inflammatory component that was not previously considered important to the mechanism.
This study, while interesting and potentially significant, does have several caveats that need to be remembered. It was a small study that looked at 74 patients (30 with schizophrenia, 16 with bipolar disorder and 28 healthy controls.) All of the patients were of Han Chinese descent and were inpatients in Taiwan. It is possible that this population has unique genetic characteristics that were being picked up, though they were compared with people of similar descent and in a similar location in the world. Also, all of the patients were undergoing treatment with antipsychotics. It is possible that the medications were causing some of the changes noted in the blood and that could account for some of the difference between schizophrenia patients and healthy controls. Antipsychotics for example, may have a small pro-inflammatory effect which could cause the inflammatory markers to be positive perhaps. Larger studied, with more diverse population and preferable people who are naïve to antipsychotic medication would be ideal to study and could give a more clear answer to the questions being asked by the authors. However, it is still an important finding and worthy of future research to help identify potential markers in blood to assist in the diagnosis and genetic prediction for schizophrenia and bipolar disorder.
February 19, 2005
Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders.
Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich LA.
Method: This was an Australian population study. They looked at all women with diagnoses of schizophrenia or mood disorder who gave birth in Western Australia during 1980–1992. They looked at records in a psychiatric case register and then randomly selected a comparison sample of 3,129 births to women without a psychiatric diagnosis.
Results: They found that mothers with schizophrenia and mood disorders both had increased risks of pregnancy, birth, and neonatal (newborn) complications. These complications included placental abnormalities, bleeding and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth group and to have children with birth heart defects. Complications in the newborn were more likely to occur in winter months and low birth weight was the highest in the spring. Complications (other than low birth weight and birth defects) were higher in pregnancies that occurred after a psychiatric illness was diagnoses than in pregnancies that occurred before a diagnosis.
Discussion: Overall, this study found that relative to a nonpsychiatric comparison group, women with schizophrenia, bipolar disorder, and depression had more birth complications. Specifically, there were two pregnancy complications that stood out in the women with schizophrenia and the women with bipolar disorder (but not in women with depression). These were placenta abnormalities and bleeding. They also found that there were more birth or congenital malformations (especially heart related) diagnosed either at birth or in the first years of life for women with schizophrenia. There were no significant differences among the groups for neural tube defects, other CNS malformations, or cerebral palsy. Also, they found that while being a single, divorced, or separated mother was common in all three groups, women with schizophrenia were more likely than any other group to experience socioeconomic disadvantage, lack social support and be either younger than 20 years or older than 34 years. Also, low birth weight was the main obstetric complication that occurred only in mothers with schizophrenia in pregnancies both before and after the onset of psychotic illness and showed a seasonal variation. Low birth weight is associated with many risk factors, including maternal nutritional status, smoking, alcohol abuse, maternal physique, birth order and hypertension in pregnancy. These results emphasize the need for preventive prenatal programs that can help expecting mothers and provide education and care especially in vulnerable groups.
This study was limited because they did not have data on the dad’s psychiatric status - which could have also been a significant factor for both genetic and environmental risks. They also didn’t look at medication or illicit drug use during pregnancy. Finally, the comparison sample could have included a number of women with milder disorders who never had a psychiatric inpatient or outpatient admission but shared some of the risk factors with the other groups. Yet, this study offered advantages over other studies, since it was based on an entire population birth group, including all births to women with schizophrenia and mood disorders. They also used a comparison group of randomly selected nonpsychiatric women from the same overall group who was from a specific geographic population unaffected by outmigration. Another advantage of this study is that they prospectively (ahead of time) collected data on pregnancy complications and risk factors in the mother. Overall, this study suggests that risk factors in the mother and biological and behavioral complications due to severe mental illness are the major culprits in increasing reproductive problems. But genetic risk and gene-environment interactions may have also accounted for some outcomes and more research is needed.
Acknowledgements: This study was supported by a Theodore and Vada Stanley Foundation Research Award (319520/31951).
February 08, 2005
Brain chemistry and Prevention
Targeting synapses and myelin in the prevention of schizophrenia.
There are many research efforts that are trying to understand how the brain works and how it develops in order to try to prevent the start of psychotic symptoms in those who might be prone to schizophrenia. There a part of the brain known as the prefrontal cortex (PFC) this is above the forehead, which has been implicated in schizophrenia. This part of the brain is involved in what is known as “executive functioning” which allows us to pay attention and use our working memory (which allows us to hold several facts or thoughts in memory temporarily while solving a problem or performing a task). This article focused on summarizing some of the processes that go on at the brain level and potential ways that they could be manipulated in order to prevent the onset of schizophrenia.
Synapses are gaps between nerve cells in the brain which allow important connections within the brain. Research is suggesting that synaptic connections within the PFC may be disturbed in schizophrenia. Many of the functions of the PFC take a while to develop – usually until late teenage or early adulthood years – times which are considered to be of vulnerability and opportunity. The authors propose that in schizophrenia, during these critical teenage/early adulthood years there may be disruptions in normal developmental processes in the brain known as “synaptic pruning” in the PFC and “axonal myelination” linking various frontal brain parts with memory parts (temporal lobe structures). The authors suggest that such disturbances in normal brain development may then either directly trigger or indirectly contribute to the onset of schizophrenia symptoms. They speculate that it could also be that there maybe functional unmasking of preexisting synaptic deficits by an otherwise normal synaptic pruning process.
One preventive strategy might be to try and change the course of these developmental events in those who are at high risk such as those in the prodromal stages of the illness (prodromal means before the actual onset of psychotic symptoms). The authors go into details on brain chemistry and circuits (especially involving a brain chemicals known as GABA and 5-HT2c) that might be involved and suggest two medication based methods for how synaptic pruning and axonal myelination could potentially be manipulated. They suggest that medications that increase the transmission of GABA such as tiagabine (Gabitril) maybe the key for helping with the synaptic pruning problem. They suggest that m-chlorophenylpiperazine (m-CPP) and Trazodone (a commonly used antidepressant) could help with the axon mylenation problem.
However, so far these are just theories proposed by the authors and much more research and testing in needed to see whether these drugs are able to help in preventive efforts. Regardless, this article highlights the idea that we need to have a much better understanding of what is going on at the smallest of levels in the brain - cellular and molecular – in order to generate hypotheses of new preventive and therapeutic strategies that can perhaps help in prevention efforts.
Acknowledgements: Grant support provided by the Stanley Medical Research Institute and the National Institute of Mental Health.