Challenges and Emerging Treatments in Schizophrenia

San Francisco—Current antipsychotic medications used to treat Schizophrenia are associated with limited efficacy and adverse events; however, treatment of the disease may be improved by new drugs on the horizon or medication therapy management. These were a few of the conclusions drawn from a Satellite Symposium at the AMCP meeting titled Controlling the Cascade: New Treatments to Manage Patients with Schizophrenia.

The session included an analysis of current unmet needs in schizophrenia’s therapeutic management, a discussion of current and emerging drug therapies, and information regarding the role of medication management in treatment. Marissa Lamer, PharmD, BCPP, director of behavioral health pharmacy solutions for Magellan Health Services, began the session with an overview of the disease that affects approximately 1% of the population and has no known cure. According to Dr. Lamer, schizophrenia, which usually presents in late adolescence or early adulthood, severely limits cognitive functioning and can produce disabling negative and cognitive symptoms in patients.

Schizophrenia can reduce life expectancy by 25 to 30 years, and is also associated with comorbid conditions including cardiovascular disease, substance abuse, depressive disorders, and metabolic syndrome.

When it comes to management of schizophrenia, there are unmet needs. According to Dr. Lamer, these unmet needs include treatment of negative and cognitive symptoms, remission achievement and maintenance, management of adverse events, medication adherence, and relapse prevention.

Previous studies have found that remission rates for chronic patients range from 17% to 26% and are associated with reduced healthcare utilization. However, remission requires treatment and medication adherence.

Conversely, relapse has been associated with an increased risk of long-term psychotic symptoms, increased treatment costs, and a possible decrease in medication efficacy. It is estimated that 80% of first-episode patients will relapse within 5 years.

One of the keys to the management of schizophrenia is adherence to medications; however, adherence can be more difficult because of the adverse events associated with the medications. First-generation antipsychotics are associated with extrapyramidal symptoms, hyperprolactinemia, and sexual dysfunction, while the second-generation antipsychotics are associated with dyslipidemia, weight gain, and diabetes.

To try and minimize the effects of these adverse events, Dr. Lamer says healthcare professionals should try to promote a healthy lifestyle for their patients, lower the dose of the medications, switch to an antipsychotic with a lower risk of adverse events, change the time of day that a drug is taken, or provide adjunctive treatment for adverse events.

However, adverse events and a lack of efficacy in medications still cause about 50% of patients with schizophrenia to become nonadherent. Previous research has found that nonadherence is associated with $1.3 billion annually in rehospitalization costs and an approximately 4 to 5 times greater risk of relapse for nonadherent patients.

According to Dr. Lamer, in addition to preventing or reducing adverse events, adherence can be improved by monitoring medication usage, improving patient’s access to medications, offering patient support, and simplifying treatment regimens.

Emerging Therapies

Current antipsychotic medications work by blocking dopamine D2 receptors. It is thought that dopamine plays a large role in the development of schizophrenia symptoms. First-generation antipsychotic medications have strong binding to dopamine receptors but minimal binding to serotonin receptors.

Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, says second-generation antipsychotics (SGA) can block serotonin 5HT2A receptors and help fine-tune dopamine output. These SGAs can also help release dopamine.

The dopamine model of treatment has several limitations, however. According to Dr. Citrome, no consistent dopamine abnormalities have been discovered to date, and some medications have been shown to reduce positive symptoms by acting on glutamate receptors, but do not have an effect on dopamine.

Glutamate, the primary excitatory neurotransmitter in the central nervous system, is involved in fast synaptic transmission, plasticity, and higher cognitive functions. Many susceptibility genes of schizophrenia are involved in glutamate functioning, Dr. Citrome noted.

There are many types of glutamate receptors including ionotropic, which involves ion channels, and metabotropic, which involves chemical second messengers.

Glutamate neurons can excite dopamine neurons if they are directly connected to them or they can also inhibit dopamine function by connecting through inhibitory GABA inter-neurons.

Dr. Citrome said that drugs that work by affecting glutamate receptors can alleviate the symptoms of schizophrenia. Some of these types of medications are currently being evaluated in clinical trials. For example, an 8-week phase 2 randomized controlled trial of RG1678, a glycine reuptake inhibitor, found that there was ≥20% improvement in positive and negative syndrome scale (PANSS) negative symptom factor scores.

In addition, another 28-day phase 2 randomized controlled trial of LY2140023, an mGlu2/3 agonist, and olanzapine, found that both resulted in improvement to the PANSS, and improvements to both the positive subscale and negative subscale of the PANSS when compared with a placebo.

The Role of Managed Care

The session was concluded by Dr. Lamer, who gave an overview of schizophrenia medication management within the managed care setting. She said that disease management can improve patient outcomes by using evidence-based guidelines, identifying patients at risk for nonadherence or complications, ensuring healthcare teams have access to up-to-date clinical evidence, and promoting self-management for patients.

One management strategy, the chronic care model, strives to promote high-quality care for chronic diseases by identifying essential elements within the healthcare system and moving into a proactive model of care delivery. The benefits of this model are that it facilitates better communication between patients and caregivers, decreases the health burden of patients, improves health outcomes, and produces costs savings to patients and healthcare systems.

This model also uses the Internet, clinical information tools, and decision-support tools to provide easily accessible clinical and therapeutic information to the healthcare team and promote evidence-based practice guidelines.

Dr. Lamer said medication therapy management (MTM) programs are also designed to educate patients about the disease, monitor patient adherence, and detect drug-related adverse events. MTM programs may reduce medication-related costs, improve outcomes, and increase patient safety.

Key aspects of these programs are medication therapy reviews, a personal medication record, a medication-related action plan, pharmacist-provided interventions, and full documentation of patient services.