- Schizophrenia News Blog: Schizophrenia Research Blog

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.

Click here for the article on PubMed

Posted by Jacob at 11:09 PM | Comments (1)

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.

Click here for the article on PubMed

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February 19, 2005

Pregnacy risks

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.
Am J Psychiatry. 2005 Jan;162(1):79-91.

Introduction: Some studies have suggested that women with schizophrenia may be at a higher risk for more pregnancy problems. But, it is unclear whether these bad outcomes are specifically related to schizophrenia or some other nonspecific reasons due to being pregnant and having a severe mental illness. This study wanted to look at the frequency, nature and severity of obstetric (pregnancy related) complications in women with schizophrenia and then compare them to women with mood disorders (e.g. depression, bipolar disorder) and women without a diagnosed psychiatric disorder. They also wanted to look at the timeline between pregnancies and the start of the mother’s psychiatric illness as well as other pregnancy outcomes in relation to risk factors in the mother.

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).

Click here to find this article on PubMed

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February 08, 2005

Brain chemistry and Prevention

Targeting synapses and myelin in the prevention of schizophrenia.
Woo TU, Crowell AL.
Schizophr Res. 2005 Mar 1;73(2-3):193-207.

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.

Click here to find this article on PubMed

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January 25, 2005

Informed Consent in Schizophrenia

Wirshing DA, Sergi MJ, Mintz J.
A videotape intervention to enhance the informed consent process for medical and psychiatric treatment research.
Am J Psychiatry. 2005 Jan;162(1):186-8.

Wirshing DA, Wirshing WC, Marder SR, Liberman RP, Mintz J.
Informed consent: assessment of comprehension.
Am J Psychiatry. 1998 Nov;155(11):1508-11.

The topic of informed consent can be difficult when conducting research, particularly when mental illness is involved. The process often involves explaining complex and technical procedures to an audience who otherwise would not have knowledge of such. A skilled clinician must know how to address concerns and explain difficult concepts in language appropriate to the patient/subject. Legal requirements often add more risks than might otherwise be discussed and so it can be difficult to convey the seriousness of such risks. True informed consent is a legal definition that is usually considered to have occurred if the patient is able to have the ability to express a choice, understand the risks/benefits/alternatives to proposed treatment, appreciate the significance of the choice have or forego treatment, and to come to their decision in a rational manner.

Psychiatric patients often are considered to have difficulties in the latter part of the consent process. There are some who maintain that those with delusions or hallucinations are unable to come to rational decisions. Those who work more closely with patients who have those symptoms may disagree, but nevertheless the bias is often present. While psychiatry patients are often considered to have extra difficulties in understanding consents, it is the case that patients from a broad spectrum of disease have similar problems in understanding the complexities of modern medicine. In one survey, it was found that 60% of cancer patients could not describe even one benefit or risk as little as one day after signing a consent form for chemotherapy.

In article 1, the authors describe an experimental videotape that they made to assist in teaching patients prior to going through an informed consent process. It included explanations regarding their rights and carefully explained the process of obtaining an informed consent. Additionally, it gave examples of how patients can be active participants in the consent process, and ways that they can take the information they’ve been given to make a good decision for them. They compared patients with schizophrenia to patients with other medical disorders and to healthy university students. Patients were randomly assigned either to watch the experimental videotape or to watch a similar tape that was written with an identical tone but was an historical piece about human subject research.

The groups started with different levels of pretest knowledge. The VA medical patients scored the highest on the pretest and the schizophrenia patients the lowest. However, all groups showed a significant learning when given the experimental tape versus the historical tape. The university students had the highest gains on the post-test, but all groups showed some benefit. Schizophrenia patients who demonstrated problems with conceptual organization type of thinking tended to score the worst on the pre/post test. However, other symptoms such as hallucinations or delusions did not have any correlation with their ability on the pre or post test. It should be noted though, that the most psychotic people were generally screened out from participating in this research as they would be unlikely research candidates for other studies. However, the population studied is generally the population that will enroll in a long term study and therefore this tape may have some utility with that group of individuals.

Article 2 describes research in which they determined whether patients with schizophrenia had the ability to understand the concepts involved in informed consent. They looked at patients who were being enrolled in other studies at the VA as they were going through the consent process. Patients were given a quiz in which the main concepts of informed consent were tested. If they did not answer all questions correctly the first time, they took the quiz again until they got all the answers correct. Only after answering the questions correctly could they sign the informed consent. One week later the test was readministered and again they had to answer all questions correctly in order to participate in research. It was seen that 37% of the subjects needed 3 or more trials to pass the test completely. Again, it was conceptual disorganization, more than hallucinations or delusions, that correlated with ability to perform on the test.

Overall, these studies demonstrate that the ability to perform thorough informed consenting is challengign for physician and patient alike. There is evidence that particular symptoms, namely conceptual disorganization, make consent more difficult for schizophrenia patients than healthy people. However, symptoms such as hallucinations or delusions do not seem to impact strongly a patient's ability to understand risks and benefits and to make rational decisions regarding their treatment, particuarly if given adequate support during the consenting process.

Click here for article 1 on pubmed
Click here for article 2 on pubmed

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January 23, 2005

Risks in "at-risk" research

Prodromal interventions for schizophrenia vulnerability: the risks of being "at risk".

Corcoran C, Malaspina D, Hercher L.
Schizophr Res. 2005 Mar 1; 73(2-3):173-84.

Researchers have been trying to identify and treat teenagers and young adults who may be clinically at risk or “prodromal” for showing psychotic symptoms. This “prodromal” research (prodromal means early symptoms and signs of an illness that precede the beginning of the acute, fully developed illness) is trying to help avoid the damage that can occur once the illness begins especially since the longer the duration of untreated psychosis the worse the long term prognosis. But, this type of prodromal research has many controversies, ethical concerns and risks associated with it which are summarized in this article a leading schizophrenia researcher as follows:

Defining “at-risk”: Corcoran and colleagues point out that it is more complicated to identify those who are “at risk” for an illness than those who already show symptoms. While there are many studies that have been done to identify “at risk” factors, current standards for identifying those who are “At-Risk Mental State Prodromal” were developed in 1996 by a group of Australian researchers (Yung, McGorry and colleagues) and are seen in individuals fitting into one of three categories:
(1) attenuated positive symptoms (e.g. disturbances in perception and thought, suspiciousness)
(2) brief intermittent psychotic symptoms
(3) a steep decline in functioning plus a family history of schizophrenia.

The three groups together are estimated to have about a 40% likelihood of developing psychosis by 12 months and a 50% likelihood of developing psychosis within the next 24 months. But the authors of this paper point out that it is important to keep in mind that not all measures of vulnerability are the same. A baby of two parents with schizophrenia has a 50% chance of developing the disease, which is the same statistical risk as a 17-year-old boy who is currently experiencing attenuated psychotic symptoms. But, the teenager is immediately at risk while the baby is not. This raises the ethical question of how useful is a preventive intervention that interrupts a time that could have been one of relative health and normalcy as compared to an intervention that actually addresses the immediate threat of a disease.

False Positives: In prodromal studies there is also a risk of false positives, i.e. many people who are identified to be “at-risk” do not go on to experience psychosis, at least not within the 2-year time frame that has been studied so far. This raises the risk of over-treatment for those who are unfortunate to fall in this false positive group. In any case, the use of antipsychotic medication for those who have not developed psychotic symptoms is controversial and the research is inconclusive about whether it is effective and safe. Some studies have suggested that newer medications like Risperdal and Zyprexa can be effective prodromally, although side effects have been prominent in these studies. Yet, it appears that antipsychotic medications are already being prescribed prodromally in the community and so the authors argue that there is a need for many more controlled studies to measure the effectiveness of such prescribing practices on preventing the onset of psychosis.

Stigma: There is also the risk that prodromal research subjects may experience stigma due to being “labeled” at risk for psychosis which can impact their sense of self, relationships with friends and family and possibly their choices in terms of education, employment, or other life plans. It could also impact the extent to which such plans and aspirations are supported by other family members. Interviews with parents of patients at prodromal clinics have shown that their concerns about stigma are strongly dependent on the behavior and symptoms of the patient prior to interaction with the clinic.

However, the authors point out that the stakes change if patients are younger or less symptomatic. In such a group that is not immediately at risk or impaired, the idea of being vulnerable for psychosis could leave false positive individuals with a lasting sense of being fragile or damaged. In some families this knowledge of risk could be productive, allowing them to protect the at risk person from stress and help redefine behavioral problems as due to the illness rather than character flaws. But in other families, the protective impulse might mean that the family stops encouraging growth and progress in the person identified as being “at-risk”. As a result, the authors suggest that it is important for family education be a part of prodromal research programs, especially since sometimes people forget that there is difference between being “at risk” and already having an illness.

Confidentiality: Confidentiality is an important tool for protecting the at-risk population from insurance discrimination and other forms of stigma. There are new laws involving the Health Insurance Portability and Accountability Act of 1996 and a Certificate of Confidentiality, issued by the Department of Health and Human Services, which protect privacy but yet they have no jurisdiction over what research subjects themselves disclose. The authors point out that it is important to evaluate what information is available to third parties, either directly or by implication. Relevant third parties can be insurance companies, as well as employers, schools, religious organizations and other community groups. It is not safe to assume that all people or institutions will appreciate the difference between a risk assessment and a diagnosis. As such, public education becomes important especially since these same issues have been debated in medicine for studies of insulin treatment for children at risk of Type 1 diabetes, women with a family history of breast cancer who pursue genetic testing and in pre-symptomatic testing for Huntington’s disease.

Autonomy or Self-rule: The right to make your own decisions or autonomy involves going through the informed consent process in research. The authors point out that in the prodromal period, patients are on the edge of competence – with respect to their age and mental status. Intervention at such an early stage suggests that these patients will be helped in terms of their future symptoms, but since they’re younger they would be less able to participate in the decision-making process. The authors suggest that there is no easy formula for balancing the obligation of families and doctors to protect vulnerable individuals while giving them some latitude for self-determination. But, there is a burden on the researcher or clinician to provide a high standard of informed consent since there are many who stand to gain from research in schizophrenia: families, particularly in light of familial predisposition; pharmaceutical companies with treatments to market; society at large in what can be learned about the disease. Nonetheless, the authors make it clear that these benefits cannot be earned at the expense of a vulnerable population.

Risks for true positives: Early intervention may pose some hazards for true positives as well, i.e. those who are in fact truly at risk (vs. false positives). The extent to which a treatment is a risk for true positives is directly related to two variables: current quality of life and the length of the interval between intervention and the onset of disease. But as much as early intervention looks promising, there are no guarantees that medical care is going to change the outcome for schizophrenia. Families are faced with many important questions prior to enrolling in prodromal interventions. Given that in some instances a bad result may be inevitable, and that the problem is perhaps years down the road, would a family prefer to have prior knowledge of the event? Or would they prefer to have the intervening years of relative normalcy? The authors point out that there has been limited interest in pre-symptomatic genetic testing for Huntington’s’ disease and breast cancer genetic research. This suggests that people put a high value on preserving their ability to be hopeful. While concern with insurance discrimination may have resulted in the avoidance of testing for these diseases, it also seems that when push came to shove, many people simply did not want to know their genetic risk status for these diseases. It is yet to be determined what lies ahead for schizophrenia.

Conclusions: Exploring the ethical and social implications of early intervention in schizophrenia gives us a chance to consider what measures might be taken that minimize risks without stopping improvements in treatment. It is important to keep in mind that despite the risks, current prodromal populations receiving treatment are symptomatic and well defined. But in considering people for early intervention, there is an important question of protecting any period of normalcy that the at-risk individual might have had prior to diagnosis or prior to the onset of symptoms that interfere with functioning and quality of life. Overall, decisions by doctors, patients and family members can be facilitated by being sensitive to all the ethics and risks involved, along with gaining accurate and balanced information on the proposed therapies that may impact the course of schizophrenia.

Support: This work was supported by RO1 MH59114: MH01699 K24 and by the G. Harold and Leila Mathers Charitable Foundation.

Click here to find this article on PubMed

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January 12, 2005

Risk from short birth intervals

Association between short birth intervals and schizophrenia in the offspring.

Smits L, Pedersen C, Mortensen P, van Os J.
Schizophr Res. 2004 Sep 1;70(1):49-56.

Background: Conceiving immediately after delivering a baby has been found to increase risk for premature births, maturity problems and birth defects in the child. Some have hypothesized that this increased risk may be due to incomplete restoring of nutrients such as folic acid, vitamins B6 and B12 in the mother at the time of conception. These nutrients usually take up to 1 year to return to recommended levels. Since there may be a link between prenatal deficiencies of these nutrients and schizophrenia, this study looked at the relationship between the length of the preceding birth interval and the risk of schizophrenia in the offspring.

Method: This was a Danish study that collected information from a huge number of individuals - over 1.4 million Danish-born individuals and their families - and linked it to data from the Danish Psychiatric Central Register which contained data on all admissions to Danish psychiatric inpatient facilities over a certain time period. Using this database, they calculated birth order, size of family and birth interval to nearest older and younger sibling and did various other analyses.

Results: From their group, they found that a total of 5095 persons were diagnosed with schizophrenia. They found that schizophrenia risk changed depending on the birth interval. Those born after long birth intervals (27 months and longer) had the lowest chance of having schizophrenia, while those with moderately short birth intervals (15 to 20 months) showed highest rates. Contrary to what you would expect, they found that there was less risk in those born after very short birth intervals (<15 months) or after intermediate birth intervals (21 to 26 months). All these associations were independent of history of mental illness in a parent or sibling, season of birth, parental age, birth order, level of urbanization at birth, or calendar year.

Interpretation and Limitations: This study suggests that there is a link between birth spacing and the risk of schizophrenia in the child. Individuals born after birth intervals of up to 26 months, and predominantly those born within 15 to 20 months after their preceding sibling, had higher risks of developing schizophrenia than those born after birth intervals of 45 months or more. However, they had an interesting finding where the shortest interval did not result in the greatest risk, as you’d expect if the hypothesis is true about incomplete restoration of maternal nutrients of B-vitamins such as folic acid and vitamin B6. The authors try to explain this contradiction by suggesting that the shortest birth intervals may have occurred in non-lactating women who tend to have more favorable folic acid levels than lactating women. But this is just a hypothesis and needs to be researched further. Also, while this study focused on those with at least one older sibling, they also looked at data from first-born individuals and found that the highest rates associated with short birth interval was about the same as being an only child.

There are several limitations to this study. Since the authors did not have information on duration of pregnancy, they used birth intervals as estimation for inter-pregnancy interval – which might result in overrepresentations of things like premature births in the shortest birth intervals. Since prematurity may also be a risk factor for schizophrenia, this may have biased the results. Also, this study did not look at the effects of some other hypothesized environmental risk factors of schizophrenia possibly associated with birth interval such as maternal stress during pregnancy, later infections or others such as smoking, socio-economic status, planned pregnancy etc. Additionally, since this was a Danish study, their sample may not be representative of other countries with different levels of nutritional problems in the population.

Support: This study was supported by the Stanley Medical Research Institute, the Maastricht Care and Prevention Research Institute (CAPHRI) and the European Graduate School for Neuroscience (EURON) and the National Centre for Register-based Research is funded by the Danish National Research Foundation.

Click here to find this article on PubMed

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December 30, 2004

Schizophrenia and cannabis

New Perspectives in the Studies on Endocannabinoid and Cannabis: Cannabinoid Receptors and Schizophrenia

Hiroshi Ujike and Yukitaka Morita

J Pharmacol Sci 96, 376 – 381 (2004)

This article reviews the evidence of cannabis (marijuana) with respect to psychosis and schizophrenia. The authors pose adding another element to the model of schizophrenia that includes cannabinoid receptors. These receptors (referred to as CB-1 receptors) are increased in the brains of many people with schizophrenia. Recently, there was an attempt at using a medication designed to target these receptors that did not show a benefit over a placebo (Click here for my review). However, there is evidence that cannabis can cause similar cognitive (thinking) deficits in someone acutely intoxicated from THC (the active ingredient in marijuana).

Additionally, many people experience some degree of psychosis/hallucination while under the influence of THC. Some have described a more persistent “cannabinoid psychosis” in ultra-high level users. In people with schizophrenia, positive symptoms are typically worsened by the use of cannabis, even if the person is regularly taking antipsychotic medications. Some studies have also argued that the use of cannabis in a high risk population may precipitate the development of schizophrenia. In other words, people with a genetic predisposition may receive the trigger to develop schizophrenia from using marijuana heavily, though this is not fully proven yet.

Cannabinoid receptors are found in both the brain and the body’s periphery. When they are in the brain they are referred to as CB-1 and in the rest of the body they are called CB2. Why has the human body got receptors for use with THC? It is because there are endogenous (produced by our own body) molecules that have evolved to fit in these receptors .The most studied is called anandamide and it is a fatty-acid derivative. When rodents have been given synthesized anandamide, they behaved just as if they were given marijuana. In one study of the fluid around the brain and spinal cord (CSF) of people with schizophrenia, it was found that there was a 2-fold increase in the amount of anandamide compared to healthy controls. This level did not change even with the administration of antipsychotic medications. In people with schizophrenia, there is an increase in the CB-1 receptors located in the caudate and putamen (areas of the brain associated with the dysfunctions found in schizophrenia.) It is thought that this increase in receptors may have to do with negative symptoms and with some of the cognitive (thinking) disturbances found in schizophrenia.

There are many genetic variations of the CB-1 receptor. It is possible that having a particular genotype (genetic variation) of the receptor may put someone at greater risk of cannabinoid psychosis. Some have described this type of condition as “amotivational syndrome” because of the profound negative symptom quality to it. One particular genotype has been most clearly linked to people with disorganized type of schizophrenia; a type more characterized by inability to maintain activities of daily living than with positive/psychotic symptoms. This variation has also been seen in people with the amotivational syndrome due to marijuana but not with psychosis due to amphetamine (speed, etc.) or other drug use. However, this genetic variation is merely an association and not yet determined to actually be a testable risk factor for schizophrenia. The role of cannabinoids will be the subject of much further research over the upcoming years.

Click here for the ariticle on PubMed

For more information on Marijuana/cannabis and schizophrenia risk, see:

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December 28, 2004

Post mortem research

Reliability of psychiatric diagnosis in postmortem research.

Deep-Soboslay A, Akil M, Martin CE, Bigelow LB, Herman MM, Hyde TM, Kleinman JE.
Biol Psychiatry. 2005 Jan 1;57(1):96-101.

Background: To further understand how the brain works in various diseases, postmortem (after death) research is very important. Such studies look at a person’s brain after death to examine genetic, molecular, cellular, and neurochemical characteristics. Such postmortem research is only done if permission is given to donate the brain for research.

One challenge that many of these post mortem researchers face, is determining psychiatric diagnoses after death. Some researchers tend to do thorough psychiatric record reviews retrospectively, using structured questionnaires such as the Diagnostic Evaluation After Death, while other researchers conduct postmortem family interviews (i.e., the psychologic autopsy). The purpose of this study was to see what the level of agreement is between these two diagnostic ways of determining psychiatric diagnosis after death.

Methods: The researchers got informed consent to look at the donated brains from next of kin. After starting with 119 subjects with a history of psychiatric illness or substance abuse, they were able to obtain both psychiatric records and postmortem family interviews for a total of 37 subjects. The family interviews were completed within about 2 years of the donor’s death. Interviews were structured and semistructured and gathered information such as demographic, educational, social, occupational, and psychological information, as well as information regarding family history, suicide history, and medical history related to circumstances and cause of death. Requests for written authorization for release of medical records were sent to families after completion of the family interviews. Once records were obtained, the Diagnostic Evaluation After Death questionnaire was used to extract information systematically from psychiatric records, and the last psychiatric diagnosis available before death was recorded. Then, psychiatric diagnoses from family interviews were compared with the last available psychiatric record diagnoses.

Results: The rate of agreement between psychiatric diagnoses derived from record reviews and diagnoses derived from postmortem family interviews was relatively high for subjects with a diagnosis of schizophrenia, but the rate of agreement for subjects with mood disorders was only moderate.

Interpretations and Limitations: It seems that record reviews alone may be adequate for arriving at the postmortem psychiatric diagnosis for schizophrenia. This could be because individuals with schizophrenia generally have more frequent and lengthy inpatient admissions, longer medical records, and more problems in social, educational, and occupational functioning that are more severe and therefore more identifiable by doctors and family members. On the other hand, those with mood disorders (eg depression) may have more subtleties in such areas and for them it may be more difficult to come up with a postmortem diagnosis. Limitations in this study include: lack of 100% agreement with final cohort diagnoses (record diagnoses =70.3% and family interview diagnoses=78.4%) and long time lag between dates of death and postmortem family interviews (which was done out of respect for family’s grieving process). Overall, it seems that although the family interviews can provoke powerful emotions to surface, families are generally grateful for an opportunity to discuss their family member’s mental illness and to make a contribution to psychiatric research.

This research was supported by the Section on Neuropathology of the Clinical Brain Disorders Branch, in the Intramural Research Program at the National Institute of Mental Health (NIMH) in Bethesda, Maryland

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December 24, 2004

Olanzapine vs. Haloperidol?

Effectiveness and Cost of Olanzapine and Haloperidol in the Treatment of Schizophrenia: A Randomized Controlled Trial

Robert Rosenheck; Deborah Perlick; Stephen Bingham; Wen Liu-Mares; Joseph Collins; Stuart Warren; Douglas Leslie; Edward Allan; E. Cabrina Campbell; Stanley Caroff; June Corwin; Lori Davis; Richard Douyon; Lawrence Dunn; Denise Evans; Ede Frecska; John Grabowski; David Graeber; Lawrence Herz; Kong Kwon; William Lawson; Felicitas Mena; Javaid Sheikh; David Smelson; Valerie Smith-Gamble

JAMA, Nov 2003; 290: 2693 - 2702.

Article 2:
Robert A. Rosenheck
Open Forum: Effectiveness Versus Efficacy of Second-Generation Antipsychotics: Haloperidol Without Anticholinergics as a Comparator
Psychiatr Serv 56:85-92, January 2005

Article 1 is a study that came out last year which challenges the conventional wisdom that the newer medications are inherently better than properly dosed older medications. While many studies are funded by pharamaceutical companies and tend to favor newer medications in their outcomes, this study was designed to give both the newer medications (olanzapine/Zyprexa) and an older medication (haloperidol/Haldol) a fair chance to be dosed as the clinician in the study wanted to and was given a liberal ability to utilize medications to treat the common side effects. The authors wanted to determine if the newer medications were more effective, had fewer side effects and what the difference would be in overall costs to the Veterans Affairs System for patients on either treatment. Olanzapine costs over $4000/year versus approximately 20 dollars per year for haloperidol. However, if it is true that there is better efficacy and/or fewer side effects from the newer medication (i.e. if it reduced the number of hospital days for the average patient per year) it would make fiscal sense as well as clinical sense to prescribe it automatically and as a first line treatment. However, if that was not the case, then perhaps the conventional wisdom required challenging.

The data prior to the study was already controversial. A leading authority on the quality of research, the Cochrane group, did an analysis where they looked at all the data regarding the differences between olanzapine and haloperidol. While most studies published favored olanzapine, the Cochrane group found that there were sufficient flaws in enough of the studies that they advocated restraint and a more cautious approach. They found that with the number of patients who left studies early, it was hard to draw a strong conclusions that olanzapine was in fact better.

To put their question to the test, the authors recruited approximately 300 patients in the VA system. Patients were randomly assigned to receive either 5-20mg of olanzapine or 5-20mg of haloperidol. The pills looked identical so that the study could be blinded (to help eliminate potential bias.) Also, patients on haloperidol were given 1-4mg of benztropine (Cogentin) automatically, while the olanzapine patients received a placebo. However, both groups could add more active benztropine if there were side effects that warranted such treatment. The authors recorded data on clinical response, side effects, quality of life and overall costs to the VA and to society for the patients. They also tested patients for memory and other tests of their ability to think.

Ultimately, the authors found that the group that received olanzapine and the group that received haloperidol were nearly identical. There were statistically significant differences in a few areas though. The group that received olanzapine performed better on 2 memory tests and also reported less akathisia (severe restlessness) than the group on haloperidol. However, the olanzapine group had a significantly higher amount of weight gain, problems with cholesterol and with diabetes than did the haloperidol group. Lastly, the costs for the olanzapine were significantly higher than the haloperidol group.

The authors conclude that the difference between the groups, being so minimal, means that it is likely that starting a patient with haloperidol and well managed benztropine is an acceptable alternative to starting directly with the more expensive medication. However, they note a few limitations to this study. First, it was conducted exclusively at the VA and with a predominantly male population. This may limit the ability to generalize the results to the overall population. Second, there were many patients recruited who did not participate and many that dropped out of the study after they started. While they followed many of the dropouts, there were some lost to follow-up. This can skew the data towards finding less of a difference between the groups, though the patients that dropped out were equally in the olanzapine and haloperidol group. Also, there were overall about half of the number of patients they initially wanted to recruit. While they did have enough to make their statistics meaningful, they would have been able to make stronger arguments with more patients. Lastly, the overall cost/benefit analysis is still unknown. While the costs were higher with olanzapine, it is hard to determine the overall costs to society and to the patients or the VA. Additionally, the side effect profiles are different between the medications. For some, weight gain is not an issue or can be managed more by diet than for others. While for other patients, having movement or cognitive effects can be more debilitating. It is also possible that the use of benztropine may have contributed to some of the cognitive flattening seen in the haloperidol group as benztropine can have a negative effect on cognition (ability to think.) However, these are all reasons why the debate rages strongly as to the best way to start a patient on antipsychotic medication. It is not right or wrong to start on haloperidol or any other medication first, as long as the patient and physician work closely to assess that the started medication is in fact right for that patient. If it isn’t, it is important to know that it is ok to switch to something that works better, especially if a full trial does not work on an original medication. However, once a medication works, it is useful to stick with it rather than change based on these results especially. Lastly, it goes without saying that this article was/is quite controversial. However, it is an interesting perspective and one that is not frequently presented.

Funding/Support: This study was supported by Lilly, which provided study drug and placebo, and the VA Cooperative Studies Program.

Role of the Sponsor: Employees of Lilly (Alan Breier, MD, Robert Obenchain, PhD, and John Kreuger) participated in the study design and commented on the analyses and on the manuscript. The analyses and writing of the manuscript were carried out by the authors independent of the sponsor.

Article 2 is a very interesting discussion of the factors that may have caused the results of studies that compared haldol with newer antipsychotics to come out so strongly in favor of the newer drugs. While there is always excitement, and also financial pressures from pharmaceutical companies, when new drugs come out, perhaps the excitement got in the way of the best science.

The second article describes a research concept called "effectiveness vs. efficacy." When a drug has "efficacy" it means that it can be demonstrated under controlled circumstances to work better than a comparator drug. To demonstrate "effectiveness" a drug must demonstrate that it works better than a comparitor in regular use, in essence, how it would be used in the general community. In order to perform cleaner reserch, many patients or other treatments must be excluded when doing a trial such that there are only few variables being manipulated and an explanation can therefore be lent to those manipulations. What Rosenheck argues in article 2 is that most trials that compared new antipsychotics with haldol failed to utilize cogentin (an anti-side effect medication) appropriately and therefore patients placed on haldol often had unnecessarily, and unfairly, high levels of side effects compared with what they might have had if they were treated more appropriately. On the flip side, the use of Cogentin (benztropine) is associated with mental slowing, often a side effect that patients do not tolerate. However, as noted above, newer medications have greater cost and have other side effect (weight gain, etc.) Overall, this research is helpful as we have more experience now with the newer medications. Maybe it is not such a bad thing to use older medications, if they are used appropriately? What will work for some patients will not for others and so it is important to keep the factors in mind that will make one medication, and its inherent possible side effects, a better choice for the individual, rather than contemplating the benefits for an entire population at once.

Click here to look up this article on PubMed

Click here for article 2 abstract on PubMed

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December 23, 2004

Schizophrenia and Paternal Age

Paternal age and risk of developing schizophrenia

Nobody knows why certain people get schizophrenia. However, there are many possibilities that have been investigated. There is evidence of a genetic component to developing schizophrenia, but that precise link is currently under investigation and while there are certain spots that appear relevant, it is not known exactly what the mechanism is precisely.

Many articles, of which these are some, have postulated that there is an increased risk of schizophrenia based upon an increased age of the father. This theory is not unique to schizophrenia. Diseases such as achondroplasia (a type of dwarfism), certain cancers, and other disorders are linked to increased paternal age. Increased maternal age is linked to increased risk of Down’s syndrome and other developmental disorders. The reason that increased age is thought to be relevant to developmental and genetic diseases is complex. As men age, they produce billions of sperm. With each sperm that is generated, there is a risk that the man’s DNA will not be translated exactly perfectly. These are called mutations and these mutations increase with age. There are many mechanisms that prevent mutations and they are thought to become less precise with age. Therefore, older men are thought to have what are called, “de novo” mutations more as they age. De novo means that they are new and spontaneous mutations. They are considered spontaneous because they are not seen in the previous generations of the family. Were it not for spontaneous mutations, evolution would eliminate many genetic diseases through lack of reproduction of the person with the disorder.

It is difficult to explain what might be unique about paternal DNA that might cause these effects. It is postulated that it might be linked to the father's X-chromosome. Maternal DNA is easier to follow because of a type of DNA called "mitochondrial" DNA. That is a special type of DNA associated with a part of the cell called the mitochondria. This is nearly exclusively passed down from the mother to the child rather and almost never has a paternal contribution. It is more difficult to trace paternal DNA patterns.

There are some things that are difficult to sort out with this research however. Older fathers are typically having children with older mothers. There are statistical methods to control for the age of mothers while looking at rates of schizophrenia. Using these methods, they were able to find that paternal age was more statistically relevant than maternal age.

Lastly, when looking at epidemiological studies of risk, it is important to keep some principles in mind. First, these studies show associations and while they usually provide a hypothesis (educated guess) as to what the cause is based on these association, they are not able to make the definitive cause known. Therefore, it is not certain that other factors not thought of by investigators, are related to older fathers and schizophrenia and that in fact the father’s age is just part of the story. An example of this was when it was found that coffee drinking was linked with certain cancers. It turned out that people who drank coffee were more likely to be using cigarettes and the cigarettes were responsible for the cancer risk and not the coffee, even though there was an association with coffee and cancer nonetheless. Second, the generally considered risk of schizophrenia in the general population is approximately 1% of the population. This is a large risk compared to certain diseases, but is still small. Therefore, when a risk factor is doubled, it is still a small risk overall, meaning that there are likely other factors besides just paternal age that are part of the picture, but these studies are focusing on paternal age. Lastly, these studies all look at schizophrenia diagnosed at the time of the study. They usually look for several years through the main time of diagnosis (late teens to twenties.) However, they do miss the later onset schizophrenia which may be a lower proportion of patients, is nonetheless important.

1: Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D.

Paternal age and schizophrenia: a population based cohort study.

BMJ. 2004 Nov 6;329(7474):1070. Epub 2004 Oct 22.

This study looked at a population of 750,000 people in Sweden born between 1973 and 1980. They looked at patients who were admitted with a schizophrenia diagnosis. They found that fathers over the age of 45 had an approximately two-fold increase in schizophrenia risk. They showed no increased risk with fathers over fifty, but the sample was too small to draw a conclusion. Since they only looked at hospitalized patients, it is possible that they may have missed certain cases that did not present as inpatients.

Click here for a link to this article on PubMed

2: Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES.

Advancing paternal age and the risk of schizophrenia.

Arch Gen Psychiatry. 2001 Apr;58(4):361-7.

This research group used a database generated in Israel. They looked at 90,000 people born and followed for 30 years. In Israel, there is a database kept on all citizens regarding psychiatric illness. Using these databases, they found that as fathers aged, for every ten years above 30, there was a 40% increase in risk. This was up to 2.5 fold risk in fathers over 50 (though this was a small enough sample to be as low as 1.5 fold increased risk.) This study also looked at years of marriage as another correlate and found that the risk of schizophrenia decreased with longer marriages. They ultimately believe that approximately 26% of schizophrenia cases can be attributed to paternal age.

Click here for a link to this article on PubMed

3: Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB.
Parental age and risk of schizophrenia: a case-control study.
Arch Gen Psychiatry. 2003 Jul;60(7):673-8.

This study was done as a "case-control" study of a Danish population. This means that the authors took people who already were diagnosed with schizophrenia (cases), and compared with age, sex, demographic matched people without schizophrenia (controls.) They looked at 7700 cases and had 25 controls for each case (192,000). This way, they are able to try and compare what is different in the groups while still having many similarities and therefore fewer variables. They seperated out cases that also had a family history to help to isolate the sporadic mutations verus inherited cases.The authors found that with fathers over 50 years of age the risk was approximately two fold the risk of younger parents. They also found that the risk was increased for females with older fathers than for males, though this was only a slight difference.

Click here for a link to this article on PubMed

4: Dalman C, Allebeck P.

Paternal age and schizophrenia: further support for an association.

Am J Psychiatry. 2002 Sep;159(9):1591-2.

This is another case-control study that looked at a small population of people in Stockholm. They also found an approximately double risk of schizophrenia with paternal age greater than fifty years old no impact on risk based on the maternal age. One potential problem in this study is that while they looked at maternal psychotic illness history, they were unable to do so with the fathers and therefore some inherited cases may have been included in that respect.

Click here for a link to this article on PubMed

5: El-Saadi O, Pedersen CB, McNeil TF, Saha S, Welham J, O'Callaghan E, Cantor-Graae E, Chant D, Mortensen PB, McGrath J.

Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia.

Schizophr Res. 2004 Apr 1;67(2-3):227-36.

This study did another population based study. They used populations from all of Denmark; Malmo, Sweden; and Brisbane, Australia. In both the Swedish and Danish populations they found approximately 2 fold difference in fathers above the age of 35 years old. However, in the Australian sample, they were unable to find a difference with age though this group was far smaller than the other groups and may not have had the statistical power needed to find a difference.

Click here for a link to this article on PubMed

6: Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, Lewis G.

Paternal age and risk for schizophrenia.

Br J Psychiatry. 2003 Nov;183:405-8.

This is a cohort study, meaning that they looked at a large population at birth and then followed the whole group and recorded who among the group developed schizophrenia. Then, they looked at the various variables they wanted to test (paternal age for example) and made conclusions. They looked at a group of 50000 births in Sweden and used hospital discharge diagnoses to determine the cases of schizophrenia in the cohort. This group also found a between 2 and 3 fold increase in risk with fathers over the age of fifty. These authors postulated that perhaps there were social factors in fathers that had children at older ages that might predispose their children to developing schizophrenia. To test this hypothesis, the authors of the study controlled for social integration factors, parental drug use and IQ. These factors did not have any influence on the data and the authors then concluded that social factors of older fathers was less likely to have an influence than the de novo mutations postulated by the other authors above.

Click here for a link to this article on PubMed

7: Brown AS, Schaefer CA, Wyatt RJ, Begg MD, Goetz R, Bresnahan MA,
Harkavy-Friedman J, Gorman JM, Malaspina D, Susser ES.

Paternal age and risk of schizophrenia in adult offspring.

Am J Psychiatry. 2002 Sep;159(9):1528-33.

This is another small cohort study in which the authors looked at approximately 20,000 live births from Kaiser Family Health in Alameda, California. They followed the population for an average of thirty years. This is the first study of patients in the United States amongst those above. It adds to the data already from Scandinavia and Israel and makes the results more generalizable to the overall population. The authors here found that if they controlled for numerous other variables, the rate of increased risk of schizophrenia increased about 80% for each decade older the father was after age 20. This put the age of forty at a more than 2 fold increased risk. However, this was a smaller study than some of the others and many of the potential subjects were excluded for various reasons. Nonetheless, this study demonstrates a "dose-response" relationship meaning that it is possible to demonstrate a linear increase in risk that correlates with a similar linear increase in age.

Click here for a link to this article on PubMed

8: Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S, Gorman J.
Paternal age and sporadic schizophrenia: evidence for de novo mutations.

Am J Med Genet. 2002 Apr 8;114(3):299-303.

In this study the authors looked at consecutive admissions to the New York State Psychiatric Institute in New York City. They did comprehensive interviews and family histories on each patient and analyzed the results. They found that families without a history of schizophrenia had a higher risk of schizophrenia in older parents. They also attempted to describe differences in disease process amongst familial versus sporadic cases, but that would require further research to be fully described.

Click here for a link to this article on PubMed

I hope this review of the topic was interesting. There are a lot of possible causes of schizophrenia and nobody knows what is most important. These studies are but one theory of something that is related to increased risk of schizophrenia, but it is merely an association and the full mechanism remains to be described.

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Paroxetine and negative symptoms?

Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: a double-blind placebo-controlled study

M. C. Jockers-Scherübl, A. Bauer, F. Godemann, F. M. Reischies, F. Selig and P. Schlattmann

International Clinical Psychopharmacology 2005, 20:27–31

Schizophrenia is often discussed in terms of three types of symptoms: Positive symptoms, negative symptoms and cognitive symptoms. The positive symptoms are the most widely discussed and include delusions, hallucinations (most commonly auditory or voices), paranoia and other bizarre thinking. Negative symptoms include blunted affect (affect meaning the way that emotion is expressed), social withdrawal, apathy and difficulty with relating to other people. Cognitive symptoms reflect the way that many people with schizophrenia have problems with working memory and/or have other deficits in their ability to think.

Antipsychotic medications are primarily agents that work on the positive symptoms. They help to take away voices and diminish paranoid feelings and often will make the feelings of having delusional thoughts less concerning. However, they rarely help with negative symptoms. Clozapine is the only medicine that has ever been shown to help with negative symptoms and it does so only modestly. There are many theories about the genesis of negative symptoms and many believe that they represent a different dysfunction in the brain than the cognitive symptoms. That theory would perhaps explain why medicines that treat positive symptoms are ineffective on negative symptoms. However, that alternate pathway, while the source of many theories, is largely unknown.

One feature of negative symptoms that has interested the research community is that it shares many features with major depression. The social isolation, lack of motivation and withdrawn emotions are similar to symptoms one might experience in a depression. This study looks at using an SSRI (selective serotonin reuptake inhibitor) medication, paroxetine (Paxil) to see if it might help with negative symptoms.

The authors designed a study that utilized “randomized, placebo-controlled, double blind” technique. Randomized means that every subject was equally likely to get placebo (dummy pill) or the experimental agent (paroxetine). Placebo controlled means that they were using a placebo, an inert pill, to compare with an active treatment, paroxetine. This helps to determine if any benefit seen may be from the “placebo effect” which is where some patients (often up to 30% or more) can benefit from taking the inert treatment. Double blind means that the researchers and the patients did not know what they were on until after the data was collected, thereby decreasing the risk that someone might unconsciously report better results for the group they wanted to do better (typically the experimental group.) The researchers limited their study to patients with a stable recent history (no antipsychotic changes in the last 6 months) and they could not have any alcohol/drug problems, had to have minimal positive symptoms, and could not have any current evidence of depression (based on 2 depression rating scales.) This leaves a very select group of patients to study, but one that would hopefully give results that would not be as open to questions of confounding variables.

The authors found that adding paroxetine helped with 3 areas of negative symptoms. There were modest effects seen in ratings of affective blunting, impaired abstract thinking and spontaneous speech and spontaneity. The paroxetine was no different from placebo in other measures of negative symptoms (emotional withdrawal, poor rapport, passive social withdrawal and stereotyped thinking.) The authors stated that there were few side effects reported, however there were 3 patients who dropped out from the paroxetine group and one patient from the placebo group with side effects (out of 29 patients that started the study.)

Ultimately, the benefit from the paroxetine is modest at best. The side effects however are generally minimal (though not always.) It is unknown still why paroxetine might be influential though there are theories ranging from influence on the neurotransmitter serotonin to perhaps ways that paroxetine might subtly influence the release of dopamine in specific parts of the brain. Dopamine is thought to have an influence in positive symptoms when it is too high in some parts of the brain, however it is a neurotransmitter that is also associated with pleasure and reward centers in the brain and perhaps the paroxetine has an effect more in those regions than in the areas associated with positive symptoms. This study does not provide the evidence needed to say that everyone should be on paroxetine if they have negative symptoms. It does suggest that it might be a safe medication to try if that is a problem however and that it might help some people.

Conflict of interest: The study was supported as an investigator initiated trial by GlaxoSmithKline (maker of paroxetine (Paxil).

Click here to find the article on PubMed

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