Categories: General
      Date: Apr 28, 2010
     Title: Rx Primer: New Developments in the Maintenance and Treatment of Schizophrenia
With the advent of atypical antipsychotics such as clozapine (Clozaril), risperidone (Risperdal), and olanzapine (Zyprexa) in the late 1980s and 1990s, many patients with schizophrenia were, for the first time, able to get relief not only from their positive symptoms (hallucinations, delusions, disorganization) but also from their negative symptoms (emotional blunting, apathy, lack of drive, lack of personal care). Consequently, the number of patients in psychiatric institutions dropped significantly over the past 20 years. However, many patients continued to suffer from the devastating effects of the disease.

By Maria C. Poor, M.D., and David R. Diaz, M.D.

With the advent of atypical antipsychotics such as clozapine (Clozaril), risperidone (Risperdal), and olanzapine (Zyprexa) in the late 1980s and 1990s, many patients with schizophrenia were, for the first time, able to get relief not only from their positive symptoms (hallucinations, delusions, disorganization) but also from their negative symptoms (emotional blunting, apathy, lack of drive, lack of personal care). Consequently, the number of patients in psychiatric institutions dropped significantly over the past 20 years. However, many patients continued to suffer from the devastating effects of the disease. Many of these individuals are noncompliant with treatment, particularly medication.
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) revealed 74% of patients discontinued their medication within 18 months due to poor tolerability or lack of efficacy (Lieberman et al., 2005). Predictors of noncompliance from other studies suggest additional factors that include substance use, lack of insight, unsupportive families, and poor therapeutic alliances during their hospitalization (Olfson et al. 2008).
Over the years, there have been many innovations in care aimed at overcoming noncompliance, including assertive case management, outpatient civil commitments, and new formulations of medications. Assertive case management, where mental health workers go out into the community to meet the patient, is felt to help, as are psychoeducation, family support, and development of drugs that may lead to increased compliance. The first generation (typical) antipsychotics appeared in the 1950s. This resulted in great increase in positive symptoms and many patients were able to be released from psychiatric institutions. However, noncompliance remained an issue.
In the 1960s through the early 1980s, several products appeared in the form of depot injections. The depot medications are injected intramuscularly, and the earliest ones contained both a medication and an oily substance that slowed the rate of absorption. This allows for a more constant and reliable dosage to enter the patient’s blood stream than with oral medicines. The depot forms of medication needed to be injected only every few weeks instead of daily. This was another gigantic step forward. Unfortunately these medications, including haloperidol (Haldol) decanoate and fluphenazine (Prolixin) decanoate, still subjected patients to risks of tardive dyskinesia at a rate similar to the other first generation medications and did not address negative symptoms. Tardive dyskinesia is a long-term adverse effect that may be irreversible. It involves uncontrollable movements of limbs, mouth, face, and trunk; the etiology is uncertain.
Second generation (atypical) antipsychotics represent another revolution in the care of schizophrenia patients. These medications include clozapine, risperidone, olanzapine, quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega). They are antagonists of the dopamine type 2 and serotonin 2A receptors. As a group they have differences, but share several common actions, including the treatment of negative symptoms, less extrapyramidal symptoms (which may improve compliance), and a tendency toward less tardive dyskinesia. On the down side, second generation antipsychotics as a class can cause metabolic syndrome, which includes dyslipidemia, abdominal obesity, elevated blood pressure, a proinflammatory state with elevations of C-reactive protein, and a prothrombotic state (Grundy et al.). All of these medications carry a warning about their use in elderly demented patients. Oral paliperidone is a metabolite of risperidone and as such has a similar mechanism of action—blocking dopamine D2 and serotonin HT2 receptors. It also has a blocking effect on adrenergic alpha 1 and alpha 2 as well as histamine 1 receptors. It is contained in a hardened container that has a semipermeable membrane and as such has a controlled, sustained osmotic-driven release over time.
Overall, these medications have led to significant improvement in the quality of life of many patients suffering from schizophrenia. Several atypical antipsychotics are available in wafer forms that dissolve on contact with the tongue. These are felt to reduce the incidence of “cheeking” medications and therefore may increase compliance. Risperidone has been available as a long-acting intramuscular injection for several years. Until recently, it was the only atypical available in a long-acting form. It usually is administered biweekly and requires oral medication to supplement it for several weeks after its initiation.
The newest development in this form has been the introduction of paliperidone palmitate (Invega Sustenna), now approved by the Food and Drug Administration for the acute and maintenance treatment of schizophrenia. It appears to have several significant advantages over the other atypical extended formulation such as the ability to administer the product monthly instead of biweekly injections.
As the newest entry in the market, a closer look at the advantages of paliperidone palmitate is warranted. The drug is generally well tolerated and was found to be safe and effective in premarketing studies. Unlike the long-acting risperidone product, paliperidone palmitate  does not require oral supplementation at treatment initiation. A long-term maintenance study (paliperidone vs. placebo) was terminated early for humanitarian reasons after analysis showed paliperidone was significantly more likely to delay the time to recurrence of symptoms. The usual starting dose for adults is an injection of 234 mg followed by another injection of 156 mg one week later. After that, the recommended monthly dose is 117 mg. This medication actually achieves better serum levels with deltoid injections over gluteal injections. Since this is a new product, only extensive clinical experience will reveal its place in the therapeutic armamentarium for the treatment of schizophrenia, but for now it gives providers another option for patients which have potentially critical advantages.

References
Grundy SM, Brewer Jr. HB, Cleeman JI, Smith Jr SC, Lenfant MD. NHBLI/AHA Conference Proceedings: Definition of Metabolic Syndrome. Circulation 2004; 109:433-8.
Hough D, Gopal S, Vijapaurkar U, et al. Paliperidone palmitate, an atypical injectable antipsychotic, in prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study [poster]. Presented at American Psychiatric Association 161st Annual Meeting; Washington, DC; May 3-8, 2008.
Hough D, Jindenmayer, J-P, Gopal S, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate ini schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2009; 33:1022-31.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209-23.
Olfson M, Mechanic D, Hansell S. Predicting medication noncompliance after hospital discharge among patients with schizophrenia. Psychiatric Services 2000; 51:216-22.
Rainer MK. Risperdone long-acting injection: a review of its long term safety and efficacy. Neuropsychiatric disease and treatment 2008; 4:919-27.

Tags: Schizophrenia, CATIE study, atypical antipsychotics, Dr. Robert O'Block