Medscape: The most recent results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), published in March 2007, indicate that patients' psychosocial improvement was modest no matter which medication they received during the 18 months of observation. The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) from Britain also found that the type of antipsychotic medication was not all that important for outcome. What do you think are the implications of these studies?

Henry A. Nasrallah, MD: These 2 effectiveness studies have caused some confusion because they suggest that there are few differences in effectiveness between the first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). However, there are variables in the studies that may modify that conclusion. In CATIE, for instance, the objective was to compare FGAs with SGAs and to compare SGAs with each other. But unfortunately, for ethical reasons, investigators did not expose patients with tardive dyskinesia to an FGA. Tardive dyskinesia is a severe extrapyramidal side effect (EPS) that develops in patients who usually first have acute EPS. The 231 subjects with tardive dyskinesia represented the patients with chronic schizophrenia who are most vulnerable to acute EPS, and clinicians often choose SGAs precisely to avoid EPS. In CATIE, we missed the opportunity -- for understandable, ethical reasons -- to learn whether, during an 18-month period, patients with tardive dyskinesia randomly assigned to an FGA or an SGA would have fared differently in terms of acute movement disorders, intolerability, rates of discontinuation, and treatment response. In these patients, investigators could only compare the SGAs among themselves.

The patients with tardive dyskinesia were different in other ways from the other patients: they had significantly more substance abuse and a higher severity of illness as measured by the Positive and Negative Syndrome Scale (PANSS). By assigning them only to SGAs, investigators also missed the opportunity to examine the differential response of patients with severe illness and concurrent substance-use disorders to old and new drugs.

CUtLASS was different. Many of its patients took FGAs and often received them as depot injections, unlike CATIE in which more patients took SGAs. The CUtLASS study had flaws, including the fact that sulpiride, which many patients took, was considered to be an FGA. Quite a few psychiatrists consider sulpiride to be an SGA.

Medscape: You mentioned depot medication, and you recently wrote an article advocating for more use of depot antipsychotic medication. Can you discuss your rationale?

Dr. Nasrallah: Yes, I have long advocated for depot medications, even before CATIE, because as a clinician and researcher, I have no doubt that one of the greatest problems in the treatment of schizophrenia is lack of adherence and repeated psychotic relapse. My opinion, which is shared by many researchers, is that recurrent relapses are neurotoxic and may account for the deteriorating course of patients with schizophrenia. It is of utmost importance to help patients with schizophrenia stay on their medications and avoid relapse.

In community and outpatient settings, 70%-80% of patients are either partially or totally noncompliant. This is unacceptable if the goal is to achieve recovery. Patients with schizophrenia would have much better outcomes than we usually achieve if they were protected from relapses by ensuring treatment adherence from the first episode. But we have no study of first-episode patients assigned to a guaranteed-adherence regimen, which would be depot medication, vs treatment as usual with oral medication.

Medscape: We now have a choice between the first-generation depot antipsychotics and risperidone depot. How important do you think the decision is to use depot vs oral medication? Do you think it matters whether a clinician chooses one or the other?

Dr. Nasrallah: The FGA depot medications do protect against relapse; however, they do not appear to restore the patient's functioning over time. A confounder in looking at outcomes with FGA depot medications is that we have tended to use them in the patients who have had repeated relapses, [which is] an unrepresentative group of patients who have already deteriorated, who lead chaotic lives, and who likely have substance abuse, poor insight, cognitive deficits, and low motivation. These difficult patients, the 5%-10% who, during the past 30 years, received haloperidol decanoate or fluphenazine decanoate, do not represent the possible outcome of patients who might receive depot medication early in the course of illness.

Clinicians were reluctant to use injectable FGAs because of concern about tardive dyskinesia, but the oral FGAs have the same risk. So we never learned, even though these depot FGAs have been around for 30 years, much about their efficacy in the average patient except in some small studies in which the injectable form was superior to the oral form of the same medication. They do protect relapse better than the oral medication.

Now we have risperidone depot, the first long-acting SGA, and I hope others come to the market in the near future. In my experience with risperidone depot, it not only protects against relapse, it also helps restore function, especially after about 1 year of use. Patients have to stick with it, and in the second year they may experience a restoration of social functioning, such as a capacity for part-time employment or school enrollment, which may become even more striking in the third year. I have had patients stay on it for 4 years, and it is amazing to me how much better these patients function.

Medscape: Do you have any data or a study you could point me toward that documents these outcomes?

Dr. Nasrallah: So far there are no published data. What I just described is my experience with a few patients who remained on risperidone depot after the original 3-month clinical trial ended in the late 1990s and early 2000. Several of my colleagues had similar experiences with patients who were kept on risperidone depot. I urged the company to gather information on those patients and publish at least a descriptive report, but it never did.

I believe that SGAs have a therapeutic effect in addition to relapse prevention, which I attribute to a neuroprotective effect. The FGAs do not seem to reverse brain-tissue loss or induce brain-derived neurotrophic factor, whereas research has accumulated during the last few years indicating that SGAs are likely to do that and thereby may allow the brain to restore some of the tissue it has lost. I think that's why it takes a long time to see the beneficial effects of SGAs. Initially, their effects look the same as FGAs, although they may cause slightly less EPS. After a year or more, the beneficial effect of enhanced neurogenesis may start paying off.

Medscape: I'd like to switch topics now. Would you discuss any new antipsychotic agents that are in late-stage development or any medications with novel mechanisms of action that might be coming on the scene?

Dr. Nasrallah: Yes. We have a couple of new formulations. One of them may be considered a new drug, which is paliperidone, or 9-hydroxy risperidone, an active metabolite of risperidone. At first blush, it looks like the same drug, but it behaves differently and is in a special formulation. It has minimal requirements for cytochrome oxidation and is excreted directly by the kidney, unlike risperidone, which is oxidized completely. This offers an advantage for patients with advanced liver disease, severe alcoholism, or hepatitis. Moreover, paliperidone does not compete for metabolism with other medications that another physician may prescribe, and it causes no cytochrome inhibition or induction that could lead to drug interactions. A third advantage is the osmotic release oral delivery system (OROS) technology that enables paliperidone to be released slowly during its transit through the gastrointestinal tract, which means fewer side effects because of the gradual rise in blood level. The recommended dose is 6 mg starting from day 1 -- no need to titrate, and in my opinion, patients get better somewhat quicker.

The other product coming to market very soon, probably within a month, is quetiapine extended-release. Quetiapine is not a new drug, but the slow-release formulation will enable clinicians to use doses of 300, 600, or 900 mg once a day, which may improve compliance because regular quetiapine is taken twice daily.

A drug that may be marketed later this year is bifeprunox, a partial D-2 agonist like aripiprazole. It doesn't yet have a trade name and is a joint venture of Solvay and Wyeth. Its advantage is a good metabolic profile, with minimal weight gain and minimal serum lipid and glucose elevations.

No new-mechanism drugs are coming to market. I wish there were some. Researchers are frantically working to understand the glutamate pathways, and especially the N-methly-D-aspartate (NMDA) receptor, which we highly suspect is involved in schizophrenia. But we do not yet have any breakthroughs.

Medscape: You are involved in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Is there anything that you can tell readers about progress in that endeavor?

Dr. Nasrallah: Cognition is the single most important area in schizophrenia right now, and cognitive deficits are a core feature of the illness, perhaps more than positive symptoms. Clinicians know how to eliminate or reduce positive symptoms -- delusions and hallucinations -- pretty quickly, yet are left with patients who cannot go back to school or work. Cognitive deficits are keeping patients from working and being socially adept. In fact, we have a whole body of literature now showing that patients with schizophrenia have cognitive deficits in several domains that place them at 1-2 standard deviations below the general population. They are not mentally retarded, but they are impaired in memory, attention, visuospatial abilities, learning abilities, and executive function. When we treat schizophrenia for the psychosis, we hardly touch cognition. The SGAs have been touted as helping cognitive function, but when you look at the data, the improvement is not enough to write home about.

The National Institutes of Mental Health has funded MATRICS to stimulate research and development of medications for treating cognitive dysfunction in schizophrenia. Several potential mechanisms of drug action are being investigated, including alpha-7 nicotinic receptor agonists, because nicotinic receptors seem to be related to the P50 abnormality in schizophrenia. Dopamine-1 receptor agonists are also relevant to cognition, and in the glutamate system, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor may be more involved in cognitive deficits than dopamine pathways, although low dopamine in the frontal lobe is thought to account for some of the executive dysfunction. Other approaches are NMDA receptor agonists, metabotropic glutamate receptor agonists, glycine reuptake inhibitors, muscarinic type-1 receptor agonists, and GABA-subtype receptor agonists. These mechanisms are being studied by various groups, and I am participating in one study that is now underway and one that starts within a couple of months using agents specifically to improve cognition in schizophrenia.

If any of these agents turns out to improve cognitive function significantly better than placebo, clinicians will likely use it in combination with an antipsychotic and perhaps a third drug for mood or negative symptoms. We should eventually be able to devise rational combination therapies for schizophrenia.

Medscape: The ultimate goal of treatment is to improve a patient's function, and we know that certain psychosocial interventions help in that regard, but they are often not that available to our patients. What do you think the outlook is for improving availability of these interventions for the majority of patients with schizophrenia?

Dr. Nasrallah: Psychosocial interventions are offered in some community mental health centers, but I'm not sure they're done properly and in a focused way. I think that in order for a psychosocial intervention to pay off, you need to improve the patients' cognitive function. You can talk to the patients all day long, do social skills training and vocational rehabilitation, but if the brain isn't absorbing the knowledge it's wasted effort. So once we develop effective cognitive enhancers, it will help the psychosocial interventions tremendously.

Medscape: A growing concern is the metabolic disorder that patients with schizophrenia develop. You recently investigated heart disease, diabetes, and weight gain in the CATIE data.

Dr. Nasrallah: Yes, I analyzed data from CATIE as part of the metabolic working group and am presenting the findings at the 2007 Society of Biological Psychiatry and American Psychiatric Association meetings. Because several investigators had found that patients who gain weight seem to respond better, a statistician and I examined the relationship between weight gain and therapeutic response. We found a strong relationship between weight gain and improvement on PANSS positive-symptom and total scores across all the medications prescribed in CATIE, whether FGA or SGA. In each case, the more the weight gain, the lower the psychosis score at the end of the study.

This finding suggests that weight gain is part and parcel of improvement, although excessive weight gain, which happens with some of the SGAs, is not necessary. We know that patients with schizophrenia already have high risk for metabolic syndrome with and without antipsychotic treatment, and they tend to be poorly treated for diabetes, hyperlipidemia, and hypertension.

MEDSCAPE: Not to mention their high prevalence of tobacco use, of course.

Dr. Nasrallah: Yes, smoking and limited physical activity contribute to their early mortality; the latest studies show that the average patient with schizophrenia loses as many as 30 years of life compared with people in the general population. This is a public health emergency, and we should make efforts to give them better medical care, not just mental-health care.

You asked me about psychosocial treatment a minute ago, and I said some patients are receiving it but it's not paying off. What should be done more urgently, because it's a matter of life and death, is have community mental health centers provide a physician or nurse practitioner to do annual physical examinations, appropriate laboratory tests, and provide treatment when needed to prevent unnecessary disability and early death.