Treating Cognition in Schizophrenia: Atomoxetine and Cognitive Remediation
Persons with schizophrenia, despite receiving optimal doses of antipsychotic medications that reduce or entirely obliterate psychotic symptoms, still fail to fully recover function. Research has shown that it is the cognitive dysfunction along with the negative symptoms that account for persistent psychosocial dysfunction.
The field has recently taken on the task of identifying, testing, and developing new treatments for cognitive dysfunction in schizophrenia through the NIMH-sponsored MATRICS and TURNS projects. The work of these groups is partially completed and they have defined for us (1) the nature of the cognitive dysfunction, (2) a battery of recommended neuropsychological tests to assess these cognitive features, and (3) likely molecular targets for cognitive enhancement (Psychopharmacology, June, 2004).
Based on a considerable basic literature, we have been impressed that it may not only be a drug treatment (e.g., atomoxetine in this application) but also psychological approaches (e.g., cognitive remediation, in this application) that are needed to work together to optimally improve cognition in schizophrenia. Therefore, we have developed the hypothesis that the use of cognitive remediation in the context of a cognitive enhancing medication will be necessary for optimal cognitive improvement in schizophrenia.
But, little direct preliminary data exist to suggest which drug and which cognitive approach may be effective, nor what the parameters of response to expect (e.g., effect size; response rate; attrition). Therefore, we are piloting the medication atomoxetine (to target one of MATRICS’s highest-scored molecular targets: the D1 dopamine receptor in prefrontal cortex) along with a cognitive remediation routine (one that is already developed and has shown promise by itself in preliminary studies) for the treatment of cognitive dysfunction in schizophrenia. We apply each putative treatment alone and combined, in a standard four cell design, and evaluate neuropsychological function as the primary outcome measure, and we collect preliminary data on psychosocial improvements occurring with treatment, to determine its time course.
A Randomized Double-Blind, Placebo-Controlled Study to Demonstrate the Cognitive Enhancing Effects of BF2.649 in Schizophrenia and Schizoaffective Patients
BF2.649 is an antagonist at the histamine H3 receptor, and an indirect acting agonist of the histamine system by way of its H3 autoreceptor affinity. This protocol will test BF2.649 for its effect on improving cognitive function in schizophrenia.
We will recruit persons with schizophrenia or schizoaffective disease who are currently in a stable phase of their illness, but still display cognitive symptoms and have consequent psychosocial dysfunction. Each qualifying recruit will either be taking a second generation antipsychotic drug (APD) (the specific allowed drugs, to be discussed) or be willing to change to such a drug. We will select an antipsychotic drug(s) with low histamine affinity; aripiprazole is a qualifying antipsychotic. Each study subject will spend 4 weeks on a fixed dose of APD with stable symptoms, during which time the baseline workup will be completed. At the beginning of the double-blind phase of the protocol (study week 5), each study subject will have a full symptom assessment, side effects, and neuropsychological battery along with the full chemistry and baseline safety study workup. Then, each subject (while remaining on their APD) will be randomized to BF2.649 or placebo. The dose of BF2.649 will be 40 mg/day.
Assessment of safety parameters and side effects will occur once weekly for the first 4 weeks (through study week 8) and then every other week for the next 8 weeks (to study week 16). Symptomatic outcome measures will be measured during the double blind phase weekly for the first 4 weeks (through study week 8) and monthly thereafter. The neuropsychological battery will be done first at medication start (study week 4) and repeated at the end of the 12 week double blind phase (study week 16). At the end of 12 weeks (study week 16), the double blinded drug will be stopped and the patient followed weekly for the next 4 weeks with clinical, safety, and side effect measures( study week 20). Each study participant will be seen weekly throughout the protocol for clinical assessment.
A Randomized Double-Blind, Placebo-Controlled Study to Demonstrate the Effects of Pramlintide on Weight Reduction in Clozapine- and Olanzapine- Induced Weight Gain in Obese People Diagnosed with Schizophrenia
The majority of people with schizophrenia are treated with second generation antipsychotic drugs, the best of which are clozapine and olanzapine. Each of these drugs cause significant weight gain at an average of 2 kg/month and often greater in individual people. Over the course of 1 year of treatment, reports of 60 pounds of weight gain are not uncommon.
In addition, associated with the weight gain but often expressed independently, these drugs can produce aspects of the metabolic syndrome, including increases in cholesterol, triglycerides, and frank diabetes with insulin insensitivity. Olanzapine is an antipsychotic drug with demonstrated effectiveness in the treatment of schizophrenia; there are some indications that it has some superior action; therefore, a mechanism to treat olanzapine-induced weight gain and the associated metabolic symptoms would be a great asset to patients using this drug.
Drug treatments that could reduce or treat the weight gain and metabolic symptoms would permit many people with schizophrenia to continue to receive the benefits of olanzapine and clozapine with reduced side effect burden. Providing effective treatments for the drug-induced weight gain and metabolic symptoms could also influence the choice of these drugs prescribed for this indication.
Pramlintide is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Amylin is a 37-amino peptide; it is colocalized with insulin in secretory granules in the pancreas and co-secreted with insulin by pancreatic beta cells in response to food intake. Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms. Amylin slows gastric emptying, without altering the overall absorption of nutrients.
In addition, amylin suppresses glucagon secretion, which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally mediated modulation of appetite. Pramlintide demonstrates these actions of amylin in the animal and human. It augments the effects of insulin on glucose control in diabetes and it reduces appetite, suggesting its independent application in treating obesity. Moreover, pramlintide has been shown to reduce weight gain in olanzapine-treated laboratory animals (Amylin data), suggesting its application in olanzapine-induced weight gain in humans.