Schizophrenia Research Blog

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: http://www.schizophrenia.com/hypo.html#street

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

Click here to find this article on PubMed

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

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.

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

CBT vs Psychoeducation

A randomized comparison of group cognitive-behavioural therapy and group psychoeducation in patients with schizophrenia

A. Bechdolf, B. Knost, C. Kuntermann, S. Schiller, J. Klosterkötter, M. Hambrecht, R. Pukrop

Acta Psychiatrica Scandinavica Volume 110 Issue 1 Page 21 (July 2004)

Cognitive Behavioral Therapy (CBT) is a type of psychotherapy in which the patient is instructed on different possible ways to interpret events and behaviors which can be used to lead to more positive outcomes in his/her life. CBT was originally created for use with depression, but its use has been shown in most mental illness including schizophrenia. Earlier in this blog (see October 4) for two articles that are about using CBT in acute schizophrenia. This study is another that was designed to determine if there was a benefit to the CBT style of training or if Psychoeducation (PE) was more or less effective. Psychoeducation is a method of teaching families and patients about their psychiatric disease.

In this study, the authors conducted a randomized comparison meaning that patients were assigned either to CBT or PE randomly, so as to limit potential biases in group placement for a desired effect. Also, this study utilized psychotherapy groups while the other papers addressed using CBT on an individual basis. Using groups allows for a more practical approach that could be applied in non-research settings in the community. CBT is often limited by the need for an individual therapist per patient which makes it very time consuming and expensive. Utilizing groups would make it more cost effective for more patients.

This is how the authors describe the CBT modules that they taught, “The intervention included 16 sessions in 8 weeks. Sessions followed a semi-structured format and lasted between 60 and 90 min, interrupted by a 5 - 10 min break. Treatment involved the following elements: (i) assessment and engagement (sharing information about voices and delusions, models of psychosis), (ii) improving self-esteem, (iii) formulation of key-problems, (iv) interventions directed at reducing the severity and the occurrence of key problems, (v) relapse prevention/keeping well. The following specific CBT strategies were used: formulation, guided recovery, symptom monitoring, exposure/focusing strategies for managing voices, hypothesis/reality testing, reframing attributions, rational responding, coping strategy enhancement, distraction techniques, role play, anxiety management, depression and self-esteem work, medication compliance/motivational interviewing, schema work, relapse prevention and keeping well strategies.” These are all techniques that one can use to increase insight and work on finding ways to minimize disturbance from various symptoms and also increase adherence to treatment regimen. The PE curriculum was described as, “The program included eight sessions in 8 weeks. Sessions followed a semi-structured format and lasted between 60 and 90 min, occasionally interrupted by a 5 10 min break. It covered the following topics: symptoms of psychosis, models of psychosis, effects and side-effects of medication, maintenance medication, early symptoms of relapse, relapse prevention.”

After six months, the authors report that patients who received CBT had a statistically significant decrease in rehospitalizations compares to the PE group. However, both groups showed improvement over the course of the six month follow-up. In fact, there was not significant difference between the groups with respect to general symptomatology. This might have been because the groups were too small to detect a difference statistically or may relate to the make up of the studied population. It is also possible that the group CBT, while cost effective on the larger scheme, may not work as effectively as originally thought. Despite this equivocal aspect to the results, the overall benefit appears to be promising for CBT and the group effect was ultimately minimal.

Overall, the potential benefits from CBT far outweigh the risks. Patients demonstrated fewer hospitalizations while working in their groups. It is important to note though, that the PE group was similar to the CBT in most other measures. This may be also because simply having a group to be responsible towards may have been helpful for the subjects. Ultimately, CBT would be nice to have for most/all patients (and many people in the non-schizophrenia population.) Its possible effectiveness in the group setting is especially promising for those in heavily populated areas, where it can be difficult to fine, much less afford, a therapist for long enough to do any work. While there is still much more room for research, and this paper did have a few small methodological flaws, it does present a cogent argument for using CBT in conjunction with antipsychotic medication as a way to help people with schizophrenia to improve.

Click here to view the abstract in PubMed.

Lamotrigine: Adjunct for Schizophrenia Treatment?

1. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial

Jari Tiihonen, Tero Hallikainen, Olli-Pekka Ryynänen, Eila Repo-Tiihonen, Irma Kotilainen, Markku Eronen, Päivi Toivonen, Kristian Wahlbeck and Anu Putkonen

Biological Psychiatry
Volume 54, Issue 11 , 1 December 2003, Pages 1241-1248

2. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia

Ilana Kremer, Agnes Vass, Ielena Gorelik, Gali Bar, Monica Blanaru, Daniel C. Javitt, and Uriel Heresco-Levy

Biological Psychiatry Volume 56, Issue 6 , 15 September 2004, Pages 441-446

Lamotrigine (Lamictal) is an anticonvulsant medication (meaning it was originally created to help control seizures) that has been shown to have benefit in patients with bipolar disorder. It has an indication for the long term mood stabilization in bipolar disorder, and has been shown to have a slight anti-depressant effect in bipolar patients who are more prone to periods of depression. Small studies with lamotrigine used to augment clozapine (Clozaril) have shown some improvement in BPRS (Brief Psychotic Rating Scale) scores which indicates a decrease level of symptoms. In one study, symptoms were decreased by up to 75% in chronic treatment-resistant patients. In another study, Lamotrigine works primarily by blocking the neurotransmitter glutamate. Neurotransmitters are the chemicals in the brain that signal brain cells (neurons) to fire and do their job. All antipsychotics work, at varying levels of potency, by blocking the neurotransmitter dopamine. This led to the theory that schizophrenia must be caused in large part by an overabundance of dopamine related activity. However, recent studies have implicated the role of glutamate as also potentially being involved in the problems with schizophrenia.

In the first study, the authors utilized a “crossover” design to try and ascertain the effect of adding lamotrigine to clozapine in severe, treatment-resistant patients that were institutionalized in Finland. The crossover design means that subjects are assigned randomly to either receive a placebo or the active drug for the first half of the study and then are switched halfway through to receive the other. Neither the patient nor the researcher knows which part of the study the patient is on until the end of the trial when the schedule can be revealed. This design is helpful because it allows for patients to be compared with themselves minimizing the risk of bias that can be caused by differences between groups. The authors found that at the end of the study, there was a slight improvement in patients who took the lamotrigine. However, this was an average improvement that while statistically significant, is not very clinically meaningful. In other words, the benefit is measurable in a research setting, but is of overall very little meaning in the outside world. However, they noted that in 20% of the people, when they were on the labotrigine, they showed a very significant benefit (Decrease in the PANSS or Positive and Negative Symptoms in Schizophrenia Scale of 3 points) and in the other 80% of the time, the benefit was negligible. In a population of people who have not responded to medication in the past, improvements in 20% is a meaningful number in terms of benefit to the public.

In the second study, the authors wanted to look at lamotrigine in addition to other antipsychotics besides clozapine. They included patients with severe, treatment-resistant schizophrenia but who were taking antipsychotics other than clozapine. They assigned subjects randomly to either receive a placebo (dummy pill) or to receive lamotrigine at a slowly escalating dose up to 400mg per day (a typical maximum dose.) They assessed the patients after ten weeks and found that among patients that completed the study, those who received the lamotrigine had an improved symptom profile. Generally, it is considered to be a more rigorous research standard to consider all patients enrolled in a study, even if they don’t complete the study, as the reasons for a patient to discontinue the study may be related to a problem with the study medication and therefore should be considered a negative outcome unless there is a specific reason not to believe so. When the authors did that kind of analysis, they found that there was no statistically significant difference between the groups. This does not mean that the medication did not work; rather it implies that further research needs to be done to fully understand the effect.

Based on these data, it may be helpful to add lamotrigine to a patient’s drug regimen if they are not achieving therapeutic success with more conventional treatments. It is a reasonable choice to try as many patients did benefit however there were also several that did not. Research gives answers for overall populations however, and does not necessarily indicate if something will work or not work for a unique individual. There are risks to lamotrigine, not the least of which is a serious and potentially fatal skin rash called Stevens-Johnson syndrome, so the medication must be started and stopped slowly and carefully under guidance from a physician.

Funding notes:
1. The study was supported by funding from Annual EVO Financing (Special government subsidies). No support was provided by any pharmaceutical company.
2. This research was supported by a grant from the National Institute for Psychobiology in Israel (IK, UH-L). DJC and UH-L served as consultants at the GlaxoSmithKline Advisory Meeting on lamotrigine use in schizophrenia held at the American College of Neuropsychopharmacology 42nd Annual Meeting, December 7–11, 2003, San Juan, Puerto Rico.

Click Here for the First article on PubMed
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Different sexual side effects of antipsychotics?

Antipsychotic treatment and sexual functioning in first-time neuroleptic-treated schizophrenic patients

István Bitter, Bruce R. Basson and Martin R. Dossenbach

International Clinical Psychopharmacology 2005, 20:19–21

This small study attempts to determine if particular antipsychotic medications have a more significant impact on sexual functioning. Sexual function is important and a decrease in function can be a reason for discontinuing medication. The authors were particularly interested in understanding the experience of people who were new to antipsychotic medication. They started by asking a simple questionnaire to patients to see what their level of sexual functioning was like before they started medication. They then followed the patients for six months and assessed their sexual functioning at months 3 and 6. They did this by using clinical ratings and by again asking patients for their rating.

The authors found that many patients with schizophrenia (up to 20% of their sample) have a baseline dysfunction sexually. This may be a decreased libido or other forms of sexual dysfunction. However, the numbers mostly stayed the same as patients began antipsychotic treatment. They found a small difference between patients taking risperidone and olanzapine and that olanzapine patients had a slightly better outcome. One might hypothesize that a reason that risperidone and some of the first generation antipsychotics might have a worse effect on sexual functioning could be related to the sometimes seen side effect of an increased prolactin level. Prolactin is a hormone in the blood that helps to produce milk and is involved in breast development. However, increased prolactin can lead to a decrease in libido when it is not needed.

The difference was very small and there were several methodological compromises made in this study that make the result even less impressive. First, the study was sponsored by the manufacturer of olanzapine and the raters generally worked for the company. Additionally, there was no randomization, control group for comparison and the raters were not blinded to treatment condition as they were the primary psychiatrists for the patients. This further leads to possible bias in the ratings.

Overall, sexual function is important consideration in the treatment of any patient, including those with psychiatric illness. Sexual dysfunction is one of the leading causes of treatment nonadherance and can lead to other morbidities as a result. However, this study does not demonstrate a significant negative effect sexually with second generation antipsychotics. Further research, including more rigorous studies, could help to demonstrate a more meaningful difference clinically and one that might prompt a change of medication if indicated. However, this study does not provide such evidence, though the concept is interesting.

Conflict of interest: B.R. Basson and Martin R. Dossenbach are employees and shareholders of Eli Lilly and Company. Eli Lilly and Company funded the study
István Bitter was an employee of Eli Lilly and Company between November 2000 and August 2003. Olanzapine is made by Eli Lilly and Company.

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Does funding source effect research outcomes?

An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia

John H. Montgomery, Matthew Byerly, Thomas Carmody, Baitao Li,
Daniel R. Miller, Femina Varghese, Rhiannon Holland

Controlled Clinical Trials 25 (2004) 598–612

This paper attempts to address the differences between studies of the second generation antipsychotics funded by pharmaceutical companies versus studies that are funded by alternate sources (government, nonprofit foundations, etc.) When these types of analyses have been performed for medications for other diseases, the studies funded by pharmaceutical companies have been nearly universally in favor of the new medication that the sponsoring company produces. There are many possible reasons for such a finding. Pharmaceutical companies have been known to pressure investigators not to publish negative studies or have maintained the data within the company and unpublished when a study does not show favorable response. The greater desire to publish “positive” results leading to increased publication of such studies is called publication bias. This can lead to misleading positive conclusions, especially when multiple trial results are put together in “meta-analysis.” There are other reasons that negative studies do not get published. Pharmaceutical companies will often end a study if it does not appear to be working as planned or seems to involve danger to the patients. While some of these results or trial terminations become public knowledge, often they are not published. One other issue that can lead to data that favors newer agents is when a new drug is compared to an older drug in such a way as to not allow the proper usage of the older drug. For example, in some comparisons with Haldol (haloperidol) investigators are not allowed to use medications to help with side effects, such as Cogentin (benztropine). This causes the Haldol group to have an increased rate of problematic side effects unfairly.

In this study, the authors systematically reviewed the medical literature for studies that involved schizophrenia and were organized as “double-blind, controlled, randomized trials.” A “double-blind” trial is one in which neither the investigators nor the patient knows which drug (or placebo) the patient is receiving. This helps to prevent the bias that one might unconsciously have towards favoring the patients on an active drug or assuming that they should be doing better than the subjects receiving an alternative treatment. “Controlled” means that the trial had an active group that received the experimental medication and the other group received either a placebo or an established treatment (like Haldol.). Randomized means that it was equally likely that a patient ended up in either group and that something like a computer or a coin toss was responsible for making the decision and not the investigators (who might be tempted to put particular patients in particular groups.)

The authors found that indeed in their analysis, industry sponsored trials did have a higher likelihood of showing that the experimental medication would be shown more positively. However, they also looked to see what might be responsible for that. They first looked at the methods of the studies to see if the pharmaceutical sponsored studies were not done as rigorously. They found that while there was some decrease in the quality of the pharmaceutical studies, it was not very significant and not likely responsible for the discrepancy. They also looked publication bias, but also conclude that journals do not have editorial policy to favor positive studies, nor did they appear to be more likely to be accepted for publication than negative studies. However, the issue of whether researchers are less likely to submit negative trials still exists. It is hard to know for sure how many studies are never submitted. However, due to recent political pressure, pharmaceutical companies are now going to be placing all trials online so that negative and positive results will all be available to the public.

However, this study is not without its limitations. First, it is hard to say that the groups of patients that are studied in industry sponsored versus non-industry sponsored research are the same groups. For example, the non-industry sponsored studies included a much higher proportion of studies using clozapine for treatment resistant patients. These patients have already shown that other medicines did not work for them and therefore are less likely to show response to clozapine perhaps. Also, this study was not done in a blinded fashion. The authors knew the funding sources of studies prior to rating them, leaving them open to the very same risk of bias that we demand to be absent from the trials they were reviewing.

Overall, this study provides further evidence that we need to use caution when interpreting data. Industry sponsored studies are the vast majority of studies in the literature, and while they provide useful data, they do not always provide complete answers. It will help to have the online data base for making it more easy to monitor for negative outcomes, but it will always be up to the informed consumer/physician to critically read studies and ascertain levels of bias in order to put together a complete understanding of the data.

The authors note no external source of funding for this project.

Click here for the abstract on PubMed

Click here for link to online database of clinical trials

Ethics in research

Influence of ethical safeguards on research participation: comparison of perspectives of people with schizophrenia and psychiatrists.

Roberts LW, Hammond KA, Warner TD, Lewis R.
Am J Psychiatry. 2004 Dec;161(12):2309-11.

Background: Participation in research comes with the assumption that researchers will respect and take care of the volunteer’s rights in an ethical and fair manner. In the United States, there are many safeguards to make sure that rights of participants are not violated. Five of these safeguards are: the use of informed consent procedures, alternative decision makers, institutional review boards, data safety monitoring boards, as well as utmost care towards confidentiality and privacy protection. Such safeguards are especially important for the rights and well-being of those with serious mental illnesses, who may have severe symptoms or fluctuating decision-making abilities and may be at risk for stigma, poverty, institutionalization, and limited access to care. This study wanted to look at how “key stakeholders” (those with schizophrenia and psychiatrists) view these safeguards regarding how well they feel protected and what influences their decisions to participate in research.

Method: The researchers developed a 2.5-3 hour questionnaire for people with schizophrenia that asked ethically important questions in mental illness research and related areas. A trained interviewer administered the survey by reading each question and recording responses. They also developed a written questionnaire for psychiatrists, who were asked to evaluate the protectiveness of various safeguard activities and to predict their influence on patients’ willingness to participate in research. Both groups were asked to rate the protection of the five safeguard activities (see Background section above) on a scale of 1=not protective at all to 5=very much protects. People with schizophrenia also rated the influence of the safeguards on their willingness to volunteer for research on a 5-point scale on which 1=much less willing, 3=no influence, and 5=much more willing, and psychiatrists predicted the influence of these safeguards on patients’ willingness to volunteer.

Results: Their sample included 48 men and 12 women with schizophrenia, majority of whom were unmarried and were an average of 44 years old. Most were white, and 22% were of Hispanic origin. Of the psychiatrist group, 55% were men with a mean age of 42 years, and most were married or living with a partner. Overall, both groups reported that all five of the safeguards were protective. Confidentiality protection, institutional review boards, informed consent, and data and safety monitoring boards were rated as more protective than alternative decision makers. Psychiatrists rated strict confidentiality as more protective than other safeguards. People with schizophrenia rated alternative decision makers as less protective than other safeguards. Psychiatrists’ ratings matched those of the people with schizophrenia and ratings did not differ by gender. Perceived protectiveness influenced willingness to participate in research, more strongly for people with schizophrenia than for psychiatrists.

Interpretation & Limitations: Overall, the researchers found that people with schizophrenia and psychiatrists see all five safeguard efforts as protective and that they perceive most of them as influencing decisions to participate in research. The authors highlight the need to further study safeguard practices in mental health research since such safeguard efforts seem to inspire confidence in prospective research volunteers. Accurate information about these safeguards can help recruit more people to participate in research studies. Limitations of this study are small sample sizes and reliance only on self-report data, which limits the generalizability of these results to everyone in the population. Nevertheless, it highlights the importance of considering the views of those with schizophrenia and their psychiatrists for ethical issues involved in research participation.

Supported by NIMH Career Development Award 1K02 MH-01918 and by National Institute on Drug Abuse grant 1R01 DA-13139.

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Voices and the brain

Temporal course of auditory hallucinations.

Shergill SS, Brammer MJ, Amaro E, Williams SC, Murray RM, McGuire PK.
Br J Psychiatry. 2004 Dec;185:516-7.

Background: Researchers are still unclear about why voices or “auditory verbal hallucinations” occur in schizophrenia. Some think that voices are due to a person’s own inner speech that gets misperceived as sounds that come from outside. Others think that it is because of extra activity in a particular part of the brain known as the auditory cortex (which is responsible for hearing and language). Brain imaging helps take pictures of the brain while someone is thinking or even while hallucinating. Some of this imaging work has found that areas that are involved in both speech generation and perception get activated during auditory verbal hallucinations, but the sequence in which these areas get activated remains unclear. So, the current study used a type of brain imaging known as functional magnetic resonance imaging (fMRI) to look at how brain activity that is thought to be involved with voices in schizophrenia changes while someone is having auditory hallucinations.

Method: This study was conducted in London, England. The researchers asked 8 people with schizophrenia who frequently heard voices to give permission to have their brain scanned while they heard voices. They were able to get brain images of hallucinations for only 2 of the 8 patients. The first participant was 47 years old with a 22-year history of illness, and was being treated with Clozaril, Solian and Sodium valproate. The second was 26 years old, had a 6-year history of illness and was being treated with Zyprexa. In both cases the hallucinations involved people making derogatory remarks to the person. The participants were asked to lie in a brain scanner and press a button each time a auditory hallucination started and to release the button when it stopped. This was repeated for every hallucination they experienced during the 5 min session.

Results: They found that each auditory verbal hallucination lasted an average of 16 seconds with a range of 3–42 secs. They found specific areas of the brain were activated 6–9 secs before the person signalled the onset of the hallucination. These were areas that are involved in generation of inner speech (left inferior frontal, right middle temporal gyri). Different areas of the brain, which are involved in perception of auditory material or hearing, were active once the person became aware of the hallucination (bilateral temporal gyri, left insula).

Interpretations & Limitations: These results supports the hypothesis that when a person hears voices, there is activation in brain regions that are involved in generating inner speech which occurs before activation in areas that help us understand or perceive a sound. Overall, this study argues that hallucinations are due to the misidentification of self-generated verbal material and that different areas of the brain are involved at various times during the hallucinations. However, as with most studies that have tried to image the brain during hallucinations, the size of the group that was studied is very small. It is difficult to say with certainty whether the results obtained from these 2 participants will extend to all those who hear voices. Also, the researchers used a type of scanner (1.5T) that is not as sensitive as other more powerful scanners, so there maybe be other regions of the brain that are involved in voices that may not have been properly picked up in this study. Nevertheless, they provide some interesting insights into what happens in the brain when people hear voices.

The researchers are supported by the Wellcome Trust and the National Alliance for Research on Schizophrenia and Depression.

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