Schizophrenia Research Blog

Safety and Effectiveness of Long-acting Risperdal

Safety and Efficacy of Long-Acting Risperidone in Schizophrenia: A 12-Week, Multicenter, Open-Label Study in Stable Patients Switched From Typical and Atypical Oral Antipsychotics.

Lindenmayer JP, Eerdekens E, Berry SA, Eerdekens M.
J Clin Psychiatry. 2004 Aug;65(8):1084-1089.

Pharmaceutical companies have recently been touting long-acting injectable medications as the answer to maintaining reliable, consistent levels of medication and helping with preventing relapse through medication compliance in those with schizophrenia. Risperidone has been the first such atypical medication available in such a long-acting injectable form. This study aimed to look at the safety and effectiveness of this type of medication in a clinically stable group of people with schizophrenia. The study involved a 12 week open label, multicenter, exploratory clinical trial, where they collected data from a from clinics, hospitals, and physicians' offices.

Participants with schizophrenia entered a 4 week period where they continued to receive the same dose of their current oral medication (which was Haldol, Seroquel or Zyprexa). They received 25mg of long acting injectable risperodone at baseline and then every 2 weeks, with allowance for the doctor to change the dose upto a certain point. Safety measurements were based on the patient’s self-report, clinical observation, lab reports and physical exams. They measured the effectiveness of the medication based on symptom checklists (PANSS & CGI).

The authors report that long-acting risperidone was well tolerated. Of the 141 patients who completed the study, the most frequently reported adverse events were insomnia (16%), headache (15%), psychosis (11%), and agitation (11%). There was a slight increase in body weight (0.4 kg). 5 patients experienced adverse effects that resulted in the discontinuation of the study and a few experienced serious side effects that that included psychosis and agitation. The authors do not report any significant lab abnormalities or ECG results. They also report that the severities of certain side effects (extrapyramidal symptoms) were reduced during treatment and there were improvements in symptoms of schizophrenia that started during the 4th week and continued through the 12-week period.

Limitations of this study are the open label and lack of a control group. This means that the raters were not blind to the medication the patients were on, and this could have biased their ratings of symptoms. Also, since this study allowed other medications to be used at the same time, it is difficult to parse out the unique contributions of the injectable risperidone while the flexible dose approach used could have also biased the results.

The authors have disclosed financial support from Lilly, Pfizer, Janssen, AstraZeneca, Bristol Myers-Squibb, Repligan & Johnson & Johnson (see article for details

Click here to link to PubMed for this article

Doctors Recommendations for Monitoring Health

Physical health monitoring of patients with schizophrenia.

Marder SR, Essock SM, Miller AL, Buchanan RW, Casey DE, Davis JM, Kane JM, Lieberman JA, Schooler NR, Covell N, Stroup S, Weissman EM, Wirshing DA, Hall CS, Pogach L, Pi-Sunyer X, Bigger JT Jr, Friedman A, Kleinberg D, Yevich SJ, Davis B, Shon S.
Am J Psychiatry. 2004 Aug;161(8):1334-49.

Individuals with schizophrenia seem to have a 20% shorter life expectancy than the population and have more vulnerability to illnesses such as diabetes, coronary heart disease, hypertension, and emphysema. This could be because of lifestyle choices (eg poor dietary habits, obesity, high rates of smoking, alcohol and street drugs) and side effects from certain antipsychotic medications (prolactin elevation, cataract formation, movement disorders, sexual dysfunction, weight gain, onset of diabetes, increases in plasma lipids, and abnormal ECGs).

A conference was organized by some who believed that the health needs of people with schizophrenia who take antipsychotic medications are not adequately addressed by clinicians in specialty mental health programs or in primary care settings. This Mount Sinai Conference (2002) aimed to develop recommendations for the systematic health monitoring of individuals with schizophrenia for whom antipsychotic medication is prescribed. This was based on a consensus meeting of leading psychiatric and other medical experts who evaluated the existing literature and developed recommendations for physical health monitoring of patients with schizophrenia. They reviewed the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis.

Their consensus recommendations were as follows: regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. They recommend that information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were also made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. They suggested that patients who receive both older and newer antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia and receive regular visual examinations.

It is worthwhile to retrieve this article and look through their specific recommendations (Table 1 in the article). This can help with being well informed during clinical appointments with doctors – especially since the conference recommended that mental health care providers be involved in performing physical health monitoring since not all patients receive such physical health monitoring in their primary care settings.

The consensus meeting on which this article is based did not receive financial support from the pharmaceutical industry. However, individual conference participants have disclosed support from various pharmaceutical companies. See the article for full list.

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Family Warmth in Schizophrenia

Ethnicity, Expressed Emotion, Attributions, and Course of Schizophrenia: Family Warmth Matters.

By López, SR; Nelson Hipke, K; Polo, AJ; Jenkins, JH; Karno, M; Vaughn, C; Snyder, KS.
Journal of Abnormal Psychology. 2004 Aug Vol 113(3) 428-439

There is a line of research called family “expressed emotion” that suggests that family factors can influence the course of schizophrenia. Particularly, it is thought that low levels of criticism, hostility, or emotional overinvolvement are less likely to cause relapse in the person with schizophrenia, and vice versa for high levels of these qualities. Some researchers have proposed an “attribution theory” which claims that those relatives who judge the patient as being responsible for their symptoms will tend to show more negatively affect (anger, bother, annoyance), whereas those who judge the patient as not being responsible for their illness will tend to feel positive or supportive affect (sympathy, compassion, concern). These “expressed emotions” then are thought to influence the course of schizophrenia. These ideas are hotly debated and not all researchers believe in them.

This current study was designed to extend attribution theory by looking at the relationship between families' attributions of control, families' negative and positive emotions and patients' relapse. They looked at interviews and questionnaire data from two previous studies involving Anglo American and Mexican American families. They found that the relationship between families and the course of schizophrenia is quite diverse. The data indicated that for Mexican Americans, family warmth is a significant protective factor, whereas for Anglo Americans, family criticism is a significant risk factor. As such they suggest that family warmth can be just as significant to the course of schizophrenia as family criticism, depending on the sociocultural context. They also suggest that family warmth can serve as an important buffer and family interventions that focus on prosocial family factors can potentially balance the emphasis of past research on negative family functioning, and focus on family strengths.

There are limitations in this line of work due to small sample sizes, and lack of determination of how attributions and affective reactions relate to families' behavior. While this line of work provides helpful information about the role of cognitive appraisal in perceptions of illness and response to it, it is also important to note that there are other studies showing that expressed emotion does not necessarily influence the course of schizophrenia. Nevertheless, this research can help highlight family intervention strategies that are based on self and illness psychoeducation, communication, and problem-solving skills training.

This research was supported by Grants R03-MH53589 and K08-MH01499 from the National Institute of Mental Health. Preparation of this article was supported in part by a Minority International Research Training grant (TW00061) from the Fogarty International Center of the National Institute of Health awarded to UCLA-Instituto Mexicano de Psiquiatria.

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Measuring Schizotypy Personality through Questionnaires

The Psychometric Detection of Schizotypy: Do Putative Schizotypy Indicators Identify the Same Latent Class?

Horan, WP; Blanchard, JJ; Gangestad, SW; Kwapil, TR.
Journal of Abnormal Psychology. 2004 Aug Vol 113(3) 339-357

There is a lot of research being done to identify personalities of individuals prone to the development of schizophrenia, so that early intervention is possible. One type of personality that is involved with a risk for schizophrenia is called schizotypy. People with this type of personality have features known as anhedonia (difficulty experiencing pleasure), cognitive slippage, ambivalence (uncertainty) and interpersonal aversiveness (preference to be alone). One theory is that individuals with some schizophrenia genes (schizotaxia) will have a necessary but not sufficient condition for the development of schizophrenia. In other words, they are members of a latent class (or taxon) within the general population who carry the genes but do not express schizophrenia fully. Instead they may show schizotypal personality traits. Some of the questionnaires that measure schizotypy include the Perceptual Aberration Scale (PAS), Magical Ideation Scale (MIS) and the Revised Social Anhedonia Scale (RSAS).

This study argues that it is unclear whether all 3 of these questionnaires are able to identify a common group of individuals who constitute the same (presumably genetically determined) latent group. So, the researchers used statistics to look at the independent and joint latent structures of the RSAS, MIS, and PAS in students from public universities. They wanted to see if the positive and negative traits in these questionnaires are able to identify a common group in the general population. They found that these 3 questionnaires, that were thought to tap the same latent class that was assumed to be schizotypy, actually do not share this property. They suggest that this might explain why there have been differences in studies that have used these questionnaires since they actually measure different causal processes within the clinical syndrome of schizophrenia or psychosis proneness more generally. Further research is needed to look at the characteristics and outcomes of individuals who actually have the taxa that is measured by both the RSAS and the PAS and/or MIS, so that we can understand what their roels are in schizophrenia. The authors argue that it doesn’t make sense to use these questionnaires to idenify a common latent class of people.

This research was supported by Grant MH-51240 from the National Institute of Mental Health.

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A Two-way Communication Checklist for Doctors Appointments

Evaluation of the Two-Way Communication Checklist as a clinical intervention. Results of a multinational randomized controlled trial.

Van Os J, Altamura AC, Bobes J, Gerlach J, Hellewell JS, Kasper S, Naber D, Robert P. Br J Psychiatry. 2004 Jan;184:79-83.

This European study used the Two-Way Communication Checklist (2-COM), which is a questionnaire that was developed with the aim of improving communication between patient and professionals. The 2-COM is a simple list of 20 common problems, or areas of perceived need that might be experienced by those with severe mental illness. The list includes problems with housing, relationships, money, lack of activities, psychological distress, sexuality, symptoms and treatment side-effects. In the study, patients are provided with the 2-COM prior to seeing their doctor and given simple instructions to help with its completion, guided on indicating which of the 20 problems apply to them and highlighting things they would like to discuss with their doctor during their clinic appointment. The authors report that using a completed checklist to guide discussion during the clinical interview extends the appointment by an average of 13 min.

In the study, individuals with schizophrenia were randomly assigned to either standard care with their doctor or additional use of the Two-Way Communication Checklist (2-COM) with their doctor. Before seeing their doctor for a routine follow-up, participants in the active intervention group were given the 2-COM. Outcomes were assessed immediately and again after 6 weeks. Using 2-COM resulted in a stable improvement of patient-reported quality of patient–doctor communication and perceived changes in management immediately after the intervention. The authors also report that although reported improvements in quality of communication were not influenced by the number or type of need, treatment change was more likely to occur in patients with higher levels of perceived need (e.g. inpatients). Furthermore, some needs such as the need for information about illness and treatment, were more likely to induce treatment changes than others. They suggest that the 2-COM produces needs-related changes in treatment immediately after the intervention, followed by a stable and durable improvement in quality of communication as perceived by the patient. As such, the 2-COM is a simple tool that can help people discuss their needs so that there can be better communication and changes in clinical management.

The limitations in this study include the possibility of bias by clinicians and patients in order to show that the 2-COM worked. Also, since the effect of the intervention was investigated over a period of 6 weeks; no conclusions can be drawn beyond that period. Furthermore, the results from this study suggest that patients with more perceived needs and greater levels of impairment are the ones who would benefit the most from 2-COM. Nevertheless, this study shows that structured communication about perceived needs can help in the treatment process.

The study was supported by an unrestricted grant from AstraZeneca. The authors state that AstraZeneca had no input into the design, conduct, analysis or reporting of the study.

The Checklist is available in various languages at:
Two-Way Communications Checklist (scroll to bottom of page for actual lists)

Click here to find the journal article on PubMed

Can the receptor for nicotine be a target for a new drug?

Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia

Laura F. Martin, William R. Kem and Robert Freedman

Psychopharmacology (Berl). 2004 Jun;174(1):54-64. Epub 2004 Feb 19.

People with schizophrenia have long been known to have high rates of cigarette smoking compared to the rest of the population. While many theories abound regarding the reason, it has been shown that people with schizophrenia often have a different reaction to nicotine in their brain compared to people without schizophrenia. This reaction to nicotine occurs at the nicotinic receptor. One thought is that nicotine may help with some of the difficulty people with schizophrenia have in regulating sensation. Many with schizophrenia have problems in sorting out important from unimportant stimuli. This ability is called "gating" and the authors of this study argue that perhaps nicotine (and also clozapine) may help improve this gating phenomenon in people with schizophrenia and therefore the nicotinic receptor may be a target for future medications to help with this problem.

So far, a prototype drug (called DMXBA) has been shown to have some benefit on learning and memory in mice (they are able to do a maze and a couple of other tasks seemingly better with this medicine.) To this point, it has shown this possible benefit in mice and has appeared to be safe for use in mice (though humans often react differently to medicines than mice.) There has been one study published with the prototype drug that showed some improvement in simple memory and organizational tasks for humans. Though there have only been small studies thus far, it appears that side effects are similar to placebo (sugar pill) even at doses higher than would be used for treatment. There were a few people who had a negative reaction in their liver (increased liver enzymes) as a result of this medication and clearly, larger studies would need to be done to evaluate safety in a larger population.

Overall, this may be a potential new target of therapy. Most likely, a drug of this type would not be used for the complete treatment of schizophrenia, but may help in addition to regular antipsychotic treatment. However, it will take some more years of research to further evaluate the safety and effectiveness of this type of medication before it can come to market.

This work was supported by the VA Medical Research Service, USPHS MH-61412, NARSAD, the Stanley Foundation, and the Institute for Children s Mental Disorders.

Click here for link to article on Pubmed

Patient and family attitudes toward schizophrenia treatment

Irani F, Dankert M, Siegel SJ.

Current Psychiatry Reports. 2004 Aug;6(4):283-8.

While each person has their own unique experiences and beliefs, this review focused on highlighting the current research on attitudes towards illness, medications, non-pharmacological treatment and psychiatric research.

This review highlighted the importance of considering both patient and family member attitudes for the treatment of schizophrenia. It discussed the involvement of family members in caring for affected loved ones, despite their subjective burden. Furthermore, it described studies showing that individuals with schizophrenia can sometimes have contradictory ideas (eg endorsing the need for continuous use of medication, yet reporting that they do not need psychiatric medication once they feel better and that they would not get sick if they stopped taking psychiatric medicine). In contrast, family members consistently report overwhelming support for the need for their loved one to take psychiatric medicine, even if they may be relatively hesitant to take medicine for their own physical ailments. The review further suggests that family members are also more aware of the risks associated with discontinuing treatment than individuals with schizophrenia. Furthermore, the review found that even when individuals with schizophrenia accept that they have a psychiatric illness, they are less likely to report symptoms and diagnoses consistent with their doctors. Such discrepancies between doctors and patients highlight the need for more open discussions about attitudes so that treatment plans can be most effective. This is particularly relevant when assessing side effect profiles of various medications. In terms of non-pharmacological treatments, the review suggests that therapy interventions with highly individualized and heterogeneous concepts of illness, etiology and a positive view regarding prognosis are most effective.

Attitudes towards depot, extended release medications and implantable medicine are also reviewed. Most studies convey a positive opinion of depot medication, although in one Australian study depots were seen as being unhelpful. Patients taking extended release formulation of psychiatric medications such as weekly fluoxetine have been reported to consider once-weekly dosing more convenient than daily dosing. Long-term delivery will be extended with the introduction of surgically implantable medicine that can provide uninterrupted access to psychiatric medication for up to one year. Results of a survey suggest that patients are almost equally split between favorably and not favorably considering such implantable medications.

With the advent of new treatments, the attitudes of patients, family members and health providers towards biomedical research can provide valuable direction for future interventions. This review found that patients, family and psychiatrists strongly support research participation due to increased hope and benefits to others that research participation provides. The data further suggested that patients may not be against clinical trials in principal, but maybe less likely to participate in placebo-controlled clinical trials. Furthermore, individuals with schizophrenia and family members offer strengths in assessing not only ethically important design elements of research in psychiatry, but also provide crucial information to guide the treatment of schizophrenia.

This work was supported in part by Stanley Medical Research Institute. The surveys and more information are available at http://stanley.med.upenn.edu/Surveys.html or scetp@bbl.med.upenn.edu

Click here to find this article on PubMed

Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q

Paunio T, Tuulio-Henriksson A, Hiekkalinna T, Perola M, Varilo T, Partonen T, Cannon TD, Lonnqvist J, Peltonen L.

Hum Mol Genet. 2004 Aug 15;13(16):1693-702. Epub 2004 Jun 15.

There is an endless search for genes involved in schizophrenia. The search has been difficult so far because there seem to be many genes affecting a number of functions in the brain. In this study, the authors tried to find genetic loci (loci=position for a gene) contributing to certain cognitive functions, by performing certain statistical analyses of genes collected from 168 Finnish schizophrenia families. Their strategy was unique since it identified the benefits of using traits (traits=characteristics that are inherited from parents) instead of clinical diagnoses. They analyzed traits associated with vulnerability to schizophrenia and those that appeared to be heritable in families.

They found evidence for loci for verbal learning and memory on chromosome 4q21 and for visual working memory on 2q36. Both of these chromosomes have been previously implicated in genetic susceptibility for schizophrenia. Some evidence also emerged for a locus for recognition memory on 10p13 (which other researchers have also found), visual attention on 15q22 and executive function on 9p22. They also found evidence for delayed memory on 8q12, semantic clustering and intrusions on 1q42 and visual attention on 3p25. In addition to these regions, some evidence of linkage was observed for 2q, 6q, 7q, 11q, 13q, 14q, 18q and 22q.

The authors state that their results emphasize the value of trait components in the search for susceptibility loci for complex illnesses. This is because in all these loci the information was increased by looking at quantitative traits instead of just a dichotomous trait definition. Although we have a long way to go before we can clearly identify the genes involved in this complex illness, such work provides another strategy for trying to find these genes so that we can understand their role in affecting the brain. Hopefully in the future, finding the genes involved in schizophrenia can help with early identification and intervention strategies.

All data, including the complete list of markers as well as the two-point and multipoint LOD scores in all samples, can also be found at their website: http://www.ktl.fi/mols/wwwpub.htm.

This work was supported in part by Millennium Pharmaceuticals, Inc., Wyeth-Ayerst Research Division and Emil Aaltonen Foundation (T.H).

Click here to find this article on PubMed

Social cognition and face processing in schizophrenia

Hall J, Harris JM, Sprengelmeyer R, Sprengelmeyer A, Young AW, Santos IM, Johnstone EC, Lawrie SM. The British Journal of Psychiatry (2004) 185: 169-170

Many people with schizophrenia describe difficulty with social function. Different areas of the brain are thought to be involved in recognizing emotion in faces (ie. parts of the brain known as the amygdala, insula and basal ganglia). More complex social judgments are believed to depend upon an interaction between different parts of the brain (prefrontal cortex and temporal lobe). Researchers have suggested that some of these brain regions (e.g. amygdala, prefrontal and superior temporal cortex) are reduced in volume in schizophrenia.

Since a lot of social information is gathered by observing faces, this study focused on how people recognize emotions and make social judgments based on faces. The researchers asked 20 people with schizophrenia and 20 without the illness, to identify faces, recognize emotions on faces and make social judgments based on faces. They found that while everyone did well in identifying faces, those with schizophrenia had difficulties recognizing emotion on people’s faces and making social judgments based on facial expressions. This was particularly true for those experiencing positive symptoms (e.g. voices, thought disturbances). They used statistical analyses to confirm that none of the effects could be accounted for by variations in illness duration, medications or depression. The authors argue that their results are unlikely to be due to a general problem in facial information processing, since everyone in their study was able to recognize the identity of faces. Instead, since making complex social judgments from faces requires interaction between certain areas of the brain that seem to be structurally abnormal in schizophrenia (i.e. frontal and temporal regions), they suggest that difficulties in social thinking may be a core difficulty of schizophrenia, which is likely to be related to these abnormal brain regions.

They also suggest that since positive symptoms seem to affect the ability to identify basic facial emotions, the brain regions involved in facial emotion recognition (e.g. amygdala) may get impaired during psychotic episodes, or the ability to compensate for deficits in these regions may fail when positive symptoms develop. Such work has implications for treatment since such information can be used to help strengthen weaknesses in such social and emotional recognition dimensions during clinical psychosocial treatments.

The study was funded by the Stanley Medical Research Institute.

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Impact of multiple-family groups for outpatients with schizophrenia on caregivers' distress and resources.

Hazel NA, McDonell MG, Short RA, Berry CM, Voss WD, Rodgers ML, Dyck DG.
Psychiatric Services. 2004 Jan;55(1):35-41.

Family-member caregivers of people with schizophrenia can have substantial demands placed on their personal, financial, social, and/or emotional resources. Multiple-family group family treatment integrates elements of psychoeducation and behavioral family therapy in a group format with two clinicians and six to eight families. This approach provides information and problem-solving experiences to family members and consumers. The treatment begins with a three-session joining phase, where the clinician’s goal is to develop a solid alliance with the family and consumer, gain information about history, impact of illness and resources available for managing it. Next there is a one-day psychoeducational workshop, followed by one year of bimonthly group sessions focusing on relapse prevention. Finally, there is a year of monthly group sessions that focus on social and career rehabilitation.

Research suggests that multiple-family group treatment has a positive effect on consumers' negative symptoms, use of inpatient and outpatient services and relapse. But, the literature is inconclusive about this treatment’s effect on caregivers' well-being. As a result, this study reexamined the impact of multiple-family group treatment on caregivers' outcomes by focusing more specifically on caregivers' distress. They found that over the two-year course of the intervention, caregivers of persons who received multiple-family group treatment experienced greater reductions in distress when compared to caregivers of consumers who received standard psychiatric care.

They also found that contrary to what they expected, there were no significant differences between the multiple-family and standard treatment groups, with respect to increases in caregivers' resources. This could have been because of statistical reasons (low power because people dropped out) or the measures used to assess resources. Also, there is question about whether the baseline for the groups was different to begin with. It is also possible that multiple-family group treatment simply does not have an effect on psychosocial resources of caregivers.

This study suggests that modifications to multiple-family group intervention may be necessary to positively affect the resources of family caregivers. This could include breakout groups designed to address assessment and improvement of caregivers' resources. Also, further research is needed to see whether multiple-family group treatment can also affect caregivers' physical and psychological health, as well as to determine the mechanisms by which this treatment helps caregivers. Nevertheless it is encouraging to see research on more family driven treatments that focus on both the consumer and the caregiver.

This study was supported by grant R01-52259 from the National Institute of Mental Health

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online medical dictionary

While we try to make sure that all the difficult terms are defined in each writeup, inevitably some may still be hard to understand. Here is a good online, searchable medical dictionary put on by pubmed that may help alleviate some problems with understanding the vocabulary you may encounter while looking at some of these articles. Let us know if this is helpful...
Jake and Farzin

link to online medical dictionary

An initial trial of 4 new possible meds for schizophrenia

Meltzer HY, et al., Placebo-Controlled Evaluation of Four Novel Compounds for the Treatment of Schizophrenia and Schizoaffective Disorder. Am J Psychiatry 2004; 161:975–984.

This article is about a trial of 4 new types of antipsychotic medications at the beginning of their testing on people with schizophrenia. As the mechanism of schizophrenia is only partially understood, there is still room to discover new activities in the brain that may contribute to the symptoms that are visible on the outside. Traditionally, antipsychotic medications have focused on the neurotransmitter dopamine which is a chemical in the brain that when too abundant in particular areas can cause hallucinations, delusions and other symptoms. Newer antipsychotics have become more focused in certain dopamine receptors and have also targeted other neurotransmitters receptor sites in order to help minimize side effects. The medications in this study all target new receptors in the brain and work in ways significantly differently than the medications currently on the market. Each of these receptors are like keyholes in which a molecule called a neurotransmitter is the key that helps turn on or turn off various activity in brain cells. They naturally exist in the brain for various purposes but can be altered in schizophrenia and therefore may be targets for new medications. Of the 4 medications in this trial, one targets a cannabinoid receptor, another works on a specific type of serotonin receptor, another works at a neurokinin receptor and the last works as a blocker of the neurotensin receptor.

To study these medications, the authors of the study compared these new compounds to haloperidol (Haldol ®) and to a sugar pill or placebo. Ultimately, 2 of the medicines (the one that worked on the neurokinin receptor and the serotonin receptor drug) worked as well as haloperidol in certain aspects and will warrant further study. Neither drug worked better than Haldol though each may ultimately have subtle benefits that might make them more useful in particular patients. Also, they may have fewer side effects than Haldol, however longer term studies will need to be done in order better estimate side effect profiles. It is encouraging that in this study, none of the drugs studied had any more side effects than placebo.

This study is encouraging because it shows that there are new molecules being tested to treat schizophrenia. While none of these are a magic bullet, two of the four medicines will be further studied and may make contributions to the armamentarium we have to treat schizophrenia. Despite these advances, much more testing will be needed on these medications, both in terms of safety and effectiveness, before they will be ready to come to market.

This trial was sponsored by Sanofi-Synthelabo Research which developed each of these medicines.

link to the article on pubmed

Schizophrenia, the metabolic syndrome and diabetes

Holt RIG, et al., Schizophrenia, the metabolic syndrome and diabetes. Diabetic Medicine 21, 515–523 (2004)

Diabetes has been associated with schizophrenia for over a hundred years. However, it has become increasingly problematic as many of the 2nd generation antipsychotics have been linked to insulin resistance and diabetes. This article discusses the relationship between diabetes, the metabolic syndrome (which includes low HDL [good cholesterol], high LDL [bad cholesterol], elevated triglycerides, obesity, and hypertension.) This is a review article which looked at 289 papers about this subject. The metabolic syndrome and diabetes are associated with significantly higher risk for heart disease and early death. There are hereditary factors involved in schizophrenia, metabolic syndrome and diabetes and nearly 30% of people with schizophrenia have a first degree relative with type 2 (adult onset) diabetes. There also may be psychosocial and societal factors (including poverty and poor nutrition) that have an impact on these factors. Further research needs to be done to fully uncover the mechanism behind why 2nd generation antipsychotics cause these problems and why people with schizophrenia have a higher risk for metabolic complications. Ultimately, this article makes the point that diabetes, hypertension, obesity and lipid levels need to be followed by members of the healthcare system who take care of patients with schizophrenia.

link to the article on pubmed

Can Pepcid help people with weight loss? Unfortunately, not likely...

Poyurovsky M, et al., The effect of famotidine addition on olanzapine-induced weight gain in first-episode schizophrenia patients: a double-blind placebo-controlled pilot study. European Neuropsychopharmacology 14 (2004) 332–336

It is widely known that olanzapine (Zyprexa®) is one of the 2nd generation antipsychotic medications that is most strongly associated with weight gain. These authors investigated the use of the drug famotidine (Pepcid®) which blocks histamine receptors (H2 receptors) and is normally used in the prevention of heartburn. Histimine is a neurotransmitter (neurotransmitters are chemicals in the brain that turn on or turn off brain cells) that has influence on many processes in the brain, including weight gain. (Histamine is probably more familiar though as a part of allergies, which is why people take antihistamines like benadryl or claritin, however histamine in that context is working at a different receptor, call H1, while here we are talking about the H2 receptor.)There has been some evidence in rats that blocking the H2 receptor (receptor is where the drug or the neurotransmitter acts on a brain cell, like the lock where the chemical is the key) may help to prevent weight gain, however it has not been shown in humans. In this study, First episode patients were chosen because they seem to be at a highest risk for weight gain with olanzapine. This study showed that there was no difference in weight gain between those who took famotidine and those who received a placebo. This study is limited by the fact that it had a small number of patients, the protocol did not allow for changes in dose with either the famotidine or the olanzapine, and the trial was short. However, in a previous study with another H2 antagonist (same mechanism of drug as famotidine), the beneficial effect on weight gain was only seen initially and was gone by week 16 of the trial. Overall, this study supports the evidence that H2 antagonists do not have an effect on the weight gain risks associated with olanzapine.

link to article on pubmed

Topical anesthetics help with depot injections

Psychiatr Serv. 2004 Aug;55(8):940-1.

Use of topical application of lidocaine-prilocaine cream to reduce
injection-site pain of depot antipsychotics.

Bloch Y, Levkovitz Y, Atshuler A, Dvoretzki V, Fenning S, Ratzoni G

This article explores a new way to help make giving long term injectable (depot) medicines less painful. Long term medications are useful because they help to insure adherence to a medication program in that a patient only has to come to a clinic one time every two weeks or every month to receive a shot and does not have to take pills every day. As more of the newer antipsychotics are being prepared in this fashion (i.e. long acting risperidone aka Risperdal Consta, but the other drugs are being developed in long term preparations) this method of dispensing medication is likely to increase. However, this leads to many injections over the course of the year and patients often complain of and can be fearful of the pain associated with the injection. The technique in this article involves putting on an anesthetic (numbing) cream one hour prior to receiving the injection. Fifteen patients were selected and received either the cream or a moisturizer (placebo) on one injection and then received the other on their next injection. In both cases, neither the nurse who gave the shot nor the patient knew what kind of cream they received. Patients were then asked to rate the pain they experienced with the injection by pointing to visual or picture representation of pain.

As what was expected, the patients who received the anesthetic cream had significantly less pain reported compared to those who received simply a moisturizing cream. The authors note that one drawback of this type of pain relief is that it takes an hour prior to the injection for the cream to work. However, patients could be given the cream to take at home or would have to spend an extra hour in the clinic to wait for the medicine to work. Either way, for patients currently on depot medications, like Haldol Decanoate, Prolixin Decanoate or Risperdal Consta this may be something to ask for before receiving what can be a painful injection.

link to the article on pubmed

A review of Valproate (Depakote) as a booster medicine for schizophrenia

Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials.
Basan A, Kissling W, Leucht S.
Schizophr Res. 2004 Sep 1;70(1):33-7.

This article takes a systematic look at the literature regarding the efficacy of using valproic acid (Depakote) as an adjunctive (additional to an antipsychotic) medication for schizophrenia. This medicine is a mood stabilizer and is typically a first line drug for treating bipolar disorder. However, it has properties that may make it useful in people with schizophrenia. It targets a neurotransmitter (chemical in the brain that turns on or off neurons or brain cells) called GABA which is a neurotransmitter that typically has a turning-off effect on brain cells. Some of these cells are involved in the production of dopamine which is a neurotransmitter that is associated, when in too high of a level, with the positive symptoms of schizophrenia (hallucinations, delusions, paranoia, bizarre thinking) and when in too little concentration, with the movement side effects seen with certain medications, like haloperidol/Haldol.

These authors searched the literature and came up with several articles that seemed relevant. Upon applying certain standards, five articles met the eligibility requirement to be included in the review and meta-analysis. (A meta-analysis is where the data from several studies are compiled together and analyzed as a group.) The results presented in this paper are equivocal at best. There are upsides and downsides to polypharmacy (the use of more than one medication to treat a particular condition.) On the one hand, the more meds you have someone take, the greater risk there is for side effects and drug interactions. Valproic acid has problems with weight gain and liver toxicity and that is true with other antipsychotics which can make for a problem. However, there is some minor evidence that valproic acid may help speed up the initial recovery of someone when starting or restarting them on antipsychotic medication. That can be useful if they only have a short time in the hospital and cannot afford to wait the couple of weeks to get full effect by the antipsychotic alone. However, the benefit wears out and was gone by the end of the study that showed this benefit, so it is unclear whether it means that the valproic acid should be continued or stopped after the acute situation resolves. Small trials have suggested that there may be a general decrease in negative symptoms (flat affect, constricted emotions, low energy, low motivation, poor hygiene) that is sometimes the most debilitating aspect of schizophrenia for many people. It does seem though, that valproic acid is useful in the case of schizoaffective disorder when there is a need for mood stability. It also seems to have a place for the aggressive or violent patient who has frequent outbursts and can benefit from some stabilization of their mood.

Overall, should you ask the doctor to start valproic acid for you or your loved one? Well, if they are already stable on medication, it is not something that they need to have. If they aren’t doing well, it might be worth a try to add it if there are no strong reasons to stay away from it (poor liver function, pregnancy or intent to become pregnant or history of weight gain or nonresponse to valproic acid.) The data currently is inconclusive to the benefit for valproic acid augmentation and therefore it is not possible to give a blanket recommendation one way or the other. However, if things are not working, it might be worth a try if it hasn’t been tried in the past.

link to abstract on pubmed

Medical decision making in antipsychotic drug choice for schizophrenia.

Medical decision making in antipsychotic drug choice for schizophrenia.
Hamann J, Langer B, Leucht S, Busch R, Kissling W
Am J Psychiatry. 2004 Jul;161(7):1301-4.

This article seeks to discern what factors are associated with prescribing patterns amongst physicians in the community. The authors looked at practices in Germany; 50 hospital based and 50 private practice psychiatrists. They conducted survey and followed prescriptions patterns with these doctors to see what their attitudes were towards newer versus older medications and other important treatment decisions. The groups differed in a couple of important ways. The hospital based psychiatrists were on the average 10 years younger and had been in practice less time, though were closer to their training.

The authors report that older patients, patients with more severe positive symptoms (hallucinations, delusions, paranoia, bizarre thinking), and those with a longer duration of illness were more likely to receive the first generation antipsychotics (i.e. haloperidol/Haldol, fluphenazine/Prolixin, etc.) versus the second generation antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, clozapine, aripiprazole.) However, people who requested newer medications or who had a history of a bad reaction with particular med were more likely to receive the newer medications. However, the only statistically significant predictor of receiving an older medication was the age of the physician (by up to 5 fold.) The other factors were important, but did not meet statistical significance. However, there were a small number of physicians polled and a small number of prescriptions written for older antipsychotics regardless of any factor.

While older physicians were more likely to use older drugs, that may be a factor of their being more used to them than the younger doctors. This may not always be a bad thing, new drugs are expensive and not always more effective or with fewer side effects than older meds, however it just brings to light the importance of advocacy for yourself or your loved one when a physician suggests a treatment. Advocacy on your own behalf for a newer medication may make the difference between trying an older one first or just going to the newer medicine right away. This decision is not always totally the doctor’s decision, but when funding is not an impediment to drug choice, appropriate assertiveness by patients and families can help influence the ultimate choice in treatment.

This work was funded by unrestricted grants from Sanofi Synthelabo, Germany, and Astra Zeneca, Germany.

link to article on pubmed

Predictors of antipsychotic treatment response in patients with first-episode schizophrenia

Br J Psychiatry. 2004 Jul;185:18-24

Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders.

Perkins D, Lieberman J, Gu H, Tohen M, McEvoy J, Green A, Zipursky R, Strakowski S, Sharma T, Kahn R, Gur R, Tollefson G; HGDH Research Group.

This article addresses factors that are correlated with better treatment outcomes in people newly diagnosed with schizophrenia. They primarily are looking at the duration of untreated psychosis (DUP). The subjects were chosen from a study looking at haloperidol and olanzapine in new onset schizophrenia/psychotic disorder. Looking at a number of different factors, the authors conclude that there is evidence that the earlier someone with psychosis is treated and the higher level of function they have when treated, the faster they are likely to respond to antipsychotic medications. This effect is small however, meaning that there are still several other factors that effect treatment response, though many of those are not fully known.

This is an interesting study though the results are not terribly surprising. This study does a reasonable job of trying to account for various variables that could confound the results by controlling for them in the two groups. It is not done perfectly, there are patients who drop out of the study and we do not know what happened to them, but overall the authors make a very valid point that if someone has new onset psychotic symptoms, it is better to get them treatment as soon as possible and before they lose their ability to function.

Declaration of interest This work was supported by Lilly Research Laboratories and USPHS grants MH01905-01 (D.O.P.) MH00537, MH33127 ( J.A.L.) the UNC Mental Health and Neuroscience Clinical Research Centre, the North Carolina Foundation of Hope,MH52376 andMH62157 (A.I.G.).

link to the article on pubmed

Family-based clusters of cognitive test performance in familial schizophrenia

Authors: Fabian Hoti, Annamari Tuulio-Henriksson, Jari Haukka, Timo Partonen, Lasse Holmstrom and Jouko Lonnqvist

BMC Psychiatry, 4(20), July 2004

Previous studies have shown that schizophrenia results in impairments on some neuropsychological tests involving attention, memory, executive functioning, and intelligence. As a result, traits derived from neuropsychological tests have been suggested as one type of endophenotype, which is an expression of an underlying genetic vulnerability. This study is the first to use a new visually aided clustering approach (for statistical analysis) to look at cognitive performance of families as well as individuals with schizophrenia.

The authors gave neuropsychological tests to 54 randomly selected families where at least two siblings had schizophrenia. They found three types of clusters - well-performing, impaired, and intermediate clusters. In the well-performing cluster, both patients and family members received the highest scores in each cognitive test. The intermediate cluster scored consistently between the impaired and well performing cluster. However, clusters of families did not differ from each other in age, sex distribution and other clinical features. The well-performing cluster was significantly more educated than the others, but controlling for education years did not change the main results. This finding brings up the issue that further research is needed to identify factors that protect cognitive development in some people. But, from this study it seems that it may be possible to identify high risk for future schizophrenia by using multiple cognitive measures as possible endophenotypes.

However, this study is limited since it only included families where multiple individuals suffered from schizophrenia, which represents only about one fifth of all schizophrenia cases. So, the results may not be generalizable to families where there is only one person suffering from the illness. Also, the set of neuropsychological measures that were used did not cover all the cognitive domains that previous studies have suggested as endophenotypes. The lack of a control group also prevents testing the possibility that the same clustering solution could also emerge in families where there is no schizophrenia. Nevertheless, this study provides further support for the use of cognitive traits as valid endophenotypes to be used in genetic studies of schizophrenia.

Abstract: Family-based clusters of cognitive test performance in familial schizophrenia